CFR 2020 Title21 Vol7

Title 21
Food and Drugs

Parts 600 to 799
Revised as of April 1, 2020
Containing a codification of documents

of general applicability and future effect
As of April 1, 2020
Published by the Office of the Federal Register

National Archives and Records Administration
as a Special Edition of the Federal Register
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Table of Contents
Page
Explanation ................................................................................................ v
Title 21:
Chapter I—Food and Drug Administration, Department of Health

and Human Services (Continued) ................................................. 3
Finding Aids:
Table of CFR Titles and Chapters ....................................................... 169
Alphabetical List of Agencies Appearing in the CFR ......................... 189
List of CFR Sections Affected ............................................................. 199

iii
Cite this Code: CFR
To cite the regulations in

this volume use title,
part and section num-
ber. Thus, 21 CFR 600.2
refers to title 21, part
600, section 2.
iv
Explanation
The Code of Federal Regulations is a codification of the general and permanent
rules published in the Federal Register by the Executive departments and agen-
cies of the Federal Government. The Code is divided into 50 titles which represent
broad areas subject to Federal regulation. Each title is divided into chapters
which usually bear the name of the issuing agency. Each chapter is further sub-
divided into parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year and issued
on a quarterly basis approximately as follows:
Title 1 through Title 16..............................................................as of January 1
Title 17 through Title 27 .................................................................as of April 1
Title 28 through Title 41 ..................................................................as of July 1
Title 42 through Title 50 .............................................................as of October 1
The appropriate revision date is printed on the cover of each volume.
LEGAL STATUS
The contents of the Federal Register are required to be judicially noticed (44
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given rule.
EFFECTIVE AND EXPIRATION DATES
Each volume of the Code contains amendments published in the Federal Reg-
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to display an OMB control number with their information collection request.
Many agencies have begun publishing numerous OMB control numbers as amend-
ments to existing regulations in the CFR. These OMB numbers are placed as
close as possible to the applicable recordkeeping or reporting requirements.
PAST PROVISIONS OF THE CODE
Provisions of the Code that are no longer in force and effect as of the revision
date stated on the cover of each volume are not carried. Code users may find
the text of provisions in effect on any given date in the past by using the appro-
priate List of CFR Sections Affected (LSA). For the convenience of the reader,
a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume.
For changes to the Code prior to the LSA listings at the end of the volume,
consult previous annual editions of the LSA. For changes to the Code prior to
2001, consult the List of CFR Sections Affected compilations, published for 1949-
1963, 1964-1972, 1973-1985, and 1986-2000.
‘‘[RESERVED]’’ TERMINOLOGY
The term ‘‘[Reserved]’’ is used as a place holder within the Code of Federal
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a portion of the CFR was left vacant and not dropped in error.
INCORPORATION BY REFERENCE
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will approve an incorporation by reference only when the requirements of 1 CFR
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(b) The matter incorporated is in fact available to the extent necessary to
afford fairness and uniformity in the administrative process.
(c) The incorporating document is drafted and submitted for publication in
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vi
The Federal Register Index is issued monthly in cumulative form. This index
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revision dates of the 50 CFR titles.
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OLIVER A. POTTS,
Director,
Office of the Federal Register
April 1, 2020
vii
THIS TITLE
Title 21—FOOD AND DRUGS is composed of nine volumes. The parts in these
volumes are arranged in the following order: Parts 1–99, 100–169, 170–199, 200–299,
300–499, 500–599, 600–799, 800–1299 and 1300–end. The first eight volumes, containing
parts 1–1299, comprise Chapter I—Food and Drug Administration, Department of
Health and Human Services. The ninth volume, containing part 1300 to end, in-
cludes Chapter II—Drug Enforcement Administration, Department of Justice, and
Chapter III—Office of National Drug Control Policy. The contents of these vol-
umes represent all current regulations codified under this title of the CFR as
of April 1, 2020.
For this volume, Robert J. Sheehan, III was Chief Editor. The Code of Federal
Regulations publication program is under the direction of John Hyrum Martinez,
assisted by Stephen J. Frattini.
ix
Title 21—Food and
Drugs
(This book contains parts 600 to 799)
Part
CHAPTER I—Food and Drug Administration, Department of

Health and Human Services (Continued) ........................... 600
CHAPTER I—FOOD AND DRUG
ADMINISTRATION, DEPARTMENT OF HEALTH
AND HUMAN SERVICES (CONTINUED)
EDITORIAL NOTE: Nomenclature changes to chapter I appear at 59 FR 14366, Mar. 28, 1994,
and 66 FR 56035, Nov. 6, 2001.
SUBCHAPTER F—BIOLOGICS
Part Page
600 Biological products: general .................................... 5
601 Licensing ................................................................. 23
606 Current good manufacturing practice for blood and
blood components ................................................. 45
607 Establishment registration and product listing for
manufacturers of human blood and blood prod-
ucts and licensed devices ...................................... 59
610 General biological products standards .................... 65
630 Requirements for blood and blood components in-
tended for transfusion or for further manufac-
turing use ............................................................. 83
640 Additional standards for human blood and blood
products ............................................................... 94
660 Additional standards for diagnostic substances for
laboratory tests .................................................... 116
680 Additional standards for miscellaneous products ... 134
SUBCHAPTER G—COSMETICS
700 General .................................................................... 137

701 Cosmetic labeling .................................................... 145
710 Voluntary registration of cosmetic product estab-
lishments .............................................................. 158
720 Voluntary filing of cosmetic product ingredient
composition statements ....................................... 159
740 Cosmetic product warning statements .................... 163
741–799 [Reserved]
SUBCHAPTER F—BIOLOGICS
PART 600—BIOLOGICAL tion, Center for Biologics Evaluation

PRODUCTS: GENERAL and Research, Document Control Cen-
ter, 10903 New Hampshire Ave., Bldg.
Subpart A—General Provisions 71, Rm. G112, Silver Spring, MD 20993–
0002. Examples of such submissions in-
Sec. clude: Biologics license applications
600.2 Mailing addresses. (BLAs) and their amendments and sup-
600.3 Definitions. plements, biological product deviation
Subpart B—Establishment Standards reports, fatality reports, and other cor-
respondence. Biological products sam-
600.10 Personnel. ples must not be sent to this address
600.11 Physical establishment, equipment, but must be sent to the address in
animals, and care. paragraph (c) of this section.
600.12 Records. (b) Licensed biological products regu-
600.13 Retention samples.
lated by the Center for Drug Evaluation
600.14 Reporting of biological product devi-
ations by licenses manufacturers. and Research (CDER). Unless otherwise
600.15 Temperatures during shipment. stated in paragraphs (b)(1), (b)(2), or (c)
of this section, or as otherwise pre-
Subpart C—Establishment Inspection scribed by FDA regulation, all submis-
sions to CDER referenced in parts 600,
600.20 Inspectors.
601, and 610 of this chapter, as applica-
600.21 Time of inspection.
600.22 [Reserved] ble, must be sent to: CDER Central
Document Room, Center for Drug Eval-
Subpart D—Reporting of Adverse uation and Research, Food and Drug
Experiences Administration, 5901B Ammendale Rd.,
Beltsville, MD 20705. Examples of such
600.80 Postmarketing reporting of adverse submissions include: BLAs and their
experiences.
amendments and supplements, and
600.81 Distribution reports.
600.82 Notification of a permanent dis- other correspondence.
continuance or an interruption in manu- (1) Biological Product Deviation Report-
facturing. ing (CDER). All biological product devi-
600.90 Waivers. ation reports required under § 600.14
AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, must be sent to: Division of Compli-
356c, 356e, 360, 360i, 371, 374, 379k–l; 42 U.S.C. ance Risk Management and Surveil-
216, 262, 263, 263a, 264. lance, Office of Compliance, Center for
CROSS REFERENCES: For U.S. Customs
Drug Evaluation and Research, Food
Service regulations relating to viruses, se- and Drug Administration, 10903 New
rums, and toxins, see 19 CFR 12.21–12.23. For Hampshire Ave., Silver Spring, MD
U.S. Postal Service regulations relating to 20993–0002.
the admissibility to the United States mails (2) Advertising and Promotional Label-
see parts 124 and 125 of the Domestic Mail ing (CDER). All advertising and pro-
Manual, that is incorporated by reference in motional labeling supplements re-
39 CFR part 111. quired under § 601.12(f) of this chapter
must be sent to: Division of Drug Mar-
Subpart A—General Provisions keting, Advertising and Communica-
tion, Center for Drug Evaluation and
§ 600.2 Mailing addresses. Research, Food and Drug Administra-
(a) Licensed biological products regu- tion, 5901–B Ammendale Rd., Beltsville,
lated by the Center for Biologics Evalua- MD 20705–1266.
tion and Research (CBER). Unless other- (c) Samples and Protocols for licensed
wise stated in paragraph (c) of this sec- biological products regulated by CBER or
tion, or as otherwise prescribed by CDER. (1) Biological product samples
FDA regulation, all submissions to and/or protocols, other than radio-
CBER referenced in parts 600 through active biological product samples and
680 of this chapter, as applicable, must protocols, required under §§ 600.13,

be sent to: Food and Drug Administra- 600.22, 601.15, 610.2, 660.6, 660.36, or 660.46
§ 600.3 21 CFR Ch. I (4–1–20 Edition)
of this chapter must be sent by courier (e) State means a State or the Dis-
service to: Food and Drug Administra- trict of Columbia, Puerto Rico, or the
tion, Center for Biologics Evaluation Virgin Islands.
and Research, ATTN: Sample Custo- (f) Possession includes among other
dian, 10903 New Hampshire Ave., Bldg. possessions, Puerto Rico and the Vir-
75, Rm. G707, Silver Spring, MD 20993– gin Islands.
0002. The protocol(s) may be placed in (g) Products includes biological prod-
the box used to ship the samples to ucts and trivalent organic arsenicals.
CBER. A cover letter should not be in- (h) Biological product means a virus,
cluded when submitting the protocol therapeutic serum, toxin, antitoxin,
with the sample unless it contains per- vaccine, blood, blood component or de-
tinent information affecting the re- rivative, allergenic product, protein, or
lease of the lot. analogous product, or arsphenamine or
(2) Radioactive biological products derivative of arsphenamine (or any
required under § 610.2 of this chapter other trivalent organic arsenic com-
must be sent by courier service to: pound), applicable to the prevention,
Food and Drug Administration, Center treatment, or cure of a disease or con-
for Biologics Evaluation and Research, dition of human beings.
ATTN: Sample Custodian, c/o White (1) A virus is interpreted to be a prod-
Oak Radiation Safety Program, 10903 uct containing the minute living cause
New Hampshire Ave., Bldg. 52–72, Rm. of an infectious disease and includes
G406A, Silver Spring, MD 20993–0002. but is not limited to filterable viruses,
(d) Address information for submis- bacteria, rickettsia, fungi, and pro-
sions to CBER and CDER other than tozoa.
those listed in parts 600 through 680 of (2) A therapeutic serum is a product
this chapter are included directly in obtained from blood by removing the
the applicable regulations. clot or clot components and the blood
(e) Obtain updated mailing address cells.
information for biological products (3) A toxin is a product containing a
regulated by CBER at http:// soluble substance poisonous to labora-
www.fda.gov/BiologicsBloodVaccines/de- tory animals or to man in doses of 1
fault.htm, or for biological products milliliter or less (or equivalent in
regulated by CDER at http:// weight) of the product, and having the
www.fda.gov/Drugs/default.htm. property, following the injection of
non-fatal doses into an animal, of caus-
[70 FR 14981, Mar. 24, 2005, as amended at 74 ing to be produced therein another
FR 13114, Mar. 26, 2009; 78 FR 19585, Apr. 2, soluble substance which specifically
2013; 80 FR 18091, Apr. 3, 2015; 79 FR 33090, neutralizes the poisonous substance
June 10, 2014]
and which is demonstrable in the
§ 600.3 Definitions. serum of the animal thus immunized.
(4) An antitoxin is a product con-
As used in this subchapter: taining the soluble substance in serum
(a) Act means the Public Health Serv- or other body fluid of an immunized
ice Act (58 Stat. 682), approved July 1, animal which specifically neutralizes
1944. the toxin against which the animal is
(b) Secretary means the Secretary of immune.
Health and Human Services and any (5) A product is analogous:
other officer or employee of the De- (i) To a virus if prepared from or with
partment of Health and Human Serv- a virus or agent actually or potentially
ices to whom the authority involved infectious, without regard to the de-
has been delegated. gree of virulence or toxicogenicity of
(c) Commissioner of Food and Drugs the specific strain used.
means the Commissioner of the Food (ii) To a therapeutic serum, if com-
and Drug Administration. posed of whole blood or plasma or con-
(d) Center for Biologics Evaluation and taining some organic constituent or
Research means Center for Biologics product other than a hormone or an
Evaluation and Research of the Food amino acid, derived from whole blood,
and Drug Administration. plasma, or serum.
Food and Drug Administration, HHS § 600.3
(iii) To a toxin or antitoxin, if in- safety, purity, and potency of such

tended, irrespective of its source of ori- products.
gin, to be applicable to the prevention, (o) The word continued as applied to
treatment, or cure of disease or inju- the safety, purity and potency of prod-
ries of man through a specific immune ucts is interpreted to apply to the dat-
process. ing period.
(6) A protein is any alpha amino acid (p) The word safety means the rel-
polymer with a specific, defined se- ative freedom from harmful effect to
quence that is greater than 40 amino persons affected, directly or indirectly,
acids in size. When two or more amino by a product when prudently adminis-
acid chains in an amino acid polymer tered, taking into consideration the
are associated with each other in a character of the product in relation to
manner that occurs in nature, the size the condition of the recipient at the
of the amino acid polymer for purposes time.
of this paragraph (h)(6) will be based on (q) The word sterility is interpreted to
the total number of amino acids in mean freedom from viable contami-
those chains, and will not be limited to nating microorganisms, as determined
the number of amino acids in a contig- by the tests conducted under § 610.12 of
uous sequence. this chapter.
(i) Trivalent organic arsenicals means (r) Purity means relative freedom
arsphenamine and its derivatives (or from extraneous matter in the finished
any other trivalent organic arsenic product, whether or not harmful to the
compound) applicable to the preven- recipient or deleterious to the product.
tion, treatment, or cure of diseases or Purity includes but is not limited to
injuries of man. relative freedom from residual mois-
(j) A product is deemed applicable to ture or other volatile substances and
the prevention, treatment, or cure of dis- pyrogenic substances.
eases or injuries of man irrespective of (s) The word potency is interpreted to
the mode of administration or applica- mean the specific ability or capacity of
tion recommended, including use when the product, as indicated by appro-
intended through administration or ap- priate laboratory tests or by ade-
plication to a person as an aid in diag- quately controlled clinical data ob-
nosis, or in evaluating the degree of tained through the administration of
susceptibility or immunity possessed the product in the manner intended, to
by a person, and including also any effect a given result.
other use for purposes of diagnosis if (t) Manufacturer means any legal per-
the diagnostic substance so used is pre- son or entity engaged in the manufac-
pared from or with the aid of a biologi- ture of a product subject to license
cal product. under the act; ‘‘Manufacturer’’ also in-
(k) Proper name, as applied to a prod- cludes any legal person or entity who
uct, means the name designated in the is an applicant for a license where the
license for use upon each package of applicant assumes responsibility for
the product. compliance with the applicable product
(l) Dating period means the period be- and establishment standards.
yond which the product cannot be ex- (u) Manufacture means all steps in
pected beyond reasonable doubt to propagation or manufacture and prepa-
yield its specific results. ration of products and includes but is
(m) Expiration date means the cal- not limited to filling, testing, labeling,
endar month and year, and where ap- packaging, and storage by the manu-
plicable, the day and hour, that the facturer.
dating period ends. (v) Location includes all buildings,
(n) The word standards means speci- appurtenances, equipment and animals
fications and procedures applicable to used, and personnel engaged by a man-
an establishment or to the manufac- ufacturer within a particular area des-
ture or release of products, which are ignated by an address adequate for
prescribed in this subchapter or estab- identification.
lished in the biologics license applica- (w) Establishment has the same mean-
tion designed to insure the continued ing as ‘‘facility’’ in section 351 of the
§ 600.3 21 CFR Ch. I (4–1–20 Edition)
Public Health Service Act and includes (ii) Control means having responsi-
all locations. bility for maintaining the continued
(x) Lot means that quantity of uni- safety, purity, and potency of the prod-
form material identified by the manu- uct and for compliance with applicable
facturer as having been thoroughly product and establishment standards,
mixed in a single vessel. and for compliance with current good
(y) A filling refers to a group of final manufacturing practices.
containers identical in all respects, (jj) Assess the effects of the change, as
which have been filled with the same used in § 601.12 of this chapter, means
product from the same bulk lot with- to evaluate the effects of a manufac-
out any change that will affect the in- turing change on the identity,
tegrity of the filling assembly. strength, quality, purity, and potency
(z) Process refers to a manufacturing of a product as these factors may re-
step that is performed on the product late to the safety or effectiveness of
itself which may affect its safety, pu- the product.
rity or potency, in contrast to such
(kk) Specification, as used in § 601.12 of
manufacturing steps which do not af-
this chapter, means the quality stand-
fect intrinsically the safety, purity or
potency of the product. ard (i.e., tests, analytical procedures,
and acceptance criteria) provided in an
(aa) Selling agent or distributor means
any person engaged in the unrestricted approved application to confirm the
distribution, other than by sale at re- quality of products, intermediates, raw
tail, of products subject to license. materials, reagents, components, in-
(bb) Container (referred to also as process materials, container closure
‘‘final container’’) is the immediate systems, and other materials used in
unit, bottle, vial, ampule, tube, or the production of a product. For the
other receptacle containing the prod- purpose of this definition, acceptance
uct as distributed for sale, barter, or criteria means numerical limits, ranges,
exchange. or other criteria for the tests de-
(cc) Package means the immediate scribed.
carton, receptacle, or wrapper, includ- (ll) Complete response letter means a
ing all labeling matter therein and written communication to an applicant
thereon, and the contents of the one or from FDA usually describing all of the
more enclosed containers. If no pack- deficiencies that the agency has identi-
age, as defined in the preceding sen- fied in a biologics license application
tence, is used, the container shall be or supplement that must be satisfac-
deemed to be the package. torily addressed before it can be ap-
(dd) Label means any written, print- proved.
ed, or graphic matter on the container (mm) Resubmission means a submis-
or package or any such matter clearly sion by the biologics license applicant
visible through the immediate carton, or supplement applicant of all mate-
receptacle, or wrapper. rials needed to fully address all defi-
(ee) Radioactive biological product ciencies identified in the complete re-
means a biological product which is la- sponse letter. A biologics license appli-
beled with a radionuclide or intended cation or supplement for which FDA
solely to be labeled with a radio- issued a complete response letter, but
nuclide. which was withdrawn before approval
(ff) Amendment is the submission of and later submitted again, is not a re-
information to a pending license appli- submission.
cation or supplement, to revise or mod-
ify the application as originally sub- [38 FR 32048, Nov. 20, 1973, as amended at 40
mitted. FR 31313, July 25, 1975; 55 FR 11014, Mar. 26,
(gg) Supplement is a request to ap- 1990; 61 FR 24232, May 14, 1996; 62 FR 39901,
prove a change in an approved license July 24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR
application. 66634, Nov. 7, 2000; 69 FR 18766, Apr. 8, 2004; 70
FR 14982, Mar. 24, 2005; 73 FR 39610, July 10,
(hh) Distributed means the biological
2008; 77 FR 26174, May 3, 2012; 85 FR 10063,

product has left the control of the li- Feb. 21, 2020]
censed manufacturer.
Subpart B—Establishment oratory clothing before entering a live

Standards vaccine processing unit. Persons caring
for animals used in the manufacture of
§ 600.10 Personnel. live vaccines shall be excluded from
(a) [Reserved] other animal quarters and from con-
(b) Personnel. Personnel shall have tact with other animals during the
capabilities commensurate with their same working day.
assigned functions, a thorough under- [38 FR 32048, Nov. 20, 1973, as amended at 49
standing of the manufacturing oper- FR 23833, June 8, 1984; 55 FR 11014, Mar. 26,
ations which they perform, the nec- 1990; 62 FR 53538, Oct. 15, 1997; 68 FR 75119,
essary training and experience relating Dec. 30, 2003]
to individual products, and adequate
§ 600.11 Physical establishment, equip-
information concerning the application ment, animals, and care.
of the pertinent provisions of this sub-
chapter to their respective functions. (a) Work areas. All rooms and work
Personnel shall include such profes- areas where products are manufactured
sionally trained persons as are nec- or stored shall be kept orderly, clean,
essary to insure the competent per- and free of dirt, dust, vermin and ob-
formance of all manufacturing proc- jects not required for manufacturing.
esses. Precautions shall be taken to avoid
(c) Restrictions on personnel—(1) Spe- clogging and back-siphonage of drain-
cific duties. Persons whose presence can age systems. Precautions shall be
affect adversely the safety and purity taken to exclude extraneous infectious
of a product shall be excluded from the agents from manufacturing areas.
room where the manufacture of a prod- Work rooms shall be well lighted and
uct is in progress. ventilated. The ventilation system
(2) Sterile operations. Personnel per- shall be arranged so as to prevent the
forming sterile operations shall wear dissemination of microorganisms from
clean or sterilized protective clothing one manufacturing area to another and
and devices to the extent necessary to to avoid other conditions unfavorable
protect the product from contamina- to the safety of the product. Filling
tion. rooms, and other rooms where open,
(3) Pathogenic viruses and spore-form- sterile operations are conducted, shall
ing organisms. Persons working with vi- be adequate to meet manufacturing
ruses pathogenic for man or with needs and such rooms shall be con-
spore-forming microorganisms, and structed and equipped to permit thor-
persons engaged in the care of animals ough cleaning and to keep air-borne
or animal quarters, shall be excluded contaminants at a minimum. If such
from areas where other products are rooms are used for other purposes, they
manufactured, or such persons shall shall be cleaned and prepared prior to
change outer clothing, including shoes, use for sterile operations. Refrig-
or wear protective covering prior to en- erators, incubators and warm rooms
tering such areas. shall be maintained at temperatures
(4) Live vaccine work areas. Persons within applicable ranges and shall be
may not enter a live vaccine processing free of extraneous material which
area after having worked with other in- might affect the safety of the product.
fectious agents in any other laboratory (b) Equipment. Apparatus for steri-
during the same working day. Only lizing equipment and the method of op-
persons actually concerned with propa- eration shall be such as to insure the
gation of the culture, production of the destruction of contaminating micro-
vaccine, and unit maintenance, shall be organisms. The effectiveness of the
allowed in live vaccine processing sterilization procedure shall be no less
areas when active work is in progress. than that achieved by an attained tem-
Casual visitors shall be excluded from perature of 121.5 °C maintained for 20
such units at all times and all others minutes by saturated steam or by an
having business in such areas shall be attained temperature of 170 °C main-
admitted only under supervision. tained for 2 hours with dry heat. Proc-
Street clothing, including shoes, shall essing and storage containers, filters,
be replaced or covered by suitable lab- filling apparatus, and other pieces of
§ 600.11 21 CFR Ch. I (4–1–20 Edition)
apparatus and accessory equipment, in- Spore-forming organisms used as an

cluding pipes and tubing, shall be de- additional control in sterilization pro-
signed and constructed to permit thor- cedures may be introduced into areas
ough cleaning and, where possible, in- used for the manufacture of products,
spection for cleanliness. All surfaces only for the purposes of the test and
that come in contact with products only immediately before use for such
shall be clean and free of surface solids, purposes: Provided, That (i) the orga-
leachable contaminants, and other ma- nism is not pathogenic for man or ani-
terials that will hasten the deteriora- mals and does not produce pyrogens or
tion of the product or otherwise render toxins, (ii) the culture is demonstrated
it less suitable for the intended use. to be pure, (iii) transfer of test cultures
For products for which sterility is a to culture media shall be limited to the
factor, equipment shall be sterile, un- sterility test area or areas designated
less sterility of the product is assured for work with spore-forming orga-
by subsequent procedures. nisms, (iv) each culture be labeled with
(c) Laboratory and bleeding rooms. the name of the microorganism and the
Rooms used for the processing of prod- statement ‘‘Caution: microbial spores.
ucts, including bleeding rooms, shall be See directions for storage, use and dis-
effectively fly-proofed and kept free of position.’’, and (v) the container of
flies and vermin. Such rooms shall be each culture is designed to withstand
so constructed as to insure freedom handling without breaking.
from dust, smoke and other deleterious (3) Work with spore-forming microorga-
substances and to permit thorough nisms. (i) Manufacturing processes
cleaning and disinfection. Rooms for using spore-forming microorganisms
animal injection and bleeding, and conducted in a multiproduct manufac-
rooms for smallpox vaccine animals, turing site must be performed under
shall be disinfected and be provided appropriate controls to prevent con-
with the necessary water, electrical tamination of other products and areas
and other services. within the site. Prevention of spore
(d) Animal quarters and stables. Ani- contamination can be achieved by
mal quarters, stables and food storage using a separate dedicated building or
areas shall be of appropriate construc- by using process containment if manu-
tion, fly-proofed, adequately lighted facturing is conducted in a multi-
and ventilated, and maintained in a product manufacturing building. All
clean, vermin-free and sanitary condi- product and personnel movement be-
tion. No manure or refuse shall be tween the area where the spore-form-
stored as to permit the breeding of flies ing microorganisms are manufactured
on the premises, nor shall the estab- and other manufacturing areas must be
lishment be located in close proximity conducted under conditions that will
to off-property manure or refuse stor- prevent the introduction of spores into
age capable of engendering fly breed- other areas of the facility.
ing. (ii) If process containment is em-
(e) Restrictions on building and equip- ployed in a multiproduct manufac-
ment use—(1) Work of a diagnostic na- turing area, procedures must be in
ture. Laboratory procedures of a clin- place to demonstrate adequate removal
ical diagnostic nature involving mate- of the spore-forming microorganism(s)
rials that may be contaminated, shall from the manufacturing area for subse-
not be performed in space used for the quent manufacture of other products.
manufacture of products except that These procedures must provide for ade-
manufacturing space which is used quate removal or decontamination of
only occasionally may be used for diag- the spore-forming microorganisms on
nostic work provided spore-forming and within manufacturing equipment,
pathogenic microorganisms are not in- facilities, and ancillary room items as
volved and provided the space is thor- well as the removal of disposable or
oughly cleaned and disinfected before product dedicated items from the man-
the manufacture of products is re- ufacturing area. Environmental moni-
sumed. toring specific for the spore-forming
(2) Spore-forming organisms for supple- microorganism(s) must be conducted in

mental sterilization procedure control test. adjacent areas during manufacturing
10
operations and in the manufacturing or decontaminate live vaccine orga-

area after completion of cleaning and nisms have been followed.
decontamination. (5) Equipment and supplies—contami-
(4) Live vaccine processing. Live vac- nation. Equipment and supplies used in
cine processing must be performed work on or otherwise exposed to any
under appropriate controls to prevent pathogenic or potentially pathogenic
cross contamination of other products agent shall be kept separated from
and other manufacturing areas within equipment and supplies used in the
the building. Appropriate controls manufacture of products to the extent
must include, at a minimum: necessary to prevent cross-contamina-
(i)(A) Using a dedicated manufac- tion.
turing area that is either in a separate (f) Animals used in manufacture—(1)
building, in a separate wing of a build- Care of animals used in manufacturing.
ing, or in quarters at the blind end of a Caretakers and attendants for animals
corridor and includes adequate space used for the manufacture of products
and equipment for all processing steps shall be sufficient in number and have
up to, but not including, filling into adequate experience to insure adequate
final containers; and care. Animal quarters and cages shall
be kept in sanitary condition. Animals
(B) Not conducting test procedures
on production shall be inspected daily
that potentially involve the presence of
to observe response to production pro-
microorganisms other than the vaccine
cedures. Animals that become ill for
strains or the use of tissue culture cell
reasons not related to production shall
lines other than primary cultures in
be isolated from other animals and
space used for processing live vaccine;
shall not be used for production until
or
recovery is complete. Competent vet-
(ii) If manufacturing is conducted in erinary care shall be provided as need-
a multiproduct manufacturing building ed.
or area, using procedural controls, and (2) Quarantine of animals—(i) General.
where necessary, process containment. No animal shall be used in processing
Process containment is deemed to be unless kept under competent daily in-
necessary unless procedural controls spection and preliminary quarantine
are sufficient to prevent cross contami- for a period of at least 7 days before
nation of other products and other use, or as otherwise provided in this
manufacturing areas within the build- subchapter. Only healthy animals free
ing. Process containment is a system from detectable communicable diseases
designed to mechanically isolate equip- shall be used. Animals must remain in
ment or an area that involves manufac- overt good health throughout the quar-
turing using live vaccine organisms. antine periods and particular care shall
All product, equipment, and personnel be taken during the quarantine periods
movement between distinct live vac- to reject animals of the equine genus
cine processing areas and between live which may be infected with glanders
vaccine processing areas and other and animals which may be infected
manufacturing areas, up to, but not in- with tuberculosis.
cluding, filling in final containers, (ii) Quarantine of monkeys. In addi-
must be conducted under conditions tion to observing the pertinent general
that will prevent cross contamination quarantine requirements, monkeys
of other products and manufacturing used as a source of tissue in the manu-
areas within the building, including facture of vaccine shall be maintained
the introduction of live vaccine orga- in quarantine for at least 6 weeks prior
nisms into other areas. In addition, to use, except when otherwise provided
written procedures and effective proc- in this part. Only monkeys that have
esses must be in place to adequately re- reacted negatively to tuberculin at the
move or decontaminate live vaccine or- start of the quarantine period and
ganisms from the manufacturing area again within 2 weeks prior to use shall
and equipment for subsequent manu- be used in the manufacture of vaccine.
facture of other products. Written pro- Due precaution shall be taken to pre-
cedures must be in place for vent cross-infection from any infected

verification that processes to remove or potentially infected monkeys on the
11
§ 600.11 21 CFR Ch. I (4–1–20 Edition)
premises. Monkeys to be used in the microbiological agents shall not be

manufacture of a live vaccine shall be used as a source of kidney tissue for
maintained throughout the quarantine the manufacture of vaccine. Except as
period in cages closed on all sides with provided otherwise in this subchapter,
solid materials except the front which monkeys that have been used pre-
shall be screened, with no more than viously for other experimental or test
two monkeys housed in one cage. Cage purposes may be used as a source of
mates shall not be interchanged. kidney tissue upon their return to a
(3) Immunization against tetanus. normal condition, provided all quar-
Horses and other animals susceptible antine requirements have been met.
to tetanus, that are used in the proc- (8) Necropsy examination of monkeys.
essing steps of the manufacture of bio- Each monkey used in the manufacture
logical products, shall be treated ade- of vaccine shall be examined at ne-
quately to maintain immunity to tet- cropsy under the direction of a quali-
anus. fied pathologist, physician, or veteri-
(4) Immunization and bleeding of ani- narian having experience with diseases
mals used as a source of products. Toxins of monkeys, for evidence of ill health,
or other nonviable antigens adminis- particularly for (i) evidence of tuber-
tered in the immunization of animals culosis, (ii) presence of herpes-like le-
used in the manufacture of products sions, including eruptions or plaques
shall be sterile. Viable antigens, when on or around the lips, in the buccal
so used, shall be free of contaminants, cavity or on the gums, and (iii) signs of
as determined by appropriate tests
conjunctivitis. If there are any such
prior to use. Injections shall not be
signs or other significant gross patho-
made into horses within 6 inches of
logical lesions, the tissue shall not be
bleeding site. Horses shall not be bled
used in the manufacture of vaccine.
for manufacturing purposes while
showing persistent general reaction or (g) Filling procedures. Filling proce-
local reaction near the site of bleeding. dures shall be such as will not affect
Blood shall not be used if it was drawn adversely the safety, purity or potency
within 5 days of injecting the animals of the product.
with viable microorganisms. Animals (h) Containers and closures. All final
shall not be bled for manufacturing containers and closures shall be made
purposes when they have an intercur- of material that will not hasten the de-
rent disease. Blood intended for use as terioration of the product or otherwise
a source of a biological product shall render it less suitable for the intended
be collected in clean, sterile vessels. use. All final containers and closures
When the product is intended for use shall be clean and free of surface solids,
by injection, such vessels shall also be leachable contaminants and other ma-
pyrogen-free. terials that will hasten the deteriora-
(5) [Reserved] tion of the product or otherwise render
(6) Reporting of certain diseases. In it less suitable for the intended use.
cases of actual or suspected infection After filling, sealing shall be performed
with foot and mouth disease, glanders, in a manner that will maintain the in-
tetanus, anthrax, gas gangrene, equine tegrity of the product during the dat-
infectious anemia; equine ing period. In addition, final containers
encephalomyelitis, or any of the pock and closures for products intended for
diseases among animals intended for use by injection shall be sterile and
use or used in the manufacture of prod- free from pyrogens. Except as other-
ucts, the manufacturer shall imme- wise provided in the regulations of this
diately notify the Director, Center for subchapter, final containers for prod-
Biologics Evaluation and Research or ucts intended for use by injection shall
the Director, Center for Drug Evalua- be colorless and sufficiently trans-
tion and Research (see mailing address- parent to permit visual examination of
es in § 600.2(a) or (b)). the contents under normal light. As
(7) Monkeys used previously for experi- soon as possible after filling final con-
mental or test purposes. Monkeys that tainers shall be labeled as prescribed in
have been used previously for experi- § 610.60 et seq. of this chapter, except
mental or test purposes with live that final containers may be stored
12
without such prescribed labeling pro- records of a specific manufacturing

vided they are stored in a sealed recep- step upon a showing that such records
tacle labeled both inside and outside no longer have significance for the pur-
with at least the name of the product, poses for which they were made: Pro-
the lot number, and the filling identi- vided, That a summary of such records
fication. shall be retained.
(c) Records of sterilization of equipment
[38 FR 32048, Nov. 20, 1973, as amended at 41
FR 10428, Mar. 11, 1976; 49 FR 23833, June 8,
and supplies. Records relating to the
1984; 55 FR 11013, Mar. 26, 1990; 68 FR 75119, mode of sterilization, date, duration,
Dec. 30, 2003; 70 FR 14982, Mar. 24, 2005; 72 FR temperature and other conditions re-
59003, Oct. 18, 2007; 80 FR 18092, Apr. 3, 2015] lating to each sterilization of equip-
ment and supplies used in the proc-
§ 600.12 Records. essing of products shall be made by
(a) Maintenance of records. Records means of automatic recording devices
shall be made, concurrently with the or by means of a system of recording
performance, of each step in the manu- which gives equivalent assurance of the
facture and distribution of products, in accuracy and reliability of the record.
such a manner that at any time succes- Such records shall be maintained in a
sive steps in the manufacture and dis- manner that permits an identification
tribution of any lot may be traced by of the product with the particular man-
an inspector. Such records shall be leg- ufacturing process to which the steri-
ible and indelible, shall identify the lization relates.
person immediately responsible, shall (d) Animal necropsy records. A ne-
include dates of the various steps, and cropsy record shall be kept on each
be as detailed as necessary for clear un- animal from which a biological product
derstanding of each step by one experi- has been obtained and which dies or is
enced in the manufacture of products. sacrificed while being so used.
(b) Records retention—(1) General. (e) Records in case of divided manufac-
Records shall be retained for such in- turing responsibility. If two or more es-
terval beyond the expiration date as is tablishments participate in the manu-
necessary for the individual product, to facture of a product, the records of
permit the return of any clinical report each such establishment must show
of unfavorable reactions. The retention plainly the degree of its responsibility.
period shall be no less than five years In addition, each participating manu-
after the records of manufacture have facturer shall furnish to the manufac-
been completed or six months after the turer who prepares the product in final
latest expiration date for the indi- form for sale, barter or exchange, a
vidual product, whichever represents a copy of all records relating to the man-
later date. ufacturing operations performed by
(2) Records of recall. Complete records such participating manufacturer inso-
shall be maintained pertaining to the far as they concern the safety, purity
recall from distribution of any product and potency of the lots of the product
upon notification by the Director, Cen- involved, and the manufacturer who
ter for Biologics Evaluation and Re- prepares the product in final form shall
search or the Director, Center for Drug retain a complete record of all the
Evaluation and Research, to recall for manufacturing operations relating to
failure to conform with the standards the product.
prescribed in the regulations of this [38 FR 32048, Nov. 20, 1973, as amended at 49
subchapter, because of deterioration of FR 23833, June 8, 1984; 55 FR 11013, Mar. 26,
the product or for any other factor by 1990; 70 FR 14982, Mar. 24, 2005]
reason of which the distribution of the
product would constitute a danger to § 600.13 Retention samples.
health. Manufacturers shall retain for a pe-
(3) Suspension of requirement for reten- riod of at least 6 months after the expi-
tion. The Director, Center for Biologics ration date, unless a different time pe-
Evaluation and Research or the Direc- riod is specified in additional stand-
tor, Center for Drug Evaluation and ards, a quantity of representative ma-
Research, may authorize the suspen- terial of each lot of each product, suffi-
sion of the requirement to retain cient for examination and testing for
13
§ 600.14 21 CFR Ch. I (4–1–20 Edition)
safety and potency, except Whole report biological product deviations for
Blood, Cryoprecipitated AHF, Plate- those products under this section but
lets, Red Blood Cells, Plasma, and must report in accordance with part
Source Plasma and Allergenic Products 803 of this chapter;
prepared to a physician’s prescription. (ii) Persons who manufacture blood
Samples so retained shall be selected and blood components, including li-
at random from either final container censed manufacturers, unlicensed reg-
material, or from bulk and final con- istered blood establishments, and
tainers, provided they include at least transfusion services, do not report bio-
one final container as a final package, logical product deviations for those
or package-equivalent of such filling of products under this section but must
each lot of the product as intended for report under § 606.171 of this chapter;
distribution. Such sample material (iii) Persons who manufacture Source
shall be stored at temperatures and Plasma or any other blood component
under conditions which will maintain and use that Source Plasma or any
the identity and integrity of the prod- other blood component in the further
uct. Samples retained as required in manufacture of another licensed bio-
this section shall be in addition to logical product must report:
samples of specific products required to (A) Under § 606.171 of this chapter, if a
be submitted to the Center for Bio- biological product deviation occurs
logics Evaluation and Research or the during the manufacture of that Source
Center for Drug Evaluation and Re- Plasma or any other blood component;
search (see mailing addresses in § 600.2). or
Exceptions may be authorized by the (B) Under this section, if a biological
Director, Center for Biologics Evalua- product deviation occurs after the
tion and Research or the Director, Cen- manufacture of that Source Plasma or
ter for Drug Evaluation and Research, any other blood component, and during
when the lot yields relatively few final manufacture of the licensed biological
containers and when such lots are pre- product.
pared by the same method in large (b) What do I report under this section?
number and in close succession. You must report any event, and infor-
mation relevant to the event, associ-
[41 FR 10428, Mar. 11, 1976, as amended at 49
FR 23833, June 8, 1984; 50 FR 4133, Jan. 29, ated with the manufacturing, to in-
1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, clude testing, processing, packing, la-
Mar. 24, 2005] beling, or storage, or with the holding
or distribution, of a licensed biological
§ 600.14 Reporting of biological prod- product, if that event meets all the fol-
uct deviations by licensed manufac- lowing criteria:
turers. (1) Either:
(a) Who must report under this section? (i) Represents a deviation from cur-
(1) You, the manufacturer who holds rent good manufacturing practice, ap-
the biological product license and who plicable regulations, applicable stand-
had control over the product when the ards, or established specifications that
deviation occurred, must report under may affect the safety, purity, or po-
this section. If you arrange for another tency of that product; or
person to perform a manufacturing, (ii) Represents an unexpected or un-
holding, or distribution step, while the foreseeable event that may affect the
product is in your control, that step is safety, purity, or potency of that prod-
performed under your control. You uct; and
must establish, maintain, and follow a (2) Occurs in your facility or another
procedure for receiving information facility under contract with you; and
from that person on all deviations, (3) Involves a distributed biological
complaints, and adverse events con- product.
cerning the affected product. (c) When do I report under this section?
(2) Exceptions: You should report a biological product
(i) Persons who manufacture only in deviation as soon as possible but you
vitro diagnostic products that are not must report at a date not to exceed 45-
subject to licensing under section 351 of calendar days from the date you, your
the Public Health Service Act do not agent, or another person who performs
14
a manufacturing, holding, or distribu- (3) If you make a paper filing, you

tion step under your control, acquire should identify on the envelope that a
information reasonably suggesting biological product deviation report
that a reportable event has occurred. (BPDR) is enclosed.
(d) How do I report under this section (f) How does this regulation affect other
You must report on Form FDA–3486. FDA regulations? This part supplements
(e) Where do I report under this section? and does not supersede other provisions
(1) For biological products regulated by of the regulations in this chapter. All
the Center for Biologics Evaluation biological product deviations, whether
or not they are required to be reported
and Research (CBER), send the com-
under this section, should be inves-
pleted Form FDA 3486 to the CBER
tigated in accordance with the applica-
Document Control Center (see mailing ble provisions of parts 211 and 820 of
address in § 600.2(a)), or submit elec- this chapter.
tronically using CBER’s electronic
Web-based application. [65 FR 66634, Nov. 7, 2000, as amended at 70
FR 14982, Mar. 24, 2005; 80 FR 18092, Apr. 3,
(2) For biological products regulated 2015]
by the Center for Drug Evaluation and
Research (CDER), send the completed § 600.15 Temperatures during ship-
Form FDA–3486 to the Division of Com- ment.
pliance Risk Management and Surveil- The following products shall be main-
lance (HFD–330) (see mailing addresses tained during shipment at the specified
in § 600.2). CDER does not currently ac- temperatures:
cept electronic filings. (a) Products.
Product Temperature
Cryoprecipitated AHF ....................................................... ¥18 °C or colder.

Measles and Rubella Virus Vaccine Live ......................... 10 °C or colder.
Measles Live and Smallpox Vaccine ................................ Do.
Measles, Mumps, and Rubella Virus Vaccine Live .......... Do.
Measles and Mumps Virus Vaccine Live ......................... Do.
Measles Virus Vaccine Live ............................................. Do.
Mumps Virus Vaccine Live ............................................... Do.
Fresh Frozen Plasma ....................................................... ¥18 °C or colder.
Liquid Plasma ................................................................... 1 to 10 °C.
Plasma .............................................................................. ¥18 °C or colder.
Platelet Rich Plasma ........................................................ Between 1 and 10 °C if the label indicates storage between 1 and 6
°C, or all reasonable methods to maintain the temperature as close
as possible to a range between 20 and 24 °C, if the label indicates
storage between 20 and 24 °C.
Platelets ............................................................................ Between 1 and 10 °C if the label indicates storage between 1 and 6
°C, or all reasonable methods to maintain the temperature as close
as possible to a range between 20 to 24 °C, if the label indicates
storage between 20 and 24 °C.
Poliovirus Vaccine Live Oral Trivalent .............................. 0 °C or colder.
Poliovirus Vaccine Live Oral Type I ................................. Do.
Poliovirus Vaccine Live Oral Type II ................................ Do.
Poliovirus Vaccine Live Oral Type III ............................... Do.
Red Blood Cells (liquid product) ....................................... Between 1 and 10 °C.
Red Blood Cells Frozen ................................................... ¥65 °C or colder.
Rubella and Mumps Virus Vaccine Live .......................... 10 °C or colder.
Rubella Virus Vaccine Live ............................................... Do.
Smallpox Vaccine (Liquid Product) .................................. 0 °C or colder.
Source Plasma ................................................................. ¥5 °C or colder.
Source Plasma Liquid ....................................................... 10 °C or colder.
Whole Blood ..................................................................... Blood that is transported from the collecting facility to the processing
facility shall be transported in an environment capable of continu-
ously cooling the blood toward a temperature range of 1 to 10 °C,
or at a temperature as close as possible to 20 to 24 °C for a period
not to exceed 6 hours. Blood transported from the storage facility
shall be placed in an appropriate environment to maintain a tem-
perature range between 1 to 10 °C during shipment.
Yellow Fever Vaccine ....................................................... 0 °C or colder.
15
§ 600.20 21 CFR Ch. I (4–1–20 Edition)
(b) Exemptions. Exemptions or modi- logical product in professional prac-

fications shall be made only upon writ- tice; an adverse event occurring from
ten approval, in the form of a supple- overdose of the product whether acci-
ment to the biologics license applica- dental or intentional; an adverse event
tion, approved by the Director, Center occurring from abuse of the product; an
for Biologics Evaluation and Research. adverse event occurring from with-
[39 FR 39872, Nov. 12, 1974, as amended at 49 drawal of the product; and any failure
FR 23833, June 8, 1984; 50 FR 4133, Jan. 29, of expected pharmacological action.
1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Blood Component. As defined in
Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR § 606.3(c) of this chapter.
56449, Oct. 20, 1999] Disability. A substantial disruption of
a person’s ability to conduct normal
Subpart C—Establishment life functions.
Inspection Individual case safety report (ICSR). A
description of an adverse experience re-
§ 600.20 Inspectors. lated to an individual patient or sub-
Inspections shall be made by an offi- ject.
cer of the Food and Drug Administra- ICSR attachments. Documents related
tion having special knowledge of the to the adverse experience described in
methods used in the manufacture and an ICSR, such as medical records, hos-
control of products and designated for pital discharge summaries, or other
such purposes by the Commissioner of documentation.
Food and Drugs, or by any officer, Life-threatening adverse experience.
agent, or employee of the Department Any adverse experience that places the
of Health and Human Services specifi- patient, in the view of the initial re-
cally designated for such purpose by porter, at immediate risk of death
the Secretary. from the adverse experience as it oc-
curred, i.e., it does not include an ad-
[38 FR 32048, Nov. 20, 1973] verse experience that, had it occurred
§ 600.21 Time of inspection. in a more severe form, might have
caused death.
The inspection of an establishment Serious adverse experience. Any ad-
for which a biologics license applica- verse experience occurring at any dose
tion is pending need not be made until that results in any of the following
the establishment is in operation and outcomes: Death, a life-threatening ad-
is manufacturing the complete product verse experience, inpatient hospitaliza-
for which a biologics license is desired. tion or prolongation of existing hos-
[38 FR 32048, Nov. 20, 1973, as amended at 48 pitalization, a persistent or significant
FR 26314, June 7, 1983; 64 FR 56449, Oct. 20, disability/incapacity, or a congenital
1999; 84 FR 12508, Apr. 2, 2019] anomaly/birth defect. Important med-
ical events that may not result in
§ 600.22 [Reserved] death, be life-threatening, or require
hospitalization may be considered a se-
Subpart D—Reporting of Adverse rious adverse experience when, based
Experiences upon appropriate medical judgment,
they may jeopardize the patient or sub-
SOURCE: 59 FR 54042, Oct. 27, 1994, unless ject and may require medical or sur-
otherwise noted. gical intervention to prevent one of the
outcomes listed in this definition. Ex-
§ 600.80 Postmarketing reporting of amples of such medical events include
adverse experiences. allergic bronchospasm requiring inten-
(a) Definitions. The following defini- sive treatment in an emergency room
tions of terms apply to this section: or at home, blood dyscrasias or convul-
Adverse experience. Any adverse event sions that do not result in inpatient
associated with the use of a biological hospitalization, or the development of
product in humans, whether or not drug dependency or drug abuse.
considered product related, including Unexpected adverse experience: Any ad-
the following: An adverse event occur- verse experience that is not listed in
ring in the course of the use of a bio- the current labeling for the biological
16
product. This includes events that may (1)(i) Postmarketing 15-day ‘‘Alert re-
be symptomatically and ports’’. The applicant must report each
pathophysiologically related to an adverse experience that is both serious
event listed in the labeling, but differ and unexpected, whether foreign or do-
from the event because of greater se- mestic, as soon as possible but no later
verity or specificity. For example, than 15 calendar days from initial re-
under this definition, hepatic necrosis ceipt of the information by the appli-
would be unexpected (by virtue of cant.
greater severity) if the labeling only (ii) Postmarketing 15-day ‘‘Alert re-
referred to elevated hepatic enzymes or ports’’—followup. The applicant must
hepatitis. Similarly, cerebral thrombo- promptly investigate all adverse expe-
embolism and cerebral vasculitis would riences that are the subject of these
be unexpected (by virtue of greater postmarketing 15-day Alert reports and
specificity) if the labeling only listed must submit followup reports within 15
cerebral vascular accidents. ‘‘Unex- calendar days of receipt of new infor-
pected,’’ as used in this definition, re- mation or as requested by FDA. If addi-
fers to an adverse experience that has tional information is not obtainable,
not been previously observed (i.e., in- records should be maintained of the un-
cluded in the labeling) rather than successful steps taken to seek addi-
from the perspective of such experience tional information.
not being anticipated from the pharma- (iii) Submission of reports. The re-
cological properties of the pharma- quirements of paragraphs (c)(1)(i) and
ceutical product. (c)(1)(ii) of this section, concerning the
(b) Review of adverse experiences. Any submission of postmarketing 15-day
person having a biologics license under Alert reports, also apply to any person
§ 601.20 of this chapter must promptly whose name appears on the label of a
review all adverse experience informa- licensed biological product as a manu-
tion pertaining to its product obtained facturer, packer, distributor, shared
or otherwise received by the applicant
manufacturer, joint manufacturer, or
from any source, foreign or domestic,
any other participant involved in di-
including information derived from
vided manufacturing. To avoid unnec-
commercial marketing experience,
essary duplication in the submission to
postmarketing clinical investigations,
FDA of reports required by paragraphs
postmarketing epidemiological/surveil-
(c)(1)(i) and (c)(1)(ii) of this section, ob-
lance studies, reports in the scientific
literature, and unpublished scientific ligations of persons other than the ap-
papers. Applicants are not required to plicant of the final biological product
resubmit to FDA adverse product expe- may be met by submission of all re-
rience reports forwarded to the appli- ports of serious adverse experiences to
cant by FDA; applicants, however, the applicant of the final product. If a
must submit all followup information person elects to submit adverse experi-
on such reports to FDA. Any person ence reports to the applicant rather
subject to the reporting requirements than to FDA, the person must submit,
under paragraph (c) of this section by any appropriate means, each report
must also develop written procedures to the applicant within 5 calendar days
for the surveillance, receipt, evalua- of initial receipt of the information by
tion, and reporting of postmarketing the person, and the applicant must
adverse experiences to FDA. then comply with the requirements of
(c) Reporting requirements. The appli- this section. Under this circumstance,
cant must submit to FDA post- a person who elects to submit reports
marketing 15-day Alert reports and to the applicant of the final product
periodic safety reports pertaining to its shall maintain a record of this action
biological product as described in this which must include:
section. These reports must be sub- (A) A copy of all adverse biological
mitted to the Agency in electronic for- product experience reports submitted
mat as described in paragraph (h)(1) of to the applicant of the final product;
this section, except as provided in (B) The date the report was received
paragraph (h)(2) of this section. by the person;
17
§ 600.80 21 CFR Ch. I (4–1–20 Edition)
(C) The date the report was sub- section (all serious, expected and non-
mitted to the applicant of the final serious adverse experiences). All such
product; and— ICSRs must be submitted to FDA (ei-
(D) The name and address of the ap- ther individually or in one or more
plicant of the final product. batches) within the timeframe speci-
(2) Periodic adverse experience reports. fied in paragraph (c)(2)(i) of this sec-
(i) The applicant must report each ad- tion. ICSRs must only be submitted to
verse experience not reported under FDA once.
paragraph (c)(1)(i) of this section at (iii) Periodic reporting, except for in-
quarterly intervals, for 3 years from formation regarding 15-day Alert re-
the date of issuance of the biologics li- ports, does not apply to adverse experi-
cense, and then at annual intervals. ence information obtained from post-
The applicant must submit each quar- marketing studies (whether or not con-
terly report within 30 days of the close ducted under an investigational new
of the quarter (the first quarter begin- drug application), from reports in the
ning on the date of issuance of the bio- scientific literature, and from foreign
logics license) and each annual report marketing experience.
within 60 days of the anniversary date (d) Scientific literature. A 15-day Alert
of the issuance of the biologics license. report based on information in the sci-
Upon written notice, FDA may extend entific literature must be accompanied
or reestablish the requirement that an by a copy of the published article. The
applicant submit quarterly reports, or 15-day Alert reporting requirements in
require that the applicant submit re- paragraph (c)(1)(i) of this section (i.e.,
ports under this section at different serious, unexpected adverse experi-
times than those stated. Followup in- ences) apply only to reports found in
formation to adverse experiences sub- scientific and medical journals either
mitted in a periodic report may be sub- as case reports or as the result of a for-
mitted in the next periodic report. mal clinical trial.
(ii) Each periodic report is required (e) Postmarketing studies. Applicants
to contain: are not required to submit a 15-day
(A) Descriptive information. (1) A nar- Alert report under paragraph (c) of this
rative summary and analysis of the in- section for an adverse experience ob-
formation in the report; tained from a postmarketing clinical
(2) An analysis of the 15-day Alert re- study (whether or not conducted under
ports submitted during the reporting a biological investigational new drug
interval (all 15-day Alert reports being application) unless the applicant con-
appropriately referenced by the appli- cludes that there is a reasonable possi-
cant’s patient identification code for bility that the product caused the ad-
nonvaccine biological product reports verse experience.
or by the unique case identification (f) Information reported on ICSRs for
number for vaccine reports, adverse re- nonvaccine biological products. ICSRs for
action term(s), and date of submission nonvaccine biological products include
to FDA); the following information:
(3) A history of actions taken since (1) Patient information.
the last report because of adverse expe- (i) Patient identification code;
riences (for example, labeling changes
(ii) Patient age at the time of adverse
or studies initiated);
experience, or date of birth;
(4) An index consisting of a line list-
(iii) Patient gender; and
ing of the applicant’s patient identi-
fication code for nonvaccine biological (iv) Patient weight.
product reports or by the unique case (2) Adverse experience.
identification number for vaccine re- (i) Outcome attributed to adverse ex-
ports and adverse reaction term(s) for perience;
ICSRs submitted under paragraph (ii) Date of adverse experience;
(c)(2)(ii)(B) of this section; and (iii) Date of report;
(B) ICSRs for serious, expected and, (iv) Description of adverse experience
nonserious adverse experiences. An ICSR (including a concise medical nar-
for each adverse experience not re- rative);

ported under paragraph (c)(1)(i) of this (v) Adverse experience term(s);
18
(vi) Description of relevant tests, in- (ii) Patient age at the time of vac-
cluding dates and laboratory data; and cination, or date of birth;
(vii) Other relevant patient history, (iii) Patient gender; and
including preexisting medical condi- (iv) Patient birth weight for children
tions. under age 5.
(3) Suspect medical product(s). (2) Adverse experience.
(i) Name; (i) Outcome attributed to adverse ex-
(ii) Dose, frequency, and route of ad- perience;
ministration used; (ii) Date and time of adverse experi-
(iii) Therapy dates; ence;
(iv) Diagnosis for use (indication); (iii) Date of report;
(v) Whether the product is a com- (iv) Description of adverse experience
bination product as defined in § 3.2(e) of (including a concise medical nar-
this chapter; rative);
(vi) Whether the product is a pre- (v) Adverse experience term(s);
scription or nonprescription product; (vi) Illness at the time of vaccina-
(vii) Whether adverse experience tion;
abated after product use stopped or (vii) Description of relevant tests, in-
dose reduced; cluding dates and laboratory data; and
(viii) Whether adverse experience re- (viii) Other relevant patient history,
appeared after reintroduction of the including preexisting medical condi-
product; tions.
(ix) Lot number; (3) Suspect medical product(s), includ-
(x) Expiration date; ing vaccines administered on the same
(xi) National Drug Code (NDC) num- date.
ber, or other unique identifier; and (i) Name;
(xii) Concomitant medical products (ii) Dose, frequency, and route or site
of administration used;
and therapy dates.
(iii) Number of previous vaccine
(4) Initial reporter information.
doses;
(i) Name, address, and telephone
(iv) Vaccination date(s) and time(s);
number;
(v) Diagnosis for use (indication);
(ii) Whether the initial reporter is a
(vi) Whether the product is a com-
health care professional; and bination product (as defined in § 3.2(e)
(iii) Occupation, if a health care proof this chapter);
fessional. (vii) Whether the adverse experience
(5) Applicant information. abated after product use stopped or
(i) Applicant name and contact office dose reduced;
address; (viii) Whether the adverse experience
(ii) Telephone number; reappeared after reintroduction of the
(iii) Report source, such as sponta- product;
neous, literature, or study; (ix) Lot number;
(iv) Date the report was received by (x) Expiration date;
applicant; (xi) National Drug Code (NDC) num-
(v) Application number and type; ber, or other unique identifier; and
(vi) Whether the ICSR is a 15-day (xii) Concomitant medical products
‘‘Alert report’’; and therapy dates.
(vii) Whether the ICSR is an initial (4) Vaccine(s) administered in the 4
report or followup report; and weeks prior to the vaccination date.
(viii) Unique case identification num- (i) Name of vaccine;
ber, which must be the same in the ini- (ii) Manufacturer;
tial report and any subsequent fol- (iii) Lot number;
lowup report(s). (iv) Route or site of administration;
(g) Information reported on ICSRs for (v) Date given; and
vaccine products. ICSRs for vaccine (vi) Number of previous doses.
products include the following infor- (5) Initial reporter information.
mation: (i) Name, address, and telephone
(1) Patient information. number;
(i) Patient name, address, telephone (ii) Whether the initial reporter is a
number; health care professional; and
19
§ 600.80 21 CFR Ch. I (4–1–20 Edition)
(iii) Occupation, if a health care pro- the applicant should submit the report
fessional. to the biologics license application for
(6) Facility and personnel where vac- the product listed first in the report.
cine was administered. (j) Patient privacy. For nonvaccine bi-
(i) Name of person who administered ological products, an applicant should
vaccine; not include in reports under this sec-
(ii) Name of responsible physician at tion the names and addresses of indi-
facility where vaccine was adminis- vidual patients; instead, the applicant
tered; and should assign a unique code for identi-
(iii) Name, address (including city, fication of the patient. The applicant
county, and state), and telephone num- should include the name of the reporter
ber of facility where vaccine was ad- from whom the information was re-
ministered. ceived as part of the initial reporter in-
(7) Applicant information. formation, even when the reporter is
(i) Applicant name and contact office the patient. The names of patients,
address; health care professionals, hospitals,
(ii) Telephone number; and geographical identifiers in adverse
(iii) Report source, such as sponta- experience reports are not releasable to
neous, literature, or study; the public under FDA’s public informa-
(iv) Date received by applicant; tion regulations in part 20 of this chap-
(v) Application number and type; ter. For vaccine adverse experience re-
(vi) Whether the ICSR is a 15-day ports, these data will become part of
‘‘Alert report’’; the CDC Privacy Act System 09–20–0136,
(vii) Whether the ICSR is an initial ‘‘Epidemiologic Studies and Surveil-
report or followup report; and lance of Disease Problems.’’ Informa-
(viii) Unique case identification num- tion identifying the person who re-
ber, which must be the same in the ini- ceived the vaccine or that person’s
tial report and any subsequent fol- legal representative will not be made
lowup report(s). available to the public, but may be
(h) Electronic format for submissions. available to the vaccinee or legal rep-
(1) Safety report submissions, includ- resentative.
ing ICSRs, ICSR attachments, and the (k) Recordkeeping. The applicant
descriptive information in periodic re- must maintain for a period of 10 years
ports, must be in an electronic format records of all adverse experiences
that FDA can process, review, and ar- known to the applicant, including raw
chive. FDA will issue guidance on how data and any correspondence relating
to provide the electronic submission to the adverse experiences.
(e.g., method of transmission, media, (l) Revocation of biologics license. If an
file formats, preparation and organiza- applicant fails to establish and main-
tion of files). tain records and make reports required
(2) Persons subject to the require- under this section with respect to a li-
ments of paragraph (c) of this section censed biological product, FDA may re-
may request, in writing, a temporary voke the biologics license for such a
waiver of the requirements in para- product in accordance with the proce-
graph (h)(1) of this section. These waiv- dures of § 601.5 of this chapter.
ers will be granted on a limited basis (m) Exemptions. Manufacturers of the
for good cause shown. FDA will issue following listed products are not re-
guidance on requesting a waiver of the quired to submit adverse experience re-
requirements in paragraph (h)(1) of this ports under this section:
section. Requests for waivers must be (1) Whole blood or components of
submitted in accordance with § 600.90. whole blood.
(i) Multiple reports. An applicant (2) In vitro diagnostic products, in-
should not include in reports under cluding assay systems for the detection
this section any adverse experience of antibodies or antigens to
that occurred in clinical trials if they retroviruses. These products are sub-
were previously submitted as part of ject to the reporting requirements for
the biologics license application. If a devices.
report refers to more than one biologi- (n) Disclaimer. A report or informa-
cal product marketed by an applicant, tion submitted by an applicant under
20
this section (and any release by FDA of ed should be made as a request for a
that report or information) does not waiver under § 600.90.
necessarily reflect a conclusion by the (b)(1) Electronic format. Except as pro-
applicant or FDA that the report or in- vided for in paragraph (b)(2) of this sec-
formation constitutes an admission tion, the distribution reports required
that the biological product caused or under paragraph (a) of this section
contributed to an adverse effect. An ap- must be submitted to the Agency in an
plicant need not admit, and may deny, electronic format that FDA can proc-
that the report or information sub- ess, review, and archive. FDA will issue
mitted under this section constitutes guidance on how to provide the elec-
an admission that the biological prod- tronic submission (e.g., method of
uct caused or contributed to an adverse transmission, media, file formats, prep-
effect. For purposes of this provision, aration and organization of files).
this paragraph also includes any person (2) Waivers. An applicant may re-
reporting under paragraph (c)(1)(iii) of quest, in writing, a temporary waiver
this section. of the requirements in paragraph (b)(1)
[59 FR 54042, Oct. 27, 1994, as amended at 62 of this section. These waivers will be
FR 34168, June 25, 1997; 62 FR 52252, Oct. 7, granted on a limited basis for good
1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, cause shown. FDA will issue guidance
Oct. 20, 1999; 70 FR 14982, Mar. 24, 2005; 79 FR on requesting a waiver of the require-
33090, June 10, 2014]
ments in paragraph (b)(1) of this sec-
§ 600.81 Distribution reports. tion. Requests for waivers must be sub-
mitted in accordance with § 600.90.
(a) Reporting requirements. The appli-
cant must submit to the Center for [59 FR 54042, Oct. 27, 1994, as amended at 64
Biologics Evaluation and Research or FR 56449, Oct. 20, 1999; 70 FR 14983, Mar. 24,
the Center for Drug Evaluation and Re- 2005; 79 FR 33091, June 10, 2014]
search, information about the quantity
of the product distributed under the § 600.82 Notification of a permanent
discontinuance or an interruption
biologics license, including the quan- in manufacturing.
tity distributed to distributors. The in-
terval between distribution reports (a) Notification of a permanent dis-
must be 6 months. Upon written notice, continuance or an interruption in manu-
FDA may require that the applicant facturing. (1) An applicant of a biologi-
submit distribution reports under this cal product, other than blood or blood
section at times other than every 6 components for transfusion, which is
months. The distribution report must licensed under section 351 of the Public
consist of the bulk lot number (from Health Service Act, and which may be
which the final container was filled), dispensed only under prescription
the fill lot numbers for the total num- under section 503(b)(1) of the Federal
ber of dosage units of each strength or Food, Drug, and Cosmetic Act (21
potency distributed (e.g., fifty thou- U.S.C. 353(b)(1)), must notify FDA in
sand per 10-milliliter vials), the label writing of a permanent discontinuance
lot number (if different from fill lot of manufacture of the biological prod-
number), labeled date of expiration, uct or an interruption in manufac-
number of doses in fill lot/label lot, turing of the biological product that is
date of release of fill lot/label lot for likely to lead to a meaningful disrup-
distribution at that time. If any sig- tion in supply of that biological prod-
nificant amount of a fill lot/label lot is uct in the United States if:
returned, include this information. Dis- (i) The biological product is life sup-
closure of financial or pricing data is porting, life sustaining, or intended for
not required. As needed, FDA may re- use in the prevention or treatment of a
quire submission of more detailed prod- debilitating disease or condition, in-
uct distribution information. Upon cluding any such biological product
written notice, FDA may require that used in emergency medical care or dur-
the applicant submit reports under this ing surgery; and
section at times other than those stat- (ii) The biological product is not a
ed. Requests by an applicant to submit radiopharmaceutical biological prod-

reports at times other than those stat- uct.
21
§ 600.82 21 CFR Ch. I (4–1–20 Edition)
(2) An applicant of blood or blood (4) A description of the reason for the
components for transfusion, which is permanent discontinuance or interrup-
licensed under section 351 of the Public tion in manufacturing; and
Health Service Act, and which may be (5) The estimated duration of the
dispensed only under prescription interruption in manufacturing.
under section 503(b) of the Federal (d)(1) Public list of biological product
Food, Drug, and Cosmetic Act, must shortages. FDA will maintain a publicly
notify FDA in writing of a permanent available list of biological products
discontinuance of manufacture of any that are determined by FDA to be in
product listed in its license or an inter- shortage. This biological product
ruption in manufacturing of any such shortages list will include the fol-
product that is likely to lead to a sig- lowing information:
nificant disruption in supply of that (i) The names and National Drug
product in the United States if: Codes for such biological products, or
(i) The product is life supporting, life the alternative standards for identi-
sustaining, or intended for use in the fication and labeling that have been
prevention or treatment of a debili- recognized as acceptable by the Center
tating disease or condition, including Director;
any such product used in emergency (ii) The name of each applicant for
medical care or during surgery; and such biological products;
(ii) The applicant is a manufacturer (iii) The reason for the shortage, as
of a significant percentage of the U.S. determined by FDA, selecting from the
blood supply. following categories: Requirements re-
(b) Submission and timing of notifica- lated to complying with good manufac-
tion. Notifications required by para- turing practices; regulatory delay;
graph (a) of this section must be sub- shortage of an active ingredient; short-
mitted to FDA electronically in a for- age of an inactive ingredient compo-
mat that FDA can process, review, and nent; discontinuation of the manufac-
archive: ture of the biological product; delay in
(1) At least 6 months prior to the shipping of the biological product; de-
date of the permanent discontinuance mand increase for the biological prod-
or interruption in manufacturing; or uct; or other reason; and
(2) If 6 months’ advance notice is not (iv) The estimated duration of the
possible because the permanent dis- shortage.
continuance or interruption in manu- (2) Confidentiality. FDA may choose
facturing was not reasonably antici- not to make information collected to
pated 6 months in advance, as soon as implement this paragraph available on
practicable thereafter, but in no case the biological product shortages list or
later than 5 business days after such a available under section 506C(c) of the
permanent discontinuance or interrup- Federal Food, Drug, and Cosmetic Act
tion in manufacturing occurs. (21 U.S.C. 356c(c)) if FDA determines
(c) Information included in notification. that disclosure of such information
Notifications required by paragraph (a) would adversely affect the public
of this section must include the fol- health (such as by increasing the possi-
lowing information: bility of hoarding or other disruption
(1) The name of the biological prod- of the availability of the biological
uct subject to the notification, includ- product to patients). FDA will also not
ing the National Drug Code for such bi- provide information on the public
ological product, or an alternative shortages list or under section 506C(c)
standard for identification and labeling of the Federal Food, Drug, and Cos-
that has been recognized as acceptable metic Act that is protected by 18
by the Center Director; U.S.C. 1905 or 5 U.S.C. 552(b)(4), includ-
(2) The name of the applicant of the ing trade secrets and commercial or fi-
biological product; nancial information that is considered
(3) Whether the notification relates confidential or privileged under § 20.61
to a permanent discontinuance of the of this chapter.
biological product or an interruption in (e) Noncompliance letters. If an appli-
manufacturing of the biological prod- cant fails to submit a notification as

uct; required under paragraph (a) of this
22
Food and Drug Administration, HHS Pt. 601
section and in accordance with para- Significant disruption means a change

graph (b) of this section, FDA will in production that is reasonably likely
issue a letter to the applicant inform- to lead to a reduction in the supply of
ing it of such failure. blood or blood components by a manu-
(1) Not later than 30 calendar days facturer that substantially affects the
after the issuance of such a letter, the ability of the manufacturer to fill or-
applicant must submit to FDA a writ- ders or meet expected demand for its
ten response setting forth the basis for product, and does not include interrup-
noncompliance and providing the re- tions in manufacturing due to matters
quired notification under paragraph (a) such as routine maintenance or insig-
of this section and including the infor- nificant changes in manufacturing so
mation required under paragraph (c) of long as the manufacturer expects to re-
this section; and sume operations in a short period of
(2) Not later than 45 calendar days time.
after the issuance of a letter under this [80 FR 38939, July 8, 2015]
paragraph, FDA will make the letter
and the applicant’s response to the let- § 600.90 Waivers.
ter public, unless, after review of the (a) An applicant may ask the Food
applicant’s response, FDA determines and Drug Administration to waive
that the applicant had a reasonable under this section any requirement
basis for not notifying FDA as required that applies to the applicant under
under paragraph (a) of this section. §§ 600.80 and 600.81. A waiver request
(f) Definitions. The following defini- under this section is required to be sub-
tions of terms apply to this section: mitted with supporting documentation.
Biological product shortage or shortage The waiver request is required to con-
means a period of time when the de- tain one of the following:
mand or projected demand for the bio- (1) An explanation why the appli-
logical product within the United cant’s compliance with the require-
States exceeds the supply of the bio- ment is unnecessary or cannot be
logical product. achieved,
(2) A description of an alternative
Intended for use in the prevention or submission that satisfies the purpose of
treatment of a debilitating disease or con- the requirement, or
dition means a biological product in- (3) Other information justifying a
tended for use in the prevention or waiver.
treatment of a disease or condition as- (b) FDA may grant a waiver if it
sociated with mortality or morbidity finds one of the following:
that has a substantial impact on day- (1) The applicant’s compliance with
to-day functioning. the requirement is unnecessary or can-
Life supporting or life sustaining means not be achieved,
a biological product that is essential (2) The applicant’s alternative sub-
to, or that yields information that is mission satisfies the requirement, or
essential to, the restoration or con- (3) The applicant’s submission other-
tinuation of a bodily function impor- wise justifies a waiver.
tant to the continuation of human life.
[59 FR 54042, Oct. 27, 1994, as amended at 79
Meaningful disruption means a change FR 33092, June 10, 2014]
in production that is reasonably likely
to lead to a reduction in the supply of
a biological product by a manufacturer
PART 601—LICENSING
that is more than negligible and affects
Subpart A—General Provisions
the ability of the manufacturer to fill
orders or meet expected demand for its Sec.
product, and does not include interrup- 601.2 Applications for biologics licenses;
tions in manufacturing due to matters procedures for filing.
such as routine maintenance or insig- 601.3 Complete response letter to the appli-
cant.
nificant changes in manufacturing so 601.4 Issuance and denial of license.
long as the manufacturer expects to re-
601.5 Revocation of license.

sume operations in a short period of 601.6 Suspension of license.
time. 601.7 Procedure for hearings.
23
§ 601.2 21 CFR Ch. I (4–1–20 Edition)
601.8 Publication of revocation. Subpart G—Postmarketing Studies
601.9 Licenses; reissuance.
601.70 Annual progress reports of post-
Subpart B [Reserved] marketing studies.
Subpart C—Biologics Licensing Subpart H—Approval of Biological Prod-

ucts When Human Efficacy Studies Are
601.12 Changes to an approved application. Not Ethical or Feasible
601.14 Regulatory submissions in electronic
format. 601.90 Scope.
601.91 Approval based on evidence of effec-
601.15 Foreign establishments and products:
tiveness from studies in animals.
Samples for each importation. 601.92 Withdrawal procedures.
601.20 Biologics licenses; issuance and con- 601.93 Postmarketing safety reporting.
ditions. 601.94 Promotional materials.
601.21 Products under development. 601.95 Termination of requirements.
601.22 Products in short supply; initial man-
AUTHORITY: 15 U.S.C. 1451–1561; 21 U.S.C.
ufacturing at other than licensed loca-
321, 351, 352, 353, 355, 356b, 360, 360c–360f, 360h–
tion.
360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262,
601.27 Pediatric studies. 263, 264; sec 122, Pub. L. 105–115, 111 Stat. 2322
601.28 Annual reports of postmarketing pe- (21 U.S.C. 355 note).
diatric studies.
601.29 Guidance documents. SOURCE: 38 FR 32052, Nov. 20, 1973, unless
otherwise noted.
Subpart D—Diagnostic CROSS REFERENCES: For U.S. Customs
Radiopharmaceuticals Service regulations relating to viruses, se-
rums, and toxins, see 19 CFR 12.21–12.23. For
601.30 Scope. U.S. Postal Service regulations relating to
601.31 Definition. the admissibility to the United States mails
601.32 General factors relevant to safety and see parts 124 and 125 of the Domestic Mail
effectiveness. Manual, that is incorporated by reference in
601.33 Indications. 39 CFR part 111.
601.34 Evaluation of effectiveness.
601.35 Evaluation of safety. Subpart A—General Provisions
Subpart E—Accelerated Approval of Bio- § 601.2 Applications for biologics li-
logical Products for Serious or Life- censes; procedures for filing.
Threatening Illnesses (a) General. To obtain a biologics li-
cense under section 351 of the Public
601.40 Scope.
Health Service Act for any biological
601.41 Approval based on a surrogate end-
point or on an effect on a clinical end-
product, the manufacturer shall submit
point other than survival or irreversible an application to the Director, Center
morbidity. for Biologics Evaluation and Research
601.42 Approval with restrictions to assure or the Director, Center for Drug Eval-
safe use. uation and Research (see mailing ad-
601.43 Withdrawal procedures. dresses in § 600.2(a) or (b) of this chap-
601.44 Postmarketing safety reporting. ter), on forms prescribed for such pur-
601.45 Promotional materials. poses, and shall submit data derived
601.46 Termination of requirements. from nonclinical laboratory and clin-
ical studies which demonstrate that
Subpart F—Confidentiality of Information the manufactured product meets pre-
scribed requirements of safety, purity,
601.50 Confidentiality of data and informa- and potency; with respect to each non-
tion in an investigational new drug no-
clinical laboratory study, either a
tice for a biological product.
statement that the study was con-
601.51 Confidentiality of data and informa-
tion in applications for biologics li-
ducted in compliance with the require-
censes. ments set forth in part 58 of this chap-
ter, or, if the study was not conducted
in compliance with such regulations, a
brief statement of the reason for the
noncompliance; statements regarding

each clinical investigation involving
24
human subjects contained in the appli- peptide product of 40 or fewer amino

cation, that it either was conducted in acids, monoclonal antibody product for
compliance with the requirements for in vivo use, or therapeutic recombinant
institutional review set forth in part 56 DNA-derived product, an applicant
of this chapter; or was not subject to shall submit a biologics license appli-
such requirements in accordance with cation in accordance with paragraph
§ 56.104 or § 56.105, and was conducted in (a) of this section except that the fol-
compliance with requirements for in- lowing sections in parts 600 through 680
formed consent set forth in part 50 of of this chapter shall not be applicable
this chapter. A full description of man- to such products: §§ 600.10(b) and (c),
ufacturing methods; data establishing 600.11, 600.12, 600.13, 610.53, and 610.62 of
stability of the product through the this chapter.
dating period; sample(s) representative (2) To the extent that the require-
of the product for introduction or de- ments in this paragraph (c) conflict
livery for introduction into interstate with other requirements in this sub-
commerce; summaries of results of chapter, this paragraph (c) shall super-
tests performed on the lot(s) rep- sede other requirements.
resented by the submitted sample(s); (d) Approval of a biologics license ap-
specimens of the labels, enclosures, and plication or issuance of a biologics li-
containers, and if applicable, any Medi- cense shall constitute a determination
cation Guide required under part 208 of that the establishment(s) and the prod-
this chapter proposed to be used for the uct meet applicable requirements to
product; and the address of each loca- ensure the continued safety, purity,
tion involved in the manufacture of the and potency of such products. Applica-
biological product shall be listed in the ble requirements for the maintenance
biologics license application. The ap- of establishments for the manufacture
plicant shall also include a financial of a product subject to this section
certification or disclosure statement(s) shall include but not be limited to the
or both for clinical investigators as re- good manufacturing practice require-
quired by part 54 of this chapter. An ments set forth in parts 210, 211, 600,
application for a biologics license shall 606, and 820 of this chapter.
not be considered as filed until all per- (e) Any establishment and product li-
tinent information and data have been cense for a biological product issued
received by the Food and Drug Admin- under section 351 of the Public Health
istration. The applicant shall also in- Service Act (42 U.S.C. 201 et seq.) that
clude either a claim for categorical ex- has not been revoked or suspended as
clusion under § 25.30 or § 25.31 of this of December 20, 1999, shall constitute
chapter or an environmental assess- an approved biologics license applica-
ment under § 25.40 of this chapter. The tion in effect under the same terms and
applicant, or the applicant’s attorney, conditions set forth in such product li-
agent, or other authorized official shall cense and such portions of the estab-
sign the application. An application for lishment license relating to such prod-
any of the following specified cat- uct.
egories of biological products subject (f) Withdrawal from sale of approved bi-
to licensure shall be handled as set ological products. A holder of a biologics
forth in paragraph (c) of this section: license application (BLA) must report
(1) Therapeutic DNA plasmid prod- to FDA, in accordance with the re-
ucts; quirements of §§ 207.61 and 207.65, the
(2) Therapeutic synthetic peptide withdrawal from sale of an approved bi-
products of 40 or fewer amino acids; ological product. The information must
(3) Monoclonal antibody products for be submitted to FDA within 30 working
in vivo use; and days of the biological product’s with-
(4) Therapeutic recombinant DNA-de- drawal from sale. The following infor-
rived products. mation must be submitted: The hold-
(b) [Reserved] er’s name; product name; BLA number;
(c)(1) To obtain marketing approval the National Drug Code; and the date
for a biological product subject to li- on which the product is expected to be
censure which is a therapeutic DNA no longer in commercial distribution.

