PHARMACIA UPJOHN FACILITY

RECEIVES SECOND FDA FORM 483

IN ALMOST FIVE YEARS
IS A WARNING LETTER FORTHCOMING?
A Pharmacia Upjohn subsidiary of Pfizer (Kalamazoo, MI) received a FDA Form 483
following an inspection from June 23 through July 9, 2015. This eight Observation 483
covered both non-sterile and aseptic issues. This audit used the Agency’s recently
introduced team-based inspection approach and included Thomas Cosgrove, CDER’s
Manufacturing Quality Director.
Of particular note were the following microbiologically related issues.
PRODUCTION SYSTEM
OBSERVATION #6
Procedures designed to prevent microbiological contamination of drug products
purporting to be sterile are not written and followed.
Specifically,
The rationale for the selection of representative processes for demonstration during
media fill simulations within SOP 10554, Media Fill Program, does not include an
assessment of the risks associated with various filling line speeds to capture worst case
scenarios for aseptic processing lines(b)(4). In addition, filling line speed during media
fills are not specified or recorded for evaluation at the time of fill. For example:
Media Fill lot W417J was filled on line (b)(4) simulating (b)(4) mL (b)(4) vials. The line
speed limits in the batch record are (b)(4) containers per minute (cpm) with no specified
setting stated or recorded.  Data pulled from the automated line historian indicates the
line was running at approximately (b)(4) (cpm) for most of the batch.  Media Fill lot
W411JF was filled on line (b)(4) simulating (b)(4) mL (b)(4) vials. The line speeds limits
in the batch record are (b)(4) cpm with no specified setting stated or recorded.  Line
speed data for this lot was not available from the historian.
COMMENT:
21 CFR 211.113(b) states that procedures designed to prevent microbiological
contamination of drug products purporting to be sterile are written and followed. When
media fills are performed, one of the criteria that must be included is the line speed. 
Line speeds are important since the speed of the line impacts the time the vial is being
filled and remains open prior to having the stopper seated. Please also view two Ben
Venue Form FDA  483s which were issued for not considering line fill time nor size of
lot following the development of a media fill volume.  
1. The program for managing aseptic processing personnel participation in media
fills does not ensure that a person’s participation is representative of their routine
responsibilities.  For example, a “technician” is responsible for the majority of
critical filling line setup tasks and typically performs the majority of the major
interventions required during routine processing.  However, technicians (b)(4)did
not participate in setup activities or perform major interventions in any media fills
since (b)(4). For example, (b)(4) media fill participation history consisted primarily
of manipulating vials with forceps.
COMMENT: 
CDER has periodically cited firms for their media fill management and, in particular,
their performance of setup tasks the various subsequent interventions. The FDA does
not insist that each employee perform all of the setup and intervention tasks, but that
those individuals performing the various tasks during the aseptic fill also participated in
the same tasks during the media fills (see Benue Venue 2011 Form FDA 483s). 
OBSERVATION #8
Drug products not required to be sterile are not examined to prevent objectionable
microbiological contamination.
Specifically,
API products such as Phenytoin Sodium, Toceranib Phosphate, Triazolam are not
examined to ensure they are free from objectionable microbiological contamination.
COMMENT:
21 CFR 211.113(a) states that “products that are not sterile should assure that they are
free from objectionable microbiological contamination”.  In addition USP <61>, <62>,
<1111> and <1115> all discuss various aspects of the management of non-sterile
products. What cannot be determined from the Observation is whether these non-sterile
products were ever tested for specified or objectionable microorganisms.
DOCUMENTATION ISSUES IN
PRODUCTION AND THE
LABORATORY LEAD TO UNIMARK
REMEDIES LTD RECEIVING A
WARNING LETTER FOR API
ADULTERATION
November 4, 2015 By Barry Friedman Leave a Comment
During March 18-21, 2014 the FDA inspected the pharmaceutical manufacturing facility,
Unimark Remedies Ltd., located at 337 Kerala Nalsarovar Road, Kerala Village, Bavla,
Ahmedabad District, India. The FDA identified significant deviations from current good
manufacturing practice (CGMP) for the manufacture of active pharmaceutical
ingredients (APIs).