plasmid product, therapeutic synthetic The reason for the withdrawal of the
25
§ 601.3 21 CFR Ch. I (4–1–20 Edition)
biological product is requested but not withdraw the application or supple-

required to be submitted. ment, unless the applicant has re-
[64 FR 56450, Oct. 20, 1999, as amended at 70
quested an extension of time in which
FR 14983, Mar. 24, 2005; 80 FR 18092, Apr. 3, to resubmit the application or supple-
2015; 80 FR 37974, July 2, 2015; 81 FR 60221, ment. FDA will grant any reasonable
Aug. 31, 2016] request for such an extension. FDA
may consider an applicant’s failure to
§ 601.3 Complete response letter to the resubmit the application or supple-
applicant. ment within the extended time period
(a) Complete response letter. The Food or request an additional extension to
and Drug Administration will send the be a request by the applicant to with-
biologics license applicant or supple- draw the application.
ment applicant a complete response (2) If FDA considers an applicant’s
letter if the agency determines that it failure to take action in accordance
will not approve the biologics license with paragraph (c)(1) of this section to
application or supplement in its be a request to withdraw the applica-
present form. tion, the agency will notify the appli-
(1) Description of specific deficiencies. A cant in writing. The applicant will
complete response letter will describe have 30 days from the date of the noti-
all of the deficiencies that the agency fication to explain why the application
has identified in a biologics license ap- or supplement should not be withdrawn
plication or supplement, except as stat- and to request an extension of time in
ed in paragraph (a)(2) of this section. which to resubmit the application or
(2) Inadequate data. If FDA deter- supplement. FDA will grant any rea-
mines, after a biologics license applica- sonable request for an extension. If the
tion or supplement is filed, that the applicant does not respond to the noti-
data submitted are inadequate to sup- fication within 30 days, the application
port approval, the agency might issue a or supplement will be deemed to be
complete response letter without first withdrawn.
conducting required inspections, test-
[73 FR 39611, July 10, 2008]
ing submitted product lots, and/or re-
viewing proposed product labeling. § 601.4 Issuance and denial of license.
(3) Recommendation of actions for ap-
proval. When possible, a complete re- (a) A biologics license shall be issued
sponse letter will recommend actions upon a determination by the Director,
that the applicant might take to place Center for Biologics Evaluation and
its biologics license application or sup- Research or the Director, Center for
plement in condition for approval. Drug Evaluation and Research that the
(b) Applicant actions. After receiving establishment(s) and the product meet
a complete response letter, the bio- the applicable requirements estab-
logics license applicant or supplement lished in this chapter. A biologics li-
applicant must take either of the fol- cense shall be valid until suspended or
lowing actions: revoked.
(1) Resubmission. Resubmit the appli- (b) If the Commissioner determines
cation or supplement, addressing all that the establishment or product does
deficiencies identified in the complete not meet the requirements established
response letter. in this chapter, the biologics license
(2) Withdrawal. Withdraw the applica- application shall be denied and the ap-
tion or supplement. A decision to with- plicant shall be informed of the
draw the application or supplement is grounds for, and of an opportunity for
without prejudice to a subsequent sub- a hearing on, the decision. If the appli-
mission. cant so requests, the Commissioner
(c) Failure to take action. (1) FDA may shall issue a notice of opportunity for
consider a biologics license applicant hearing on the matter pursuant to
or supplement applicant’s failure to ei- § 12.21(b) of this chapter.
ther resubmit or withdraw the applica- [42 FR 4718, Jan. 25, 1977, as amended at 42
tion or supplement within 1 year after
FR 15676, Mar. 22, 1977; 42 FR 19142, Apr. 12,

issuance of a complete response letter 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983,
to be a request by the applicant to Mar. 24, 2005]
26
§ 601.5 Revocation of license. compliance is not demonstrated or

(a) A biologics license shall be re- achieved and the licensed manufac-
voked upon application of the manu- turer does not waive the opportunity
facturer giving notice of intention to for a hearing, the Commissioner shall
discontinue the manufacture of all issue a notice of opportunity for hear-
products manufactured under such li- ing on the matter under § 12.21(b) of
cense or to discontinue the manufac- this chapter.
ture of a particular product for which a [64 FR 56451, Oct. 20, 1999]
license is held and waiving an oppor-
tunity for a hearing on the matter. § 601.6 Suspension of license.
(b)(1) The Commissioner shall notify
(a) Whenever the Commissioner has
the licensed manufacturer of the inten-
reasonable grounds to believe that any
tion to revoke the biologics license,
of the grounds for revocation of a li-
setting forth the grounds for, and offer-
cense exist and that by reason thereof
ing an opportunity for a hearing on the
proposed revocation if the Commis- there is a danger to health, the Com-
sioner finds any of the following: missioner may notify the licensed
(i) Authorized Food and Drug Admin- manufacturer that the biologics license
istration employees after reasonable is suspended and require that the li-
efforts have been unable to gain access censed manufacturer do the following:
to an establishment or a location for (1) Notify the selling agents and dis-
the purpose of carrying out the inspec- tributors to whom such product or
tion required under § 600.21 of this chap- products have been delivered of such
ter, suspension, and
(ii) Manufacturing of products or of a (2) Furnish to the Center for Bio-
product has been discontinued to an ex- logics Evaluation and Research or the
tent that a meaningful inspection or Center for Drug Evaluation and Re-
evaluation cannot be made, search, complete records of such deliv-
(iii) The manufacturer has failed to eries and notice of suspension.
report a change as required by § 601.12 (b) Upon suspension of a license, the
of this chapter, Commissioner shall either:
(iv) The establishment or any loca- (1) Proceed under the provisions of
tion thereof, or the product for which § 601.5(b) of this chapter to revoke the
the license has been issued, fails to license, or
conform to the applicable standards es- (2) If the licensed manufacturer
tablished in the license and in this agrees, hold revocation in abeyance
chapter designed to ensure the contin- pending resolution of the matters in-
ued safety, purity, and potency of the volved.
manufactured product,
(v) The establishment or the manu- [64 FR 56451, Oct. 20, 1999, as amended at 70
facturing methods have been so FR 14983, Mar. 24, 2005]
changed as to require a new showing
§ 601.7 Procedure for hearings.
that the establishment or product
meets the requirements established in (a) A notice of opportunity for hear-
this chapter in order to protect the ing, notice of appearance and request
public health, or for hearing, and grant or denial of
(vi) The licensed product is not safe hearing for a biological drug pursuant
and effective for all of its intended uses to this part, for which the exemption
or is misbranded with respect to any from the Federal Food, Drug, and Cos-
such use. metic Act in § 310.4 of this chapter has
(2) Except as provided in § 601.6 of this been revoked, shall be subject to the
chapter, or in cases involving willful- provisions of § 314.200 of this chapter
ness, the notification required in this except to the extent that the notice of
paragraph shall provide a reasonable opportunity for hearing on the matter
period for the licensed manufacturer to issued pursuant to § 12.21(b) of this
demonstrate or achieve compliance chapter specifically provides otherwise.
with the requirements of this chapter, (b) Hearings pursuant to §§ 601.4
before proceedings will be instituted through 601.6 shall be governed by part

for the revocation of the license. If 12 of this chapter.
27
§ 601.8 21 CFR Ch. I (4–1–20 Edition)
(c) When a license has been suspended (see mailing addresses in § 600.2 of this
pursuant to § 601.6 and a hearing re- chapter) about each change in the
quest has been granted, the hearing product, production process, quality
shall proceed on an expedited basis. controls, equipment, facilities, respon-
[42 FR 4718, Jan. 25, 1977, as amended at 42 sible personnel, or labeling established
FR 15676, Mar. 22, 1977; 42 FR 19143, Apr. 12, in the approved license application(s).
1977] (2) Before distributing a product
made using a change, an applicant
§ 601.8 Publication of revocation. must assess the effects of the change
The Commissioner, following revoca- and demonstrate through appropriate
tion of a biologics license under 21 CFR validation and/or other clinical and/or
601.5(b), will publish a notice in the nonclinical laboratory studies the lack
FEDERAL REGISTER with a statement of of adverse effect of the change on the
the specific grounds for the revocation. identity, strength, quality, purity, or
[74 FR 20585, May 5, 2009] potency of the product as they may re-
late to the safety or effectiveness of
§ 601.9 Licenses; reissuance. the product.
(a) Compliance with requirements. A (3) Notwithstanding the requirements
biologics license, previously suspended of paragraphs (b), (c), and (f) of this
or revoked, may be reissued or rein- section, an applicant must make a
stated upon a showing of compliance change provided for in those para-
with requirements and upon such in- graphs in accordance with a regulation
spection and examination as may be or guidance that provides for a less
considered necessary by the Director, burdensome notification of the change
Center for Biologics Evaluation and (for example, by submission of a sup-
Research or the Director, Center for plement that does not require approval
Drug Evaluation and Research. prior to distribution of the product or
(b) Exclusion of noncomplying location. in an annual report).
A biologics license, excluding a loca- (4) The applicant must promptly re-
tion or locations that fail to comply vise all promotional labeling and ad-
with the requirements in this chapter, vertising to make it consistent with
may be issued without further applica- any labeling change implemented in
tion and concurrently with the suspen- accordance with paragraphs (f)(1) and
sion or revocation of the license for (f)(2) of this section.
noncompliance at the excluded loca- (5) A supplement or annual report
tion or locations. must include a list of all changes con-
(c) Exclusion of noncomplying prod- tained in the supplement or annual re-
uct(s). In the case of multiple products port. For supplements, this list must
included under a single biologics li- be provided in the cover letter.
cense application, a biologics license (b) Changes requiring supplement sub-
may be issued, excluding the non-
mission and approval prior to distribution
compliant product(s), without further
of the product made using the change
application and concurrently with the
(major changes). (1) A supplement shall
suspension or revocation of the bio-
be submitted for any change in the
logics license for a noncompliant prod-
product, production process, quality
uct(s).
controls, equipment, facilities, or re-
[64 FR 56451, Oct. 20, 1999, as amended at 70 sponsible personnel that has a substan-
FR 14983, Mar. 24, 2005] tial potential to have an adverse effect
on the identity, strength, quality, pu-
Subpart B [Reserved] rity, or potency of the product as they
may relate to the safety or effective-
Subpart C—Biologics Licensing ness of the product.
(2) These changes include, but are not
§ 601.12 Changes to an approved appli- limited to:
cation. (i) Except as provided in paragraphs
(a) General. (1) As provided by this (c) and (d) of this section, changes in
section, an applicant must inform the the qualitative or quantitative formu-

Food and Drug Administration (FDA) lation, including inactive ingredients,
28
or in the specifications provided in the change. (1) A supplement shall be sub-

approved application; mitted for any change in the product,
(ii) Changes requiring completion of production process, quality controls,
an appropriate human study to dem- equipment, facilities, or responsible
onstrate the equivalence of the iden- personnel that has a moderate poten-
tity, strength, quality, purity, or po- tial to have an adverse effect on the
tency of the product as they may re- identity, strength, quality, purity, or
late to the safety or effectiveness of potency of the product as they may re-
the product; late to the safety or effectiveness of
(iii) Changes in the virus or adven- the product. The supplement shall be
titious agent removal or inactivation labeled ‘‘Supplement—Changes Being
method(s); Effected in 30 Days’’ or, if applicable
(iv) Changes in the source material under paragraph (c)(5) of this section,
or cell line; ‘‘Supplement—Changes Being Ef-
(v) Establishment of a new master fected.’’
cell bank or seed; and (2) These changes include, but are not
(vi) Changes which may affect prod- limited to:
uct sterility assurance, such as (i) [Reserved]
changes in product or component steri- (ii) An increase or decrease in pro-
lization method(s), or an addition, de- duction scale during finishing steps
letion, or substitution of steps in an that involves different equipment; and
aseptic processing operation.
(iii) Replacement of equipment with
(3) The applicant must obtain ap-
that of similar, but not identical, de-
proval of the supplement from FDA
sign and operating principle that does
prior to distribution of the product
not affect the process methodology or
made using the change. Except for sub-
process operating parameters.
missions under paragraph (e) of this
(iv) Relaxation of an acceptance cri-
section, the following shall be con-
terion or deletion of a test to comply
tained in the supplement:
with an official compendium that is
(i) A detailed description of the pro-
consistent with FDA statutory and reg-
posed change;
ulatory requirements.
(ii) The product(s) involved;
(iii) The manufacturing site(s) or (3) Pending approval of the supple-
area(s) affected; ment by FDA, and except as provided
(iv) A description of the methods in paragraph (c)(5) of this section, dis-
used and studies performed to evaluate tribution of the product made using
the effect of the change on the iden- the change may begin not less than 30
tity, strength, quality, purity, or po- days after receipt of the supplement by
tency of the product as they may re- FDA. The information listed in para-
late to the safety or effectiveness of graph (b)(3)(i) through (b)(3)(vii) of this
the product; section shall be contained in the sup-
(v) The data derived from such stud- plement.
ies; (4) If within 30 days following FDA’s
(vi) Relevant validation protocols receipt of the supplement, FDA in-
and data; and forms the applicant that either:
(vii) A reference list of relevant (i) The change requires approval
standard operating procedures (SOP’s). prior to distribution of the product in
(4) An applicant may ask FDA to ex- accordance with paragraph (b) of this
pedite its review of a supplement for section; or
public health reasons or if a delay in (ii) Any of the information required
making the change described in it under paragraph (c)(3) of this section is
would impose an extraordinary hard- missing; the applicant shall not dis-
ship on the applicant. Such a supple- tribute the product made using the
ment and its mailing cover should be change until FDA determines that
plainly marked: ‘‘Prior Approval Sup- compliance with this section is
plement-Expedited Review Requested. achieved.
(c) Changes requiring supplement sub- (5) In certain circumstances, FDA
mission at least 30 days prior to distribu- may determine that, based on experi-
tion of the product made using the ence with a particular type of change,
29
§ 601.12 21 CFR Ch. I (4–1–20 Edition)
the supplement for such change is usu- the change in accordance with the re-
ally complete and provides the proper quirements set forth in paragraph (b)
information, and on particular assur- of this section;
ances that the proposed change has (iii) An extension of an expiration
been appropriately submitted, the dating period based upon full shelf life
product made using the change may be data on production batches obtained
distributed immediately upon receipt from a protocol approved in the appli-
of the supplement by FDA. These cir- cation;
cumstances may include substantial (iv) A change within the container
similarity with a type of change regu- closure system for a nonsterile prod-
larly involving a ‘‘Supplement— uct, based upon a showing of equiva-
Changes Being Effected’’ supplement or lency to the approved system under a
a situation in which the applicant pre- protocol approved in the application or
sents evidence that the proposed published in an official compendium;
change has been validated in accord- (v) A change in the size and/or shape
ance with an approved protocol for of a container containing the same
such change under paragraph (e) of this number of dosage units for a nonsterile
section. solid dosage form product, without a
(6) If the agency disapproves the sup- change from one container closure sys-
plemental application, it may order tem to another;
the manufacturer to cease distribution
(vi) The addition by embossing, de-
of the products made with the manu-
bossing, or engraving of a code imprint
facturing change.
to a solid dosage form biological prod-
(d) Changes to be described in an an-
uct other than a modified release dos-
nual report (minor changes). (1) Changes
age form, or a minor change in an ex-
in the product, production process,
isting code imprint; and
quality controls, equipment, facilities,
(vii) The addition or revision of an al-
or responsible personnel that have a
ternative analytical procedure that
minimal potential to have an adverse
provides the same or increased assur-
effect on the identity, strength, qual-
ance of the identity, strength, quality,
ity, purity, or potency of the product
purity, or potency of the material
as they may relate to the safety or ef-
being tested as the analytical proce-
fectiveness of the product shall be doc-
dure described in the approved applica-
umented by the applicant in an annual
tion, or deletion of an alternative ana-
report submitted each year within 60
lytical procedure.
days of the anniversary date of ap-
proval of the application. The Director, (3) The following information for
Center for Biologics Evaluation and each change shall be contained in the
Research or the Director, Center for annual report:
Drug Evaluation and Research, may (i) A list of all products involved; and
approve a written request for an alter- (ii) A full description of the manufac-
native date to combine annual reports turing and controls changes including:
for multiple approved applications into the manufacturing site(s) or area(s) in-
a single annual report submission. volved; the date the change was made;
(2) These changes include, but are not a cross-reference to relevant validation
limited to: protocols and/or SOP’s; and relevant
(i) Any change made to comply with data from studies and tests performed
a change to an official compendium, to evaluate the effect of the change on
except a change described in paragraph the identity, strength, quality, purity,
(c)(2)(iv) of this section, that is con- or potency of the product as they may
sistent with FDA statutory and regu- relate to the safety or effectiveness of
latory requirements. the product.
(ii) The deletion or reduction of an (iii) A statement by the holder of the
ingredient intended only to affect the approved application or license that
color of the product, except that a the effects of the change have been as-
change intended only to affect Blood sessed.
Grouping Reagents requires supple- (4) The applicant shall submit the re-
ment submission and approval prior to port to the FDA office responsible for
distribution of the product made using reviewing the application. The report
30
shall include all the information required information, except for changes
quired under this paragraph for each to the package insert required in
change made during the annual report- § 201.57(a) of this chapter (which must
ing interval which ends on the anniver- be made under paragraph (f)(1) of this
sary date in the order in which they section), to accomplish any of the fol-
were implemented. lowing:
(e) An applicant may submit one or (A) To add or strengthen a contra-
more protocols describing the specific indication, warning, precaution, or ad-
tests and validation studies and accept- verse reaction for which the evidence
able limits to be achieved to dem- of a causal association satisfies the
onstrate the lack of adverse effect for standard for inclusion in the labeling
specified types of manufacturing under § 201.57(c) of this chapter;
changes on the identity, strength, (B) To add or strengthen a statement
quality, purity, or potency of the prod- about abuse, dependence, psychological
uct as they may relate to the safety or effect, or overdosage;
effectiveness of the product. Any such (C) To add or strengthen an instruc-
protocols, or change to a protocol, tion about dosage and administration
shall be submitted as a supplement re- that is intended to increase the safety
quiring approval from FDA prior to of the use of the product; and
distribution of the product which, if (D) To delete false, misleading, or un-
approved, may justify a reduced report- supported indications for use or claims
ing category for the particular change for effectiveness.
because the use of the protocol for that (E) Any labeling change normally re-
type of change reduces the potential quiring a supplement submission and
risk of an adverse effect. approval prior to distribution of the
(f) Labeling changes. (1) Labeling product that FDA specifically requests
changes requiring supplement submis- be submitted under this provision.
sion—FDA approval must be obtained (ii) Pending approval of the supple-
before distribution of the product with ment by FDA, the applicant may dis-
the labeling change. Except as de- tribute a product with a package in-
scribed in paragraphs (f)(2) and (f)(3) of sert, package label, or container label
this section, an applicant shall submit bearing such change at the time the
a supplement describing a proposed supplement is submitted. The supple-
change in the package insert, package ment shall clearly identify the change
label, container label, or, if applicable, being made and include necessary sup-
a Medication Guide required under part porting data. The supplement and its
208 of this chapter, and include the in- mailing cover shall be plainly marked:
formation necessary to support the ‘‘Special Labeling Supplement—
proposed change. An applicant cannot Changes Being Effected.’’
use paragraph (f)(2) of this section to (3) Labeling changes requiring submis-
make any change to the information sion in an annual report. (i) An appli-
required in § 201.57(a) of this chapter. cant shall submit any final printed
An applicant may report the minor package insert, package label, con-
changes to the information specified in tainer label, or Medication Guide re-
paragraph (f)(3)(i)(D) of this section in quired under part 208 of this chapter in-
an annual report. The supplement shall corporating the following changes in
clearly highlight the proposed change an annual report submitted to FDA
in the labeling. The applicant shall ob- each year as provided in paragraph
tain approval from FDA prior to dis- (d)(1) of this section:
tribution of the product with the label- (A) Editorial or similar minor
ing change. changes;
(2) Labeling changes requiring supple- (B) A change in the information on
ment submission—product with a labeling how the product is supplied that does
change that may be distributed before not involve a change in the dosage
FDA approval. (i) An applicant shall strength or dosage form;
submit, at the time such change is (C) A change in the information spec-
made, a supplement for any change in ified in § 208.20(b)(8)(iii) and (b)(8)(iv) of
the package insert, package label, or this chapter for a Medication Guide;
container label to reflect newly ac- and
31
§ 601.14 21 CFR Ch. I (4–1–20 Edition)
(D) A change to the information request internal FDA review of FDA em-
quired in § 201.57(a) of this chapter as ployee decisions under this section.
follows: [62 FR 39901, July 24, 1997, as amended at 63
(1) Removal of a listed section(s) FR 66399, Dec. 1, 1998. Redesignated at 65 FR
specified in § 201.57(a)(5) of this chapter; 59718, Oct. 6, 2000, and amended at 69 FR
and 18766, Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005;
(2) Changes to the most recent revi- 71 FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28,
2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333,
sion date of the labeling as specified in Nov. 18, 2008; 80 FR 18092, Apr. 3, 2015]
§ 201.57(a)(15) of this chapter.
(E) A change made pursuant to an ex- § 601.14 Regulatory submissions in
ception or alternative granted under electronic format.
§ 201.26 or § 610.68 of this chapter. (a) General. Electronic format sub-
(ii) The applicant may distribute a missions must be in a form that FDA
product with a package insert, package can process, review, and archive. FDA
label, or container label bearing such will periodically issue guidance on how
change at the time the change is made. to provide the electronic submission
(4) Advertisements and promotional la- (e.g., method of transmission, media,
beling. Advertisements and profile formats, preparation and organiza-
motional labeling shall be submitted to tion of files.)
the Center for Biologics Evaluation (b) Labeling. The content of labeling
and Research or Center for Drug Eval- required under § 201.100(d)(3) of this
chapter (commonly referred to as the
uation and Research in accordance
package insert or professional label-
with the requirements set forth in
ing), including all text, tables, and fig-
§ 314.81(b)(3)(i) of this chapter.
ures, must be submitted to the agency
(5) The submission and grant of a in electronic format as described in
written request for an exception or al- paragraph (a) of this section. This re-
ternative under § 201.26 or § 610.68 of this quirement is in addition to the provi-
chapter satisfies the requirements in sions of §§ 601.2(a) and 601.12(f) that re-
paragraphs (f)(1) through (f)(2) of this quire applicants to submit specimens
section. of the labels, enclosures, and con-
(6) For purposes of paragraph (f)(2) of tainers, or to submit other final print-
this section, information will be con- ed labeling. Submissions under this
sidered newly acquired if it consists of paragraph must be made in accordance
data, analyses, or other information with part 11 of this chapter except for
not previously submitted to the agen- the requirements of § 11.10(a), (c)
cy, which may include (but are not lim- through (h), and (k), and the cor-
ited to) data derived from new clinical responding requirements of § 11.30.
studies, reports of adverse events, or [68 FR 69020, Dec. 11, 2003]
new analyses of previously submitted
data (e.g., meta-analyses) if the stud- § 601.15 Foreign establishments and
ies, events or analyses reveal risks of a products: samples for each importa-
tion.
different type or greater severity or
frequency than previously included in Random samples of each importa-
submissions to FDA. tion, obtained by the District Director
(g) Failure to comply. In addition to of Customs and forwarded to the Direc-
other remedies available in law and tor, Center for Biologics Evaluation
regulations, in the event of repeated and Research or the Director, Center
for Drug Evaluation and Research (see
failure of the applicant to comply with
mailing addresses in § 600.2(c) of this
this section, FDA may require that the
chapter) must be at least two final con-
applicant submit a supplement for any
tainers of each lot of product. A copy
proposed change and obtain approval of of the associated documents which de-
the supplement by FDA prior to dis- scribe and identify the shipment must
tribution of the product made using accompany the shipment for for-
the change. warding with the samples to the Direc-
(h) Administrative review. Under § 10.75 tor, Center for Biologics Evaluation
of this chapter, an applicant may re- and Research or the Director, Center
32
for Drug Evaluation and Research (see (e) One biologics license to cover all lo-
mailing addresses in § 600.2(c)). For cations. One biologics license shall be
shipments of 20 or less final containers, issued to cover all locations meeting
samples need not be forwarded, pro- the establishment standards identified
vided a copy of an official release from in the approved biologics license appli-
the Center for Biologics Evaluation cation and each location shall be sub-
and Research or Center for Drug Eval- ject to inspection by FDA officials.
uation and Research accompanies each
shipment. [64 FR 56451, Oct. 20, 1999, as amended at 70
FR 14983, Mar. 24, 2005]
FR 18092, Apr. 3, 2015] § 601.21 Products under development.
§ 601.20 Biologics licenses; issuance A biological product undergoing de-

and conditions. velopment, but not yet ready for a bio-
logics license, may be shipped or other-
(a) Examination—compliance with re- wise delivered from one State or pos-
quirements. A biologics license applica- session into another State or posses-
tion shall be approved only upon exam- sion provided such shipment or deliv-
ination of the product and upon a de- ery is not for introduction or delivery
termination that the product complies for introduction into interstate com-
with the standards established in the merce, except as provided in sections
biologics license application and the 505(i) and 520(g) of the Federal Food,
requirements prescribed in the regula-
Drug, and Cosmetic Act, as amended,
tions in this chapter including but not
and the regulations thereunder (21 CFR
limited to the good manufacturing
parts 312 and 812).
practice requirements set forth in
parts 210, 211, 600, 606, and 820 of this [64 FR 56451, Oct. 20, 1999]
chapter.
(b) Availability of product. No bio- § 601.22 Products in short supply; ini-
logics license shall be issued unless: tial manufacturing at other than li-
censed location.
(1) The product intended for intro-
duction into interstate commerce is A biologics license issued to a manu-
available for examination, and facturer and covering all locations of
(2) Such product is available for in- manufacture shall authorize persons
spection during all phases of manufac- other than such manufacturer to con-
ture. duct at places other than such loca-
(c) Manufacturing process—impairment tions the initial, and partial manufac-
of assurances. No product shall be li- turing of a product for shipment solely
censed if any part of the process of or to such manufacturer only to the ex-
relating to the manufacture of such tent that the names of such persons
product, in the judgment of the Direc- and places are registered with the Com-
tor, Center for Biologics Evaluation missioner of Food and Drugs and it is
and Research or the Director, Center found upon application of such manu-
for Drug Evaluation and Research, facturer, that the product is in short
would impair the assurances of contin- supply due either to the peculiar
ued safety, purity, and potency as pro- growth requirements of the organism
vided by the regulations contained in involved or to the scarcity of the ani-
this chapter. mal required for manufacturing pur-
(d) Inspection—compliance with re- poses, and such manufacturer has es-
quirements. A biologics license shall be tablished with respect to such persons
issued or a biologics license application and places such procedures, inspec-
approved only after inspection of the tions, tests or other arrangements as
establishment(s) listed in the biologics will ensure full compliance with the
license application and upon a deter- applicable regulations of this sub-
mination that the establishment(s) chapter related to continued safety,
complies with the standards estab- purity, and potency. Such persons and
lished in the biologics license applica- places shall be subject to all regula-
tion and the requirements prescribed in tions of this subchapter except §§ 601.2
applicable regulations. to 601.6, 601.9, 601.10, 601.20, 601.21 to
33
§ 601.27 21 CFR Ch. I (4–1–20 Edition)
601.33, and 610.60 to 610.65 of this chap- (b) Deferred submission. (1) FDA may,
ter. For persons and places authorized on its own initiative or at the request
under this section to conduct the ini- of an applicant, defer submission of
tial and partial manufacturing of a some or all assessments of safety and
product for shipment solely to a manu- effectiveness described in paragraph (a)
facturer of a product subject to licen- of this section until after licensing of
sure under § 601.2(c), the following addi- the product for use in adults. Deferral
tional regulations shall not be applica- may be granted if, among other rea-
ble: §§ 600.10(b) and (c), 600.11, 600.12, sons, the product is ready for approval
600.13, and 610.53 of this chapter. Fail- in adults before studies in pediatric pa-
ure of such manufacturer to maintain tients are complete, pediatric studies
such procedures, inspections, tests, or should be delayed until additional safe-
other arrangements, or failure of any ty or effectiveness data have been col-
person conducting such partial manu- lected. If an applicant requests de-
facturing to comply with applicable ferred submission, the request must
regulations shall constitute a ground provide an adequate justification for
for suspension or revocation of the au- delaying pediatric studies, a descrip-
thority conferred pursuant to this section of the planned or ongoing studies,
tion on the same basis as provided in and evidence that the studies are being
§§ 601.6 to 601.8 with respect to the sus- or will be conducted with due diligence
pension and the revocation of licenses.
and at the earliest possible time.
[42 FR 4718, Jan. 25, 1977, as amended at 61 (2) If FDA determines that there is
FR 24233, May 14, 1996; 64 FR 56452, Oct. 20, an adequate justification for tempo-
1999; 80 FR 37974, July 2, 2015] rarily delaying the submission of as-
sessments of pediatric safety and effec-
§ 601.27 Pediatric studies.
tiveness, the product may be licensed
(a) Required assessment. Except as pro- for use in adults subject to the require-
vided in paragraphs (b), (c), and (d) of ment that the applicant submit the re-
this section, each application for a new quired assessments within a specified
active ingredient, new indication, new time.
dosage form, new dosing regimen, or (c) Waivers—(1) General. FDA may
new route of administration shall con- grant a full or partial waiver of the re-
tain data that are adequate to assess quirements of paragraph (a) of this sec-
the safety and effectiveness of the tion on its own initiative or at the re-
product for the claimed indications in quest of an applicant. A request for a
all relevant pediatric subpopulations, waiver must provide an adequate jus-
and to support dosing and administra- tification.
tion for each pediatric subpopulation (2) Full waiver. An applicant may re-
for which the product is safe and effec- quest a waiver of the requirements of
tive. Where the course of the disease paragraph (a) of this section if the ap-
and the effects of the product are simi- plicant certifies that:
lar in adults and pediatric patients,
(i) The product does not represent a
FDA may conclude that pediatric effec-
meaningful therapeutic benefit over
tiveness can be extrapolated from ade-
existing therapies for pediatric pa-
quate and well-controlled effectiveness
tients and is not likely to be used in a
studies in adults, usually supplemented
substantial number of pediatric pa-
with other information in pediatric pa-
tients, such as pharmacokinetic stud- tients;
ies. In addition, studies may not be (ii) Necessary studies are impossible
needed in each pediatric age group, if or highly impractical because, e.g., the
data from one age group can be extrap- number of such patients is so small or
olated to another. Assessments re- geographically dispersed; or
quired under this section for a product (iii) There is evidence strongly sug-
that represents a meaningful thera- gesting that the product would be inef-
peutic benefit over existing treatments fective or unsafe in all pediatric age
must be carried out using appropriate groups.
formulations for the age group(s) for (3) Partial waiver. An applicant may
which the assessment is required. request a waiver of the requirements of
34
paragraph (a) of this section with re- (ii) The product is in a class of prod-
spect to a specified pediatric age group, ucts or for an indication for which
if the applicant certifies that: there is a need for additional thera-
(i) The product does not represent a peutic options.
meaningful therapeutic benefit over (d) Exemption for orphan drugs. This
existing therapies for pediatric pa- section does not apply to any product
tients in that age group, and is not for an indication or indications for
likely to be used in a substantial num- which orphan designation has been
ber of patients in that age group; granted under part 316, subpart C, of
(ii) Necessary studies are impossible this chapter.
or highly impractical because, e.g., the
[63 FR 66671, Dec. 2, 1998]
number of patients in that age group is
so small or geographically dispersed; § 601.28 Annual reports of post-
(iii) There is evidence strongly sug- marketing pediatric studies.
gesting that the product would be inef-
fective or unsafe in that age group; or Sponsors of licensed biological prod-
(iv) The applicant can demonstrate ucts shall submit the following infor-
that reasonable attempts to produce a mation each year within 60 days of the
pediatric formulation necessary for anniversary date of approval of each
that age group have failed. product under the license to the Direc-
(4) FDA action on waiver. FDA shall tor, Center for Biologics Evaluation
grant a full or partial waiver, as appro- and Research or the Director, Center
priate, if the agency finds that there is for Drug Evaluation and Research (see
a reasonable basis on which to con- mailing addresses in § 600.2(a) or (b) of
clude that one or more of the grounds this chapter):
for waiver specified in paragraphs (c)(2) (a) Summary. A brief summary stat-
or (c)(3) of this section have been met. ing whether labeling supplements for
If a waiver is granted on the ground pediatric use have been submitted and
that it is not possible to develop a pedi- whether new studies in the pediatric
atric formulation, the waiver will population to support appropriate la-
cover only those pediatric age groups beling for the pediatric population
requiring that formulation. If a waiver have been initiated. Where possible, an
is granted because there is evidence estimate of patient exposure to the
that the product would be ineffective drug product, with special reference to
or unsafe in pediatric populations, this the pediatric population (neonates, in-
information will be included in the fants, children, and adolescents) shall
product’s labeling. be provided, including dosage form.
(5) Definition of ‘‘meaningful thera- (b) Clinical data. Analysis of available
peutic benefit’’. For purposes of this sec- safety and efficacy data in the pedi-
tion, a product will be considered to atric population and changes proposed
offer a meaningful therapeutic benefit in the labeling based on this informa-
over existing therapies if FDA esti- tion. An assessment of data needed to
mates that: ensure appropriate labeling for the pe-
(i) If approved, the product would diatric population shall be included.
represent a significant improvement in (c) Status reports. A statement on the
the treatment, diagnosis, or prevention current status of any postmarketing
of a disease, compared to marketed studies in the pediatric population per-
products adequately labeled for that formed by, or on behalf of, the appli-
use in the relevant pediatric popu- cant. The statement shall include
lation. Examples of how improvement whether postmarketing clinical studies
might be demonstrated include, e.g., in pediatric populations were required
evidence of increased effectiveness in or agreed to, and, if so, the status of
treatment, prevention, or diagnosis of these studies shall be reported to FDA
disease; elimination or substantial rein annual progress reports of post-
duction of a treatment-limiting drug marketing studies under § 601.70 rather
reaction; documented enhancement of than under this section.
compliance; or evidence of safety and
[65 FR 59718, Oct. 6, 2000, as amended at 65 FR

effectiveness in a new subpopulation; 64618, Oct. 30, 2000; 70 FR 14984, Mar. 24, 2005;
or 80 FR 18092, Apr. 3, 2015]
35
§ 601.29 21 CFR Ch. I (4–1–20 Edition)
§ 601.29 Guidance documents. § 601.32 General factors relevant to

safety and effectiveness.
(a) FDA has made available guidance
documents under § 10.115 of this chapter FDA’s determination of the safety
to help you comply with certain re- and effectiveness of a diagnostic radio-
quirements of this part. pharmaceutical includes consideration
(b) The Center for Biologics Evalua- of the following:
tion and Research (CBER) maintains a (a) The proposed use of the diagnostic
list of guidance documents that apply radiopharmaceutical in the practice of
to the center’s regulations. The lists medicine;
are maintained on the Internet and are (b) The pharmacological and toxi-
published annually in the FEDERAL cological activity of the diagnostic
REGISTER. You may request a copy of radiopharmaceutical (including any
the CBER list from the Food and Drug carrier or ligand component of the di-
Administration, Center for Biologics agnostic radiopharmaceutical); and
Evaluation and Research, Office of (c) The estimated absorbed radiation
dose of the diagnostic radiopharma-
Communication, Outreach and Devel-
ceutical.
opment, 10903 New Hampshire Ave.,
Bldg. 71, Rm. 3103, Silver Spring, MD § 601.33 Indications.
20993–0002.
(a) For diagnostic radiopharma-
[65 FR 56480, Sept. 19, 2000, as amended at 70 ceuticals, the categories of proposed
FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, indications for use include, but are not
2015] limited to, the following:
(1) Structure delineation;
Subpart D—Diagnostic (2) Functional, physiological, or bio-
Radiopharmaceuticals chemical assessment;
(3) Disease or pathology detection or
assessment; and
SOURCE: 64 FR 26668, May 17, 1999, unless
otherwise noted.
(4) Diagnostic or therapeutic patient
management.
§ 601.30 Scope. (b) Where a diagnostic radiopharma-
ceutical is not intended to provide dis-
This subpart applies to radiopharma- ease-specific information, the proposed
ceuticals intended for in vivo adminis- indications for use may refer to a bio-
tration for diagnostic and monitoring chemical, physiological, anatomical, or
use. It does not apply to radiopharma- pathological process or to more than
ceuticals intended for therapeutic pur- one disease or condition.
poses. In situations where a particular
radiopharmaceutical is proposed for § 601.34 Evaluation of effectiveness.
both diagnostic and therapeutic uses, (a) The effectiveness of a diagnostic
the radiopharmaceutical must be eval- radiopharmaceutical is assessed by
uated taking into account each in- evaluating its ability to provide useful
tended use. clinical information related to its pro-
posed indications for use. The method
§ 601.31 Definition.
of this evaluation varies depending
For purposes of this part,diagnostic upon the proposed indication(s) and
radiopharmaceutical means: may use one or more of the following
(a) An article that is intended for use criteria:
in the diagnosis or monitoring of a dis- (1) The claim of structure delineation
ease or a manifestation of a disease in is established by demonstrating in a
humans and that exhibits spontaneous defined clinical setting the ability to
disintegration of unstable nuclei with locate anatomical structures and to
the emission of nuclear particles or characterize their anatomy.
photons; or (2) The claim of functional, physio-
(b) Any nonradioactive reagent kit or logical, or biochemical assessment is
nuclide generator that is intended to established by demonstrating in a de-
be used in the preparation of such arti- fined clinical setting reliable measure-
cle as defined in paragraph (a) of this ment of function(s) or physiological,

section. biochemical, or molecular process(es).
36
(3) The claim of disease or pathology (1) Allergic or hypersensitivity re-

detection or assessment is established sponses,
by demonstrating in a defined clinical (2) Immunologic responses,
setting that the diagnostic radio- (3) Changes in the physiologic or bio-
pharmaceutical has sufficient accuracy chemical function of the target and
in identifying or characterizing the dis- nontarget tissues, and
ease or pathology. (4) Clinically detectable signs or
(4) The claim of diagnostic or thera- symptoms.
peutic patient management is estab- (c)(1) To establish the safety of a di-
lished by demonstrating in a defined agnostic radiopharmaceutical, FDA
clinical setting that the test is useful may require, among other information,
in diagnostic or therapeutic patient the following types of data:
management. (A) Pharmacology data,
(5) For a claim that does not fall (B) Toxicology data,
within the indication categories identi- (C) Clinical adverse event data, and
fied in § 601.33, the applicant or sponsor (D) Radiation safety assessment.
should consult FDA on how to estab- (2) The amount of new safety data re-
lish the effectiveness of the diagnostic quired will depend on the characteris-
radiopharmaceutical for the claim. tics of the product and available infor-
(b) The accuracy and usefulness of mation regarding the safety of the di-
the diagnostic information is deter- agnostic radiopharmaceutical, and its
mined by comparison with a reliable carrier or ligand, obtained from other
assessment of actual clinical status. A studies and uses. Such information
reliable assessment of actual clinical may include, but is not limited to, the
status may be provided by a diagnostic dose, route of administration, fre-
standard or standards of demonstrated quency of use, half-life of the ligand or
accuracy. In the absence of such diag- carrier, half-life of the radionuclide,
nostic standard(s), the actual clinical and results of clinical and preclinical
status must be established in another studies. FDA will establish categories
manner, e.g., patient followup. of diagnostic radiopharmaceuticals
based on defined characteristics rel-
§ 601.35 Evaluation of safety.
evant to risk and will specify the
(a) Factors considered in the safety amount and type of safety data that
assessment of a diagnostic radio- are appropriate for each category (e.g.,
pharmaceutical include, among others, required safety data may be limited for
the following: diagnostic radiopharmaceuticals with
(1) The radiation dose; a well established, low-risk profile).
(2) The pharmacology and toxicology Upon reviewing the relevant product
of the radiopharmaceutical, including characteristics and safety information,
any radionuclide, carrier, or ligand; FDA will place each diagnostic radio-
(3) The risks of an incorrect diag- pharmaceutical into the appropriate
nostic determination; safety risk category.
(4) The adverse reaction profile of the (d) Radiation safety assessment. The
drug; radiation safety assessment must es-
(5) Results of human experience with tablish the radiation dose of a diag-
the radiopharmaceutical for other uses; nostic radiopharmaceutical by radi-
and ation dosimetry evaluations in humans
(6) Results of any previous human ex- and appropriate animal models. The
perience with the carrier or ligand of maximum tolerated dose need not be
the radiopharmaceutical when the established.
same chemical entity as the carrier or
ligand has been used in a previously
studied product.
Subpart E—Accelerated Approval
(b) The assessment of the adverse re- of Biological Products for Seri-
action profile includes, but is not lim- ous or Life-Threatening Ill-
ited to, an evaluation of the potential nesses
of the diagnostic radiopharmaceutical,
including the carrier or ligand, to elic- SOURCE: 57 FR 58959, Dec. 11, 1992, unless
it the following: otherwise noted.
37
§ 601.40 21 CFR Ch. I (4–1–20 Edition)
§ 601.40 Scope. (b) The limitations imposed will be

commensurate with the specific safety
This subpart applies to certain bio-
concerns presented by the biological
logical products that have been studied
product.
for their safety and effectiveness in
treating serious or life-threatening ill- § 601.43 Withdrawal procedures.
nesses and that provide meaningful
therapeutic benefit to patients over ex- (a) For biological products approved
isting treatments (e.g., ability to treat under § 601.41 or § 601.42, FDA may with-
patients unresponsive to, or intolerant draw approval, following a hearing as
of, available therapy, or improved pa- provided in part 15 of this chapter, as
tient response over available therapy). modified by this section, if:
(1) A postmarketing clinical study
§ 601.41 Approval based on a surrogate fails to verify clinical benefit;
endpoint or on an effect on a clin- (2) The applicant fails to perform the
ical endpoint other than survival or required postmarketing study with due
irreversible morbidity. diligence;
FDA may grant marketing approval (3) Use after marketing demonstrates
for a biological product on the basis of that postmarketing restrictions are in-
adequate and well-controlled clinical adequate to ensure safe use of the bio-
trials establishing that the biological logical product;
product has an effect on a surrogate (4) The applicant fails to adhere to
endpoint that is reasonably likely, the postmarketing restrictions agreed
based on epidemiologic, therapeutic, upon;
pathophysiologic, or other evidence, to (5) The promotional materials are
predict clinical benefit or on the basis false or misleading; or
of an effect on a clinical endpoint other (6) Other evidence demonstrates that
than survival or irreversible morbidity. the biological product is not shown to
Approval under this section will be be safe or effective under its conditions
subject to the requirement that the ap- of use.
plicant study the biological product (b) Notice of opportunity for a hearing.
further, to verify and describe its clin- The Director of the Center for Bio-
ical benefit, where there is uncertainty logics Evaluation and Research or the
as to the relation of the surrogate end- Director of the Center for Drug Evalua-
point to clinical benefit, or of the ob- tion and Research will give the appli-
served clinical benefit to ultimate out- cant notice of an opportunity for a
come. Postmarketing studies would hearing on the Center’s proposal to
usually be studies already underway. withdraw the approval of an applica-
When required to be conducted, such tion approved under § 601.41 or § 601.42.
studies must also be adequate and well- The notice, which will ordinarily be a
controlled. The applicant shall carry letter, will state generally the reasons
out any such studies with due dili- for the action and the proposed
gence. grounds for the order.
(c) Submission of data and information.
§ 601.42 Approval with restrictions to (1) If the applicant fails to file a writ-
assure safe use.
ten request for a hearing within 15 days
(a) If FDA concludes that a biological of receipt of the notice, the applicant
product shown to be effective can be waives the opportunity for a hearing.
safely used only if distribution or use (2) If the applicant files a timely re-
is restricted, FDA will require such quest for a hearing, the agency will
postmarketing restrictions as are need- publish a notice of hearing in the FED-
ed to assure safe use of the biological ERAL REGISTER in accordance with
product, such as: §§ 12.32(e) and 15.20 of this chapter.
(1) Distribution restricted to certain (3) An applicant who requests a hear-
facilities or physicians with special ing under this section must, within 30
training or experience; or days of receipt of the notice of oppor-
(2) Distribution conditioned on the tunity for a hearing, submit the data
performance of specified medical proce- and information upon which the appli-
dures. cant intends to rely at the hearing.
38
(d) Separation of functions. Separation motional labeling as well as advertise-

of functions (as specified in § 10.55 of ments, intended for dissemination or
this chapter) will not apply at any publication within 120 days following
point in withdrawal proceedings under marketing approval. After 120 days fol-
this section. lowing marketing approval, unless oth-
(e) Procedures for hearings. Hearings erwise informed by the agency, the ap-
held under this section will be con- plicant must submit promotional ma-
ducted in accordance with the provi- terials at least 30 days prior to the in-
sions of part 15 of this chapter, with tended time of initial dissemination of
the following modifications: the labeling or initial publication of
(1) An advisory committee duly con- the advertisement.
stituted under part 14 of this chapter
will be present at the hearing. The § 601.46 Termination of requirements.
committee will be asked to review the If FDA determines after approval
issues involved and to provide advice that the requirements established in
and recommendations to the Commis- § 601.42, § 601.43, or § 601.45 are no longer
sioner of Food and Drugs. necessary for the safe and effective use
(2) The presiding officer, the advisory of a biological product, it will so notify
committee members, up to three rep- the applicant. Ordinarily, for biological
resentatives of the applicant, and up to products approved under § 601.41, these
three representatives of the Center requirements will no longer apply when
may question any person during or at FDA determines that the required
the conclusion of the person’s presen- postmarketing study verifies and de-
tation. No other person attending the scribes the biological product’s clinical
hearing may question a person making benefit and the biological product
a presentation. The presiding officer would be appropriate for approval
may, as a matter of discretion, permit under traditional procedures. For bio-
questions to be submitted to the pre- logical products approved under
siding officer for response by a person § 601.42, the restrictions would no
making a presentation. longer apply when FDA determines
(f) Judicial review. The Commis- that safe use of the biological product
sioner’s decision constitutes final can be assured through appropriate la-
agency action from which the appli- beling. FDA also retains the discretion
cant may petition for judicial review. to remove specific postapproval re-
Before requesting an order from a quirements upon review of a petition
court for a stay of action pending re- submitted by the sponsor in accordance
view, an applicant must first submit a with § 10.30.
petition for a stay of action under
§ 10.35 of this chapter. Subpart F—Confidentiality of
[57 FR 58959, Dec. 11, 1992, as amended at 68 Information
FR 34797, June 11, 2003; 70 FR 14984, Mar. 24,
2005] § 601.50 Confidentiality of data and in-
formation in an investigational new
§ 601.44 Postmarketing safety report- drug notice for a biological product.
ing. (a) The existence of an IND notice for
Biological products approved under a biological product will not be dis-
this program are subject to the post- closed by the Food and Drug Adminis-
marketing recordkeeping and safety tration unless it has previously been
reporting applicable to all approved bi- publicly disclosed or acknowledged.
ological products. (b) The availability for public disclo-
sure of all data and information in an
§ 601.45 Promotional materials. IND file for a biological product shall
For biological products being consid- be handled in accordance with the pro-
ered for approval under this subpart, visions established in § 601.51.
unless otherwise informed by the agen- (c) Notwithstanding the provisions of
cy, applicants must submit to the § 601.51, the Food and Drug Administra-
agency for consideration during the tion shall disclose upon request to an
preapproval review period copies of all individual on whom an investigational

promotional materials, including pro- biological product has been used a copy
39
§ 601.51 21 CFR Ch. I (4–1–20 Edition)
of any adverse reaction report relating ville, MD 20852, for investigations in-
to such use. volving an exception from informed
[39 FR 44656, Dec. 24, 1974]
consent under § 50.24 of this chapter.
Persons wishing to request this infor-
§ 601.51 Confidentiality of data and in- mation shall submit a request under
formation in applications for bio- the Freedom of Information Act.
logics licenses. (e) After a license has been issued,
(a) For purposes of this section the the following data and information in
biological product file includes all data the biological product file are imme-
and information submitted with or in- diately available for public disclosure
corporated by reference in any applica- unless extraordinary circumstances are
tion for a biologics license, IND’s in- shown:
corporated into any such application, (1) All safety and effectiveness data
master files, and other related submis- and information.
sions. The availability for public dis- (2) A protocol for a test or study, un-
closure of any record in the biological less it is shown to fall within the ex-
product file shall be handled in accord- emption established for trade secrets
ance with the provisions of this sec- and confidential commercial or finan-
tion. cial information in § 20.61 of this chap-
(b) The existence of a biological prod- ter.
uct file will not be disclosed by the (3) Adverse reaction reports, product
Food and Drug Administration before a experience reports, consumer com-
biologics license application has been plaints, and other similar data and in-
approved unless it has previously been formation, after deletion of:
publicly disclosed or acknowledged. (i) Names and any information that
The Food and Drug Administration would identify the person using the
will maintain a list available for public product.
disclosure of biological products for (ii) Names and any information that
which a license application has been would identify any third party involved
approved. with the report, such as a physician or
(c) If the existence of a biological hospital or other institution.
product file has not been publicly dis- (4) A list of all active ingredients and
closed or acknowledged, no data or in- any inactive ingredients previously
formation in the biological product file disclosed to the public, as defined in
is available for public disclosure. § 20.81 of this chapter.
(d)(1) If the existence of a biological (5) An assay method or other analyt-
product file has been publicly disclosed ical method, unless it serves no regu-
or acknowledged before a license has latory or compliance purpose and it is
been issued, no data or information shown to fall within the exemption es-
contained in the file is available for tablished in § 20.61 of this chapter.
public disclosure before such license is (6) All correspondence and written
issued, but the Commissioner may, in summaries of oral discussions relating
his discretion, disclose a summary of to the biological product file, in ac-
such selected portions of the safety and cordance with the provisions of part 20
effectiveness data as are appropriate of this chapter.
for public consideration of a specific (7) All records showing the manufac-
pending issue, e.g., at an open session turer’s testing of a particular lot, after
of a Food and Drug Administration ad- deletion of data or information that
visory committee or pursuant to an ex- would show the volume of the drug pro-
change of important regulatory infor- duced, manufacturing procedures and
mation with a foreign government. controls, yield from raw materials,
(2) Notwithstanding paragraph (d)(1) costs, or other material falling within
of this section, FDA will make avail- § 20.61 of this chapter.
able to the public upon request the in- (8) All records showing the testing of
formation in the IND that was required and action on a particular lot by the
to be filed in Docket Number 95S–0158 Food and Drug Administration.
in the Division of Dockets Management (f) The following data and informa-
(HFA–305), Food and Drug Administra- tion in a biological product file are not
tion, 5630 Fishers Lane, rm. 1061, Rock- available for public disclosure unless
40
they have been previously disclosed to (b) What to report. Each applicant of a
the public as defined in § 20.81 of this licensed biological product shall sub-
chapter or they relate to a product or mit a report to FDA on the status of
ingredient that has been abandoned postmarketing studies for each ap-
and they no longer represent a trade proved product application. The status
secret or confidential commercial or fi- of these postmarketing studies shall be
nancial information as defined in § 20.61 reported annually until FDA notifies
of this chapter: the applicant, in writing, that the
(1) Manufacturing methods or proc- agency concurs with the applicant’s de-
esses, including quality control proce- termination that the study commit-
dures. ment has been fulfilled, or that the
(2) Production, sales, distribution, study is either no longer feasible or
and similar data and information, ex- would no longer provide useful infor-
cept that any compilation of such data mation. Each annual progress report
and information aggregated and pre- shall be accompanied by a completed
pared in a way that does not reveal transmittal Form FDA–2252, and shall
data or information which is not avail- include all the information required
able for public disclosure under this under this section that the applicant
provision is available for public disclo- received or otherwise obtained during
sure. the annual reporting interval which
(3) Quantitative or semiquantitative ends on the U.S. anniversary date. The
formulas. report must provide the following in-
(g) For purposes of this regulation, formation for each postmarketing
safety and effectiveness data include study:
all studies and tests of a biological (1) Applicant’s name.
product on animals and humans and all (2) Product name. Include the ap-
studies and tests on the drug for iden- proved product’s proper name and the
tity, stability, purity, potency, and proprietary name, if any.
bioavailability. (3) Biologics license application (BLA)
[39 FR 44656, Dec. 24, 1974, as amended at 42 and supplement number.
FR 15676, Mar. 22, 1977; 49 FR 23833, June 8, (4) Date of U.S. approval of BLA.
1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, (5) Date of postmarketing study commit-
Oct. 2, 1996; 64 FR 56452, Oct. 20, 1999; 68 FR ment.
24879, May 9, 2003; 69 FR 13717, Mar. 24, 2004; (6) Description of postmarketing study
70 FR 14984, Mar. 24, 2005] commitment. The description must in-
clude sufficient information to unique-
Subpart G—Postmarketing Studies ly describe the study. This information
may include the purpose of the study,
SOURCE: 65 FR 64618, Oct. 30, 2000, unless the type of study, the patient popu-
otherwise noted. lation addressed by the study and the
indication(s) and dosage(s) that are to
§ 601.70 Annual progress reports of be studied.
postmarketing studies. (7) Schedule for completion and report-
(a) General requirements. This section ing of the postmarketing study commit-
applies to all required postmarketing ment. The schedule should include the
studies (e.g., accelerated approval clin- actual or projected dates for submis-
ical benefit studies, pediatric studies) sion of the study protocol to FDA,
and postmarketing studies that an ap- completion of patient accrual or initi-
plicant has committed, in writing, to ation of an animal study, completion of
conduct either at the time of approval the study, submission of the final
of an application or a supplement to an study report to FDA, and any addi-
application, or after approval of an ap- tional milestones or submissions for
plication or a supplement. Post- which projected dates were specified as
marketing studies within the meaning part of the commitment. In addition, it
of this section are those that concern: should include a revised schedule, as
(1) Clinical safety; appropriate. If the schedule has been
(2) Clinical efficacy; previously revised, provide both the
(3) Clinical pharmacology; and original schedule and the most recent,
(4) Nonclinical toxicology. previously submitted revision.
41
§ 601.90 21 CFR Ch. I (4–1–20 Edition)
(8) Current status of the postmarketing close any information concerning a

study commitment. The status of each postmarketing study, within the mean-
postmarketing study should be cat- ing of this section, if the agency deter-
egorized using one of the following mines that the information is nec-
terms that describes the study’s status essary to identify an applicant or to es-
on the anniversary date of U.S. ap- tablish the status of the study includ-
proval of the application or other ing the reasons, if any, for failure to
agreed upon date: conduct, complete, and report the
(i) Pending. The study has not been study. Under this section, FDA will not
initiated, but does not meet the cri- publicly disclose trade secrets, as de-
terion for delayed. fined in § 20.61 of this chapter, or infor-
(ii) Ongoing. The study is proceeding mation, described in § 20.63 of this chap-
according to or ahead of the original ter, the disclosure of which would con-
schedule described under paragraph stitute an unwarranted invasion of per-
(b)(7) of this section.
sonal privacy.
(iii) Delayed. The study is behind the
original schedule described under para- [65 FR 64618, Oct. 30, 2000, as amended at 70
graph (b)(7) of this section. FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3,
(iv) Terminated. The study was ended 2015]
before completion but a final study re-
port has not been submitted to FDA. Subpart H—Approval of Biological
(v) Submitted. The study has been Products When Human Effi-
completed or terminated and a final cacy Studies Are Not Ethical
study report has been submitted to
FDA. or Feasible
(9) Explanation of the study’s status.
Provide a brief description of the sta- SOURCE: 67 FR 37996, May 31, 2002, unless
tus of the study, including the patient otherwise noted.
accrual rate (expressed by providing
the number of patients or subjects en- § 601.90 Scope.
rolled to date, and the total planned This subpart applies to certain bio-
enrollment), and an explanation of the logical products that have been studied
study’s status identified under para- for their safety and efficacy in amelio-
graph (b)(8) of this section. If the study rating or preventing serious or life-
has been completed, include the date threatening conditions caused by expo-
the study was completed and the date sure to lethal or permanently disabling
the final study report was submitted to toxic biological, chemical, radio-
FDA, as applicable. Provide a revised logical, or nuclear substances. This
schedule, as well as the reason(s) for subpart applies only to those biological
the revision, if the schedule under products for which: Definitive human
paragraph (b)(7) of this section has efficacy studies cannot be conducted
changed since the previous report.
because it would be unethical to delib-
(c) When to report. Annual progress
erately expose healthy human volun-
reports for postmarketing study com-
teers to a lethal or permanently dis-
mitments entered into by applicants
shall be reported to FDA within 60 days abling toxic biological, chemical, radi-
of the anniversary date of the U.S. ap- ological, or nuclear substance; and
proval of the application for the prod- field trials to study the product’s effi-
uct. cacy after an accidental or hostile ex-
(d) Where to report. Submit two copies posure have not been feasible. This sub-
of the annual progress report of post- part does not apply to products that
marketing studies to the Center for can be approved based on efficacy
Biologics Evaluation and Research or standards described elsewhere in FDA’s
Center for Drug Evaluation and Re- regulations (e.g., accelerated approval
search (see mailing addresses in based on surrogate markers or clinical
§ 600.2(a) or (b) of this chapter). endpoints other than survival or irre-
(e) Public disclosure of information. Ex- versible morbidity), nor does it address
cept for the information described in the safety evaluation for the products
this paragraph, FDA may publicly dis- to which it does apply.
42
§ 601.91 Approval based on evidence of proach to postmarketing study com-

effectiveness from studies in ani- mitments in the event such studies be-
mals. come ethical and feasible.
(a) FDA may grant marketing ap- (2) Approval with restrictions to ensure
proval for a biological product for safe use. If FDA concludes that a bio-
which safety has been established and logical product shown to be effective
for which the requirements of § 601.90 under this subpart can be safely used
are met based on adequate and well- only if distribution or use is restricted,
controlled animal studies when the re- FDA will require such postmarketing
sults of those animal studies establish restrictions as are needed to ensure
that the biological product is reason- safe use of the biological product, com-
ably likely to produce clinical benefit mensurate with the specific safety con-
in humans. In assessing the sufficiency cerns presented by the biological prod-
of animal data, the agency may take uct, such as:
into account other data, including (i) Distribution restricted to certain
human data, available to the agency. facilities or health care practitioners
FDA will rely on the evidence from with special training or experience;
studies in animals to provide substan- (ii) Distribution conditioned on the
tial evidence of the effectiveness of performance of specified medical proce-
these products only when: dures, including medical followup; and
(1) There is a reasonably well-under- (iii) Distribution conditioned on
stood pathophysiological mechanism of specified recordkeeping requirements.
the toxicity of the substance and its (3) Information to be provided to patient
prevention or substantial reduction by recipients. For biological products or
the product; specific indications approved under
(2) The effect is demonstrated in this subpart, applicants must prepare,
more than one animal species expected as part of their proposed labeling, la-
to react with a response predictive for beling to be provided to patient recipi-
humans, unless the effect is dem- ents. The patient labeling must explain
onstrated in a single animal species that, for ethical or feasibility reasons,
that represents a sufficiently well- the biological product’s approval was
characterized animal model for pre- based on efficacy studies conducted in
dicting the response in humans; animals alone and must give the bio-
(3) The animal study endpoint is logical product’s indication(s), direc-
clearly related to the desired benefit in tions for use (dosage and administra-
humans, generally the enhancement of tion), contraindications, a description
survival or prevention of major mor- of any reasonably foreseeable risks, ad-
bidity; and verse reactions, anticipated benefits,
(4) The data or information on the ki- drug interactions, and any other rel-
netics and pharmacodynamics of the evant information required by FDA at
product or other relevant data or infor- the time of approval. The patient label-
mation, in animals and humans, allows ing must be available with the product
selection of an effective dose in hu- to be provided to patients prior to ad-
mans. ministration or dispensing of the bio-
(b) Approval under this subpart will logical product for the use approved
be subject to three requirements: under this subpart, if possible.
(1) Postmarketing studies. The appli-
cant must conduct postmarketing § 601.92 Withdrawal procedures.
studies, such as field studies, to verify (a) Reasons to withdraw approval. For
and describe the biological product’s biological products approved under this
clinical benefit and to assess its safety subpart, FDA may withdraw approval,
when used as indicated when such stud- following a hearing as provided in part
ies are feasible and ethical. Such post- 15 of this chapter, as modified by this
marketing studies would not be fea- section, if:
sible until an exigency arises. When (1) A postmarketing clinical study
such studies are feasible, the applicant fails to verify clinical benefit;
must conduct such studies with due (2) The applicant fails to perform the
diligence. Applicants must include as postmarketing study with due dili-

part of their application a plan or ap- gence;
43
§ 601.93 21 CFR Ch. I (4–1–20 Edition)
(3) Use after marketing demonstrates (2) The presiding officer, the advisory
that postmarketing restrictions are in- committee members, up to three rep-
adequate to ensure safe use of the bio- resentatives of the applicant, and up to
logical product; three representatives of CBER may
(4) The applicant fails to adhere to question any person during or at the
the postmarketing restrictions applied conclusion of the person’s presen-
at the time of approval under this sub- tation. No other person attending the
part; hearing may question a person making
(5) The promotional materials are a presentation. The presiding officer
false or misleading; or may, as a matter of discretion, permit
(6) Other evidence demonstrates that questions to be submitted to the pre-
the biological product is not shown to siding officer for response by a person
be safe or effective under its conditions making a presentation.
of use. (f) Judicial review. The Commissioner
(b) Notice of opportunity for a hearing. of Food and Drugs’ decision constitutes
The Director of the Center for Bio- final agency action from which the ap-
logics Evaluation and Research or the plicant may petition for judicial re-
Director of the Center for Drug Evalua- view. Before requesting an order from a
tion and Research will give the appli- court for a stay of action pending re-
cant notice of an opportunity for a view, an applicant must first submit a
hearing on the proposal to withdraw petition for a stay of action under
the approval of an application approved § 10.35 of this chapter.
under this subpart. The notice, which [67 FR 37996, May 31, 2002, as amended at 70
will ordinarily be a letter, will state FR 14984, Mar. 24, 2005]
generally the reasons for the action
and the proposed grounds for the order. § 601.93 Postmarketing safety report-
(c) Submission of data and information. ing.
(1) If the applicant fails to file a writ- Biological products approved under
ten request for a hearing within 15 days this subpart are subject to the post-
of receipt of the notice, the applicant marketing recordkeeping and safety
waives the opportunity for a hearing. reporting applicable to all approved bi-
(2) If the applicant files a timely re- ological products.
quest for a hearing, the agency will
publish a notice of hearing in the FED- § 601.94 Promotional materials.
ERAL REGISTER in accordance with For biological products being consid-
§§ 12.32(e) and 15.20 of this chapter. ered for approval under this subpart,
(3) An applicant who requests a hear- unless otherwise informed by the agen-
ing under this section must, within 30 cy, applicants must submit to the
days of receipt of the notice of oppor- agency for consideration during the
tunity for a hearing, submit the data preapproval review period copies of all
and information upon which the appli- promotional materials, including pro-
cant intends to rely at the hearing. motional labeling as well as advertise-
(d) Separation of functions. Separation ments, intended for dissemination or
of functions (as specified in § 10.55 of publication within 120 days following
this chapter) will not apply at any marketing approval. After 120 days fol-
point in withdrawal proceedings under lowing marketing approval, unless oth-
this section. erwise informed by the agency, the ap-
(e) Procedures for hearings. Hearings plicant must submit promotional ma-
held under this section will be con- terials at least 30 days prior to the in-
ducted in accordance with the provi- tended time of initial dissemination of
sions of part 15 of this chapter, with the labeling or initial publication of
the following modifications: the advertisement.
(1) An advisory committee duly con-
stituted under part 14 of this chapter § 601.95 Termination of requirements.
will be present at the hearing. The If FDA determines after approval
committee will be asked to review the under this subpart that the require-
issues involved and to provide advice ments established in §§ 601.91(b)(2),
and recommendations to the Commis- 601.92, and 601.93 are no longer nec-
sioner of Food and Drugs. essary for the safe and effective use of
44
a biological product, FDA will so no- Subpart I—Records and Reports

tify the applicant. Ordinarily, for bio-
606.160 Records.
logical products approved under 606.165 Distribution and receipt; procedures
§ 601.91, these requirements will no and records.
longer apply when FDA determines 606.170 Adverse reaction file.
that the postmarketing study verifies 606.171 Reporting of product deviations by
and describes the biological product’s licensed manufacturers, unlicensed reg-
clinical benefit. For biological prod- istered blood establishments, and trans-
ucts approved under § 601.91, the re- fusion services.
strictions would no longer apply when AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355,
FDA determines that safe use of the bi- 360, 360j, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
ological product can be ensured SOURCE: 40 FR 53532, Nov. 18, 1975, unless
through appropriate labeling. FDA also otherwise noted.
retains the discretion to remove spe-
cific postapproval requirements upon Subpart A—General Provisions
review of a petition submitted by the
sponsor in accordance with § 10.30 of § 606.3 Definitions.
this chapter. As used in this part:
(a) Blood means a product that is a
PART 606—CURRENT GOOD MAN- fluid containing dissolved and sus-
UFACTURING PRACTICE FOR pended elements which was collected
BLOOD AND BLOOD COMPO- from the vascular system of a human.
NENTS (b) Unit means the volume of blood or
one of its components in a suitable vol-
Subpart A—General Provisions ume of anticoagulant obtained from a
single collection of blood from one
Sec. donor.
606.3 Definitions. (c) Blood component means a product
containing a part of human blood sepa-
Subpart B—Organization and Personnel rated by physical or mechanical means.
606.20 Personnel. (d) Plasma for further manufacturing
means that liquid portion of blood sep-
Subpart C—Plant and Facilities arated and used as material to prepare
another product.
606.40 Facilities. (e) Plasmapheresis means the proce-
dure in which blood is removed from
Subpart D—Equipment
the donor, the plasma is separated
606.60 Equipment. from the formed elements and at least
606.65 Supplies and reagents. the red blood cells are returned to the
donor.
Subpart E [Reserved] (f) Plateletpheresis means the proce-
dure in which blood is removed from a
Subpart F—Production and Process
donor, a platelet concentrate is sepa-
Controls
rated, and the remaining formed ele-
606.100 Standard operating procedures. ments are returned to the donor along
606.110 Plateletpheresis, leukapheresis, and with a portion of the residual plasma.
plasmapheresis. (g) Leukapheresis means the proce-
dure in which blood is removed from
Subpart G—Additional Labeling Standards the donor, a leukocyte concentrate is
for Blood and Blood Components separated, and the remaining formed
606.120 Labeling, general requirements. elements and residual plasma are re-
606.121 Container label. turned to the donor.
606.122 Circular of information. (h) Facilities means any area used for
the collection, processing, compat-
Subpart H—Laboratory Controls ibility testing, storage or distribution
606.140 Laboratory controls. of blood and blood components.
(i) Processing means any procedure
606.145 Control of bacterial contamination

of platelets. employed after collection, and before
606.151 Compatibility testing. or after compatibility testing of blood,
45
§ 606.20 21 CFR Ch. I (4–1–20 Edition)
and includes the identification of a provisions of this part to their respec-

unit of donor blood, the preparation of tive functions.
components from such unit of donor (c) Persons whose presence can ad-
blood, serological testing, labeling and versely affect the safety and purity of
associated recordkeeping. the products shall be excluded from
(j) Compatibility testing means the areas where the collection, processing,
procedures performed to establish the compatibility testing, storage or dis-
matching of a donor’s blood or blood tribution of blood or blood components
components with that of a potential re- is conducted.
cipient.
(k) Distributed means: FR 23833, June 8, 1984; 55 FR 11014, Mar. 26,
(1) The blood or blood components 1990; 62 FR 53538, Oct. 15, 1997]
have left the control of the licensed
manufacturer, unlicensed registered Subpart C—Plant and Facilities
blood establishment, or transfusion
service; or § 606.40 Facilities.
(2) The licensed manufacturer has
Facilities shall be maintained in a
provided Source Plasma or any other
clean and orderly manner, and shall be
blood component for use in the manu-
of suitable size, construction and loca-
facture of a licensed biological product.
tion to facilitate adequate cleaning,
(l) Control means having responsi- maintenance and proper operations.
bility for maintaining the continued The facilities shall:
safety, purity, and potency of the prod-
(a) Provide adequate space for the
uct and for compliance with applicable
following when applicable:
product and establishment standards,
(1) Private and accurate examina-
and for compliance with current good
tions of individuals to determine their
manufacturing practices.
eligibility as blood donors.
[40 FR 53532, Nov. 18, 1975, as amended at 64 (2) The withdrawal of blood from do-
FR 45370, Aug. 19, 1999; 65 FR 66635, Nov. 7, nors with minimal risk of contamina-
2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, tion, or exposure to activities and
Aug. 6, 2001; 72 FR 45886, Aug. 16, 2007; 80 FR equipment unrelated to blood collec-
29894, May 22, 2015]
tion.
(3) The storage of blood or blood com-
Subpart B—Organization and ponents pending completion of tests.
Personnel (4) The quarantine storage of blood or
blood components in a designated loca-
§ 606.20 Personnel. tion pending repetition of those tests
(a) [Reserved] that initially gave questionable sero-
(b) The personnel responsible for the logical results.
collection, processing, compatibility (5) The storage of finished products
testing, storage or distribution of blood prior to distribution.
or blood components shall be adequate (6) The quarantine storage, handling
in number, educational background, and disposition of products and re-
training and experience, including pro- agents not suitable for use.
fessional training as necessary, or com- (7) The orderly collection, processing,
bination thereof, to assure competent compatibility testing, storage and dis-
performance of their assigned func- tribution of blood and blood compo-
tions, and to ensure that the final nents to prevent contamination.
product has the safety, purity, po- (8) The adequate and proper perform-
tency, identity and effectiveness it pur- ance of all steps in plasmapheresis,
ports or is represented to possess. All plateletpheresis and leukapheresis pro-
personnel shall have capabilities com- cedures.
mensurate with their assigned func- (9) The orderly conduction of all
tions, a thorough understanding of the packaging, labeling and other finishing
procedures or control operations they operations.
perform, the necessary training or ex- (b) Provide adequate lighting, ven-
perience, and adequate information tilation and screening of open windows

concerning the application of pertinent and doors.
46
(c) Provide adequate, clean, and con- Subpart D—Equipment

venient handwashing facilities for per-
sonnel, and adequate, clean, and con- § 606.60 Equipment.
venient toilet facilities for donors and (a) Equipment used in the collection,
personnel. Drains shall be of adequate processing, compatibility testing, stor-
size and, where connected directly to a age and distribution of blood and blood
sewer, shall be equipped with traps to components shall be maintained in a
prevent back-siphonage. clean and orderly manner and located
(d) Provide for safe and sanitary dis- so as to facilitate cleaning and mainte-
posal for the following: nance. The equipment shall be ob-
(1) Trash and items used during the served, standardized and calibrated on
collection, processing and compat- a regularly scheduled basis as pre-
ibility testing of blood and blood com- scribed in the Standard Operating Pro-
ponents. cedures Manual and shall perform in
(2) Blood and blood components not the manner for which it was designed
so as to assure compliance with the of-
suitable for use or distribution.
ficial requirements prescribed in this
[40 FR 53532, Nov. 18, 1975, as amended at 80 chapter for blood and blood products.
FR 29895, May 22, 2015] (b) Equipment that shall be observed,
standardized and calibrated with at
least the following frequency, include
but are not limited to:
Equipment Performance check Frequency Frequency of calibration
Temperature recorder .... Compare against thermometer ............. Daily ................... As necessary.
Refrigerated centrifuge .. Observe speed and temperature .......... Each day of use Do.
Hematocrit centrifuge .... ............................................................... ............................ Standardize before initial use, after re-
pairs or adjustments, and annually.
Timer every 3 mo.
General lab centrifuge ... ............................................................... ............................ Tachometer every 6 mo.
Automated blood-typing Observe controls for correct results ..... Each day of use.
machine.
Hemoglobinometer ........ Standardize against ......do.
cyanmethemoglobin standard.
Refractometer ................ Standardize against distilled water ....... ......do.
Blood container scale .... Standardize against container of known ......do ................. As necessary.
weight.
Water bath ..................... Observe temperature ............................ ......do ................. Do.
Rh view box ................... ......do .................................................... ......do ................. Do.
Autoclave ....................... ......do .................................................... Each time of use Do.
Serologic rotators .......... Observe controls for correct results ..... Each day of use Speed as necessary.
Laboratory thermom- ............................................................... ............................ Before initial use.
eters.
Electronic thermometers ............................................................... ............................ Monthly.
Vacuum blood agitator .. Observe weight of the first container of Each day of use Standardize with container of known
blood filled for correct results. mass or volume before initial use,
and after repairs or adjustments.
(c) Equipment employed in the steri- attained temperature of 170 °C (338 °F)
lization of materials used in blood col- maintained for 2 hours with dry heat.
lection or for disposition of contami- [40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec.
nated products shall be designed, main- 2, 1975, as amended at 45 FR 9261, Feb. 12,
tained and utilized to ensure the de- 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862,
struction of contaminating microorga- Apr. 13, 1992]
nisms. The effectiveness of the steri-
§ 606.65 Supplies and reagents.
lization procedure shall be no less than
that achieved by an attained tempera- All supplies and reagents used in the
ture of 121.5 °C (251 °F) maintained for collection, processing, compatibility
20 minutes by saturated steam or by an testing, storage and distribution of
blood and blood components shall be
stored in a safe, sanitary and orderly

manner.
47
§ 606.100 21 CFR Ch. I (4–1–20 Edition)
(a) All surfaces coming in contact Subpart F—Production and

with blood and blood components in- Process Controls
tended for transfusion shall be sterile,
pyrogen-free, and shall not interact § 606.100 Standard operating proce-
with the product in such a manner as dures.
to have an adverse effect upon the safe- (a) In all instances, except clinical
ty, purity, potency or effectiveness of investigations, standard operating pro-
the product. All final containers and cedures shall comply with published
closures for blood and blood compo- additional standards in part 640 of this
nents not intended for transfusion chapter for the products being proc-
shall be clean and free of surface solids essed; except that, references in part
and other contaminants. 640 relating to licenses, licensed estab-
(b) Each blood collecting container lishments and submission of material
and its satellite container(s), if any, or data to or approval by the Director,
shall be examined visually for damage Center for Biologics Evaluation and
or evidence of contamination prior to Research, are not applicable to estab-
its use and immediately after filling. lishments not subject to licensure
Such examination shall include inspec- under section 351 of the Public Health
tion for breakage of seals, when indi- Service Act.
cated, and abnormal discoloration. (b) Establishments must establish,
Where any defect is observed, the con- maintain, and follow written standard
tainer shall not be used, or, if detected operating procedures for all steps in
after filling, shall be properly dis- the collection, processing, compat-
carded. ibility testing, storage, and distribu-
(c) Representative samples of each tion of blood and blood components for
lot of the following reagents or solu- allogeneic transfusion, autologous
tions shall be tested on a regularly transfusion, and further manufacturing
scheduled basis by methods described purposes; for all steps in the investiga-
in the Standard Operating Procedures tion of product deviations related to
Manual to determine their capacity to § 606.171; and for all steps in record-
perform as required: keeping related to current good manu-
facturing practice and other applicable
Reagent or solution Frequency of testing requirements and standards. Such pro-
Anti-human globulin ............... Each day of use.
cedures must be available to the per-
Blood grouping reagents ....... Do. sonnel for use in the areas where the
Lectins ................................... Do. procedures are performed. The written
Antibody screening and re- Do. standard operating procedures must in-
verse grouping cells. clude, but are not limited to, descrip-
Hepatitis test reagents ........... Each run.
Syphilis serology reagents .... Do.
tions of the following, when applicable:
Enzymes ................................ Each day of use. (1) Criteria used to determine donor
eligibility, including acceptable med-
(d) Supplies and reagents that do not ical history criteria.
bear an expiration date shall be stored (2) Methods of performing donor
in such a manner that the oldest is qualifying tests and measurements, in-
used first. cluding minimum and maximum values
(e) Supplies and reagents shall be for a test or procedure when a factor in
used in a manner consistent with in- determining acceptability.
structions provided by the manufac- (3) Solutions and methods used to
turer. prepare the site of phlebotomy to give
(f) Items that are required to be ster- maximum assurance of a sterile con-
ile and come into contact with blood tainer of blood.
should be disposable whenever possible. (4) Method of accurately relating the
product(s) to the donor.
[40 FR 53532, Nov. 18, 1975, as amended at 59 (5) Blood collection procedure, in-
FR 23636, May 6, 1994] cluding in-process precautions taken to
measure accurately the quantity of