These deviations caused the APIs to be adulterated within the meaning of Section
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C.
351(a)(2)(B).  The investigator observed specific CGMP deviations during the
inspection, including, but not limited to, the following.
1.    Failure to document production and analytical testing activities at the time they
are performed.
During our inspection, we found that test results and other entries in the production
records were not entered while batches were in production.  For example,The
investigator observed (b)(4) batch (b)(4)production on March 18, 2014. The start and
stop times and (b)(4) for Step #(b)(4) were not recorded or signed in the batch record
contemporaneously.
COMMENT: 
As noted above, start and stop times were not recorded or signed at the time of
performance. A number of other Indian manufacturing operations have also been
cited for a failure to enter information in a timely manner.
For your (b)(4) products returned due to the presence of extraneous threads, the
investigator found many inconsistencies in your reprocessing batch records.
Specifically, operators signed batch records for periods when they were not in your
facility, indicating these activities were documented by personnel who did not perform
them.  During the inspection, and in your written responses, your managers admitted
that the batch records were created after the manufacturing process.
COMMENT: 
Several lots were returned because of the presence of extraneous threads. By
operators signing batch records when they were not in the facility, they were
falsifying data. Again, there exists a history of this within Indian facilities (Click
Here).
Water testing records for sampling point (b)(4) on March 19, 2014, were incomplete.
Specifically, the analyst did not record observations at the time they were made on
March 18, 2014.  Your microbiology records did not identify who prepared the samples,
when they began incubation, who read the samples, or when the samples were read.
According to your responses to these FDA 483 observations, your manufacturing staff
did not exhibit acceptable documentation practices, and your chemist or microbiologist
each neglected his work. However, your management is responsible for routine
oversight of manufacturing and testing operations, including the activities of operators
and other personnel, and your responses do not address the failure of management and
the flaws in your overall quality system.
COMMENT:
The Company was found to have incomplete microbiological testing records for
their water. Both the chemist and microbiologist neglected their work and did not
follow acceptable documentation practices. Interestingly, not only were the
analysts blamed for the problems, but also management since they remain
responsible for the overall Quality system. Often one finds that the individuals
within a Department are blamed for the unacceptable practice. However, in this
case, management is sharing in this blame (Click Here).
In response to this letter, (1) conduct and provide the results of a comprehensive
investigation into your poor documentation practices. Your investigation
should (2) address the flaws in your quality systems and management oversight that led
to these serious deficiencies. (3) Provide your plans to revise your procedures so that
all CGMP operations are documented at the time they occur.  Also (4) provide your
plans to revise your procedures so that you preserve original or true copies of data in
the batch records.  Also (5)provide your procedures for addressing deviations from
acceptable documentation practices, (6) including training and oversight of personnel
whose duties require preparation and review of API records.
COMMENTS: 
The above paragraph represents a very good summary of areas management
should supervise and manage if they find themselves in a similar situation. The
highlighted numbers in the previous paragraph have been inserted by the author
to draw attention to these pertinent issues. 
2.   Failure to prevent unauthorized access or changes to data and to provide
adequate controls to prevent omission of data.
Your laboratory systems lacked access controls to prevent raw data from being deleted
or altered.  For example:
a.    During the inspection, we noted that you had no unique usernames, passwords, or
user access levels for analysts on multiple laboratory systems.  All laboratory
employees were granted full privileges to the computer systems. They could delete or
alter chromatograms, methods, integration parameters, and data acquisition date and
time stamps. You used data generated by these unprotected and uncontrolled systems
to evaluate API quality.
b.    Multiple instruments had no audit trail functions to record data changes.
COMMENT: 
A lack of usernames, passwords, or user access levels for analysts as well as full
privileges to the computer systems allow each individual to behave as an
administrator. This particular citation is not unusual and has occurred with
Sandoz (Click Here).