Subpart E [Reserved] blood removed from the donor.
48
(6) Methods of component prepara- by such a donor that are intended for
tion, including any time restrictions use in another person or further manu-
for specific steps in processing. facture into injectable products, except
(7) All tests and repeat tests per- pooled components intended solely for
formed on blood and blood components further manufacturing into products
during manufacturing. that are manufactured using validated
(8) Pretransfusion testing, where ap- viral clearance procedures;
plicable, including precautions to be (iii) To notify consignees to quar-
taken to identify accurately the recipi- antine in-date blood and blood compo-
ent blood samples and crossmatched nents previously donated by such a
donor units. donor intended for use in another per-
(9) Procedures for investigating ad- son or for further manufacture into
verse donor and recipient reactions. injectable products, except pooled com-
(10) Storage temperatures and meth- ponents intended solely for further
ods of controlling storage temperatures manufacturing into products that are
for all blood products and reagents as manufactured using validated viral
prescribed in §§ 600.15 and 610.53 of this clearance procedures;
chapter. (iv) To determine the suitability for
(11) Length of expiration dates, if release, destruction, or relabeling of
any, assigned for all final products as quarantined in-date blood and blood
prescribed in § 610.53 of this chapter. components;
(12) Criteria for determining whether
(v) To notify consignees of the re-
returned blood is suitable for reissue.
sults of the HIV or HCV testing per-
(13) Procedures used for relating a
formed on the donors of such blood and
unit of blood or blood component from
blood components;
the donor to its final disposition.
(14) Quality control procedures for (vi) To notify the transfusion recipi-
supplies and reagents employed in ent, the recipient’s physician of record,
blood collection, processing and or the recipient’s legal representative
pretransfusion testing. that the recipient received blood or
(15) Schedules and procedures for blood components at increased risk of
equipment maintenance and calibra- transmitting HIV or HCV, respectively.
tion. (20) Procedures for donor deferral as
(16) Labeling procedures, including prescribed in § 610.41 of this chapter.
safeguards to avoid labeling mixups. (21) Procedures for donor notification
(17) Procedures of plasmapheresis, and notification of the referring physi-
plateletpheresis, and leukapheresis, if cian of an autologous donor, including
performed, including precautions to be procedures for the appropriate followup
taken to ensure reinfusion of a donor’s if the initial attempt at notification
own cells. fails, as prescribed in § 630.40 of this
(18) Procedures for preparing recov- chapter.
ered plasma, if performed, including (22) Procedures to control the risks of
details of separation, pooling, labeling, bacterial contamination of platelets,
storage, and distribution. including all steps required under
(19) Procedures under §§ 610.46 and § 606.145.
610.47 of this chapter: (c) All records pertinent to the lot or
(i) To identify previously donated unit maintained pursuant to these reg-
blood and blood components from a ulations shall be reviewed before the
donor who later tests reactive for evi- release or distribution of a lot or unit
dence of human immunodeficiency of final product. The review or portions
virus (HIV) infection or hepatitis C of the review may be performed at ap-
virus (HCV) infection when tested propriate periods during or after blood
under § 610.40 of this chapter, or when a collecting, processing, compatibility
blood establishment is made aware of testing and storing. A thorough inves-
other reliable test results or informa- tigation, including the conclusions and
tion indicating evidence of HIV or HCV followup, of any unexplained discrep-
infection; ancy or the failure of a lot or unit to
(ii) To quarantine in-date blood and meet any of its specifications shall be
blood components previously donated made and recorded.
49
§ 606.110 21 CFR Ch. I (4–1–20 Edition)
(d) In addition to the requirements of Subpart G—Additional Labeling

this subpart and in conformity with Standards for Blood and
this section, any facility may utilize Blood Components
current standard operating procedures
such as the manuals of the organiza- § 606.120 Labeling, general require-
tions, as long as such specific proce- ments.
dures are consistent with, and at least (a) Labeling operations shall be sepa-
as stringent as, the requirements con- rated physically or spatially from
tained in this part. other operations in a manner adequate
(1) American Association of Blood to prevent mixups.
Banks. (b) The labeling operation shall in-
(2) American National Red Cross. clude the following labeling controls:
(3) Other organizations or individual (1) Labels shall be held upon receipt,
blood banks, subject to approval by the pending review and proofing against an
Director, Center for Biologics Evalua- approved final copy, to ensure accuracy
tion and Research. regarding identity, content, and con-
formity with the approved copy.
FR 23833, June 8, 1984; 55 FR 11013, Mar. 26,
(2) Each type of label representing
1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, different products shall be stored and
Aug. 19, 1999; 66 FR 31176, June 11, 2001; 72 FR maintained in a manner to prevent
48798, Aug. 24, 2007; 80 FR 80651, Dec. 28, 2015; mixups, and stocks of obsolete labels
80 FR 29895, May 22, 2015] shall be destroyed.
(3) All necessary checks in labeling
§ 606.110 Plateletpheresis, procedures shall be utilized to prevent
leukapheresis, and plasmapheresis. errors in translating test results to
(a) The use of plateletpheresis and container labels.
leukapheresis procedures to obtain a (c) All labeling shall be clear and leg-
product for a specific recipient may be ible.
at variance with the additional stand- [50 FR 35469, Aug. 30, 1985]
ards for specific products prescribed in
this part provided that: (1) A physician § 606.121 Container label.
has determined that the recipient must (a) The container label requirements
be transfused with the leukocytes or are designed to facilitate the use of a
platelets from a specific donor, and (2) uniform container label for blood and
the procedure is performed under the blood components intended for use in
supervision of a responsible physician transfusion or further manufacture by
who is aware of the health status of the all blood establishments.
donor, and the physician has deter- (b) The label provided by the col-
mined and documented that the do- lecting facility and the initial proc-
nor’s health permits plateletpheresis or essing facility must not be removed, al-
leukapheresis. tered, or obscured, except that the
(b) Plasmapheresis of donors who do label may be altered to indicate the
not meet the donor requirements of proper name of the product, with any
§§ 630.10, 630.15, 640.64 and 640.65 of this appropriate modifiers and attributes,
chapter for the collection of plasma and other information required to iden-
containing rare antibodies shall be per- tify accurately the contents of a con-
mitted only with the prior approval of tainer after blood components consid-
the Director, Center for Biologics Eval- ered finished products have been pre-
uation and Research. pared.
(c) The container label must include
[40 FR 53532, Nov. 18, 1975, as amended at 49 the following information, as well as
FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, other specialized information as re-
1990; 80 FR 29895, May 22, 2015] quired in this section for specific prod-
ucts:
(1) The proper name of the product in
a prominent position, with any appro-

priate modifiers and attributes.
50
(2) The name, address, unique facility (C) Benefits, such as time off from
identifier, and, if a licensed product, work, membership in blood assurance
the license number of each manufac- programs, and cancellation of non-
turer; except the container label for replacement fees that are not readily
blood and blood components for further convertible to cash, do not constitute
manufacture is not required to include monetary payment within the meaning
a unique facility identifier. of this paragraph.
(3) The donor or lot number relating (9) If the product is intended for
the unit to the donor. If pooled, all transfusion or as is otherwise appro-
donor numbers, all donation numbers, priate, the ABO group and Rh type of
or a pool number that is traceable to the donor must be designated conspicu-
each individual unit comprising the ously. For Cryoprecipitated
pool. Antihemophiliac Factor (AHF), the Rh
(4)(i) The expiration date, including type may be omitted. The Rh type
the day, month, and year, and, if the must be designated as follows:
dating period for the product is 72 (i) If the test using Anti-D Blood
hours or less, including any product Grouping Reagent is positive, the prod-
prepared in a system that might com- uct must be labeled: ‘‘Rh positive.’’
promise sterility, the hour of expira- (ii) If the test using Anti-D Blood
tion. Grouping Reagent is negative, but the
(ii) If Source Plasma intended for
test for weak D (formerly Du) is posi-
manufacturing into noninjectable
tive, the product must be labeled: ‘‘Rh
products is pooled, the expiration date
positive.’’
for the pool is determined from the col-
lection date of the oldest unit in the (iii) If the test using Anti-D Blood
pool, and the pooling records must Grouping Reagent is negative and the
show the collection date for each unit test for weak D (formerly Du) is nega-
in the pool. tive, the product must be labeled: ‘‘Rh
(5) For Whole Blood, Plasma, Plate- negative.’’
lets, and partial units of Red Blood (10) If the product is not intended for
Cells, the volume of the product, accu- transfusion, a statement as applicable:
rate to within ±10 percent; or option- ‘‘Caution: For Manufacturing Use
ally for Platelets, the volume or vol- Only,’’ or ‘‘Caution: For Use in Manu-
ume range within reasonable limits. facturing Noninjectable Products
(6) Where applicable, the name and Only,’’ or other cautionary statement
volume of source material. as approved by the Director, Center for
(7) The recommended storage tem- Biologics Evaluation and Research
perature (in degrees Celsius). (CBER).
(8) If the product is intended for (11) If the product is intended for fur-
transfusion, the statements: ther manufacturing use, a statement
(i) ‘‘Rx only.’’ listing the results of all the tests for
(ii) ‘‘See circular of information for relevant transfusion-transmitted infec-
indications, contraindications, cautions required under § 610.40 of this
tions, and methods of infusion.’’ chapter for which the donation has
(iii) ‘‘Properly identify intended re- been tested and found negative; except
cipient.’’ that the container label for Source
(iv) ‘‘This product may transmit in- Plasma is not required to list the nega-
fectious agents.’’ tive results of serological syphilis test-
(v) The appropriate donor classifica- ing under § 640.65(b) of this chapter.
tion statement, i.e., ‘‘paid donor’’ or (12) The blood and blood components
‘‘volunteer donor,’’ in no less promi- must be labeled in accordance with
nence than the proper name of the § 610.40 of this chapter, when the dona-
product. tion is tested and demonstrates evi-
(A) A paid donor is a person who re- dence of infection due to a relevant
ceives monetary payment for a blood transfusion-transmitted infection(s).
donation. (13) The container label of blood or
(B) A volunteer donor is a person who blood components intended for trans-
does not receive monetary payment for fusion must bear encoded information
a blood donation. in a format that is machine-readable
51
§ 606.121 21 CFR Ch. I (4–1–20 Edition)
and approved for use by the Director, outline on a white background for
CBER. ABO.
(i) Who is subject to this machine-read- (2) The proper name of the product,
able requirement? All blood establish- with any appropriate modifiers and at-
ments that manufacture, process, re- tributes, the donor classification state-
pack, or relabel blood or blood compo- ment, and the statement ‘‘properly
nents intended for transfusion and reg- identify intended recipient’’ may be
ulated under the Federal Food, Drug, printed in solid red or in solid black.
and Cosmetic Act or the Public Health (3) The following color scheme may
Service Act. be used for differentiating ABO Blood
(ii) What blood products are subject to groups:
this machine-readable requirement? All Color of
blood and blood components intended Blood group label
for transfusion are subject to the ma-
O ......................................................................... Blue
chine-readable information label re- A ......................................................................... Yellow
quirement in this section. B ......................................................................... Pink
(iii) What information must be ma- AB ....................................................................... White
chine-readable? Each label must have
machine-readable information that (4) Special labels, such as those de-
contains, at a minimum: scribed in paragraphs (h) and (i) of this
(A) A unique facility identifier; section, may be color-coded.
(B) Lot number relating to the donor; (e) Container label requirements for
(C) Product code; and particular products or groups of prod-
ucts.
(D) ABO and Rh of the donor, except
(1) Whole Blood labels must include:
as described in paragraphs (c)(9) and
(i) The name of the applicable anti-
(i)(5) of this section.
coagulant approved for use by the Di-
(iv) How must the machine-readable in- rector, CBER.
formation appear? The machine-read- (ii) The volume of anticoagulant.
able information must: (iii) If tests for unexpected antibodies
(A) Be unique to the blood or blood are positive, blood intended for trans-
component; fusion must be labeled: ‘‘Contains
(B) Be surrounded by sufficient blank (name of antibody).’’
space so that the machine-readable in- (2) Except for frozen, deglycerolized,
formation can be scanned correctly; or washed Red Blood Cell products, Red
and Blood Cell labels must include:
(C) Remain intact under normal con- (i) The type of anticoagulant, and if
ditions of use. applicable, the volume of Whole Blood
(v) Where does the machine-readable in- and type of additive solution, with
formation go? The machine-readable in- which the product was prepared.
formation must appear on the label of (ii) If tests for unexpected antibodies
any blood or blood component which is are positive and the product is in-
or can be transfused to a patient or tended for transfusion, the statement:
from which the blood or blood compo- ‘‘Contains (name of antibody).’’
nent can be taken and transfused to a (3) If tests for unexpected antibodies
patient. are positive, Plasma intended for
(d) Unless otherwise approved by the transfusion must be labeled: ‘‘Contains
Director, CBER, the container label for (name of antibody).’’
blood and blood components intended (4) Recovered plasma labels must in-
for transfusion must be white and print clude:
must be solid black, with the following (i) In lieu of an expiration date, the
additional exceptions: date of collection of the oldest mate-
(1) The ABO and Rh blood groups rial in the container.
must be printed as follows: (ii) For recovered plasma not meet-
(i) Rh positive: Use black print on ing the requirements for manufacture
white background and use solid black into licensable products, the state-
or other solid color for ABO. ment: ‘‘Not for Use in Products Subject
(ii) Rh negative: Use white print on to License Under Section 351 of the
black background for Rh and use black Public Health Service Act.’’
52
(iii) The type of anticoagulant with (h) The following additional informa-
which the product was prepared. tion must appear on the label for blood
(5) Source Plasma labels must in- and blood components shipped in an
clude the following information: emergency prior to completion of re-
(i) The cautionary statement, as quired tests, in accordance with
specified in paragraph (c)(10) of this § 610.40(g) of this chapter:
section, must follow the proper name (1) The statement: ‘‘FOR EMER-
with any appropriate modifiers and at- GENCY USE ONLY BY ll .’’
tributes and be of similar prominence (2) Results of any tests prescribed
as the proper name. under §§ 610.40 and 640.5(b) or (c) of this
(ii) The statement ‘‘Store at ¥20 °C chapter completed before shipment.
or colder,’’ provided, that where plas- (3) Indication of any tests prescribed
ma is intended for manufacturing into under §§ 610.40 and 640.5(b) or (c) of this
noninjectable products, this statement chapter not completed before ship-
may be replaced by a statement of the ment.
temperature appropriate for manufac- (i) The following additional informa-
ture of the final product to be prepared tion must appear on the label for blood
from the plasma. and blood components intended for
(iii) The total volume or weight of autologous transfusion:
plasma and total quantity and type of (1) Information adequately identi-
anticoagulant used. fying the patient, e.g., name, date of
(iv) When plasma collected from a birth, hospital, and identification num-
donor is reactive for a serologic test for ber.
syphilis, a statement that the plasma (2) Date of donation.
is reactive and must be used only for (3) The statement: ‘‘AUTOLOGOUS
the manufacturing of positive control DONOR.’’
reagents for the serologic test for (4) The ABO and Rh blood group and
syphilis. type, except as provided in paragraph
(v) Source Plasma diverted for (c)(9) of this section.
Source Plasma Salvaged must be re- (5) Each container of blood and blood
labeled ‘‘Source Plasma Salvaged’’ as component intended for autologous use
prescribed in § 640.76 of this chapter. and obtained from a donor who fails to
Immediately following the proper meet any of the donor eligibility re-
name of the product, with any appro- quirements under § 630.10 of this chap-
priate modifiers and attributes, the later or who is reactive to or positive for
beling must prominently state as appli- one or more tests for evidence of infec-
cable, ‘‘STORAGE TEMPERATURE tion due to relevant transfusion-trans-
EXCEEDED ¥20 °C’’ or ‘‘SHIPPING mitted infections under § 610.40 of this
TEMPERATURE EXCEEDED ¥5 °C.’’ chapter must be prominently and per-
(vi) A statement as to whether the manently labeled ‘‘FOR AUTOLOGOUS
plasma was collected from normal do- USE ONLY’’ and as otherwise required
nors, or from donors in specific collec- under § 610.40 of this chapter. Such
tion programs approved by the Direc- units also may have the ABO and Rh
tor, CBER. In the case of specific col- blood group and type on the label.
lection programs, the label must state (6) Units of blood and blood compo-
the defining characteristics of the plas- nents originally intended for
ma. In the case of immunized donors, autologous use, except those labeled as
the label must state the immunizing prescribed under paragraph (i)(5) of this
antigen. section, may be issued for allogeneic
(f) Blood and blood components de- transfusion provided the container
termined to be unsuitable for trans- label complies with all applicable pro-
fusion must be prominently labeled visions of paragraphs (b) through (e) of
‘‘NOT FOR TRANSFUSION,’’ and the this section. In such case, the special
label must state the reason the unit is label required under paragraphs (i)(1),
considered unsuitable. The provision (i)(2), and (i)(3) of this section must be
does not apply to blood and blood com- removed or otherwise obscured.
ponents intended solely for further (j) A tie-tag attached to the con-
manufacture. tainer may be used for providing the

(g) [Reserved] information required by paragraphs
53
§ 606.122 21 CFR Ch. I (4–1–20 Edition)
(e)(1)(iii), (e)(2)(ii), and (e)(3), (h), or (1) The approximate volume of plas-
(i)(1), (i)(2), and (i)(3) of this section. ma from which a sample unit of Plate-
lets is prepared.
[77 FR 16, Jan. 3, 2012, as amended at 80 FR
29895, May 22, 2015]
(2) Instructions to begin administra-
tion as soon as possible, but not more
§ 606.122 Circular of information. than 4 hours after entering the con-
tainer.
A circular of information must be (m) For Plasma, the circular of infor-
available for distribution if the product mation must contain:
is intended for transfusion. The cir- (1) A warning against further proc-
cular of information must provide ade- essing of the frozen product if there is
quate directions for use, including the evidence of breakage or thawing.
following information: (2) Instructions to thaw the frozen
(a) Instructions to mix the product product at a temperature appropriate
before use. for the product.
(b) Instructions to use a filter in the (3) When applicable, instructions to
administration equipment. begin administration of the product
(c) The statement ‘‘Do Not Add Medi- within a specified time after thawing.
cations’’ or an explanation concerning (4) Instructions to administer to
allowable additives. ABO-group-compatible recipients.
(d) A description of the product, its (5) A statement that this product has
source, and preparation, including the the same risk of transmitting infec-
name and proportion of the anticoagu- tious agents as Whole Blood; other
lant used in collecting the Whole Blood plasma volume expanders without this
from each product is prepared. risk are available for treating
(e) A statement that the product was hypovolemia.
prepared from blood that was found (n) For Cryoprecipitated AHF, the
negative when tested for relevant circular of information must contain:
transfusion-transmitted infections, as (1) A statement that the average po-
required under § 610.40 of this chapter tency is 80 or more International Units
(include each test that was performed). of antihemophilic factor.
(f) The statement: ‘‘Warning: The (2) The statement: ‘‘Usually contains
risk of transmitting infectious agents at least 150 milligrams of fibrinogen’’;
is present. Careful donor selection and or, alternatively, the average
available laboratory tests do not elimi- fibrinogen level determined by assay of
nate the hazard.’’ representative units.
(g) The names of cryoprotective (3) A warning against further proc-
agents and other additives that may essing of the product if there is evi-
still be present in the product. dence of breakage or thawing.
(4) Instructions to thaw the product
(h) The names and results of all tests
for no more than 15 minutes at a tem-
performed when necessary for safe and
perature of between 30 and 37 °C.
effective use.
(5) Instructions to store at room tem-
(i) The use of the product, indica- perature after thawing and to begin ad-
tions, contradications, side effects and ministration as soon as possible but no
hazards, dosage and administration more than 4 hours after entering the
recommendations. container or after pooling and within 6
(j) [Reserved] hours after thawing.
(k) For Red Blood Cells, the circular (6) A statement that 0.9 percent So-
of information must contain: dium Chloride Injection U.S.P. is the
(1) Instructions to administer a suit- preferred diluent.
able plasma volume expander if Red (7) Adequate instructions for pooling
Blood Cells are substituted when Whole to ensure complete removal of all con-
Blood is the indicated product. centrated material from each con-
(2) A warning not to add Lactated tainer.
Ringer’s Injection U.S.P. solution to (8) The statement: ‘‘Good patient
Red Blood Cell products. management requires monitoring
(l) For Platelets, the circular of in- treatment responses to

formation must contain: Cryoprecipitated AHF transfusions
54
with periodic plasma factor VIII or lishment or a laboratory to identify

fibrinogen assays in hemophilia A and the organism. The transfusion service
hypofibrinogenemic recipients, respec- must further notify the blood collec-
tively.’’ tion establishment either by providing
[50 FR 35470, Aug. 30, 1985, as amended at 53 information about the species of the
FR 116, Jan. 5, 1988; 64 FR 45371, Aug. 19, 1999; contaminating organism when the
77 FR 18, Jan. 3, 2012; 80 FR 29895, May 22, transfusion service has been able to
2015] identify it, or by advising the blood
collection establishment when the
Subpart H—Laboratory Controls transfusion service has determined
that the species cannot be identified.
§ 606.140 Laboratory controls.
(d) In the event that a contaminating
Laboratory control procedures shall organism is identified under paragraph
include: (b) or (c) of this section, the collection
(a) The establishment of scientif- establishment’s responsible physician,
ically sound and appropriate specifica-
as defined in § 630.3(i) of this chapter,
tions, standards and test procedures to
must determine whether the contami-
assure that blood and blood compo-
nents are safe, pure, potent and effec- nating organism is likely to be associ-
tive. ated with a bacterial infection that is
(b) Adequate provisions for moni- endogenous to the bloodstream of the
toring the reliability, accuracy, preci- donor, in accordance with a standard
sion and performance of laboratory operating procedure developed under
test procedures and instruments. § 606.100(b)(22). This determination may
(c) Adequate identification and han- not be further delegated.
dling of all test samples so that they
[80 FR 29895, May 22, 2015]
are accurately related to the specific
unit of product being tested, or to its § 606.151 Compatibility testing.
donor, or to the specific recipient,
where applicable. Standard operating procedures for
compatibility testing shall include the
§ 606.145 Control of bacterial contami- following:
nation of platelets. (a) A method of collecting and identi-
(a) Blood collection establishments fying the blood samples of recipients to
and transfusion services must assure ensure positive identification.
that the risk of bacterial contamina- (b) The use of fresh recipient serum
tion of platelets is adequately con- or plasma samples less than 3 days old
trolled using FDA approved or cleared for all pretransfusion testing if the re-
devices or other adequate and appro- cipient has been pregnant or transfused
priate methods found acceptable for within the previous 3 months.
this purpose by FDA.
(c) Procedures to demonstrate incom-
(b) In the event that a blood collec-
patibility between the donor’s cell type
tion establishment identifies platelets
as bacterially contaminated, that es- and the recipient’s serum or plasma
tablishment must not release for trans- type.
fusion the product or any other compo- (d) A provision that, if the unit of do-
nent prepared from the same collec- nor’s blood has not been screened by a
tion, and must take appropriate steps method that will demonstrate aggluti-
to identify the organism. nating, coating and hemolytic anti-
(c) In the event that a transfusion bodies, the recipient’s cells shall be
service identifies platelets as tested with the donor’s serum (minor
bacterially contaminated, the trans- crossmatch) by a method that will so
fusion service must not release the demonstrate.
product and must notify the blood col- (e) Procedures to expedite trans-
lection establishment that provided fusion in life-threatening emergencies.
the platelets. The transfusion service Records of all such incidents shall be
must take appropriate steps to identify
maintained, including complete docu-

the organism; these steps may include mentation justifying the emergency
contracting with the collection estab-
55
§ 606.160 21 CFR Ch. I (4–1–20 Edition)
action, which shall be signed by a phy- notification of a transfusion recipient,

sician. the recipient’s physician of record, or
the recipient’s legal representative;
FR 45371, Aug. 19, 1999; 66 FR 1835, Jan. 10, and disposition.
2001; 66 FR 40889, Aug. 6, 2001] (ix) The donor’s postal address pro-
vided at the time of donation where the
Subpart I—Records and Reports donor may be contacted within 8 weeks
after donation.
§ 606.160 Records. (x) Records of notification of donors
(a)(1) Records shall be maintained deferred or determined not to be eligi-
concurrently with the performance of ble for donation, including appropriate
each significant step in the collection, followup if the initial attempt at noti-
processing, compatibility testing, stor- fication fails, performed under § 630.40
age and distribution of each unit of of this chapter.
blood and blood components so that all (xi) Records of notification of the re-
steps can be clearly traced. All records ferring physician of a deferred
shall be legible and indelible, and shall autologous donor, including appro-
identify the person performing the priate followup if the initial attempt
work, include dates of the various en- at notification fails, performed under
tries, show test results as well as the § 630.40 of this chapter.
interpretation of the results, show the (2) Processing records:
expiration date assigned to specific (i) Blood processing, including results
products, and be as detailed as nec- and interpretation of all tests and
essary to provide a complete history of retests.
the work performed. (ii) Component preparation, includ-
(2) Appropriate records shall be avail- ing all relevant dates and times.
able from which to determine lot num- (iii) Separation and pooling of recov-
bers of supplies and reagents used for ered plasma.
specific lots or units of the final prod- (iv) Centrifugation and pooling of
uct. source plasma.
(b) Records shall be maintained that (v) Labeling, including initials of the
include, but are not limited to, the fol- person(s) performing the procedure.
lowing when applicable: (3) Storage and distribution records:
(1) Donor records: (i) Distribution and disposition, as
(i) Donor selection, including medical appropriate, of blood and blood prod-
interview and examination and where ucts.
applicable, informed consent. (ii) Visual inspection of whole blood
(ii) Permanent and temporary defer- and red blood cells during storage and
rals for health reasons including rea- immediately before distribution.
son(s) for deferral. (iii) Storage temperature, including
(iii) Donor adverse reaction com- initialed temperature recorder charts.
plaints and reports, including results of (iv) Reissue, including records of
all investigations and followup. proper temperature maintenance.
(iv) Therapeutic bleedings, including (v) Emergency release of blood, in-
signed requests from attending physi- cluding signature of requesting physi-
cians, the donor’s disease and disposi- cian obtained before or after release.
tion of units. (4) Compatibility test records:
(v) Immunization, including informed (i) Results of all compatibility tests,
consent, identification of the antigen, including crossmatching, testing of pa-
dosage and route of administration. tient samples, antibody screening and
(vi) Blood collection, including iden- identification.
tification of the phlebotomist. (ii) Results of confirmatory testing.
(vii) Records to relate the donor with (5) Quality control records:
the unit number of each previous dona- (i) Calibration and standardization of
tion from that donor. equipment.
(viii) Records concerning the fol- (ii) Performance checks of equipment
lowing activities performed under and reagents.
§§ 610.46 and 610.47 of this chapter: Quar- (iii) Periodic check on sterile tech-
antine; consignee notification; testing; nique.
56
(iv) Periodic tests of capacity of ship- reactive under § 610.40(a)(1) of this

ping containers to maintain proper chapter for evidence of infection due to
temperature in transit. HIV, HBV, or HCV. In addition, estab-
(v) Proficiency test results. lishments other than Source Plasma
(6) Transfusion reaction reports and establishments must include in this cu-
complaints, including records of inves- mulative record donors deferred from
tigations and followup. donation under § 610.41 of this chapter
(7) General records: because their donation tested reactive
(i) Sterilization of supplies and re- under § 610.40(a)(2) of this chapter for
agents prepared within the facility, in- evidence of infection due to HTLV or
cluding date, time interval, tempera- Chagas disease.
ture and mode. (3) The cumulative record described
(ii) Responsible personnel. in paragraph (e)(2) of this section must
(iii) Biological product deviations. be updated at least monthly to add do-
(iv) Maintenance records for equip- nors newly deferred under § 610.41 of
ment and general physical plant. this chapter due to reactive tests for
(v) Supplies and reagents, including evidence of infection due to HIV, HBV,
name of manufacturer or supplier, lot or HCV, and, if applicable, HTLV or
numbers, expiration date and date of Chagas disease.
receipt. (4) Establishments must revise the
(vi) Disposition of rejected supplies cumulative record described in para-
and reagents used in the collection, graph (e)(2) of this section to remove
processing and compatibility testing of donors who have been requalified under
blood and blood components. § 610.41(b) of this chapter.
(c) A donor number shall be assigned
to each accepted donor, which relates [40 FR 53532, Nov. 18, 1975, as amended at 61
the unit of blood collected to that FR 47422, Sept. 9, 1996; 64 FR 45371, Aug. 19,
1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176,
donor, to his medical record, to any
June 11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR
component or blood product from that 80651, Dec. 28, 2015; 80 FR 29895, May 22, 2015]
donor’s unit of blood, and to all records
describing the history and ultimate § 606.165 Distribution and receipt; pro-
disposition of these products. cedures and records.
(d) Records shall be retained for such
(a) Distribution and receipt proce-
interval beyond the expiration date for
dures shall include a system by which
the blood or blood component as nec-
the distribution or receipt of each unit
essary to facilitate the reporting of
can be readily determined to facilitate
any unfavorable clinical reactions. You
its recall, if necessary.
must retain individual product records
no less than 10 years after the records (b) Distribution records shall contain
of processing are completed or 6 information to readily facilitate the
months after the latest expiration date identification of the name and address
for the individual product, whichever is of the consignee, the date and quantity
the later date. When there is no expira- delivered, the lot number of the unit(s),
tion date, records shall be retained in- the date of expiration or the date of
definitely. collection, whichever is applicable, or
(e) Records of deferred donors. (1) Es- for crossmatched blood and blood com-
tablishments must maintain at each ponents, the name of the recipient.
location a record of all donors found to (c) Receipt records shall contain the
be ineligible or deferred at that loca- name and address of the collecting fa-
tion so that blood and blood compo- cility, date received, donor or lot num-
nents from an ineligible donor are not ber assigned by the collecting facility
collected and/or released while the and the date of expiration or the date
donor is ineligible or deferred; and of collection, whichever is applicable.
(2) Establishments must maintain at
all locations operating under the same § 606.170 Adverse reaction file.
license or under common management (a) Records shall be maintained of
a cumulative record of donors deferred any reports of complaints of adverse
from donation under § 610.41 of this reactions regarding each unit of blood
chapter because their donation tested or blood product arising as a result of
57
§ 606.171 21 CFR Ch. I (4–1–20 Edition)
blood collection or transfusion. A thor- verse events concerning the affected

ough investigation of each reported ad- product.
verse reaction shall be made. A written (b) What do I report under this section?
report of the investigation of adverse You must report any event, and infor-
reactions, including conclusions and mation relevant to the event, associ-
followup, shall be prepared and main- ated with the manufacturing, to in-
tained as part of the record for that lot clude testing, processing, packing, la-
or unit of final product by the col- beling, or storage, or with the holding
lecting or transfusing facility. When it or distribution, of both licensed and
is determined that the product was at unlicensed blood or blood components,
fault in causing a transfusion reaction, including Source Plasma, if that event
copies of all such written reports shall meets all the following criteria:
be forwarded to and maintained by the (1) Either:
manufacturer or collecting facility. (i) Represents a deviation from cur-
(b) When a complication of blood col- rent good manufacturing practice, ap-
lection or transfusion is confirmed to plicable regulations, applicable stand-
be fatal, the Director, Office of Compli- ards, or established specifications that
may affect the safety, purity, or po-
ance and Biologics Quality, CBER,
tency of that product; or
must be notified by telephone, fac-
(ii) Represents an unexpected or un-
simile, express mail, or electronically
foreseeable event that may affect the
transmitted mail as soon as possible. A
safety, purity, or potency of that prod-
written report of the investigation
uct; and
must be submitted to the Director, Of- (2) Occurs in your facility or another
fice of Compliance and Biologics Qual- facility under contract with you; and
ity, CBER, by mail, facsimile, or elec- (3) Involves distributed blood or
tronically transmitted mail (for mail- blood components.
ing address, see § 600.2(a) of this chap- (c) When do I report under this section?
ter), within 7 days after the fatality by You should report a biological product
the collecting facility in the event of a deviation as soon as possible but you
donor reaction, or by the facility that must report at a date not to exceed 45-
performed the compatibility tests in calendar days from the date you, your
the event of a transfusion reaction. agent, or another person who performs
[40 FR 53532, Nov. 18, 1975, as amended at 49 a manufacturing, holding, or distribu-
FR 23833, June 8, 1984; 50 FR 35471, Aug. 30, tion step under your control, acquire
1985; 55 FR 11014, Mar. 26, 1990; 64 FR 45371, information reasonably suggesting
Aug. 19, 1999; 67 FR 9586, Mar. 4, 2002; 77 FR that a reportable event has occurred.
18, Jan. 3, 2012; 80 FR 18092, Apr. 3, 2015] (d) How do I report under this section?
You must report on Form FDA–3486.
§ 606.171 Reporting of product devi- (e) Where do I report under this section?
ations by licensed manufacturers, You must send the completed Form
unlicensed registered blood estab-
lishments, and transfusion services. FDA 3486 to the Center for Biologics
Evaluation and Research (CBER), ei-
(a) Who must report under this section? ther in paper or electronic format.
You, a licensed manufacturer of blood (1) If you make a paper filing, send
and blood components, including the completed form to the CBER Docu-
Source Plasma; an unlicensed reg- ment Control Center (see mailing ad-
istered blood establishment; or a trans- dress in § 600.2(a) of this chapter), and
fusion service who had control over the identify on the envelope that a BPDR
product when the deviation occurred, (biological product deviation report) is
must report under this section. If you enclosed; or
arrange for another person to perform (2) If you make an electronic filing,
a manufacturing, holding, or distribu- send the completed Form FDA3486 elec-
tion step, while the product is in your tronically using CBER’s electronic
control, that step is performed under Web-based application.
your control. You must establish, (f) How does this regulation affect other
maintain, and follow a procedure for FDA regulations? This part supplements
receiving information from that person and does not supersede other provisions
on all deviations, complaints, and ad- of the regulations in this chapter. All
58
biological product deviations, whether Subpart D—Exemptions

or not they are required to be reported
607.65 Exemptions for blood product estab-
under this section, should be inves- lishments.
tigated in accordance with the applica-
ble provisions of parts 211, 606, and 820 Subpart E—Establishment Registration and
of this chapter. Product Listing Of Licensed Devices
[65 FR 66635, Nov. 7, 2000, as amended at 70 607.80 Applicability of part 607 to licensed
FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, devices.
2015] AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355,
360, 371, 374, 381, 393; 42 U.S.C. 262, 264, 271.
PART 607—ESTABLISHMENT REG- SOURCE: 40 FR 52788, Nov. 12, 1975, unless
ISTRATION AND PRODUCT LIST- otherwise noted.
ING FOR MANUFACTURERS OF
HUMAN BLOOD AND BLOOD Subpart A—General Provisions
PRODUCTS AND LICENSED DE- § 607.1 Scope.
VICES
(a) This part establishes establish-
Subpart A—General Provisions ment registration and product listing
requirements for manufacturers of
Sec. human blood and blood products.
607.1 Scope. (b) This part establishes establish-
607.3 Definitions. ment registration and product listing
607.7 Establishment registration and prod- requirements for manufacturers of
uct listing of blood banks and other products that meet the definition of a
firms manufacturing human blood and device under the Federal Food, Drug,
blood products. and Cosmetic Act and that are licensed
under section 351 of the Public Health
Subpart B—Procedures for Domestic Blood Service Act, as well as licensed biologi-
Product Establishments cal products used in the manufacture
607.20 Who must register and submit a blood of a licensed device.
product list. [81 FR 60221, Aug. 31, 2016]
607.21 Times for establishment registration
and blood product listing. § 607.3 Definitions.
607.22 How to register establishments and
list blood products.
(a) The term act means the Federal
607.25 Information required for establish-
Food, Drug, and Cosmetic Act approved
ment registration and blood product list- June 25, 1938 (52 Stat. 1040 et seq., as
ing. amended, 21 U.S.C. 301–392).
607.26 Amendments to establishment reg- (b) Blood and blood product means a
istration. drug which consists of human whole
607.30 Updating blood product listing infor- blood, plasma, or serum or any product
mation. derived from human whole blood, plas-
607.31 Additional blood product listing in- ma, or serum, hereinafter referred to as
formation. ‘‘blood product.’’ For the purposes of
607.35 Blood product establishment registra- this part only, blood and blood product
tion number. also means those products that meet
607.37 Public disclosure of establishment the definition of a device under the
registration and blood product listing in- Federal Food, Drug, and Cosmetic Act
formation. and that are licensed under section 351
607.39 Misbranding by reference to estab- of the Public Health Service Act, as
lishment registration, validation of reg- well as licensed biological products
istration, or to registration number. used in the manufacture of a licensed
device.
Subpart C—Procedures for Foreign Blood
(c) Establishment means a place of
Product Establishments
business under one management at one
general physical location. The term in-
607.40 Establishment registration and blood

product listing requirements for foreign cludes, among others, human blood and
blood product establishments. plasma donor centers, blood banks,
59
§ 607.7 21 CFR Ch. I (4–1–20 Edition)
transfusion services, other blood prod- manufacturing of a blood product be-

uct manufacturers and independent comes an active ingredient or a fin-
laboratories that engage in quality ished dosage form of such product.
control and testing for registered blood (h) Advertising and labeling include
product establishments. the promotional material described in
(d) Manufacture means the collection, § 202.1(l) (1) and (2) of this chapter, re-
preparation, processing or compat- spectively.
ibility testing by chemical, physical, (i) The definitions and interpreta-
biological, or other procedures of any tions contained in sections 201 and 510
blood product which meets the defini- of the act shall be applicable to such
tion of a drug as defined in section terms when used in this part 607.
201(g) of the act, and including manipu-
(j) United States agent means a person
lation, sampling, testing, or control
residing or maintaining a place of busi-
procedures applied to the final product
or to any part of the process. The term ness in the United States whom a for-
includes packaging, labeling, repack- eign establishment designates as its
aging or otherwise changing the con- agent. This definition excludes mail-
tainer, wrapper, or labeling of any boxes, answering machines or services,
blood product package in furtherance or other places where an individual
of the distribution of the blood product acting as the foreign establishment’s
from the original place of manufacture agent is not physically present.
to the person who makes final delivery (k) Importer means a person in the
or sale to the ultimate consumer. United States that is an owner, con-
(e) Commercial distribution means any signee, or recipient, at the time of
distribution of a blood product except entry, of a foreign establishment’s
under the investigational use provi- blood product that is imported into the
sions of part 312 of this chapter, but United States.
does not include internal or interplant (l) Foreign for the purpose of registra-
transfer of a bulk product substance tion and listing under this part when
between registered establishments used to modify the term ‘‘establish-
within the same parent, subsidiary, ment’’ refers to an establishment that
and/or affiliate company. For foreign is located in a foreign country and is
establishments, the term ‘‘commercial the site where a blood product that is
distribution’’ shall have the same imported or offered for import into the
meaning except that the term shall not United States was manufactured.
include distribution of any blood or
blood product that is neither imported
FR 11014, Mar. 26, 1990; 66 FR 59158, Nov. 27,
nor offered for import into the United 2001; 81 FR 60222, Aug. 31, 2016]
States.
(f) Any material change includes but is § 607.7 Establishment registration and
not limited to any change in the name product listing of blood banks and
of the blood product, in the quantity or other firms manufacturing human
identity of the active ingredient(s) or blood and blood products.
in the quantity or identity of the inac-
All owners or operators of establish-
tive ingredient(s) where quantitative
ments that engage in the manufac-
listing of all ingredients is required
turing of blood products are required to
pursuant to § 607.31(a)(2) and any sig-
register, pursuant to section 510 of the
nificant change in the labeling of a
Federal Food, Drug, and Cosmetic Act.
blood product. Changes that are not
Registration and listing of blood prod-
significant include changes in arrange-
ucts must comply with this part. Reg-
ment or printing or changes of an edi-
istration does not permit any blood
torial nature.
bank or similar establishment to ship
(g) Bulk product substance means any
blood products in interstate commerce.
substance that is represented for use in
a blood product and when used in the [81 FR 60222, Aug. 31, 2016]
60
Subpart B—Procedures for Domes- chapter) for which a license is required,

tic Blood Product Establish- registration shall follow within 5 days
ments after the submission of a biologics li-
cense application in order to manufac-
§ 607.20 Who must register and submit ture blood products. Owners or opera-
a blood product list. tors of all establishments so engaged
(a) Owners or operators of all estab- must register annually between Octo-
lishments, not exempt under section ber 1 and December 31 and must update
510(g) of the act or subpart D of this their blood product listing every June
part, that engage in the manufacture and December.
of blood products shall register and [40 FR 52788, Nov. 12, 1975, as amended at 64
submit a list of every blood product in FR 56453, Oct. 20, 1999; 81 FR 60222, Aug. 31,
commercial distribution (except that 2016]
registration and listing information
may be submitted by the parent, sub- § 607.22 How to register establish-
sidiary, and/or affiliate company for all ments and list blood products.
establishments when operations are (a) Initial and subsequent registra-
conducted at more than one establish- tions and product listings must be sub-
ment and there exists joint ownership mitted electronically through the
and control among all the establish- Blood Establishment Registration and
ments). Blood products manufactured,
Product Listing system, or any future
prepared, propagated, compounded, or
superseding electronic system. This in-
processed in any State as defined in
formation must be submitted in ac-
section 201(a)(1) of the act must be list-
cordance with part 11 of this chapter,
ed whether or not the output of such
except for the requirements in
blood product establishment or any
particular blood product so listed en- § 11.10(b), (c), and (e), and the cor-
ters interstate commerce. responding requirements in § 11.30. All
(b) Preparatory to engaging in the information submitted under this part
manufacture of blood products, owners must be transmitted to FDA electroni-
or operators of establishments who are cally unless FDA has granted a request
submitting a biologics license applica- for waiver of this requirement prior to
tion to manufacture blood products are the date on which the information is
required to register before the bio- due. Submission of a request for waiver
logics license application is approved. does not excuse timely compliance
(c) Except in the case of licensed de- with the registration and listing re-
vice manufacturers, no registration fee quirements. FDA will grant a waiver
is required. Establishment registration request if FDA determines that the use
and blood product listing do not con- of electronic means for submission of
stitute an admission or agreement or registration and listing information is
determination that a blood product is a not reasonable for the registrant mak-
‘‘drug’’ within the meaning of section ing the waiver request.
201(g) of the act. (b) Waiver requests under this sec-
tion must be submitted in writing and
FR 56452, Oct. 20, 1999; 66 FR 59158, Nov. 27, must include the specific reasons why
2001; 81 FR 60222, Aug. 31, 2016] electronic submission is not reasonable
for the registrant and a U.S. telephone
§ 607.21 Times for establishment reg- number and mailing address where
istration and blood product listing. FDA can contact the registrant. All
The owner or operator of an estab- waiver requests must be sent to the Di-
lishment entering into an operation de- rector of FDA’s Center for Biologics
fined in § 607.3(d) shall register such es- Evaluation and Research through the
tablishment within 5 days after the be- Document Control Center (see address-
ginning of such operation and submit a es in § 600.2).
list of every blood product in commer- (c) If FDA grants the waiver request,
cial distribution at the time. If the FDA may limit its duration and will
owner or operator of the establishment specify terms of the waiver and provide
has not previously entered into such information on how to submit estab-
operation (defined in § 607.3(d) of this lishment registration, drug listings,
61
§ 607.25 21 CFR Ch. I (4–1–20 Edition)
other information, and updates, as ap- Identifier of the parent establishment.

plicable. An establishment not owned, operated,
[81 FR 60222, Aug. 31, 2016]
or controlled by another firm or estab-
lishment is its own parent establish-
§ 607.25 Information required for es- ment.
tablishment registration and blood [81 FR 60222, Aug. 31, 2016]
product listing.
(a) The Blood Establishment Reg- § 607.26 Amendments to establishment
istration and Product Listing system registration.
requires furnishing or confirming reg- Changes in individual ownership, cor-
istration information required by the porate or partnership structure, loca-
Federal Food, Drug, and Cosmetic Act. tion, or blood product handling activ-
This information includes the name ity must be submitted electronically
and street address of the establish- through the Blood Establishment Reg-
ment, including post office code; a registration and Product Listing system,
istration number if previously assigned or any future superseding electronic
by FDA and a Unique Facility Identi- system, as an amendment to registra-
fier in accordance with the system tion within 5 calendar days of such
specified under section 510 of the Fed- changes. Changes in the names of offi-
eral Food, Drug, and Cosmetic Act; all cers and directors of the corporations
trade names used by the establishment; do not require such amendment but
the kind of ownership or operation must be shown at time of annual reg-
(that is, individually owned partner- istration.
ship, or corporation); and the name of
the owner or operator of such estab- FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31,
lishment. The term ‘‘name of the 2016]
owner or operator’’ must include, in
the case of a partnership, the name of § 607.30 Updating blood product list-
each partner and, in the case of a cor- ing information.
poration, the name and title of each (a) After submission of the initial
corporate officer and director and the blood product listing information,
name of the State of incorporation. every person who is required to list
The information required must be blood products under § 607.20 must sub-
given separately for each establish- mit electronically through the Blood
ment, as defined in § 607.3(c). Establishment Registration and Prod-
(b) The following information must uct Listing system, or any future su-
also be provided: perseding electronic system, at a min-
(1) A list of blood products by estab- imum once in June and December of
lished name as defined in section 502(e) every year, the following information:
of the Federal Food, Drug, and Cos- (1) A list of each blood product intro-
metic Act and by proprietary name, if duced by the registrant for commercial
any, which are being manufactured for distribution which has not been in-
commercial distribution at the identi- cluded in any list previously sub-
fied establishment and which have not mitted. All of the information required
been included in any list previously by § 607.25(b) shall be provided for each
submitted to FDA through the Blood such blood product.
Establishment Registration and Prod- (2) A list of each blood product for-
uct Listing system or any future super- merly listed pursuant to § 607.25(b) for
seding electronic system. which commercial distribution has
(2) For each blood product so listed been discontinued, including for each
that is subject to section 351 of the blood product so listed the identity by
Public Health Service Act, the license established name and proprietary
number of the manufacturer issued by name, and date of discontinuance. It is
the Center for Biologics Evaluation requested but not required that the
and Research, Food and Drug Adminis- reason for discontinuance of distribu-
tration. tion be included with this information.
(3) For each blood product listed, the (3) A list of each blood product for
registration number if previously as- which a notice of discontinuance was

signed by FDA and the Unique Facility submitted pursuant to paragraph (a)(2)
62
of this section and for which commer- § 607.37 Public disclosure of establish-
cial distribution has been resumed, in- ment registration and blood prod-
cluding for each blood product so listed uct listing information.
the identity by established name as de- (a) Except as provided in paragraph
fined in section 502(e) of the act and by (b) of this section, all registration and
any proprietary name, the date of re- listing information obtained under
sumption, and any other information §§ 607.25, 607.26, and 607.30 will be made
required by § 607.25(b) not previously available for public disclosure through
submitted. the Center for Biologics Evaluation
(4) Any material change in any infor- and Research (CBER) Blood Establish-
mation previously submitted. ment Registration Database Web site
(b) When no changes have occurred by using the CBER electronic Web-
since the previously submitted list, no based application or by going in person
listing information is required. to the Food and Drug Administration,
[40 FR 52788, Nov. 12, 1975, as amended at 81 Division of Freedom of Information
FR 60222, Aug. 31, 2016] Public Reading Room (see addresses in
§ 20.120(a) of this chapter).
§ 607.31 Additional blood product list- (b) FDA may find, in limited cir-
ing information. cumstances and on a case-by-case
(a) In addition to the information basis, that it would be consistent with
routinely required by §§ 607.25 and the protection of the public health to
607.30, the Director of the Center for exempt from public disclosure specific
Biologics Evaluation and Research listing information obtained under
may require submission of the fol- § 607.25 or § 607.30.
lowing information by letter or by (c) Other requests for information re-
FEDERAL REGISTER notice: garding blood establishment registra-
(1) For a particular blood product so tions and blood product listings should
listed, upon request made by the Direc- be directed to the Food and Drug Ad-
tor of the Center for Biologics Evalua- ministration, Center for Biologics
tion and Research for good cause, a Evaluation and Research Office of
copy of all advertisements. Communication, Outreach, and Devel-
(2) For a particular blood product so opment, 10903 New Hampshire Ave.,
listed, upon a finding by the Director Bldg. 71, Rm. 3103, Silver Spring, MD
of the Center for Biologics Evaluation 20993–0002.
and Research that it is necessary to [81 FR 60223, Aug. 31, 2016]
carry out the purposes of the act, a
quantitative listing of all ingredients. § 607.39 Misbranding by reference to
(3) For each registrant, upon a find- establishment registration, valida-
ing by the Director of the Center for tion of registration, or to registra-
Biologics Evaluation and Research tion number.
that it is necessary to carry out the Registration of an establishment,
purposes of the act, a list of each listed validation of registration, or assign-
blood product containing a particular ment of a registration number does not
ingredient. in any way denote approval of the firm
(b) [Reserved] or its products nor does it mean that
the products may be legally marketed.
[66 FR 59158, Nov. 27, 2001]
Any representation that creates an im-
§ 607.35 Blood product establishment pression of official approval because of
registration number. establishment registration, validation
of registration, or possession of a reg-
An establishment registration num-
istration number is misleading and
ber will be assigned to each blood prod-
constitutes misbranding.
uct establishment registered in accord-
ance with this part. [81 FR 60223, Aug. 31, 2016]
[81 FR 60223, Aug. 31, 2016]
63
§ 607.40 21 CFR Ch. I (4–1–20 Edition)
Subpart C—Procedures for Foreign tablishment must designate only one

Blood Product Establishments United States agent.
(1) The United States agent shall re-
§ 607.40 Establishment registration side or maintain a place of business in
and blood product listing require- the United States.
ments for foreign blood product es- (2) Upon request from FDA, the
tablishments. United States agent shall assist FDA
(a) Every foreign establishment shall in communications with the foreign es-
comply with the establishment reg- tablishment, respond to questions con-
istration and blood product listing re- cerning the foreign establishment’s
quirements contained in subpart B of products that are imported or offered
this part, unless exempt under subpart for import into the United States, and
D of this part or unless the blood prod- assist FDA in scheduling inspections of
uct enters a foreign trade zone and is the foreign establishment. If the agen-
re-exported from that foreign trade cy is unable to contact the foreign es-
zone without having entered U. S. com- tablishment directly or expeditiously,
merce. FDA may provide information or docu-
(b) No blood product may be im- ments to the United States agent, and
ported or offered for import into the such an action shall be considered to be
United States unless it is the subject of equivalent to providing the same infor-
a blood product listing as required mation or documents to the foreign es-
tablishment.
under subpart B of this part and is
manufactured, prepared, propagated, (3) The foreign establishment or the
compounded, or processed at a reg- United States agent must report
istered foreign establishment; however, changes in the United States agent’s
this restriction does not apply to a name, address, telephone number, or
email address to FDA within 30 cal-
blood product imported or offered for
endar days of the change.
import under the investigational use
provisions of part 312 of this chapter or (e) Each foreign establishment re-
to a blood product imported under sec- quired to register under paragraph (a)
tion 801(d)(4) of the act. The establish- of this section must register and list
blood products using the Blood Estab-
ment registration and blood product
lishment Registration and Product
listing information shall be in the
Listing system, or any superseding
English language.
electronic system, unless FDA waives
(c) Each foreign establishment re- the electronic submission requirement
quired to register under paragraph (a) in accordance with § 607.22.
of this section shall, as part of the es-
tablishment registration and blood [66 FR 59159, Nov. 27, 2001, as amended at 81
product listing, submit the name and FR 60223, Aug. 31, 2016]
address of the establishment and the
name of the individual responsible for Subpart D—Exemptions
submitting establishment registration
and blood product listing information. § 607.65 Exemptions for blood product
Any changes in this information shall establishments.
be reported to the Food and Drug Ad- The following classes of persons are
ministration at the intervals specified exempt from registration and blood
for updating establishment registra- product listing in accordance with this
tion information in § 607.26 and blood part 607 under the provisions of section
product listing information in 510(g)(1), (g)(2), and (g)(3) of the act, or
§ 607.30(a). because the Commissioner of Food and
(d) Each foreign establishment re- Drugs has found, under section
quired to register under paragraph (a) 510(g)(5), that such registration is not
of this section must submit the name, necessary for the protection of the pub-
address, telephone number, and email lic health. The exemptions in para-
address of its United States agent as graphs (a), (b), (f), and (g) of this sec-
part of its initial and updated registration are limited to those classes of per-
tion information in accordance with sons located in any State as defined in

subpart B of this part. Each foreign es- section 201(a)(1) of the act.
64
(a) Pharmacies that are operating cells for transfusion are not acts re-
under applicable local laws regulating quiring such transfusion services to
dispensing of prescription drugs and register.
that are not manufacturing blood prod- (g) Persons who engage solely in the
ucts for sale other than in the regular production of any plasma derivative,
course of the practice of the profession including, but not limited to, albumin,
of pharmacy including the business of Immune Globulin, Factor VIII and Fac-
dispensing and selling blood products tor IX, bulk product substances such as
at retail. The supplying by such phar- fractionation intermediates or pastes,
macies of blood products to a practi- or recombinant versions of plasma de-
tioner licensed to administer such rivatives or animal derived plasma de-
blood products for his use in the course rivatives. These persons must register
of his professional practice or to other and list under part 207 of this chapter.
pharmacies to meet temporary inven- [40 FR 52788, Nov. 12, 1975, as amended at 43
tory shortages are not acts which re- FR 37997, Aug. 25, 1978; 45 FR 85729, Dec. 30,
quire such pharmacies to register. 1980; 49 FR 34449, Aug. 31, 1984; 66 FR 31162,
(b) Practitioners who are licensed by June 11, 2001; 66 FR 59159, Nov. 27, 2001; 72 FR
law to prescribe or administer drugs 45886, Aug. 16, 2007; 81 FR 60223, Aug. 31, 2016]
and who manufacture blood products
solely for use in the course of their pro- Subpart E—Establishment Registra-
fessional practice. tion and Product Listing Of Li-
(c) Persons who manufacture blood censed Devices
products which are not for sale, rather,
are solely for use in research, teaching, § 607.80 Applicability of part 607 to li-
or analysis, including laboratory sam- censed devices.
ples. Manufacturers of products that meet
(d) Carriers, by reason of their re- the definition of a device under the
ceipt, carriage, holding, or delivery of Federal Food, Drug, and Cosmetic Act
blood products in the usual course of and that are licensed under section 351
business as carriers. of the Public Health Service Act, as
(e) Persons who engage solely in the well as licensed biological products
manufacture of in vitro diagnostic used in the manufacture of a licensed
blood products and reagents not sub- device, must register and list following
ject to licensing under section 351 of the procedures under this part, with re-
the Public Health Service Act (42 spect to their manufacture of those
U.S.C. 262). This paragraph does not ex- products, unless otherwise noted in
empt such persons from registration this section.
and listing for medical devices required [81 FR 60223, Aug. 31, 2016]
under part 807 of this chapter.
(f) Transfusion services which are a
part of a facility that is certified under PART 610—GENERAL BIOLOGICAL
the Clinical Laboratory Improvement PRODUCTS STANDARDS
Amendments of 1988 (42 U.S.C. 263a)
and 42 CFR part 493 or has met equiva- Subpart A—Release Requirements
lent requirements as determined by the Sec.
Centers for Medicare and Medicaid 610.1 Tests prior to release required for each
Services and which are engaged in the lot.
compatibility testing and transfusion 610.2 Requests for samples and protocols; of-
of blood and blood components, but ficial release.
which neither routinely collect nor
Subpart B—General Provisions
process blood and blood components.
The collection and processing of blood 610.9 Equivalent methods and processes.
and blood components in an emergency 610.10 Potency.
situation as determined by a respon- 610.11–610.11a [Reserved]
sible person and documented in writ- 610.12 Sterility.
610.13 Purity.
ing, therapeutic collection of blood or 610.14 Identity.
plasma, the preparation of recovered
610.15 Constituent materials.

human plasma for further manufac- 610.16 Total solids in serums.
turing use, or preparation of red blood 610.17 Permissible combinations.
65
§ 610.1 21 CFR Ch. I (4–1–20 Edition)
610.18 Cultures. Subpart A—Release Requirements
Subpart C [Reserved] § 610.1 Tests prior to release required
for each lot.
610.20–610.21 [Reserved]
No lot of any licensed product shall
Subpart D—Mycoplasma be released by the manufacturer prior
to the completion of tests for con-
610.30 Test for Mycoplasma. formity with standards applicable to
such product. Each applicable test
Subpart E—Testing Requirements for shall be made on each lot after comple-
Relevant Transfusion-Transmitted Infections tion of all processes of manufacture
610.39 Definitions. which may affect compliance with the
610.40 Test requirements. standard to which the test applies. The
610.41 Donor deferral. results of all tests performed shall be
610.42 Restrictions on use for further manu- considered in determining whether or
facture of medical devices. not the test results meet the test ob-
610.44 Use of reference panels by manufac- jective, except that a test result may
turers of test kits. be disregarded when it is established
610.46 Human immunodeficiency virus (HIV) that the test is invalid due to causes
‘‘lookback’’ requirements. unrelated to the product.
610.47 Hepatitis C virus (HCV) ‘‘lookback’’
requirements. § 610.2 Requests for samples and pro-
610.48 [Reserved] tocols; official release.
(a) Licensed biological products regu-
Subpart F—Dating Period Limitations lated by CBER. Samples of any lot of
any licensed product together with the
610.50 Date of manufacture for biological
products.
protocols showing results of applicable
610.53 Dating periods for Whole Blood and
tests, may at any time be required to
blood components. be sent to the Director, Center for Bio-
logics Evaluation and Research (see
Subpart G—Labeling Standards mailing addresses in § 600.2(c) of this
chapter). Upon notification by the Di-
610.60 Container label. rector, Center for Biologics Evaluation
610.61 Package label. and Research, a manufacturer shall not
610.62 Proper name; package label; legible distribute a lot of a product until the
type. lot is released by the Director, Center
610.63 Divided manufacturing responsibility for Biologics Evaluation and Research:
to be shown. Provided, That the Director, Center for
610.64 Name and address of distributor. Biologics Evaluation and Research,
610.65 Products for export.
shall not issue such notification except
610.67 Bar code label requirements.
when deemed necessary for the safety,
610.68 Exceptions or alternatives to labeling
purity, or potency of the product.
requirements for biological products held
by the Strategic National Stockpile.
(b) Licensed biological products regu-
lated by CDER. Samples of any lot of
AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, any licensed product together with the
355, 360, 360c, 360d, 360h, 360i, 371, 372, 374, 381; protocols showing results of applicable
42 U.S.C. 216, 262, 263, 263a, 264. tests, may at any time be required to
SOURCE: 38 FR 32056, Nov. 20, 1973, unless be sent to the Director, Center for
otherwise noted. Drug Evaluation and Research (see
CROSS REFERENCES: For U.S. Customs
chapter) for official release. Upon noti-
Service regulations relating to viruses, se-
rums, and toxins, see 19 CFR 12.21–12.23. For fication by the Director, Center for
U.S. Postal Service regulations relating to Drug Evaluation and Research, a man-
the admissibility to the United States mails ufacturer shall not distribute a lot of a
see parts 124 and 125 of the Domestic Mail biological product until the lot is re-
Manual, that is incorporated by reference in leased by the Director, Center for Drug
39 CFR part 111. Evaluation and Research: Provided,
That the Director, Center for Drug

Evaluation and Research shall not
66
issue such notification except when each biological product’s final con-
deemed necessary for the safety, pu- tainer material or other material, as
rity, or potency of the product. appropriate and as approved in the bio-
[40 FR 31313, July 25, 1975, as amended at 49
logics license application or supple-
FR 23834, June 8, 1984; 50 FR 10941, Mar. 19, ment for that product.
1985; 55 FR 11013, 11014, Mar. 26, 1990; 67 FR (b) Test requirements. (1) The sterility
9587, Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005; 80 test must be appropriate to the mate-
FR 18093, Apr. 3, 2015] rial being tested such that the material
does not interfere with or otherwise
Subpart B—General Provisions hinder the test.
(2) The sterility test must be vali-
§ 610.9 Equivalent methods and proc- dated to demonstrate that the test is
esses. capable of reliably and consistently de-
Modification of any particular test tecting the presence of viable contami-
method or manufacturing process or nating microorganisms.
the conditions under which it is con- (3) The sterility test and test compo-
ducted as required in this part or in the nents must be verified to demonstrate
additional standards for specific bio- that the test method can consistently
logical products in parts 620 through detect the presence of viable contami-
680 of this chapter shall be permitted nating microorganisms.
only under the following conditions: (c) Written procedures. Manufacturers
(a) The applicant presents evidence, must establish, implement, and follow
in the form of a license application, or written procedures for sterility testing
a supplement to the application sub- that describe, at a minimum, the fol-
mitted in accordance with § 601.12(b) or lowing:
(c), demonstrating that the modifica- (1) The sterility test method to be
tion will provide assurances of the safe- used;
ty, purity, potency, and effectiveness (i) If culture-based test methods are
of the biological product equal to or used, include, at a minimum:
greater than the assurances provided (A) Composition of the culture
by the method or process specified in media;
the general standards or additional (B) Growth-promotion test require-
standards for the biological product; ments; and
and (C) Incubation conditions (time and
(b) Approval of the modification is temperature).
received in writing from the Director, (ii) If non-culture-based test methods
Center for Biologics Evaluation and are used, include, at a minimum:
Research or the Director, Center for (A) Composition of test components;
Drug Evaluation and Research. (B) Test parameters, including ac-
[62 FR 39903, July 24, 1997, as amended at 70 ceptance criteria; and
FR 14984, Mar. 24, 2005] (C) Controls used to verify the meth-
od’s ability to detect the presence of
§ 610.10 Potency. viable contaminating microorganisms.
Tests for potency shall consist of ei- (2) The method of sampling, includ-
ther in vitro or in vivo tests, or both, ing the number, volume, and size of ar-
which have been specifically designed ticles to be tested;
for each product so as to indicate its (3) Written specifications for the ac-
potency in a manner adequate to sat- ceptance or rejection of each lot; and
isfy the interpretation of potency given (4) A statement of any other function
by the definition in § 600.3(s) of this critical to the particular sterility test
chapter. method to ensure consistent and accu-
rate results.
§ 610.11–610.11a [Reserved] (d) The sample. The sample must be
appropriate to the material being test-
§ 610.12 Sterility. ed, considering, at a minimum:
(a) The test. Except as provided in (1) The size and volume of the final
paragraph (h) of this section, manufac- product lot;
turers of biological products must per- (2) The duration of manufacturing of

form sterility testing of each lot of the drug product;
67
§ 610.13 21 CFR Ch. I (4–1–20 Edition)
(3) The final container configuration the repeat test must be conducted with
and size; comparable product that is reflective
(4) The quantity or concentration of of the initial sample in terms of sample
inhibitors, neutralizers, and preserva- location and the stage in the manufac-
tives, if present, in the tested material; turing process from which it was ob-
(5) For a culture-based test method, tained.
the volume of test material that re- (g) Records. The records related to
sults in a dilution of the product that the test requirements of this section
is not bacteriostatic or fungistatic; and must be prepared and maintained as re-
(6) For a non-culture-based test quired by §§ 211.167 and 211.194 of this
method, the volume of test material chapter.
that results in a dilution of the product (h) Exceptions. Sterility testing must
that does not inhibit or otherwise be performed on final container mate-
hinder the detection of viable contami- rial or other appropriate material as
nating microorganisms. defined in the approved biologics li-
(e) Verification. (1) For culture-based
cense application or supplement and as
test methods, studies must be con-
described in this section, except as fol-
ducted to demonstrate that the per-
lows:
formance of the test organisms and
culture media are suitable to consist- (1) This section does not require ste-
ently detect the presence of viable con- rility testing for Whole Blood,
taminating microorganisms, including Cryoprecipitated Antihemophilic Fac-
tests for each lot of culture media to tor, Platelets, Red Blood Cells, Plasma,
verify its growth-promoting properties Source Plasma, Smallpox Vaccine, Re-
over the shelf-life of the media. agent Red Blood Cells, Anti-Human
(2) For non-culture-based test meth- Globulin, and Blood Grouping Re-
ods, within the test itself, appropriate agents.
controls must be used to demonstrate (2) A manufacturer is not required to
the ability of the test method to con- comply with the sterility test require-
tinue to consistently detect the pres- ments if the Director of the Center for
ence of viable contaminating micro- Biologics Evaluation and Research or
organisms. the Director of the Center for Drug
(f) Repeat test procedures. (1) If the ini- Evaluation and Research, as appro-
tial test indicates the presence of priate, determines that data submitted
microorganisms, the product does not in the biologics license application or
comply with the sterility test require- supplement adequately establish that
ments unless a thorough investigation the route of administration, the meth-
by the quality control unit can ascribe od of preparation, or any other aspect
definitively the microbial presence to a of the product precludes or does not ne-
laboratory error or faulty materials cessitate a sterility test to assure the
used in conducting the sterility test- safety, purity, and potency of the prod-
ing. uct.
(2) If the investigation described in
[77 FR 26174, May 3, 2012]
paragraph (f)(1) of this section finds
that the initial test indicated the pres- § 610.13 Purity.
ence of microorganisms due to labora-
tory error or the use of faulty mate- Products shall be free of extraneous
rials, a sterility test may be repeated material except that which is unavoid-
one time. If no evidence of microorga- able in the manufacturing process de-
nisms is found in the repeat test, the scribed in the approved biologics li-
product examined complies with the cense application. In addition, products
sterility test requirements. If evidence shall be tested as provided in para-
of microorganisms is found in the re- graphs (a) and (b) of this section.
peat test, the product examined does (a)(1) Test for residual moisture. Each
not comply with the sterility test re- lot of dried product shall be tested for
quirements. residual moisture and shall meet and
(3) If a repeat test is conducted, the not exceed established limits as speci-
same test method must be used for fied by an approved method on file in
both the initial and repeat tests, and the biologics license application. The
68
test for residual moisture may be ex- may be repeated once using five other
empted by the Director, Center for Bio- rabbits. The temperature rises recorded
logics Evaluation and Research or the for all eight rabbits used in testing
Director, Center for Drug Evaluation shall be included in determining
and Research, when deemed not nec- whether the requirements are met. The
essary for the continued safety, purity, lot meets the requirements for absence
and potency of the product. of pyrogens if not more than three of
(2) Records. Appropriate records for the eight rabbits show individual rises
residual moisture under paragraph in temperature of 0.6 °C or more, and if
(a)(1) of this section shall be prepared the sum of the eight individual max-
and maintained as required by the ap- imum temperature rises does not ex-
plicable provisions of §§ 211.188 and ceed 3.7 °C.
211.194 of this chapter.
(b) Test for pyrogenic substances. Each FR 29710, July 15, 1975; 41 FR 10429, Mar. 11,
lot of final containers of any product 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289,
intended for use by injection shall be July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR
tested for pyrogenic substances by in- 15187, Apr. 18, 1984; 50 FR 4134, Jan. 29, 1985;
travenous injection into rabbits as pro- 55 FR 28381, July 11, 1990; 64 FR 56453, Oct. 20,
vided in paragraphs (b) (1) and (2) of 1999; 67 FR 9587, Mar. 4, 2002; 70 FR 14985,
this section: Provided, That notwith- Mar. 24, 2005]
standing any other provision of Sub-
§ 610.14 Identity.
chapter F of this chapter, the test for
pyrogenic substances is not required The contents of a final container of
for the following products: Products each filling of each lot shall be tested
containing formed blood elements; for identity after all labeling oper-
Cryoprecipitate; Plasma; Source Plas- ations shall have been completed. The
ma; Normal Horse Serum; bacterial, identity test shall be specific for each
viral, and rickettsial vaccines and product in a manner that will ade-
antigens; toxoids; toxins; allergenic ex- quately identify it as the product des-
tracts; venoms; diagnostic substances ignated on final container and package
and trivalent organic arsenicals. labels and circulars, and distinguish it
(1) Test dose. The test dose for each from any other product being processed
rabbit shall be at least 3 milliliters per in the same laboratory. Identity may
kilogram of body weight of the rabbit be established either through the phys-
and also shall be at least equivalent ical or chemical characteristics of the
proportionately, on a body weight product, inspection by macroscopic or
basis, to the maximum single human microscopic methods, specific cultural
dose recommended, but need not ex- tests, or in vitro or in vivo
ceed 10 milliliters per kilogram of body immunological tests.
weight of the rabbit, except that: (i)
Regardless of the human dose rec- § 610.15 Constituent materials.
ommended, the test dose per kilogram (a) Ingredients, preservatives, diluents,
of body weight of each rabbit shall be adjuvants. All ingredients used in a li-
at least 1 milliliter for immune censed product, and any diluent pro-
globulins derived from human blood; vided as an aid in the administration of
(ii) for Streptokinase, the test dose the product, shall meet generally ac-
shall be at least equivalent proportion- cepted standards of purity and quality.
ately, on a body weight basis, to the Any preservative used shall be suffi-
maximum single human dose rec- ciently nontoxic so that the amount
ommended. present in the recommended dose of the
(2) Test procedure, results, and interpre- product will not be toxic to the recipi-
tation; standards to be met. The test for ent, and in the combination used it
pyrogenic substances shall be per- shall not denature the specific sub-
formed according to the requirements stances in the product to result in a de-
specified in United States Pharma- crease below the minimum acceptable
copeia XX. potency within the dating period when
(3) Retest. If the lot fails to meet the stored at the recommended tempera-
test requirements prescribed in para- ture. Products in multiple-dose con-

graph (b)(2) of this section, the test tainers shall contain a preservative,
69
§ 610.16 21 CFR Ch. I (4–1–20 Edition)
except that a preservative need not be such exceptions or alternatives must

added to Yellow Fever Vaccine; Polio- be in writing.
virus Vaccine Live Oral; viral vaccines
labeled for use with the jet injector; FR 51903, Oct. 23, 1981; 48 FR 13025, Mar. 29,
dried vaccines when the accompanying 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834,
diluent contains a preservative; or to June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR
an Allergenic Product in 50 percent or 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990;
more volume in volume (v/v) glycerin. 70 FR 14985, Mar. 24, 2005; 76 FR 20518, Apr. 13,
An adjuvant shall not be introduced 2011; 80 FR 18093, Apr. 3, 2015]
into a product unless there is satisfac-
§ 610.16 Total solids in serums.
tory evidence that it does not affect
adversely the safety or potency of the Except as otherwise provided by reg-
product. The amount of aluminum in ulation, no liquid serum or antitoxin
the recommended individual dose of a shall contain more than 20 percent
biological product shall not exceed: total solids.
(1) 0.85 milligrams if determined by
§ 610.17 Permissible combinations.
assay;
(2) 1.14 milligrams if determined by Licensed products may not be com-
calculation on the basis of the amount bined with other licensed products ei-
of aluminum compound added; or ther therapeutic, prophylactic or diag-
(3) 1.25 milligrams determined by nostic, except as a license is obtained
assay provided that data dem- for the combined product. Licensed
onstrating that the amount of alu- products may not be combined with
minum used is safe and necessary to nonlicensable therapeutic, prophy-
produce the intended effect are sub- lactic, or diagnostic substances except
mitted to and approved by the Direc- as a license is obtained for such com-
tor, Center for Biologics Evaluation bination.
and Research or the Director, Center § 610.18 Cultures.
for Drug Evaluation and Research (see
mailing addresses in § 600.2(a) or (b) of (a) Storage and maintenance. Cultures
this chapter). used in the manufacture of products
(b) Extraneous protein; cell culture pro- shall be stored in a secure and orderly
duced vaccines. Extraneous protein manner, at a temperature and by a
known to be capable of producing aller- method that will retain the initial
genic effects in human subjects shall characteristics of the organisms and
not be added to a final virus medium of insure freedom from contamination
cell culture produced vaccines intended and deterioration.
for injection. If serum is used at any (b) Identity and verification. Each cul-
stage, its calculated concentration in ture shall be clearly identified as to
the final medium shall not exceed source strain. A complete identifica-
tion of the strain shall be made for
1:1,000,000.
each new stock culture preparation.
(c) Antibiotics. A minimum concentra-
Primary and subsequent seed lots shall
tion of antibiotics, other than peni-
be identified by lot number and date of
cillin, may be added to the production
preparation. Periodic tests shall be per-
substrate of viral vaccines. formed as often as necessary to verify
(d) The Director of the Center for the integrity of the strain characteris-
Biologics Evaluation and Research or tics and freedom from extraneous orga-
the Director of the Center for Drug nisms. Results of all periodic tests for
Evaluation and Research may approve verification of cultures and determina-
an exception or alternative to any re- tion of freedom from extraneous orga-
quirement in this section. Requests for nisms shall be recorded and retained.
(c) Cell lines used for manufacturing bi-
ological products—(1) General require-
ments. Cell lines used for manufac-
turing biological products shall be:

(i) Identified by history;
70
(ii) Described with respect to cyto- plates of at least two agar media. No less
genetic characteristics and than 1.0 ml. of sample shall be inoculated
tumorigenicity; into each of four tubes containing 10 ml. of
a semisolid broth medium. The media shall
(iii) Characterized with respect to in be such as have been shown to be capable of
vitro growth characteristics and life detecting known Mycoplasma and each test
potential; and shall include control cultures of at least two
(iv) Tested for the presence of detect- known strains of Mycoplasma, one of which
able microbial agents. must be M. pneumoniae. One half of the
(2) Tests. Tests that are necessary to plates and two tubes of broth shall be incu-
assure the safety, purity, and potency bated aerobically at 36 °C ±1 °C and the re-
maining plates and tubes shall be incubated
of a product may be required by the Di- anaerobically at 36 °C ±1 °C in an environ-
rector, Center for Biologics Evaluation ment of 5–10 percent CO2 in N2. Aerobic incu-
and Research or the Director, Center bation shall be for a period of no less than 14
for Drug Evaluation and Research. days and the broth in the two tubes shall be
(3) Applicability. This paragraph ap- tested after 3 days and 14 days, at which
plies to diploid and nondiploid cell times 0.5 ml. of broth from each of the two
lines. Primary cell cultures that are tubes shall be combined and subinoculated
on to no less than 4 additional plates and in-
not subcultivated and primary cell cul-
cubated aerobically. Anaerobic incubation
tures that are subsequently subcul- shall be for no less than 14 days and the
tivated for only a very limited number broth in the two tubes shall be tested after 3
of population doublings are not subject days and 14 days, at which times 0.5 ml. of
to the provisions of this paragraph (c). broth from each of the two tubes shall be
(d) Records. The records appropriate combined and subinoculated onto no less
for cultures under this section shall be than four additional plates and incubated
prepared and maintained as required by anaerobically. All inoculated plates shall be
incubated for no less than 14 days, at which
the applicable provisions of §§ 211.188 time observation for growth of Mycoplasma
and 211.194 of this chapter. shall be made at a magnification of no less
[38 FR 32056, Nov. 20, 1973, as amended at 51 than 300 × . If the Dienes Methylene Blue-
FR 44453, Dec. 10, 1986; 55 FR 11013, Mar. 26, Azure dye or an equivalent staining proce-
1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, dure is used, no less than a one square cm.
Mar. 24, 2005] plug of the agar shall be excised from the in-
oculated area and examined for the presence
of Mycoplasma. The presence of the Myco-
Subpart C [Reserved] plasma shall be determined by comparison of
the growth obtained from the test samples
§§ 610.20–610.21 [Reserved] with that of the control cultures, with re-
spect to typical colonial and microscopic
Subpart D—Mycoplasma morphology. The virus pool is satisfactory
for vaccine manufacture if none of the tests
§ 610.30 Test for Mycoplasma. on the samples show evidence of the presence
of Mycoplasma.
Except as provided otherwise in this
subchapter, prior to clarification or fil-
FR 16685, Apr. 6, 1998]
tration in the case of live virus vac-
cines produced from in vitro living cell
cultures, and prior to inactivation in Subpart E—Testing Requirements
the case of inactivated virus vaccines for Relevant Transfusion-Trans-
produced from such living cell cul- mitted Infections
tures, each virus harvest pool and con-
trol fluid pool shall be tested for the § 610.39 Definitions.
presence of Mycoplasma, as follows: The definitions set out in § 630.3 of
this chapter apply to this subpart.
Samples of the virus for this test shall be
stored either (1) between 2 and 8 °C for no [80 FR 29896, May 22, 2015]
longer than 24 hours, or (2) at ¥20 °C or
lower if stored for longer than 24 hours. The § 610.40 Test requirements.
test shall be performed on samples of the
(a) Human blood and blood components.
viral harvest pool and on control fluid pool
obtained at the time of viral harvest, as fol- Except as specified in paragraphs (c)
and (d) of this section, you, an estab-
lows: No less than 2.0 ml. of each sample

shall be inoculated in evenly distributed lishment that collects blood and blood
amounts over the surface of no less than 10 components for transfusion or for use
71
§ 610.40 21 CFR Ch. I (4–1–20 Edition)
in manufacturing a product, including in § 630.3(h)(1)(viii) through (x) of this

donations intended as a component of, chapter (CJD, vCJD, malaria) and
or used to manufacture, a medical de- § 630.3(h)(2) of this chapter (other trans-
vice, must comply with the following fusion-transmitted infections):
requirements: (i) You must test for evidence of in-
(1) Test each donation for evidence of fection when the following conditions
infection due to the relevant trans- are met:
fusion-transmitted infections described (A) A test(s) for the relevant trans-
in § 630.3(h)(1)(i) through (iii) of this fusion-transmitted infection is li-
chapter (HIV, HBV, and HCV). censed, approved or cleared by FDA for
(2) Test each donation for evidence of use as a donor screening test and is
infection due to the relevant trans- available for such use; and
fusion-transmitted infections described (B) Testing for the relevant trans-
in § 630.3(h)(1)(iv) through (vii) of this fusion-transmitted infection is nec-
chapter (HTLV, syphilis, West Nile essary to reduce adequately and appro-
virus, and Chagas disease). The fol- priately the risk of transmission of the
lowing exceptions apply: relevant transfusion-transmitted infec-
(i) To identify evidence of infection tion by blood, or blood component, or
with syphilis in donors of Source Plas- blood derivative product manufactured
ma, you must test donors for evidence from the collected blood or blood com-
of such infection in accordance with ponent.
§ 640.65(b) of this chapter, and not under (ii) You must perform this testing on
this section. each donation, unless one of the fol-
(ii) You are not required to test dona- lowing exceptions applies:
tions of Source Plasma for evidence of (A) Testing of each donation is not
infection due to the relevant trans- necessary to reduce adequately and ap-
fusion-transmitted infections described propriately the risk of transmission of
in § 630.3(h)(1)(iv), (vi), and (vii) of this such infection by blood, blood compo-
chapter (HTLV, West Nile virus, and nent, or blood derivative product man-
Chagas disease). ufactured from the collected blood or
(iii) For each of the relevant trans- blood component. When evidence re-
fusion-transmitted infections described lated to the risk of transmission of
in § 630.3(h)(1)(iv) through (vii) of this such infection supports this determina-
chapter (HTLV, syphilis, West Nile tion, you may adopt an adequate and
virus, and Chagas disease): appropriate alternative testing proce-
(A) If, based on evidence related to dure that has been found acceptable for
the risk of transmission of that rel- this purpose by FDA.
evant transfusion-transmitted infec- (B) Testing of each donation is not
tion, testing each donation is not nec- necessary to reduce adequately and ap-
essary to reduce adequately and appro- propriately the risk of transmission of
priately the risk of transmission of such infection by blood, blood compo-
such infection by blood or a blood com- nent, or blood derivative product man-
ponent, you may adopt an adequate ufactured from the collected blood or
and appropriate alternative testing blood component. When evidence re-
procedure that has been found accept- lated to the risk of transmission of
able for this purpose by FDA. such infection supports this determina-
(B) If, based on evidence related to tion, you may stop such testing in ac-
the risk of transmission of that rel- cordance with procedures found accept-
evant transfusion-transmitted infec- able for this purpose by FDA.
tion, testing previously required for (4) Evidence related to the risk of
that infection is no longer necessary to transmission of a relevant transfusion-
reduce adequately and appropriately transmitted infection that would sup-
the risk of transmission of such infec- port a determination that testing is
tion by blood or a blood component, not necessary, or that testing of each
you may stop such testing in accord- donation is not necessary, to reduce
ance with procedures found acceptable adequately and appropriately the risk
for this purpose by FDA. of transmission of such infection by
(3) For each of the relevant trans- blood or blood component, as described
fusion-transmitted infections described in paragraphs (a)(2)(iii)(A) and (B) of
72
this section, or by blood, blood compo- nation must also have the following
nent, or blood derivative, as described label, as appropriate:
in paragraphs (a)(3)(ii)(A) and (B) of
Donor Testing Status Label
this section, includes epidemiological
or other scientific evidence. It may in- Tests negative Label as required under § 606.121
clude evidence related to the Tested negative within ‘‘DONOR TESTED WITHIN THE
the last 30 days LAST 30 DAYS’’
seasonality or geographic limitation of
risk of transmission of such infection (2) Medical device. (i) You are not re-
by blood or blood component, or other quired to test donations of human
information related to when and how a blood or blood components intended
donation is at risk of transmitting a solely as a component of, or used to
relevant transfusion-transmitted infec- prepare, a medical device for evidence
tion. It may also include evidence re- of infection due to the relevant trans-
lated to the effectiveness of manufac- fusion-transmitted infections listed in
turing steps (for example, the use of § 630.3(h)(iv) of this chapter unless the
pathogen reduction technology) that final device contains viable leukocytes.
reduce the risk of transmission of the (ii) Donations of human blood and
relevant transfusion-transmitted infec- blood components intended solely as a
tion by blood, blood components, or component of, or used to prepare, a
blood derivatives, as applicable. medical device must be labeled ‘‘Cau-
(b) Testing using one or more licensed, tion: For Further Manufacturing Use
approved, or cleared screening tests. To as a Component of, or to Prepare, a
perform testing for evidence of infec- Medical Device.’’
tion due to relevant transfusion-trans- (3) Samples. You are not required to
mitted infections as required in para- test samples of blood, blood compo-
graph (a) of this section, you must use nents, plasma, or sera if used or dis-
screening tests that FDA has licensed, tributed for clinical laboratory testing
approved, or cleared for such use, in ac- or research purposes and not intended
cordance with the manufacturer’s infor administration to humans or in the
structions. You must perform one or manufacture of a product.
more such tests as necessary to reduce (d) Autologous donations. You, an es-
adequately and appropriately the risk tablishment that collects human blood
of transmission of relevant trans- or blood components from autologous
fusion-transmitted infections. donors, or you, an establishment that
(c) Exceptions to testing for dedicated is a consignee of a collecting establish-
donations, medical devices, and sam- ment, are not required to test dona-
ples.—(1) Dedicated donations. (i) You tions of human blood or blood compo-
must test donations of human blood nents from autologous donors for evi-
and blood components from a donor dence of infection due to relevant
whose donations are dedicated to and transfusion-transmitted infections list-
used solely by a single identified re- ed in paragraph (a) of this section, ex-
cipient under paragraphs (a), (b), and cept:
(e) of this section; except that, if the (1) If you allow any autologous dona-
donor makes multiple donations for a tion to be used for allogeneic trans-
single identified recipient, you may fusion, you must assure that all
perform such testing only on the first autologous donations are tested under
donation in each 30-day period. If an this section.
untested dedicated donation is made (2) If you ship autologous donations
available for any use other than trans- to another establishment that allows
fusion to the single, identified recipi- autologous donations to be used for
ent, then this exemption from the test- allogeneic transfusion, you must as-
ing required under this section no sure that all autologous donations
longer applies. shipped to that establishment are test-
(ii) Each donation must be labeled as ed under this section.
required under § 606.121 of this chapter (3) If you ship autologous donations
and with a label entitled ‘‘INTENDED to another establishment that does not
RECIPIENT INFORMATION LABEL’’ allow autologous donations to be used
containing the name and identifying for allogeneic transfusion, you must
information of the recipient. Each do- assure that, at a minimum, the first
73
§ 610.40 21 CFR Ch. I (4–1–20 Edition)
donation in each 30-day period is tested fusion-transmitted infections des-

under this section. ignated in paragraph (a) of this section
(4) Each autologous donation must be may be released or shipped prior to
labeled as required under § 606.121 of completion of testing in the following
this chapter and with the following circumstances provided that you label
label, as appropriate: the blood or blood components under
Donor Testing Status Label § 606.121(h) of this chapter, you com-
plete the tests for evidence of infection
Untested ‘‘DONOR UNTESTED’’ due to relevant transfusion-trans-
Tests negative Label as required under § 606.121
Reactive on current col- ‘‘BIOHAZARD’’ legend in mitted infections as soon as possible
lection/reactive in the § 610.40(h)(2)(ii)(B) after release or shipment, and that you
last 30 days
Tested negative within ‘‘DONOR TESTED WITHIN THE
provide the results promptly to the
the last 30 days LAST 30 DAYS’’ consignee:
(1) Only in appropriately documented
(e) Further testing. You must further medical emergency situations; or
test each donation, including (2) For further manufacturing use as
autologous donations, found to be reac- approved in writing by FDA.
tive by a donor screening test per- (h) Restrictions on shipment or use—(1)
formed under paragraphs (a) and (b) of Reactive screening test. You must not
this section using a licensed, approved, ship or use human blood or blood com-
or cleared supplemental test, when
ponents that have a reactive screening
available. If no such supplemental test
test for evidence of infection due to
is available, you must perform one or
more licensed, approved, or cleared relevant transfusion-transmitted infec-
tests as adequate and appropriate to tion(s) designated in paragraph (a) of
provide additional information con- this section or that are collected from
cerning the reactive donor’s infection a donor with a previous record of a re-
status. Except: active screening test for evidence of in-
(1) For autologous donations: fection due to relevant transfusion-
(i) You must further test under this transmitted infection(s) designated in
section, at a minimum, the first reac- paragraph (a) of this section, except as
tive donation in each 30 calendar day provided in paragraphs (h)(2)(i) through
period; or (h)(2)(vii) of this section.
(ii) If you have a record for that (2) Exceptions. (i) You may ship or use
donor of a positive result on further blood or blood components intended for
testing performed under this section, autologous use, including reactive do-
you do not have to further test an nations, as described in paragraph (d)
autologous donation. of this section.
(2) You are not required to perform (ii) You must not ship or use human
further testing of a donation found to blood or blood components that have a
be reactive by a treponemal donor reactive screening test for evidence of
screening test for syphilis. infection due to a relevant transfusion-
(f) Testing responsibility. Required transmitted infection(s) designated in
testing under this section, must be per- paragraph (a) of this section or that
formed by a laboratory registered in
are collected from a donor deferred
accordance with part 607 of this chap-
under § 610.41(a) unless you meet the
ter and either certified to perform such
following conditions:
testing on human specimens under the
Clinical Laboratory Improvement (A) Except for autologous donations,
Amendments of 1988 (42 U.S.C. 263a) you must obtain from FDA written ap-
under 42 CFR part 493 or has met equiv- proval for the shipment or use;
alent requirements as determined by (B) You must appropriately label
the Centers for Medicare and Medicaid such blood or blood components as re-
Services in accordance with those pro- quired under § 606.121 of this chapter,
visions. and with the ‘‘BIOHAZARD’’ legend;
(g) Release or shipment prior to testing. (C) Except for autologous donations,
Human blood or blood components that you must label such human blood and
are required to be tested for evidence blood components as reactive for the
of infection due to relevant trans- appropriate screening test for evidence
74
of infection due to the identified rel- ing test for syphilis as required under
evant transfusion-transmitted infec- paragraph (a) of this section if, the do-
tion(s); nation is further tested by an adequate
(D) If the blood or blood components and appropriate test which dem-
are intended for further manufacturing onstrates that the reactive screening
use into injectable products, you must test is a biological false positive. You
include a statement on the container must label the blood or blood compo-
label indicating the exempted use spe- nents with both test results.
cifically approved by FDA. (vii) You may use Source Plasma
(E) Each blood or blood component from a donor who tests reactive by a
with a reactive screening test and in- screening test for syphilis as required
tended solely as a component of, or under § 640.65(a)(2)(ii) and (b)(1)(i) of
used to prepare a medical device, must this chapter, if the donor meets the re-
be labeled with the following label, as quirements of § 640.65(b)(2)(i) through
appropriate: (b)(2)(iv) of this chapter.
Type of Medical Device Label [66 FR 31162, June 11, 2001, as amended at 77
A medical device other ‘‘Caution: For Further Manufac- FR 18, Jan. 3, 2012; 80 FR 29896, May 22, 2015]
than an in vitro diag- turing Use as a Component of a
nostic reagent Medical Device For Which There § 610.41 Donor deferral.
Are No Alternative Sources’’
An in vitro diagnostic ‘‘Caution: For Further Manufac- (a) You, an establishment that col-
reagent turing Into In Vitro Diagnostic Re- lects human blood or blood compo-
agents For Which There Are No nents, must defer donors testing reac-
Alternative Sources’’
tive by a screening test for evidence of
(iii) The restrictions on shipment or infection due to a relevant transfusion-
use do not apply to samples of blood, transmitted infection(s) under
blood components, plasma, or sera if § 610.40(a), from future donations of
used or distributed for clinical labora- human blood and blood components,
tory testing or research purposes, and except:
not intended for administration in hu- (1) You are not required to defer a
mans or in the manufacture of a prod- donor who tests reactive for anti-HBc
uct. or anti-HTLV, types I and II, on only
(iv) You may use human blood or one occasion. However, you must defer
blood components from a donor with a the donor if further testing for HBV or
previous record of a reactive screening HTLV has been performed under
test(s) for evidence of infection due to § 610.40(e) and the donor is found to be
a relevant transfusion-transmitted in- positive, or if a second, licensed,
fection(s) designated in paragraph (a) cleared, or approved screening test for
of this section, if: HBV or HTLV has been performed on
(A) At the time of donation, the the same donation under § 610.40(a) and
donor is shown or was previously is reactive, or if the donor tests reac-
shown to be eligible by a requalifica- tive for anti-HBc or anti-HTLV, types I
tion method or process found accept- and II, on more than one occasion;
able for such purposes by FDA under (2) A deferred donor who tests reac-
§ 610.41(b); and tive for evidence of infection due to a
(B) tests performed under paragraphs relevant transfusion-transmitted infec-
(a) and (b) of this section are nonreac- tion(s) under § 610.40(a) may serve as a
tive. donor for blood or blood components
(v) Anti-HBc reactive donations, oth- shipped or used under § 610.40(h)(2)(ii);
erwise nonreactive when tested as re- (3) A deferred donor who showed evi-
quired under this section, may be used dence of infection due to hepatitis B
for further manufacturing into plasma surface antigen (HBsAg) when pre-
derivatives without prior FDA ap- viously tested under § 610.40(a), (b), and
proval or a ‘‘BIOHAZARD’’ legend as (e) subsequently may donate Source
required under paragraphs (h)(2)(ii)(A) Plasma for use in the preparation of
and (h)(2)(ii)(B) of this section. Hepatitis B Immune Globulin (Human)
(vi) You may use human blood or provided the current donation tests
blood components, excluding Source nonreactive for HBsAg and the donor is
Plasma, that test reactive by a screen- otherwise determined to be eligible;
75
§ 610.42 21 CFR Ch. I (4–1–20 Edition)
(4) A deferred donor, who otherwise is § 610.44 Use of reference panels by

determined to be eligible for donation manufacturers of test kits.
and tests reactive for anti-HBc or for (a) When available and appropriate to
evidence of infection due to HTLV, verify acceptable sensitivity and speci-
types I and II, may serve as a donor of ficity, you, a manufacturer of test kits,
Source Plasma; must use a reference panel you obtain
(5) A deferred donor who tests reac- from FDA or from an FDA designated
tive for a relevant transfusion-trans- source to test lots of the following
mitted infections(s) under § 610.40(a), products. You must test each lot of the
may serve as an autologous donor following products, unless FDA informs
under § 610.40(d). you that less frequent testing is appro-
(b) A deferred donor subsequently priate, based on your consistent prior
may be found to be eligible as a donor production of products of acceptable
of blood or blood components by a re- sensitivity and specificity:
qualification method or process found (1) A test kit approved for use in test-
acceptable for such purposes by FDA. ing donations of human blood and
Such a donor is considered no longer blood components for evidence of infec-
deferred. tion due to relevant transfusion-trans-
mitted infections under § 610.40(a); and
(c) You must comply with the re-
(2) Human immunodeficiency virus
quirements under §§ 610.46 and 610.47
(HIV) test kit approved for use in the
when a donor tests reactive by a diagnosis, prognosis, or monitoring of
screening test for HIV or HCV required this relevant transfusion-transmitted
under § 610.40(a) and (b), or when you infection.
are aware of other reliable test results (b) You must not distribute a lot that
or information indicating evidence of is found to be not acceptable for sensi-
HIV or HCV infection. tivity and specificity under § 610.44(a).
[66 FR 31164, June 11, 2001, as amended at 72 FDA may approve an exception or al-
FR 48798, Aug. 24, 2007; 80 FR 29897, May 22, ternative to this requirement. Appli-
2015] cants must submit such requests in
writing. However, in limited cir-
§ 610.42 Restrictions on use for further cumstances, such requests may be
manufacture of medical devices. made orally and permission may be
(a) In addition to labeling require- given orally by FDA. Oral requests and
ments in subchapter H of this chapter, approvals must be promptly followed
when a medical device contains human by written requests and written ap-
blood or a blood component as a com- provals.
ponent of the final device, and the [66 FR 31164, June 11, 2001, as amended at 80
human blood or blood component was FR 29897, May 22, 2015]
found to be reactive by a screening test
performed under § 610.40(a) and (b), then § 610.46 Human immunodeficiency
virus (HIV) ‘‘lookback’’ require-
you must include in the device labeling ments.
a statement of warning indicating that
the product was manufactured from a (a) If you are an establishment that
donation found to be reactive by a collects Whole Blood or blood compo-
screening test for evidence of infection nents, including Source Plasma and
due to the identified relevant trans- Source Leukocytes, you must estab-
fusion-transmitted infection(s). lish, maintain, and follow an appro-
priate system for the following actions:
(b) FDA may approve an exception or
(1) Within 3 calendar days after a
alternative to the statement of warn-
donor tests reactive for evidence of
ing required in paragraph (a) of this
human immunodeficiency virus (HIV)
section based on evidence that the re-
infection when tested under § 610.40(a)
activity of the human blood or blood
and (b) or when you are made aware of
component in the medical device pre-
other reliable test results or informa-
sents no significant health risk
tion indicating evidence of HIV infec-
through use of the medical device. tion, you must review all records re-
[66 FR 31164, June 11, 2001, as amended at 80 quired under § 606.160(d) of this chapter,
FR 29897, May 22, 2015] to identify blood and blood components
76
previously donated by such a donor. graph (a)(2) of this section or the re-
For those identified blood and blood sults of the reactive screening test if
components collected: further testing is not available, or if
(i) Twelve months and less before the under an IND or IDE, exempted for
donor’s most recent nonreactive such use by FDA.
screening tests, or (b) If you are a consignee of Whole
(ii) Twelve months and less before Blood or blood components, including
the donor’s reactive direct viral detec- Source Plasma and Source Leukocytes,
tion test, e.g., nucleic acid test or HIV you must establish, maintain, and fol-
p24 antigen test, and nonreactive anti- low an appropriate system for the fol-
body screening test, whichever is the lowing actions:
lesser period, you must: (1) You must quarantine all pre-
(A) Quarantine all previously col- viously collected in-date blood and
lected in-date blood and blood compo- blood components identified under
nents identified under paragraph (a)(1) paragraph (a)(1) of this section, except
of this section if intended for use in an- pooled blood components intended sole-
other person or for further manufac- ly for further manufacturing into prod-
ture into injectable products, except ucts that are manufactured using vali-
pooled blood components intended sole- dated viral clearance procedures, when
ly for further manufacturing into prod- notified by the collecting establish-
ucts that are manufactured using vali- ment.
dated viral clearance procedures; and
(2) You must release from quar-
(B) Notify consignees to quarantine
antine, destroy, or relabel quarantined
all previously collected in-date blood
in-date blood and blood components
and blood components identified under
consistent with the results of the fur-
paragraph (a)(1) of this section if in-
tended for use in another person or for ther testing performed under para-
further manufacture into injectable graph (a)(2) of this section, or the re-
products, except pooled blood compo- sults of the reactive screening test if
nents intended solely for further manu- further testing is not available, or if
facturing into products that are manu- under an IND or IDE, is exempted for
factured using validated viral clear- such use by FDA.
ance procedures; (3) When further testing for HIV is
(2) You must perform further testing positive or when the screening test is
for HIV as required under § 610.40(e) of reactive and further testing is not
this chapter on the reactive donation. available, or if under an IND or IDE is
(3) You must notify consignees of the exempted for such use by FDA, you
results of further testing for HIV, or must notify transfusion recipients of
the results of the reactive screening previous collections of blood and blood
test if further testing under paragraph components at increased risk of trans-
(a)(2) of this section is not available, or mitting HIV infection, or the recipi-
if under an investigational new drug ent’s physician of record, of the need
application (IND) or investigational de- for recipient HIV testing and coun-
vice exemption (IDE), is exempted for seling. You must notify the recipient’s
such use by FDA, within 45 calendar physician of record or a legal rep-
days after the donor tests reactive for resentative or relative if the recipient
evidence of HIV infection under is a minor, deceased, adjudged incom-
§ 610.40(a) and (b) of this chapter. Noti- petent by a State court, or, if the re-
fication of consignees must include the cipient is competent but State law per-
test results for blood and blood compo- mits a legal representative or relative
nents identified under paragraph (a)(1) to receive information on behalf of the
of this section that were previously recipient. You must make reasonable
collected from donors who later test re- attempts to perform the notification
active for evidence of HIV infection. within 12 weeks after receiving the re-
(4) You must release from quar- sults of further testing for evidence of
antine, destroy, or relabel quarantined HIV infection from the collecting es-
in-date blood and blood components, tablishment, or after receiving the do-
consistent with the results of the fur- nor’s reactive screening test result for
ther testing performed under para- HIV if further testing is not available,
77
§ 610.47 21 CFR Ch. I (4–1–20 Edition)
or if under an IND or IDE is exempted (2) You must perform further testing
for such use by FDA. for HCV as required under § 610.40(e) on
(c) Actions under this section do not the reactive donation.
constitute a recall as defined in § 7.3 of (3) You must notify consignees of the
this chapter. results of further testing for HCV, or
[72 FR 48799, Aug. 24, 2007, as amended at 80 the results of the reactive screening
FR 29897, May 22, 2015] test if further testing is not available,
or if under an investigational new drug
§ 610.47 Hepatitis C virus (HCV) application (IND) or investigational de-
‘‘lookback’’ requirements. vice exemption (IDE), is exempted for
(a) If you are an establishment that such use by FDA, within 45 calendar
collects Whole Blood or blood compo- days after the donor tests reactive for
nents, including Source Plasma and evidence of HCV infection under
Source Leukocytes, you must estab- § 610.40(a) and (b). Notification of con-
lish, maintain, and follow an appro- signees must include the test results
priate system for the following actions: for blood and blood components identi-
(1) Within 3 calendar days after a fied under paragraph (a)(1) of this sec-
donor tests reactive for evidence of tion that were previously collected
hepatitis C virus (HCV) infection when from donors who later test reactive for
tested under § 610.40(a) and (b) of this evidence of HCV infection.
chapter or when you are made aware of (4) You must release from quar-
other reliable test results or informa- antine, destroy, or relabel quarantined
tion indicating evidence of HCV infec- in-date blood and blood components
tion, you must review all records re- consistent with the results of the fur-
quired under § 606.160(d) of this chapter, ther testing performed under para-
to identify blood and blood components graph (a)(2) of this section, or the re-
previously donated by such a donor. sults of the reactive screening test if
For those identified blood and blood further testing is not available, or if
components collected: under an IND or IDE, exempted for
(i) Twelve months and less before the such use by FDA.
donor’s most recent nonreactive (b) If you are a consignee of Whole
screening tests, or Blood or blood components, including
(ii) Twelve months and less before Source Plasma or Source Leukocytes,
the donor’s reactive direct viral detec- you must establish, maintain, and fol-
tion test, e.g., nucleic acid test and low an appropriate system for the fol-
nonreactive antibody screening test, lowing actions:
whichever is the lesser period, you (1) You must quarantine all pre-
must: viously collected in-date blood and
(A) Quarantine all previously col- blood components identified under
lected in-date blood and blood compo- paragraph (a)(1) of this section, except
nents identified under paragraph (a)(1) pooled blood components intended sole-
of this section if intended for use in an- ly for further manufacturing into prod-
other person or for further manufac- ucts that are manufactured using vali-
ture into injectable products, except dated viral clearance procedures, when
pooled blood components intended sole- notified by the collecting establish-
ly for further manufacturing into prod- ment.
ucts that are manufactured using vali- (2) You must release from quar-
dated viral clearance procedures; and antine, destroy, or relabel quarantined
(B) Notify consignees to quarantine in-date blood and blood components,
all previously collected in-date blood consistent with the results of the fur-
and blood components identified under ther testing performed under para-
paragraph (a)(1) of this section if in- graph (a)(2) of this section, or the re-
tended for use in another person or for sults of the reactive screening test if
further manufacture into injectable further testing is not available, or if
products, except pooled blood compo- under an IND or IDE, is exempted for
nents intended solely for further manu- such use by FDA.
facturing into products that are manu- (3) When the further testing for HCV
factured using validated viral clear- is positive or when the screening test is
ance procedures; reactive and further testing is not
78
available, or if under an IND or IDE, is plication or supplement to the applica-

exempted for such use by FDA, you tion;
must notify transfusion recipients of (2) Removal from animals or humans;
previous collections of blood and blood (3) Extraction;
components at increased risk of trans- (4) Solution;
mitting HCV infection, or the recipi- (5) Cessation of growth;
ent’s physician of record, of the need (6) Final sterile filtration of a bulk
for recipient HCV testing and coun- solution;
seling. You must notify the recipient’s (7) Manufacture as described in part
physician of record or a legal rep- 660 of this chapter; or
resentative or relative if the recipient (8) Other specific manufacturing ac-
is a minor, adjudged incompetent by a tivity described in a biologics license
State court, or if the recipient is com- application or supplement to the bio-
petent but State law permits a legal logics license application.
representative or relative to receive in- (c) Determining the date of manufac-
formation on behalf of the recipient. ture for Whole Blood and blood compo-
You must make reasonable attempts to nents. (1) The date of manufacture for
perform the notification within 12
Whole Blood and blood components
weeks after receiving the results of fur-
must be one of the following, which-
ther testing for evidence of HCV infec-
ever is applicable:
tion from the collecting establishment,
(i) Collection date and/or time;
or after receiving the donor’s reactive
screening test result for HCV if further (ii) Irradiation date;
testing is not available, or if under an (iii) The time the red blood cell prod-
IND or IDE, is exempted for such use uct was removed from frozen storage
by FDA. for deglycerolization;
(c) Actions under this section do not (iv) The time the additive or reju-
constitute a recall as defined in § 7.3 of venation solution was added;
this chapter. (v) The time the product was entered
for washing or removing plasma (if pre-
[72 FR 48799, Aug. 24, 2007, as amended at 80 pared in an open system);
FR 29897, May 22, 2015]
(vi) As specified in the instructions
§ 610.48 [Reserved] for use by the blood collection, proc-
essing, and storage system approved or
cleared for such use by FDA; or
Subpart F—Dating Period (vii) As approved by the Director,
Limitations Center for Biologics Evaluation and
§ 610.50 Date of manufacture for bio- Research, in a biologics license appli-
logical products. cation or supplement to the applica-
tion.
(a) When the dating period begins. The (2) For licensed Whole Blood and
dating period for a product must begin blood components, the date of manu-
on the date of manufacture as de- facture must be identified in the ap-
scribed in paragraphs (b) and (c) of this proved biologics license application or
section. The dating period for a com- supplement to the application.
bination of two or more products must
be no longer than the dating period of [81 FR 26691, May 4, 2016]
the component with the shortest dat-
ing period. § 610.53 Dating periods for Whole
(b) Determining the date of manufac- Blood and blood components.
ture for biological products other than (a) General. Dating periods for Whole
Whole Blood and blood components. The Blood and blood components are speci-
date of manufacture for biological fied in the table in paragraph (b) of this
products, other than Whole Blood and section.
blood components, must be identified (b) Table of dating periods. In using
in the approved biologics license appli- the table in this paragraph, when a
cation as one of the following, which- product in column A is stored at the
ever is applicable: The date of: storage temperature prescribed in col-
(1) Potency test or other specific test umn B, storage of a product must not
as described in a biologics license ap- exceed the dating period specified in
79
§ 610.53 21 CFR Ch. I (4–1–20 Edition)
column C, unless a different dating pe- for such use by FDA. Container labels
riod is specified in the instructions for for each product must include the rec-
use by the blood collection, processing ommended storage temperatures.
and storage system approved or cleared
WHOLE BLOOD AND BLOOD COMPONENTS STORAGE TEMPERATURES AND DATING PERIODS
A B C
Product Storage temperature Dating period
Whole Blood
ACD, CPD, CP2D ...................................... Between 1 and 6 °C ................................ 21 days from date of collection.
CPDA–1 ..................................................... do 1 .......................................................... 35 days from date of collection.
Red Blood Cells
ACD, CPD, CP2D ...................................... Between 1 and 6 °C ................................ 21 days from date of collection.
CPDA–1 ..................................................... do ............................................................. 35 days from date of collection.
Additive solutions ...................................... do ............................................................. 42 days from date of collection.
Open system ............................................. do ............................................................. 24 hours after entering bag.
(e.g., deglycerolized, washed) ..................
Deglycerolized in closed system with ad- do ............................................................. 14 days after entering bag.
ditive solution added.
Irradiated ................................................... do ............................................................. 28 days from date of irradiation or origi-
nal dating, whichever is shorter.
Frozen ........................................................ ¥65 °C or colder .................................... 10 years from date of collection.
Platelets
Platelets ..................................................... Between 20 and 24 °C ............................ 5 days from date of collection.

Platelets ..................................................... Other temperatures according to storage As specified in the instructions for use
bag instructions. by the blood collection, processing
and storage system approved or
cleared for such use by FDA.
Plasma
Fresh Frozen Plasma ................................ ¥18 °C or colder .................................... 1 year from date of collection.
Plasma Frozen Within 24 Hours After do ............................................................. 1 year from date of collection.
Phlebotomy.
Plasma Frozen Within 24 Hours After do ............................................................. 1 year from date of collection.
Phlebotomy Held at Room Temperature
Up To 24 Hours After Phlebotomy.
Plasma Cryoprecipitate Reduced .............. do ............................................................. 1 year from date of collection.
Plasma ....................................................... do ............................................................. 5 years from date of collection.
Liquid Plasma ............................................ Between 1 and 6 °C ................................ 5 days from end of Whole Blood dating
period.
Source Plasma (frozen injectable) ............ ¥20 °C or colder .................................... 10 years from date of collection.
Source Plasma Liquid (injectable) ............. 10 °C or colder ........................................ According to approved biologics license
application.
Source Plasma (noninjectable) ................. Temperature appropriate for final prod- 10 years from date of collection.
uct.
Therapeutic Exchange Plasma ................. ¥20 °C or colder .................................... 10 years from date of collection.
Cryoprecipitated AHF
Cryoprecipitated AHF ................................ ¥18 °C or colder .................................... 1 year from date of collection of source
blood or from date of collection of old-
est source blood in pre-storage pool.
Source Leukocytes
Source Leukocytes .................................... Temperature appropriate for final prod- In lieu of expiration date, the collection
uct. date must appear on the label.
1 The abbreviation ‘‘do.’’ for ditto is used in the table to indicate that the previous line is being repeated.
80
[81 FR 26691, May 4, 2016] circumference to permit inspection of
the contents.
Subpart G—Labeling Standards [38 FR 32056, Nov. 20, 1973, as amended at 47
FR 22518, May 25, 1982; 63 FR 66400, Dec. 1,
§ 610.60 Container label. 1998; 67 FR 4907, Feb. 1, 2002]
(a) Full label. The following items
§ 610.61 Package label.
shall appear on the label affixed to
each container of a product capable of The following items shall appear on
bearing a full label: the label affixed to each package con-
(1) The proper name of the product; taining a product:
(a) The proper name of the product;
(2) The name, address, and license
(b) The name, address, and license
number of manufacturer;
number of manufacturer;
(3) The lot number or other lot iden- (c) The lot number or other lot iden-
tification; tification;
(4) The expiration date; (d) The expiration date;
(5) The recommended individual dose, (e) The preservative used and its con-
for multiple dose containers. centration, or if no preservative is used
(6) The statement: ‘‘ ‘Rx only’ ’’ for and the absence of a preservative is a
prescription biologicals. safety factor, the words ‘‘no preserva-
(7) If a Medication Guide is required tive’’;
under part 208 of this chapter, the (f) The number of containers, if more
statement required under § 208.24(d) of than one;
this chapter instructing the authorized (g) The amount of product in the con-
dispenser to provide a Medication tainer expressed as (1) the number of
Guide to each patient to whom the doses, (2) volume, (3) units of potency,
drug is dispensed and stating how the (4) weight, (5) equivalent volume (for
Medication Guide is provided, except dried product to be reconstituted), or
where the container label is too small, (6) such combination of the foregoing
the required statement may be placed as needed for an accurate description of
on the package label. the contents, whichever is applicable;
(b) Package label information. If the (h) The recommended storage tem-
container is not enclosed in a package, perature;
all the items required for a package (i) The words ‘‘Shake Well’’, ‘‘Do not
label shall appear on the container Freeze’’ or the equivalent, as well as
label. other instructions, when indicated by
the character of the product;
(c) Partial label. If the container is ca-
(j) The recommended individual dose
pable of bearing only a partial label,
if the enclosed container(s) is a mul-
the container shall show as a minimum tiple-dose container;
the name (expressed either as the prop- (k) The route of administration rec-
er or common name), the lot number or ommended, or reference to such direc-
other lot identification and the name tions in an enclosed circular;
of the manufacturer; in addition, for (l) Known sensitizing substances, or
multiple dose containers, the rec- reference to an enclosed circular con-
ommended individual dose. Containers taining appropriate information;
bearing partial labels shall be placed in (m) The type and calculated amount
a package which bears all the items re- of antibiotics added during manufac-
quired for a package label. ture;
(d) No container label. If the container (n) The inactive ingredients when a
is incapable of bearing any label, the safety factor, or reference to an en-
items required for a container label closed circular containing appropriate
may be omitted, provided the container information;
is placed in a package which bears all (o) The adjuvant, if present;
the items required for a package label. (p) The source of the product when a
(e) Visual inspection. When the label factor in safe administration;
has been affixed to the container a suf- (q) The identity of each microorga-
ficient area of the container shall re- nism used in manufacture, and, where
main uncovered for its full length or applicable, the production medium and
81
§ 610.62 21 CFR Ch. I (4–1–20 Edition)
the method of inactivation, or ref- the label provided that the name, ad-
erence to an enclosed circular con- dress, and license number of the manu-
taining appropriate information; facturer also appears on the label and
(r) Minimum potency of product ex- the name of the distributor is qualified
pressed in terms of official standard of by one of the following phrases: ‘‘Man-
potency or, if potency is a factor and ufactured for lllll’’, ‘‘Distributed
no U.S. standard of potency has been by llllll’’, ‘‘Manufactured by
prescribed, the words ‘‘No U.S. stand- lllll for lllll’’, ‘‘Manufac-
ard of potency.’’ tured for lllll by llll’’, ‘‘Dis-
(s) The statement: ‘‘ ‘Rx only’ ’’ for tributor: lllll’’, or ‘‘Marketed by
prescription biologicals.
lllll’’. The qualifying phrases
[38 FR 32056, Nov. 20, 1973, as amended at 47 may be abbreviated.
FR 22518, May 25, 1982; 55 FR 10423, Mar. 21,
1990; 67 FR 4907, Feb. 1, 2002] [61 FR 57330, Nov. 6, 1996]
§ 610.62 Proper name; package label; § 610.65 Products for export.

legible type.
Labels on packages or containers of
(a) Position. The proper name of the products for export may be adapted to
product on the package label shall be meet specific requirements of the regu-
placed above any trademark or trade lations of the country to which the
name identifying the product and sym- product is to be exported provided that
metrically arranged with respect to in all such cases the minimum label re-
other printing on the label.
quirements prescribed in § 610.60 are ob-
(b) Prominence. The point size and
served.
typeface of the proper name shall be at
least as prominent as the point size § 610.67 Bar code label requirements.
and typeface used in designating the
trademark and trade name. The con- Biological products must comply
trast in color value between the proper with the bar code requirements at
name and the background shall be at § 201.25 of this chapter. However, the
least as great as the color value be- bar code requirements do not apply to
tween the trademark and trade name devices regulated by the Center for
and the background. Typography, lay- Biologics Evaluation and Research or
out, contrast, and other printing fea- to blood and blood components in-
tures shall not be used in a manner tended for transfusion. For blood and
that will affect adversely the promi- blood components intended for trans-
nence of the proper name. fusion, the requirements at
(c) Legible type. All items required to § 606.121(c)(13) of this chapter apply in-
be on the container label and package stead.
label shall be in legible type. ‘‘Legible
type’’ is type of a size and character [69 FR 9171, Feb. 26, 2004]
which can be read with ease when held
in a good light and with normal vision. § 610.68 Exceptions or alternatives to
labeling requirements for biological
§ 610.63 Divided manufacturing re- products held by the Strategic Na-
sponsibility to be shown. tional Stockpile.
If two or more licensed manufactur- (a) The appropriate FDA Center Di-
ers participate in the manufacture of a rector may grant an exception or alter-
biological product, the name, address, native to any provision listed in para-
and license number of each must ap- graph (f) of this section and not explic-
pear on the package label, and on the itly required by statute, for specified
label of the container if capable of lots, batches, or other units of a bio-
bearing a full label. logical product, if the Center Director
[64 FR 56453, Oct. 20, 1999] determines that compliance with such
labeling requirement could adversely
§ 610.64 Name and address of dis- affect the safety, effectiveness, or
tributor. availability of such product that is or
The name and address of the dis- will be included in the Strategic Na-
tributor of a product may appear on tional Stockpile.
82
(b)(1)(i) A Strategic National Stock- and effective use of the product, given
pile official or any entity that manu- the anticipated circumstances of use.
factures (including labeling, packing, (e) If you are a sponsor receiving a
relabeling, or repackaging), distrib- grant of a request for an exception or
utes, or stores a biological product alternative to the labeling require-
that is or will be included in the Stra- ments under this section:
tegic National Stockpile may submit, (1) You need not submit a supplement
with written concurrence from a Stra- under § 601.12(f)(1) through (f)(2) of this
tegic National Stockpile official, a chapter; however,
written request for an exception or al- (2) You must report any grant of a re-
ternative described in paragraph (a) of quest for an exception or alternative
this section to the Center Director. under this section as part of your an-
(ii) The Center Director may grant nual report under § 601.12(f)(3) of this
an exception or alternative described chapter.
in paragraph (a) of this section on his (f) The Center Director may grant an
or her own initiative. exception or alternative under this sec-
(2) A written request for an exception tion to the following provisions of this
or alternative described in paragraph chapter, to the extent that the require-
(a) of this section must: ments in these provisions are not ex-
(i) Identify the specified lots, plicitly required by statute:
batches, or other units of the biological (1) § 610.60;
product that would be subject to the (2) § 610.61(c) and (e) through (r);
exception or alternative; (3) § 610.62;
(ii) Identify the labeling provision(s) (4) § 610.63;
listed in paragraph (f) of this section (5) § 610.64;
that are the subject of the exception or (6) § 610.65; and
alternative request; (7) § 312.6.
(iii) Explain why compliance with
such labeling provision(s) could ad- [72 FR 73600, Dec. 28, 2007]
versely affect the safety, effectiveness,
or availability of the specified lots, PART 630—REQUIREMENTS FOR
batches, or other units of the biological BLOOD AND BLOOD COMPO-
product that are or will be included in NENTS INTENDED FOR TRANS-
the Strategic National Stockpile; FUSION OR FOR FURTHER MANU-
(iv) Describe any proposed safeguards FACTURING USE
or conditions that will be implemented
so that the labeling of the product in- Subpart A—General Provisions
cludes appropriate information nec-
essary for the safe and effective use of 630.1 Purpose and scope.
the product, given the anticipated cir- 630.3 Definitions.
cumstances of use of the product;
(v) Provide a draft of the proposed la- Subpart B—Donor Eligibility Requirements
beling of the specified lots, batches, or 630.5 Medical supervision.
other units of the biological product 630.10 General donor eligibility require-
subject to the exception or alternative; ments.
and 630.15 Donor eligibility requirements spe-
(vi) Provide any other information cific to Whole Blood, Red Blood Cells and
Plasma collected by apheresis.
requested by the Center Director in
630.20 Exceptions for certain ineligible do-
support of the request. nors.
(c) The Center Director must respond 630.25 Exceptions from certain donor eligi-
in writing to all requests under this bility requirements for infrequent plas-
section. ma donors.
(d) A grant of an exception or alter- 630.30 Donation suitability requirements.
native under this section will include 630.35 Requalification of previously deferred
any safeguards or conditions deemed donors.
appropriate by the Center Director so
Subpart C—Donor Notification
that the labeling of product subject to
the exception or alternative includes 630.40 Requirements for notifying deferred

the information necessary for the safe donors.
83
§ 630.1 21 CFR Ch. I (4–1–20 Edition)
AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, nors weighing more than 175 pounds) in
360, 371; 42 U.S.C. 216, 262, 264. the past year.
SOURCE: 66 FR 31176, June 11, 2001, unless (f) Intimate contact with risk for a rel-
otherwise noted. evant transfusion-transmitted infection
means having engaged in an activity
Subpart A—General Provisions that could result in the transfer of po-
tentially infectious body fluids from
SOURCE: 80 FR 29898, May 22, 2015, unless one person to another.
otherwise noted. (g) Physician substitute means a
trained and qualified person(s) who is:
§ 630.1 Purpose and scope. (1) A graduate of an education pro-
(a) What is the purpose of subparts A, gram for health care workers that in-
B, and C of this part? The purpose of cludes clinical training;
these subparts, together with §§ 610.40 (2) Currently licensed or certified as
and 610.41 of this chapter, is to provide a health care worker in the jurisdiction
certain minimum criteria for each do- where the collection establishment is
nation of blood and blood components, located;
for: (3) Currently certified in
(1) Determining the eligibility of a cardiopulmonary resuscitation; and
donor of blood and blood components; (4) Trained and authorized under
(2) Determining the suitability of the State law, and/or local law when appli-
donation of blood and blood compo- cable, to perform the specified func-
nents; and tions under the direction of the respon-
(3) Notifying a donor who is deferred sible physician.
from donation. (h) Relevant transfusion-transmitted in-
(b) Who must comply with subparts A, fection means:
B, and C of this part? Blood establish- (1) Any of the following transfusion-
ments that manufacture blood and transmitted infections:
blood components, as defined in (i) Human immunodeficiency virus,
§ 630.3(a) and (b), must comply with types 1 and 2 (referred to, collectively,
subparts A, B, and C of this part. as HIV);
(ii) Hepatitis B virus (referred to as
§ 630.3 Definitions. HBV);
As used in this part and in part 610, (iii) Hepatitis C virus (referred to as
subpart E, and part 640 of this chapter: HCV);
(a) Blood means a product that is a (iv) Human T-lymphotropic virus,
fluid containing dissolved and sus- types I and II (referred to, collectively,
pended elements which was collected as HTLV);
from the vascular system of a human. (v) Treponema pallidum (referred to as
(b) Blood component means a product syphilis);
containing a part of blood separated by (vi) West Nile virus;
physical or mechanical means. (vii) Trypanosoma cruzi (referred to as
(c) Donor means a person who: (1) Do- Chagas disease);
nates blood or blood components for (viii) Creutzfeldt-Jakob disease (re-
transfusion or for further manufac- ferred to as CJD);
turing use; or (ix) Variant Creutzfeldt-Jakob dis-
(2) Presents as a potential candidate ease (referred to as vCJD); and
for such donation. (x) Plasmodium species (referred to as
(d) Eligibility of a donor means the de- malaria).
termination that the donor is qualified (2) A transfusion-transmitted infec-
to donate blood and blood components. tion not listed in paragraph (h)(1) of
(e) Infrequent plasma donor means a this section when the following condi-
donor who has: tions are met:
(1) Not donated plasma by plasma- (i) Appropriate screening measures
pheresis or a co-collection of plasma for the transfusion-transmitted infec-
with another blood component in the tion have been developed and/or an ap-
preceding 4 weeks; and propriate screening test has been li-
(2) Not donated more than 12.0 liters censed, approved, or cleared for such
of plasma (14.4 liters of plasma for do- use by FDA and is available; and
84
(ii) The disease or disease agent: Subpart B—Donor Eligibility

(A) May have sufficient incidence Requirements
and/or prevalence to affect the poten-
tial donor population; or SOURCE: 80 FR 29898, May 22, 2015, unless
(B) May have been released acciden- otherwise noted.
tally or intentionally in a manner that
could place potential donors at risk of § 630.5 Medical supervision.
infection. (a) Who must determine the eligibility of
(i) Responsible physician means an in- a donor? The responsible physician
dividual who is: must determine the eligibility of a
(1) Licensed to practice medicine in donor of blood or blood components in
the jurisdiction where the collection accordance with this subchapter.
establishment is located; (b) Which activities related to the col-
(2) Adequately trained and qualified lection of blood and blood components,
to direct and control personnel and rel- other than Source Plasma and plasma col-
evant procedures concerning the deter- lected by plasmapheresis, may the respon-
mination of donor eligibility; collec- sible physician delegate?
tion of blood and blood components; (1) The responsible physician may
the immunization of a donor; and the delegate the following activities to a
physician substitute or other trained
return of red blood cells or other blood
person:
components to the donor during collec-
(i) Determining the eligibility of a
tion of blood component(s) by
donor and documenting assessments re-
apheresis; and lated to that determination, except the
(3) Designated by the collection es- responsible physician must not dele-
tablishment to perform the activities gate:
described in paragraph (i)(2) of this sec- (A) The examination and determina-
tion. tion of the donor’s health required in
(j) Suitability of the donation means a § 630.10(f)(2) for donors with blood pres-
determination of whether the donation sure measurements outside specified
is acceptable for transfusion or for fur- limits, or for certain more frequent do-
ther manufacturing use. nations under § 630.15(a)(1)(ii);
(k) Trained person means an indi- (B) The determination of the health
vidual, including a physician sub- of the donor required in §§ 630.10(f)(4),
stitute, who is authorized under State 630.20(a), and 640.21(e)(4) of this chap-
law, and/or local law when applicable, ter. The responsible physician may
and adequately instructed and quali- make this determination by telephonic
fied to perform the specified functions or other offsite consultation; or
under the direction of the responsible (C) The determination of the health
physician. of the donor and the determination
(l) Transfusion-transmitted infection that the blood or blood component col-
means a disease or disease agent: lected would present no undue medical
risk to the transfusion recipient, as re-
(1) That could be fatal or life-threat-
quired in § 630.20(c). The responsible
ening, could result in permanent im-
physician may make these determina-
pairment of a body function or perma-
tions by telephonic or other offsite
nent damage to a body structure, or consultation.
could necessitate medical or surgical (ii) Collecting blood or blood compo-
intervention to preclude permanent nents;
impairment of body function or perma- (iii) Returning red blood cells to the
nent damage to a body structure; and donor during apheresis;
(2) For which there may be a risk of (iv) Obtaining the informed consent
transmission by blood or blood compo- of a plateletpheresis donor as described
nents, or by a blood derivative product in § 640.21(g) of this chapter; or
manufactured from blood or blood com- (v) Other activities provided that the
ponents, because the disease or disease Director, Center for Biologics Evalua-
agent is potentially transmissible by tion and Research, determines that del-
that blood, blood component, or blood egating the activities would present no
derivative product. undue medical risk to the donor or to
85
§ 630.5 21 CFR Ch. I (4–1–20 Edition)
the transfusion recipient, and author- with § 640.65(b)(2)(iii) of this chapter;

izes the delegation of such activities. and
(2) The responsible physician need (5) The determination to permit plas-
not be present at the collection site mapheresis of a donor with a reactive
when activities delegated under para- serological test for syphilis in accord-
graph (b)(1) of this section are per- ance with § 640.65(b)(2)(iv) of this chap-
formed, provided that the responsible ter.
physician has delegated oversight of (B) The collection of Source Plasma
these activities to a trained person who in an approved collection program
is adequately trained and experienced from a donor who is otherwise deter-
in the performance of these activities mined to be ineligible.
and is also adequately trained and ex- (C) The collection of a blood sample
perienced in the recognition of and rein accordance with § 640.65(b)(1)(i) of
sponse to the known adverse responses this chapter.
associated with blood collection proce- (ii) The responsible physician, who
dures. may or may not be present when these
(c) Which activities related to the collec- activities are performed, may delegate
tion of Source Plasma and plasma col- to a physician substitute the following
lected by plasmapheresis may the respon- activities:
sible physician delegate? (A) Approval and signature for a plas-
(1) Donor eligibility and blood compo- mapheresis procedure as provided in
nent collection activities. (i) The respon- § 640.65(b)(1)(ii) of this chapter; and
sible physician may delegate to a phy- (B) Review and signature for accumu-
sician substitute or other trained per- lated laboratory data, the calculated
son any of the activities described in values of each component, and the col-
paragraph (c)(1)(i)(A) of this section, lection records in accordance with
provided that the responsible physician § 640.65(b)(2)(i) of this chapter. However,
or a physician substitute is on the the responsible physician must not del-
premises at the collection site: egate the decision to reinstate the de-
(A) The activities listed in para- ferred donor in accordance with that
graphs (b)(1)(i) through (iii) and provision.
(b)(1)(v) of this section, with respect to (2) Donor immunization. The respon-
Source Plasma and plasma collected by sible physician must not delegate ac-
plasmapheresis. However, the respon- tivities performed in accordance with
sible physician must not delegate: § 640.66 of this chapter, except that:
(1) The examination and determina- (i) The responsible physician may
tion of the donor’s health required in delegate to a physician substitute or
§ 630.10(f)(2) for donors with blood pres- other trained person the administra-
sure measurements outside specified tion of an immunization other than red
limits, or in § 630.15(b)(7) for certain do- blood cells to a donor in an approved
nors who have experienced red blood collection program, provided that the
cell loss; responsible physician or a physician
(2) The determination of the health substitute is on the premises at the
of the donor required in §§ 630.10(f)(4) collection site when the immunization
and 630.20(a) and (b). The responsible is administered.
physician may make this determina- (ii) The responsible physician may
tion by telephonic or other offsite con- delegate to a physician substitute the
sultation; administration of red blood cells to a
(3) The determination of the health donor in an approved collection pro-
of the donor and the determination gram, provided that the responsible
that the blood component would physician has approved the procedure
present no undue medical risk to the and is on the premises at the collection
transfusion recipient, as required in site when the red blood cells are ad-
§ 630.20(c). The responsible physician ministered.
may make this determination by tele- (3) Medical history, physical examina-
phonic or other offsite consultation. tion, informed consent, and examination
(4) The determination related to a do- before immunization. Provided that such
nor’s false-positive reaction to a sero- activities are performed under the su-
logic test for syphilis in accordance pervision of the responsible physician,
86
the responsible physician may delegate tified in cardiopulmonary resuscitation

to a physician substitute the activities is located on the premises whenever
described in § 630.15(b)(1), (2), and (5). collections of blood or blood compo-
The responsible physician is not re- nents are performed.
quired to be present at the collection
site when the physician substitute per- § 630.10 General donor eligibility re-
forms these activities under super- quirements.
vision. (a) What factors determine the eligi-
(4) Infrequent plasma donors. (i) For bility of a donor? You, an establishment
infrequent plasma donors other than that collects blood or blood compo-
those described in paragraph (c)(4)(ii) nents, must not collect blood or blood
of this section, the responsible physi- components before determining that
cian may delegate to a trained person the donor is eligible to donate or before
the activities listed in paragraphs determining that an exception to this
(b)(1)(i) through (iii) and (b)(1)(v) of provision applies. To be eligible, the
this section and the informed consent donor must be in good health and free
requirements described in § 630.15(b)(2). from transfusion-transmitted infec-
The responsible physician or a physi- tions as can be determined by the proc-
cian substitute need not be present at esses in this subchapter. A donor is not
the collection site when any of these eligible if the donor is not in good
activities are performed, provided that health or if you identify any factor(s)
the responsible physician has delegated that may cause the donation to ad-
oversight of these activities to a versely affect:
trained person who is not only ade-
(1) The health of the donor; or
quately trained and experienced in the
performance of these activities but (2) The safety, purity, or potency of
also adequately trained and experi- the blood or blood component.
enced in the recognition of and re- (b) What educational material must you
sponse to the known adverse responses provide to the donor before determining
associated with blood collection proce- eligibility? You must provide edu-
dures. However, the responsible physi- cational material concerning relevant
cian must not delegate: transfusion-transmitted infections to
(A) The examination and determina- donors before donation when donor
tion of the donor’s health required in education about that relevant trans-
§ 630.10(f)(2) for donors with blood pres- fusion-transmitted infection, such as
sure measurements outside specified HIV, is necessary to assure the safety,
limits, or in § 630.15(b)(7) for certain do- purity, and potency of blood and blood
nors who have experienced red blood components. The educational material
cell loss; or must include an explanation of the
(B) The determination of the health readily identifiable risk factors closely
of the donor required in § 630.10(f)(4). associated with exposure to the rel-
(ii) For infrequent plasma donors evant transfusion-transmitted infec-
who are otherwise ineligible or are par- tion. You must present educational
ticipating in an approved immuniza- material in an appropriate form, such
tion program, the responsible physi- as oral, written or multimedia, and in
cian may delegate only in accordance a manner designed to be understood by
with paragraphs (c)(1) through (3) of the donor. The educational material
this section. must instruct the donor not to donate
(d) Must rapid emergency medical serv- blood and blood components when a
ices be available? Establishments that risk factor is present. When providing
collect blood or blood components educational material to donors under
must establish, maintain, and follow this section, you may include in those
standard operating procedures for ob- materials the information required to
taining rapid emergency medical serv- be provided to donors under paragraph
ices for donors when medically nec- (g)(2)(ii)(E) of this section.
essary. In addition, establishments (c) When must you determine the eligi-
must assure that an individual (respon- bility of a donor? You must determine
sible physician, physician substitute, donor eligibility on the day of dona-

or trained person) who is currently cer- tion, and before collection. Except:
87
§ 630.10 21 CFR Ch. I (4–1–20 Edition)
(1) When a donor is donating blood (1) Factors that make the donor in-
components that cannot be stored for eligible to donate because of an in-
more than 24 hours, you may deter- creased risk for, or evidence of, a rel-
mine the donor’s eligibility and collect evant transfusion-transmitted infec-
a sample for testing required under tion. A donor is ineligible to donate
§ 610.40 of this chapter, no earlier than when information provided by the
2 calendar days before the day of dona- donor or other reliable evidence indi-
tion, provided that your standard oper- cates possible exposure to a relevant
ating procedures address these activi- transfusion-transmitted infection if
ties. that risk of exposure is still applicable
(2) In the event that, upon review, at the time of donation. Information
you find that a donor’s responses to the and evidence indicating possible expo-
donor questions before collection were sure to a relevant transfusion-trans-
incomplete, within 24 hours of the time mitted infection include:
of collection, you may clarify a donor’s (i) Behaviors associated with a rel-
response or obtain omitted information evant transfusion-transmitted infec-
required under paragraph (e) of this tion;
section, provided that your standard (ii) Receipt of blood or blood compo-
operating procedures address these ac- nents or other medical treatments and
tivities. procedures associated with possible ex-
(d) How must you determine the eligi- posure to a relevant transfusion-trans-
bility of a donor? You must determine mitted infection;
the donor’s eligibility before collection (iii) Signs and/or symptoms of a rel-
of blood or blood components, by the evant transfusion-transmitted infec-
following procedures: tion;
(iv) Institutionalization for 72 hours
(1) You must consult the records of
or more consecutively in the past 12
deferred donors maintained under
months in a correctional institution;
§ 606.160(e)(1) and (2) of this chapter. Ex-
(v) Intimate contact with risk for a
ception: If pre-collection review of the
relevant transfusion-transmitted infec-
record described in § 606.160(e)(2) of this
tion; and
chapter is not feasible because you can- (vi) Nonsterile percutaneous inocula-
not consult the cumulative record at tion.
the collection site, you must consult (2) Other factors that make the donor
the cumulative record prior to release ineligible to donate. A donor is ineli-
of any blood or blood component pre- gible to donate when donating could
pared from the collection. adversely affect the health of the
(2) Assure that the interval since the donor, or when the safety, purity, or
donor’s last donation is appropriate; potency of the blood or blood compo-
(3) Assess the donor’s medical his- nent could be affected adversely. Your
tory; and assessment of the donor must include
(4) Perform a physical assessment of each of the following factors:
the donor. (i) Symptoms of a recent or current
(e) How do you assess the donor’s med- illness;
ical history? Before collection you must (ii) Certain medical treatments or
conduct a medical history interview as medications;
described in this section to determine (iii) Travel to, or residence in, an
if the donor is in good health; to iden- area endemic for a transfusion-trans-
tify risk factors closely associated with mitted infection, when such screening
exposure to, or clinical evidence of a is necessary to assure the safety, pu-
relevant transfusion-transmitted infec- rity, and potency of blood and blood
tion; and to determine if there are components due to the risks presented
other conditions that may adversely by donor travel and the risk of trans-
affect the health of the donor or the mission of that transfusion-trans-
safety, purity, or potency of the blood mitted infection by such donors;
or blood components or any product (iv) Exposure or possible exposure to
manufactured from the blood or blood an accidentally or intentionally re-
components. Your assessment must in- leased disease or disease agent relating
clude each of the following factors: to a transfusion-transmitted infection,
88
if you know or suspect that such a re- limits for female donors, you may col-
lease has occurred; lect blood from female allogeneic do-
(v) Pregnancy at the time of, or with- nors who have a hemoglobin level be-
in 6 weeks prior to, donation; tween 12.0 and 12.5 grams per deciliter
(vi) Whether, in the opinion of the of blood, or a hematocrit value between
interviewer, the donor appears to be 36 and 38 percent, provided that you
under the influence of any drug, alco- have taken additional steps to assure
hol or for any reason does not appear that this alternative standard is ade-
to be providing reliable answers to quate to ensure that the health of the
medical history questions, or if the donor will not be adversely affected
donor says that the purpose of donat- due to the donation, in accordance
ing is to obtain test results for a rel- with a procedure that has been found
evant transfusion-transmitted infec- acceptable for this purpose by FDA.
tion; and (B) Male allogeneic donors must have
(vii) The donor is a a hemoglobin level that is equal to or
xenotransplantation product recipient. greater than 13.0 grams of hemoglobin
(f) How do you perform a physical as- per deciliter of blood, or a hematocrit
sessment of the donor? You must deter- value that is equal to or greater than
mine on the day of donation, and be- 39 percent.
fore collection that the donor is in (ii) An autologous donor must have a
good health based on the following, at hemoglobin level no less than 11.0
a minimum: grams of hemoglobin per deciliter of
(1) Temperature. The donor’s oral blood, or a hematocrit value no less
body temperature must not exceed 37.5 than 33 percent.
°C (99.5 °F), or the equivalent if meas- (4) Pulse. The donor’s pulse must be
ured at another body site; regular and between 50 and 100 beats
(2) Blood pressure. The donor’s sys- per minute. A donor with an irregular
tolic blood pressure must not measure pulse or measurements outside these
above 180 mm of mercury, or below 90 limits may be permitted to donate only
mm of mercury, and the diastolic blood when the responsible physician deter-
pressure must not measure above 100 mines and documents that the health
mm of mercury or below 50 mms of of the donor would not be adversely af-
mercury. A donor with measurements fected by donating.
outside these limits may be permitted (5) Weight. The donor must weigh a
to donate only when the responsible minimum of 50 kilograms (110 pounds).
physician examines the donor and de- (6) Skin examination. (i) The donor’s
termines and documents that the phlebotomy site must be free of infec-
health of the donor would not be ad- tion, inflammation, and lesions; and
versely affected by donating. (ii) The donor’s arms and forearms
(3) Hemoglobin or hematocrit determina- must be free of punctures and scars in-
tion. You must determine the donor’s dicative of injected drugs of abuse.
hemoglobin level or hematocrit value (g) Are there additional requirements
by using a sample of blood obtained by for determining the eligibility of the
fingerstick, venipuncture, or by a donor? You must obtain the following
method that provides equivalent re- from the donor on the day of donation:
sults. Blood obtained from the earlobe (1) Proof of identity and postal address.
is not acceptable. You must obtain proof of identity of
(i) Allogeneic donors must have a he- the donor and a postal address where
moglobin level or hematocrit value the donor may be contacted for 8 weeks
that is adequate to assure donor safety after donation; and
and product potency. The following (2) Donor’s acknowledgement. (i) Prior
minimum standards apply. to each donation, you must provide in-
(A) Female allogeneic donors must formation to the donor addressing the
have a hemoglobin level that is equal elements specified in paragraphs
to or greater than 12.5 grams of hemo- (g)(2)(ii)(A) through (E) of this section
globin per deciliter of blood, or a hem- and obtain the donor’s acknowledge-
atocrit value that is equal to or greater ment that the donor has reviewed the
than 38 percent. Recognizing that information. You must establish proce-

lower levels are also within normal dures in accordance with § 606.100 of
89
§ 630.15 21 CFR Ch. I (4–1–20 Edition)
this chapter to assure that the donor (1) Donation frequency must be con-
has reviewed this material, and provide sistent with protecting the health of the
for a signature or other documented donor.
acknowledgement. (i) For a collection resulting in a sin-
(ii) The donor acknowledgement gle unit of Whole Blood or Red Blood
must not include any exculpatory lan- Cells collected by apheresis, donation
guage through which the donor is made frequency must be no more than once
to waive or appear to waive any of the in 8 weeks, and for apheresis collec-
donor’s legal rights. It must, at a min- tions resulting in two units of Red
imum clearly address the following: Blood Cells, the donor must not donate
(A) The donor has reviewed the edu- more than once in 16 weeks.
cational material provided under para- (ii) The limitations in paragraph
graph (b) of this section regarding rel- (a)(1)(i) of this section apply unless the
evant transfusion-transmitted infec- responsible physician examines the
tions; donor at the time of donation and one
(B) The donor agrees not to donate if of the following conditions exists:
the donation could result in a potential (A) The donation is for autologous
risk to recipients as described in the use as prescribed by the donor’s physi-
educational material; cian and the responsible physician de-
(C) A sample of the donor’s blood will termines and documents that the dona-
be tested for specified relevant trans- tion may proceed; or
fusion-transmitted infections; (B) The donation is a dedicated dona-
(D) If the donation is determined to tion based on the intended recipient’s
be not suitable under § 630.30(a) or if documented exceptional medical need
the donor is deferred from donation and the responsible physician deter-
under § 610.41 of this chapter, the do- mines and documents that the health
nor’s record will identify the donor as of the donor would not be adversely af-
ineligible to donate and the donor will fected by donating.
be notified under § 630.40 of the basis for (2) Therapeutic phlebotomy. When a
the deferral and the period of deferral; donor who is determined to be eligible
(E) The donor has been provided and under § 630.10 undergoes a therapeutic
reviewed information regarding the phlebotomy under a prescription to
risks and hazards of the specific dona- promote the donor’s health, you may
tion procedure; and collect from the donor more frequently
(F) The donor has the opportunity to than once in 8 weeks for collections re-
ask questions and withdraw from the sulting in a single unit of Whole Blood
donation procedure. or Red Blood Cells, or once in 16 weeks
(h) What must you do when a donor is for apheresis collections resulting in
not eligible? You must not collect blood two units of Red Blood Cells, provided
or blood components from a donor that the container label conspicuously
found to be ineligible prior to collec- states the disease or condition of the
tion based on criteria in §§ 630.10 or donor that necessitated phlebotomy.
630.15, or deferred under § 610.41 of this However, no labeling for the disease or
chapter or § 630.30(b)(2), unless this sub- condition is required under this section
chapter provides an exception. You if:
must defer donors found to be ineli- (i) The donor meets all eligibility cri-
gible and you must notify the donor of teria;
their deferral under § 630.40. (ii) The donor undergoes a thera-
peutic phlebotomy as prescribed by a
§ 630.15 Donor eligibility requirements licensed health care provider treating
specific to Whole Blood, Red Blood the donor for:
Cells and Plasma collected by (A) Hereditary hemochromatosis; or
apheresis. (B) Another disease or condition,
(a) What additional donor eligibility re- when the health of a donor with that
quirements apply when you, an establish- disease or condition will not be ad-
ment that collects blood or blood compo- versely affected by donating, and the
nents, collect Whole Blood or Red Blood donor’s disease or condition will not
Cells by apheresis? adversely affect the safety, purity, and
90
potency of the blood and blood compo- special collection program, the respon-
nents, or any products manufactured sible physician must again obtain an
from them, and the collection is in ac- informed consent specific for that pro-
cordance with a procedure that has gram.
been found acceptable for this purpose (3) Weight. You must weigh a donor
by FDA; and at each donation.
(iii) You perform without charge (4) Total protein level. You must deter-
therapeutic phlebotomies for all indi- mine the donor’s total plasma protein
viduals with that disease or condition. level before each plasmapheresis proce-
(b) What additional donor eligibility re- dure. The donor must have a total plas-
quirements apply when you, an establish- ma protein level of no less than 6.0
ment that collects blood or blood compo- grams per deciliter and no more than
nents, collect Source Plasma or plasma by 9.0 grams per deciliter in a plasma sam-
plasmapheresis? ple or a serum sample.
(1) Medical history and physical exam- (5) Examination before immunization.
ination. Except as provided in § 630.25: (i) No more than 1 week before the first
(i) The responsible physician must immunization injection for the produc-
conduct an appropriate medical history tion of high-titer antibody plasma, the
and physical examination of the donor responsible physician must conduct an
on the day of the first donation or no appropriate medical history and phys-
more than 1 week before the first dona- ical examination, as described in para-
tion and at subsequent intervals of no graph (b)(1) of this section, in addition
longer than 1 year. to assessing the general donor eligi-
(ii) The responsible physician must bility requirements under § 630.10. It is
examine the donor for medical condi- not necessary to repeat the medical
tions that would place the donor at history and physical examination re-
risk from plasmapheresis. If the donor quirement in paragraph (b)(1) of this
is determined to be at risk, you must section, if the immunized donor’s plas-
defer the donor from donating. ma is collected within 3 weeks of the
(iii) The responsible physician must first immunization injection.
conduct a new medical history and (ii) You are not required to repeat
physical examination of a donor who the medical history and physical exam-
does not return for 6 months. ination required under paragraph (b)(1)
(2) What requirements apply to obtain- of this section for a donor currently
ing informed consent? participating in a plasmapheresis col-
(i) The responsible physician must lection program and determined to be
obtain the informed consent of a plas- eligible under § 630.10 unless the med-
ma donor on the first day of donation ical history and physical examination
or no more than 1 week before the first are due under paragraph (b)(1)(i) or
donation, and at subsequent intervals (b)(1)(iii) of this section.
of no longer than 1 year. (6) Deferral of donors due to red blood
(ii) The responsible physician must cell loss. (i) You must defer a donor
obtain the informed consent of a plas- from donating plasma by plasma-
ma donor who does not return within 6 pheresis for 8 weeks if the donor has
months of the last donation. donated a unit of Whole Blood, or a sin-
(iii) The responsible physician must gle unit of Red Blood Cells by
explain the risks and hazards of the apheresis. However, you may collect
procedure to the donor. The expla- plasma by plasmapheresis after a dona-
nation must include the risks of a he- tion of Whole Blood or a single unit of
molytic transfusion reaction if the Red Blood Cells by apheresis after at
donor is given the cells of another least 2 calendar days have passed, pro-
donor and the risks involved if the vided that the extracorporeal volume
donor is immunized. The explanation of the apheresis device is less than 100
must be made in such a manner that milliliters.
the donor may give their consent and (ii) You must defer a donor from do-
has a clear opportunity to refuse the nating plasma by plasmapheresis for a
procedure. period of 16 weeks if the donor donates
(iv) If a donor is enrolled in a new two units of Red Blood Cells during a
program, such as an immunization or single apheresis procedure;
91
§ 630.20 21 CFR Ch. I (4–1–20 Edition)
(iii) You must defer a donor for 8 (b) The donation is collected under a
weeks or more if the cumulative red Source Plasma collection program
blood cell loss in any 8 week period which has received prior written ap-
could adversely affect donor health. proval from the Director, Center for
(7) Exceptions to deferral due to red Biologics Evaluation and Research, to
blood cell loss. You are not required to collect plasma for further manufac-
defer a Source Plasma donor from do- turing use into in vitro products for
nating plasma by plasmapheresis due which there are no alternative sources,
to red blood cell loss if the following the donor meets the criteria in
conditions are met: § 630.10(f)(1) through (6), and the respon-
(i) The responsible physician exam- sible physician determines and docu-
ines the donor at the time of the cur- ments for each donation that the do-
rent donation and determines and doc- nor’s health permits the collection pro-
uments that the donor is in good cedure, and the collection takes place
health and the donor’s health permits under the medical oversight specified
the plasmapheresis; in the approved plasmapheresis pro-
(ii) The donor’s plasma possesses a gram.
property, such as an antibody, antigen, (c) The donation is restricted for use
or protein deficiency that is transitory, solely by a specific transfusion recipi-
of a highly unusual or infrequent speci- ent based on documented exceptional
ficity, or of an unusually high titer; medical need, and the responsible phy-
(iii) The special characteristics of the sician determines and documents that
donor’s plasma and the need for plas- the donor’s health permits the collec-
mapheresis of the donor under tion procedure, and that the donation
§ 630.20(b) are documented at your es- presents no undue medical risk to the
tablishment; and transfusion recipient.
(iv) The extracorporeal volume of the
apheresis device is less than 100 milli- § 630.25 Exceptions from certain donor
liters. eligibility requirements for infre-
(8) Malaria. Freedom from risk of ma- quent plasma donors.
laria is not required for a donor of For an infrequent plasma donor who
Source Plasma. is not participating in an immuniza-
(9) You must comply with other re- tion program, establishments are not
quirements for collection of plasma in required to:
part 640 of this chapter and this part (a) Perform a medical history and
including restrictions on frequency of physical examination of the donor
collection as specified in §§ 640.32 and under § 630.15(b)(1);
640.65 of this chapter.
(b) Perform a test for total protein
§ 630.20 Exceptions for certain ineli- under § 630.15(b)(4);
gible donors. (c) Determine the total plasma or
serum protein and immunoglobulin
After assessing donor eligibility
composition under § 640.65(b)(1)(i) of
under §§ 630.10 and 630.15, an establish-
this chapter; or
ment may collect blood and blood com-
ponents from a donor who is deter- (d) Review the data and records as re-
mined to be not eligible to donate quired in § 640.65(b)(2)(i) of this chapter.
under any provision of § 630.10(e) and (f)
§ 630.30 Donation suitability require-
or § 630.15(a) if one of the following sets ments.
of conditions are met:
(a) The donation is for autologous (a) When is a donation suitable? A do-
use only as prescribed by the donor’s nation is suitable when:
physician, the donor has a hemoglobin (1) The donor is not currently de-
level no less than 11.0 grams of hemo- ferred from donation as determined by
globin per deciliter of blood or a hem- review of the records of deferred donors
atocrit value no less than 33 percent, required under § 606.160(e) of this chap-
and the responsible physician deter- ter;
mines and documents that the donor’s (2) The results in accordance with
health permits the collection proce- §§ 630.10 through 630.25 indicate that the
dure; or donor is in good health and procedures
92
were followed to ensure that the dona- (b) For a donor deferred for reasons
tion would not adversely affect the other than under § 610.41(a) of this
health of the donor; chapter, you determine that the donor
(3) The results in accordance with has met criteria for requalification by
§ 630.10(e) indicate that the donor is a method or process found acceptable
free from risk factors for, or evidence for such purpose by FDA.
of, relevant transfusion-transmitted in-
fections and other factors that make Subpart C—Donor Notification
the donor ineligible to donate;
(4) The donor’s blood is tested in ac-
cordance with § 610.40 of this chapter, SOURCE: 80 FR 29898, May 22, 2015, unless
otherwise noted.
and is negative or nonreactive, unless
an exception applies under § 610.40(h) of § 630.40 Requirements for notifying de-
this chapter; and ferred donors.
(5) The donation meets other require-
ments in this subchapter. (a) Notification of donors. You, an es-
(b) What must you do when the dona- tablishment that collects blood or
tion is not suitable? (1) You must not re- blood components, must make reason-
lease the donation for transfusion or able attempts to notify any donor, in-
further manufacturing use unless it is cluding an autologous donor, who has
an autologous donation, or an excep- been deferred based on the results of
tion is provided in this chapter. tests for evidence of infection with a
(2) You must defer the donor when a relevant transfusion-transmitted infec-
donation is determined to be unsuit- tion(s) as required by § 610.41(a) of this
able based on the criteria in para- chapter; any donor who has been de-
graphs (a)(1) through (4) of this section. ferred as required under § 630.30(b)(3)
(3) You must defer the donor of because their donated platelets have
bacterially contaminated platelets been determined under § 606.145(d) of
when the contaminating organism is this chapter to be contaminated with
identified in accordance with an organism that is identified as likely
§ 606.145(d) of this chapter as likely to to be associated with a bacterial infec-
be associated with a bacterial infection tion that is endogenous to the blood-
that is endogenous to the bloodstream stream of the donor; and any donor
of the donor. who has been determined not to be eli-
(4) You must notify the deferred gible as a donor based on eligibility
donor in accordance with the notifica- criteria under §§ 630.10 and 630.15. You
tion requirements in § 630.40. must attempt to obtain the results of
further testing required under
§ 630.35 Requalification of previously § 610.40(e) of this chapter prior to noti-
deferred donors. fying a donor of the deferral. If notifi-
Establishments may determine a de- cation occurs prior to receipt of such
ferred donor to be eligible as a donor of results, you must also notify a deferred
blood and blood components if, at the donor of the results of the further test-
time of the current collection, the ing. You must notify a donor as de-
donor meets the eligibility criteria in scribed in paragraph (b) of this section.
this part, except for the record of the (b) Content of notification. You must
previous deferral, and you determine provide the following information to a
that the criteria that were the basis for donor deferred or determined not to be
the previous deferral are no longer ap- eligible as a donor as described in para-
plicable. Criteria for the previous de- graph (a) of this section:
ferral are no longer applicable if the (1) That the donor is deferred or de-
following conditions are met: termined not to be eligible for dona-
(a) The previous deferral was for a de- tion and the reason for that decision;
fined period of time and that time pe- (2) Where appropriate, the types of
riod has passed, or the deferral was donation of blood or blood components
otherwise temporary, such as a deferral that the donor should not donate in the
based on eligibility criteria described future;
in §§ 630.10(f)(1) through (5) or (3) Where applicable, the results of