We acknowledge your commitment to take corrective actions and preventive actions to
ensure that your laboratory instruments and systems are fully compliant by January 15,
2015. In response to this letter, provide a copy of your system qualification to
demonstrate that your electronic data systems prevent deletion and alteration of
electronic data. Describe steps you will take (e.g., installing better systems or software)
if your qualification efforts determine that the current system infrastructure does not
assure adequate data integrity. Explain the archival process your firm has implemented
to address these issues and how you will evaluate the effectiveness of these
corrections. Provide a detailed summary of the steps taken to train your personnel on
the proper use of computerized systems.   
INDIAN MFG FACILITIES RECEIVE
WARNING LETTER FOR PROBLEMS
ASSOIATED WITH THE ASEPTIC
PROCESSING AREA (APA) (102215)
December 3, 2015 By Barry Friedman Leave a Comment
The U.S. Food and Drug Administration (FDA) inspected the following two
pharmaceutical manufacturing facilities:
1. August 25-29, 2014: Sandoz Private Limited, MIDC Plot Nos. 8-A/2 & 8-B, TTC
Industrial Area, Kalwe Block, Village Dinghe, Navi Mumbai 400 708, Maharashtra,
India (Kalwe facility)
2. August 12-28, 2014: Sandoz Private Limited, Plot Nos. D31 & D32, MIDC, TTC
Industrial Area, Turbhe, Thane-Belapur Road, Navi Mumbai 400 705 Maharashtra,
India (Turbhe facility)
At both sites, the FDA identified significant violations of current good manufacturing
practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal
Regulations, Parts 210 and 211.
The following Blog includes only the Turbhe facility and focuses upon the Indian Mfg
Facilities Aseptic Processing Area (APA). 
We (the FDA) are aware of your plan to shut down and/or divest the Turbhe
facility. Nevertheless, because several CGMP violations at the Turbhe facility relate to
aseptic process controls, and are similar to violations cited in Warning Letter 320-12-05
issued to Novartis International AG on November 18, 2011, we note the following
violations at this site.
1.  Your firm failed to establish and follow appropriate written procedures that are
designed to prevent microbiological contamination of drug products purporting to
be sterile, and that include validation of all aseptic and sterilization processes (21
CFR § 211.113(b)).
You failed to perform adequate unidirectional airflow studies (smoke studies) on the
aseptic filling line used to produce sterile finished drug products.  Portions of a
videotaped smoke study reviewed by the investigator did not adequately document
airflow patterns during manual interventions.  In some instances, airflow patterns could
not be observed and evaluated.  Insufficient smoke and poor camera angles made it
impossible to determine unidirectional airflow.
COMMENT 
Unidirectional airflow studies, i.e., smoke studies have become a standard
element of what the FDA desires to review when they visit an APA. As noted,
airflow patterns during manual interventions need to be reviewed and evaluated.
Where the FDA finds insufficient evidence based on their observations, they will
request the firm to repeat these studies and submit the information to them.
Interestingly, the Compliance Officer for this Warning Letter has been on the
forefront of those auditing APA and reviewing smoke studies. Please visit the
following Blogs (Click Here) to view similar 483s and Warning Letters. 
1. Your firm failed to establish procedures to remove units following interventions,
periodic adjustments, set-up, and end of fill.  Furthermore, your firm rejected units
with intact container/closure systems from media fills without written justification or
explanation.
According to the SFDF/MF/12/07 media fill batch record (filling end date July 3, 2012),
359 media-filled vials were rejected after interventions due to machine set-up and
periodic adjustments, and after the end of the filling process.  None of these vials were
incubated as part of the media fill.
According to the SFDF/MF/14/01 media fill batch record (filling end date May 13, 2014),
177 media-filled vials were rejected after interventions due to machine set-up and
periodic adjustments, and after the end of the filling process.  None of these vials were
incubated as part of the media fill.
COMMENT 
Procedures should be in place and followed for units removed following
interventions, periodic adjustments, set-up and end of fill. In addition, rejected
vials with intact container/closure systems involved in media fills should only be
removed with written justification or explanation. In addition, incubation of the
vials should have been completed. Please visit FDA’s Guidance for Industry
Aseptic Processing (September 2004) (Click Here)  to learn more. 
2. Your firm failed to establish an adequate system for monitoring environmental
conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
You have inadequate scientific justification for your environmental monitoring sampling
plans in manufacturing areas for aseptically-filled injectable drug products.  This
includes the locations of viable airborne particulate sampling, settle plates, and contact
surface monitoring.
We acknowledge your SOP/CB/QC/510, “Microbiological Monitoring of Air, Surfaces
and Personnel in Production Area.” You used a chart contained in this SOP to justify
your choice of environmental sampling locations.  However, you did not supply data to
support your current locations.  In addition, neither your environmental monitoring
procedures nor your sampling records clearly identify where environmental monitoring
samples are taken.
COMMENT 
ICH Q9 Risk Management (Click Here) should be observed when developing data
to clearly identify where environmental monitoring samples are to be taken. When
developing environmental sampling locations, it becomes necessary to sample
more than the minimum to establish that the best locations are being used for
sampling purposes.
ANOTHER PHARMACEUTICAL
RECEIVES A WARNING LETTER
FOR INADEQUATE AIRFLOW
STUDIES (12/17/15)
January 5, 2016 By Barry Friedman Leave a Comment
Over the past several years the FDA has issued Warning Letters to a number of aseptic
processing facilities that have encountered difficulties with their management of air flow.
While the management of airflow appears to be an easy area to manage within the
Aseptic Processing Area (APA), the number of Warning Letters (Click Here) has
suggested otherwise.
The “speed” in which a recent Form FDA 483 turned into a Warning Letter suggests that
the FDA was quite concerned with what they observed within Sun Pharmaceutical
Industries Ltd, India. Investigators from  the U.S. Food and Drug Administration
(FDA) inspected their pharmaceutical manufacturing facility at Sun Pharmaceutical
Industries Ltd., Halol-Baroda Highway, Halol, Gujarat between September 8-19, 2014,
and following an exchange of letters, which found Sun Pharmaceutical’s actions
insufficient, issued a Warning Letter (Click Here) on December 17, 2015.
The FDA reviewed the October 10, 2014, response in detail and found It lacking
sufficient corrective actions. The FDA also acknowledged receipt of correspondence of
December 12, 2014; February 10, 2015; and May 5, 2015. Please note that any
additional information following an initial response may, or may not, be considered in
the formation and issuance of a subsequent Warning Letter.
The Warning Letter included a number of Sections as part of Observation 1. They
included:
1. Your firm failed to establish and follow appropriate written procedures that are
designed to prevent microbiological contamination of drug products purporting to
be sterile, and that include validation of all aseptic and sterilization processes (21
CFR 211.113(b)).
COMMENT:
21 CFR 211.113(b) is the second of two sections within 21 CFR 211.113. 113(a)
represents non-sterile drug products, while 113(b) references sterile drug
products. The “following of appropriate written procedures” represent one mode
in which 211.113 may be used.  
1. “You failed to perform adequate unidirectional airflow studies (smoke studies)
under dynamic conditions to determine how the movement of air and personnel
during aseptic operations could pose risks to product sterility. In addition, the
studies indicate that your aseptic processing equipment is not properly designed.
For example, an audit of your smoke studies found:
 Significant airflow turbulence, including air moving in an (b)(4)direction, in the
laminar airflow (LAF) unit in which aseptic (b)(4) and tubing connections are made
for the (b)(4)  Also, the studies lacked dynamic simulation of this critical
intervention.
 No dynamic smoke studies to demonstrate unidirectional airflow during the
manual aseptic transfer of (b)(4)units into the (b)(4) used for transport to the (b)
(4).
 Inadequate evaluation of airflow patterns in your stopper (b)(4) area, and
turbulence around the stopper (b)(4).
 Lack of smoke studies during aseptic filling line setup activities.
 Operators (b)(4)open filled vials when adjusting the stopper (b)(4), which is a
hazard to sterility assurance.
Without smoke study data to demonstrate unidirectional airflows over all aseptic
operations and processing steps, you cannot show that your processes are designed to
prevent microbiological contamination or provide adequate assurance of product
sterility.”