630.15(b)(4); or tests for evidence of infection due to
93
Pt. 640 21 CFR Ch. I (4–1–20 Edition)
relevant transfusion-transmitted infec- reasonable attempts to notify the phy-

tion(s) that were a basis for deferral sician.
under § 610.41 of this chapter, including [66 FR 31176, June 11, 2001. Redesignated and
results of further testing as required in amended at 80 FR 29898, May 22, 2015]
§ 610.40(e) of this chapter; and,
(4) Where appropriate, information PART 640—ADDITIONAL STAND-
concerning medical followup and coun-
seling.
ARDS FOR HUMAN BLOOD AND
(c) Time period for notification. You
BLOOD PRODUCTS
must make reasonable attempts to no-
Subpart A—Whole Blood
tify the donor within 8 weeks after de-
termining that the donor is deferred or Sec.
determined not to be eligible for dona- 640.1 Whole Blood.
tion as described in paragraph (a) of 640.2 General requirements.
this section. You must document that 640.4 Collection of the blood.
640.5 Testing the blood.
you have successfully notified the 640.6 Modifications of Whole Blood.
donor or when you are unsuccessful
that you have made reasonable at- Subpart B—Red Blood Cells
tempts to notify the donor.
640.10 Red Blood Cells.
(d) Autologous donors. (1) You also 640.11 General requirements.
must provide the following information 640.12 Eligibility of donor.
to the referring physician of an 640.13 Collection of the blood.
autologous donor who is deferred based 640.14 Testing the blood.
on the results of tests for evidence of 640.15 Segments for testing.
infection with a relevant transfusion- 640.16 Processing.
transmitted infection(s) or whose 640.17 Modifications for specific products.
platelets indicate evidence of a bac- Subpart C—Platelets
terial infection that is endogenous to
the bloodstream of the donor as de- 640.20 Platelets.
scribed in paragraph (a) of this section: 640.21 Eligibility of donors.
640.22 Collection of source material.
(i) Information that the autologous
640.23 Testing the blood.
donor is deferred based on the results 640.24 Processing.
of tests for evidence of infection due to 640.25 General requirements.
tion(s), as required under § 610.41 of this Subpart D—Plasma
chapter, and the reason for that deci-
640.30 Plasma.
sion; 640.31 Eligibility of donors.
(ii) Where appropriate, the types of 640.32 Collection of source material.
donation of blood or blood components 640.33 Testing the blood.
that the autologous donor should not 640.34 Processing.
donate in the future; and
(iii) The results of tests for evidence Subpart E [Reserved]
of infection due to relevant trans- Subpart F—Cryoprecipitate
fusion-transmitted infection(s), that
were a basis for deferral under § 610.41 640.50 Cryoprecipitate AHF.
of this chapter, including results of fur- 640.51 Eligibility of donors.
ther testing as required in § 610.40(e) of 640.52 Collection of source material.
this chapter. 640.53 Testing the blood.
640.54 Processing.
(2) You must make reasonable at- 640.55 U.S. Standard preparation.
tempts to notify the autologous do- 640.56 Quality control test for potency.
nor’s referring physician within 8
weeks after determining that the Subpart G—Source Plasma
autologous donor is deferred as de-
640.60 Source Plasma.
scribed in paragraph (a) of this section.
640.64 Collection of blood for Source Plas-
You must document that you have suc- ma.
cessfully notified the autologous do-
640.65 Plasmapheresis.
nor’s referring physician or when you 640.66 Immunization of donors.
are unsuccessful that you have made 640.67 Laboratory tests.
94
640.68 Processing. as blood collected from human donors
640.69 General requirements. for transfusion to human recipients.
640.71 Manufacturing responsibility.
640.72 Records. [38 FR 32089, Nov. 20, 1973, as amended at 50
640.73 Reporting of fatal donor reactions. FR 4138, Jan. 29, 1985]
640.74 Modification of Source Plasma.
640.76 Products stored or shipped at unac- § 640.2 General requirements.
ceptable temperatures.
(a) Manufacturing responsibility. All
Subpart H—Albumin (Human) manufacturing of Whole Blood, includ-
ing donor examination, blood collec-
640.80 Albumin (Human). tion, laboratory tests, labeling, storage
640.81 Processing. and issue, shall be done under the su-
640.82 Tests on final product.
pervision and control of the same li-
640.83 General requirements.
640.84 Labeling. censed establishment except that the
Director, Center for Biologics Evalua-
Subpart I—Plasma Protein Fraction tion and Research, may approve ar-
(Human) rangements, upon joint request of two
or more licensed establishments, which
640.90 Plasma Protein Fraction (Human). he finds are of such a nature as to as-
640.91 Processing.
640.92 Tests on final product.
sure compliance otherwise with the
640.93 General requirements. provisions of this subchapter.
640.94 Labeling. (b) Blood container. The blood con-
tainer shall not be entered prior to
Subpart J—Immune Globulin (Human) issue for any purpose except for blood
collection or when the method of proc-
640.100 Immune Globulin (Human).
640.101 General requirements. essing requires use of a different con-
640.102 Manufacture of Immune Globulin tainer. The container shall be
(Human). uncolored and transparent to permit
640.103 The final product. visual inspection of the contents and
640.104 Potency. any closure shall be such as will main-
tain a hermetic seal and prevent con-
Subpart K [Reserved] tamination of the contents. The con-
Subpart L—Alternative Procedures tainer material shall not interact with
the contents under the customary con-
640.120 Alternative procedures. ditions of storage and use, in such a
manner as to have an adverse effect
Subpart M—Definitions and Medical upon the safety, purity, or potency of
Supervision the blood.
640.125 Definitions. (c) Reissue of blood. Blood that has
640.130 Medical supervision. been removed from storage controlled
AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, by a licensed establishment shall not
360, 371; 42 U.S.C. 216, 262, 263, 263a, 264. be reissued by a licensed establishment
unless the following conditions are ob-
SOURCE: 38 FR 32089, Nov. 20, 1973, unless
served:
otherwise noted.
(1) The container has a tamper-proof
CROSS REFERENCES: For U.S. Customs seal when originally issued and this
seal remains unbroken;
U.S. Postal Service regulations relating to (2) A segment is properly attached
the admissibility to the United States mails and has not been removed, except that
see parts 124 and 125 of the Domestic Mail blood lacking a properly attached seg-
Manual, that is incorporated by reference in ment may be reissued in an emergency
39 CFR part 111. provided it is accompanied by instruc-
tions for sampling and for use within 6
Subpart A—Whole Blood hours after entering the container for
sampling;
§ 640.1 Whole Blood. (3) The blood has been stored con-
The proper name of this product shall tinuously at 1 to 6 °C and shipped be-
be Whole Blood. Whole Blood is defined tween 1 and 10 °C;
95
§ 640.4 21 CFR Ch. I (4–1–20 Edition)
(4) The blood is held for observation (1) One or more segments shall be
until a significant inspection con- provided with each unit of blood when
sistent with the requirements of issued or reissued except as provided in
§ 640.5(e) can be made. § 640.2(c)(2) and all segments shall be
[38 FR 32089, Nov. 20, 1973, as amended at 41 from the donor who is the source of the
FR 4015, Jan. 28, 1976; 42 FR 59878, Nov. 22, unit of blood.
1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, (2) All samples for laboratory tests
Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR performed by the manufacturer and all
4138, Jan. 29, 1985; 53 FR 116, Jan. 5, 1988; 55 segments accompanying a unit of blood
FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6,
shall be collected at the time of filling
1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836,
Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR the original blood container.
40889, Aug. 6, 2001; 67 FR 9587, Mar. 4, 2002] (3) All containers for all samples
shall bear the donor’s identification be-
§ 640.4 Collection of the blood. fore collecting the samples.
(a) [Reserved] (4) All segments accompanying a unit
(b) The donor center. The pertinent re- of blood shall be attached to the whole
quirements of §§ 600.10 and 600.11 of this blood container before blood collection,
chapter shall apply at both the blood in a tamperproof manner that will con-
establishment and at any other place spicuously indicate removal and re-
where the bleeding is performed. attachment.
(c) Blood containers. Blood containers (5) Segments for compatibility test-
and donor sets shall be pyrogen-free, ing shall contain blood mixed with the
sterile and identified by lot number. appropriate anticoagulant.
The amount of anticoagulant required (h) Storage. Whole Blood must be
for the quantity of blood to be col- placed in storage at a temperature be-
lected shall be in the blood container tween 1 and 6 °C immediately after col-
when it is sterilized. In addition, all lection unless the blood is to be further
container and donor set surfaces that processed into another component or
come in contact with blood used in the the blood must be transported from the
processing of Heparin Whole Blood donor center to the processing labora-
shall be water repellent. tory. If transported, the blood must be
(d) The anticoagulant solution. The
placed in temporary storage having
anticoagulant solution shall be sterile
sufficient refrigeration capacity to
and pyrogen-free. Anticoagulant solu-
cool the blood continuously toward a
tions shall be compounded and used ac-
temperature range between 1 and 10 °C
cording to a formula approved by the
Director, Center for Biologics Evalua- until arrival at the processing labora-
tion and Research. tory. At the processing laboratory, the
(e) Donor identification. Each unit of blood must be stored at a temperature
blood shall be so marked or identified between 1 and 6 °C. Blood from which a
by number or other symbol as to relate component is to be prepared must be
it to the individual donor whose iden- held in an environment maintained at
tity shall be established to the extent a temperature range specified for that
necessary for compliance with § 630.10 component in the directions for use for
of this chapter. the blood collecting, processing, and
(f) Prevention of contamination of the storage system approved for such use
blood. The skin of the donor at the site by the Director, CBER.
of phlebotomy shall be prepared thor- [38 FR 32089, Nov. 20, 1973, as amended at 42
oughly and carefully by a method that FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4,
gives maximum assurance of a sterile 1978; 49 FR 23834, June 8, 1984; 50 FR 4138,
container of blood. The blood shall be Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR
collected by aseptic methods in a ster- 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001;
ile system which may be closed or may 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16,
be vented if the vent protects the blood 2007; 73 FR 7464, Feb. 8, 2008; 80 FR 29904, May
against contamination. 22, 2015]
(g) Samples and segments for laboratory
tests. Samples and segments for labora- § 640.5 Testing the blood.
tory tests shall meet the following All laboratory tests shall be made on
standards: a specimen of blood taken from the
96
donor, and these tests shall include the tions as required under § 610.40 of this
following: chapter.
(a) [Reserved]
(b) Determination of blood group. Each FR 4138, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988;
container of Whole Blood shall be clas- 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19,
sified as to ABO blood group. At least 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165,
two blood group tests shall be made June 11, 2001; 66 FR 40889, Aug. 6, 2001; 80 FR
and the unit shall not be issued until 29904, May 22, 2015]
grouping tests by different methods or
with different lots of antiserums are in § 640.6 Modifications of Whole Blood.
agreement. Only those Anti-A and Upon approval by the Director, Cen-
Anti-B Blood Grouping Reagents liter for Biologics Evaluation and Re-
censed under, or that otherwise meet search, of a supplement to the biologics
the requirements of, the regulations of license application for Whole Blood a
this subchapter shall be used, and the manufacturer may prepare Whole
technique used shall be that for which Blood from which the antihemophilic
the serum is specifically designed to be factor has been removed, provided the
effective. Whole Blood meets the applicable re-
(c) Determination of the Rh factors. quirements of this subchapter and the
Each container of Whole Blood shall be following conditions are met:
classified as to Rh type on the basis of (a) The antihemophilic factor shall
tests done on the sample. The label be removed in accordance with para-
shall indicate the extent of typing and graphs (a), (b), and (c) of § 640.52.
the results of all tests performed. If the
(b) Although the closed system be-
test, using Anti-D Blood Grouping Rea-
tween the red blood cells and plasma
gent, is positive, the container may be
labeled ‘‘Rh Positive.’’ If the test is shall be maintained, the red blood cells
negative, the results shall be confirmed shall be maintained between 1 and 6 °C
by further testing which shall include at all times, including that time when
tests for the ‘‘weak D (formerly Du).’’ the plasma is being frozen for removal
Blood may be labeled ‘‘Rh Negative’’ if of the antihemophilic factor.
further testing is negative. Units test- [38 FR 32089, Nov. 20, 1973, as amended at 49
ing positive after additional more spe- FR 23834, June 8, 1984; 50 FR 4138, Jan. 29,
cific testing shall be labeled as ‘‘Rh 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351,
Positive.’’ Only Anti-Rh Blood Group- Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR
ing Reagents licensed under, or that 56453, Oct. 20, 1999]
otherwise meet the requirements of,
this subchapter shall be used, and the Subpart B—Red Blood Cells
technique used shall be that for which
the reagent is specifically designed to § 640.10 Red Blood Cells.
be effective. The proper name of this product shall
(d) Sterility test. Whole Blood intended be Red Blood Cells. The product is de-
for transfusion shall not be tested for fined as red blood cells remaining after
sterility by a method that entails en- separating plasma from human blood.
tering the final container before the
blood is used for transfusion. [38 FR 32089, Nov. 20, 1973, as amended at 50
FR 4138, Jan. 29, 1985]
(e) Inspection. Whole Blood shall be
inspected visually during storage and § 640.11 General requirements.
immediately prior to issue. If the color
or physical appearance is abnormal or (a) Storage. Immediately after proc-
there is any indication or suspicion of essing, the Red Blood Cells shall be
microbial contamination the unit of placed in storage and maintained at a
Whole Blood shall not be issued for temperature between 1 and 6 °C.
transfusion. (b) Inspection. The product shall be
(f) Test for relevant transfusion-trans- inspected immediately after separation
mitted infections. Whole Blood shall be of the plasma, periodically during stor-
tested for evidence of infection due to age, and at the time of issue. The prod-
relevant transfusion-transmitted infec- uct shall not be issued if there is any
97
§ 640.12 21 CFR Ch. I (4–1–20 Edition)
abnormality in color or physical ap- tend to increase the temperature of the

pearance or if there is any indication of blood, or by normal undisturbed sedi-
microbial contamination. mentation. A portion of the plasma
[38 FR 32089, Nov. 20, 1973, as amended at 41 sufficient to insure optimal cell preser-
FR 18292, May 3, 1976; 42 FR 59878, Nov. 11, vation shall be left with the red cells
1977; 50 FR 4139, Jan. 29, 1985] except when a cryoprotective sub-
stance or additive solution is added for
§ 640.12 Eligibility of donor. prolonged storage.
Establishments must determine the (b) Sterile system. All surfaces that
eligibility of donors of the source blood come in contact with the red cells shall
for Red Blood Cells in accordance with be sterile and pyrogen-free.
§§ 630.10 and 630.15 of this chapter. (c) Final containers. Final containers
[80 FR 29904, May 22, 2015] used for Red Blood Cells shall be the
original blood containers unless the
§ 640.13 Collection of the blood. method of processing requires a dif-
(a) The source blood shall be col- ferent container. The final container
lected as prescribed in § 640.4. shall meet the requirements for blood
(b) Source blood may also be derived containers prescribed in § 640.2(c). At
from Whole Blood manufactured in ac- the time of filing, if a different con-
cordance with applicable provisions of tainer is used, it shall be marked or
this subchapter. identified by number or other symbol
[38 FR 32089, Nov. 20, 1973, as amended at 50 so as to relate it to the donor of that
FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, unit of red cells.
1999]
§ 640.14 Testing the blood. FR 34460, Aug. 4, 1978; 50 FR 4139, Jan. 29,
1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836,
Blood from which Red Blood Cells are Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]
prepared shall be tested as prescribed
in § 610.40 of this chapter and § 640.5 (b) § 640.17 Modifications for specific
and (c). products.
[53 FR 117, Jan. 5, 1988, as amended at 66 FR Red Blood Cells Frozen: A
31165, June 11, 2001; 80 FR 29904, May 22, 2015] cryophylactic substance may be added
to the Red Blood Cells for extended
§ 640.15 Segments for testing.
manufacturers’ storage at ¥65 °C or
Segments collected in integral tub- colder, provided the manufacturer sub-
ing shall meet the following standards: mits data considered by the Director,
(a) One or more segments shall be Center for Biologics Evaluation and
provided with each unit of Whole Blood Research, as adequately demonstrating
or Red Blood Cells when issued or re-
through in vivo cell survival and other
issued.
appropriate tests that the addition of
(b) Before they are filled, all seg-
ments shall be marked or identified so the substance, the materials used and
as to relate them to the donor of that the processing methods results in a
unit of red cells. final product that meets the required
(c) All segments accompanying a unit standards of safety, purity, and po-
of Red Blood Cells shall be filled at the tency for Red Blood Cells, and that the
time the blood is collected or at the frozen product will maintain those
time the final product is prepared. properties for the prescribed dating pe-
riod. Section 640.11 (a) and (b) do not
[66 FR 40890, Aug. 6, 2001]
apply while a cryophylactic substance
§ 640.16 Processing. is present.
(a) Separation. Within the timeframe [38 FR 32089, Nov. 20, 1973, as amended at 41
specified in the directions for use for FR 18292, May 3, 1976; 49 FR 23834, June 8,
the blood collecting, processing, and 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013,
storage system used, Red Blood Cells Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998]
may be prepared either by centrifuga-

tion, done in a manner that will not
98
Subpart C—Platelets platelet count indicates that the do-

nor’s platelet count is at least 150,000
§ 640.20 Platelets. platelets/μL; and
(a) Proper name and definition. The (3) You must take appropriate steps
proper name of this product shall be to assure that the donor’s intended
Platelets. The product is defined as post-donation platelet count will be no
platelets collected from one unit of less than 100,000 platelets/μL.
blood and resuspended in an appro- (e) Frequency of plateletpheresis collec-
priate volume of original plasma, as tion. (1) The donor may donate no more
prescribed in § 640.24(d). than a total of 24 plateletpheresis col-
(b) Source. The source material for lections during a 12-month rolling pe-
Platelets is plasma which may be ob- riod.
tained by whole blood collection or by (2) When you collect fewer than 6 ×
plateletpheresis. 1011 platelets, you must wait at least 2
calendar days before any subsequent
[40 FR 4304, Jan. 29, 1975, as amended at 47
plateletpheresis collection. You must
FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29,
1985; 72 FR 45887, Aug. 16, 2007] not attempt to collect more than 2 col-
lections within a 7 calendar day period.
§ 640.21 Eligibility of donors. (3) When you collect 6 × 1011 or more
(a) Establishments must determine platelets, you must wait at least 7 cal-
the eligibility of donors of platelets de- endar days before any subsequent
rived from Whole Blood and donors of plateletpheresis collection.
platelets collected by plateletpheresis (4) Exception. For a period not to ex-
in accordance with §§ 630.10 and 630.15 of ceed 30 calendar days, a donor may
this chapter, except as provided in this serve as a dedicated plateletpheresis
section. donor for a single recipient, in accord-
(b) A plateletpheresis donor must not ance with § 610.40(c)(1) of this chapter,
serve as the source of platelets for as often as is medically necessary, pro-
transfusion if the donor has recently vided that the donor is in good health,
ingested a drug that adversely affects as determined and documented by the
platelet function. responsible physician, and the donor’s
(c) A Whole Blood donor must not platelet count is at least 150,000 plate-
serve as the source of platelets for lets/μL, measured at the conclusion of
transfusion if the donor has recently the previous donation or before initi-
ingested a drug that adversely affects ating plateletpheresis for the current
platelet function unless the unit is la- donation.
beled to identify the ingested drug that (f) Deferral of plateletpheresis donors
adversely affects platelet function. due to red blood cell loss. (1) You must
(d) If you are collecting platelets by defer a donor from donating platelets
plateletpheresis, you must assess and by plateletpheresis or a co-collection of
monitor the donor’s platelet count. platelets and plasma by apheresis for 8
(1) You must take adequate and ap- weeks if the donor has donated a unit
propriate steps to assure that the do- of Whole Blood, or a single unit of Red
nor’s platelet count is at least 150,000 Blood Cells by apheresis unless at least
platelets per microliter (/μL) before 2 calendar days have passed and the
plateletpheresis begins. Exception: If extracorporeal volume of the apheresis
you do not have records of a donor’s device is less than 100 milliliters.
platelet count from prior donations (2) You must defer a donor from do-
and you are not able to assess the donating platelets for a period of 16
nor’s platelet count either prior to or weeks if the donor donates two units of
immediately following the initiation of Red Blood Cells during a single
the collection procedure, you may col- apheresis procedure.
lect platelets by plateletpheresis, but (3) You must defer a donor for 8
you must not collect 9.0 × 1011 or more weeks or more if the cumulative red
platelets from that donor. blood cell loss in any 8 week period
(2) You must defer from platelet do- could adversely affect donor health.
nation a donor whose pre-donation (g) The responsible physician must
platelet count is less than 150,000 plate- obtain the informed consent of a
lets/μL until a subsequent pre-donation plateletpheresis donor on the first day
99
§ 640.22 21 CFR Ch. I (4–1–20 Edition)
of donation, and at subsequent inter- fied in the directions for use for the
vals no longer than 1 year. blood collecting, processing, and stor-
(1) The responsible physician must age system approved for such use by
explain the risks and hazards of the the Director, Center for Biologics Eval-
procedure to the donor; and uation and Research.
(2) The explanation must be made in (b) Immediately after collection, the
such a manner that the donor may give whole blood or plasma shall be held in
consent, and has a clear opportunity to
storage between 20 and 24 °C unless it
refuse the procedure.
must be transported from the collec-
[80 FR 29904, May 22, 2015] tion center to the processing labora-
tory. During such transport, all reason-
§ 640.22 Collection of source material.
able methods shall be used to maintain
(a) Whole blood used as the source of the temperature as close as possible to
Platelets shall be collected as pre- a range between 20 and 24 °C until it ar-
scribed in § 640.4. rives at the processing laboratory
(b) [Reserved] where it shall be held between 20 and 24
(c) If plateletpheresis is used, the °C until the platelets are separated.
procedure for collection must be as
The platelet concentrate shall be sepa-
prescribed in §§ 640.21, 640.64 (except
paragraph (c)), and 640.65, or as de- rated within 4 hours or within the
scribed in an approved biologics license timeframe specified in the directions
application (BLA) or an approved sup- for use for the blood collecting, proc-
plement to a BLA. essing, and storage system.
(d) The phlebotomy shall be per- (c) The time and speed of centrifuga-
formed by a single uninterrupted tion must have been demonstrated to
venipuncture with minimal damage to, produce an unclumped product, with-
and minimal manipulation of, the do- out visible hemolysis, that yields a
nor’s tissue. count of not less than 5.5 × 1010 plate-
[40 FR 4304, Jan. 29, 1975, as amended at 45 lets per unit in at least 75 percent of
FR 27927, Apr. 25, 1980; 49 FR 23834, June 8, the units tested.
1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, (d) The volume of original plasma
Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR used for resuspension of the platelets
45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; shall be determined by the mainte-
72 FR 45887, Aug. 16, 2007; 80 FR 29904, May 22,
2015] nance of a pH of not less than 6.2 dur-
ing the storage period. The pH shall be
§ 640.23 Testing the blood. measured on a sample of platelets
(a) Blood from which plasma is sepa- which has been stored for the max-
rated for the preparation of Platelets imum dating period at the selected
shall be tested as prescribed in § 610.40 storage temperature. One of the fol-
of this chapter and § 640.5 (b) and (c). lowing storage temperatures shall be
(b) The tests shall be performed on a used continuously:
sample of blood collected at the time of (1) 20 to 24 °C.
collecting the source blood, and such (2) 1 to 6 °C.
sample container shall be labeled with (e) Final containers used for Plate-
the donor’s number before the con- lets shall be colorless and transparent
tainer is filled. to permit visual inspection of the con-
[40 FR 4304, Jan. 29, 1975, as amended at 50 tents; any closure shall maintain a her-
FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; metic seal and prevent contamination
64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, of the contents. The container material
2001; 66 FR 31165, June 11, 2001; 80 FR 29904, shall not interact with the contents,
May 22, 2015]
under the customary conditions of
§ 640.24 Processing. storage and use, in such a manner as to
have an adverse effect upon the safety,
(a) Separation of plasma and plate-
lets and resuspension of the platelets purity, potency, or efficacy of the prod-
must be in a closed system. Platelets uct. At the time of filling, the final
must not be pooled during processing container shall be marked or identified

unless the platelets are pooled as speci-
100
by number so as to relate it to the resentative of the Food and Drug Ad-

donor. ministration.
[40 FR 4304, Jan. 29, 1975, as amended at 42 (2) The licensed Platelets manufac-
FR 10983, Feb. 25, 1977; 47 FR 49021, Oct. 29, turer has obtained a written agreement
1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, that the testing laboratory will permit
Apr. 6, 1998; 64 FR 45372, Aug. 19, 1999; 66 FR an authorized representative of the
1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 Food and Drug Administration to in-
FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8,
2008]
spect its testing procedures and facili-
ties during reasonable business hours.
§ 640.25 General requirements. (3) The testing laboratory will par-
(a) Storage. Immediately after re- ticipate in any proficiency testing pro-
suspension, Platelets shall be placed in grams undertaken by the Center for
storage at the selected temperature Biologics Evaluation and Research,
range. If stored at 20 to 24 °C, a contin- Food and Drug Administration.
uous gentle agitation of the platelet [40 FR 4304, Jan. 29, 1975, as amended at 47
concentrate shall be maintained FR 49021, Oct. 29, 1982; 49 FR 23834, June 8,
throughout the storage period. Agita- 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013,
tion is optional if stored at a tempera- Mar. 26, 1990; 66 FR 1836, Jan. 10, 2001; 72 FR
ture between 1 and 6 °C. 45888, Aug. 16, 2007]
(b) Quality control testing. Each
month four units prepared from dif- Subpart D—Plasma
ferent donors shall be tested at the end
of the storage period as follows: § 640.30 Plasma.
(1) Platelet count.
(2) pH of not less than 6.2 measured (a) Proper name and definition. The
at the storage temperature of the unit. proper name of this component is Plas-
(3) Measurement of actual plasma ma. The component is defined as:
volume. (1) The fluid portion of one unit of
(4) If the results of the quality con- human blood intended for intravenous
trol testing indicate that the product use which is collected in a closed sys-
does not meet the prescribed require- tem, stabilized against clotting, and
ments, immediate corrective action separated from the red cells; or
shall be taken and a record maintained (2) The fluid portion of human blood
of such action. intended for intravenous use which is
(c) Manufacturing responsibility. All prepared by apheresis methods as spec-
manufacturing of Platelets shall be ified in the directions for use for the
performed at the same licensed estab- blood collecting, processing, and stor-
lishment, except that the quality con- age system including closed and open
trol testing under paragraph (b) of this systems.
section may be performed by a clinical (b) Source. (1) Plasma shall be ob-
laboratory which meets the standards tained by separating plasma from blood
of the Clinical Laboratories Improve- collected from blood donors or by plas-
ment Amendments of 1988 (CLIA) (42
mapheresis.
U.S.C. 263a) and is qualified to perform
platelet counts. Such arrangements (2) Plasma may be obtained from a
must be approved by the Director, Cen- unit of Whole Blood collected by an-
ter for Biologics Evaluation and Re- other licensed establishment.
search, Food and Drug Administration. [42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar.
Such testing shall not be considered as 29, 1983, as amended at 50 FR 4139, Jan. 29,
divided manufacturing, as described in 1985; 72 FR 45888, Aug. 16, 2007]
§ 610.63 of this chapter, provided the fol-
lowing conditions are met: § 640.31 Eligibility of donors.
(1) The results of each test are re- (a) Whole Blood donors must meet
ceived within 10 days of the prepara- the criteria for donor eligibility pre-
tion of the platelet concentrate, and scribed in §§ 630.10 and 630.15 of this
are maintained by the establishment
chapter.
licensed for Platelets so that they may
be reviewed by an authorized rep-
101
§ 640.32 21 CFR Ch. I (4–1–20 Edition)
(b) Collection establishments must blood collecting, processing, and stor-

determine the eligibility of plasma- age system unless the product is to be
pheresis donors in accordance with stored as Liquid Plasma.
§§ 630.10 and 630.15 of this chapter. (b) Fresh Frozen Plasma. Fresh frozen
[80 FR 29904, May 22, 2015] plasma shall be prepared from blood
collected by a single uninterrupted
§ 640.32 Collection of source material. venipuncture with minimal damage to
(a) Whole Blood must be collected, and minimal manipulation of the do-
transported, and stored as prescribed in nor’s tissue. The plasma must be sepa-
§ 640.4. When whole blood is intended rated from the red blood cells or col-
for Plasma, Fresh Frozen Plasma, and lected by an apheresis procedure, and
Liquid Plasma, until the plasma is replaced in a freezer within 8 hours or
moved, the whole blood must be main- within the timeframe specified in the
tained at a temperature between 1 and directions for use for the blood col-
6 °C or as specified in the directions for lecting, processing, and storage sys-
use for the blood collecting, processing, tem, and stored at ¥18 °C or colder.
and storage system approved for such (c) Liquid Plasma. Liquid Plasma
use by the Director, Center for Bio- shall be separated from the red blood
logics Evaluations and Research. cells and shall be stored at a tempera-
Whole blood intended for Platelet Rich ture of 1 to 6 °C within 4 hours after
Plasma must be maintained as pre- filling the final container or within the
scribed in § 640.24 until the plasma is
timeframe specified in the directions
removed. The red blood cells must be
for use for the blood collecting, proc-
placed in storage at a temperature be-
essing, and storage system.
tween 1 and 6 °C immediately after the
plasma is separated. (d) Platelet Rich Plasma. Platelet rich
(b) Plasma obtained by plasma- plasma shall be prepared from blood
pheresis shall be collected as pre- collected by a single uninterrupted
scribed in § 640.64 (except that para- venipuncture with minimal damage to
graph (c)(3) of § 640.64 shall not apply), and manipulation of the donor’s tissue.
and § 640.65. The plasma shall be separated from the
red blood cells by centrifugation within
FR 27927, Apr. 25, 1980; 50 FR 4139, Jan. 29, 4 hours after completion of the phle-
1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, botomy or within the timeframe speci-
Aug. 16, 2007; 80 FR 29905, May 22, 2015] fied in the directions for use for the
blood collecting, processing, and stor-
§ 640.33 Testing the blood. age system. The time and speed of the
(a) Blood from which plasma is sepa- centrifugation shall have been shown
rated shall be tested as prescribed in to produce a product with at least
§ 610.40 of this chapter and § 640.5 (b) and 250,000 platelets per microliter. The
(c). plasma shall be stored at a tempera-
(b) Manufacturers of Plasma col- ture between 20 and 24 °C immediately
lected by plasmapheresis shall have after filling the final container. A
testing and recordkeeping responsibil- gentle and continuous agitation of the
ities equivalent to those prescribed in product shall be maintained through-
§§ 640.71 and 640.72. out the storage period, if stored at a
[42 FR 59878, Nov. 22, 1977, as amended at 44 temperature of 20 to 24 °C.
FR 17658, Mar. 23, 1979; 50 FR 4139, Jan. 29, (e) Modifications of Plasma. It is pos-
1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June sible to separate Platelets and/or
11, 2001; 80 FR 29905, May 22, 2015]
Cryoprecipitated AHF from Plasma.
§ 640.34 Processing. When these components are to be sepa-
rated, the plasma shall be collected as
(a) Plasma. Plasma shall be separated described in § 640.32 for Plasma.
from the red blood cells and shall be
(1) Platelets shall be separated as
stored at ¥18 °C or colder within 6
hours after transfer to the final con- prescribed in subpart C of part 640,
tainer or within the timeframe speci- prior to freezing the plasma. The re-
fied in the directions for use for the maining plasma may be labeled as
102
‘‘Fresh Frozen Plasma,’’ if frozen with- (3) No preservative shall be added to

in 6 hours after filling the final con- the final product.
tainer or within the timeframe speci-
fied in the directions for use for the FR 34460, Aug. 4, 1978; 48 FR 13026, Mar. 29,
blood collecting, processing, and stor- 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373,
age system. Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR
(2) Cryoprecipitated AHF shall be re- 40890, Aug. 6, 2001; 72 FR 45888, Aug. 16, 2007]
moved as prescribed in subpart F of
part 640. The remaining plasma shall be Subpart E [Reserved]
labeled ‘‘Plasma, Cryoprecipitate Re-
duced.’’ Subpart F—Cryoprecipitate
(3) Plasma remaining after both
Platelets and Cryoprecipitated AHF § 640.50 Cryoprecipitated AHF.
have been removed may be labeled
(a) Proper name and definition. The
‘‘Plasma, Cryoprecipitate Reduced.’’
proper name of this product shall be
(f) The final container. (1) The final Cryoprecipitated AHF. The product is
container shall have no color added to defined as a preparation of
the plastic and shall be transparent to antihemophilic factor, which is ob-
permit visual inspection of the contained from a single unit of plasma col-
tents; any closure shall maintain a her- lected and processed in a closed sys-
metic seal and prevent contamination tem.
of the contents. (b) Source. The source material for
(2) The final container material shall Cryoprecipitated AHF shall be plasma
not interact with the contents, under which may be obtained by whole blood
the customary conditions of storage collection or by plasmapheresis.
and use, in such a manner as to have an
adverse effect upon the safety, purity, [42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar.
potency, and effectiveness of the prod- 29, 1983, as amended at 50 FR 4139, Jan. 29,
1985]
uct.
(3) Prior to filling, the final con- § 640.51 Eligibility of donors.
tainer shall be identified by number so
as to relate it to the donor. (a) Whole blood donors must meet
(g) The final product. (1) The final the criteria for eligibility prescribed in
product shall be inspected immediately §§ 630.10 and 630.15 of this chapter.
after separation of the plasma and (b) Collection establishments must
shall not be issued for transfusion if determine the eligibility of plasma-
there is (i) any abnormality in color or pheresis donors in accordance with
physical appearance, or (ii) any indica- §§ 630.10 and 630.15 of this chapter.
tion of contamination. [80 FR 29905, May 22, 2015]
(2) With the exception of Platelet
Rich Plasma and Liquid Plasma the § 640.52 Collection of source material.
final product shall be inspected for evi- (a) Whole blood used as a source of
dence of thawing or breakage at the Cryoprecipitated AHF shall be col-
time of issuance, however, the con- lected as prescribed in § 640.4. Whole
tainers need not be stored in a manner blood from which both Platelets and
that shows evidence of thawing if Cryoprecipitated AHF is derived shall
records of continuous monitoring of be maintained as required under § 640.24
the storage temperature establish that until the platelets are removed.
the temperature remained at ¥18 °C or (b) If plasmapheresis is used, the pro-
colder. If continuous monitoring of the cedure for collection shall be as pre-
product is not available, the final prod- scribed in § 640.64 (except that para-
uct shall be stored in a manner that graph (c)(3) of that section shall not
will show evidence of thawing and shall apply), and 640.65.
not be issued if there is any evidence of
[42 FR 21774, Apr. 29, 1977, as amended at 50

thawing. FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19,
1999; 80 FR 29905, May 22, 2015]
103
§ 640.53 21 CFR Ch. I (4–1–20 Edition)
§ 640.53 Testing the blood. less and transparent to permit visual

(a) Blood from which plasma is sepa- inspection of the contents; any closure
rated for the preparation of shall maintain a hermetic seal and pre-
Cryoprecipitated AHF shall be tested vent contamination of the contents.
as prescribed in § 610.40 of this chapter The container material shall not inter-
and § 640.5 (b) and (c). act with the contents under customary
(b) The tests shall be performed on a conditions of storage and use in such a
sample of blood collected at the time of manner as to have an adverse effect
collecting the source blood, and such upon the safety, purity, potency and ef-
sample container shall be labeled with fectiveness of the product. At the time
the donor’s number before the con- of filling, the final container shall be
tainer is filled. identified by a number so as to relate
(c) Manufacturers of it to the donor.
Cryoprecipitated AHF obtained from [42 FR 21774, Apr. 29, 1977, as amended at 47
plasma collected by plasmapheresis FR 15330, Apr. 9, 1982; 50 FR 4139, Jan. 29,
shall have testing and record-keeping 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837,
responsibilities equivalent to those Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]
prescribed in §§ 640.71 and 640.72.
§ 640.55 U.S. Standard preparation.
[42 FR 21774, Apr. 29, 1977, as amended at 42 A U.S. Standard Antihemophilic Fac-
FR 37546, July 22, 1977; 42 FR 43063, Aug. 26,
1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan.
tor (Factor VIII) preparation may be
5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, obtained from the Center for Biologics
May 22, 2015] Evaluation and Research, (HFM–407)
(see mailing addresses in § 600.2 of this
§ 640.54 Processing. chapter) for use in the preparation of a
(a) Processing the plasma. (1) The plas- working reference to be employed in a
ma shall be separated from the red quality control potency test of
blood cells by centrifugation to obtain Cryoprecipitated AHF.
essentially cell-free plasma. [42 FR 21774, Apr. 29, 1977, as amended at 49
(2) The plasma shall be placed in a FR 23834, June 8, 1984; 50 FR 4140, Jan. 29,
freezer within 8 hours after blood col- 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985,
lection or within the timeframe speci- Mar. 24, 2005]
fied in the directions for use for the
blood collecting, processing, and stor- § 640.56 Quality control test for po-
age system. A combination of dry ice tency.
and organic solvent may be used for (a) Quality control tests for potency
freezing: Provided, That the procedure of antihemophilic factor shall be con-
has been shown not to cause the sol- ducted each month on at least four rep-
vent to penetrate the container or resentative containers of
leach plasticizer from the container Cryoprecipitated AHF.
into the plasma. (b) The results of each test are re-
(3) Immediately after separation and ceived by the establishment licensed
freezing of the plasma, the plasma for Cryoprecipitated AHF within 30
shall be stored and maintained at ¥18 days of the preparation of the
°C or colder until thawing of the plas- cryoprecipitated antihemophilic factor
ma for further processing to remove and are maintained at that establish-
the Cryoprecipitated AHF. ment so that they may be reviewed by
(b) Processing the final product. (1) The an authorized representative of the
Cryoprecipitated AHF shall be sepa- Food and Drug Administration.
rated from the plasma by a procedure (c) The quality control test for po-
that has been shown to produce an av- tency may be performed by a clinical
erage of no less than 80 units of laboratory which meets the standards
antihemophilic factor per final con- of the Clinical Laboratories Improve-
tainer. ment Amendments of 1988 (CLIA) (42
(2) No diluent shall be added to the U.S.C. 263a) and is qualified to perform
product by the manufacturer prior to potency tests for antihemophilic fac-
freezing. tor. Such arrangements must be ap-
(3) The final container used for proved by the Director, Center for Bio-
Cryoprecipitated AHF shall be color- logics Evaluation and Research, Food
104
and Drug Administration. Such testing (d) Donor identification. Each unit of
shall not be considered as divided man- blood and plasma shall be so marked or
ufacturing, as described in § 610.63 of identified by number or other symbol
this chapter, provided the following so as to relate it directly to the donor.
conditions are met: (e) Prevention of contamination of the
(1) The establishment licensed for blood and plasma. The skin of the donor
Cryoprecipitated AHF has obtained a at the site of phlebotomy shall be pre-
written agreement that the testing lab- pared thoroughly and carefully by a
oratory will permit an authorized rep- method that gives maximum assurance
resentative of the Food and Drug Ad- of a sterile container of blood. The
ministration to inspect its testing pro- blood shall be collected, the plasma
cedures and facilities during reason- separated, and the cells returned to the
able business hours. donor by aseptic methods in a sterile
(2) The testing laboratory will par- system which may be closed, or may be
ticipate in any proficiency testing pro- vented if the vent protects the blood
grams undertaken by the Center for cells and plasma against contamina-
Biologics Evaluation and Research, tion.
Food and Drug Administration. [38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr.
(d) If the average potency level of 16, 1974, as amended at 41 FR 10768, Mar. 12,
antihemophilic factor in the containers 1976; 49 FR 23834, June 8, 1984; 50 FR 4140,
tested is less than 80 units of Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR
antihemophilic factor per container, 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998;
immediate corrective actions shall be 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16,
taken and a record maintained of such 2007; 80 FR 29905, May 22, 2015]
action.
§ 640.65 Plasmapheresis.
(a) Procedure-general. The plasma-
FR 23834, June 8, 1984; 50 FR 4140, Jan. 29,
1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, pheresis procedure is a procedure in
Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001] which, during a single visit to the es-
tablishment, blood is removed from a
donor, the plasma separated from the
Subpart G—Source Plasma formed elements, and at least the red
§ 640.60 Source Plasma. blood cells returned to the donor. This
procedure shall be described in detail
The proper name of the product shall in the biologics license application.
be Source Plasma. The product is de- (b) Procedures-specific requirements.
fined as the fluid portion of human The plasmapheresis procedure shall
blood collected by plasmapheresis and meet the following requirements:
intended as source material for further (1)(i) Except as provided under § 630.25
manufacturing use. The definition ex- of this chapter, the responsible physi-
cludes single donor plasma products in- cian must draw a sample of blood from
tended for intravenous use. each donor on the day of the initial
[41 FR 10768, Mar. 12, 1976, as amended at 50 physical examination or plasma-
FR 4140, Jan. 29, 1985] pheresis, whichever comes first, and at
least every 4 months thereafter. A se-
§ 640.64 Collection of blood for Source rologic test for syphilis, a total plasma
Plasma. or serum protein determination, and a
(a) [Reserved] plasma or serum protein electro-
(b) Blood containers. Blood containers phoresis or quantitative immuno-diffu-
and donor sets must be pyrogen-free, sion test or an equivalent test to deter-
sterile, and identified by lot number. mine immunoglobulin composition of
(c) The anticoagulant solution. The the plasma or serum shall be performed
anticoagulant solution must be sterile on the sample.
and pyrogen-free. Anticoagulant solu- (ii) A repeat donor who does not re-
tions must be compounded and used ac- turn for plasmapheresis at the time the
cording to a formula that has been ap- 4-month sample is due to be collected
proved for the applicant by the Direc- may be plasmapheresed on the day he
tor, Center for Biologics Evaluation appears: Provided, That no longer than
and Research. 6 months has elapsed since the last
105
§ 640.65 21 CFR Ch. I (4–1–20 Edition)
sample was collected, and the respon- false-positive reaction is not the result
sible physician approves the plasma- of an underlying disorder that would
pheresis procedure and so indicates by disqualify the donor from participation
signing the donor’s record before such in the plasmapheresis program. If the
procedure is performed. The sample for serologic test for syphilis is performed
the 4–month tests shall be collected on at a facility other than the plasma-
the day of the donor’s return. pheresis center, all applicable provi-
(iii) A repeat donor from whom the sions of § 640.71 shall be met.
plasmapheresis center is unable to ob- (iv) A donor with a reactive serologic
tain a sample for testing as prescribed test for syphilis may be
in paragraph (b)(1)(i) of this section for plasmapheresed only to obtain plasma
a total period exceeding 6 months shall to be used for further manufacturing
be processed as a new donor. into control serum for the serologic
(2)(i) Except as provided under § 630.25 test for syphilis: Provided, That the re-
of this chapter, the responsible physi- sponsible physician approves the dona-
cian must review the accumulated lab- tion, the donor’s file contains a signed
oratory data, including any tracings of statement from a physician or clinic
the plasma or serum protein electro- establishing that treatment for syphi-
phoresis pattern, the calculated values lis has been initiated and that continu-
of the protein composition of each ance in the plasmapheresis program
component, and the collection records will not interfere with or jeopardize
within 14 calendar days after the sam- the treatment of the syphilitic donor.
ple is drawn to determine whether or
(3) A donor identification system
not the donor should be deferred from
shall be established that positively
further donation. If a determination is
identifies each donor and relates such
not made within 14 calendar days, the
donor directly to his blood and its com-
donor must be deferred pending such a
ponents as well as to his accumulated
determination. The responsible physi-
records and laboratory data. Such sys-
cian must sign the review. If the pro-
tem shall include either a photograph
tein composition is not within normal
of each donor which shall be used on
limits established by the testing lab-
each visit to confirm the donor’s iden-
oratory, or if the total protein level is
tity, or some other method that pro-
less than 6.0 grams per deciliter or
more than 9.0 grams per deciliter in a vides equal or greater assurance of
plasma sample or serum sample, the positively identifying the donor.
donor must be deferred from donation (4) The amount of whole blood, not
until the protein composition returns including anticoagulant, removed from
to acceptable levels. Reinstatement of a donor during a manual plasma-
the donor into the plasmapheresis pro- pheresis procedure or in any 2-day pe-
gram when the donor’s protein com- riod shall not exceed 1,000 milliliters
position values have returned to an ac- unless the donor’s weight is 175 pounds
ceptable level must first be approved or greater, in which case the amount of
by the responsible physician. whole blood, not including anticoagu-
(ii) A donor with a reactive serologic lant, removed from the donor during a
test for syphilis shall not be manual plasmapheresis procedure or in
plasmapheresed again until the donor’s any 2-day period shall not exceed 1,200
serum is tested and found to be non- milliliters.
reactive to a serologic test for syphilis, (5) The amount of whole blood, not
except as provided in paragraph (b)(2) including anticoagulant, removed from
(iii) and (iv) of this section. a donor during a manual plasma-
(iii) A donor whose serum is deter- pheresis procedure within a 7-day pe-
mined to have a biologic false-positive riod shall not exceed 2,000 milliliters
reaction to a serologic test for syphilis unless the donor’s weight is 175 pounds
may be plasmapheresed: Provided, That or greater, in which case the amount of
the donor’s file identifies the serologic whole blood, not including anticoagu-
test for syphilis and results used to lant, removed from a donor during a
confirm the biologic false-positive re- manual plasmapheresis procedure
action and indicates that the respon- within a 7-day period shall not exceed
sible physician has determined the 2,400 milliliters.
106
(6) No more than 500 milliliters of § 640.68 Processing.

whole blood shall be removed from a
(a) Sterile system. All administration
donor at one time, unless the donor’s and transfer sets inserted into blood
weight is 175 pounds or greater, in containers used for processing Source
which case no more than 600 milliliters Plasma intended for manufacturing
of whole blood shall be removed from into injectable or noninjectable prod-
the donor at one time. ucts and all interior surfaces of plasma
(7) The plasma shall be separated containers used for processing Source
from the red blood cells immediately Plasma intended for manufacturing
after blood collection. The maximum into injectable products shall be ster-
feasible volume of red blood cells shall ile, pyrogen-free, nontoxic, and com-
be returned to the donor before another patible with the contents under normal
unit is collected. conditions of use. Only Sodium Chlo-
(8) The volume of plasma collected ride Injection USP shall be used as a
during an automated plasmapheresis red blood cell diluent. If the method of
collection procedure shall be con- separation of the plasma intended for
sistent with the volumes specifically injectable products involves a system
approved by the Director, Center for in which an airway must be inserted
Biologics Evaluation and Research, and into the plasma container, the airway
collection shall not occur less than 2 shall be sterile and constructed so as to
days apart or more frequently than exclude microorganisms and maintain
twice in a 7-day period. a sterile system.
(b) Final containers. Final containers
[38 FR 32089, Nov. 20, 1973, as amended at 41 used for Source Plasma, whether inte-
FR 10769, Mar. 12, 1976; 64 FR 45373, Aug. 19, grally attached or separated from the
1999; 64 FR 56453, Oct. 20, 1999; 80 FR 29905, original blood container, shall not be
May 22, 2015]
entered prior to issuance for any pur-
pose except for filling with the plasma.
§ 640.66 Immunization of donors.
Such containers shall be uncolored and
If specific immunization of a donor is hermetically sealed, and shall permit
to be performed, the selection, sched- clear visibility of the contents. Final
uling and administration of the anti- containers and their components shall
gen, and the evaluation of each donor’s not interact with the plasma contents
clinical response, shall be by the re- under conditions of storage and use so
sponsible physician. Any material used as to alter the safety, quality, purity,
for immunization shall be either a or potency of the plasma and shall pro-
product licensed under section 351 of vide adequate protection against exter-
the Public Health Service Act for such nal factors that may cause deteriora-
purpose or one specifically approved by tion or contamination. Prior to filling,
the Director, Center for Biologics Eval- the final container shall be marked or
uation and Research, Food and Drug identified by number or other symbol
Administration. Immunization proce- which will relate it directly to the
dures shall be on file at each plasma- donor.
pheresis center where immunizations (c) Preservative. Source Plasma shall
are performed. not contain a preservative.
[38 FR 32089, Nov. 20, 1973, as amended at 49 [38 FR 32089, Nov. 20, 1973, as amended at 41
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, FR 10769, Mar. 12, 1976; 50 FR 4140, Jan. 29,
1990; 80 FR 29905, May 22, 2015] 1985]
§ 640.67 Laboratory tests. § 640.69 General requirements.

(a) Pooling. Two units of Source Plas-
Each unit of Source Plasma shall be
ma from the same donor may be pooled
tested for evidence of infection due to
if such units are collected during one
plasmapheresis procedure: Provided,
tions as required under § 610.40 of this
That the pooling is done by a procedure
chapter.
that does not introduce a risk of con-
[66 FR 31165, June 11, 2001, as amended at 80 tamination of the red blood cells and,
FR 29905, May 22, 2015] for plasma intended for injectable
107
§ 640.71 21 CFR Ch. I (4–1–20 Edition)
products, gives maximum assurance of (4) All samples shall be collected in a

a sterile container of plasma. manner that does not contaminate the
(1) The pooling of plasma from two or contents of the final container.
more donors is not permitted in the (e) Restrictions on distribution. Estab-
manufacture of Source Plasma in- lishments must ensure that Source
tended for manufacturing into Plasma donated by paid donors not be
injectable products. used for further manufacturing into
(2) The pooling of plasma from two or injectable products until the donor has
more donors by the manufacturer of a record of being found eligible to do-
Source Plasma intended for manufac- nate in accordance with § 630.10 of this
chapter and a record of negative test
turing into noninjectable products is
results on all tests required under
permitted: Provided, That the plasma
§ 610.40(a) of this chapter on two occa-
from two or more donors is pooled after
sions in the past 6 months.
the plasma has been removed from the (f) Hold. Source Plasma donated by
red blood cells, and after the red blood paid donors determined to be suitable
cell containers are sealed. for further manufacturing into
(b) Storage. Immediately after filling, injectable products must be held in
plasma intended for manufacturing quarantine for a minimum of 60 cal-
into injectable products shall be stored endar days before it is released for fur-
at a temperature not warmer than ¥20 ther manufacturing. If, after placing a
°C, except for plasma collected as pro- donation in quarantine under this sec-
vided in § 640.74. Plasma intended for tion, the donor is subsequently de-
manufacturing into noninjectable ferred under § 610.41 of this chapter, or
products may be stored at tempera- you subsequently determine a donor to
tures appropriate for the intended use be ineligible under § 630.10 of this chap-
of the final product, provided these ter due to risk factors closely associ-
temperatures are included in the ated with exposure to, or clinical evi-
Source Plasma license application. dence of, infection due to a relevant
(c) Inspection. Source Plasma in- transfusion-transmitted infection, you
tended for manufacturing into must not distribute quarantined dona-
injectable products shall be inspected tions from that donor for further man-
for evidence of thawing at the time of ufacturing use to make an injectable
issuance, except that inspection of in- product.
dividual plasma containers need not be [38 FR 32089, Nov. 20, 1973, as amended at 41
made if the records of continuous mon- FR 10769, Mar. 12, 1976; 41 FR 14367, Apr. 5,
itoring of the storage temperature es- 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685,
tablish that the temperature remained Apr. 6, 1998; 64 FR 45374, Aug. 19, 1999; 80 FR
at ¥20 °C or colder. If there is evidence 29905, May 22, 2015]
that the storage temperature has not § 640.71 Manufacturing responsibility.
been maintained at ¥20 °C or colder,
the plasma may be relabeled and issued (a) All steps in the manufacturing of
as provided in § 640.76(a). Source Plasma, including donor exam-
ination, blood collection, plasma-
(d) Samples. If samples are provided,
pheresis, laboratory testing, labeling,
they shall meet the following stand-
storage, and issuing shall be performed
ards:
by personnel of the establishment li-
(1) Prior to filling, all samples shall censed to manufacture Source Plasma,
be marked or identified so as to relate except that testing performed in ac-
them directly to the donor of that unit cordance with § 610.40 of this chapter
of plasma. and § 640.65(b) may be performed by per-
(2) All samples shall be filled at the sonnel of an establishment licensed for
time the final product is prepared by blood and blood derivatives under sec-
the person who prepares the final prod- tion 351(a) of the Public Health Service
uct. Act, or by a clinical laboratory that
(3) All samples shall be representa- meets the standards of the Clinical
tive of the contents of the final product Laboratories Improvement Amend-
or be collected from the donor at the ments of 1988 (CLIA) (42 U.S.C. 263a):
time of filling the collection container. Provided, The establishment or clinical
108
laboratory is qualified to perform the such information is maintained on the

assigned test(s). premises of the plasmapheresis center
(b) Such testing shall not be consid- where the donor’s plasma has been col-
ered divided manufacturing, which re- lected.
quires two biologics licenses for Source (3) The original or a clear copy or
Plasma: Provided, That other durable record which may be
(1) The results of such tests are main- electronic of the donor’s consent for
tained by the licensed manufacturer of participation in the plasmapheresis
the Source Plasma whereby such re- program or for immunization.
sults may be reviewed by a responsible (4) Records of the medical history
physician as required in § 640.65(b)(2) of and physical examination of the donor
this chapter and by an authorized rep- conducted in accordance with
resentative of the Food and Drug Ad- § 630.15(b)(1) of this chapter and, where
ministration. applicable, § 630.15(b)(5) of this chapter
(2) The Source Plasma manufacturer must document the eligibility of the
has obtained a written agreement that donor as a plasmapheresis donor and,
the testing laboratory will permit au- when applicable, as an immunized
thorized representatives of the Food donor.
and Drug Administration to inspect its (5) If plasma that is reactive to a se-
testing procedures and facilities during rologic test for syphilis is issued as
reasonable business hours. prescribed in § 640.65(b)(2)(iv), the dis-
(3) The testing laboratory will par- tribution records shall indicate by
ticipate in any proficiency testing pro- number those units that are reactive.
grams undertaken by the Center for (b) Each donor record must be di-
Biologics Evaluation and Research, rectly cross-referenced to the unit(s) of
Food and Drug Administration. Source Plasma associated with the
[41 FR 10770, Mar. 12, 1976, as amended at 49 donor.
FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, (c) If a repeat donor is rejected or a
1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. donor’s plasma is found unsuitable, the
26, 1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, donor’s record shall contain a full ex-
Oct. 20, 1999; 66 FR 1837, Jan. 10, 2001; 80 FR planation for the rejection.
29905, May 22, 2015]
(d) If a donor has a reaction while on
§ 640.72 Records. the plasmapheresis premises, or a
donor reaction is reported to the center
(a) In addition to the recordkeeping after the donor has left the premises,
requirements of this subchapter, the the donor’s record shall contain a full
following records shall be maintained: explanation of the reaction, including
(1) Documentation shall be available the measures taken to assist the donor
to ensure that the shipping tempera- and the outcome of the incident.
ture requirements of § 600.15 of this
title and of § 640.74(b)(2) are being met [41 FR 10770, Mar. 12, 1976, as amended at 50
for Source Plasma intended for manu- FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988;
facture into injectable products. 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4,
2002; 80 FR 29905, May 22, 2015]
(2)(i) For each donor, establishments
must maintain records including a sep- § 640.73 Reporting of fatal donor reac-
arate and complete record of initial tions.
and periodic examinations, tests, lab-
oratory data, and interviews, etc., as If a donor has a fatal reaction which,
required in §§ 630.10 and 630.15 of this in any way, may be associated with
chapter and §§ 640.65, 640.66, and 640.67, plasmapheresis the Director of the Cen-
except as provided in paragraph ter for Biologics Evaluation and Re-
(a)(2)(ii) of this section. search shall be notified by telephone as
(ii) Negative results for testing for soon as possible. If the facility is lo-
evidence of infection due to relevant cated outside of the continental United
transfusion-transmitted infections re- States, notification by cable or tele-
quired in § 610.40 of this chapter, and gram shall be acceptable.
the volume or weight of plasma with-

drawn from a donor need not be re- FR 23834, June 8, 1984; 55 FR 11013, Mar. 26,
corded on the individual donor record if 1990]
109
§ 640.74 21 CFR Ch. I (4–1–20 Edition)
§ 640.74 Modification of Source Plas- the unit of Source Plasma Liquid shall
ma. not be issued.
(a) Upon approval by the Director, [38 FR 32089, Nov. 20, 1973. Redesignated and
Center for Biologics Evaluation and amended at 41 FR 10770, Mar. 12, 1976; 49 FR
Research, Food and Drug Administra- 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55
tion, of a supplement to the biologics FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28,
1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56454,
license application for Source Plasma,
Oct. 20, 1999; 77 FR 18, Jan. 3, 2012]
a manufacturer may prepare Source
Plasma as a liquid product for a li- § 640.76 Products stored or shipped at
censed blood derivative manufacturer unacceptable temperatures.
who has indicated a need for a liquid
(a) Storage temperature. (1) Except as
product.
provided in paragraph (a)(2) of this sec-
(b) Source Plasma Liquid shall meet tion, Source Plasma intended for man-
all standards of the frozen Source Plas- ufacture into injectable products that
ma except: is inadvertently exposed (i.e., an un-
(1) Source Plasma Liquid shall be foreseen occurrence in spite of compli-
stored in nonleachable containers so ance with good manufacturing prac-
that the containers and their compo- tice) to a storage temperature warmer
nents will not interact with the plasma than ¥20 °C and colder than + 10 °C
contents under conditions of storage may be issued only if labeled as
and use so as to alter the safety, qual- ‘‘Source Plasma Salvaged.’’ The label
ity, purity, or potency of the plasma shall be revised before issuance, and
and shall provide adequate protection appropriate records shall be main-
against external factors that may tained identifying the units involved,
cause deterioration or contamination. describing their disposition, and ex-
(2) Source Plasma Liquid shall be plaining fully the conditions that
shipped, stored and labeled for storage caused the inadvertent temperature ex-
at a temperature of 10 °C or colder. An posure.
exception to the shipping or storage (2) Source Plasma intended for manu-
temperature shall be approved by the facture into injectable products that is
Director, Center for Biologics Evalua- exposed inadvertently (i.e., an unfore-
tion and Research, Food and Drug Ad- seen occurrence in spite of compliance
ministration, based upon his receipt of with good manufacturing practice) to
substantial evidence to support an- one episode of storage temperature
other temperature. Such evidence may fluctuation that is warmer than ¥20 °C
be submitted by either the licensed and colder than ¥5 °C for not more
manufacturer of the Source Plasma than 72 hours is exempt from the label-
Liquid or the manufacturer of the final ing requirements of paragraph (a)(1) of
blood derivative product who has re- this section, provided that the plasma
quested the Source Plasma Liquid. has been and remains frozen solid. Ap-
(3) The label for the Source Plasma propriate records shall be maintained
Liquid shall be easily distinguished identifying the units involved, describ-
from that of the frozen product. Color ing their disposition, explaining fully
coding shall not be used for this pur- the conditions that caused the inad-
pose. vertent temperature exposure, and doc-
(4) The label affixed to each con- umenting that the episode of tempera-
tainer of Source Plasma Liquid shall ture elevation did not exceed 72 hours,
contain, in addition to the information that the temperature did not rise to
required by § 606.121 of this chapter, but warmer than ¥5 °C in storage, and that
excluding § 606.121(e)(5)(ii) of this chap- the plasma remained frozen solid
ter, the name of the manufacturer of throughout the period of elevated tem-
the final blood derivative product for perature. When requested, copies of the
whom it was prepared. records shall be provided to the plasma
(5) Source Plasma Liquid shall be in- derivative manufacturer.
spected immediately prior to issuance. (b) Shipping temperature. If Source
If the color or physical appearance is Plasma for manufacture into injectable
abnormal, or there is any indication or products is exposed inadvertently (i.e.,

suspicion of microbial contamination, an unforeseen occurrence in spite of
110
compliance with good manufacturing (b) Processing method. The processing

practice) to a shipping temperature method shall not affect the integrity of
warmer than ¥5 °C and colder than + 10 the product, and shall have been shown
°C, the plasma derivative manufacturer to yield consistently a product which is
shall label it ‘‘Source Plasma safe for intravenous injection.
Salvaged.’’ Appropriate records shall (c) Microbial contamination. All proc-
be maintained identifying the units in- essing steps shall be conducted in a
volved, describing their disposition, manner to minimize the risk of con-
and explaining fully the conditions tamination from microorganisms,
that caused the inadvertent tempera- pyrogens, or other impurities. Preserv-
ture exposure. atives to inhibit growth of microorga-
(c) Relabeling. If Source Plasma is re- nisms shall not be used during proc-
quired to be relabeled as ‘‘Source Plas- essing.
ma Salvaged’’ under paragraph (a)(1) or (d) Storage of bulk fraction. Bulk con-
(b) of this section, the person respon- centrate to be held more than 1 week
sible for the relabeling shall cover the prior to further processing shall be
original label with either (1) a com- stored in clearly identified closed ves-
plete new label containing the appro- sels at a temperature of ¥5 °C or cold-
priate information or (2) a partial label er. Any other bulk form of the product,
affixed to the original label and con- exclusive of the sterile bulk solution,
taining the appropriate new informa- to be held more than 1 week prior to
tion, which covers the incorrect infor- further processing shall be stored in
mation regarding storage temperature. clearly identified closed vessels at a
temperature of 5 °C or colder. Any bulk
[45 FR 80501, Dec. 5, 1980, as amended at 50 fraction to be held one week or less
FR 4140, Jan. 29, 1985] prior to further processing shall be
stored in clearly identified closed ves-
Subpart H—Albumin (Human) sels at a temperature of 5 °C or colder.
(e) Heat treatment. Heating of the
§ 640.80 Albumin (Human). final containers of Albumin (Human)
(a) Proper name and definition. The shall begin within 24 hours after com-
proper name of the product shall be Al- pletion of filling. Heat treatment shall
bumin (Human). The product is defined be conducted so that the solution is
as a sterile solution of the albumin de- heated continuously for not less than
rived from human plasma. 10, or more than 11 hours, at an at-
(b) Source material. The source mate- tained temperature of 60±0.5 °C.
rial of Albumin (Human) shall be plas- (f) Stabilizer. Either 0.08±0.016
ma recovered from Whole Blood pre- millimole sodium caprylate, or
pared as prescribed in §§ 640.1 through 0.08±0.016 millimole sodium
640.5, or Source Plasma prepared as acetyltryptophanate and 0.08±0.016
prescribed in §§ 640.60 through 640.76. millimole sodium caprylate per gram
(c) Additives in source material. Source of protein shall be present as a sta-
material shall not contain an additive bilizer(s). Calculations of the stabilizer
unless it is shown that the processing concentration may employ the labeled
method yields a final product free of value for the protein concentration of
the additive to such extent that the the product as referred to in § 640.84(d).
continued safety, purity, potency, and (g) Incubation. All final containers of
effectiveness of the final product will Albumin (Human) shall be incubated at
not be adversely affected. 20 to 35 °C for at least 14 days following
the heat treatment prescribed in para-
[42 FR 27582, May 31, 1977, as amended at 50 graph (e) of this section. At the end of
FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, this incubation period, each final con-
1999] tainer shall be examined and all con-
tainers showing any indication of tur-
§ 640.81 Processing. bidity or microbial contamination
(a) Date of manufacture. The date of shall not be issued. The contents of
manufacture shall be the date of final turbid final containers shall be exam-
sterile filtration of a uniform pool of ined microscopically and tested for ste-
bulk solution. rility. If growth occurs, organisms
111
§ 640.82 21 CFR Ch. I (4–1–20 Edition)
shall be identified as to genus, and the temperature that shall not exceed the
material from such containers shall recommended storage temperature of
not be used for further manufacturing. the final product prescribed in § 610.53
[42 FR 27582, May 31, 1977, as amended at 50
of this chapter.
FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, [42 FR 27582, May 31, 1977]
1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018,
Aug. 28, 2000] § 640.84 Labeling.
§ 640.82 Tests on final product. In addition to the labeling require-
ments of §§ 610.60, 610.61, and 610.62 of
Tests shall be performed on the final this chapter, the container and pack-
product to determine that it meets the age labels shall contain the following
following standards: information:
(a) Protein concentration. Final prod- (a) The osmotic equivalent in terms
uct shall conform to one of the fol- of plasma, and the sodium concentra-
lowing concentrations: 4.0 ±0.25 per- tion in terms of a value or a range in
cent; 5.0 ±0.30 percent; 20.0 ±1.2 percent; milliequivalents per liter;
and 25.0 ±1.5 percent solution of pro- (b) The cautionary statement placed
tein. in a prominent position on the label,
(b) Protein composition. At least 96
‘‘Do Not Use if Turbid. Do Not Begin
percent of the total protein in the final
Administration More Than 4 Hours
product shall be albumin, as deter-
After the Container Has Been En-
mined by a method that has been ap-
tered.’’;
proved for each manufacturer by the
(c) The need for additional fluids
when 20 percent or 25 percent albumin
tion and Research, Food and Drug Ad-
is administered to a patient with
ministration.
marked dehydration;
(c) pH. The pH shall be 6.9 ±0.5 when
(d) The protein concentration, ex-
measured in a solution of the final
pressed as a 4 percent, 5 percent, 20 per-
product diluted to a concentration of 1
cent, or 25 percent solution.
percent protein with 0.15 molar sodium
chloride. [42 FR 27582, May 31, 1977, as amended at 49
(d) Sodium concentration. The sodium FR 2244, Jan. 19, 1984; 64 FR 26286, May 14,
concentration of the final product shall 1999]
be 130 to 160 milliequivalents per liter.
(e) Potassium concentration. The po- Subpart I—Plasma Protein Fraction
tassium concentration of the final (Human)
product shall not exceed 2 milli-
equivalents per liter. SOURCE: 42 FR 27583, May 31, 1977, unless
(f) Heat stability. A final container otherwise noted.
sample of Albumin (Human) shall re-
main unchanged, as determined by vis- § 640.90 Plasma Protein Fraction
ual inspection, after heating at 57 °C (Human).
for 50 hours, when compared to its con- (a) Proper name and definition. The
trol consisting of a sample, from the proper name of the product shall be
same lot, which has not undergone this Plasma Protein Fraction (Human). The
heating. product is defined as a sterile solution
[42 FR 27582, May 31, 1977, as amended at 49 of protein composed of albumin and
FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, globulin, derived from human plasma.
1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, (b) Source material. The source mate-
May 14, 1999] rial of Plasma Protein Fraction
(Human) shall be plasma recovered
§ 640.83 General requirements. from Whole Blood prepared as pre-
(a) Preservative. The final product scribed in §§ 640.1 through 640.5, or
shall not contain a preservative. Source Plasma prepared as prescribed
(b) Storage of bulk solution. After all in §§ 640.60 through 640.76.
processing steps have been completed, (c) Additives in source material. Source
the sterile bulk solution shall be stored material shall not contain an additive
in a manner that will ensure the con- unless it is shown that the processing
tinued sterility of the product, and at a method yields a final product free of
112
the additive to such extent that the (f) Stabilizer. Either 0.08±0.016
continued safety, purity, potency, and millimole sodium caprylate, or
effectiveness of the final product will 0.08±0.016 millimole sodium
not be adversely affected. acetyltryptophanate and 0.08±0.016
millimole sodium caprylate per gram
of protein shall be present as a sta-
FR 26286, May 14, 1999]
bilizer(s). Calculations of the stabilizer
§ 640.91 Processing. concentration may employ the labeled
value 5 percent for the protein con-
(a) Date of manufacture. The date of centration of the product.
manufacture shall be the date of final (g) Incubation. All final containers of
sterile filtration of a uniform pool of Plasma Protein Fraction (Human)
bulk solution. shall be incubated at 20 to 35 °C for at
(b) Processing method. The processing least 14 days following the heat treat-
method shall not affect the integrity of ment prescribed in paragraph (e) of this
the product, and shall have been shown section. At the end of this incubation
to yield consistently a product which: period, each final container shall be ex-
(1) After the heating prescribed in amined and all containers showing any
paragraph (e) of this section does not indication of turbidity or microbial
show an increase in the components contamination shall not be issued. The
with electrophoretic mobility similar contents of turbid final containers
to that of alpha globulin that amounts shall be examined microscopically and
to more than 5 percent of the total pro- tested for sterility. If growth occurs,
tein. the types of organisms shall be identi-
(2) Contains less than 5 percent pro- fied as to genus and the material from
tein with a sedimentation coefficient such containers shall not be used for
greater than 7.0 S. further manufacturing.
(3) Is safe for intravenous injection. [42 FR 27583, May 31, 1977, as amended at 64
(c) Microbial contamination. All proc- FR 26286, May 14, 1999]
essing steps shall be conducted in a
manner to minimize the risk of con- § 640.92 Tests on final product.
tamination from microorganisms, Tests shall be performed on the final
pyrogens, or other impurities. Preserv- product to determine that it meets the
atives to inhibit growth of microorga- following standards:
nisms shall not be used during proc- (a) Protein concentration. The final
essing. product shall be a 5.0 ±0.30 percent so-
(d) Storage of bulk fraction. Bulk con- lution of protein.
centrate to be held more than 1 week (b) Protein composition. The total pro-
prior to further processing shall be tein in the final product shall consist
stored in clearly identified closed ves- of at least 83 percent albumin, and no
sels at a temperature of ¥5 °C or cold- more than 17 percent globulins. No
er. Any other bulk form of the product more than 1 percent of the total pro-
(exclusive of the sterile bulk solution) tein shall be gamma globulin. The pro-
to be held more than 1 week prior to tein composition shall be determined
further processing, shall be stored in by a method that has been approved for
clearly identified closed vessels at a each manufacturer by the Director,
temperature of 5 °C or colder. Any bulk Center for Biologics Evaluation and
fraction to be held one week or less Research, Food and Drug Administra-
prior to further processing shall be tion.
stored in clearly identified closed ves- (c) pH. The pH shall be 7.0 ±0.3 when
sels at a temperature of 5 °C or colder. measured in a solution of the final
(e) Heat treatment. Heating of the product diluted to a concentration of 1
final containers of Plasma Protein percent protein with 0.15 molar sodium
Fraction (Human) shall begin within 24 chloride.
hours after completion of filling. Heat (d) Sodium concentration. The sodium
treatment shall be conducted so that concentration of the final product shall
the solution is heated continuously for be 130 to 160 milliequivalents per liter.
not less than 10 or more than 11 hours (e) Potassium concentration. The po-
at an attained temperature of 60±0.5 °C. tassium concentration of the final
113
§ 640.93 21 CFR Ch. I (4–1–20 Edition)
product shall not exceed 2 milli- (b) Source material. The source mate-
equivalents per liter. rial of Immune Globulin (Human) shall
(f) Heat stability. A final container be plasma recovered from Whole Blood
sample of Plasma Protein Fraction prepared as prescribed in §§ 640.1
(Human) shall remain unchanged, as through 640.5, or Source Plasma pre-
determined by visual inspection, after pared as prescribed in §§ 640.60 through
heating at 57 °C for 50 hours, when 640.76.
compared to its control consisting of a (c) Additives in source material. The
sample, from the same lot, which has source material shall contain no addi-
not undergone this heating. tives other than citrate or acid citrate
dextrose anticoagulant solution, unless
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26,
it is shown that the processing method
1990; 64 FR 26286, May 14, 1999; 65 FR 13679, yields a product free of the additive to
Mar. 14, 2000] such an extent that the safety, purity,
and potency of the product will not be
§ 640.93 General requirements. affected adversely.
(a) Preservative. The final product [38 FR 32089, Nov. 20, 1973, as amended at 50
shall not contain a preservative. FR 4140, Jan. 29, 1985; 64 FR 26287, May 14,
(b) Storage of bulk solution. After all 1999]
processing steps have been completed,
the sterile bulk solution shall be stored § 640.101 General requirements.
in a manner that will ensure the con- (a) Heat stability test. Approximately 2
tinued sterility of the product, and at a ml. of completely processed material of
temperature that shall not exceed the each lot shall not show any visible sign
recommended storage temperature of of gelation after heating in a 12 × 75
the final product prescribed in § 610.53 mm. stoppered glass tube at 57 °C for 4
of this chapter. hours.
(b) pH. The pH of final container ma-
§ 640.94 Labeling. terial shall be 6.8 ±0.4 when measured
In addition to the labeling require- in a solution diluted to 1 percent pro-
ments of §§ 610.60, 610.61, and 610.62 of tein with 0.15 molar sodium chloride.
this chapter, the container and pack- (c) Turbidity. The product shall be
age labels shall contain the following free of turbidity as determined by vis-
information: ual inspection of final containers.
(a) The osmotic equivalent in terms (d) Date of manufacture. The date of
of plasma, and the sodium concentra- manufacture is the date of initiating
tion in terms of a value or a range in the last valid measles or poliomyelitis
milliequivalents per liter. antibody test (§ 640.104(b) (2) and (3))
(b) The cautionary statement placed whichever date is earlier.
in a prominent position on the label, (e) Labeling. In addition to complying
‘‘Do Not Use if Turbid. Do Not Begin with all applicable labeling required in
Administration More than 4 Hours this subchapter, labeling shall indicate
After the Container Has Been En- that:
tered.’’ (1) There is no prescribed potency for
viral hepatitis antibodies.
[42 FR 27583, May 31, 1977, as amended at 49 (2) The product is not recommended
FR 2244, Jan. 19, 1984; 64 FR 26286, May 14,
for intravenous administration.
1999]
[38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar.
29, 1983, as amended at 49 FR 23834, June 8,
Subpart J—Immune Globulin 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611,
(Human) Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 63 FR
16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999]
§ 640.100 Immune Globulin (Human).
(a) Proper name and definition. The § 640.102 Manufacture of Immune
proper name of this product shall be Globulin (Human).
Immune Globulin (Human). The prod- (a) Processing method. The processing
uct is defined as a sterile solution con- method shall be one that has been
taining antibodies derived from human shown: (1) To be capable of concen-

plasma. trating tenfold from source material at
114
least two different antibodies; (2) not § 640.104 Potency.

to affect the integrity of the globulins;
(a) Antibody levels and tests. Each lot
(3) to consistently yield a product
of final product shall contain at least
which is safe for subcutaneous and the minimum levels of antibodies for
intramuscular injection and (4) not to diphtheria, measles, and for at least
transmit viral hepatitis. one type of poliomyelitis. In the event
(b) Microbial contamination. Low tem- the final bulk solution is stored at a
peratures or aseptic techniques shall be temperature above 5 °C the antibody
used to minimize contamination by level tests shall be performed after
microorganisms. Preservatives to in- such storage with a sample of the
hibit growth of microorganisms shall stored material.
not be used during processing. (b) Minimum levels. The minimum
(c) Bulk storage. The globulin fraction antibody levels are as follows:
may be stored in bulk prior to further (1) No less than 2 units of diphtheria
processing provided it is stored in antitoxin per ml.
clearly identified hermetically closed (2) A measles neutralizing antibody
vessels. Globulin as either a liquid con- level that, when compared with that of
centrate or a solid and containing alco- a reference material designated by the
hol or more than 5 percent moisture Center for Biologics Evaluation and
shall be stored at a temperature of ¥10 Research (CBER), Food and Drug Ad-
°C or lower. Globulin as a solid free ministration, as indicated in paragraph
from alcohol and containing less than 5 (c) of this section, demonstrates ade-
percent moisture, shall be stored at a quate potency. The Director, CBER,
temperature of 0 °C or lower. shall notify manufacturers when a new
(d) Determination of the lot. Each lot reference material will be used and will
of Immune Globulin (Human) shall rep- advise manufacturers of an appropriate
resent a pooling of approximately antibody level taking into account a
equal amounts of material from not comparison of the new reference mate-
less than 1,000 donors. rial to the previous reference material.
(e) Sterilization and heating. The final (3) A poliomyelitis Type 1, Type 2, or
product shall be sterilized promptly Type 3 neutralizing antibody level
after solution. At no time during proc- that, when compared with that of a ref-
essing shall the product be exposed to erence material designated by the Cen-
temperatures above 45 °C, and after ter for Biologics Evaluation and Re-
sterilization the product shall not be search, Food and Drug Administration,
exposed to temperatures above 32 °C for as indicated in paragraph (c) of this
more than 72 hours. section, demonstrates adequate po-
tency. The Director, CBER, shall no-
tify manufacturers when a new ref-
FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6,
1998; 64 FR 26287, May 14, 1999; 65 FR 13679,
erence material will be used and will
Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000] advise manufacturers of an appropriate
antibody level taking into account a
§ 640.103 The final product. comparison of the new reference mate-
rial to the previous reference material.
(a) Final solution. The final product
(c) Reference materials. The following
shall be a 16.5 ±1.5 percent solution of
reference materials shall be obtained
globulin containing 0.3 molar glycine
from the Center for Biologics Evalua-
and a preservative. tion and Research:
(b) Protein composition. At least 96 (1) Reference Immune Globulin for
percent of the total protein shall be correlation of measles antibody titers.
immunoglobulin G (IgG), as deter- (2) Reference Immune Globulin for
mined by a method that has been ap- correlation of poliomyelitis antibody
proved for each manufacturer by the titers, Types 1, 2, and 3.
tion and Research, Food and Drug Ad- [38 FR 32089, Nov. 20, 1973, as amended at 39
ministration. FR 9661, Mar. 13, 1974; 49 FR 23834, June 8,
1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013,

[38 FR 32089, Nov. 20, 1973, as amended at 64 Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR
FR 26287, May 14, 1999] 26287, May 14, 1999]
115
§ 640.120 21 CFR Ch. I (4–1–20 Edition)
Subpart K [Reserved] § 640.125 Definitions.

The definitions set out in § 630.3 of
Subpart L—Alternative Procedures this chapter apply to the use of those
defined terms in this part.
§ 640.120 Alternative procedures.
§ 640.130 Medical supervision.
(a) The Director, Center for Biologics
Evaluation and Research, may issue an The requirements for medical super-
exception or alternative to any revision established in § 630.5 of this
quirement in subchapter F of chapter I chapter supplement the regulations in
of title 21 of the Code of Federal Regu- this part.
lations regarding blood, blood compo-
nents, or blood products. The Director PART 660—ADDITIONAL STAND-
may issue such an exception or alter- ARDS FOR DIAGNOSTIC SUB-
native in response to: STANCES FOR LABORATORY
(1) A written request from an estab- TESTS
lishment. Licensed establishments
must submit such requests in accord- Subpart A—Antibody to Hepatitis B Surface
ance with § 601.12 of this chapter; Antigen
(2) An oral request from an establish-
ment, if there are difficult cir- Sec.
660.1 Antibody to Hepatitis B Surface Anti-
cumstances and submission of a writ-
gen.
ten request is not feasible. Establish- 660.2 General requirements.
ments must follow up such oral request 660.3 Reference panel.
by submitting written requests under 660.4 Potency test.
paragraph (a)(1) of this section within 5 660.5 Specificity.
working days. 660.6 Samples; protocols; official release.
(b) To respond to a public health
Subpart B [Reserved]
need, the Director may issue a notice
of exception or alternative to any re- Subpart C—Blood Grouping Reagent
quirement in subchapter F of chapter I
of title 21 of the Code of Federal Regu- 660.20 Blood Grouping Reagent.
lations regarding blood, blood compo- 660.21 Processing.
660.22 Potency requirements with reference
nents, or blood products, if a variance preparations.
under this section is necessary to as- 660.25 Potency tests without reference prep-
sure that blood, blood components, or arations.
blood products will be available in a 660.26 Specificity tests and avidity tests.
specified location or locations to ad- 660.28 Labeling.
dress an urgent and immediate need for
blood, blood components, or blood Subpart D—Reagent Red Blood Cells
products or to provide for appropriate 660.30 Reagent Red Blood Cells.
donor screening and testing. 660.31 Eligibility of donor.
(c) If the Director issues such an ex- 660.32 Collection of source material.
ception or alternative orally, the Di- 660.33 Testing of source material.
660.34 Processing.
rector will follow up by issuing a writ-
660.35 Labeling.
ten notice of the exception or alter- 660.36 Samples and protocols.
native. Periodically, FDA will provide
a list of approved exceptions and alter- Subpart E—Hepatitis B Surface Antigen
native procedures on the FDA Center
660.40 Hepatitis B Surface Antigen.
for Biologics Evaluation and Research
660.41 Processing.
Web site. 660.43 Potency test.
[80 FR 29906, May 22, 2015] 660.44 Specificity.
660.45 Labeling.
660.46 Samples; protocols; official release.
Subpart M—Definitions and
Medical Supervision Subpart F—Anti-Human Globulin
660.50 Anti-Human Globulin.