COMMENT:
Dynamic as opposed to static studies are critical within an APA to demonstrate
the movement of air in the presence of personnel and filling and stoppering of
vials. As noted in the Warning Letter, the results observed, even with their (Sun’s)
rudimentary studies, suggest the APA equipment is not properly designed. The
balance of the “bullets” noted above are self-explanatory.  
“In your response to the FDA-483, you acknowledged the need for design
improvements and new airflow studies. You also proposed to revise your smoke study
protocol (b)(4) to cover all aseptic interventions and material movement, and to conduct
smoke studies by November 15, 2014. Your firm has submitted neither a revised smoke
test (b)(4), nor a satisfactory new smoke study.
In response to this letter, perform and send a video of new dynamic smoke studies that
fully evaluate unidirectional airflow during your aseptic manufacturing operations, and a
copy of your revised smoke test (b)(4). Also explain how your firm will be
comprehensively evaluating the design of your aseptic processing operation, and
describe any major equipment and facility upgrades that are planned. 
COMMENT:
Promises to submit revised protocols and to conduct studies should always be
followed with the utmost urgency. A failure to follow through, e.g., neither a
revised smoke study…, nor a satisfactory new smoke study, was provided by the
time of the issuance of this Warning Letter (December 17,2015).
Please note that several other Blogs will be forthcoming regarding this Warning
Letter.

Frequently Asked Questions (FAQ)

About Combination Products
January 13, 2016 By Barry Friedman Leave a Comment
Recently the Office of Combination Products published a list of ”Frequently Asked
Questions (FAQ)” that are often asked of the Office.  This list of approximately twenty
eight questions include several questions with rather obvious answers as well as
questions that include where to obtain additional information regarding annual reports.
The list includes the roles of the “Office” and its staff members.  My personal experience
is that these staff members are easy to contact and one should not hesitate to contact
them if you have any questions.  Patricia Love, MD, Deputy Director, will always
respond in a timely fashion.  Her phone number is 301/796-8930.
There exists a section entitled “Product Jurisdiction/Assignment of Combination and
Non-Combination Products” which discusses how combination products are assigned
for review.  It also discusses which Center will review your combination or non-
combination product.  The Request For Designation (RFD) process is outlined in 21
CFR Part 3.
To determine what investigational application should be used for a combination product,
you may want to review the sections that discusses “How many applications”, and also
to decide if an IND/Ide may be required.  You can also learn which center has the lead.
Types of marketing applications that may be required is explained as well as whether
OCP reviews marketing applications.  It doesn’t, the appropriate center does.
A variety of miscellaneous questions include 1) what GMPs apply to combination
products, 2) how are adverse events reported, 3) how about user fees, 4) the
requirements for safety and effectiveness information, 5) guidance on master files
relative to the submission of information, etc.
To view the entire document, please visit the FDA web site at: (Click Here)

Compounding Pharmacies’
Observations Correlate With Those
From Large Pharma ISO 5 Facilities
March 9, 2016 By Barry Friedman Leave a Comment
Compounding pharmacies continue to receive citations from the FDA (both Form FDA
483s and Warning Letters) for a continuing failure to meet 21 CFR 210/211
requirements.  All one needs to do is visit FDA’s Electronic Reading Room to learn of
the ORA audits and the subsequent citations.  Even after the New England
Compounding Center issues that resulted in both death and injury, these compounding
centers have continued to operate and, now not only have had initial visits, but
subsequent visits as well as received both 483s and Warning Letters.
Roy Sturgeon, PhD, Lachman Consultant Services, recently posted several Blogs (Click
on Blogs) regarding this lack of compliance and has provided a list of the “Top Ten”
most frequently cited FDA observations.  If one would compare this list to any list of
observations from a large pharm ISO Class 5 aseptic filling operation, one would note
how similar each is to the other.  These include:
1. “Inadequate or lack of environmental monitoring of facility and people
2. Inadequate laboratory procedures and controls (definition of a “batch”, sampling
and testing controls)
3. Lack of Standard Operating Procedures to prevent microbial contamination
 4. Inadequate deviation/variance controls and lack of adequate investigation
5. Stability program nonexistent or does not support beyond use dating
6. Validation of final sterilization (filter or terminal), media fill design
7. Inadequate cleaning and disinfecting programs
8. Batch release (most done at risk or with no testing for sterility, potency, identity,
and pyrogens)
9. Control of equipment (preventive maintenance and calibration program
inadequate or nonexistent)
10. Inadequate facilities designs and controls, inadequate smoke studies”
“The top ten are now followed by: Lack of validated analytical methods for stability and
potency testing, lack of analytical methods for determining impurities and extraneous
peaks in chromatography, personnel qualifications, training and skill maintenance, no
segregation of beta lactams for other preparations, ineffective quality unit, labeling
matters, personnel not trained in GMPS, change control, incoming supplies acquisition
and approval, inadequate raw material controls, inadequate separation of operations,
record keeping, and inadequate SOPs for operations, environment that poses a
significant contamination risk.”
A recent example of a Warning Letter was issued to Oregon Compounding Center,
Inc. (Click Here) that illustrates the similarity between the summary of Dr. Sturgeon and
the Warning Letters that continue to be issued.  The FDA indicated that they had issued
a Form FDA-483 to the facility on August 28, 2014, and issued as an amended Form
FDA-483 on September 12, 2014.  A Warning Letter was subsequently issued on
January 27, 2015.  An extensive list of FDA 483s, Warning Letters and Recalls relating
to Compounding Centers may be found (Click Here).  Within the Warning Letter many of
the same elements were noted as within the “Top Ten” most frequently cited FDA
observations.  These include:
1. Your firm failed to establish an adequate system for cleaning and disinfecting the
room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
2. Your firm failed to establish and follow appropriate written procedures that are
designed to prevent microbiological contamination of drug products purporting to
be sterile, and that include validation of all aseptic and sterilization processes (21
CFR 211.113(b)).
 3. Your firm failed to ensure that manufacturing personnel wear clothing appropriate
to protect drug product from contamination (21 CFR 211.28(a)).
4. Your firm failed to establish an adequate system for monitoring environmental
conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
5. Your firm failed to establish and follow an adequate written testing program
designed to assess the stability characteristics of drug products and to use results
of such stability testing to determine appropriate storage conditions and expiration
dates (21 CFR 211.166(a)).
6. Your firm failed to thoroughly investigate any unexplained discrepancy or failure
of a batch or any of its components to meet any of its specifications, whether or
not the batch has already been distributed (21 CFR 211.192).
The FDA further states the Company should:
“Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary
conditions applies regardless of whether the drugs are compounded and distributed
after receipt of a prescription for an identified individual patient. In addition, should you
manufacture and distribute domperidone drug products or drug products without valid
prescriptions for individually-identified patients, the manufacture of such drugs would be
subject to FDA’s drug CGMP regulations (21 CFR Parts 210 and 211), among other
requirements described above, and, before doing so, you should fully implement
corrections that meet the minimum requirements of 21 CFR Part 211 in order to provide
assurance that the drug product(s) produced by your firm conform to the basic quality
standards that ensure safety, identity, strength, quality, and purity.
FDA strongly recommends your management immediately undertake a comprehensive
assessment of your operations, including facility design, procedures, personnel,
processes, materials, and systems. In particular, this review should assess your aseptic
processing operations.”
Just because a Company is not a multi-national biopharmaceutical and only performs
compounding does not make it exempt from following 21 CFR 210/211.
COMPANY RECEIVES WARNING
LETTER FOR EXCEEDING
MICROBIAL SPECIFICATIONS
March 18, 2016 By Barry Friedman Leave a Comment
Chemolee Lab Corporation Receives Warning Letter (022316) (Click Here)
Investigators from the U.S. Food and Drug Administration (FDA) inspected Chemolee
Lab Corporation, located at 3820 Conflans Road, Irving, Texas from January 12 thru
February 13, 2015 and found a number of CGMP violations for exceeding microbial
specifications. These included:
1.    Your firm failed to thoroughly investigate any unexplained discrepancy or
failure of a batch or any of its components to meet any of its specifications,
whether or not the batch has already been distributed, and failed to extend the
investigation to other batches that may have been associated with the specific
failure [21 CFR 211.192]. Please note that this represents a repeat Observation
from September 2011.