SOURCE: 80 FR 29906, May 22, 2015, unless 660.51 Processing.
otherwise noted. 660.52 Reference preparations.
116
660.53 Controls for serological procedures. used in the performance of the test as
660.54 Potency tests, specificity tests, tests described by the manufacturer’s rec-
for heterospecific antibodies, and addi- ommended test procedures shall have
tional tests for nonspecific properties.
660.55 Labeling. been shown not to adversely affect the
product within the prescribed dating
AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, period.
355, 360, 360c, 360d, 360h, 360i, 371, 372; 42
U.S.C. 216, 262, 263, 263a, 264. (c) Labeling. (1) In addition to the
items required by other applicable la-
CROSS REFERENCES: For U.S. Customs beling provisions of this subchapter,
the following shall also be included:
U.S. Postal Service regulations relating to (i) Indication of the source of the
the admissibility to the United States mails product immediately following the
see parts 124 and 125 of the Domestic Mail proper name on both the final con-
Manual, that is incorporated by reference in tainer and package label, e.g., human,
39 CFR part 111. guinea pig.
(ii) Name of the test method(s) rec-
Subpart A—Antibody to Hepatitis ommended for the product on the pack-
B Surface Antigen age label and on the final container
label when capable of bearing a full
§ 660.1 Antibody to Hepatitis B Surface label (see § 610.60(a) of this chapter).
Antigen.
(iii) A warning on the package label
(a) Proper name and definition. The and on the final container label if capa-
proper name of this product shall be ble of bearing a full label (see § 610.60(a)
Antibody to Hepatitis B Surface Anti- of this chapter) indicating that the
gen. The product is defined as a prepa- product and antigen if supplied, shall
ration of serum containing antibody to be handled as if capable of transmit-
hepatitis B surface antigen. ting hepatitis.
(b) Source. The source of this product
(iv) If the product is dried, the final
shall be plasma or blood, obtained
container label shall indicate ‘‘Recon-
aseptically from animals immunized
stitution date: lll’’ and a statement
with hepatitis B surface antigen, which
indicating the period within which the
have met the applicable requirements
of § 600.11 of this chapter, or from product may be used after reconstitu-
human donor whose blood is positive tion.
for hepatitis B surface antigen. (v) The package shall include a pack-
age enclosure providing:
[40 FR 29711, July 15, 1975] (A) Adequate instructions for use;
§ 660.2 General requirements. (B) A description of all recommended
test methods; and
(a) Processing. The processing method (C) Warnings as to possible hazards,
shall be one that has been shown to including hepatitis, in handling the
consistently yield a specific and potent product and any ancillary reagents and
final product free of properties which materials accompanying the product.
would adversely affect the test results
(2) The applicant may provide the la-
when the product is tested by the
beling information referenced in para-
methods recommended by the manu-
graph (c)(1) of this section in the form
facturer in the package enclosure.
(b) Ancillary reagents and materials. of:
All ancillary reagents and materials (i) A symbol accompanied by explan-
supplied in the package with the prod- atory text adjacent to the symbol;
uct shall meet generally accepted (ii) A symbol not accompanied by ad-
standards of purity and quality and jacent explanatory text that:
shall be effectively segregated and oth- (A) Is contained in a standard that
erwise manufactured in a manner (such FDA recognizes under its authority in
as heating at 60 °C. for 10 hours) that section 514(c) of the Federal Food,
will reduce the risk of contaminating Drug, and Cosmetic Act;
the product and other biological prod- (B) Is used according to the specifica-
ucts. Ancillary reagents and materials tions for use of the symbol set forth in
accompanying the product which are FDA’s section 514(c) recognition; and
117
§ 660.2 21 CFR Ch. I (4–1–20 Edition)
(C) Is explained in a paper or elec- (4) For purposes of paragraph (c)(2) of

tronic symbols glossary that is in- this section:
cluded in the labeling for the device (i) An SDO is an organization that is
and the labeling on or within the pack- nationally or internationally recog-
age containing the device bears a nized and that follows a process for
prominent and conspicuous statement standard development that is trans-
identifying the location of the symbols parent, (i.e., open to public scrutiny),
glossary that is written in English or, where the participation is balanced,
in the case of articles distributed sole- where an appeals process is included,
ly in Puerto Rico or in a Territory where the standard is not in conflict
where the predominant language is one with any statute, regulation, or policy
other than English, the predominant under which FDA operates, and where
language may be used; or the standard is national or inter-
(iii) A symbol not accompanied by national in scope.
adjacent explanatory text that: (ii) The term ‘‘symbols glossary’’
(A) Is established in a standard devel- means a compiled listing of:
oped by a standards development orga- (A) Each SDO-established symbol
nization (SDO); used in the labeling for the device;
(B) Is not contained in a standard (B) The title and designation number
that is recognized by FDA under its au- of the SDO-developed standard con-
thority in section 514(c) of the Federal taining the symbol;
Food, Drug, and Cosmetic Act or is (C) The title of the symbol and its
contained in a standard that is recog- reference number, if any, in the stand-
nized by FDA but is not used according ard; and
to the specifications for use of the sym- (D) The meaning or explanatory text
bol set forth in FDA’s section 514(c) for the symbol as provided in the FDA
recognition; recognition or, if FDA has not recog-
(C) Is determined by the manufac- nized the standard or portion of the
turer to be likely to be read and under- standard in which the symbol is lo-
stood by the ordinary individual under cated or the symbol is not used accord-
customary conditions of purchase and ing to the specifications for use of the
use in compliance with section 502(c) of symbol set forth in FDA’s section
the Federal Food, Drug, and Cosmetic 514(c) recognition, the explanatory text
Act; as provided in the standard.
(D) Is used according to the specifica- (d) Final container. A final container
tions for use of the symbol set forth in shall be sufficiently transparent to per-
the SDO-developed standard; and mit visual inspection of the contents
(E) Is explained in a paper or elec- for presence of particulate matter and
tronic symbols glossary that is in- increased turbidity. The effectiveness
cluded in the labeling for the device of the contents of a final container
and the labeling on or within the pack- shall be maintained throughout its dat-
age containing the device bears a ing period.
prominent and conspicuous statement (e) Date of manufacture. The date of
identifying the location of the symbols manufacture of Antibody to Hepatitis
glossary that is written in English or, B surface Antigen that has been iodi-
in the case of articles distributed sole- nated with radioactive iodine (125I)
ly in Puerto Rico or in a Territory shall be the day of labeling the anti-
where the predominant language is one body with the radionuclide.
other than English, the predominant (f) Retention samples. Each manufac-
language may be used. turer shall retain representative sam-
(3) The use of symbols to provide the ples of the product in accordance with
labeling information referenced in § 600.13 of this chapter except for that
paragraph (c)(1) of this section which which has been iodinated with radio-
do not meet the requirements of para- active iodine. Retention samples of
graph (c)(2) of this section renders a de- Antibody to Hepatitis B Surface Anti-
vice misbranded under section 502(c) of gen iodinated with 125I shall consist of
the Federal Food, Drug, and Cosmetic a minimum of two complete finished
Act. packages of each lot of the diagnostic
118
test kit and shall be retained for a pe- nostic test kits in a finished package,
riod of at least 90 days from the date of including all ancillary reagents and
manufacture. materials.
[38 FR 32098, Nov. 20, 1973, as amended at 40 (2) Unless the Director, Center for
FR 29711, July 15, 1975; 46 FR 36134, July 14, Biologics Evaluation and Research, de-
1981; 49 FR 1684, Jan. 13, 1984; 81 FR 38924, termines that the reliability and con-
June 15, 2016] sistency of the finished product can be
assured with a smaller quantity of
§ 660.3 Reference panel. sample or no sample and specifically
A Reference Hepatitis B Surface reduces or eliminates the required
Antigen Panel shall be obtained from quantity of sample, each manufacturer
the Food and Drug Administration, shall submit the following samples to
Center for Biologics Evaluation and the Director, Center for Biologics Eval-
Research, Reagents and Standards uation and Research (see mailing ad-
Shipping, 10903 New Hampshire Ave., dresses in § 600.2(c) of this chapter),
Bldg. 75, Rm. G704, Silver Spring, MD within 5 working days after the manu-
20993–0002 and shall be used for deter- facturer has satisfactorily completed
mining the potency and specificity of all tests on the samples:
Antibody to Hepatitis B Surface Anti- (i) One sample until written notifica-
gen. tion of official release is no longer re-
[40 FR 29711, July 15, 1975, as amended at 49 quired under paragraph (c)(2) of this
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, section.
1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, (ii) One sample at periodic intervals
Apr. 3, 2015] of 90 days, beginning after written no-
tification of official release is no
§ 660.4 Potency test.
longer required under paragraph (c)(2)
To be satisfactory for release, each of this section. The sample submitted
filling of Antibody to Hepatitis B Sur- at the 90-day interval shall be from the
face Antigen shall be tested against the first lot or filling, as applicable, re-
Reference Hepatitis B Surface Antigen leased by manufacturer, under the re-
Panel and shall be sufficiently potent quirements of § 610.1 of this chapter,
to detect the antigen in the appro- after the end of the previous 90-day in-
priate sera of the reference panel by all terval. The sample shall be identified
test methods recommended by the as ‘‘surveillance sample’’ and shall in-
manufacturer in the package insert. clude the date of manufacture.
[40 FR 29711, July 15, 1975] (iii) Samples may at any time be re-
quired to be submitted to the Director,
§ 660.5 Specificity. Center for Biologics Evaluation and
Each filling of the product shall be Research, if the Director finds that
specific for antibody to hepatitis B sur- continued evaluation is necessary to
face antigen, as determined by speci- ensure the potency, quality, and reli-
ficity tests found acceptable by the Di- ability of the product.
rector, Center for Biologics Evaluation (b) Protocols. For each sample sub-
and Research. mitted as required in paragraph (a)(1)
[40 FR 29712, July 15, 1975, as amended at 49 of this section, the manufacturer shall
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, send a protocol that consists of a sum-
1990] mary of the history of manufacture of
the product, including all results of
§ 660.6 Samples; protocols; official re- each test for which test results are re-
lease. quested by the Director, Center for
(a) Samples. (1) For the purposes of Biologics Evaluation and Research.
this section, a sample of product not The protocols submitted with the sam-
iodinated with 125I means a sample ples at periodic intervals as provided in
from each filling of each lot packaged paragraph (a)(2)(ii) of this section shall
as for distribution, including all ancil- be identified by the manufacturer as
lary reagents and materials; and a ‘‘surveillance test results.’’
sample of product iodinated with 125I (c) Official release. (1) The manufac-
means a sample from each lot of diag- turer shall not distribute the product
119
§ 660.20 21 CFR Ch. I (4–1–20 Edition)
until written notification of official re- cell lines maintained either in tissue
lease is received from the Director, cultures or in secondary hosts.
Center for Biologics Evaluation and
Research, except as provided in para- FR 77499, Dec. 12, 2000; 81 FR 38925, June 15,
graph (c)(2) of this section. Official re- 2016]
lease is required for samples from at
least five consecutive lots or fillings, § 660.21 Processing.
as applicable, manufactured after li-
(a) Processing method. (1) The proc-
censure of the product.
essing method shall be one that has
(2) After written notification of offi- been shown to yield consistently a spe-
cial release is received from the Direc- cific, potent final product, free of prop-
tor, Center for Biologics Evaluation erties that would affect adversely the
and Research, for at least five consecu- intended use of the product throughout
tive lots or fillings, as applicable, man- its dating period. Stability testing
ufactured after licensure of the prod- shall be performed on an adequate
uct, and after the manufacturer re- number of representative samples of
ceives from the Director, Center for each group of products manufactured
Biologics Evaluation and Research, in the same fashion.
written notification that official re- (2) Only that material that has been
lease is no longer required, subsequent fully processed, thoroughly mixed in a
lots or fillings may be released by the single vessel, and filtered shall con-
manufacturer under the requirements stitute a lot.
of § 610.1 of this chapter. (3) A lot may be subdivided into
(3) The manufacturer shall not dis- sublots. If lots are to be subdivided, the
tribute lots or fillings, as applicable, of manufacturer shall include this infor-
products that required sample submis- mation in the biologics license applica-
sion under paragraph (a)(2)(iii) of this tion. The manufacturer shall describe
section until written notification of of- the test specifications to verify that
ficial release or notification that offi- each sublot is identical to other
cial release is no longer required is re- sublots of the lot.
ceived from the Director, Center for (4) Each lot of Blood Grouping Rea-
Biologics Evaluation and Research. gent shall be identified by a lot num-
[48 FR 20407, May 6, 1983, as amended at 49 ber. Each sublot shall be identified by
FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, that lot number to which a distinctive
1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR prefix or suffix shall be added. Final
14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] container and package labels shall bear
the lot number and all distinctive pre-
Subpart B [Reserved] fixes and suffixes that have been ap-
plied to identify the sublot from which
filling was accomplished.
Subpart C—Blood Grouping
(b) Color coding of reagents. Blood
Reagent Grouping Reagents may be colored pro-
vided the added colorant does not ad-
SOURCE: 53 FR 12764, Apr. 19, 1988, unless versely affect the safety, purity, or po-
otherwise noted. tency of the product and the colorant
is approved by the Director, Center for
§ 660.20 Blood Grouping Reagent. Biologics Evaluation and Research.
(a) Proper name and definition. The (c) Final containers and dropper assem-
proper name of this product shall be blies. Final containers and dropper pi-
Blood Grouping Reagent and it shall pettes shall be colorless and suffi-
consist of an antibody-containing fluid ciently transparent to permit observa-
containing one or more of the blood tion of the contents to detect particu-
grouping antibodies listed in late matter or increased turbidity dur-
§ 660.28(a)(4). ing use.
(b) Source. The source of this product (d) Volume of final product. Each man-
shall be blood, plasma, serum, or pro- ufacturer shall identify the possible
tein-rich fluids, such as those derived final container volumes in the bio-
from stable immunoglobulin-secreting logics license application.
120
(e) Date of manufacture. The date of (b) Products recommended for slide tests
manufacture shall be the date the man- or microplate techniques. Blood Grouping
ufacturer begins the last entire group Reagent recommended for slide test
of potency tests. methods or microplate techniques shall
produce clearly positive macroscopic
FR 56454, Oct. 20, 1999; 65 FR 77499, Dec. 12, results when both undiluted reagent
2000; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, and reagent diluted with an equal vol-
Mar. 24, 2005] ume of diluent are tested by all meth-
ods recommended in the manufactur-
§ 660.22 Potency requirements with er’s package insert using red blood
reference preparations. cells showing heterozygous or dimin-
(a) Potency requirements. Products for ished expression of the corresponding
which reference Blood Grouping Re- antigen. The dilution shall be made
agents are available shall have a po- with an equal volume of compatible
tency titer value at least equal to that serum or approved diluent.
of the reference preparation. (c) Products recomended for use in an
(b) Reference preparations. Reference automated system. The manufacturer of
Blood Grouping Reagents shall be ob- Blood Grouping Reagent that is rec-
tained from the Food and Drug Admin- ommended for use in an automated sys-
istration, Center for Biologics Evalua- tem shall demonstrate that its product
tion and Research, Reagents and when used both undiluted and diluted
Standards Shipping, 10903 New Hamp- with an equal volume of diluent satis-
shire Ave., Bldg. 75, Rm. G704, Silver factorily performs when tested with
Spring, MD 20993–0002, and shall be used cells representing heterozygous or di-
as described in the accompanying minished expression of the cor-
package insert for determining the po- responding antigen.
tency of Blood Grouping Reagents. [53 FR 12764, Apr. 19, 1988, as amended at 67
[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24,
FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]
2005; 80 FR 18093, Apr. 3, 2015]
§ 660.26 Specificity tests and avidity
§ 660.25 Potency tests without ref- tests.
erence preparations. Specificity and avidity tests shall be
Products for which Reference Blood performed using test procedures ap-
Grouping Reagents are not available proved by the Director, Center for Bio-
shall be tested for potency by a method logics Evaluation and Research.
approved by the Director, Center for [53 FR 12764, Apr. 19, 1988, as amended at 67
Biologics Evaluation and Research. FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24,
(a) Potency requirements. Blood Group- 2005]
ing Reagents recommended for the test
tube methods, including the indirect § 660.28 Labeling.
antiglobulin tests, shall have the fol- (a) In addition to the applicable la-
lowing potency titer values, unless beling requirements of §§ 610.62 through
other values are approved by the Direc- 610.65 and § 809.10 of this chapter, and in
tor, Center for Biologics Evaluation lieu of the requirements in §§ 610.60 and
and Research. 610.61 of this chapter, the following re-
(1) For Anti-K, Anti-k̄, Anti-Jk a, quirements shall be met:
Anti-Fy a, Anti-C w, at least 1 + reac- (1) Final container label—(i) Color cod-
tion with a 1:8 dilution of the reagent. ing. The final container label of all
(2) For Anti-S, Anti-s̄, Anti-P1, Anti- Blood Grouping Reagents shall be com-
M, Anti-I, Anti-e (saline), Anti-c̄ (sa- pletely white, except that all or a por-
line), and Anti-A1, at least 1 + reaction tion of the final container label of the
with a 1:4 dilution of the reagent. following Blood Grouping Reagents
(3) For Anti-U, Anti-Kpa, Anti-Kpb, may be color coded with the specified
Anti-Jsa, Anti-Jsb, Anti-Fyb, Anti-N, color which shall be a visual match to
Anti-Lea, Anti-Leb, Anti-Lua, Anti-Lub, a specific color sample designated by
Anti-Dia, Anti-Mg, Anti-Jkb, Anti-Cob, the Director, Center for Biologics Eval-
Anti-Wra, and Anti-Xga, at least 2 + re- uation and Research. Printing on all
action with undiluted reagent. final container labels shall be in solid
121
§ 660.28 21 CFR Ch. I (4–1–20 Edition)
black. A logo or company name may be (iv) Visual inspection. When the label
placed on the final container label; has been affixed to the final container,
however, the logo or company name a sufficient area of the container shall
shall be located along the bottom or remain uncovered for its full length or
end of the label, outside the main no less than 5 millimeters of the lower
panel. circumference to permit inspection of
the contents. The label on a final prod-
Color of
Blood grouping reagent label paper uct container for antibodies Anti-c,
Anti-k, or Anti-s shall display a bar
Anti-A ............................................................. Blue. immediately over the specificity letter
Anti-B ............................................................. Yellow.
Slide and rapid tube test blood grouping re-
used in the name, i.e., Anti-c̄, Anti-k̄,
agents only: or Anti-s̄.
Anti-C .............................................. Pink. (2) Package label. The following infor-
Anti-D .............................................. Gray. mation shall appear either on the pack-
Anti-E ............................................... Brown.
Anti-CDE ......................................... Orange.
age label or on the final container label
Anti-c̄ ............................................... Lavender. if it is visible within the package.
Anti-e ............................................... Green. (i) Proper name of the product.
(ii) Name of the antibody or anti-
(ii) Required information. The proper bodies present as set forth in paragraph
name ‘‘Blood Grouping Reagent’’ need (a)(4) of this section.
not appear on the final container label (iii) Name, address (including ZIP
provided the final container is distrib- Code), and license number of the manu-
uted in a package and the package facturer.
label bears the proper name. The final (iv) Lot number, including sublot
container label shall bear the following designations.
information: (v) Expiration date.
(A) Name of the antibody or anti- (vi) Preservative used and its con-
bodies present as set forth in paragraph centration.
(a)(4) of this section. (vii) Number of containers, if more
(B) Name, address (including ZIP than one.
code), and license number of the manu- (viii) Volume or equivalent volume
facturer. for dried products when reconstituted,
(C) Lot number, including sublot des- and precautions for adequate mixing
ignations. when reconstituting.
(D) Expiration date. (ix) Recommended storage tempera-
(E) Source of product if other than ture in degrees Celsius.
human plasma or serum. (x) Source of the product if other
(F) Test method(s) recommended. than human serum or plasma.
(G) Recommended storage tempera- (xi) Reference to enclosed package
ture in degrees Celsius. insert.
(H) Volume of product if a liquid, or (xii) If a dried product, a statement
equivalent volume for a dried product indicating the period within which the
if it is to be reconstituted. product may be used after reconstitu-
(I) If a dried product, to remind users tion.
to record the reconstitution date on (xiii) The statement: ‘‘FOR IN
the label, the statement ‘‘RECON- VITRO DIAGNOSTIC USE.’’
STITUTION DATE lll. EXPIRES 1 (xiv) The statement: ‘‘MEETS FDA
YEAR AFTER RECONSTITUTION POTENCY REQUIREMENTS.’’
DATE.’’ (xv) If human blood was used in man-
(iii) Lettering size. The type size for ufacturing the product, the statement:
the specificity of the antibody designa- ‘‘CAUTION: ALL BLOOD PRODUCTS
tion on the labels of a final container SHOULD BE TREATED AS POTEN-
with a capacity of less than 5 milli- TIALLY INFECTIOUS. SOURCE MA-
liters shall be not less than 12 point. TERIAL FROM WHICH THIS PROD-
The type size for the specificity of the UCT WAS DERIVED WAS FOUND
antibody designations on the label of a NEGATIVE WHEN TESTED IN AC-
container with a capacity of 5 milli- CORDANCE WITH CURRENT FDA RE-
liters or more shall be not less than 18 QUIRED TESTS. NO KNOWN TEST
point. METHODS CAN OFFER ASSURANCE
122
THAT PRODUCTS DERIVED FROM identifying the location of the symbols

HUMAN BLOOD WILL NOT TRANS- glossary that is written in English or,
MIT INFECTIOUS AGENTS.’’ in the case of articles distributed sole-
(xvi) A statement of an observable in- ly in Puerto Rico or in a Territory
dication of an alteration of the prod- where the predominant language is one
uct, e.g., turbidity, color change, pre- other than English, the predominant
cipitate, that may indicate possible de- language may be used; or
terioration of the product. (3) A symbol not accompanied by ad-
(3) Package insert. Each final con- jacent explanatory text that:
tainer of Blood Grouping Reagent shall (i) Is established in a standard devel-
be accompanied by a package insert oped by a standards development orga-
meeting the requirements of § 809.10. If nization (SDO);
two or more final containers requiring (ii) Is not contained in a standard
identical package inserts are placed in that is recognized by FDA under its au-
a single package, only one package in- thority in section 514(c) of the Federal
sert per package is required. Food, Drug, and Cosmetic Act or is
(4) Names of antibodies. contained in a standard that is recog-
nized by FDA but is not used according
BLOOD GROUP DESIGNATION FOR CONTAINER to the specifications for use of the sym-
LABEL bol set forth in FDA’s section 514(c)
recognition;
Anti-A Anti-Jkb
(iii) Is determined by the manufac-
Anti-A1 Anti-Jsa
Anti-A, B Anti-Jsb turer to be likely to be read and under-
Anti-A and B Anti-K stood by the ordinary individual under
Anti-B Anti-k̄ customary conditions of purchase and
Anti-C Anti-Kpa use in compliance with section 502(c) of
Anti-Cw Anti-Kpb the Federal Food, Drug, and Cosmetic
Anti- c̄ Anti-Lea Act;
Anti-CD Anti-Leb
Anti-CDE Anti-Lua
(iv) Is used according to the speci-
Anti-Cob Anti-Lub fications for use of the symbol set forth
Anti-D Anti-M in the SDO-developed standard; and
Anti-DE Anti-Mg (v) Is explained in a paper or elec-
Anti-Dia Anti-N tronic symbols glossary that is in-
Anti-E Anti-P1 cluded in the labeling for the device
Anti-e Anti-S
and the labeling on or within the pack-
Anti-Fya Anti-s̄
Anti-Fyb Anti-U age containing the device bears a
Anti-I Anti-Wra prominent and conspicuous statement
Anti-Jka Anti-Xga identifying the location of the symbols
glossary that is written in English or,
(b) The applicant may provide the la- in the case of articles distributed sole-
beling information referenced in para- ly in Puerto Rico or in a Territory
graph (a) of this section in the form of: where the predominant language is one
(1) A symbol accompanied by explan- other than English, the predominant
atory text adjacent to the symbol; language may be used.
(2) A symbol not accompanied by ad- (c) The use of symbols in device la-
jacent explanatory text that: beling to provide the labeling informa-
(i) Is contained in a standard that tion referenced in paragraph (a) of this
FDA recognizes under its authority in section which do not meet the require-
section 514(c) of the Federal Food, ments in paragraph (b) of this section
Drug, and Cosmetic Act; renders a device misbranded under sec-
(ii) Is used according to the specification 502(c) of the Federal Food, Drug,
tions for use of the symbol set forth in and Cosmetic Act.
FDA’s section 514(c) recognition; and (d) For purposes of paragraph (b) of
(iii) Is explained in a paper or elec- this section:
tronic symbols glossary that is in- (1) An SDO is an organization that is
cluded in the labeling for the device nationally or internationally recog-
and the labeling on or within the pack- nized and that follows a process for
age containing the device bears a standard development that is trans-

prominent and conspicuous statement parent, (i.e., open to public scrutiny),
123
§ 660.30 21 CFR Ch. I (4–1–20 Edition)
where the participation is balanced, criteria for donor eligibility under

where an appeals process is included, §§ 630.10 and 630.15 of this chapter.
where the standard is not in conflict
[80 FR 29906, May 22, 2015]
with any statute, regulation, or policy
under which FDA operates, and where § 660.32 Collection of source material.
the standard is national or inter-
national in scope. Blood for Reagent Red Blood Cells
(2) The term ‘‘symbols glossary’’ from donors of peripheral blood shall
means a compiled listing of: be collected as prescribed under § 640.4
(i) Each SDO-established symbol used of this chapter, except that paragraphs
in the labeling for the device; (c), (d), (g), and (h) of § 640.4 shall not
apply.
(ii) The title and designation number
of the SDO-developed standard con- § 660.33 Testing of source material.
taining the symbol;
(iii) The title of the symbol and its Except as provided in this section, a
reference number, if any, in the stand- sample of each blood incorporated into
ard; and the Reagent Red Blood Cell product
(iv) The meaning or explanatory text shall be individually tested, with no
for the symbol as provided in the FDA fewer than two donor sources of each
recognition or, if FDA has not recog- antibody specificity employed, to con-
nized the standard or portion of the firm the identification of all blood
standard in which the symbol is lo- group antigens specified in the labeling
cated or the symbol is not used accord- as present or absent. The manufacturer
ing to the specifications for use of the shall perform at least one of the re-
symbol set forth in FDA’s section quired tests for each factor. The Rea-
514(c) recognition, the explanatory text gent Red Blood Cell product may be
as provided in the standard. tested with a single donor source of
antibody specificity if only one source
[81 FR 38925, June 15, 2016] of antibody is available, and the Direc-
tor, Center for Biologics Evaluation
Subpart D—Reagent Red Blood and Research, has approved the use of
Cells a single donor source of antiserum.
Each of these tests shall be conducted
and interpreted independently, and any
SOURCE: 52 FR 37450, Oct. 7, 1987, unless discrepancy between the results of
otherwise noted.
these two tests shall be resolved by
§ 660.30 Reagent Red Blood Cells. testing with at least one additional
antiserum before concluding that the
(a) Proper name and definition. The antigen is present or absent. Where
proper name of the product shall be Re- fewer than three donor sources of an
agent Red Blood Cells, which shall con- antibody specificity are available, test
sist of a preparation of human red discrepancies shall be resolved in ac-
blood cells used to detect or identify cordance with the manufacturer’s bio-
human blood-group antibodies. logics license application. Group O Re-
(b) Source. Reagent Red Blood Cells agent Red Blood Cells used in the de-
shall be prepared from human periph- tection or identification of unexpected
eral blood meeting the criteria of antibodies shall include at least the
§§ 660.31 and 660.32 of this chapter, or following common antigens in each lot
from umbilical cord cells which shall of the product: D, C, E, c̄, e, K, k̄, Fya,
be collected and prepared according to Fyb, Jka, Jkb, Lea, Leb, P1, M, N, S, and
the manufacturer’s biologics license s̄.
application.
[52 FR 37450, Oct. 7, 1987, as amended at 64 FR 11013, Mar. 26, 1990; 64 FR 56454, Oct. 20, 1999]
56454, Oct. 20, 1999]
§ 660.34 Processing.
§ 660.31 Eligibility of donor. (a) Processing method. The processing
Donors of peripheral blood for Rea- method shall be one that has been
gent Red Blood Cells must meet all the shown to yield consistently a product
124
that is capable of detecting, through- § 600.13 of this chapter, except that

out the dating period, alloantibodies samples must be retained only
corresponding to all required blood throughout the dating period of the
group antigens specified in the labeling product.
as present. [52 FR 37450, Oct. 7, 1987, as amended at 55 FR
(b) Products prepared from pooled red 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002]
blood cells. If the product is rec-
ommended for the detection of unex- § 660.35 Labeling.
pected antibodies, the pool shall be (a) In addition to the items required
prepared by combining equal amounts by § 809.10 of this chapter and other ap-
of cells from no more than two donors. plicable labeling provisions of this
Umbilical cord cells are exempt from chapter, the following information
this requirement. Pooled cells shall not shall be included in the labeling:
be recommended for pretransfusion (1)(i) A logo or company name may
tests, done in lieu of a major cross- be placed on the final container label,
match, to detect unexpected antibodies however, the logo or company name
in patients’ samples. shall be located along the bottom or
(c) Absence of antibodies. Each lot of end of the label, outside of the main
final product shall be free of demon- panel.
strable antibodies, including anti-A (ii) If washing the cells is required by
and anti-B, unless the package insert the manufacturer, the container label
and container lable include instruc- shall include appropriate instructions;
tions to wash the cells before use. The if the cells should not be washed before
final product shall also be direct use, e.g., if washing will adversely af-
antiglobulin test negative when tested fect the product, the package insert
with polyspecific anti-human globulin. shall explain.
(d) Final container. The final con- (2) The container label of Group O
tainers used for each lot of product cells shall state:
shall be clean and shall permit observa- ‘‘FOR USE IN DETECTION OF UN-
tion of the contents for hemolysis or a EXPECTED ANTIBODIES’’ or ‘‘FOR
change in color. The final container USE IN IDENTIFICATION OF UNEX-
label, container cap, and dropper bulb PECTED ANTIBODIES’’ or ‘‘NOT FOR
of a Reagent Red Blood Cell product USE IN DETECTION OR IDENTIFICA-
may be color-coded with a visual TION OF UNEXPECTED ANTI-
match to a specific color approved by BODIES’’.
the Director, Center for Biologics Eval- (3) Except as provided in this section,
uation and Research. the container and package labels shall
(e) Date of manufacture. The date of state the percentage of red blood cells
manufacture of the product shall be in the suspension either as a discrete
the date that the blood is withdrawn figure with a variance of more than [±]
from the donor or obtained from umbil- 1 percentage unit or as a range the ex-
ical cords. The period during which the tremes of which differ by no more than
reagent red blood cell source material 2 percentage units. If the stated red
is kept by the manufacturer in storage blood cell concentration is less than 2
in a frozen state at ¥65 °C or colder is percent, the variance shall be no more
excluded from the dating period. If the than [±] 0.5 percentage unit.
product consists of red blood cells from (4) The words ‘‘pooled cells’’ shall ap-
two or more donors, the date of manu- pear on the container and package la-
facture of the final product shall be the bels of products prepared from pooled
date of withdrawal of blood from the cells. The package label or package in-
donor of the oldest constituent blood. sert shall state that pooled cells are
When a product consists of more than not recommended for pre-transfusion
one container, e.g., cell panel, the date tests, done in lieu of a major cross-
of manufacture of each container of the match, to detect unexpected antibodies
product shall be the earliest date that in patients’ samples.
blood was withdrawn from a donor for (5) The package insert of a pooled
any container of the product. product intended for detection of unex-
(f) Retention samples. Retention sam- pected antibodies shall identify the
ples shall be maintained as required by number of donors contributing to the
125
§ 660.35 21 CFR Ch. I (4–1–20 Edition)
pool. Products designed exclusively for manufacture or the length of the dat-
ABO Serum Grouping and umbilical ing period.
cord cells need not identify the number (13) Manufacturers shall identify
of donors in the pool. with a permanent donor code in the
(6) When the product is a multicon- product labeling each donor of periph-
tainer product, e.g., a cell panel, the eral blood used for detection or identi-
container label and package label shall fication of unexpected antibodies.
be assigned the same identifying lot (b) The applicant may provide the la-
number, and shall also bear a number beling information referenced in para-
or symbol to distinguish one container graph (a) of this section in the form of:
from another. Such number or symbol (1) A symbol accompanied by explan-
shall also appear on the antigenic con- atory text adjacent to the symbol;
stitution matrix. (2) A symbol not accompanied by ad-
(7) The package label or package in- jacent explanatory text that:
sert shall state the blood group anti- (i) Is contained in a standard that
gens that have been tested for and FDA recognizes under its authority in
found present or absent on the cells of section 514(c) of the Federal Food,
each donor, or refer to such informa- Drug, and Cosmetic Act;
tion in an accompanying antigenic con- (ii) Is used according to the specifica-
stitution matrix. Cells for ABO Serum tions for use of the symbol set forth in
Grouping are exempt from this require- FDA’s section 514(c) recognition; and
ment. The package insert or antigen (iii) Is explained in a paper or elec-
constitution matrix shall list each of tronic symbols glossary that is in-
the antigens tested with only one cluded in the labeling for the device
source of antibody. and the labeling on or within the pack-
(8) The package label or package in- age containing the device bears a
sert shall bear the cautionary state- prominent and conspicuous statement
ment: ‘‘The reactivity of the product identifying the location of the symbols
may decrease during the dating pe- glossary that is written in English or,
riod.’’ in the case of articles distributed sole-
(9) The package insert of a product ly in Puerto Rico or in a Territory
intended for the detection or identi- where the predominant language is one
fication of unexpected antibodies shall other than English, the predominant
note that the rate at which antigen re- language may be used; or
activity (e.g., agglutinability) is lost is (3) A symbol not accompanied by ad-
partially dependent upon individual jacent explanatory text that:
donor characteristics that are neither (i) Is established in a standard devel-
controlled nor predicted by the manu- oped by a standards development orga-
facturer. nization (SDO);
(10) The package insert shall provide (ii) Is not contained in a standard
adequate directions for use. that is recognized by FDA under its au-
(11) The package insert shall bear the thority in section 514(c) of the Federal
statement: Food, Drug, and Cosmetic Act or is
‘‘CAUTION: ALL BLOOD PRODUCTS contained in a standard that is recog-
SHOULD BE TREATED AS POTEN- nized by FDA but is not used according
TIALLY INFECTIOUS. SOURCE MA- to the specifications for use of the sym-
TERIAL FROM WHICH THIS PROD- bol set forth in FDA’s section 514(c)
UCT WAS DERIVED WAS FOUND recognition;
NEGATIVE WHEN TESTED IN AC- (iii) Is determined by the manufac-
CORDANCE WITH CURRENT FDA RE- turer to be likely to be read and under-
QUIRED TESTS. NO KNOWN TEST stood by the ordinary individual under
METHODS CAN OFFER ASSURANCE customary conditions of purchase and
THAT PRODUCTS DERIVED FROM use in compliance with section 502(c) of
HUMAN BLOOD WILL NOT TRANS- the Federal Food, Drug, and Cosmetic
MIT INFECTIOUS AGENTS.’’ Act;
(12) The package insert or the anti- (iv) Is used according to the speci-
genic constitution matrix for each lot fications for use of the symbol set forth
of product shall specify the date of in the SDO-developed standard; and
126
(v) Is explained in a paper or elec- § 660.36 Samples and protocols.

tronic symbols glossary that is in-
(a) The following shall be submitted
cluded in the labeling for the device
to the Center for Biologics Evaluation
and the labeling on or within the pack-
and Research Sample Custodian (see
age containing the device bears a
prominent and conspicuous statement
chapter), within 30 days after each rou-
identifying the location of the symbols
tine establishment inspection by FDA.
(1) From a lot of final product, sam-
in the case of articles distributed sole-
ples from a cell panel intended for
ly in Puerto Rico or in a Territory
identification of unexpected anti-
where the predominant language is one
bodies. The sample shall be packaged
other than English, the predominant
as for distribution and shall have at
language may be used.
least 14 days remaining in the dating
(c) The use of symbols in device la-
period when shipped to the Center for
beling to provide the labeling informa-
Biologics Evaluation and Research.
tion referenced in paragraph (a) of this
(2) A protocol which shall include the
section which do not meet the require-
following:
ments of paragraph (b) of this section
(i) Complete test records of at least
renders a device misbranded under sec-
two donors of the samples submitted,
tion 502(c) of the Federal Food, Drug,
including original and confirmation
and Cosmetic Act.
phenotyping records.
(d) For purposes of paragraph (b) of
(ii) Bleeding records or receipt
this section:
records which indicate collection date,
(1) An SDO is an organization that is
volume, and HBsAg test results.
nationally or internationally recog-
(iii) Manufacturing records which
nized and that follows a process for
standard development that is trans- document all steps involved in the
parent, (i.e., open to public scrutiny), preparation of the product.
where the participation is balanced, (iv) Test results which verify that
where an appeals process is included, the final product meets specifications.
where the standard is not in conflict (v) Identity test results.
with any statute, regulation, or policy (b) A copy of the antigenic constitu-
under which FDA operates, and where tion matrix specifying the antigens
the standard is national or inter- present or absent shall be submitted to
national in scope. the Director, Center for Biologics Eval-
(2) The term ‘‘symbols glossary’’ uation and Research (see mailing ad-
means a compiled listing of: dresses in § 600.2(c) of this chapter), at
(i) Each SDO-established symbol used the time of initial distribution of each
in the labeling for the device; lot of Reagent Red Blood Cells for de-
(ii) The title and designation number tection or identification of unexpected
of the SDO-developed standard con- antibodies. Products designed exclu-
taining the symbol; sively to identify Anti-A, Anti-A1, and
(iii) The title of the symbol and its Anti-B, as well as products composed
reference number, if any, in the stand- entirely of umbilical cord cells, are ex-
ard; and cluded from this requirement.
(iv) The meaning or explanatory text (c) Except for umbilical cord sam-
for the symbol as provided in the FDA ples, whenever a new donor is used, a
recognition or, if FDA has not recog- sample of red blood cells from each new
nized the standard or portion of the donor used in a cell panel intended for
standard in which the symbol is lo- the identification of unexpected anti-
cated or the symbol is not used accord- bodies shall be submitted by the manu-
ing to the specifications for use of the facturer to the Director, Center for
symbol set forth in FDA’s section Biologics Evaluation and Research (see
514(c) recognition, the explanatory text mailing addresses in § 600.2(c) of this
as provided in the standard. chapter). The sample should contain a

[81 FR 38926, June 15, 2016]
127
§ 660.40 21 CFR Ch. I (4–1–20 Edition)
minimum volume of 0.5 milliliter of red been shown not to affect adversely the
blood cells. product within the prescribed dating
period.
11013, 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, (c) Final container. A final container
2002; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, shall be sufficiently transparent to per-
Apr. 3, 2015] mit visual inspection of the contents
for presence of particulate matter and
Subpart E—Hepatitis B Surface increased turbidity. The effectiveness
of the contents of a final container
Antigen shall be maintained throughout its dat-
ing period.
SOURCE: 44 FR 36382, June 22, 1979, unless (d) Date of manufacture. The date of
otherwise noted. manufacture of Hepatitis B Surface
§ 660.40 Hepatitis B Surface Antigen. Antigen that has been iodinated with
radioactive iodine (125I) shall be the
(a) Proper name and definition. The day of labeling the antibody with the
proper name of this product shall be radionuclide.
Hepatitis B Surface Antigen (HBsAg),
which shall consist of a serum or tissue [44 FR 36382, June 22, 1979, as amended at 49
FR 1685, Jan. 13, 1984]
preparation containing one or more
subtypes of the Hepatitis B Surface § 660.43 Potency test.
Antigen.
(b) Source. The source of the product To be satisfactory for release, each
shall be blood, plasma, serum, or tis- filling of Hepatitis B Surface Antigen
sue, obtained aseptically from shall be tested against the Reference
nonhuman primates that have met the Hepatitis B Antiserum Panel and shall
applicable requirements of § 600.11 of be sufficiently potent to be able to de-
this chapter, or from human donors tect the antibody in the appropriate
whose blood is positive for the Hepa- sera of the reference panel by all test
titis B Surface Antigen. methods recommended by the manu-
facturer in the package insert.
§ 660.41 Processing.
§ 660.44 Specificity.
(a) Method. The processing method
shall be one that has been shown to Each filling of the product shall be
yield consistently a specific and potent specific for Hepatitis B Surface Anti-
final product, free of properties which gen as determined by specificity tests
would adversely affect the test results found acceptable to the Director, Cen-
when the product is tested by the ter for Biologics Evaluation and Re-
methods recommended by the manu- search.
facturer in the package insert. The [44 FR 36382, June 22, 1979, as amended at 49
product and all ancillary reagents and FR 23834, June 8, 1984; 55 FR 11013, Mar. 26,
materials supplied in the package with 1990]
the product shall be manufactured in a
manner that will reduce the risk of § 660.45 Labeling.
transmitting type B viral hepatitis. (a) In addition to the requirements of
(b) Ancillary reagents and materials. §§ 610.60, 610.61, and 809.10 of this chap-
All ancillary reagents and materials ter, the labeling shall bear the fol-
supplied in the package with the prod- lowing:
uct shall meet generally accepted (1) The ‘‘d and y’’ antigen subtype
standards of purity and quality and and the source of the product to follow
shall be effectively segregated and oth- immediately the proper name on both
erwise manufactured in a manner that the final container label and the pack-
will reduce the risk of contaminating age label. If the product is intended to
the product and other biological prod- identify antibodies to the ‘‘r and w’’
ucts. Ancillary reagents and materials antigen subtype, the antigen subtype
accompanying the product, which are designation shall include the ‘‘r and w’’
used in the performance of the test as antigen subtype.
described by the manufacturer’s rec- (2) The name of the test method(s)
ommended test procedures, shall have recommended for use of the product on
128
the package label and on the final con- bol set forth in FDA’s section 514(c)
tainer label, when capable of bearing a recognition;
full label (see § 610.60(a) of this chap- (iii) Is determined by the manufac-
ter). turer to be likely to be read and under-
(3) A warning on the package label stood by the ordinary individual under
and on the final container label stating customary conditions of purchase and
that the product is capable of trans- use in compliance with section 502(c) of
mitting hepatitis and should be han- the Federal Food, Drug, and Cosmetic
dled accordingly. Act;
(4) The package shall include a pack- (iv) Is used according to the speci-
age insert providing: fications for use of the symbol set forth
(i) Detailed instructions for use, in the SDO-developed standard; and
(ii) An adequate description of all (v) Is explained in a paper or elec-
recommended test methods, and tronic symbols glossary that is in-
(iii) Warnings as to possible hazards, cluded in the labeling for the device
including hepatitis transmitted in han- and the labeling on or within the pack-
dling the product and any ancillary re- age containing the device bears a
agents and materials accompanying prominent and conspicuous statement
the product. identifying the location of the symbols
(b) The applicant may provide the la-
in the case of articles distributed sole-
beling information referenced in para-
ly in Puerto Rico or in a Territory
graph (a) of this section in the form of:
where the predominant language is one
(1) A symbol accompanied by explan-
other than English, the predominant
atory text adjacent to the symbol;
language may be used.
(2) A symbol not accompanied by ad- (c) The use of symbols in device la-
jacent explanatory text that: beling to provide the labeling informa-
(i) Is contained in a standard that tion referenced in paragraph (a) of this
FDA recognizes under its authority in section which do not meet the require-
section 514(c) of the Federal Food, ments of paragraph (b) of this section
Drug, and Cosmetic Act; renders a device misbranded under sec-
(ii) Is used according to the specification 502(c) of the Federal Food, Drug,
tions for use of the symbol set forth in and Cosmetic Act.
FDA’s section 514(c) recognition; and (d) For purposes of paragraph (b) of
(iii) Is explained in a paper or elec- this section:
tronic symbols glossary that is in- (1) An SDO is an organization that is
cluded in the labeling for the device nationally or internationally recog-
and the labeling on or within the pack- nized and that follows a process for
age containing the device bears a standard development that is trans-
prominent and conspicuous statement parent, (i.e., open to public scrutiny),
identifying the location of the symbols where the participation is balanced,
glossary that is written in English or, where an appeals process is included,
in the case of articles distributed sole- where the standard is not in conflict
ly in Puerto Rico or in a Territory with any statute, regulation, or policy
where the predominant language is one under which FDA operates, and where
other than English, the predominant the standard is national or inter-
language may be used; or national in scope.
(3) A symbol not accompanied by ad- (2) The term ‘‘symbols glossary’’
jacent explanatory text that: means a compiled listing of:
(i) Is established in a standard devel- (i) Each SDO-established symbol used
oped by a standards development orga- in the labeling for the device;
nization (SDO); (ii) The title and designation number
(ii) Is not contained in a standard of the SDO-developed standard con-
that is recognized by FDA under its au- taining the symbol;
thority in section 514(c) of the Federal (iii) The title of the symbol and its
Food, Drug, and Cosmetic Act or is reference number, if any, in the stand-
contained in a standard that is recog- ard; and
nized by FDA but is not used according (iv) The meaning or explanatory text
to the specifications for use of the sym- for the symbol as provided in the FDA
129
§ 660.46 21 CFR Ch. I (4–1–20 Edition)
recognition or, if FDA has not recog- Research, if the Director finds that
nized the standard or portion of the continued evaluation is necessary to
standard in which the symbol is lo- ensure the potency, quality, and reli-
cated or the symbol is not used accord- ability of the product.
ing to the specifications for use of the (b) Protocols. For each sample sub-
symbol set forth in FDA’s section mitted as required in paragraph (a)(1)
514(c) recognition, the explanatory text of this section, the manufacturer shall
as provided in the standard. send a protocol that consists of a sum-
[81 FR 38928, June 15, 2016] mary of the history of manufacture of
the product, including all results of
§ 660.46 Samples; protocols; official re- each test for which test results are re-
lease.
quested by the Director, Center for
(a) Samples. (1) For the purposes of Biologics Evaluation and Research.
this section, a sample of product not The protocols submitted with the sam-
iodinated with 125I means a sample ples at periodic intervals as provided in
from each filling of each lot packaged
paragraph (a)(2)(ii) of this section shall
as for distribution, including all ancil-
be identified by the manufacturer as
lary reagents and materials; and a
sample of product iodinated with 125I or ‘‘surveillance test results.’’
unlyophilized HBsAg-coated red blood (c) Official release. (1) The manufac-
cells means a sample from each lot of turer shall not distribute the product
diagnostic test kits in a finished pack- until written notification of official re-
age, including all ancillary reagents lease is received from the Director,
and materials. Center for Biologics Evaluation and
(2) Unless the Director, Center for Research, except as provided in para-
Biologics Evaluation and Research, de- graph (c)(2) of this section. Official re-
termines that the reliability and con- lease is required for at least five con-
sistency of the finished product can be secutive lots or fillings, as applicable,
assured with a smaller quantity of manufactured after licensure of the
sample or no sample and specifically product.
reduces or eliminates the required (2) After written notification of offi-
quantity of sample, each manufacturer cial release is received from the Direc-
shall submit the following samples to
tor, Center for Biologics Evaluation
the Director, Center for Biologics Eval-
and Research, for at least five consecu-
uation and Research (see mailing ad-
tive lots or fillings manufactured after
dresses in § 600.2(c) of this chapter),
within 5 working days after the manu- licensure of the products, and after the
facturer has satisfactorily completed manufacturer receives from the Direc-
all tests on the samples: tor, Center for Biologics Evaluation
(i) One sample until written notifica- and Research, written notification that
tion of official release is no longer re- official release is no longer required,
quired under paragraph (c)(2) of this subsequent lots or fillings may be re-
section. leased by the manufacturer under the
(ii) One sample of product at periodic requirements of § 610.1 of this chapter.
intervals of 90 days, beginning after (3) The manufacturer shall not dis-
written notification of official release tribute lots or fillings, as applicable, of
is no longer required under paragraph products that require sample submis-
(c)(2) of this section. The sample sub- sion under paragraph (a)(2)(iii) of this
mitted at the 90-day interval shall be section until written notification of of-
from the first lot or filling, as applica- ficial release or notification that offi-
ble, released by the manufacturer, cial release is no longer required is re-
under the requirements of § 610.1 of this ceived from the Director, Center for
chapter, after the end of the previous Biologics Evaluation and Research.
90-day interval. The sample shall be
identified as ‘‘surveillance sample’’ and [48 FR 20407, May 6, 1983, as amended at 49
shall include the date of manufacture. FR 23834, June 8, 1984; 51 FR 15611, Apr. 25,
(iii) Samples may at any time be re- 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR
quired to be submitted to the Director, 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]
Center for Biologics Evaluation and
130
Subpart F—Anti-Human Globulin ufacturer begins the last entire group

of potency tests.
§ 660.50 Anti-Human Globulin.
[50 FR 5579, Feb. 11, 1985, as amended at 50
(a) Proper name and definition. The FR 16474, Apr. 26, 1985; 65 FR 77499, Dec. 12,
proper name of this product shall be 2000; 67 FR 9587, Mar. 4, 2002]
Anti-Human Globulin which shall con-
sist of one or more antiglobulin anti- § 660.52 Reference preparations.
bodies identified in § 660.55(a)(4). Reference Anti-Human Globulin
(b) Source. The source of this product preparations shall be obtained from the
shall be either serum from animals im- Food and Drug Administration, Center
munized with one or more human for Biologics Evaluation and Research,
serum globulins or protein-rich fluids Reagents and Standards Shipping, 10903
derived from stable immunoglobulin- New Hampshire Ave., Bldg. 75, Rm.
secreting cell lines maintained either G704, Silver Spring, MD 20993–0002, and
in tissue cultures or in secondary shall be used as described in the ac-
hosts. companying package insert for deter-
mining the potency of Anti-Human
[50 FR 5579, Feb. 11, 1985, as amended at 65
Globulin.
FR 77499, Dec. 12, 2000; 81 FR 38928, June 15,
2016] [50 FR 5579, Feb. 11, 1985, as amended at 50
FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25,
§ 660.51 Processing. 1986; 55 FR 11015, Mar. 26, 1990; 67 FR 9587,
Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005; 80 FR
(a) Processing method. (1) The proc- 18093, Apr. 3, 2015]
essing method shall be one that has
been shown to yield consistently a spe- § 660.53 Controls for serological proce-
cific, potent final product, free of prop- dures.
erties that would adversely affect the
Red blood cells sensitized with com-
product for its intended use throughout plement shall be tested with appro-
its dating period. priate positive and negative control
(2) Anti-IgG, –C3d (polyspecific) re- antisera. All tests shall be performed
agents and anti-IgG products may be in accordance with serological testing
colored green. procedures approved by the Director,
(3) Only that material which has been Center for Biologics Evaluation and
fully processed, thoroughly mixed in a Research.
single vessel, and filtered shall con-
stitute a lot. Each lot shall be identi- [50 FR 5579, Feb. 11, 1985, as amended at 50
FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25,
fied by a lot number. 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587,
(4) A lot may be subdivided into Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005]
sublots which shall be identified by the
lot number to which has been added a § 660.54 Potency tests, specificity tests,
distinctive prefix or suffix. If lots are tests for heterospecific antibodies,
to be subdivided, the manufacturer and additional tests for nonspecific
shall include this information in the li- properties.
cense application . The manufacturer The following tests shall be per-
shall describe the test specifications to formed using test procedures approved
verify that each sublot is identical to by the Director, Center for Biologics
other sublots of the lot. Evaluation and Research:
(b) Final containers and dropper assem- (a) Potency tests for determining
blies. (1) Final containers and dropper anti-IgG and anti-complement activ-
assemblies shall be clean. ity.
(2) Final containers and dropper pi- (b) Specificity tests, tests for
pettes shall be colorless and suffi- heterospecific antibodies, and addi-
ciently transparent to permit observa- tional tests for nonspecific properties.
tion of the contents for presence of par- [50 FR 5579, Feb. 11, 1985, as amended at 50
ticulate matter or increased turbidity.
FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25,

(c) Date of manufacture. The date of 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587,
manufacture shall be the date the man- Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005]
131
§ 660.55 21 CFR Ch. I (4–1–20 Edition)
§ 660.55 Labeling. IMMUNOGLOBULINS’’ or ‘‘DOES NOT

(a) In addition to the applicable la- CONTAIN ANTIBODIES TO COM-
beling requirements of §§ 610.62 through PLEMENT COMPONENTS.’’
610.65 and § 809.10 of this chapter, and in (I) If the final container is not en-
lieu of the requirements in §§ 610.60 and closed in a package, all items required
610.61 of this chapter, the following re- for a package label shall appear on the
quirements shall be met: container label.
(1) Final container label—(i) Color cod- (iii) Lettering size. The type size for
ing. The main panel of the final con- the designation of the specific antibody
tainer label of all Anti-IgG, -C3d on the label of a final container shall
(polyspecific) reagents shall be white be not less than 12 point, unless other-
or colorless and printing shall be solid wise approved by the Director, Center
dark contrasting lettering. The main for Biologics Evaluation and Research.
panel of the final container label of all The prefix anti- and other parts of the
other Anti-Human Globulin reagents name such as polyspecific may appear
shall be black with solid white let- in smaller type.
tering. A logo or company name may (iv) Visual inspection. When the label
be placed on the final container label; has been affixed to the final container,
however, the logo or company name a sufficient area of the container shall
shall be located along the bottom or remain uncovered for its full length or
end of the label, outside of the main for no less than 5 millimeters of the
panel. lower circumference to permit inspec-
(ii) Required information. The proper tion of the contents.
name ‘‘Anti-Human Globulin’’ need not (2) Package label. The following items
appear on the final container label pro- shall appear either on the package
vided the final container is distributed label or on the final container label if
in a package and the package label see-through packaging is used:
bears the proper name. The final con- (i) Proper name of the product, and
tainer label shall bear the following in- the name of the antibody or antibodies
formation: as listed in paragraph (a)(4) of this sec-
(A) Name of the antibody or anti- tion.
bodies present as set forth in paragraph (ii) Name, address (including ZIP
(a)(4) of this section. Anti-Human Glob- code), and license number of the manu-
ulin may contain one or more anti- facturer.
bodies to either immunoglobulins or (iii) Lot number, including any
complement components but the name sublot designations.
of each significant antibody must ap- (iv) Expiration date.
pear on the final container label (e.g., (v) Preservative(s) used and its con-
anti-C3b, -C3d, -C4d). The final concentration.
tainer labels of polyspecific Anti- (vi) Number of containers, if more
Human Globulin are not required to than one.
identify antibody specificities other
(vii) Recommended storage tempera-
than anti-IgG and anti-C3d but the re-
ture in degrees Celsius.
activity of the Anti-Human Globulin
(viii) Source of the product.
shall be accurately described in the
package insert. (ix) Reference to enclosed package
(B) Name, address, and license num- insert.
ber of the manufacturer. (x) The statement: ‘‘For In Vitro Di-
(C) Lot number, including any sublot agnostic Use.’’
designations. (xi) The statement: ‘‘Meets FDA Po-
(D) Expiration date. tency Requirements.’’
(E) Source of the product. (xii) A statement of an observable in-
(F) Recommended storage tempera- dication of an alteration of the prod-
ture in degrees Celsius. uct, e.g., turbidity, color change, pre-
(G) Volume of product. cipitate, that may indicate possible de-
(H) Appropriate cautionary state- terioration of the product.
ment if the Anti-Human Globulin is (xiii) Appropriate cautions.
not polyspecific. For example, ‘‘DOES (3) Package insert. Each final con-
NOT CONTAIN ANTIBODIES TO tainer of Anti-Human Globulin shall be
132
accompanied by a package insert meet- (4) Names of antibodies. Anti-Human

ing the requirements of § 809.10 of this Globulin preparations may contain one
chapter. If two or more final containers or more of the antibody specificities
requiring identical package inserts are listed in this paragraph as described in
placed in a single package, only one paragraph (a)(1)(ii)(A) of this section.
package insert per package is required.
Antibody designation on Definition
container label
(1) Anti-IgG, -C3d; Polyspecific Contains anti-IgG and anti-C3d (may contain other anticomplement and anti-immunoglobulin
antibodies).
(2) Anti-IgG ............................... Contains anti-IgG with no anti-complement activity (not necessarily gamma chain specific).
(3) Anti-IgG; heavy chains ....... Contains only antibodies reactive against human gamma chains.
(4) Anti-C3b .............................. Contains only C3b antibodies with no anti-immunoglobulin activity. Note: The antibody pro-
duced in response to immunization is usually directed against the antigenic determinant
which is located in the C3c subunit; some persons have called this antibody ‘‘anti-C3c.’’ In
product labeling, this antibody should be designated anti-C3b.
(5) Anti-C3d .............................. Contains only C3d antibodies with no anti-immunoglobulin activity.
(6) Anti-C4b .............................. Contains only C4b antibodies with no anti-immunoglobulin activity.
(7) Anti-C4d .............................. Contains only C4d antibodies with no anti-immunoglobulin activity.
(b) The applicant may provide the la- forth in FDA’s section 514(c) recogni-
beling information referenced in this tion;
section in the form of: (iii) Is determined by the manufac-
(1) A symbol accompanied by explan- turer to be likely to be read and under-
atory text adjacent to the symbol; stood by the ordinary individual under
(2) A symbol not accompanied by ad- customary conditions of purchase and
jacent explanatory text that: use in compliance with section 502(c) of
(i) Is contained in a standard that the Federal Food, Drug, and Cosmetic
FDA recognizes under its authority in Act;
section 514(c) of the Federal Food, (iv) Is used according to the speci-
Drug, and Cosmetic Act; fications for use of the symbol set forth
(ii) Is used according to the specifica- in the SDO-developed standard; and
tions for use of the symbol set forth in (v) Is explained in a paper or elec-
FDA’s section 514(c) recognition; and tronic symbols glossary that is in-
(iii) Is explained in a paper or elec- cluded in the labeling for the device
tronic symbols glossary that is in- and the labeling on or within the pack-
cluded in the labeling for the device age containing the device bears a
and the labeling on or within the pack- prominent and conspicuous statement
age containing the device bears a identifying the location of the symbols
prominent and conspicuous statement glossary that is written in English or,
identifying the location of the symbols in the case of articles distributed sole-
glossary that is written in English or, ly in Puerto Rico or in a Territory
in the case of articles distributed sole- where the predominant language is one
ly in Puerto Rico or in a Territory other than English, the predominant
where the predominant language is one language may be used.
other than English, the predominant (c) The use of symbols in device la-
language may be used; or beling to provide the labeling informa-
(3) A symbol not accompanied by ad- tion referenced in paragraph (a) of this
jacent explanatory text that: section which do not meet the require-
(i) Is established in a standard devel- ments of paragraph (b) of this section
oped by a standards development orga- renders a device misbranded under sec-
nization (SDO); tion 502(c) of the Federal Food, Drug,
(ii) Is not contained in a standard and Cosmetic Act.
that is recognized by FDA under its au- (d) For purposes of paragraph (b) of
thority in section 514(c) or is contained this section:
in a standard that is recognized by (1) An SDO is an organization that is
FDA but is not used according to the nationally or internationally recog-

specifications for use of the symbol set nized and that follows a process for
133
standard development that is trans- fied allergenic source materials that

parent, (i.e., open to public scrutiny), contain no more than a total of 1.0 per-
where the participation is balanced, cent of detectable foreign materials
where an appeals process is included, shall be used in the manufacture of Al-
where the standard is not in conflict lergenic Products, except that this re-
with any statute, regulation, or policy quirement shall not apply to molds and
under which FDA operates, and where animals described under paragraphs (b)
the standard is national or inter- (2) and (3) of this section, respectively.
national in scope. Source materials such as pelts, feath-
(2) The term ‘‘symbols glossary’’ ers, hairs, and danders shall be col-
means a compiled listing of: lected in a manner that will minimize
(i) Each SDO-established symbol used contamination of the source material.
in the labeling for the device; (2) Molds. (i) Molds (excluding rusts
(ii) The title and designation number and smuts) used as source material in
of the SDO-developed standard con- the manufacture of Allergenic Prod-
taining the symbol; ucts shall meet the requirements of
(iii) The title of the symbol and its § 610.18 of this chapter and § 680.2 (a) and
reference number, if any, in the stand- (b).
ard; and (ii) Mold cultures shall be free of con-
(iv) The meaning or explanatory text taminating materials (including micro-
for the symbol as provided in the FDA organisms) prior to harvest, and care
recognition or, if FDA has not recog- shall be taken to minimize contamina-
nized the standard or portion of the tion during harvest and subsequent
standard in which the symbol is lo- processing.
cated or the symbol is not used accord- (iii) Mold manufacturers shall main-
ing to the specifications for use of the tain written standard operating proce-
symbol set forth in FDA’s section dures, developed by a qualified indi-
514(c) recognition, the explanatory text vidual, that will ensure the identity of
as provided in the standard. the seed culture, prescribe adequate
[81 FR 38928, June 15, 2016] processing of the mold, and specify the
acceptable limits and kinds of con-
PART 680—ADDITIONAL STAND- tamination. These limits shall be based
ARDS FOR MISCELLANEOUS on results of appropriate tests per-
formed by the manufacturer on at least
PRODUCTS three consecutive lots of a mold that is
Sec.
a representative species of mold sub-
680.1 Allergenic Products. ject to the standard operating proce-
680.2 Manufacture of Allergenic Products. dures. The tests shall be performed at
680.3 Tests. each manufacturing step during and
AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, subsequent to harvest, as specified in
360, 371; 42 U.S.C. 216, 262, 263, 263a, 264. the standard operating procedures. Be-
fore use of the mold as a source mate-
SOURCE: 38 FR 32100, Nov. 20, 1973, unless
otherwise noted.
rial for Allergenic Products, in accord-
ance with 21 CFR 601.2, the standard
CROSS REFERENCES: For U.S. Customs operating procedures and test data
Service regulations relating to viruses, se- from the three representative lots de-
U.S. Postal Service regulations relating to
scribed above shall be submitted to and
the admissibility to the United States mails approved by the Director, Center for
see parts 124 and 125 of the Domestic Mail Biologics Evaluation and Research (see
Manual, that is incorporated by reference in mailing address in § 600.2(a) of this
39 CFR part 111. chapter).
(3) Mammals and birds—(i) Care of ani-
§ 680.1 Allergenic Products. mals. Animals intended as a source ma-
(a) Definition. Allergenic Products are terial for Allergenic Products shall be
products that are administered to man maintained by competent personnel in
for the diagnosis, prevention or treat- facilities or designated areas that will
ment of allergies. ensure adequate care. Competent vet-
(b) Source materials—(1) Criteria for erinary care shall be provided as need-
source material. Only specifically identi- ed.
134
(ii) Health of animals. Only animals in under other acceptable conditions so

good health and free from detectable that the postmortal decomposition
skin diseases shall be used as a source processes do not adversely affect the
material for Allergenic Products. The allergen.
determination of good health prior to (c) Listing of source materials and sup-
collection of the source material shall pliers. Each licensed manufacturer
be made by a licensed veterinarian or a shall initially list with the Director,
competent individual under the super- Center for Biologics Evaluation and
vision and instruction of a licensed vet- Research (see mailing address in
erinarian provided that the licensed § 600.2(a) of this chapter), the name and
veterinarian certifies in writing that address of each of the manufacturer’s
the individual is capable of deter- source material suppliers. The listing
mining the good health of the animals.
shall identify each source material ob-
(iii) Immunization against tetanus.
tained from each source material sup-
Animals of the equine genus intended
plier. The licensed manufacturers shall
as a source material for Allergenic
update the listing annually to include
Products shall be treated to maintain
immunity to tetanus. new source material suppliers or to de-
(iv) Reporting of certain diseases. In lete those no longer supplying source
cases of actual or suspected infection materials.
with foot and mouth disease, glanders, (d) Exemptions. (1) Exemptions or
tetanus, anthrax, gas gangrene, equine modifications from the requirements
infectious anemia, equine under paragraph (b) of this section
encephalomyelitis, or any of the pock shall be made only upon written ap-
diseases among animals intended for proval by the Director, Center for Bio-
use or used as source material in the logics Evaluation and Research.
manufacture of Allergenic Products, (2) Nonlicensed source material sup-
the manufacturer shall immediately pliers are exempt from drug registra-
notify the Director, Center for Bio- tion.
logics Evaluation and Research (see
mailing address in § 600.2(a) of this
FR 25432, June 21, 1984; 49 FR 31395, Aug. 7,
chapter). 1984; 55 FR 11014, Mar. 26, 1990; 67 FR 9587,
(v) Dead animals. Dead animals may Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005; 80 FR
be used as source material in the man- 18093, Apr. 3, 2015]
ufacture of Allergenic Products: Pro-
vided, That (a) the carcasses shall be § 680.2 Manufacture of Allergenic
frozen or kept cold until the allergen Products.
can be collected, or shall be stored (a) Extraneous allergenic substances.
under other acceptable conditions so All manufacturing steps shall be per-
that the postmortal decomposition
formed so as to insure that the product
processes do not adversely affect the
will contain only the allergenic and
allergen, and (b) when alive, the animal
other substances intended to be in-
met the applicable requirements pre-
cluded in the final product.
scribed in paragraphs (b)(3) (i), (ii), and
(iii) of this section. (b) Cultures derived from microorga-
(vi) Mammals and birds inspected by nisms. Culture media into which orga-
the U.S. Department of Agriculture. nisms are inoculated for the manufac-
Mammals and birds, subject to inspec- ture of Allergenic Products shall con-
tion by the U.S. Department of Agri- tain no allergenic substances other
culture at the time of slaughter and than those necessary as a growth re-
found suitable as food, may be used as quirement. Neither horse protein nor
a source material, and the require- any allergenic derivative of horse pro-
ments of paragraph (b)(3) (i) through tein shall be used in culture media.
(iv) of this section do not apply in such (c) Liquid products for oral administra-
a case. Notwithstanding U.S. Depart- tion. Liquid products intended for oral
ment of Agriculture inspection, the administration that are filled in mul-
carcasses of such inspected animals tiple dose final containers shall con-
shall be frozen or kept cold until the tain a preservative in a concentration

allergen is collected, or shall be stored adequate to inhibit microbial growth.
135
§ 680.3 21 CFR Ch. I (4–1–20 Edition)
(d) Residual pyridine. Products for in sufficient detail to verify the iden-
which pyridine is used in manufac- tity of the product.
turing shall have no more residual pyr- (b) [Reserved]
idine in the final product than 25 (c) Sterility. A sterility test shall be
micrograms per milliliter. performed on each lot of each Aller-
(e) [Reserved] genic Product as required by § 610.12 of
(f) Records. A record of the history of this chapter.
the manufacture or propagation of (d) [Reserved]
(e) Potency. The potency of each lot
each lot of source material intended
of each Allergenic Product shall be de-
for manufacture of final Allergenic
termined as prescribed in § 610.10 of this
Products shall be available at the es-
chapter. Except as provided in this sec-
tablishment of the manufacturer of the tion, the potency test methods shall
source material, as required by § 211.188 measure the allergenic activity of the
of this chapter. A summary of the his- product. Until manufacturers are noti-
tory of the manufacture or propagation fied by the Director, Center for Bio-
of the source material shall be avail- logics Evaluation and Research, of the
able at the establishment of the manu- existence of a potency test that meas-
facturer of the final product. ures the allergenic activity of an aller-
[38 FR 32100, Nov. 20, 1973, as amended at 49 genic product, manufacturers may con-
FR 25433, June 21, 1984; 67 FR 9587, Mar. 4, tinue to use unstandardized potency
2002] designations.
(f) Records. The records related to the
§ 680.3 Tests. testing requirements of this section
shall be prepared and maintained as re-
(a) Identity. When a specific identity
quired by §§ 211.165, 211.167, 211.188, and
test meeting the provisions of § 610.14 of 211.194 of this chapter.
this chapter cannot be performed, the
manufacture of each lot shall be sepa- [38 FR 32100, Nov. 20, 1973, as amended at 39
rated from the manufacture of other FR 19777, June 6, 1974; 41 FR 4015, Jan. 28,
1976; 52 FR 37607, Oct. 8, 1987; 55 FR 11013,
products in a manner that will pre- Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 77 FR
clude adulteration, and records made 26175, May 3, 2012; 77 FR 30884, May 24, 2012;
in the course of manufacture shall be 80 FR 37974, July 2, 2015]
136
SUBCHAPTER G—COSMETICS
PART 700—GENERAL stances used solely to impart an odor

to a cosmetic product.
Subpart A—General Provisions (e) The term ingredient means any
single chemical entity or mixture used
Sec. as a component in the manufacture of
700.3 Definitions. a cosmetic product.
Subpart B—Requirements for Specific (f) The term proprietary ingredient
Cosmetic Products means any cosmetic product ingredient
whose name, composition, or manufac-
700.11 Cosmetics containing bithionol. turing process is protected from com-
700.13 Use of mercury compounds in cos- petition by secrecy, patent, or copy-
metics including use as skinbleaching right.
agents in cosmetic preparations also re-
garded as drugs.
(g) The term chemical description
700.14 Use of vinyl chloride as an ingredient, means a concise definition of the chem-
including propellant of cosmetic aerosol ical composition using standard chem-
products. ical nomenclature so that the chemical
700.15 Use of certain halogenated salicyl- structure or structures of the compo-
anilides as ingredients in cosmetic prod- nents of the ingredient would be clear
ucts. to a practicing chemist. When the com-
700.16 Use of aerosol cosmetic products con- position cannot be described chemi-
taining zirconium.
cally, the substance shall be described
700.18 Use of chloroform as an ingredient in
cosmetic products.
in terms of its source and processing.
700.19 Use of methylene chloride as an in- (h) The term cosmetic raw material
gredient of cosmetic products. means any ingredient, including an in-
700.23 Chlorofluorocarbon propellants. gredient that is a mixture, which is
700.25 Tamper-resistant packaging require- used in the manufacture of a cosmetic
ments for cosmetic products. product for commercial distribution
700.27 Use of prohibited cattle materials in and is supplied to a cosmetic product
cosmetic products. manufacturer, packer, or distributor
700.35 Cosmetics containing sunscreen in-
gredients.
by a cosmetic raw material manufac-
turer or supplier.
AUTHORITY: 21 U.S.C. 321, 331, 352, 355, 361, (i) The term commercial distribution of
362, 371, 374.
a cosmetic product means annual gross
SOURCE: 39 FR 10054, Mar. 15, 1974, unless sales in excess of $1,000 for that prod-
otherwise noted. uct.
(j) Establishment means a place of
Subpart A—General Provisions business where cosmetic products are
manufactured or packaged.
§ 700.3 Definitions. (k) The term manufacture of a cos-
As used in this subchapter: metic product means the making of
(a) The term act means the Federal any cosmetic product by chemical,
Food, Drug, and Cosmetic Act. physical, biological, or other proce-
(b) The term cosmetic product means a dures, including manipulation, sam-
finished cosmetic the manufacture of pling, testing, or control procedures
which has been completed. Any cos- applied to the product.
metic product which is also a drug or (l) The term packaging of a cosmetic
device or component thereof is also product means filling or labeling the
subject to the requirements of Chapter product container, including changing
V of the act. the immediate container or label (but
(c) The term flavor means any nat- excluding changing other labeling) at
ural or synthetic substance or sub- any point in the distribution of the
stances used solely to impart a taste to cosmetic product from the original
a cosmetic product. place of manufacture to the person who
(d) The term fragrance means any makes final delivery or sale to the ulti-
natural or synthetic substance or sub- mate consumer.
137
§ 700.11 21 CFR Ch. I (4–1–20 Edition)
(m) The term all business trading when evaluated by a filed screening
names used by the establishment means procedure.
any name which is used on a cosmetic [39 FR 10054, Mar. 15, 1974, as amended at 46
product label and owned by the cos- FR 38073, July 24, 1981]
metic product manufacturer or packer,
but is different from the principal Subpart B—Requirements for
name under which the cosmetic prod- Specific Cosmetic Products
uct manufacturer or packer is reg-
istered. § 700.11 Cosmetics containing
(n) The definitions and interpreta- bithionol.
tions contained in sections 201, 601, and (a) Bithionol has been used to some
602 of the act shall be applicable to extent as an antibacterial agent in cos-
such terms when used in the regula- metic preparations such as detergent
tions in this subchapter. bars, shampoos, creams, lotions, and
(o) System of commercial distribution of bases used to hide blemishes. New evi-
a cosmetic product means any distribu- dence of clinical experience and
tion outside the establishment manu- photopatch tests indicate that
facturing the product, whether for sale, bithionol is capable of causing
to promote future sales (including free photosensitivity in man when used
samples of the product), or to gage con- topically and that in some instances
sumer acceptance through market test- the photosensitization may persist for
ing, in excess of $1,000 in cost of goods. prolonged periods as severe reactions
without further contact with sensi-
(p) Filed screening procedure means a
tizing articles. Also, there is evidence
procedure that is:
to indicate that bithionol may produce
(1) On file with the Food and Drug cross-sensitization with other com-
Administration and subject to public monly used chemicals such as certain
inspection; halogenated salicylanilides and
(2) Designed to determine that there hexachlorophene. It is, therefore, the
is a reasonable basis for concluding view of the Food and Drug Administra-
that an alleged injury did not occur in tion that bithionol is a deleterious sub-
conjunction with the use of the cos- stance which may render any cosmetic
metic product; and product that contains it injurious to
(3) Which is subject, upon request by users. Accordingly, any cosmetic con-
the Food and Drug Administration, to taining bithionol is deemed to be adul-
an audit conducted by the Food and terated under section 601(a) of the Fed-
Drug Administration at reasonable eral Food, Drug, and Cosmetic Act.
times and, where an audit is conducted, (b) Regulatory proceedings may be
such audit shows that the procedure is initiated with respect to any cosmetic
consistently being applied and that the preparation containing bithionol
procedure is not disregarding report- shipped within the jurisdiction of the
able information. act after March 15, 1968.
(q) Reportable experience means an ex-
§ 700.13 Use of mercury compounds in
perience involving any allergic reac- cosmetics including use as
tion, or other bodily injury, alleged to skinbleaching agents in cosmetic
be the result of the use of a cosmetic preparations also regarded as
product under the conditions of use drugs.
prescribed in the labeling of the prod- (a) Mercury-containing cosmetic
uct, under such conditions of use as are preparations have been represented for
customary or reasonably foreseeable many years as skin-bleaching agents or
for the product or under conditions of as preparations to remove or prevent
misuse, that has been reported to the freckles and/or brown spots (so-called
manufacturer, packer, or distributor of age spots). Preparations intended for
the product by the affected person or such use are regarded as drugs as well
any other person having factual knowl- as cosmetics. In addition to such use as
edge of the incident, other than an al- skin-bleaching agents, mercury com-
leged experience which has been deter- pounds have also been widely used as
mined to be unfounded or spurious preservatives in cosmetics such as
138
hand and body creams and lotions; hair is warranted because mercury com-
shampoos, hair sets and rinses, hair pounds are exceptionally effective in
straighteners, hair coloring, and other preventing Pseudomonas contamination
preparations; bath oils, bubble bath, of cosmetics and Pseudomonas infection
and other bath preparations; makeup; of the eye can cause serious injury, in-
antiperspirants and deodorants; and cluding blindness. Therefore:
eye-area cosmetics. (1) The Food and Drug Administra-
(b) The toxicity of mercury com- tion withdraws the opinion expressed
pounds is extensively documented in in trade correspondence TC–9 (issued
scientific literature. It is well known May 13, 1939) and concludes that any
that mercury compounds are readily
product containing mercury as a skin-
absorbed through the unbroken skin as
bleaching agent and offered for sale as
well as through the lungs by inhalation
and by intestinal absorption after in- skin-bleaching, beauty, or facial prepa-
gestion. Mercury is absorbed from top- ration is misbranded within the mean-
ical application and is accumulated in ing of sections 502(a), 502(f)(1) and (2),
the body, giving rise to numerous ad- and 502(j), and may be a new drug with-
verse effects. Mercury is a potent aller- out approval in violation of section 505
gen and sensitizer, and skin irritation of the Federal Food, Drug, and Cos-
is common after topical application. metic Act. Any such preparation
Cosmetic preparations containing mer- shipped within the jurisdiction of the
cury compounds are often applied with Act after January 5, 1973 will be the
regularity and frequency for prolonged subject of regulatory action.
periods. Such chronic use of mercury- (2) The Food and Drug Administra-
containing skin-bleaching preparations tion withdraws the opinion expressed
has resulted in the accumulation of in trade correspondence TC–412 (issued
mercury in the body and the occur- Feb. 11, 1944) and will regard as adul-
rence of severe reactions. Recently it terated within the meaning of section
has also been determined that micro- 601(a) of the Act any cosmetic con-
organisms in the environment can containing mercury unless the cosmetic
vert various forms of mercury into meets the conditions of paragraph
highly toxic methyl mercury which has (d)(2) (i) or (ii) of this section.
been found in the food supply and is
(i) It is a cosmetic containing no
now considered to be a serious environ-
mental problem. more than a trace amount of mercury
(c) The effectiveness of mercury-con- and such trace amount is unavoidable
taining preparations as skin-bleaching under conditions of good manufac-
agents is questionable. The Food and turing practice and is less than 1 part
Drug Administration has not been proper million (0.0001 percent), calculated
vided with well controlled studies to as the metal; or
document the effectiveness of these (ii) It is a cosmetic intended for use
preparations. Although mercurial pre- only in the area of the eye, it contains
servatives are recognized as highly ef- no more than 65 parts per million
fective, less toxic and satisfactory sub- (0.0065 percent) of mercury, calculated
stitutes are available except in the as the metal, as a preservative, and
case of certain eye-area cosmetics. there is no effective and safe nonmer-
(d) Because of the known hazards of curial substitute preservative available
mercury, its questionable efficacy as a for use in such cosmetic.
skin-bleaching agent, and the avail-
ability of effective and less toxic non- § 700.14 Use of vinyl chloride as an in-
mercurial preservatives, there is no gredient, including propellant of
justification for the use of mercury in cosmetic aerosol products.
skin-bleaching preparations or its use (a) Vinyl chloride has been used as an
as a preservative in cosmetics, with the ingredient in cosmetic aerosol products
exception of eye-area cosmetics for including hair sprays. Where such aer-
which no other effective and safe non-
osol products are used in the confines
mercurial preservative is available.
of a small room, as is often the case,

The continued use of mercurial pre-
the level of vinyl chloride to which the
servatives in such eye-area cosmetics
139
§ 700.15 21 CFR Ch. I (4–1–20 Edition)
individual may be exposed could be sig- dient at any level for any purpose is
nificantly in excess of the safe level es- deemed to be adulterated under section
tablished in connection with occupa- 601(a) of the Federal Food, Drug, and
tional exposure. Evidence indicates Cosmetic Act.
that vinyl chloride inhalation can re- (c) Any cosmetic product containing
sult in acute toxicity, manifested by these halogenated salicylanilides as an
dizziness, headache, disorientation, and ingredient that is initially introduced
unconsciousness where inhaled at high into interstate commerce after Decem-
concentrations. Studies also dem- ber 1, 1975, that is not in compliance
onstrate carcinogenic effects in ani- with this section is subject to regu-
mals as a result of inhalation exposure latory action.
to vinyl chloride. Furthermore, vinyl
chloride has recently been linked to [40 FR 50531, Oct. 30, 1975]
liver disease, including liver cancer, in
workers engaged in the polymerization § 700.16 Use of aerosol cosmetic prod-
of vinyl chloride. It is the view of the ucts containing zirconium.
Commissioner that vinyl chloride is a (a) Zirconium-containing complexes
deleterious substance which may have been used as an ingredient in cos-
render any cosmetic aerosol product metics and/or cosmetics that are also
that contains it as an ingredient inju- drugs, as, for example, aerosol anti-
rious to users. Accordingly, any cos- perspirants. Evidence indicates that
metic aerosol product containing vinyl certain zirconium compounds have
chloride as an ingredient is deemed to caused human skin granulomas and
be adulterated under section 601(a) of toxic effects in the lungs and other or-
the Federal Food, Drug, and Cosmetic gans of experimental animals. When
Act. used in aerosol form, some zirconium
(b) Any cosmetic aerosol product will reach the deep portions of the
containing vinyl chloride as an ingre- lungs of users. The lung is an organ,
dient shipped within the jurisdiction of like skin, subject to the development
the Act is subject to regulatory action. of granulomas. Unlike the skin, the
[39 FR 30830, Aug. 26, 1974] lung will not reveal the presence of
granulomatous changes until they have
§ 700.15 Use of certain halogenated become advanced and, in some cases,
salicylanilides as ingredients in cos- permanent. It is the view of the Com-
metic products. missioner that zirconium is a delete-
(a) Halogenated salicylanilides (tri- rious substance that may render any
bromsalan (TBS,3,4′,5–tribromosalicyl- cosmetic aerosol product that contains
anilide), dibromsalan (DBS,4′5–dibro- it injurious to users.
mosalicylanilide), metabromsalan (b) Any aerosol cosmetic product
(MBS, 3,5–dibromosalicylanilide) and containing zirconium is deemed to be
3,3′,4,5′–tetrachlorosalicylanilide adulterated under section 601(a) of the
(TCSA)) have been used as anti- Federal Food, Drug, and Cosmetic Act.
microbial agents for a variety of pur- (c) Any such cosmetic product intro-
poses in cosmetic products. These halo- duced in interstate commerce after
genated salicylanilides are potent September 15, 1977 is subject to regu-
photosensitizers and cross-sensitizers latory action.
and can cause disabling skin disorders.
In some instances, the [42 FR 41376, Aug. 16, 1977]
photosensitization may persist for pro-
longed periods as a severe reaction § 700.18 Use of chloroform as an ingre-
dient in cosmetic products.
without further exposure to these
chemicals. Safer alternative anti- (a) Chloroform has been used as an
microbial agents are available. ingredient in cosmetic products. Re-
(b) These halogenated salicylanilides cent information has become available
are deleterious substances which associating chloroform with carcino-
render any cosmetic that contains genic effects in animals. Studies con-
them injurious to users. Therefore, any ducted by the National Cancer Insti-
cosmetic product that contains such a tute have demonstrated that the oral
halogenated salicylanilide as an ingre- administration of chloroform to mice
140
and rats induced hepatocellular car- § 700.23 Chlorofluorocarbon propel-

cinomas (liver cancer) in mice and lants.
renal tumors in male rats. Scientific The use of chlorofluorocarbons in
literature indicates that chloroform is cosmetics as propellants in self-pres-
absorbed from the gastrointestinal surized containers is prohibited as pro-
tract, through the respiratory system, vided in § 2.125 of this chapter.
and through the skin. The Commis-
[43 FR 11317, Mar. 17, 1978]
sioner concludes that, on the basis of
these findings, chloroform is a delete- § 700.25 Tamper-resistant packaging
rious substance which may render inju- requirements for cosmetic prod-
rious to users any cosmetic product ucts.
that contains chloroform as an ingre- (a) General. Because most cosmetic
dient. liquid oral hygiene products and vag-
(b) Any cosmetic product containing inal products are not now packaged in
chloroform as an ingredient is adulter- tamper-resistant retail packages, there
ated and is subject to regulatory action is the opportunity for the malicious
under sections 301 and 601(a) of the adulteration of those cosmetic prod-
Federal Food, Drug, and Cosmetic Act. ucts with health risks to individuals
Any cosmetic product containing chlo- who unknowingly purchase adulterated
roform in residual amounts from its products and with loss of consumer
use as a processing solvent during man- confidence in the security of cosmetic
ufacture, or as a byproduct from the product packages. The Food and Drug
synthesis of an ingredient, is not, for Administration has the authority and
responsibility under the Federal Food,
the purpose of this section, considered
Drug, and Cosmetic Act (the act) to es-
to contain chloroform as an ingredient.
tablish a uniform national requirement
[41 FR 26845, June 29, 1976] for tamper-resistant packaging of cos-
metic liquid oral hygiene products or
§ 700.19 Use of methylene chloride as products used vaginally that will im-
an ingredient of cosmetic products. prove the packaging security and help
(a) Methylene chloride has been used assure the safety of those products.
as an ingredient of aerosol cosmetic Such a cosmetic product for retail sale
products, principally hair sprays, at that is not packaged in a tamper-re-
concentrations generally ranging from sistant package or that is not properly
labeled under this section is adulter-
10 to 25 percent. In a 2-year animal in-
ated under section 601 of the act or
halation study sponsored by the Na-
misbranded under section 602 of the
tional Toxicology Program, methylene act, or both.
chloride produced a significant in- (b) Requirement for tamper-resistant
crease in benign and malignant tumors package. Each manufacturer and pack-
of the lung and liver of male and fe- er who packages a cosmetic liquid oral
male mice. Based on these findings and hygiene product or vaginal product for
on estimates of human exposure from retail sale shall package the product in
the customary use of hair sprays, the a tamper-resistant package, if this
Food and Drug Administration con- product is accessible to the public
cludes that the use of methylene chlo- while held for sale. A tamper-resistant
ride in cosmetic products poses a sig- package is one having an indicator or
nificant cancer risk to consumers, and barrier to entry which, if breached or
that the use of this ingredient in cos- missing, can reasonably be expected to
metic products may render these prod- provide visible evidence to consumers
ucts injurious to health. that tampering has occurred. To reduce
(b) Any cosmetic product that con- the likelihood of substitution of a tam-
tains methylene chloride as an ingre- per-resistant feature after tampering,
dient is deemed adulterated and is sub- the indicator or barrier to entry is re-
ject to regulatory action under sec- quired to be distinctive by design (e.g.,
tions 301 and 601(a) of the Federal an aerosol product container) or by the
use of an identifying characteristic
Food, Drug, and Cosmetic Act.

(e.g., a pattern, name, registered trade-
[54 FR 27342, June 29, 1989] mark, logo, or picture). For purposes of
141
§ 700.25 21 CFR Ch. I (4–1–20 Edition)
this section, the term ‘‘distinctive by this section is unnecessary or cannot

design’’ means the packaging cannot be be achieved.
duplicated with commonly available (3) A description of alternative steps
materials or through commonly avail- that are available, or that the peti-
able processes. For purposes of this sec- tioner has already taken, to reduce the
tion, the term ‘‘aerosol product’’ likelihood that the product will be the
means a product which depends upon subject of malicious adulteration.
the power of a liquified or compressed (4) Other information justifying an
gas to expel the contents from the con- exemption.
tainer. A tamper-resistant package This information collection require-
may involve an immediate-container ment has been approved by the Office
and closure system or secondary-con- of Management and Budget under num-
tainer or carton system or any com- ber 0910–0149.
bination of systems intended to provide (e) Effective date. Cosmetic products
a visual indication of package integ- covered by this section are required to
rity. The tamper-resistant feature comply with the requirements of this
shall be designed to and shall remain section on the dates listed below except
intact when handled in a reasonable to the extent that a product’s manufac-
manner during manufacture, distribu- turer or packer has obtained an exemp-
tion, and retail display. tion from a packaging or labeling re-
(c) Labeling. Each retail package of a quirement.
cosmetic product covered by this sec- (1) Initial effective date for packaging
tion, except aerosol products as defined requirements. (i) The packaging require-
in paragraph (b) of this section, is re- ment in paragraph (b) of this section is
quired to bear a statement that is effective on Feburary 7, 1983 for each
prominently placed so that consumers affected cosmetic product (except vag-
are alerted to the specific tamper-re- inal tablets) packaged for retail sale on
sistant feature of the package. The la- or after that date, except for the re-
beling statement is also required to be quirement in paragraph (b) of this sec-
so placed that it will be unaffected if tion for a distinctive indicator or bar-
the tamper-resistant feature of the rier to entry.
package is breached or missing. If the (ii) The packaging requirement in
tamper-resistant feature chosen to paragraph (b) of this section is effec-
meet the requirement in paragraph (b) tive on May 5, 1983 for each cosmetic
of this section is one that uses an iden- product that is a vaginal tablet pack-
tifying characteristic, that char- aged for retail sale on or after that
acteristic is required to be referred to date.
in the labeling statement. For exam- (2) Initial effective date for labeling re-
ple, the labeling statement on a bottle quirements. The requirement in para-
with a shrink band could say ‘‘For your graph (b) of this section that the indi-
protection, this bottle has an im- cator or barrier to entry be distinctive
printed seal around the neck.’’ by design and the requirement in para-
(d) Requests for exemptions from pack- graph (c) of this section for a labeling
aging and labeling requirements. A man- statement are effective on May 5, 1983
ufacturer or packer may request an ex- for each affected cosmetic product
emption from the packaging and label- packaged for retail sale on or after
ing requirements of this section. A re- that date, except that the requirement
quest for an exemption is required to for a specific label reference to any
be submitted in the form of a citizen identifying characteristic is effective
petition under § 10.30 of this chapter on February 6, 1984 for each affected
and should be clearly identified on the cosmetic product packaged for retail
envelope as a ‘‘Request for Exemption sale on or after that date.
from Tamper-resistant Rule.’’ The peti- (3) Retail level effective date. The tam-
tion is required to contain the fol- per-resistant packaging requirement of
lowing: paragraph (b) of this section is effec-
(1) The name of the product. tive February 6, 1984 for each affected
(2) The reasons that the product’s cosmetic product held for sale on or
compliance with the tamper-resistant after that date that was packaged for
packaging or labeling requirements of retail sale before May 5, 1983. This does
142
not include the requirement in para- tion that prescribes the standard of
graph (b) of this section that the indi- identity for MS (Species).
cator or barrier to entry be distinctive (4) Nonambulatory disabled cattle
by design. Products packaged for retail means cattle that cannot rise from a
sale after May 5, 1983, as required to be recumbent position or that cannot
in compliance with all aspects of the walk, including, but not limited to,
regulations without regard to the re- those with broken appendages, severed
tail level effective date. tendons or ligaments, nerve paralysis,
[47 FR 50451, Nov. 5, 1982; 48 FR 1707, Jan. 14,
fractured vertebral column, or meta-
1983; 48 FR 11427, Mar. 18, 1983, as amended at bolic conditions.
48 FR 16664, Apr. 19, 1983; 48 FR 37624, Aug. 19, (5) Specified risk material means the
1983] brain, skull, eyes, trigeminal ganglia,
EFFECTIVE DATE NOTE: See 48 FR 41579,
spinal cord, vertebral column (exclud-
Sept. 16, 1983, for a document announcing an ing the vertebrae of the tail, the trans-
interim stay of the effective date of certain verse processes of the thoracic and
provisions in paragraph (e)(3) of § 700.25. lumbar vertebrae, and the wings of the
sacrum), and dorsal root ganglia of cat-
§ 700.27 Use of prohibited cattle mate- tle 30 months of age and older and the
rials in cosmetic products. tonsils and distal ileum of the small in-
(a) Definitions. The definitions and intestine of all cattle.
terpretations of terms contained in (6) Tallow means the rendered fat of
section 201 of the Federal Food, Drug, cattle obtained by pressing or by ap-
and Cosmetic Act (the FD&C Act) plying any other extraction process to
apply to such terms when used in this tissues derived directly from discrete
part. The following definitions also adipose tissue masses or to other car-
apply: cass parts and tissues. Tallow must be
(1) Prohibited cattle materials mean produced from tissues that are not pro-
specified risk materials, small intes- hibited cattle materials or must con-
tine of all cattle except as provided in tain no more than 0.15 percent insol-
paragraph (b)(2) of this section, mate- uble impurities as determined by the
rial from nonambulatory disabled cat- method entitled ‘‘Insoluble Impurities’’
tle, material from cattle not inspected (AOCS Official Method Ca 3a–46),
and passed, or mechanically separated American Oil Chemists’ Society
(MS) (Beef). Prohibited cattle mate- (AOCS), 5th Edition, 1997, incorporated
rials do not include the following: by reference in accordance with 5
(i) Tallow that contains no more U.S.C. 552(a) and 1 CFR part 51, or an-
than 0.15 percent insoluble impurities, other method equivalent in accuracy,
tallow derivatives, gelatin, hides and precision, and sensitivity to AOCS Offi-
hide-derived products, and milk and cial Method Ca 3a–46. You may obtain
milk products, and copies of the method from AOCS (http://
(ii) Cattle materials inspected and www.aocs.org) 2211 W. Bradley Ave.
passed from a country designated Champaign, IL 61821. Copies may be ex-
under paragraph (e) of this section. amined at the Food and Drug Adminis-
(2) Inspected and passed means that tration’s Main Library, 10903 New
the product has been inspected and Hampshire Ave., Bldg. 2, Third Floor,
passed for human consumption by the Silver Spring, MD 20993, 301–796–2039 or
appropriate regulatory authority, and at the National Archives and Records
at the time it was inspected and Administration (NARA). For informa-
passed, it was found to be not adulter- tion on the availability of this mate-
ated. rial at NARA, call 202–741–6030, or go to
(3) Mechanically separated (MS) (Beef) http://www.archives.gov/federallregister/
means a meat food product that is fine- codeloflfederallregulations/
ly comminuted, resulting from the me- ibrllocations.html.
chanical separation and removal of (7) Tallow derivative means any chem-
most of the bone from attached skel- ical obtained through initial hydrol-
etal muscle of cattle carcasses and ysis, saponification, or trans-
parts of carcasses that meets the speci- esterification of tallow; chemical con-
fications contained in 9 CFR 319.5, the version of material obtained by hydrol-

U.S. Department of Agriculture regula- ysis, saponification, or trans-
143
§ 700.27 21 CFR Ch. I (4–1–20 Edition)
esterification may be applied to obtain wise containing, cattle material must

the desired product. affirm that the cosmetic was manufac-
(8) Gelatin means a product that has tured from, processed with, or other-
been obtained by the partial hydrolysis wise contains, cattle material and
of collagen derived from hides, connec- must affirm that the cosmetic was
tive tissue, and/or bone bones of cattle manufactured in accordance with this
and swine. Gelatin may be either Type section. If a cosmetic is manufactured
A (derived from an acid-treated pre- from, processed with, or otherwise con-
cursor) or Type B (derived from an al- tains, cattle material, then the im-
kali-treated precursor) that has gone porter of record must, if requested, pro-
through processing steps that include vide within 5 days records sufficient to
filtration and sterilization or an equiv- demonstrate that the cosmetic is not
alent process in terms of infectivity re- manufactured from, processed with, or
duction. does not otherwise contain, prohibited
(b) Requirements. (1) No cosmetic cattle material.
shall be manufactured from, processed (7) Records established or maintained
with, or otherwise contain, prohibited to satisfy the requirements of this sub-
cattle materials. part that meet the definition of elec-
(2) The small intestine is not consid- tronic records in § 11.3(b)(6) of this
ered prohibited cattle material if the chapter are exempt from the require-
distal ileum is removed by a procedure ments of part 11 of this chapter.
that removes at least 80 inches of the Records that satisfy the requirements
uncoiled and trimmed small intestine,
of this subpart but that are also re-
as measured from the caeco-colic junc-
quired under other applicable statutory
tion and progressing proximally to-
provisions or regulations remain sub-
wards the jejunum, or by a procedure
ject to part 11 of this chapter.
that the establishment can dem-
onstrate is equally effective in ensur- (d) Adulteration. Failure of a manu-
ing complete removal of the distal facturer or processor to operate in
ileum. compliance with the requirements of
(c) Records. (1) Manufacturers and paragraph (b) or (c) of this section ren-
processors of a cosmetic that is manu- ders a cosmetic adulterated under sec-
factured from, processed with, or oth- tion 601(c) of the act.
erwise contains, material from cattle (e) Process for designating countries. A
must establish and maintain records country seeking designation must send
sufficient to demonstrate that the cos- a written request to the Director, Of-
metic is not manufactured from, proc- fice of the Center Director, Center for
essed with, or does not otherwise con- Food Safety and Applied Nutrition,
tain, prohibited cattle materials. Food and Drug Administration, at the
(2) Records must be retained for 2 address designated in 21 CFR 5.1100.
years after the date they were created. The request shall include information
(3) Records must be retained at the about a country’s bovine spongiform
manufacturing or processing establish- encephalopathy (BSE) case history,
ment or at a reasonably accessible lo- risk factors, measures to prevent the
cation. introduction and transmission of BSE,
(4) The maintenance of electronic and any other information relevant to
records is acceptable. Electronic determining whether specified risk ma-
records are considered to be reasonably terials, the small intestine of cattle ex-
accessible if they are accessible from cept as provided in paragraph (b)(2) of
an onsite location. this section, material from non-
(5) Records required by this section ambulatory disabled cattle, or MS
and existing records relevant to com- (Beef) from cattle from the country
pliance with this section must be avail- should be considered prohibited cattle
able to FDA for inspection and copy- materials. FDA shall respond in writ-
ing. ing to any such request and may im-
(6) When filing entry with U.S. Cus- pose conditions in granting any such
toms and Border Protection, the im- request. A country designation granted
porter of record of a cosmetic manufac- by FDA under this paragraph will be

tured from, processed with, or other- subject to future review by FDA, and
144
may be revoked if FDA determines terminology used in the labeling. For

that it is no longer appropriate. example: ‘‘Contains a sunscreen—to
[70 FR 53068, Sept. 7, 2005, as amended at 71 protect product color.’’
FR 59668, Oct. 11, 2006; 73 FR 20794, Apr. 17, [64 FR 27693, May 21, 1999]
2008; 81 FR 5596, Feb. 3, 2016; 81 FR 14732, Mar.
18, 2016]
PART 701—COSMETIC LABELING
§ 700.35 Cosmetics containing sun-
screen ingredients. Subpart A—General Provisions
(a) A product that includes the term
‘‘sunscreen’’ in its labeling or in any Sec.
other way represents or suggests that 701.1 Misbranding.
701.2 Form of stating labeling requirements.
it is intended to prevent, cure, treat, or
701.3 Designation of ingredients.
mitigate disease or to affect a struc-
701.9 Exemptions from labeling require-
ture or function of the body comes
ments.
within the definition of a drug in sec-
tion 201(g)(1) of the act. Sunscreen ac- Subpart B—Package Form
tive ingredients affect the structure or
function of the body by absorbing, re- 701.10 Principal display panel.
flecting, or scattering the harmful, 701.11 Identity labeling.
burning rays of the sun, thereby alter- 701.12 Name and place of business of manu-
ing the normal physiological response facturer, packer, or distributor.
to solar radiation. These ingredients 701.13 Declaration of net quantity of con-
also help to prevent diseases such as tents.
sunburn and may reduce the chance of
premature skin aging, skin cancer, and Subpart C—Labeling of Specific
other harmful effects due to the sun Ingredients
when used in conjunction with limiting 701.20 Detergent substances, other than
sun exposure and wearing protective soap, intended for use in cleansing the
clothing. When consumers see the term body.
‘‘sunscreen’’ or similar sun protection 701.30 Ingredient names established for cos-
terminology in the labeling of a prod- metic ingredient labeling.
uct, they expect the product to protect
AUTHORITY: 21 U.S.C. 321, 352, 361, 362, 363,
them in some way from the harmful ef- 371, 374; 15 U.S.C. 1454, 1455.
fects of the sun, irrespective of other
labeling statements. Consequently, the SOURCE: 39 FR 10056, Mar. 15, 1974, unless
use of the term ‘‘sunscreen’’ or similar otherwise noted.
sun protection terminology in a prod-
uct’s labeling generally causes the Subpart A—General Provisions
product to be subject to regulation as a
drug. However, sunscreen ingredients § 701.1 Misbranding.
may also be used in some products for (a) Among representations in label-
nontherapeutic, nonphysiologic uses ing of a cosmetic which render such
(e.g., as a color additive or to protect
cosmetic misbranded is a false or mis-
the color of the product). To avoid con-
leading representation with respect to
sumer misunderstanding, if a cosmetic
product contains a sunscreen ingre- another cosmetic or a food, drug, or de-
dient and uses the term ‘‘sunscreen’’ or vice.
similar sun protection terminology (b) The labeling of a cosmetic which
anywhere in its labeling, the term contains two or more ingredients may
must be qualified by describing the be misleading by reason (among other
cosmetic benefit provided by the sun- reasons) of the designation of such cos-
screen ingredient. metic in such labeling by a name which
(b) The qualifying information re- includes or suggests the name of one or
quired under paragraph (a) of this sec- more but not all such ingredients, even
tion shall appear prominently and con- though the names of all such ingredi-
spicuously at least once in the labeling ents are stated elsewhere in the label-
in conjunction with the term ‘‘sun- ing.

screen’’ or other similar sun protection
145
§ 701.2 21 CFR Ch. I (4–1–20 Edition)
§ 701.2 Form of stating labeling re- than English, the predominant lan-
quirements. guage may be substituted for English.
(2) If the label contains any represen-
(a) A word, statement, or other infor-
tation in a foreign language, all words,
mation required by or under authority
statements, and other information re-
of the Act to appear on the label may
quired by or under authority of the Act
lack that prominence and conspicuous-
to appear on the label shall appear
ness required by section 602(c) of the
thereon in the foreign language.
Act by reason (among other reasons)
(3) If the labeling contains any rep-
of:
resentation in a foreign language, all
(1) The failure of such word, state- words, statements, and other informa-
ment, or information to appear on the tion required by or under authority of
part or panel of the label which is pre- the Act to appear on the label or label-
sented or displayed under customary ing shall appear on the labeling in the
conditions of purchase; foreign language.
(2) The failure of such word, state-
ment, or information to appear on two § 701.3 Designation of ingredients.
or more parts or panels of the label, (a) The label on each package of a
each of which has sufficient space cosmetic shall bear a declaration of the
therefor, and each of which is so de- name of each ingredient in descending
signed as to render it likely to be, order of predominance, except that fra-
under customary conditions of pur- grance or flavor may be listed as fra-
chase, the part or panel displayed; grance or flavor. An ingredient which
(3) The failure of the label to extend is both fragrance and flavor shall be
over the area of the container or pack- designated by each of the functions it
age available for such extension, so as performs unless such ingredient is
to provide sufficient label space for the identified by name. No ingredient may
prominent placing of such word, state- be designated as fragrance or flavor un-
ment, or information; less it is within the meaning of such
(4) Insufficiency of label space (for term as commonly understood by con-
the prominent placing of such word, sumers. Where one or more ingredients
statement, or information) resulting is accepted by the Food and Drug Ad-
from the use of label space for any ministration as exempt from public
word, statement, design, or device disclosure pursuant to the procedure
which is not required by or under au- established in § 720.8(a) of this chapter,
thority of the Act to appear on the in lieu of label declaration of identity
label; the phrase ‘‘and other ingredients’’
(5) Insufficiency of label space (for may be used at the end of the ingre-
the prominent placing of such word, dient declaration.
statement, or information) resulting (b) The declaration of ingredients
from the use of label space to give ma- shall appear with such prominence and
terially greater conspicuousness to any conspicuousness as to render it likely
other word, statement, or information, to be read and understood by ordinary
or to any design or device; individuals under normal conditions of
(6) Smallness or style of type in purchase. The declaration shall appear
which such word, statement, or infor- on any appropriate information panel
mation appears, insufficient back- in letters not less than 1⁄16 of an inch in
ground contrast, obscuring designs or height and without obscuring design,
vignettes, or crowding with other writ- vignettes, or crowding. In the absence
ten, printed, or graphic matter. of sufficient space for such declaration
(b)(1) All words, statements, and on the package, or where the manufac-
other information required by or under turer or distributor wishes to use a
authority of the Act to appear on the decorative container, the declaration
label or labeling shall appear thereon may appear on a firmly affixed tag,
in the English language: Provided, how- tape, or card. In those cases where
ever, That in the case of articles dis- there is insufficient space for such dec-
tributed solely in the Commonwealth laration on the package, and it is not
of Puerto Rico or in a Territory where practical to firmly affix a tag, tape, or

the predominant language is one other card, the Commissioner may establish
146
by regulation an acceptable alternate, Acid Red 252

e.g., a smaller type size. A petition re- Acid Red 259
questing such a regulation as an Acid Violet 73
Acid Violet 76
amendment to this paragraph shall be
Acid Violet 99
submitted pursuant to part 10 of this Acid Yellow 114
chapter. Acid Yellow 127
(c) A cosmetic ingredient shall be Direct Yellow 81
identified in the declaration of ingredi- Solvent Black 5
ents by: Solvent Brown 43
(1) The name specified in § 701.30 as Solvent Yellow 63
established by the Commissioner for Solvent Yellow 90
that ingredient for the purpose of cos- (b) The following names are adopted
metic ingredient labeling pursuant to for the purpose of cosmetic ingredient
paragraph (e) of this section; labeling, provided the respective mono-
(2) In the absence of the name speci- graphs are revised to describe their
fied in § 701.30, the name adopted for otherwise disclosed chemical composi-
that ingredient in the following editions, or describe their chemical com-
tions and supplements of the following positions more precisely, and such re-
compendia, listed in order as the vised monographs are published in sup-
source to be utilized: plements to this dictionary edition by
(i) CTFA (Cosmetic, Toiletry and July 18, 1980.
Fragrance Association, Inc.) Cosmetic
Acid Black 2
Ingredient Dictionary, Second Ed., 1977
Benzophenone-11
(available from the Cosmetic, Toiletry Carbomer 934
and Fragrance Association, Inc. 1110 Carbomer 934P
Vermont Ave. NW., Suite 800, Wash- Carbomer 940
ington, DC 20005, or at the National Ar- Carbomer 941
chives and Records Administration Carbomer 960
(NARA), which is incorporated by ref- Carbomer 961
erence, except for the following dele- Chlorofluorocarbon 11S
Dimethicone Copolyol
tions and revisions. (For information
Disperse Red 17
on the availability of this material at Pigment Green 7
NARA, call 202–741–6030, or go to: http:// Polyamino Sugar Condensate
www.archives.gov/federallregister/ SD Alcohol (all 27 alphanumeric designa-
codeloflfederallregulations/ tions)
ibrllocations.html.) Sodium Chondroitin Sulfate
(a) The following names are not Synthetic Beeswax
adopted for the purpose of cosmetic in- (c) The following names are adopted
gredient labeling: for the purpose of cosmetic ingredient
Acid Black 58 labeling until January 19, 1981.
Acid Black 107
Amphoteric (all 20 numeric designations)
Acid Black 139
Quaternium (all 49 numeric designations)
Acid Blue 168
Acid Blue 170 (ii) United States Pharmacopeia, 19th
Acid Blue 188 Ed., 1975, and Second Supplement to
Acid Blue 209 the USP XIX and NF XIV, 1976. (Copies
Acid Brown 19
are available from the U.S.
Acid Brown 30
Acid Brown 44 Pharmacopeial Convention, Inc., 12601
Acid Brown 45 Twinbrook Parkway, Rockville, MD
Acid Brown 46 20852, or at the National Archives and
Acid Brown 48 Records Administration (NARA). For
Acid Brown 224 information on the availability of this
Acid Orange 80 material at NARA, call 202–741–6030, or
Acid Orange 85 go to: http://www.archives.gov/fed-
Acid Orange 86
erallregister/
Acid Orange 88
Acid Orange 89 codeloflfederallregulations/
ibrllocations.html.).
Acid Orange 116

Acid Red 131 (iii) National Formulary, 14th Ed.,
Acid Red 213 1975, and Second Supplement to the
147
§ 701.3 21 CFR Ch. I (4–1–20 Edition)
USP XIX and NF XIV, 1976. (Copies are (f) As an alternative to listing all in-
available from the U.S. Pharmacopeial gredients in descending order of pre-
Convention, Inc., 12601 Twinbrook dominance, ingredients may be grouped
Parkway, Rockville, MD 20852, or at and the groups listed in the following
the National Archives and Records Ad- manner and order:
ministration (NARA). For information (1) Ingredients, other than color addi-
on the availability of this material at tives, present at a concentration great-
NARA, call 202–741–6030, or go to: http:// er than 1 percent, in descending order
www.archives.gov/federallregister/ of predominance; followed by
codeloflfederallregulations/
(2) Ingredients, other than color addi-
ibrllocations.html.).
tives, present at a concentration of not
(iv) Food Chemicals Codex, 2d Ed.,
1972; First Supplement, 1974, and Sec- more than 1 percent, without respect
ond Supplement, 1975, which are incor- to order of predominance; followed by
porated by reference. Copies are avail- (3) Color additives, without respect
able from the Center for Food Safety to order of predominance. Ingredients
and Applied Nutrition, Food and Drug specified in paragraph (f)(2) of this sec-
Administration, 5001 Campus Dr., Col- tion may be included with those speci-
lege Park, MD 20740, or at the National fied in paragraph (f)(1) of this section
Archives and Records Administration and listed in descending order of pre-
(NARA). For information on the avail- dominance.
ability of this material at NARA, call (g) A declaration of ingredients may
202–741–6030, or go to: http:// include an ingredient not in the prod-
www.archives.gov/federallregister/ uct if the ingredient is identified by
codeloflfederallregulations/ the phrase ‘‘may contain’’ and:
ibrllocations.html. (1) It is a color additive added to
(v) USAN and the USP dictionary of some batches of the product for pur-
drug names, USAN 1975, 1961–1975 cu- poses of color matching; or
mulative list. (Copies are available
(2)(i) The same declaration of ingre-
from the U.S. Pharmacopeial Conven-
dients is also used for other products
tion, Inc., 12601 Twinbrook Parkway,
Rockville, MD 20852, or at the National similar in composition and intended
Archives and Records Administration for the same use, including products
(NARA). For information on the avail- which may be assortments of products
ability of this material at NARA, call similar in composition and intended
202–741–6030, or go to: http:// for the same use; and
www.archives.gov/federallregister/ (ii) Such products are ‘‘shaded’’ prod-
codeloflfederallregulations/ ucts, i.e., those falling within the prod-
ibrllocations.html.) uct categories identified in § 720.4 (c)(3),
(3) In the absence of such a listing, (7) and (8)(v) of this chapter; and
the name generally recognized by con- (iii) All products sharing the common
sumers. declaration of ingredients are sold by
(4) In the absence of any of the above, the labeler under a common trade
the chemical or other technical name name or brand designation, and no
or description. trade name or brand designation not
(d) Where a cosmetic product is also common to all such products appears
an over-the-counter drug product, the in the labeling of any of them; and
declaration shall declare the active (iv) The ingredient is a color addi-
drug ingredients as set forth in tive.
§ 201.66(c)(2) and (d) of this chapter, and
(h) As an alternative to a declaration
the declaration shall declare the cos-
metic ingredients as set forth in of color additive ingredients for each
§ 201.66(c)(8) and (d) of this chapter. product, the color additives of an as-
(e) Interested persons may submit a sortment of cosmetic products that are
petition requesting the establishment sold together in the same package may
of a specific name for a cosmetic ingre- be declared in a single composite list in
dient pursuant to part 10 of this chap- a manner that is not misleading and
ter. The Commissioner may also pro- that indicates that the list pertains to
pose such a name on his own initiative. all the products.
148
(i) As an alternative to the declara- or chart under customary conditions of

tion of ingredients specified in para- retail sale, or by the notice required by
graph (b) of this section, the declara- provisions in paragraph (k)(3) of this
tion of ingredients may appear in let- section, if conspicuous at all times; or
ters not less than 1⁄16 of an inch in (3) The labeling is on a side of the
height in labeling accompanying the display unit or chart, but not on the
product, as for example, on padded top, back, or bottom, and is accom-
sheets or in leaflets, if the total surface panied by a conspicuous notice on the
area of the package is less than 12 front of the display unit or chart de-
square inches. This paragraph is inap- scribing the location of such labeling
plicable to any packaged cosmetic in letters not less than 3⁄16 of an inch in
product enclosed in an outer container, height, e.g., ‘‘Ingredient lists located
e.g., a folding carton. In addition, this
on right side of display’’, that can be
paragraph is applicable only to cos-
read by a purchaser facing the display
metic products meeting one of the fol-
unit or chart under customary condi-
lowing requirements:
tions of retail sale.
(1) The cosmetic products are held
and displayed for sale in tightly com- (k) Any use of a display unit or chart
partmented trays or racks of a display bearing labeling under the provisions
unit. The holder of the labeling bearing of paragraph (i) of this section shall
the declaration of ingredients shall be meet the following requirements:
attached to the display unit; or (1) All articles of labeling bearing in-
(2) The cosmetic products are gredient declarations and used in con-
‘‘shaded’’ products, i.e., those falling junction with any one display unit or
within the product categories identi- chart shall be identical and shall de-
fied in § 720.4 (c)(3), (7) and (8)(v) of this clare the ingredients of all products
chapter, and are held for sale in tightly sold in conjunction with the display
compartmented trays or racks. The unit or chart for which the ingredient
holder of the labeling bearing the dec- declaration is made pursuant to para-
laration of ingredients shall be at- graph (i) of this section.
tached to a display chart bearing sam- (2) Any display unit or chart in-
ples of the product shades, which is dis- tended for such use shall be shipped to-
played to purchasers. Such a display gether with the labeling intended to be
chart shall be of such construction and attached to it.
design as to permit its continuous use (3) Every display unit or chart and/or
as a display, such as on a counter, and labeling system shall be designed so
shall be designed for the primary pur-
that the words ‘‘Federal law requires
pose of displaying samples of the
ingredient lists to be displayed here’’
shades of the products.
in letters not less than 3⁄16 of an inch in
(j) The holder of labeling bearing a
height (i) become conspicuous when no
declaration of ingredients and used in
ingredient declarations are displayed
accordance with paragraph (i) of this
section shall be attached to the display and when the last list has been taken,
unit or chart and shall meet one of the or (ii) are conspicuous at all times ad-
following conditions: jacent to the place where ingredient
(1) The labeling is on the front of the declarations are to be attached.
display unit or chart and can be read in (4) Any labeling containing a declara-
full by a purchaser facing the display tion of ingredients which reflects a for-
unit or chart under customary condi- mulation change and not shipped ac-
tions of retail sale; or companying a display unit or chart
(2) The labeling is on the front of the shall be dated. Whenever any formula-
display unit or chart, is partially visi- tion change is made, and the labeling
ble, and is accompanied by a con- containing the declaration of ingredi-
spicuous notice on the front of the dis- ents is thereby required to be used in
play unit or chart describing the loca- conjunction with products of both the
tion of such labeling in letters not less old and new formulations, the labeling
than 3⁄16 of an inch in height, e.g., ‘‘In- shall declare the ingredients of both
gredient lists above’’, that can be read the old and new formulations sepa-
by a purchaser facing the display unit rately in a way that is not misleading
149
§ 701.3 21 CFR Ch. I (4–1–20 Edition)
and in a way that permits the pur- technical or functional effect in the
chaser to identify the ingredient dec- processing, are converted to substances
laration applicable to each package, or the same as constituents of declared
which clearly advises the purchaser ingredients, and do not significantly
that the formulation has been changed increase the concentration of those
and that either declaration may be ap- constituents.
plicable. (iii) Substances that are added to a
(5) Sufficient copies of the declara- cosmetic during the processing of such
tion of ingredients shall be provided cosmetic for their technical and func-
with each shipment of a cosmetic so tional effect in the processing but are
that a purchaser may obtain a copy of present in the finished cosmetic at in-
the declaration with each purchase. significant levels and do not have any
Display units and replacement labeling technical or functional effect in that
for display units shall be accompanied cosmetic.
by instructions to the retailer, which (m) In the event that there is a cur-
when followed will result in compli-
rent or anticipated shortage of a cos-
ance with the requirements of this sec-
metic ingredient, the declaration re-
tion. Copies of the declaration accom-
quired by this section may specify al-
panying refills shall be attached to the
ternatives to any ingredients that may
specific refill items to which they per-
be affected. An alternative ingredient
tain, or shall be packed with the spe-
shall be declared either (1) imme-
cific refill items to which they pertain,
diately following the normally used in-
in a container that does not contain
gredient for which it substitutes, in
other cosmetic products.
which case it shall be identified as an
(6) The firm whose name appears on a
alternative ingredient by the word
product pursuant to § 701.12 shall
promptly mail a copy of the declara- ‘‘or’’ following the name of the nor-
tion of ingredients to any person re- mally used ingredient and any other al-
questing it. ternative ingredient, or (2) following
(7) The display unit or chart shall be the declaration of all normally used in-
designed and located such that the la- gredients, in which case the alternative
beling is easily accessible to a pur- ingredients in the group so listed shall
chaser facing the display unit or chart be listed in expected descending order
under customary conditions of retail of predominance or in accordance with
sale. the provisions of paragraph (f) of this
(l) The provisions of this section do section and shall be identified as alter-
not require the declaration of inci- native ingredients by the phrase ‘‘may
dental ingredients that are present in a also contain’’. This paragraph is inap-
cosmetic at insignificant levels and plicable to any ingredient mentioned
that have no technical or functional ef- in advertising, or in labeling other
fect in the cosmetic. For the purpose of than in the declaration of ingredients
this paragraph, incidental ingredients required by this section.
are: (n) In the event that the shortage of
(1) Substances that have no technical a cosmetic ingredient necessitates a
or functional effect in the cosmetic but formulation change, packages bearing
are present by reason of having been labels declaring the ingredients of the
incorporated into the cosmetic as an old formulation may be used if the re-
ingredient of another cosmetic ingre- vised ingredient declaration appears (1)
dient. on a firmly affixed tag, tape, card, or
(2) Processing aids, which are as fol- sticker or similar overlabeling at-
lows: tached to the package and bearing the
(i) Substances that are added to a conspicuous words ‘‘new ingredient
cosmetic during the processing of such list’’ in letters not less than 1⁄16 of an
cosmetic but are removed from the cos- inch in height, or (2) on labeling inside
metic in accordance with good manu- an unsealed package and the package
facturing practices before it is pack- bears the conspicuous words, on a
aged in its finished form. sticker or similar overlabeling, ‘‘new
(ii) Substances that are added to a ingredient list inside’’ in letters not
cosmetic during processing for their less than 1⁄16 of an inch in height.
150
(o) The ingredients of products that present. The color additive ingredients
are similar in composition and in- shall be declared in accordance with
tended for the same use may be de- the provisions of paragraph (g) of this
clared as follows: section.
(1) The declaration of ingredients for (4) The declaration of ingredients for
an assortment of such products that an assortment of such cosmetic prod-
are sold together in the same package, ucts that bears a label that is shared
e.g., eyeshadows of different colors, with other products pursuant to the
may declare the ingredients that are provisions of paragraph (g)(2) of this
common to all the products, in a single section, e.g., one of several compacts in
list in their cumulative order of pre- a line of compacts, may declare the in-
dominance or in accordance with the gredients that are common to all such
provisions of paragraph (f) of this sec-
products, in a single list in their cumu-
tion, together with a statement, in
lative order of predominance or in ac-
terms that are as informative as prac-
cordance with the provisions of para-
ticable and that are not misleading, de-
graph (f) of this section, together with
claring the other ingredients and iden-
tifying the products in which they are a statement, in terms that are as in-
present. The color additive ingredients formative as practicable and that are
of all the products in such an assort- not misleading, declaring the other in-
ment, whether or not common to all gredients in such products and identi-
the products, may be declared in a sin- fying the products in which they are
gle composite list following the dec- present. The color additive ingredients
laration of the other ingredients with- shall be declared in accordance with
out identifying the products in which the provisions of paragraph (g) of this
they are present. section.
(2) The ingredients of an assortment (p) As an alternative to the declara-
of such products that are sold together tion of ingredients in letters not less
in the same package, e.g., eyeshadows than 1⁄16 of an inch in height, letters
of different colors, may be declared in may be not less than 1⁄32 of an inch in
a single list in their cumulative order height if the package is designed such
of predominance or in accordance with that it has a total surface area avail-
the provisions of paragraph (f) of this able to bear labeling of less than 12
section, if the package is designed such square inches. For the purpose of this
that it has a total surface area avail- paragraph, surface area is not available
able to bear labeling of less than 12 for labeling if physical characteristics
square inches. For the purpose of this of the package surface, e.g., decorative
paragraph, surface area is not available relief, make application of a label im-
for labeling if physical characteristics practical.
of the package surface, e.g., decorative (q) The inside containers in a multi-
relief, make application of a label im-
unit or multicomponent retail cos-
practical.
metic package are not required to bear
(3) The declaration of ingredients for
a declaration of ingredients when the
such a product that is individually
packaged and bears a label that is labeling of the multiunit or multi-
shared with other products pursuant to component retail cosmetic package
the provisions of paragraph (g)(2) of meets all the requirements of this sec-
this section, e.g., one lipstick in a line tion and the inside containers are not
of lipsticks, may declare the ingredi- intended to be, and are not custom-
ents that are common to all such prod- arily, separated from the retail pack-
ucts, in a single list in their cumu- age for retail sale.
lative order of predominance or in ac- (r) In the case of cosmetics distrib-
cordance with the provisions of para- uted to the consumers by direct mail,
graph (f) of this section, together with as an alternative to the declaration of
a statement, in terms that are as in- ingredients on an information panel,
formative as practicable and that are the declaration of ingredients may ap-
not misleading, declaring the other in- pear in letters not less than 1⁄16 of an
gredients in such products, and identi- inch in height in labeling that accom-
fying the products in which they are panies and specifically relates to the
151
§ 701.9 21 CFR Ch. I (4–1–20 Edition)
cosmetic(s) mailed, or in labeling fur- such establishment, from compliance

nished to each consumer for his per- with the labeling requirements of sec-
sonal use and from which he orders cos- tions 601(a) and 602(b) of the act if:
metics through the mail, e.g., a direct (1) The person who introduced such
mail sales catalog or brochure, pro- shipment or delivery into interstate
vided all of the following additional re- commerce is the operator of the estab-
quirements are met: lishment where such cosmetic is to be
(1) The declarations of ingredients processed, labeled, or repacked; or
are conspicuous and presented in a way (2) In case such person is not such op-
that permits the consumer to identify erator, such shipment or delivery is
the declaration of ingredients applica- made to such establishment under a
ble to each cosmetic. written agreement, signed by and con-
(2) The package mailed to the containing the post office addresses of
sumer is accompanied by a notice lo-
such person and such operator, and
cated on, or affixed to, the top of the
containing such specifications for the
package or on top of the contents in-
processing, labeling, or repacking, as
side the package, or on the face of the
the case may be, of such cosmetic in
package platform surrounding and
holding the product(s), readily visible such establishment as will insure, if
to the consumer on opening of the such specifications are followed, that
package, and provides the following in- such cosmetic will not be adulterated
formation in letters not less than 3⁄16 of or misbranded within the meaning of
an inch in height: the act upon completion of such proc-
(i) The location of the declarations of essing, labeling, or repacking. Such
ingredients, e.g., in an accompanying person and such operator shall each
brochure, or in a sales catalog used for keep a copy of such agreement until 2
ordering; years after the final shipment or deliv-
(ii) A statement that a copy of the ery of such cosmetic from such estab-
declaration of ingredients will be lishment, and shall make such copies
mailed promptly to any person request- available for inspection at any reason-
ing it; and able hour to any officer or employee of
(iii) The name and place of business the Department who requests them.
of the mail order distributor, (b) An exemption of a shipment or
(3) The mail order distributor other delivery of a cosmetic under
promptly mails a copy of the declara- paragraph (a)(1) of this section shall, at
tion of ingredients to any person re- the beginning of the act of removing
questing it. such shipment or delivery, or any part
[39 FR 10056, Mar. 15, 1974, as amended at 40 thereof, from such establishment, be-
FR 8922, Mar. 3, 1975; 40 FR 18426, Apr. 28, come void ab initio if the cosmetic
1975; 42 FR 4718, Jan. 25, 1977; 42 FR 15676, comprising such shipment, delivery, or
Mar. 22, 1977; 42 FR 24255, May 31, 1977; 42 FR part is adulterated or misbranded with-
46516, Sept. 16, 1977; 42 FR 61257, Dec. 2, 1977; in the meaning of the act when so re-
45 FR 3577, Jan. 18, 1980; 47 FR 9397, Mar. 5, moved.
1982; 54 FR 24900, June 12, 1989; 64 FR 13297,
Mar. 17, 1999; 69 FR 18803, Apr. 9, 2004; 81 FR (c) An exemption of a shipment or
49897, July 29, 2016] other delivery of a cosmetic under
paragraph (a)(2) of this section shall
§ 701.9 Exemptions from labeling re- become void ab initio with respect to
quirements. the person who introduced such ship-
(a) Except as provided by paragraphs ment or delivery into interstate com-
(b) and (c) of this section, a shipment merce upon refusal by such person to
or other delivery of a cosmetic which make available for inspection a copy of
is, in accordance with the practice of the agreement, as required by such
the trade, to be processed, labeled, or clause.
repacked in substantial quantity at an (d) An exemption of a shipment or
establishment other than that where other delivery of a cosmetic under
originally processed or packed, shall be paragraph (a)(2) of this section shall
exempt, during the time of introduc- expire:
tion into and movement in interstate (1) At the beginning of the act of re-
commerce and the time of holding in moving such shipment or delivery, or
152
any part thereof, from such establish- toms, flanges at the tops and bottoms
ment if the cosmetic comprising such of cans, and shoulders and necks of bot-
shipment, delivery, or part is adulter- tles or jars. In the case of cylindrical
ated or misbranded within the meaning or nearly cylindrical containers, infor-
of the act when so removed; or mation required by this part to appear
(2) Upon refusal by the operator of on the principal display panel shall ap-
the establishment where such cosmetic pear within that 40 percent of the cir-
is to be processed, labeled, or repacked, cumference which is most likely to be
to make available for inspection a copy displayed, presented, shown, or exam-
of the agreement, as required by such ined under customary conditions of dis-
clause.
play for retail sale.
Subpart B—Package Form § 701.11 Identity labeling.
§ 701.10 Principal display panel. (a) The principal display panel of a
cosmetic in package form shall bear as
The term principal display panel as it
applies to cosmetics in package form one of its principal features a state-
and as used in this part, means the part ment of the identity of the commodity.
of a label that is most likely to be dis- (b) Such statement of identity shall
played, presented, shown, or examined be in terms of:
under customary conditions of display (1) The common or usual name of the
for retail sale. The principal display cosmetic; or
panel shall be large enough to accom- (2) An appropriately descriptive name
modate all the mandatory label infor- or, when the nature of the cosmetic is
mation required to be placed thereon obvious, a fanciful name understood by
by this part with clarity and conspicu- the public to identify such cosmetic; or
ousness and without obscuring designs, (3) An appropriate illustration or vi-
vignettes, or crowding. Where packages gnette representing the intended cos-
bear alternate principal display panels, metic use.
information required to be placed on (c) The statement of identity shall be
the principal display panel shall be du- presented in bold type on the principal
plicated on each principal display display panel, shall be in a size reason-
panel. For the purpose of obtaining ably related to the most prominent
uniform type size in declaring the
printed matter on such panel, and shall
quantity of contents of all packages of
be in lines generally parallel to the
substantially the same size, the term
base on which the package rests as it is
‘‘area of the principal display panel’’
means the area of the side or surface designed to be displayed.
that bears the principal display panel, § 701.12 Name and place of business of
which area shall be: manufacturer, packer, or dis-
(a) In the case of a rectangular pack- tributor.
age where one entire side properly can
be considered to be the principal dis- (a) The label of a cosmetic in pack-
play panel side, the product of the age form shall specify conspicuously
height times the width of that side; the name and place of business of the
(b) In the case of a cylindrical or manufacturer, packer, or distributor.
nearly cylindrical container, 40 percent (b) The requirement for declaration
of the product of the height of the con- of the name of the manufacturer, pack-
tainer times the circumference; and er, or distributor shall be deemed to be
(c) In the case of any other shape of satisfied in the case of a corporation
container, 40 percent of the total sur- only by the actual corporate name,
face of the container: Provided, how- which may be preceded or followed by
ever, That where such container pre- the name of the particular division of
sents an obvious ‘‘principal display the corporation. Abbreviations for
panel’’ such as the top of a triangular ‘‘Company,’’ ‘‘Incorporated,’’ etc., may
or circular package, the area shall con- be used and ‘‘The’’ may be omitted. In
sist of the entire top surface. the case of an individual, partnership,
In determining the area of the prin- or association, the name under which
cipal display panel, exclude tops, bot- the business is conducted shall be used.
153
§ 701.13 21 CFR Ch. I (4–1–20 Edition)
(c) Where the cosmetic is not manu- existing practice of declaring net quan-
factured by the person whose name ap- tity of contents by weight, measure,
pears on the label, the name shall be numerical count, or a combination of
qualified by a phrase that reveals the these does not facilitate value com-
connection such person has with such parisons by consumers, he shall by reg-
cosmetic; such as, ‘‘Manufactured for ulation designate the appropriate term
lllllll’’, ‘‘Distributed by or terms to be used for such cosmetic.
llllllll’’, or any other wording (b) Statements of weight shall be in
that expresses the facts. terms of avoirdupois pound and ounce.
(d) The statement of the place of Statements of fluid measure shall be in
business shall include the street ad- terms of the U.S. gallon of 231 cubic
dress, city, State, and ZIP Code; how- inches and quart, pint, and fluid-ounce
ever, the street address may be omitted subdivisions thereof and shall express
if it is shown in a current city direc- the volume at 68 °F. (20 °C.).
tory or telephone directory. The re- (c) When the declaration of quantity
quirement for inclusion of the ZIP of contents by numerical count, linear
Code shall apply only to consumer measure, or measure of area does not
commodity labels developed or revised give accurate information as to the
after the effective date of this section. quantity of cosmetic in the package, it
In the case of nonconsumer packages, shall be augmented by such statement
the ZIP Code shall appear either on the of weight, measure, or size of the indi-
label or the labeling (including the in- vidual units or the total weight or
voice). measure of the cosmetic as will give
(e) If a person manufactures, packs, such information.
or distributes a cosmetic at a place (d) The declaration may contain
other than his principal place of busi- common or decimal fractions. A com-
ness, the label may state the principal mon fraction shall be in terms of
place of business in lieu of the actual halves, quarters, eighths, sixteenths, or
place where such cosmetic was manu- thirty-seconds; except that if there ex-
factured or packed or is to be distrib- ists a firmly established, general con-
uted, unless such statement would be sumer usage and trade custom of em-
misleading. ploying different common fractions in
the net quantity declaration of a par-
§ 701.13 Declaration of net quantity of ticular commodity they may be em-
contents. ployed. A common fraction shall be re-
(a) The label of a cosmetic in pack- duced to its lowest terms; a decimal
age form shall bear a declaration of the fraction shall not be carried out to
net quantity of contents. This shall be more than two places. A statement
expressed in terms of weight, measure, that includes small fractions of an
numerical count, or a combination of ounce shall be deemed to permit small-
numerical count and weight or meas- er variations than one which does not
ure. The statement shall be in terms of include such fractions.
fluid measure if the cosmetic is liquid (e) The declaration shall be located
or in terms of weight if the cosmetic is on the principal display panel of the
solid, semisolid, or viscous, or a mix- label; with respect to packages bearing
ture of solid and liquid. If there is a alternate principal display panels, it
firmly established, general consumer shall be duplicated on each principal
usage and trade custom of declaring display panel: Provided, That:
the net quantity of a cosmetic by nu- (1) The principal display panel of a
merical count, linear measure, or cosmetic marketed in a ‘‘boudoir-type’’
measure of area, such respective term container including decorative cos-
may be used. If there is a firmly estab- metic containers of the ‘‘cartridge,’’
lished, general consumer usage and ‘‘pill box,’’ ‘‘compact,’’ or ‘‘pencil’’ va-
trade custom of declaring the contents riety, and those with a capacity of one-
of a liquid cosmetic by weight, or a fourth ounce or less, may be considered
solid, semisolid, or viscous cosmetic by to be a tear-away tag or tape affixed to
fluid measure, it may be used. When- the decorative container and bearing
ever the Commissioner determines for the mandatory label information as re-
a specific packaged cosmetic that an quired by this part, but the type size of
154
the net quantity of contents statement metic under pressure, the declaration
shall be governed by the dimensions of shall state the net quantity of the con-
the decorative container; and tents that will be expelled when the in-
(2) The principal display panel of a structions for use as shown on the con-
cosmetic marketed on a display card to tainer are followed. The propellant is
which the immediate container is af- included in the net quantity declara-
fixed may be considered to be the dis- tion; and
play panel of the card, and the type (2) In the case of a package which
size of the net quantity of content contains the integral components mak-
statement is governed by the dimen- ing up a complete kit, and which is de-
sions of the display card. signed to deliver the components in the
(f) The declaration shall appear as a manner of an application (for example,
distinct item on the principal display a home permanent wave kit), the dec-
panel, shall be separated (by at least a laration may state the net quantity of
space equal to the height of the let- the contents in nondeceptive terms of
tering used in the declaration) from the number of applications available in
other printed label information appear- the kit when the instructions for use as
ing above or below the declaration and shown on the container are followed.
(by at least a space equal to twice the (h) The declaration shall appear in
width of the letter ‘‘N’’ of the style of conspicuous and easily legible boldface
type used in the quantity of contents print or type in distinct contrast (by
statement) from other printed label in- typography, layout, color, embossing,
formation appearing to the left or right or molding) to other matter on the
of the declaration. It shall not include package; except that a declaration of
any term qualifying a unit of weight, net quantity blown, embossed, or mold-
measure, or count (such as ‘‘giant ed on a glass or plastic surface is per-
pint’’ and ‘‘full quart’’) that tends to missible when all label information is
exaggerate the amount of the cosmetic
so formed on the surface. Requirements
in the container. It shall be placed on
of conspicuousness and legibility shall
the principal display panel within the
include the specifications that:
bottom 30 percent of the area of the
(1) The ratio of height to width (of
label panel in line generally parallel to
the letter) shall not exceed a differen-
the base on which the package rests as
tial of 3 units to 1 unit (no more than
it is designed to be displayed: Provided,
3 times as high as it is wide).
That:
(1) On packages having a principal (2) Letter heights pertain to upper
display panel of 5 square inches or less, case or capital letters. When upper and
the requirement for placement within lower case or all lower case letters are
the bottom 30 percent of the area of the used, it is the lower case letter ‘‘o’’ or
label panel shall not apply when the its equivalent that shall meet the min-
declaration of net quantity of contents imum standards.
meets the other requirements of this (3) When fractions are used, each
part; and component numeral shall meet one-
(2) In the case of a cosmetic that is half the minimum height standards.
marketed with both outer and inner re- (i) The declaration shall be in letters
tail containers bearing the mandatory and numerals in a type size established
label information required by this part, in relationship to the area of the prin-
and the inner container is not intended cipal display panel of the package and
to be sold separately, the net quantity shall be uniform for all packages of
of contents placement requirement of substantially the same size by com-
this section applicable to such inner plying with the following type speci-
containers is waived. fications:
(g) The declaration shall accurately (1) Not less than one-sixteenth inch
reveal the quantity of cosmetic in the in height on packages the principal dis-
package exclusive of wrappers and play panel of which has an area of 5
other material packed therewith: Pro- square inches or less.
vided, That: (2) Not less than one-eighth inch in
(1) In the case of cosmetics packed in height on packages the principal dis-
containers designed to deliver the cos- play panel of which has an area of more
155
§ 701.13 21 CFR Ch. I (4–1–20 Edition)
than 5 but not more than 25 square declaration shall be expressed in

inches. pounds for weight units with any re-
(3) Not less than three-sixteenths mainder in terms of ounces or common
inch in height on packages the prin- or decimal fractions of the pound; in
cipal display panel of which has an the case of fluid measure, it shall be
area of more than 25 but not more than expressed in the largest whole unit
100 square inches. (gallons, followed by common or dec-
(4) Not less than one-fourth inch in imal fractions of a gallon or by the
height on packages the principal dis- next smaller whole unit or units
play panel of which has an area of more (quarts or quarts and pints)) with any
than 100 square inches, except not less remainder in terms of fluid ounces or
than one-half inch in height if the area common or decimal fractions of the
is more than 400 square inches. pint or quart (as set forth in paragraph
Where the declaration is blown, em- (m)(5) of this section).
bossed, or molded on a glass or plastic (l) [Reserved]
surface rather than by printing, typ- (m) Examples: (1) A declaration of 11⁄2
ing, or coloring, the lettering sizes pounds weight shall be expressed as
specified in paragraphs (i)(1) through ‘‘Net wt. 24 oz. (1 lb. 8 oz.)’’, ‘‘Net wt. 24
(4) of this section shall be increased by oz. (11⁄2 lb.)’’, or ‘‘Net wt. 24 oz. (1.5
one-sixteenth of an inch. lb.)’’.
(j) On packages containing less than (2) A declaration of three-fourths
4 pounds or 1 gallon and labeled in pound avoirdupois weight shall be ex-
terms of weight or fluid measure: pressed as ‘‘Net wt. 12 oz.’’
(1) The declaration shall be expressed (3) A declaration of 1 quart liquid
both in ounces, with identification by measure shall be expressed as ‘‘Net
weight or by liquid measure and, if ap- contents 32 fl. oz. (1 qt.)’’.
plicable (1 pound or 1 pint or more), fol- (4) A declaration of 13⁄4 quarts liquid
lowed in parentheses by a declaration measure shall be expressed as ‘‘Net
in pounds for weight units, with any re- contents 56 fl. oz. (1 qt. 11⁄2 pt.)’’ or
mainder in terms of ounces or common ‘‘Net contents 56 fl. oz. (1 qt. 1 pt. 8
or decimal fractions of the pound (as oz.)’’ but not in terms of quart and
set forth in paragraphs (m)(1) and (2) of ounce such as ‘‘Net content 56 fl. oz. (1
this section), or in the case of liquid qt. 24 oz.)’’.
measure, in the largest whole units (5) A declaration of 21⁄2 gallons liquid
(quarts, quarts and pints, or pints, as measure shall be expressed in the alter-
appropriate) with any remainder in native as ‘‘Net contents 2 gal. 2 qt.’’
terms of fluid ounces or common or and not as ‘‘2 gal. 4 pt.’’
decimal fractions of the pint or quart (n) For quantities, the following ab-
(as set forth in paragraphs (m)(3) and breviations and none other may be em-
(4) of this section). Net weight or fluid ployed (periods and plural forms are
measure of less than 1 ounce shall be optional):
expressed in common or decimal frac- weight wt. inch in.
tions of the respective ounce and not in square sq. gallon gal.
drams. fluid fl. quart qt.
(2) The declaration may appear in yard yd. pint pt.
more than one line. The term ‘‘net feet or foot ft. ounce oz.
pound lb.
weight’’ shall be used when stating the
net quantity of contents in terms of (o) On packages labeled in terms of
weight. Use of the terms ‘‘net’’ or ‘‘net linear measure, the declaration shall
contents’’ in terms of fluid measure or be expressed both in terms of inches
numerical count is optional. It is suffi- and, if applicable (1 foot or more), the
cient to distinguish avoirdupois ounce largest whole units (yards, yards and
from fluid ounce through association of feet, feet). The declaration in terms of
terms; for example, ‘‘Net wt. 6 oz.’’ or the largest whole units shall be in pa-
‘‘6 oz. net wt.’’ and ‘‘Net contents 6 fl. rentheses following the declaration in
oz.’’ or ‘‘6 fl. oz.’’ terms of inches and any remainder
(k) On packages containing 4 pounds shall be in terms of inches or common
or 1 gallon or more and labeled in or decimal fractions of the foot or

terms of weight or fluid measure, the yard. Examples are ‘‘86 inches (2 yd. 1
156
ft. 2 inches)’’, ‘‘90 inches (21⁄2 yd.)’’, ‘‘30 practice or by unavoidable deviations
inches (2.5 ft.)’’, etc. in good manufacturing practice will be
(p) On packages labeled in terms of recognized. Variations from stated
area measure, the declaration shall be quantity of contents shall not be un-
expressed in terms of square inches reasonably large.
and, if applicable (1 square foot or
more), the largest whole square unit Subpart C—Labeling of Specific
(square yards, square yards and square
feet, square feet). The declaration in
Ingredients
terms of the largest whole units shall § 701.20 Detergent substances, other
be in parentheses following the dec- than soap, intended for use in
laration in terms of square inches and cleansing the body.
any remainder shall be in terms of
(a) In its definition of the term cos-
square inches or common or decimal
metic, the Federal Food, Drug, and Cos-
fractions of the square foot or square
metic Act specifically excludes soap.
yard; for example, ‘‘158 sq. inches (1 sq.
The term soap is nowhere defined in
ft. 14 sq. inches)’’, etc.
the act. In administering the act, the
(q) Nothing in this section shall pro-
Food and Drug Administration inter-
hibit supplemental statements at loca-
prets the term ‘‘soap’’ to apply only to
tions other than the principal display
panel(s) describing in nondeceptive articles that meet the following condi-
terms the net quantity of contents, tions:
provided that such supplemental state- (1) The bulk of the nonvolatile mat-
ments of net quantity of contents shall ter in the product consists of an alkali
not include any term qualifying a unit salt of fatty acids and the detergent
of weight, measure, or count that tends properties of the article are due to the
to exaggerate the amount of the cos- alkali-fatty acid compounds; and
metic contained in the package; for ex- (2) The product is labeled, sold, and
ample, ‘‘giant pint’’ and ‘‘full quart.’’ represented only as soap.
Dual or combination declarations of (b) Products intended for cleansing
net quantity of contents as provided the human body and which are not
for in paragraphs (a), (c), and (j) of this ‘‘soap’’ as set out in paragraph (a) of
section (for example, a combination of this section are ‘‘cosmetics,’’ and ac-
net weight plus numerical count) are cordingly they are subject to the re-
not regarded as supplemental net quan- quirements of the act and the regula-
tity statements and shall be located on tions thereunder. For example, such a
the principal display panel. product in bar form is subject to the
(r) A separate statement of the net requirement, among others, that it
quantity of contents in terms of the shall bear a label containing an accu-
metric system is not regarded as a sup- rate statement of the weight of the bar
plemental statement and an accurate in avoirdupois pounds and ounces, this
statement of the net quantity of con- statement to be prominently and con-
tents in terms of the metric system of spicuously displayed so as to be likely
weight or measure may also appear on to be read under the customary condi-
the principal display panel or on other tions of purchase and use.
panels.
(s) The declaration of net quantity of § 701.30 Ingredient names established
contents shall express an accurate for cosmetic ingredient labeling.
statement of the quantity of contents The Commissioner establishes the
of the package. Reasonable variations following names for the purpose of cos-
caused by loss or gain of moisture dur- metic ingredient labeling pursuant to
ing the course of good distribution paragraph (e) of § 701.3:
Chemical name or description Chemical formula Established label name
Trichlorofluoromethane .............................................................. CCl3F .................. Chlorofluorocarbon 11.

Trichlorofluoromethane and 0.3 pct nitromethane .................... CCl3F + CH3NO2 Chlorofluorocarbon 11 S.
Dichlorodifluoromethane ............................................................ CCl2F2 ................ Chlorofluorocarbon 12.
Chlorodifluoromethane ............................................................... CHClF2 ............... Hydrochlorofluorocarbon 22.

1, 2-dichloro-1, 1, 2, 2-tetrafluoroethane ................................... CClF2CClF2 ........ Chlorofluorocarbon 114.
1-Chloro-1, 1-difluoroethane ...................................................... CH3CClF2 ........... Hydrochlorofluorocarbon 142 B.
157
Chemical name or description Chemical formula Established label name
1, 1-difluoroethane ..................................................................... CH3CHF2 ............ Hydrofluorocarbon 152 A.

Ethyl ester of hydrolyzed animal protein is the ester of ethyl ............................. Ethyl ester of hydrolyzed animal protein.
alcohol and the hydrolysate of collagen or other animal pro-
tein, derived by acid, enzyme, or other form of hydrolysis.
[42 FR 24255, May 13, 1977, as amended at 45 FR 3577, Jan. 18, 1980]
PART 710—VOLUNTARY REGISTRA- College Park, MD 20740, or at any Food

TION OF COSMETIC PRODUCT and Drug Administration district of-
fice. The completed form should be
ESTABLISHMENTS mailed to Cosmetic Product Establish-
ment Registration, Food and Drug Ad-
Sec.
710.1 Who should register. ministration, 5001 Campus Dr., College
710.2 Time for registration. Park, MD 20740.
710.3 How and where to register. [39 FR 10059, Mar. 15, 1974, as amended at 68
710.4 Information requested. FR 15355, Mar. 31, 2003; 81 FR 49897, July 29,
710.5 Amendments to registration. 2016]
710.6 Notification of registrant; cosmetic
product establishment registration num- § 710.4 Information requested.
ber.
710.7 Inspection of registrations. Form FD–2511 requests information
710.8 Misbranding by reference to registra- on the name and address of the cos-
tion or to registration number. metic product establishment, including
710.9 Exemptions. post office ZIP code; all business trad-
AUTHORITY: 21 U.S.C. 321, 331, 361, 362, 371, ing names used by the establishment;
374. and the type of business (manufacturer
SOURCE: 39 FR 10059, Mar. 15, 1974, unless and/or packer). The information re-
otherwise noted. quested should be given separately for
each establishment as defined in
§ 710.1 Who should register. § 700.3(j) of this chapter.
The owner or operator of a cosmetic [39 FR 10059, Mar. 15, 1974, as amended at 46
product establishment which is not ex- FR 38073, July 24, 1981; 54 FR 39640, Sept. 27,
empt under § 710.9 and engages in the 1989]
manufacture or packaging of a cos-
metic product is requested to register § 710.5 Amendments to registration.
for each such establishment, whether Within 30 days after a change in any
or not the product enters interstate of the information contained on a sub-
commerce. This request extends to any mitted Form FD–2511, a new Form FD–
foreign cosmetic product establish- 2511 should be submitted to amend the
ment whose products are exported for registration. This amendment is also
sale in any State as defined in section necessary when a registration is to be
201(a)(1) of the act. No registration fee canceled because an establishment has
is required. changed its name and no longer con-
ducts business under the original
§ 710.2 Time for registration. name.
The owner or operator of an estab-
lishment entering into the manufac- § 710.6 Notification of registrant; cos-
ture or packaging of a cosmetic prod- metic product establishment reg-
uct should register his establishment istration number.
within 30 days after the operation be- The Commissioner of Food and Drugs
gins. will provide the registrant with a vali-
dated copy of Form FD–2511 as evi-
§ 710.3 How and where to register. dence of registration. This validated
Form FD–2511 (‘‘Registration of Cos- copy will be sent only to the location
metic Product Establishment’’) is ob- shown for the registering establish-
tainable on request from the Food and ment. A permanent registration num-
Drug Administration, 5001 Campus Dr., ber will be assigned to each cosmetic
158
product establishment registered in ac- PART 720—VOLUNTARY FILING OF

cordance with the regulations in this COSMETIC PRODUCT INGRE-
part. DIENT COMPOSITION STATE-
§ 710.7 Inspection of registrations. MENTS
A copy of the Form FD–2511 filed by Sec.
the registrant will be available for in- 720.1 Who should file.
spection at the Food and Drug Admin- 720.2 Times for filing.
istration, 5001 Campus Dr., College 720.3 How and where to file.
Park, MD 20740. 720.4 Information requested about cosmetic
products.
[39 FR 10059, Mar. 15, 1974, as amended at 68 720.5 [Reserved]
FR 15355, Mar. 31, 2003; 81 FR 49897, July 29, 720.6 Amendments to statement.
2016] 720.7 Notification of person submitting cos-
metic product ingredient statement.
§ 710.8 Misbranding by reference to 720.8 Confidentiality of statements.
registration or to registration num- 720.9 Misbranding by reference to filing or
ber. to statement number.
Registration of a cosmetic product AUTHORITY: 21 U.S.C. 321, 331, 361, 362, 371,
establishment or assignment of a reg- 374.
istration number does not in any way SOURCE: 39 FR 10060, Mar. 15, 1974, unless
denote approval of the firm or its prod- otherwise noted.
ucts by the Food and Drug Administra-
tion. Any representation in labeling or § 720.1 Who should file.
advertising that creates an impression Either the manufacturer, packer, or
of official approval because of registra- distributor of a cosmetic product is re-
tion or possession of a registration quested to file Form FDA 2512 (‘‘Cos-
number will be considered misleading. metic Product Ingredient Statement’’),
whether or not the cosmetic product
§ 710.9 Exemptions. enters interstate commerce. This re-
The following classes of persons are quest extends to any foreign manufac-
not requested to register in accordance turer, packer, or distributor of a cos-
with this part 710 because the Commis- metic product exported for sale in any
sioner has found that such registration State as defined in section 201(a)(1) of
is not justified: the Federal Food, Drug, and Cosmetic
Act. No filing fee is required.
(a) Beauty shops, cosmetologists, re-
tailers, pharmacies, and other persons [57 FR 3129, Jan. 28, 1992]
and organizations that compound cos-
metic products at a single location and § 720.2 Times for filing.
administer, dispense, or distribute Within 180 days after forms are made
them at retail from that location and available to the industry, Form FDA
who do not otherwise manufacture or 2512 should be filed for each cosmetic
package cosmetic products at that lo- product being commercially distrib-
cation. uted as of the effective date of this
(b) Physicians, hospitals, clinics, and part. Form FDA 2512 should be filed
public health agencies. within 60 days after the beginning of
(c) Persons who manufacture, pre- commercial distribution of any product
pare, compound, or process cosmetic not covered within the 180-day period.
products solely for use in research, [57 FR 3129, Jan. 28, 1992]
pilot plant production, teaching, or
chemical analysis, and who do not sell § 720.3 How and where to file.
these products. Forms FDA 2512 and FDA 2514 (‘‘Dis-
continuance of Commercial Distribu-
tion of Cosmetic Product Formula-
tion’’) are obtainable on request from
the Food and Drug Administration,

5001 Campus Dr., College Park, MD
159
§ 720.4 21 CFR Ch. I (4–1–20 Edition)
20740, or at any Food and Drug Admin- (ii) Lotions, oils, powders, and
istration district office. The completed creams.
form should be mailed or delivered to: (iii) Other baby products.
Cosmetic Product Statement, Food and (2) Bath preparations. (i) Bath oils,
Drug Administration, 5001 Campus Dr., tablets, and salts.
College Park, MD 20740, according to (ii) Bubble baths.
the instructions provided with the (iii) Bath capsules.
forms. (iv) Other bath preparations.
[57 FR 3129, Jan. 28, 1992, as amended at 68
(3) Eye makeup preparations. (i) Eye-
FR 15355, Mar. 31, 2003; 81 FR 49897, July 29, brow pencil.
2016] (ii) Eyeliner.
(iii) Eye shadow.
§ 720.4 Information requested about (iv) Eye lotion.
cosmetic products. (v) Eye makeup remover.
(a) Form FDA–2512 requests informa- (vi) Mascara.
tion on: (vii) Other eye makeup preparations.
(1) The name and address, including (4) Fragrance preparations. (i) Co-
post office ZIP code of the person lognes and toilet waters.
(manufacturer, packer, or distributor) (ii) Perfumes.
designated on the label of the product. (iii) Powders (dusting and talcum)
(2) The name and address, including (excluding aftershave talc).
post office ZIP code, of the manufac- (iv) Sachets.
turer or packer of the product if dif- (v) Other fragrance preparations.
ferent from the person designated on (5) Hair preparations (noncoloring). (i)
the label of the product, when the man- Hair conditioners.
ufacturer or packer submits the infor- (ii) Hair sprays (aerosol fixatives).
mation requested under this paragraph. (iii) Hair straighteners.
(3) The brand name or names of the (iv) Permanent waves.
cosmetic product. (v) Rinses (noncoloring).
(4) The cosmetic product category or (vi) Shampoos (noncoloring).
categories. (vii) Tonics, dressings, and other hair
(5) The ingredients in the product. grooming aids.
(b) The person filing Form FDA–2512 (viii) Wave sets.
should: (ix) Other hair preparations.
(1) Provide the information requested (6) Hair coloring preparations. (i) Hair
in paragraph (a) of this section. dyes and colors (all types requiring
(2) Have the form signed by an au- caution statement and patch test).
thorized individual. (ii) Hair tints.
(3) Provide poison control centers (iii) Hair rinses (coloring).
with ingredient information and/or (iv) Hair shampoos (coloring).
adequate diagnostic and therapeutic (v) Hair color sprays (aerosol).
procedures to permit rapid evaluation (vi) Hair lighteners with color.
and treatment of accidental ingestion (vii) Hair bleaches.
or other accidental use of the cosmetic (viii) Other hair coloring prepara-
product. tions.
(4) Provide ingredient information (7) Makeup preparations (not eye). (i)
(and, when requested, ingredient sam- Blushers (all types).
ples) to a licensed physician who, in (ii) Face powders.
connection with the treatment of a pa- (iii) Foundations.
tient, requests assistance in deter- (iv) Leg and body paints.
mining whether an ingredient in the (v) Lipstick.
cosmetic product is the cause of the (vi) Makeup bases.
problem for which the patient is being (vii) Rouges.
treated. (viii) Makeup fixatives.
(c) One or more of the following cos- (ix) Other makeup preparations.
metic product categories should be (8) Manicuring preparations. (i)
cited to indicate the product’s intended Basecoats and undercoats.
use. (ii) Cuticle softeners.

(1) Baby products. (i) Baby shampoos. (iii) Nail creams and lotions.
160
(iv) Nail extenders. Drug Administration (FDA) for the in-

(v) Nail polish and enamel. gredient pursuant to § 701.3(c) of this
(vi) Nail polish and enamel removers. chapter.
(vii) Other manicuring preparations. (3) In the absence of a name adopted
(9) Oral hygiene products. (i) by FDA pursuant to § 701.3(c) of this
Dentifrices (aerosol, liquid, pastes, and chapter, its common or usual name, if
powders). it has one, or its chemical or technical
(ii) Mouthwashes and breath fresh- name should be listed.
eners (liquids and sprays). (4) If an ingredient is a mixture, each
(iii) Other oral hygiene products. ingredient of the mixture should be
(10) Personal cleanliness. (i) Bath listed in accordance with paragraphs
soaps and detergents. (d)(2) and (d)(3) of this section, unless
(ii) Deodorants (underarm). such mixture is a formulation volun-
(iii) Douches. tarily registered on Form FDA 2512, in
(iv) Feminine hygiene deodorants. which case such mixture should be
(v) Other personal cleanliness prod- identified as ‘‘fragrance,’’ ‘‘flavor,’’
ucts. ‘‘fragrance and flavor’’ or ‘‘base formu-
(11) Shaving preparations. (i) lation,’’ as appropriate, and by stating
Aftershave lotions. its FDA-assigned cosmetic product in-
(ii) Beard softeners. gredient statement number.
(iii) Men’s talcum. (5) When the manufacturer or sup-
(iv) Preshave lotions (all types). plier of a fragrance and/or flavor re-
(v) Shaving cream (aerosol, fuses to disclose ingredient data, the
brushless, and lather). fragrance and/or flavor should be listed
(vi) Shaving soap (cakes, sticks, as such. The nonconfidential listing of
etc.). the product name and/or trade name or
(vii) Other shaving preparation prod- name of the manufacturer or supplier
ucts.
of each proprietary fragrance and/or
(12) Skin care preparations, (creams, lo-
flavor mixture is optional.
tions, powder, and sprays). (i) Cleansing
(e) A separate Form FDA–2512 should
(cold creams, cleansing lotions, liquids,
be filed for each different formulation
and pads).
of a cosmetic product. However, except
(ii) Depilatories.
for the hair coloring preparations list-
(iii) Face and neck (excluding shav-
ed in paragraph (c)(6) of this section for
ing preparations).
(iv) Body and hand (excluding shav- which a statement for each shade of
ing preparations). such product is required, a single Form
(v) Foot powders and sprays. FDA–2512 may be filed for two or more
(vi) Moisturizing. shades of a cosmetic product where
(vii) Night. only the amounts of the color additive
(viii) Paste masks (mud packs). ingredient used are varied or in the
(ix) Skin fresheners. case of flavors and fragrances where
(x) Other skin care preparations. only the amounts of the flavors and
(13) Suntan preparations. (i) Suntan fragrances used are varied.
gels, creams, and liquids. (Information collection requirements in this
(ii) Indoor tanning preparations. section were approved by the Office of Man-
(iii) Other suntan preparations. agement and Budget (OMB) and assigned
(d) Ingredients in the product should OMB control number 0910–0030)
be listed as follows: [39 FR 10060, Mar. 15, 1974, as amended at 46
(1) A list of each ingredient of the FR 38073, July 24, 1981; 57 FR 3129, Jan. 28,
cosmetic product in descending order 1992]
of predominance by weight (except that
the fragrance and/or flavor may be des- § 720.5 [Reserved]
ignated as such without naming each
individual ingredient when the manu- § 720.6 Amendments to statement.
facturer or supplier of the fragrance Changes in the information requested
and/or flavor refuses to disclose ingre- under §§ 720.4 (a)(3) and (a)(5) on the in-
dient data). gredients or brand name of a cosmetic
(2) An ingredient should be listed by product should be submitted by filing

the name adopted by the Food and an amended Form FDA 2512 within 60
161
§ 720.7 21 CFR Ch. I (4–1–20 Edition)
days after the product is entered into should contain a full statement, in a
commercial distribution. Other well-organized format, of the factual
changes do not justify immediate and legal grounds for that request, in-
amendment, but should be shown by cluding all data and other information
filing an amended Form FDA 2512 with- on which the petitioner relies, as well
in a year after such changes. Notice of as representative information known
discontinuance of commercial distribu- to the petitioner that is unfavorable to
tion of a cosmetic product formulation the petitioner’s position. The state-
should be submitted by Form FDA 2514 ment of the factual grounds should in-
within 180 days after discontinuance of clude, but should not be limited to, sci-
commercial distribution becomes entific or technical data, reports, tests,
known to the person filing. and other relevant information ad-
[57 FR 3130, Jan. 28, 1992, as amended at 67 dressing the following factors that
FR 9587, Mar. 4, 2002] FDA will consider in determining
whether the identity of an ingredient
§ 720.7 Notification of person submit- qualifies as a trade secret:
ting cosmetic product ingredient
statement. (1) The extent to which the identity
of the ingredient is known outside peti-
When Form FDA 2512 is received, tioner’s business;
FDA will either assign a permanent (2) The extent to which the identity
cosmetic product ingredient statement of the ingredient is known by employ-
number or a Food and Drug Adminis- ees and others involved in petitioner’s
tration (FDA) reference number in
business;
those cases where a permanent number
(3) The extent of measures taken by
cannot be assigned. Receipt of the form
will be acknowledged by sending the the petitioner to guard the secrecy of
individual signing the statement an ap- the information;
propriate notice bearing either the (4) The value of the information
FDA reference number or the perma- about the identity of the claimed trade
nent cosmetic product ingredient secret ingredient to the petitioner and
statement number. If the person sub- to its competitors;
mitting Form FDA 2512 has not com- (5) The amount of effort or money ex-
plied with §§ 720.4 (b)(1) and (b)(2), the pended by petitioner in developing the
person will be notified as to the man- ingredient; and
ner in which the statement is incom- (6) The ease or difficulty with which
plete. the identity of the ingredient could be
properly acquired or duplicated by oth-
[57 FR 3130, Jan. 28, 1992]
ers.
§ 720.8 Confidentiality of statements. (c) The request for confidentiality
should also be accompanied by a state-
(a) Data and information contained
ment that the identity of the ingre-
in, attached to, or included with Forms
dient for which confidentiality is re-
FDA 2512 and FDA 2514, and amend-
ments thereto are submitted volun- quested has not previously been pub-
tarily to the Food and Drug Adminis- lished or disclosed to anyone other
tration (FDA). Any request for con- than as provided in § 20.81(a) of this
fidentiality of a cosmetic ingredient chapter.
submitted with such forms or sepa- (d) FDA will return to the petitioner
rately will be handled in accordance any request for confidentiality that
with the procedure set forth in this contains insufficient data to permit a
section. The request for confidentiality review of the merits of the request.
will also be subject to the provisions of FDA will also advise the petitioner
§ 20.111 of this chapter, as well as to the about the additional information that
exemptions in subpart D of part 20 of is necessary to enable the agency to
this chapter and to the limitations on proceed with its review of the request.
exemption in subpart E of part 20 of (e) If, after receiving all of the data
this chapter. that are necessary to make a deter-
(b) Any request for confidentiality of mination about whether the identity of
the identity of a cosmetic ingredient an ingredient is a trade secret, FDA
162
tentatively decides to deny the re- proval because of such filing or such
quest, the agency will inform the per- number will be considered misleading.
son requesting trade secrecy of its ten-
[57 FR 3130, Jan. 28, 1992]
tative determination in writing. FDA
will set forth the grounds upon which
it relied in making this tentative de- PART 740—COSMETIC PRODUCT
termination. The petitioner may with- WARNING STATEMENTS
draw the records for which FDA has
tentatively denied a request for con- Subpart A—General
fidentiality or may submit, within 60 Sec.
days from the date of receipt of the 740.1 Establishment of warning statements.
written notice of the tentative denial, 740.2 Conspicuousness of warning state-
additional relevant information and ar- ments.
guments and request that the agency
reconsider its decision in light of both Subpart B—Warning Statements
the additional material and the infor- 740.10 Labeling of cosmetic products for
mation that it originally submitted. which adequate substantiation of safety
(f) If the petitioner submits new data has not been obtained.
in response to FDA’s tentative denial 740.11 Cosmetics in self-pressurized con-
of trade secret status, the agency will tainers.
consider that material together with 740.12 Feminine deodorant sprays.
the information that was submitted 740.17 Foaming detergent bath products.
740.18 Coal tar hair dyes posing a risk of
initially before making its final deter-
cancer.
mination. 740.19 Suntanning preparations.
(g) A final determination that an in-
gredient is not a trade secret within AUTHORITY: 21 U.S.C. 321, 331, 352, 355, 361,
362, 371, 374.
the meaning of § 20.61 of this chapter
constitutes final agency action that is
subject to judicial review under 5 Subpart A—General
U.S.C. Chapter 7. If suit is brought
within 30 calendar days after such a de- § 740.1 Establishment of warning state-
ments.
termination, FDA will not disclose the
records involved or require that the (a) The label of a cosmetic product
disputed ingredient or ingredients be shall bear a warning statement when-
disclosed in labeling until the matter ever necessary or appropriate to pre-
is finally determined in the courts. If vent a health hazard that may be asso-
suit is not brought within 30 calendar ciated with the product.
days after a final determination that (b) The Commissioner of Food and
an ingredient is not a trade secret Drugs, either on his own initiative or
within the meaning of 21 CFR 20.61, and on behalf of any interested person who
the petitioner does not withdraw the has submitted a petition, may publish
records for which a request for con- a proposal to establish or amend, under
fidentiality has been denied, the subpart B of this part, a regulation pre-
records involved will be made a part of scribing a warning for a cosmetic. Any
FDA files and will be available for pub- such petition shall include an adequate
lic disclosure upon request. factual basis to support the petition,
shall be in the form set forth in part 10
of this chapter, and will be published
FR 3130, Jan. 28, 1992; 68 FR 25288, May 12,
2003] for comment if it contains reasonable
grounds for the proposed regulation.
§ 720.9 Misbranding by reference to fil- [40 FR 8917, Mar. 3, 1975, as amended at 42 FR
ing or to statement number. 15676, Mar. 22, 1977]
The filing of Form FDA 2512 or as-
signment of a number to the statement § 740.2 Conspicuousness of warning
does not in any way denote approval by statements.
the Food and Drug Administration of (a) A warning statement shall appear
the firm or the product. Any represen- on the label prominently and conspicu-
tation in labeling or advertising that ously as compared to other words,

creates an impression of official ap- statements, designs, or devices and in
163
§ 740.10 21 CFR Ch. I (4–1–20 Edition)
bold type on contrasting background to (3) Adequate studies are being con-
render it likely to be read and under- ducted to determine expeditiously the
stood by the ordinary individual under safety of the ingredient or product.
customary conditions of purchase and (c) Paragraph (b) of this section does
use, but in no case may the letters and/ not constitute an exemption to the
or numbers be less than 1⁄16 inch in adulteration provisions of the Act or to
height, unless an exemption pursuant any other requirement in the Act or
to paragraph (b) of this section is es- this chapter.
tablished.
[40 FR 8917, Mar. 3, 1975]
(b) If the label of any cosmetic pack-
age is too small to accommodate the § 740.11 Cosmetics in self-pressurized
information as required by this sec- containers.
tion, the Commissioner may establish
(a)(1) The label of a cosmetic pack-
by regulation an acceptable alternative
aged in a self-pressurized container and
method, e.g., type size smaller than 1⁄16
intended to be expelled from the pack-
inch in height. A petition requesting
age under pressure shall bear the fol-
such a regulation, as an amendment to
lowing warning:
this section, shall be submitted to the
Division of Dockets Management in the Warning—Avoid spraying in eyes. Contents
form established in part 10 of this chap- under pressure. Do not puncture or incin-
ter. erate. Do not store at temperature above 120
°F. Keep out of reach of children.
[40 FR 8917, Mar. 3, 1975, as amended at 42 FR
15676, Mar. 22, 1977; 69 FR 13717, Mar. 24, 2004] (2) In the case of products intended
for use by children, the phrase ‘‘except
under adult supervision’’ may be added
Subpart B—Warning Statements at the end of the last sentence in the
§ 740.10 Labeling of cosmetic products warning required by paragraph (a)(1) of
for which adequate substantiation this section.
of safety has not been obtained. (3) In the case of products packaged
in glass containers, the word ‘‘break’’
(a) Each ingredient used in a cos- may be substituted for the word
metic product and each finished cos- ‘‘puncture’’ in the warning required by
metic product shall be adequately sub- paragraph (a)(1) of this section.
stantiated for safety prior to mar-
(4) The words ‘‘Avoid spraying in
keting. Any such ingredient or product eyes’’ may be deleted from the warning
whose safety is not adequately sub- required by paragraph (a)(1) of this sec-
stantiated prior to marketing is mis- tion in the case of a product not ex-
branded unless it contains the fol- pelled as a spray.
lowing conspicuous statement on the (b)(1) In addition to the warning re-
principal display panel: quired by paragraph (a)(1) of this sec-
Warning—The safety of this product has tion, the label of a cosmetic packaged
not been determined. in a self-pressurized container in which
the propellant consists in whole or in
(b) An ingredient or product having a part of a halocarbon or a hydrocarbon
history of use in or as a cosmetic may shall bear the following warning:
at any time have its safety brought
into question by new information that Warning—Use only as directed. Intentional
in itself is not conclusive. The warning misuse by deliberately concentrating and in-
required by paragraph (a) of this sec- haling the contents can be harmful or fatal.
tion is not required for such an ingre- (2) The warning required by para-
dient or product if: graph (b)(1) of this section is not re-
(1) The safety of the ingredient or quired for the following products:
product had been adequately substan- (i) Products expelled in the form of a
tiated prior to development of the new foam or cream, which contain less than
information; 10 percent propellant in the container.
(2) The new information does not (ii) Products in a container with a
demonstrate a hazard to human health; physical barrier that prevents escape of

and the propellant at the time of use.
164
(iii) Products of a net quantity of § 740.17 Foaming detergent bath prod-

contents of less than 2 ozs. that are de- ucts.
signed to release a measured amount of (a) For the purpose of this section, a
product with each valve actuation. foaming detergent bath product is any
(iv) Products of a net quantity of product intended to be added to a bath
contents of less than 1⁄2 oz. for the purpose of producing foam that
(c) Labeling requirements for cos- contains a surface-active agent serving
metics packaged in a self- pressurized as a detergent or foaming ingredient.
container containing or manufactured (b) The label of foaming detergent
with a chlorofluorocarbon propellant bath products within the meaning of
or other ozone-depleting substance des- paragraph (a) of this section, except for
ignated by the Environmental Protec- those products that are labeled as in-
tion Agency (EPA) are set forth in 40 tended for use exclusively by adults,
shall bear adequate directions for safe
CFR part 82.
use and the following caution:
[40 FR 8917, Mar. 3, 1975, as amended at 42 FR Caution—Use only as directed. Excessive
22033, Apr. 29, 1977; 54 FR 39640, Sept. 27, 1989; use or prolonged exposure may cause irrita-
61 FR 20101, May 3, 1996] tion to skin and urinary tract. Discontinue
use if rash, redness, or itching occurs. Con-
§ 740.12 Feminine deodorant sprays. sult your physician if irritation persists.
(a) For the purpose of this section, Keep out of reach of children.
the term ‘‘feminine deodorant spray’’ (c) In the case of products intended
means any spray deodorant product for use by children, the phrase ‘‘except
whose labeling represents or suggests under adult supervision’’ may be added
that the product is for use in the fe- at the end of the last sentence in the
male genital area or for use all over caution required by paragraph (b) of
the body. this section.
(b) The label of a feminine deodorant [51 FR 20475, June 5, 1986]
spray shall bear the following state-
ment: § 740.18 Coal tar hair dyes posing a
risk of cancer.
Caution—For external use only. Spray at
(a) The principal display panel of the
least 8 inches from skin. Do not apply to bro-
ken, irritated, or itching skin. Persistent,
label and any labeling accompanying a
unusual odor or discharge may indicate con- coal tar hair dye containing any ingre-
ditions for which a physician should be con- dient listed in paragraph (b) of this sec-
sulted. Discontinue use immediately if rash, tion shall bear, in accordance with the
irritation, or discomfort develops. requirements of § 740.2, the following:
Warning—Contains an ingredient that can
The sentence ‘‘Spray at least 8 inches penetrate your skin and has been determined
from skin’’ need not be included in the to cause cancer in laboratory animals.
cautionary statement for products
whose expelled contents do not contain (b) Hair dyes containing any of the
following ingredients shall comply
a liquified gas propellant such as a
with the requirements of this section:
halocarbon or hydrocarbon propellant.
(1) 4-methoxy-m-phenylenediamine (2,4-
(c) Use of the word ‘‘hygiene’’ or diaminoanisole) and (2) 4-methoxy-m-
‘‘hygienic’’ or a similar word or words phenylenediamine sulfate (2,4-
renders any such product misbranded diaminoanisole sulfate).
under section 602(a) of the Federal
Food, Drug, and Cosmetic Act. The use [44 FR 59522, Oct. 16, 1979]
of any word or words which represent EFFECTIVE DATE NOTE: At 47 FR 7829, Feb.
or suggest that such products have a 23, 1982, § 740.18 was stayed until further no-
medical usefulness renders such prod- tice, effective Sept. 18, 1980.
ucts misbranded under section 502(a) of § 740.19 Suntanning preparations.
the Act and illegal new drugs marketed
The labeling of suntanning prepara-
in violation of section 505 of the Act.
tions that do not contain a sunscreen
[40 FR 8929, Mar. 3, 1975] ingredient must display the following

warning: ‘‘Warning—This product does
165
§ 740.19 21 CFR Ch. I (4–1–20 Edition)
not contain a sunscreen and does not pearance of a tan by imparting color to
protect against sunburn. Repeated ex- the skin through the application of ap-
posure of unprotected skin while tan- proved color additives (e.g.,
ning may increase the risk of skin dihydroxyacetone) without the need for
aging, skin cancer, and other harmful exposure to UV radiation. The term
effects to the skin even if you do not ‘‘suntanning preparations’’ does not in-
burn.’’ For purposes of this section, the clude products intended to provide sun
term ‘‘suntanning preparations’’ in- protection or otherwise intended to af-
cludes gels, creams, liquids, and other fect the structure or any function of
topical products that are intended to the body.
provide cosmetic effects on the skin
while tanning through exposure to UV [64 FR 27693, May 21, 1999]
radiation (e.g., moisturizing or condi-
tioning products), or to give the ap- PARTS 741–799 [RESERVED]
166
FINDING AIDS
A list of CFR titles, subtitles, chapters, subchapters and parts and an alphabet-
ical list of agencies publishing in the CFR are included in the CFR Index and
Finding Aids volume to the Code of Federal Regulations which is published sepa-
rately and revised annually.
Table of CFR Titles and Chapters
Alphabetical List of Agencies Appearing in the CFR
List of CFR Sections Affected
167
Table of CFR Titles and Chapters
(Revised as of April 1, 2020)
Title 1—General Provisions
I Administrative Committee of the Federal Register (Parts 1—49)

II Office of the Federal Register (Parts 50—299)
III Administrative Conference of the United States (Parts 300—399)
IV Miscellaneous Agencies (Parts 400—599)
VI National Capital Planning Commission (Parts 600—699)
Title 2—Grants and Agreements
SUBTITLE A—OFFICE OF MANAGEMENT AND BUDGET GUIDANCE FOR

GRANTS AND AGREEMENTS
I Office of Management and Budget Governmentwide Guidance for
Grants and Agreements (Parts 2—199)
II Office of Management and Budget Guidance (Parts 200—299)
SUBTITLE B—FEDERAL AGENCY REGULATIONS FOR GRANTS AND
AGREEMENTS
III Department of Health and Human Services (Parts 300—399)
IV Department of Agriculture (Parts 400—499)
VI Department of State (Parts 600—699)
VII Agency for International Development (Parts 700—799)
VIII Department of Veterans Affairs (Parts 800—899)
IX Department of Energy (Parts 900—999)
X Department of the Treasury (Parts 1000—1099)
XI Department of Defense (Parts 1100—1199)
XII Department of Transportation (Parts 1200—1299)
XIII Department of Commerce (Parts 1300—1399)
XIV Department of the Interior (Parts 1400—1499)
XV Environmental Protection Agency (Parts 1500—1599)
XVIII National Aeronautics and Space Administration (Parts 1800—
1899)
XX United States Nuclear Regulatory Commission (Parts 2000—2099)
XXII Corporation for National and Community Service (Parts 2200—
2299)
XXIII Social Security Administration (Parts 2300—2399)
XXIV Department of Housing and Urban Development (Parts 2400—
2499)
XXV National Science Foundation (Parts 2500—2599)

XXVI National Archives and Records Administration (Parts 2600—2699)
169
Title 2—Grants and Agreements—Continued
Chap.
XXVII Small Business Administration (Parts 2700—2799)

XXVIII Department of Justice (Parts 2800—2899)
XXIX Department of Labor (Parts 2900—2999)
XXX Department of Homeland Security (Parts 3000—3099)
XXXI Institute of Museum and Library Services (Parts 3100—3199)
XXXII National Endowment for the Arts (Parts 3200—3299)
XXXIII National Endowment for the Humanities (Parts 3300—3399)
XXXIV Department of Education (Parts 3400—3499)
XXXV Export-Import Bank of the United States (Parts 3500—3599)
XXXVI Office of National Drug Control Policy, Executive Office of the
President (Parts 3600—3699)
XXXVII Peace Corps (Parts 3700—3799)
LVIII Election Assistance Commission (Parts 5800—5899)
LIX Gulf Coast Ecosystem Restoration Council (Parts 5900—5999)
Title 3—The President
I Executive Office of the President (Parts 100—199)
Title 4—Accounts
I Government Accountability Office (Parts 1—199)
Title 5—Administrative Personnel
I Office of Personnel Management (Parts 1—1199)

II Merit Systems Protection Board (Parts 1200—1299)
III Office of Management and Budget (Parts 1300—1399)
IV Office of Personnel Management and Office of the Director of
National Intelligence (Parts 1400—1499)
V The International Organizations Employees Loyalty Board
(Parts 1500—1599)
VI Federal Retirement Thrift Investment Board (Parts 1600—1699)
VIII Office of Special Counsel (Parts 1800—1899)
IX Appalachian Regional Commission (Parts 1900—1999)
XI Armed Forces Retirement Home (Parts 2100—2199)
XIV Federal Labor Relations Authority, General Counsel of the Fed-
eral Labor Relations Authority and Federal Service Impasses
Panel (Parts 2400—2499)
XVI Office of Government Ethics (Parts 2600—2699)
XXI Department of the Treasury (Parts 3100—3199)
XXII Federal Deposit Insurance Corporation (Parts 3200—3299)
XXIII Department of Energy (Parts 3300—3399)
XXIV Federal Energy Regulatory Commission (Parts 3400—3499)
XXV Department of the Interior (Parts 3500—3599)

XXVI Department of Defense (Parts 3600—3699)
170
Title 5—Administrative Personnel—Continued
Chap.
XXVIII Department of Justice (Parts 3800—3899)

XXIX Federal Communications Commission (Parts 3900—3999)
XXX Farm Credit System Insurance Corporation (Parts 4000—4099)
XXXI Farm Credit Administration (Parts 4100—4199)
XXXIII U.S. International Development Finance Corporation (Parts
4300—4399)
XXXIV Securities and Exchange Commission (Parts 4400—4499)
XXXV Office of Personnel Management (Parts 4500—4599)
XXXVI Department of Homeland Security (Parts 4600—4699)
XXXVII Federal Election Commission (Parts 4700—4799)
XL Interstate Commerce Commission (Parts 5000—5099)
XLI Commodity Futures Trading Commission (Parts 5100—5199)
XLII Department of Labor (Parts 5200—5299)
XLIII National Science Foundation (Parts 5300—5399)
XLV Department of Health and Human Services (Parts 5500—5599)
XLVI Postal Rate Commission (Parts 5600—5699)
XLVII Federal Trade Commission (Parts 5700—5799)
XLVIII Nuclear Regulatory Commission (Parts 5800—5899)
XLIX Federal Labor Relations Authority (Parts 5900—5999)
L Department of Transportation (Parts 6000—6099)
LII Export-Import Bank of the United States (Parts 6200—6299)
LIII Department of Education (Parts 6300—6399)
LIV Environmental Protection Agency (Parts 6400—6499)
LV National Endowment for the Arts (Parts 6500—6599)
LVI National Endowment for the Humanities (Parts 6600—6699)
LVII General Services Administration (Parts 6700—6799)
LVIII Board of Governors of the Federal Reserve System (Parts 6800—
6899)
LIX National Aeronautics and Space Administration (Parts 6900—
6999)
LX United States Postal Service (Parts 7000—7099)
LXI National Labor Relations Board (Parts 7100—7199)
LXII Equal Employment Opportunity Commission (Parts 7200—7299)
LXIII Inter-American Foundation (Parts 7300—7399)
LXIV Merit Systems Protection Board (Parts 7400—7499)
LXV Department of Housing and Urban Development (Parts 7500—
7599)
LXVI National Archives and Records Administration (Parts 7600—7699)
LXVII Institute of Museum and Library Services (Parts 7700—7799)
LXVIII Commission on Civil Rights (Parts 7800—7899)
LXIX Tennessee Valley Authority (Parts 7900—7999)
LXX Court Services and Offender Supervision Agency for the District
of Columbia (Parts 8000—8099)
LXXI Consumer Product Safety Commission (Parts 8100—8199)

LXXIII Department of Agriculture (Parts 8300—8399)
171
Title 5—Administrative Personnel—Continued
Chap.
LXXIV Federal Mine Safety and Health Review Commission (Parts

8400—8499)
LXXVI Federal Retirement Thrift Investment Board (Parts 8600—8699)
LXXVII Office of Management and Budget (Parts 8700—8799)
LXXX Federal Housing Finance Agency (Parts 9000—9099)
LXXXIII Special Inspector General for Afghanistan Reconstruction (Parts
9300—9399)
LXXXIV Bureau of Consumer Financial Protection (Parts 9400—9499)
LXXXVI National Credit Union Administration (Parts 9600—9699)
XCVII Department of Homeland Security Human Resources Manage-
ment System (Department of Homeland Security—Office of
Personnel Management) (Parts 9700—9799)
XCVIII Council of the Inspectors General on Integrity and Efficiency
(Parts 9800—9899)
XCIX Military Compensation and Retirement Modernization Commis-
sion (Parts 9900—9999)
C National Council on Disability (Parts 10000—10049)
CI National Mediation Board (Part 10101)
Title 6—Domestic Security
I Department of Homeland Security, Office of the Secretary

(Parts 1—199)
X Privacy and Civil Liberties Oversight Board (Parts 1000—1099)
Title 7—Agriculture
SUBTITLE A—OFFICE OF THE SECRETARY OF AGRICULTURE (PARTS

0—26)
SUBTITLE B—REGULATIONS OF THE DEPARTMENT OF AGRICULTURE
I Agricultural Marketing Service (Standards, Inspections, Mar-
keting Practices), Department of Agriculture (Parts 27—209)
II Food and Nutrition Service, Department of Agriculture (Parts
210—299)
III Animal and Plant Health Inspection Service, Department of Ag-
riculture (Parts 300—399)
IV Federal Crop Insurance Corporation, Department of Agriculture
(Parts 400—499)
V Agricultural Research Service, Department of Agriculture
(Parts 500—599)
VI Natural Resources Conservation Service, Department of Agri-
culture (Parts 600—699)
VII Farm Service Agency, Department of Agriculture (Parts 700—
799)
VIII Agricultural Marketing Service (Federal Grain Inspection Serv-
ice, Fair Trade Practices Program), Department of Agri-

172
Title 7—Agriculture—Continued
Chap.
IX Agricultural Marketing Service (Marketing Agreements and Or-

ders; Fruits, Vegetables, Nuts), Department of Agriculture
(Parts 900—999)
X Agricultural Marketing Service (Marketing Agreements and Or-
ders; Milk), Department of Agriculture (Parts 1000—1199)
XI Agricultural Marketing Service (Marketing Agreements and Or-
ders; Miscellaneous Commodities), Department of Agriculture
(Parts 1200—1299)
XIV Commodity Credit Corporation, Department of Agriculture
(Parts 1400—1499)
XV Foreign Agricultural Service, Department of Agriculture (Parts
1500—1599)
XVI [Reserved]
XVII Rural Utilities Service, Department of Agriculture (Parts 1700—
1799)
XVIII Rural Housing Service, Rural Business-Cooperative Service,
Rural Utilities Service, and Farm Service Agency, Depart-
ment of Agriculture (Parts 1800—2099)
XX [Reserved]
XXV Office of Advocacy and Outreach, Department of Agriculture
(Parts 2500—2599)
XXVI Office of Inspector General, Department of Agriculture (Parts
2600—2699)
XXVII Office of Information Resources Management, Department of
Agriculture (Parts 2700—2799)
XXVIII Office of Operations, Department of Agriculture (Parts 2800—
2899)
XXIX Office of Energy Policy and New Uses, Department of Agri-
XXX Office of the Chief Financial Officer, Department of Agriculture
(Parts 3000—3099)
XXXI Office of Environmental Quality, Department of Agriculture
(Parts 3100—3199)
XXXII Office of Procurement and Property Management, Department
of Agriculture (Parts 3200—3299)
XXXIII Office of Transportation, Department of Agriculture (Parts
3300—3399)
XXXIV National Institute of Food and Agriculture (Parts 3400—3499)
XXXV Rural Housing Service, Department of Agriculture (Parts 3500—
3599)
XXXVI National Agricultural Statistics Service, Department of Agri-
XXXVII Economic Research Service, Department of Agriculture (Parts
3700—3799)
XXXVIII World Agricultural Outlook Board, Department of Agriculture
(Parts 3800—3899)
XLI [Reserved]
XLII Rural Business-Cooperative Service and Rural Utilities Service,

Department of Agriculture (Parts 4200—4299)
173
Title 8—Aliens and Nationality
Chap.
I Department of Homeland Security (Parts 1—499)

V Executive Office for Immigration Review, Department of Justice
(Parts 1000—1399)
Title 9—Animals and Animal Products
I Animal and Plant Health Inspection Service, Department of Ag-

riculture (Parts 1—199)
II Agricultural Marketing Service (Federal Grain Inspection Serv-
ice, Fair Trade Practices Program), Department of Agri-
III Food Safety and Inspection Service, Department of Agriculture
(Parts 300—599)
Title 10—Energy
I Nuclear Regulatory Commission (Parts 0—199)

II Department of Energy (Parts 200—699)
III Department of Energy (Parts 700—999)
X Department of Energy (General Provisions) (Parts 1000—1099)
XIII Nuclear Waste Technical Review Board (Parts 1300—1399)
XVII Defense Nuclear Facilities Safety Board (Parts 1700—1799)
XVIII Northeast Interstate Low-Level Radioactive Waste Commission
(Parts 1800—1899)
Title 11—Federal Elections
I Federal Election Commission (Parts 1—9099)

II Election Assistance Commission (Parts 9400—9499)
Title 12—Banks and Banking
I Comptroller of the Currency, Department of the Treasury (Parts

1—199)
II Federal Reserve System (Parts 200—299)
III Federal Deposit Insurance Corporation (Parts 300—399)
IV Export-Import Bank of the United States (Parts 400—499)
V (Parts 500—599) [Reserved]
VI Farm Credit Administration (Parts 600—699)
VII National Credit Union Administration (Parts 700—799)
VIII Federal Financing Bank (Parts 800—899)
IX Federal Housing Finance Board (Parts 900—999)
X Bureau of Consumer Financial Protection (Parts 1000—1099)
XI Federal Financial Institutions Examination Council (Parts
1100—1199)
XII Federal Housing Finance Agency (Parts 1200—1299)

XIII Financial Stability Oversight Council (Parts 1300—1399)
174
Title 12—Banks and Banking—Continued
Chap.
XIV Farm Credit System Insurance Corporation (Parts 1400—1499)

XV Department of the Treasury (Parts 1500—1599)
XVI Office of Financial Research (Parts 1600—1699)
XVII Office of Federal Housing Enterprise Oversight, Department of
Housing and Urban Development (Parts 1700—1799)
XVIII Community Development Financial Institutions Fund, Depart-
ment of the Treasury (Parts 1800—1899)
Title 13—Business Credit and Assistance
I Small Business Administration (Parts 1—199)

III Economic Development Administration, Department of Com-
merce (Parts 300—399)
IV Emergency Steel Guarantee Loan Board (Parts 400—499)
V Emergency Oil and Gas Guaranteed Loan Board (Parts 500—599)
Title 14—Aeronautics and Space
I Federal Aviation Administration, Department of Transportation

(Parts 1—199)
II Office of the Secretary, Department of Transportation (Aviation
Proceedings) (Parts 200—399)
III Commercial Space Transportation, Federal Aviation Adminis-
tration, Department of Transportation (Parts 400—1199)
V National Aeronautics and Space Administration (Parts 1200—
1299)
VI Air Transportation System Stabilization (Parts 1300—1399)
Title 15—Commerce and Foreign Trade
SUBTITLE A—OFFICE OF THE SECRETARY OF COMMERCE (PARTS 0—

29)
SUBTITLE B—REGULATIONS RELATING TO COMMERCE AND FOREIGN
TRADE
I Bureau of the Census, Department of Commerce (Parts 30—199)
II National Institute of Standards and Technology, Department of
Commerce (Parts 200—299)
III International Trade Administration, Department of Commerce
(Parts 300—399)
IV Foreign-Trade Zones Board, Department of Commerce (Parts
400—499)
VII Bureau of Industry and Security, Department of Commerce
(Parts 700—799)
VIII Bureau of Economic Analysis, Department of Commerce (Parts
800—899)
IX National Oceanic and Atmospheric Administration, Department
of Commerce (Parts 900—999)
XI National Technical Information Service, Department of Com-

merce (Parts 1100—1199)
175
Title 15—Commerce and Foreign Trade—Continued
Chap.
XIII East-West Foreign Trade Board (Parts 1300—1399)

XIV Minority Business Development Agency (Parts 1400—1499)
SUBTITLE C—REGULATIONS RELATING TO FOREIGN TRADE AGREE-
MENTS
XX Office of the United States Trade Representative (Parts 2000—
2099)
SUBTITLE D—REGULATIONS RELATING TO TELECOMMUNICATIONS
AND INFORMATION
XXIII National Telecommunications and Information Administration,
Department of Commerce (Parts 2300—2399) [Reserved]
Title 16—Commercial Practices
I Federal Trade Commission (Parts 0—999)

II Consumer Product Safety Commission (Parts 1000—1799)
Title 17—Commodity and Securities Exchanges
I Commodity Futures Trading Commission (Parts 1—199)

II Securities and Exchange Commission (Parts 200—399)
IV Department of the Treasury (Parts 400—499)
Title 18—Conservation of Power and Water Resources
I Federal Energy Regulatory Commission, Department of Energy

(Parts 1—399)
III Delaware River Basin Commission (Parts 400—499)
VI Water Resources Council (Parts 700—799)
VIII Susquehanna River Basin Commission (Parts 800—899)
XIII Tennessee Valley Authority (Parts 1300—1399)
Title 19—Customs Duties
I U.S. Customs and Border Protection, Department of Homeland

Security; Department of the Treasury (Parts 0—199)
II United States International Trade Commission (Parts 200—299)
III International Trade Administration, Department of Commerce
(Parts 300—399)
IV U.S. Immigration and Customs Enforcement, Department of
Homeland Security (Parts 400—599) [Reserved]
Title 20—Employees’ Benefits
I Office of Workers’ Compensation Programs, Department of

Labor (Parts 1—199)
II Railroad Retirement Board (Parts 200—399)

III Social Security Administration (Parts 400—499)
176
Title 20—Employees’ Benefits—Continued
Chap.
IV Employees’ Compensation Appeals Board, Department of Labor

(Parts 500—599)
V Employment and Training Administration, Department of Labor
(Parts 600—699)
VI Office of Workers’ Compensation Programs, Department of
VII Benefits Review Board, Department of Labor (Parts 800—899)
VIII Joint Board for the Enrollment of Actuaries (Parts 900—999)
IX Office of the Assistant Secretary for Veterans’ Employment and
Training Service, Department of Labor (Parts 1000—1099)
Title 21—Food and Drugs
I Food and Drug Administration, Department of Health and

Human Services (Parts 1—1299)
II Drug Enforcement Administration, Department of Justice (Parts
1300—1399)
III Office of National Drug Control Policy (Parts 1400—1499)
Title 22—Foreign Relations
I Department of State (Parts 1—199)

II Agency for International Development (Parts 200—299)
III Peace Corps (Parts 300—399)
IV International Joint Commission, United States and Canada
(Parts 400—499)
V Broadcasting Board of Governors (Parts 500—599)
VII Overseas Private Investment Corporation (Parts 700—799)
IX Foreign Service Grievance Board (Parts 900—999)
X Inter-American Foundation (Parts 1000—1099)
XI International Boundary and Water Commission, United States
and Mexico, United States Section (Parts 1100—1199)
XII United States International Development Cooperation Agency
(Parts 1200—1299)
XIII Millennium Challenge Corporation (Parts 1300—1399)
XIV Foreign Service Labor Relations Board; Federal Labor Relations
Authority; General Counsel of the Federal Labor Relations
Authority; and the Foreign Service Impasse Disputes Panel
(Parts 1400—1499)
XV African Development Foundation (Parts 1500—1599)
XVI Japan-United States Friendship Commission (Parts 1600—1699)
XVII United States Institute of Peace (Parts 1700—1799)
Title 23—Highways
I Federal Highway Administration, Department of Transportation

(Parts 1—999)
177
Title 23—Highways—Continued
Chap.
II National Highway Traffic Safety Administration and Federal

Highway Administration, Department of Transportation
(Parts 1200—1299)
III National Highway Traffic Safety Administration, Department of
Transportation (Parts 1300—1399)
Title 24—Housing and Urban Development
SUBTITLE A—OFFICE OF THE SECRETARY, DEPARTMENT OF HOUSING

AND URBAN DEVELOPMENT (PARTS 0—99)
SUBTITLE B—REGULATIONS RELATING TO HOUSING AND URBAN DE-
VELOPMENT
I Office of Assistant Secretary for Equal Opportunity, Department
of Housing and Urban Development (Parts 100—199)
II Office of Assistant Secretary for Housing-Federal Housing Com-
missioner, Department of Housing and Urban Development
(Parts 200—299)
III Government National Mortgage Association, Department of
Housing and Urban Development (Parts 300—399)
IV Office of Housing and Office of Multifamily Housing Assistance
Restructuring, Department of Housing and Urban Develop-
ment (Parts 400—499)
V Office of Assistant Secretary for Community Planning and De-
velopment, Department of Housing and Urban Development
(Parts 500—599)
VI Office of Assistant Secretary for Community Planning and De-
velopment, Department of Housing and Urban Development
(Parts 600—699) [Reserved]
VII Office of the Secretary, Department of Housing and Urban Devel-
opment (Housing Assistance Programs and Public and Indian
Housing Programs) (Parts 700—799)
VIII Office of the Assistant Secretary for Housing—Federal Housing
Commissioner, Department of Housing and Urban Develop-
ment (Section 8 Housing Assistance Programs, Section 202 Di-
rect Loan Program, Section 202 Supportive Housing for the El-
derly Program and Section 811 Supportive Housing for Persons
With Disabilities Program) (Parts 800—899)
IX Office of Assistant Secretary for Public and Indian Housing, De-
partment of Housing and Urban Development (Parts 900—1699)
XII Office of Inspector General, Department of Housing and Urban
Development (Parts 2000—2099)
XV Emergency Mortgage Insurance and Loan Programs, Depart-
ment of Housing and Urban Development (Parts 2700—2799)
[Reserved]
XX Office of Assistant Secretary for Housing—Federal Housing
Commissioner, Department of Housing and Urban Develop-
ment (Parts 3200—3899)
XXIV Board of Directors of the HOPE for Homeowners Program (Parts
4000—4099) [Reserved]
XXV Neighborhood Reinvestment Corporation (Parts 4100—4199)
178
Title 25—Indians
Chap.
I Bureau of Indian Affairs, Department of the Interior (Parts 1—

299)
II Indian Arts and Crafts Board, Department of the Interior (Parts
300—399)
III National Indian Gaming Commission, Department of the Inte-
rior (Parts 500—599)
IV Office of Navajo and Hopi Indian Relocation (Parts 700—899)
V Bureau of Indian Affairs, Department of the Interior, and Indian
Health Service, Department of Health and Human Services
(Part 900—999)
VI Office of the Assistant Secretary, Indian Affairs, Department of
the Interior (Parts 1000—1199)
VII Office of the Special Trustee for American Indians, Department
of the Interior (Parts 1200—1299)
Title 26—Internal Revenue
I Internal Revenue Service, Department of the Treasury (Parts 1—

End)
Title 27—Alcohol, Tobacco Products and Firearms
I Alcohol and Tobacco Tax and Trade Bureau, Department of the

Treasury (Parts 1—399)
II Bureau of Alcohol, Tobacco, Firearms, and Explosives, Depart-
ment of Justice (Parts 400—699)
Title 28—Judicial Administration
I Department of Justice (Parts 0—299)

III Federal Prison Industries, Inc., Department of Justice (Parts
300—399)
V Bureau of Prisons, Department of Justice (Parts 500—599)
VI Offices of Independent Counsel, Department of Justice (Parts
600—699)
VII Office of Independent Counsel (Parts 700—799)
VIII Court Services and Offender Supervision Agency for the District
of Columbia (Parts 800—899)
IX National Crime Prevention and Privacy Compact Council (Parts
900—999)
XI Department of Justice and Department of State (Parts 1100—
1199)
Title 29—Labor
SUBTITLE A—OFFICE OF THE SECRETARY OF LABOR (PARTS 0—99)

SUBTITLE B—REGULATIONS RELATING TO LABOR

I National Labor Relations Board (Parts 100—199)
179
Title 29—Labor—Continued
Chap.
II Office of Labor-Management Standards, Department of Labor

(Parts 200—299)
III National Railroad Adjustment Board (Parts 300—399)
IV Office of Labor-Management Standards, Department of Labor
(Parts 400—499)
V Wage and Hour Division, Department of Labor (Parts 500—899)
IX Construction Industry Collective Bargaining Commission (Parts
900—999)
X National Mediation Board (Parts 1200—1299)
XII Federal Mediation and Conciliation Service (Parts 1400—1499)
XIV Equal Employment Opportunity Commission (Parts 1600—1699)
XVII Occupational Safety and Health Administration, Department of
XX Occupational Safety and Health Review Commission (Parts
2200—2499)
XXV Employee Benefits Security Administration, Department of
XXVII Federal Mine Safety and Health Review Commission (Parts
2700—2799)
XL Pension Benefit Guaranty Corporation (Parts 4000—4999)
Title 30—Mineral Resources
I Mine Safety and Health Administration, Department of Labor

(Parts 1—199)
II Bureau of Safety and Environmental Enforcement, Department
of the Interior (Parts 200—299)
IV Geological Survey, Department of the Interior (Parts 400—499)
V Bureau of Ocean Energy Management, Department of the Inte-
VII Office of Surface Mining Reclamation and Enforcement, Depart-
ment of the Interior (Parts 700—999)
XII Office of Natural Resources Revenue, Department of the Interior
(Parts 1200—1299)
Title 31—Money and Finance: Treasury
SUBTITLE A—OFFICE OF THE SECRETARY OF THE TREASURY (PARTS

0—50)
SUBTITLE B—REGULATIONS RELATING TO MONEY AND FINANCE
I Monetary Offices, Department of the Treasury (Parts 51—199)
II Fiscal Service, Department of the Treasury (Parts 200—399)
IV Secret Service, Department of the Treasury (Parts 400—499)
V Office of Foreign Assets Control, Department of the Treasury
(Parts 500—599)
VI Bureau of Engraving and Printing, Department of the Treasury
(Parts 600—699)
VII Federal Law Enforcement Training Center, Department of the

180
Title 31—Money and Finance: Treasury—Continued
Chap.
VIII Office of Investment Security, Department of the Treasury

(Parts 800—899)
IX Federal Claims Collection Standards (Department of the Treas-
ury—Department of Justice) (Parts 900—999)
X Financial Crimes Enforcement Network, Department of the
Title 32—National Defense
SUBTITLE A—DEPARTMENT OF DEFENSE

I Office of the Secretary of Defense (Parts 1—399)
V Department of the Army (Parts 400—699)
VI Department of the Navy (Parts 700—799)
VII Department of the Air Force (Parts 800—1099)
SUBTITLE B—OTHER REGULATIONS RELATING TO NATIONAL DE-
FENSE
XII Department of Defense, Defense Logistics Agency (Parts 1200—
1299)
XVI Selective Service System (Parts 1600—1699)
XVII Office of the Director of National Intelligence (Parts 1700—1799)
XVIII National Counterintelligence Center (Parts 1800—1899)
XIX Central Intelligence Agency (Parts 1900—1999)
XX Information Security Oversight Office, National Archives and
Records Administration (Parts 2000—2099)
XXI National Security Council (Parts 2100—2199)
XXIV Office of Science and Technology Policy (Parts 2400—2499)
XXVII Office for Micronesian Status Negotiations (Parts 2700—2799)
XXVIII Office of the Vice President of the United States (Parts 2800—
2899)
Title 33—Navigation and Navigable Waters
I Coast Guard, Department of Homeland Security (Parts 1—199)

II Corps of Engineers, Department of the Army, Department of De-
fense (Parts 200—399)
IV Saint Lawrence Seaway Development Corporation, Department
of Transportation (Parts 400—499)
Title 34—Education
SUBTITLE A—OFFICE OF THE SECRETARY, DEPARTMENT OF EDU-

CATION (PARTS 1—99)
SUBTITLE B—REGULATIONS OF THE OFFICES OF THE DEPARTMENT
OF EDUCATION
I Office for Civil Rights, Department of Education (Parts 100—199)
II Office of Elementary and Secondary Education, Department of

Education (Parts 200—299)
181
Title 34—Education—Continued
Chap.
III Office of Special Education and Rehabilitative Services, Depart-

ment of Education (Parts 300—399)
IV Office of Career, Technical and Adult Education, Department of
Education (Parts 400—499)
V Office of Bilingual Education and Minority Languages Affairs,
Department of Education (Parts 500—599) [Reserved]
VI Office of Postsecondary Education, Department of Education
(Parts 600—699)
VII Office of Educational Research and Improvement, Department of
Education (Parts 700—799) [Reserved]
SUBTITLE C—REGULATIONS RELATING TO EDUCATION
XI (Parts 1100—1199) [Reserved]
XII National Council on Disability (Parts 1200—1299)
Title 35 [Reserved]
Title 36—Parks, Forests, and Public Property
I National Park Service, Department of the Interior (Parts 1—199)

II Forest Service, Department of Agriculture (Parts 200—299)
III Corps of Engineers, Department of the Army (Parts 300—399)
IV American Battle Monuments Commission (Parts 400—499)
V Smithsonian Institution (Parts 500—599)
VI [Reserved]
VII Library of Congress (Parts 700—799)
VIII Advisory Council on Historic Preservation (Parts 800—899)
IX Pennsylvania Avenue Development Corporation (Parts 900—999)
X Presidio Trust (Parts 1000—1099)
XI Architectural and Transportation Barriers Compliance Board
(Parts 1100—1199)
XII National Archives and Records Administration (Parts 1200—1299)
XV Oklahoma City National Memorial Trust (Parts 1500—1599)
XVI Morris K. Udall Scholarship and Excellence in National Environ-
mental Policy Foundation (Parts 1600—1699)
Title 37—Patents, Trademarks, and Copyrights
I United States Patent and Trademark Office, Department of

II U.S. Copyright Office, Library of Congress (Parts 200—299)
III Copyright Royalty Board, Library of Congress (Parts 300—399)
IV National Institute of Standards and Technology, Department of
182
Title 38—Pensions, Bonuses, and Veterans’ Relief
Chap.
I Department of Veterans Affairs (Parts 0—199)

II Armed Forces Retirement Home (Parts 200—299)
Title 39—Postal Service
I United States Postal Service (Parts 1—999)

III Postal Regulatory Commission (Parts 3000—3099)
Title 40—Protection of Environment
I Environmental Protection Agency (Parts 1—1099)

IV Environmental Protection Agency and Department of Justice
(Parts 1400—1499)
V Council on Environmental Quality (Parts 1500—1599)
VI Chemical Safety and Hazard Investigation Board (Parts 1600—
1699)
VII Environmental Protection Agency and Department of Defense;
Uniform National Discharge Standards for Vessels of the
Armed Forces (Parts 1700—1799)
VIII Gulf Coast Ecosystem Restoration Council (Parts 1800—1899)
Title 41—Public Contracts and Property Management
SUBTITLE A—FEDERAL PROCUREMENT REGULATIONS SYSTEM

[NOTE]
SUBTITLE B—OTHER PROVISIONS RELATING TO PUBLIC CONTRACTS
50 Public Contracts, Department of Labor (Parts 50–1—50–999)
51 Committee for Purchase From People Who Are Blind or Severely
Disabled (Parts 51–1—51–99)
60 Office of Federal Contract Compliance Programs, Equal Employ-
ment Opportunity, Department of Labor (Parts 60–1—60–999)
61 Office of the Assistant Secretary for Veterans’ Employment and
Training Service, Department of Labor (Parts 61–1—61–999)
62—100 [Reserved]
SUBTITLE C—FEDERAL PROPERTY MANAGEMENT REGULATIONS
SYSTEM
101 Federal Property Management Regulations (Parts 101–1—101–99)
102 Federal Management Regulation (Parts 102–1—102–299)
103—104 [Reserved]
105 General Services Administration (Parts 105–1—105–999)
109 Department of Energy Property Management Regulations (Parts
109–1—109–99)
114 Department of the Interior (Parts 114–1—114–99)
115 Environmental Protection Agency (Parts 115–1—115–99)
128 Department of Justice (Parts 128–1—128–99)
129—200 [Reserved]
SUBTITLE D—OTHER PROVISIONS RELATING TO PROPERTY MANAGE-

MENT [RESERVED]
183
Title 41—Public Contracts and Property Management—Continued
Chap.
SUBTITLE E—FEDERAL INFORMATION RESOURCES MANAGEMENT

REGULATIONS SYSTEM [RESERVED]
SUBTITLE F—FEDERAL TRAVEL REGULATION SYSTEM
300 General (Parts 300–1—300–99)
301 Temporary Duty (TDY) Travel Allowances (Parts 301–1—301–99)
302 Relocation Allowances (Parts 302–1—302–99)
303 Payment of Expenses Connected with the Death of Certain Em-
ployees (Part 303–1—303–99)
304 Payment of Travel Expenses from a Non-Federal Source (Parts
304–1—304–99)
Title 42—Public Health
I Public Health Service, Department of Health and Human Serv-

ices (Parts 1—199)
IV Centers for Medicare & Medicaid Services, Department of Health
and Human Services (Parts 400—699)
V Office of Inspector General-Health Care, Department of Health
Title 43—Public Lands: Interior
SUBTITLE A—OFFICE OF THE SECRETARY OF THE INTERIOR (PARTS

1—199)
SUBTITLE B—REGULATIONS RELATING TO PUBLIC LANDS
I Bureau of Reclamation, Department of the Interior (Parts 400—
999)
II Bureau of Land Management, Department of the Interior (Parts
1000—9999)
III Utah Reclamation Mitigation and Conservation Commission
(Parts 10000—10099)
Title 44—Emergency Management and Assistance
I Federal Emergency Management Agency, Department of Home-

land Security (Parts 0—399)
IV Department of Commerce and Department of Transportation
(Parts 400—499)
Title 45—Public Welfare
SUBTITLE A—DEPARTMENT OF HEALTH AND HUMAN SERVICES

(PARTS 1—199)
SUBTITLE B—REGULATIONS RELATING TO PUBLIC WELFARE
II Office of Family Assistance (Assistance Programs), Administra-
tion for Children and Families, Department of Health and

Human Services (Parts 200—299)
184
Title 45—Public Welfare—Continued
Chap.
III Office of Child Support Enforcement (Child Support Enforce-

ment Program), Administration for Children and Families,
Department of Health and Human Services (Parts 300—399)
IV Office of Refugee Resettlement, Administration for Children and
Families, Department of Health and Human Services (Parts
400—499)
V Foreign Claims Settlement Commission of the United States,
Department of Justice (Parts 500—599)
VI National Science Foundation (Parts 600—699)
VII Commission on Civil Rights (Parts 700—799)
VIII Office of Personnel Management (Parts 800—899)
IX Denali Commission (Parts 900—999)
X Office of Community Services, Administration for Children and
Families, Department of Health and Human Services (Parts
1000—1099)
XI National Foundation on the Arts and the Humanities (Parts
1100—1199)
XII Corporation for National and Community Service (Parts 1200—
1299)
XIII Administration for Children and Families, Department of Health
XVI Legal Services Corporation (Parts 1600—1699)
XVII National Commission on Libraries and Information Science
(Parts 1700—1799)
XVIII Harry S. Truman Scholarship Foundation (Parts 1800—1899)
XXI Commission of Fine Arts (Parts 2100—2199)
XXIII Arctic Research Commission (Parts 2300—2399)
XXIV James Madison Memorial Fellowship Foundation (Parts 2400—
2499)
XXV Corporation for National and Community Service (Parts 2500—
2599)
Title 46—Shipping
I Coast Guard, Department of Homeland Security (Parts 1—199)

II Maritime Administration, Department of Transportation (Parts
200—399)
III Coast Guard (Great Lakes Pilotage), Department of Homeland
Security (Parts 400—499)
IV Federal Maritime Commission (Parts 500—599)
Title 47—Telecommunication
I Federal Communications Commission (Parts 0—199)

II Office of Science and Technology Policy and National Security
Council (Parts 200—299)
III National Telecommunications and Information Administration,

Department of Commerce (Parts 300—399)
185
Title 47—Telecommunication—Continued
Chap.
IV National Telecommunications and Information Administration,

Department of Commerce, and National Highway Traffic Safe-
ty Administration, Department of Transportation (Parts 400—
499)
V The First Responder Network Authority (Parts 500—599)
Title 48—Federal Acquisition Regulations System
1 Federal Acquisition Regulation (Parts 1—99)

2 Defense Acquisition Regulations System, Department of Defense
(Parts 200—299)
3 Department of Health and Human Services (Parts 300—399)
4 Department of Agriculture (Parts 400—499)
5 General Services Administration (Parts 500—599)
6 Department of State (Parts 600—699)
7 Agency for International Development (Parts 700—799)
8 Department of Veterans Affairs (Parts 800—899)
9 Department of Energy (Parts 900—999)
10 Department of the Treasury (Parts 1000—1099)
12 Department of Transportation (Parts 1200—1299)
13 Department of Commerce (Parts 1300—1399)
14 Department of the Interior (Parts 1400—1499)
15 Environmental Protection Agency (Parts 1500—1599)
16 Office of Personnel Management, Federal Employees Health
Benefits Acquisition Regulation (Parts 1600—1699)
17 Office of Personnel Management (Parts 1700—1799)
18 National Aeronautics and Space Administration (Parts 1800—
1899)
19 Broadcasting Board of Governors (Parts 1900—1999)
20 Nuclear Regulatory Commission (Parts 2000—2099)
21 Office of Personnel Management, Federal Employees Group Life
Insurance Federal Acquisition Regulation (Parts 2100—2199)
23 Social Security Administration (Parts 2300—2399)
24 Department of Housing and Urban Development (Parts 2400—
2499)
25 National Science Foundation (Parts 2500—2599)
28 Department of Justice (Parts 2800—2899)
29 Department of Labor (Parts 2900—2999)
30 Department of Homeland Security, Homeland Security Acquisi-
tion Regulation (HSAR) (Parts 3000—3099)
34 Department of Education Acquisition Regulation (Parts 3400—
3499)
51 Department of the Army Acquisition Regulations (Parts 5100—
5199) [Reserved]
52 Department of the Navy Acquisition Regulations (Parts 5200—
5299)
53 Department of the Air Force Federal Acquisition Regulation

Supplement (Parts 5300—5399) [Reserved]
186
Title 48—Federal Acquisition Regulations System—Continued
Chap.
54 Defense Logistics Agency, Department of Defense (Parts 5400—

5499)
57 African Development Foundation (Parts 5700—5799)
61 Civilian Board of Contract Appeals, General Services Adminis-
tration (Parts 6100—6199)
99 Cost Accounting Standards Board, Office of Federal Procure-
ment Policy, Office of Management and Budget (Parts 9900—
9999)
Title 49—Transportation
SUBTITLE A—OFFICE OF THE SECRETARY OF TRANSPORTATION

(PARTS 1—99)
SUBTITLE B—OTHER REGULATIONS RELATING TO TRANSPORTATION
I Pipeline and Hazardous Materials Safety Administration, De-
partment of Transportation (Parts 100—199)
II Federal Railroad Administration, Department of Transportation
(Parts 200—299)
III Federal Motor Carrier Safety Administration, Department of
IV Coast Guard, Department of Homeland Security (Parts 400—499)
V National Highway Traffic Safety Administration, Department of
VI Federal Transit Administration, Department of Transportation
(Parts 600—699)
VII National Railroad Passenger Corporation (AMTRAK) (Parts
700—799)
VIII National Transportation Safety Board (Parts 800—999)
X Surface Transportation Board (Parts 1000—1399)
XI Research and Innovative Technology Administration, Depart-
ment of Transportation (Parts 1400—1499) [Reserved]
XII Transportation Security Administration, Department of Home-
land Security (Parts 1500—1699)
Title 50—Wildlife and Fisheries
I United States Fish and Wildlife Service, Department of the Inte-

II National Marine Fisheries Service, National Oceanic and Atmos-
pheric Administration, Department of Commerce (Parts 200—
299)
III International Fishing and Related Activities (Parts 300—399)
IV Joint Regulations (United States Fish and Wildlife Service, De-
partment of the Interior and National Marine Fisheries Serv-
ice, National Oceanic and Atmospheric Administration, De-
partment of Commerce); Endangered Species Committee Reg-
ulations (Parts 400—499)

V Marine Mammal Commission (Parts 500—599)
187
Title 50—Wildlife and Fisheries—Continued
Chap.
VI Fishery Conservation and Management, National Oceanic and

Atmospheric Administration, Department of Commerce (Parts
600—699)
188
Alphabetical List of Agencies Appearing in the CFR
(Revised as of April 1, 2020)
CFR Title, Subtitle or

Agency Chapter
Administrative Conference of the United States 1, III
Advisory Council on Historic Preservation 36, VIII
Advocacy and Outreach, Office of 7, XXV
Afghanistan Reconstruction, Special Inspector General for 5, LXXXIII
African Development Foundation 22, XV
Federal Acquisition Regulation 48, 57
Agency for International Development 2, VII; 22, II
Agricultural Marketing Service 7, I, VIII, IX, X, XI; 9, II
Agricultural Research Service 7, V
Agriculture, Department of 2, IV; 5, LXXIII
Advocacy and Outreach, Office of 7, XXV
Agricultural Marketing Service 7, I, VIII, IX, X, XI; 9, II
Agricultural Research Service 7, V
Animal and Plant Health Inspection Service 7, III; 9, I
Chief Financial Officer, Office of 7, XXX
Commodity Credit Corporation 7, XIV
Economic Research Service 7, XXXVII
Energy Policy and New Uses, Office of 2, IX; 7, XXIX
Environmental Quality, Office of 7, XXXI
Farm Service Agency 7, VII, XVIII
Federal Crop Insurance Corporation 7, IV
Food and Nutrition Service 7, II
Food Safety and Inspection Service 9, III
Foreign Agricultural Service 7, XV
Forest Service 36, II
Information Resources Management, Office of 7, XXVII
Inspector General, Office of 7, XXVI
National Agricultural Library 7, XLI
National Agricultural Statistics Service 7, XXXVI
National Institute of Food and Agriculture 7, XXXIV
Natural Resources Conservation Service 7, VI
Operations, Office of 7, XXVIII
Procurement and Property Management, Office of 7, XXXII
Rural Business-Cooperative Service 7, XVIII, XLII
Rural Development Administration 7, XLII
Rural Housing Service 7, XVIII, XXXV
Rural Utilities Service 7, XVII, XVIII, XLII
Secretary of Agriculture, Office of 7, Subtitle A
Transportation, Office of 7, XXXIII
World Agricultural Outlook Board 7, XXXVIII
Air Force, Department of 32, VII
Federal Acquisition Regulation Supplement 48, 53
Air Transportation Stabilization Board 14, VI
Alcohol and Tobacco Tax and Trade Bureau 27, I
Alcohol, Tobacco, Firearms, and Explosives, Bureau of 27, II
AMTRAK 49, VII
American Battle Monuments Commission 36, IV
American Indians, Office of the Special Trustee 25, VII
Animal and Plant Health Inspection Service 7, III; 9, I

Appalachian Regional Commission 5, IX
Architectural and Transportation Barriers Compliance Board 36, XI
189
Agency Chapter
Arctic Research Commission 45, XXIII
Armed Forces Retirement Home 5, XI; 38, II
Army, Department of 32, V
Engineers, Corps of 33, II; 36, III
Bilingual Education and Minority Languages Affairs, Office of 34, V
Blind or Severely Disabled, Committee for Purchase from 41, 51
People Who Are
Broadcasting Board of Governors 22, V
Career, Technical, and Adult Education, Office of 34, IV
Census Bureau 15, I
Centers for Medicare & Medicaid Services 42, IV
Central Intelligence Agency 32, XIX
Chemical Safety and Hazard Investigation Board 40, VI
Chief Financial Officer, Office of 7, XXX
Child Support Enforcement, Office of 45, III
Children and Families, Administration for 45, II, III, IV, X, XIII
Civil Rights, Commission on 5, LXVIII; 45, VII
Civil Rights, Office for 34, I
Council of the Inspectors General on Integrity and Efficiency 5, XCVIII
Court Services and Offender Supervision Agency for the 5, LXX
District of Columbia
Coast Guard 33, I; 46, I; 49, IV
Coast Guard (Great Lakes Pilotage) 46, III
Commerce, Department of 2, XIII; 44, IV; 50, VI
Census Bureau 15, I
Economic Analysis, Bureau of 15, VIII
Economic Development Administration 13, III
Emergency Management and Assistance 44, IV
Foreign-Trade Zones Board 15, IV
Industry and Security, Bureau of 15, VII
International Trade Administration 15, III; 19, III
National Institute of Standards and Technology 15, II; 37, IV
National Marine Fisheries Service 50, II, IV
National Oceanic and Atmospheric Administration 15, IX; 50, II, III, IV, VI
National Technical Information Service 15, XI
National Telecommunications and Information 15, XXIII; 47, III, IV
Administration
National Weather Service 15, IX
Patent and Trademark Office, United States 37, I
Secretary of Commerce, Office of 15, Subtitle A
Commercial Space Transportation 14, III
Commodity Credit Corporation 7, XIV
Commodity Futures Trading Commission 5, XLI; 17, I
Community Planning and Development, Office of Assistant 24, V, VI
Secretary for
Community Services, Office of 45, X
Comptroller of the Currency 12, I
Construction Industry Collective Bargaining Commission 29, IX
Consumer Financial Protection Bureau 5, LXXXIV; 12, X
Consumer Product Safety Commission 5, LXXI; 16, II
Copyright Royalty Board 37, III
Corporation for National and Community Service 2, XXII; 45, XII, XXV
Cost Accounting Standards Board 48, 99
Council on Environmental Quality 40, V
Court Services and Offender Supervision Agency for the 5, LXX; 28, VIII
District of Columbia
Customs and Border Protection 19, I
Defense Contract Audit Agency 32, I
Defense, Department of 2, XI; 5, XXVI; 32,
Subtitle A; 40, VII
Advanced Research Projects Agency 32, I
Air Force Department 32, VII

Army Department 32, V; 33, II; 36, III; 48,
51
190
Agency Chapter
Defense Acquisition Regulations System 48, 2
Defense Intelligence Agency 32, I
Defense Logistics Agency 32, I, XII; 48, 54
National Imagery and Mapping Agency 32, I
Navy, Department of 32, VI; 48, 52
Secretary of Defense, Office of 2, XI; 32, I
Defense Contract Audit Agency 32, I
Defense Intelligence Agency 32, I
Defense Logistics Agency 32, XII; 48, 54
Defense Nuclear Facilities Safety Board 10, XVII
Delaware River Basin Commission 18, III
Denali Commission 45, IX
Disability, National Council on 5, C; 34, XII
District of Columbia, Court Services and Offender Supervision 5, LXX; 28, VIII
Agency for the
Drug Enforcement Administration 21, II
East-West Foreign Trade Board 15, XIII
Economic Analysis, Bureau of 15, VIII
Economic Development Administration 13, III
Economic Research Service 7, XXXVII
Education, Department of 2, XXXIV; 5, LIII
Bilingual Education and Minority Languages Affairs, Office 34, V
of
Career, Technical, and Adult Education, Office of 34, IV
Civil Rights, Office for 34, I
Educational Research and Improvement, Office of 34, VII
Elementary and Secondary Education, Office of 34, II
Postsecondary Education, Office of 34, VI
Secretary of Education, Office of 34, Subtitle A
Special Education and Rehabilitative Services, Office of 34, III
Educational Research and Improvement, Office of 34, VII
Election Assistance Commission 2, LVIII; 11, II
Elementary and Secondary Education, Office of 34, II
Emergency Oil and Gas Guaranteed Loan Board 13, V
Emergency Steel Guarantee Loan Board 13, IV
Employee Benefits Security Administration 29, XXV
Employees’ Compensation Appeals Board 20, IV
Employees Loyalty Board 5, V
Employment and Training Administration 20, V
Employment Policy, National Commission for 1, IV
Employment Standards Administration 20, VI
Endangered Species Committee 50, IV
Energy, Department of 2, IX; 5, XXIII; 10, II,
III, X
Federal Energy Regulatory Commission 5, XXIV; 18, I
Property Management Regulations 41, 109
Energy, Office of 7, XXIX
Engraving and Printing, Bureau of 31, VI
Environmental Protection Agency 2, XV; 5, LIV; 40, I, IV,
VII
Environmental Quality, Office of 7, XXXI
Equal Employment Opportunity Commission 5, LXII; 29, XIV
Equal Opportunity, Office of Assistant Secretary for 24, I
Executive Office of the President 3, I
Environmental Quality, Council on 40, V
Management and Budget, Office of 2, Subtitle A; 5, III,
LXXVII; 14, VI; 48, 99
National Drug Control Policy, Office of 2, XXXVI; 21, III
National Security Council 32, XXI; 47, II

Presidential Documents 3
Science and Technology Policy, Office of 32, XXIV; 47, II
191
Agency Chapter
Trade Representative, Office of the United States 15, XX
Export-Import Bank of the United States 2, XXXV; 5, LII; 12, IV
Family Assistance, Office of 45, II
Farm Credit Administration 5, XXXI; 12, VI
Farm Credit System Insurance Corporation 5, XXX; 12, XIV
Farm Service Agency 7, VII, XVIII
Federal Aviation Administration 14, I
Federal Claims Collection Standards 31, IX
Federal Communications Commission 5, XXIX; 47, I
Federal Contract Compliance Programs, Office of 41, 60
Federal Crop Insurance Corporation 7, IV
Federal Deposit Insurance Corporation 5, XXII; 12, III
Federal Election Commission 5, XXXVII; 11, I
Federal Emergency Management Agency 44, I
Federal Employees Group Life Insurance Federal Acquisition 48, 21
Regulation
Federal Employees Health Benefits Acquisition Regulation 48, 16
Federal Energy Regulatory Commission 5, XXIV; 18, I
Federal Financial Institutions Examination Council 12, XI
Federal Financing Bank 12, VIII
Federal Highway Administration 23, I, II
Federal Home Loan Mortgage Corporation 1, IV
Federal Housing Enterprise Oversight Office 12, XVII
Federal Housing Finance Agency 5, LXXX; 12, XII
Federal Housing Finance Board 12, IX
Federal Labor Relations Authority 5, XIV, XLIX; 22, XIV
Federal Law Enforcement Training Center 31, VII
Federal Management Regulation 41, 102
Federal Maritime Commission 46, IV
Federal Mediation and Conciliation Service 29, XII
Federal Mine Safety and Health Review Commission 5, LXXIV; 29, XXVII
Federal Motor Carrier Safety Administration 49, III
Federal Prison Industries, Inc. 28, III
Federal Procurement Policy Office 48, 99
Federal Property Management Regulations 41, 101
Federal Railroad Administration 49, II
Federal Register, Administrative Committee of 1, I
Federal Register, Office of 1, II
Federal Reserve System 12, II
Board of Governors 5, LVIII
Federal Retirement Thrift Investment Board 5, VI, LXXVI
Federal Service Impasses Panel 5, XIV
Federal Trade Commission 5, XLVII; 16, I
Federal Transit Administration 49, VI
Federal Travel Regulation System 41, Subtitle F
Financial Crimes Enforcement Network 31, X
Financial Research Office 12, XVI
Financial Stability Oversight Council 12, XIII
Fine Arts, Commission of 45, XXI
Fiscal Service 31, II
Fish and Wildlife Service, United States 50, I, IV
Food and Drug Administration 21, I
Food and Nutrition Service 7, II
Food Safety and Inspection Service 9, III
Foreign Agricultural Service 7, XV
Foreign Assets Control, Office of 31, V
Foreign Claims Settlement Commission of the United States 45, V
Foreign Service Grievance Board 22, IX
Foreign Service Impasse Disputes Panel 22, XIV
Foreign Service Labor Relations Board 22, XIV
Foreign-Trade Zones Board 15, IV
Forest Service 36, II
General Services Administration 5, LVII; 41, 105

Contract Appeals, Board of 48, 61
192
Agency Chapter
Federal Management Regulation 41, 102
Federal Property Management Regulations 41, 101
Federal Travel Regulation System 41, Subtitle F
General 41, 300
Payment From a Non-Federal Source for Travel Expenses 41, 304
Payment of Expenses Connected With the Death of Certain 41, 303
Employees
Relocation Allowances 41, 302
Temporary Duty (TDY) Travel Allowances 41, 301
Geological Survey 30, IV
Government Accountability Office 4, I
Government Ethics, Office of 5, XVI
Government National Mortgage Association 24, III
Grain Inspection, Packers and Stockyards Administration 7, VIII; 9, II
Gulf Coast Ecosystem Restoration Council 2, LIX; 40, VIII
Harry S. Truman Scholarship Foundation 45, XVIII
Health and Human Services, Department of 2, III; 5, XLV; 45,
Subtitle A
Centers for Medicare & Medicaid Services 42, IV
Child Support Enforcement, Office of 45, III
Children and Families, Administration for 45, II, III, IV, X, XIII
Community Services, Office of 45, X
Family Assistance, Office of 45, II
Food and Drug Administration 21, I
Indian Health Service 25, V
Inspector General (Health Care), Office of 42, V
Public Health Service 42, I
Refugee Resettlement, Office of 45, IV
Homeland Security, Department of 2, XXX; 5, XXXVI; 6, I;
8, I
Coast Guard 33, I; 46, I; 49, IV
Coast Guard (Great Lakes Pilotage) 46, III
Federal Emergency Management Agency 44, I
Human Resources Management and Labor Relations 5, XCVII
Systems
Immigration and Customs Enforcement Bureau 19, IV
Transportation Security Administration 49, XII
HOPE for Homeowners Program, Board of Directors of 24, XXIV
Housing and Urban Development, Department of 2, XXIV; 5, LXV; 24,
Subtitle B
Community Planning and Development, Office of Assistant 24, V, VI
Secretary for
Equal Opportunity, Office of Assistant Secretary for 24, I
Federal Housing Enterprise Oversight, Office of 12, XVII
Government National Mortgage Association 24, III
Housing—Federal Housing Commissioner, Office of 24, II, VIII, X, XX
Assistant Secretary for
Housing, Office of, and Multifamily Housing Assistance 24, IV
Restructuring, Office of
Inspector General, Office of 24, XII
Public and Indian Housing, Office of Assistant Secretary for 24, IX
Secretary, Office of 24, Subtitle A, VII
Housing—Federal Housing Commissioner, Office of Assistant 24, II, VIII, X, XX
Secretary for
Housing, Office of, and Multifamily Housing Assistance 24, IV
Restructuring, Office of
Immigration and Customs Enforcement Bureau 19, IV
Immigration Review, Executive Office for 8, V
Independent Counsel, Office of 28, VII
Independent Counsel, Offices of 28, VI
Indian Affairs, Bureau of 25, I, V
Indian Affairs, Office of the Assistant Secretary 25, VI

Indian Arts and Crafts Board 25, II
Indian Health Service 25, V
193
Agency Chapter
Industry and Security, Bureau of 15, VII
Information Resources Management, Office of 7, XXVII
Information Security Oversight Office, National Archives and 32, XX
Records Administration
Inspector General
Agriculture Department 7, XXVI
Health and Human Services Department 42, V
Housing and Urban Development Department 24, XII, XV
Institute of Peace, United States 22, XVII
Inter-American Foundation 5, LXIII; 22, X
Interior, Department of 2, XIV
American Indians, Office of the Special Trustee 25, VII
Endangered Species Committee 50, IV
Federal Property Management Regulations System 41, 114
Fish and Wildlife Service, United States 50, I, IV
Geological Survey 30, IV
Indian Affairs, Bureau of 25, I, V
Indian Affairs, Office of the Assistant Secretary 25, VI
Indian Arts and Crafts Board 25, II
Land Management, Bureau of 43, II
National Indian Gaming Commission 25, III
National Park Service 36, I
Natural Resource Revenue, Office of 30, XII
Ocean Energy Management, Bureau of 30, V
Reclamation, Bureau of 43, I
Safety and Enforcement Bureau, Bureau of 30, II
Secretary of the Interior, Office of 2, XIV; 43, Subtitle A
Surface Mining Reclamation and Enforcement, Office of 30, VII
Internal Revenue Service 26, I
International Boundary and Water Commission, United States 22, XI
and Mexico, United States Section
International Development, United States Agency for 22, II
International Development Cooperation Agency, United 22, XII
States
International Development Finance Corporation, U.S. 5, XXXIII; 22, VII
International Joint Commission, United States and Canada 22, IV
International Organizations Employees Loyalty Board 5, V
International Trade Administration 15, III; 19, III
International Trade Commission, United States 19, II
Interstate Commerce Commission 5, XL
Investment Security, Office of 31, VIII
James Madison Memorial Fellowship Foundation 45, XXIV
Japan–United States Friendship Commission 22, XVI
Joint Board for the Enrollment of Actuaries 20, VIII
Justice, Department of 2, XXVIII; 5, XXVIII;
28, I, XI; 40, IV
Alcohol, Tobacco, Firearms, and Explosives, Bureau of 27, II
Drug Enforcement Administration 21, II
Federal Prison Industries, Inc. 28, III
Foreign Claims Settlement Commission of the United 45, V
States
Immigration Review, Executive Office for 8, V
Independent Counsel, Offices of 28, VI
Prisons, Bureau of 28, V
Labor, Department of 2, XXIX; 5, XLII
Employee Benefits Security Administration 29, XXV
Employees’ Compensation Appeals Board 20, IV
Employment and Training Administration 20, V
Employment Standards Administration 20, VI

Federal Contract Compliance Programs, Office of 41, 60
Federal Procurement Regulations System 41, 50
194
Agency Chapter
Labor-Management Standards, Office of 29, II, IV
Mine Safety and Health Administration 30, I
Occupational Safety and Health Administration 29, XVII
Public Contracts 41, 50
Secretary of Labor, Office of 29, Subtitle A
Veterans’ Employment and Training Service, Office of the 41, 61; 20, IX
Wage and Hour Division 29, V
Workers’ Compensation Programs, Office of 20, I, VII
Labor-Management Standards, Office of 29, II, IV
Land Management, Bureau of 43, II
Legal Services Corporation 45, XVI
Libraries and Information Science, National Commission on 45, XVII
Library of Congress 36, VII
Copyright Royalty Board 37, III
U.S. Copyright Office 37, II
Management and Budget, Office of 5, III, LXXVII; 14, VI;
48, 99
Marine Mammal Commission 50, V
Maritime Administration 46, II
Merit Systems Protection Board 5, II, LXIV
Micronesian Status Negotiations, Office for 32, XXVII
Military Compensation and Retirement Modernization 5, XCIX
Commission
Millennium Challenge Corporation 22, XIII
Mine Safety and Health Administration 30, I
Minority Business Development Agency 15, XIV
Miscellaneous Agencies 1, IV
Monetary Offices 31, I
Morris K. Udall Scholarship and Excellence in National 36, XVI
Environmental Policy Foundation
Museum and Library Services, Institute of 2, XXXI
National Aeronautics and Space Administration 2, XVIII; 5, LIX; 14, V
National Agricultural Library 7, XLI
National Agricultural Statistics Service 7, XXXVI
National and Community Service, Corporation for 2, XXII; 45, XII, XXV
National Archives and Records Administration 2, XXVI; 5, LXVI; 36,
XII
Information Security Oversight Office 32, XX
National Capital Planning Commission 1, IV, VI
National Counterintelligence Center 32, XVIII
National Credit Union Administration 5, LXXXVI; 12, VII
National Crime Prevention and Privacy Compact Council 28, IX
National Drug Control Policy, Office of 2, XXXVI; 21, III
National Endowment for the Arts 2, XXXII
National Endowment for the Humanities 2, XXXIII
National Foundation on the Arts and the Humanities 45, XI
National Geospatial-Intelligence Agency 32, I
National Highway Traffic Safety Administration 23, II, III; 47, VI; 49, V
National Imagery and Mapping Agency 32, I
National Indian Gaming Commission 25, III
National Institute of Food and Agriculture 7, XXXIV
National Institute of Standards and Technology 15, II; 37, IV
National Intelligence, Office of Director of 5, IV; 32, XVII
National Labor Relations Board 5, LXI; 29, I
National Marine Fisheries Service 50, II, IV
National Mediation Board 5, CI; 29, X
National Oceanic and Atmospheric Administration 15, IX; 50, II, III, IV, VI
National Park Service 36, I
National Railroad Adjustment Board 29, III
National Railroad Passenger Corporation (AMTRAK) 49, VII
National Science Foundation 2, XXV; 5, XLIII; 45, VI
National Security Council 32, XXI

National Security Council and Office of Science and 47, II
Technology Policy
195
Agency Chapter
National Technical Information Service 15, XI
National Telecommunications and Information 15, XXIII; 47, III, IV, V
Administration
National Transportation Safety Board 49, VIII
Natural Resources Conservation Service 7, VI
Natural Resource Revenue, Office of 30, XII
Navajo and Hopi Indian Relocation, Office of 25, IV
Navy, Department of 32, VI
Neighborhood Reinvestment Corporation 24, XXV
Northeast Interstate Low-Level Radioactive Waste 10, XVIII
Commission
Nuclear Regulatory Commission 2, XX; 5, XLVIII; 10, I
Occupational Safety and Health Administration 29, XVII
Occupational Safety and Health Review Commission 29, XX
Ocean Energy Management, Bureau of 30, V
Oklahoma City National Memorial Trust 36, XV
Operations Office 7, XXVIII
Patent and Trademark Office, United States 37, I
Payment From a Non-Federal Source for Travel Expenses 41, 304
Payment of Expenses Connected With the Death of Certain 41, 303
Employees
Peace Corps 2, XXXVII; 22, III
Pennsylvania Avenue Development Corporation 36, IX
Pension Benefit Guaranty Corporation 29, XL
Personnel Management, Office of 5, I, IV, XXXV; 45, VIII
Human Resources Management and Labor Relations 5, XCVII
Systems, Department of Homeland Security
Federal Employees Group Life Insurance Federal 48, 21
Acquisition Regulation
Federal Employees Health Benefits Acquisition Regulation 48, 16
Pipeline and Hazardous Materials Safety Administration 49, I
Postal Regulatory Commission 5, XLVI; 39, III
Postal Service, United States 5, LX; 39, I
Postsecondary Education, Office of 34, VI
President’s Commission on White House Fellowships 1, IV
Presidential Documents 3
Presidio Trust 36, X
Prisons, Bureau of 28, V
Privacy and Civil Liberties Oversight Board 6, X
Procurement and Property Management, Office of 7, XXXII
Public Contracts, Department of Labor 41, 50
Public and Indian Housing, Office of Assistant Secretary for 24, IX
Public Health Service 42, I
Railroad Retirement Board 20, II
Reclamation, Bureau of 43, I
Refugee Resettlement, Office of 45, IV
Relocation Allowances 41, 302
Research and Innovative Technology Administration 49, XI
Rural Business-Cooperative Service 7, XVIII, XLII
Rural Development Administration 7, XLII
Rural Housing Service 7, XVIII, XXXV
Rural Utilities Service 7, XVII, XVIII, XLII
Safety and Environmental Enforcement, Bureau of 30, II
Saint Lawrence Seaway Development Corporation 33, IV
Science and Technology Policy, Office of 32, XXIV
Science and Technology Policy, Office of, and National 47, II
Security Council
Secret Service 31, IV
Securities and Exchange Commission 5, XXXIV; 17, II
Selective Service System 32, XVI
Small Business Administration 2, XXVII; 13, I
Smithsonian Institution 36, V

Social Security Administration 2, XXIII; 20, III; 48, 23
Soldiers’ and Airmen’s Home, United States 5, XI
196
Agency Chapter
Special Counsel, Office of 5, VIII
Special Education and Rehabilitative Services, Office of 34, III
State, Department of 2, VI; 22, I; 28, XI
Surface Mining Reclamation and Enforcement, Office of 30, VII
Surface Transportation Board 49, X
Susquehanna River Basin Commission 18, VIII
Tennessee Valley Authority 5, LXIX; 18, XIII
Trade Representative, United States, Office of 15, XX
Transportation, Department of 2, XII; 5, L
Emergency Management and Assistance 44, IV
Federal Aviation Administration 14, I
Federal Highway Administration 23, I, II
Federal Motor Carrier Safety Administration 49, III
Federal Railroad Administration 49, II
Federal Transit Administration 49, VI
Maritime Administration 46, II
National Highway Traffic Safety Administration 23, II, III; 47, IV; 49, V
Pipeline and Hazardous Materials Safety Administration 49, I
Saint Lawrence Seaway Development Corporation 33, IV
Secretary of Transportation, Office of 14, II; 49, Subtitle A
Transportation Statistics Bureau 49, XI
Transportation, Office of 7, XXXIII
Transportation Security Administration 49, XII
Transportation Statistics Bureau 49, XI
Travel Allowances, Temporary Duty (TDY) 41, 301
Treasury, Department of the 2, X; 5, XXI; 12, XV; 17,
IV; 31, IX
Alcohol and Tobacco Tax and Trade Bureau 27, I
Community Development Financial Institutions Fund 12, XVIII
Comptroller of the Currency 12, I
Engraving and Printing, Bureau of 31, VI
Federal Law Enforcement Training Center 31, VII
Financial Crimes Enforcement Network 31, X
Fiscal Service 31, II
Foreign Assets Control, Office of 31, V
Internal Revenue Service 26, I
Investment Security, Office of 31, VIII
Monetary Offices 31, I
Secret Service 31, IV
Secretary of the Treasury, Office of 31, Subtitle A
Truman, Harry S. Scholarship Foundation 45, XVIII
United States and Canada, International Joint Commission 22, IV
United States and Mexico, International Boundary and Water 22, XI
Commission, United States Section
U.S. Copyright Office 37, II
Utah Reclamation Mitigation and Conservation Commission 43, III
Veterans Affairs, Department of 2, VIII; 38, I
Veterans’ Employment and Training Service, Office of the 41, 61; 20, IX
Vice President of the United States, Office of 32, XXVIII
Wage and Hour Division 29, V
Water Resources Council 18, VI
Workers’ Compensation Programs, Office of 20, I, VII

World Agricultural Outlook Board 7, XXXVIII
197
All changes in this volume of the Code of Federal Regulations (CFR)
that were made by documents published in the FEDERAL REGISTER since
January 1, 2015 are enumerated in the following list. Entries indicate the
nature of the changes effected. Page numbers refer to FEDERAL REGISTER
pages. The user should consult the entries for chapters, parts and sub-
parts as well as sections for revisions.
For changes to this volume of the CFR prior to this listing, consult
the annual edition of the monthly List of CFR Sections Affected (LSA).
The LSA is available at www.govinfo.gov. For changes to this volume of
the CFR prior to 2001, see the ‘‘List of CFR Sections Affected, 1949–1963,
1964–1972, 1973–1985, and 1986–2000’’ published in 11 separate volumes. The
‘‘List of CFR Sections Affected 1986–2000’’ is available at
www.govinfo.gov.
2015 21 CFR—Continued 80 FR
Page
21 CFR 80 FR Chapter I—Continued
Page
(b)(19) introductory text amend-
Chapter I ed..............................................80651
600 Regulation at 79 FR 33090 eff. 606.110 (a) and (b) amended ............ 29895
date delayed ............................. 30151 606.121 (c)(11), (12), (h)(2), (3) and
Authority citation revised ...........38939 (i)(5) amended........................... 29895
600.2 (a), (c)(1) and (2) amended ...... 18091 606.122 (e) amended ....................... 29895
Regulation at 79 FR 33090 eff. 606.145 Added ................................ 29895
date delayed..............................30151 606.160 (b)(1)(ix), (x), (xi) and (e)
600.11 (f)(6) amended ..................... 18092 revised ..................................... 29895
600.14 (e)(1) revised ....................... 18092
(b)(1)(viii) amended......................80651
600.22 (e) amended......................... 18092
606.170 (b) amended ....................... 18092
600.80 Regulation at 79 FR 33090
601.171 (e) revised .......................... 18092
eff. date delayed........................ 30151
600.81 Regulation at 79 FR 33091 607.7 (b) and (c) amended ............... 18092
eff. date delayed........................ 30151 607.22 (a) amended......................... 18092
600.82 Added ................................. 38939 607.37 Revised ............................... 18092
600.90 Regulation at 79 FR 33092 610.2 (a) and (b) amended ............... 18093
eff. date delayed........................ 30151 610.11 (g)(2) amended..................... 18093
601.2 (a) amended .......................... 18092 Removed......................................37974
(c)(1) amended..............................37974 610.11a Removed ........................... 37974
601.12 (f)(4) amended ..................... 18092 610.15 (a)(3) amended..................... 18093
601.15 Amended............................. 18092 610.39—610.48 (Subpart E) Head-
601.22 Amended............................. 37974 ing revised ................................ 29896
601.28 Introductory text amend- 610.39 Added ................................. 29896
ed ............................................. 18092 610.40 (a), (b), (c) heading, (e) re-
601.29 (b) amended......................... 18092 vised; (c)(2) and (i) removed;
601.70 (d) amended......................... 18092 (c)(3) and (4) redesignated as
606.3 (a) and (c) revised .................. 29894 new (c)(2) and (3); new (c)(2)(i),
606.40 (a)(1) amended..................... 29895 (d), (f), (g) introductory text,
606.100 (b) introductory text and (h)(1), (2)(ii) introductory text,
(20) revised; (b)(1) amended; (C), (iv) introductory text, (A),

(b)(21) and (22) added ................. 29895 (vi) and (vii) amended................ 29896
199
21 CFR (4–1–20 Edition)
21 CFR—Continued 80 FR 21 CFR—Continued 80 FR
Page Page
Chapter I—Continued Chapter I—Continued
610.41 (a) introductory text, (2) 660.22 (b) amended......................... 18093
through (5) and (b) amended; 660.31 Revised ............................... 29906
(a)(1) revised ............................. 29897 660.36 (a) introductory text, (b)
610.42 (a) amended......................... 29897 and (c) amended ........................ 18093
610.44 (a)(1) and (2) amended .......... 29897 660.46 (a)(2) introductory text
610.46 (a)(2), (3), (4), (b)(2) and (3) amended................................... 18093
amended................................... 29897 660.52 Amended............................. 18093
610.47 (a)(2), (3), (4), (b)(2) and (3) 680.1 (b)(2)(iii), (3)(iv) and (c)
amended................................... 29897 amended................................... 18093
610.48 Removed............................. 80651 680.3 (b) removed........................... 37974
630 Heading revised....................... 29898
630.1—630.3 (Subpart A) Added ...... 29898 2016
630.5—630.35 (Subpart B) Added ..... 29898
630.6 Redesignated as 630.40........... 29898 21 CFR 81 FR
Page
630.40 (Subpart C) Subpart and
Chapter I
heading added........................... 29898
630.40 Redesignated from 630.6; 601 Technical correction............... 89848
heading revised; (a), (b) intro- 601.2 (f) added................................ 60221
601.25 Removed .............................. 7446
ductory text, (1), (3), (c), (d)(1)
601.26 Removed .............................. 7446
introductory text, (i) and (iii)
607 Heading revised....................... 60221
amended................................... 29898
Technical correction ...................89848
640.3 Removed .............................. 29904
607.1 Added ................................... 60221
640.4 (a) removed; (e) amended ...... 29904 607.3 (b) amended; (k) and (l)
640.5 Introductory text and (f) added........................................ 60222
amended; (a) removed ............... 29904 607.7 Revised ................................ 60222
640.12 Revised ............................... 29904 607.20 (c) amended......................... 60222
640.14 Amended............................. 29904 607.21 Amended............................. 60222
640.21 Revised ............................... 29904 607.22 Revised ............................... 60222
640.22 (c) revised ........................... 29904 607.25 Revised ............................... 60222
640.23 (a) amended......................... 29904 607.26 Amended............................. 60222
640.27 Removed............................. 29904 607.30 (a) introductory text re-
640.31 Revised ............................... 29904 vised......................................... 60222
640.32 (b) amended......................... 29905 607.35 Revised ............................... 60223
640.33 (a) amended......................... 29905 607.37 Revised ............................... 60223
640.51 Revised ............................... 29905 607.39 Revised ............................... 60223
640.52 (b) amended......................... 29905 607.40 (d) introductory text and
640.53 (a) amended......................... 29905 (3) revised; (e) added .................. 60223
640.61 Removed............................. 29905 607.65 (g) added ............................. 60223
640.62 Removed............................. 29905 607.80 (Subpart E) Added ............... 60223
640.63 Removed............................. 29905 610.20—610.21 (Subpart C) Re-
640.64 (a) removed ......................... 29905 moved ...................................... 26691
640.65 (b)(1)(i), (ii), (2)(iii) and (iv) Regulation at 81 FR 26691 eff.
amended; (b)(2)(i) revised .......... 29905 date confirmed..........................52329
640.66 Amended............................. 29905 610.50 Revised ............................... 26691
640.67 Amended............................. 29905 Regulation at 81 FR 26691 eff.
640.69 (e) and (f) added ................... 29905 date confirmed..........................52329
640.71 (a) introductory text and 610.53 Revised ............................... 26691
(b)(1) amended; (a)(1) through Regulation at 81 FR 26691 eff.
(4) removed ............................... 29905 date confirmed..........................52329
640.72 (a)(2), (3) and (4) revised ....... 29905 660.2 (c) revised ............................. 38924
640.120 Revised ............................. 29906 660.20 (a) revised ........................... 38925
640.125—640.130 (Subpart M) 660.28 Revised ............................... 38925
Added ....................................... 29906 660.35 Revised ............................... 38926
660.3 Amended .............................. 18093 660.45 Revised ............................... 38928
660.6 (a)(2) and (c) heading amend- 660.50 (a) revised ........................... 38928
ed ............................................. 18093 660.55 Revised ............................... 38928
200
21 CFR—Continued 81 FR 2019
Page
Chapter I—Continued 21 CFR 84 FR
700.27 (a)(6) amended ...................... 5596 Page
Regulations at 69 FR 42274, 70 FR Chapter I
53068 and 73 FR 20794 confirmed; 600 Authority citation revised ...... 12508
eff. 4-18-16..................................14731 600.21 Amended............................. 12508
(a) revised; eff. 4-18-16 ...................14732
600.22 Removed............................. 12508
701 Nomenclature change ............. 49897
710 Nomenclature change ............. 49897
720 Nomenclature change ............. 49897 2020
(Regulations published from January 1,
2018 2020, through April 1, 2020)
21 CFR 83 FR
21 CFR 85 FR
Page
Page
Chapter I
600.21 Amended; eff. 6-11-18 ............. 3589 Chapter I
Regulation at 83 FR 3589 with- 600.3 (h) introductory text re-
drawn .......................................19936 vised; (h)(6) added ..................... 10063
600.22 Removed; eff. 6-11-18 ............. 3589
Regulation at 83 FR 3589 with-
drawn .......................................19936
Æ
201

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Title 21

Food and Drugs

Revised as of April 1, 2020

Containing a codification of documents

Published by the Office of the Federal Register

Legal Status and Use of Seals and Logos

Use of ISBN Prefix

U.S. GOVERNMENT PUBLISHING OFFICE

U.S. Superintendent of Documents • Washington, DC 20402–0001

Phone: toll-free (866) 512-1800; DC area (202) 512-1800

Chapter I—Food and Drug Administration, Department of Health

Table of CFR Titles and Chapters ....................................................... 169

Alphabetical List of Agencies Appearing in the CFR ......................... 189

List of CFR Sections Affected ............................................................. 199

To cite the regulations in

lishing in the CFR are also included in this volume.

CHAPTER I—Food and Drug Administration, Department of

700 General .................................................................... 137

PART 600—BIOLOGICAL tion, Center for Biologics Evaluation

680 of this chapter, as applicable, must protocols, required under §§ 600.13,

(iii) To a toxin or antitoxin, if in- safety, purity, and potency of such

2008; 77 FR 26174, May 3, 2012; 85 FR 10063,

Subpart B—Establishment oratory clothing before entering a live

apparatus and accessory equipment, in- Spore-forming organisms used as an

(2) Spore-forming organisms for supple- microorganism(s) must be conducted in

operations and in the manufacturing or decontaminate live vaccine orga-

cedures must be in place for vent cross-infection from any infected

premises. Monkeys to be used in the microbiological agents shall not be

without such prescribed labeling pro- records of a specific manufacturing

a manufacturing, holding, or distribu- (3) If you make a paper filing, you

Cryoprecipitated AHF ....................................................... ¥18 °C or colder.

Yellow Fever Vaccine ....................................................... 0 °C or colder.

(b) Exemptions. Exemptions or modi- logical product in professional prac-

for each adverse experience not re- rative);

ed. Requests by an applicant to submit radiopharmaceutical biological prod-

manufacturing of the biological prod- cant fails to submit a notification as

section and in accordance with para- Significant disruption means a change

601.5 Revocation of license.

Subpart C—Biologics Licensing Subpart H—Approval of Biological Prod-

noncompliance; statements regarding

human subjects contained in the appli- peptide product of 40 or fewer amino

censure which is a therapeutic DNA no longer in commercial distribution.

biological product is requested but not withdraw the application or supple-

FR 15676, Mar. 22, 1977; 42 FR 19142, Apr. 12,

§ 601.5 Revocation of license. compliance is not demonstrated or

before proceedings will be instituted through 601.6 shall be governed by part

section, an applicant must inform the the qualitative or quantitative formu-

or in the specifications provided in the change. (1) A supplement shall be sub-

§ 601.20 Biologics licenses; issuance A biological product undergoing de-

[65 FR 59718, Oct. 6, 2000, as amended at 65 FR

§ 601.29 Guidance documents. § 601.32 General factors relevant to

cle as defined in paragraph (a) of this ment of function(s) or physiological,

(3) The claim of disease or pathology (1) Allergic or hypersensitivity re-

§ 601.40 Scope. (b) The limitations imposed will be

(d) Separation of functions. Separation motional labeling as well as advertise-

preapproval review period copies of all individual on whom an investigational

(8) Current status of the postmarketing close any information concerning a

§ 601.91 Approval based on evidence of proach to postmarketing study com-