 (b)(4) Acne Control Spot Treatment lots manufactured in August and September of
2013 were rejected because they failed established microbial specifications for total
microbial count: “Fail if any CFU is greater than (b)(4).” Your quality control unit did not
adequately investigate these specification failures.
For lot (b)(4), three different objectionable microorganism tests failed. Specifically, you
failed testing on media used for detecting Aspergillus niger (brasiliensis), Candida
albicans, and Pseudomonas aeruginosa. All three tests yielded levels that were too
numerous to count (TNTC). You concluded that insufficient cleaning of the transfer
pump was the root cause of these failures. On August 30, 2013, you implemented a
new sanitization procedure in response to these microbial testing failures.
On September 12, 2013, the (b)(4) lot manufactured after implementation of this new
sanitization procedure, lot(b)(4), failed five different objectionable microorganism tests.
Specifically, you failed testing on media used for detecting Aspergillus niger, Candida
albicans, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. You
concluded the source of this contamination “points to somewhere in the filling process.”
Your response to the initial contamination event was ineffective as contamination
continued to occur. You did not extend your investigations to other potentially affected
lots such as those manufactured with common raw materials or equipment.
Furthermore, your response to the second contamination event (lot (b)(4)) is also
deficient in that you have not provided any data to justify your conclusion that
contamination is occurring “somewhere in the filling process.” You did not find the root
cause of these contamination events, and thus you will not be able to prevent them from
recurring.
In your response to the FDA 483, you stated that 1:10 other drug lots manufactured on
the same equipment immediately before and after lots (b)(4) and (b)(4) were found to
be out-of specification (OOS) for microbial testing. You also stated that you updated
your (b)(4) procedure for non-conformances and your (b)(4)procedure for corrective and
preventive actions to extend failure investigations to other associated batches. Your
response is inadequate because you still failed to provide scientifically sound evidence
to support your conclusions about contamination sources, affected lots, and corrective
actions.
Comment: 
The FDA found that the Company failed to thoroughly investigate any unexplained
discrepancy or failure of a batch or any of its components to meet any of its
specifications, whether or not the batch has already been distributed, and failed to
extend the investigation to other batches that may have been associated with the
specific failure (21 CFR 211.192).  Chemrolee also failed to identify the “root cause”. 
Further, since this is a “repeat Observation” from September 2011 that has not been
corrected, and cited again, it is not surprising that the Company received a Warning
Letter. 
Our investigators also determined that your monitoring, inspecting, and repair of the RO
water system was inadequate in ensuring that it was maintained in a validated state.
Beyond the failure to maintain your RO system from January 8, 2014, through October
8, 2014, microbiological test results from water sampled at the RO (b)(4) were TNTC
on (b)(4) occasions. Without justification, you discontinued sampling at the RO (b)
(4) that yielded these results. We note that the finished product lots that you rejected in
2013 for microbial contamination included gross contamination with Pseudomonas
aeruginosa, a microorganism commonly found in water.
Comment: 
While Purified Water, i.e., water leaving a RO System may contain upwards of 100
CFU/mL, gross contamination of RO water with Pseudomonas aeruginosa is
unacceptable and considered a “specified organism”.  In addition, anytime that a
specific microorganism is isolated in numbers less than a specification, but still within
“gross contamination” levels (>30 or so CFU/mL), one should attempt to determine its
root cause and correct the problem.

Ps. Aeruginosa Exceeds 2.1 X 107/Gm

in Product; Where was the
Microbiologist?
April 3, 2016 By Barry Friedman Leave a Comment
Questions often arise regarding when is a microorganism “specified” vs.
“objectionable”?  USP<62> lists a total of seven individual and groups of
microorganisms to include Ps. aeruginosa that are considered “specified”.  However, in
a broader category they are also considered as “objectionable”.   A recent Warning
Letter discusses the microbiological results from a manufacturer of both gels and
shampoos.
The U.S. Food and Drug Administration (FDA) conducted an inspection of Gilchrist &
Soames, Inc., cosmetic manufacturing facility, Plainfield, Indiana, from September 22 to
October 5, 2015 to determine their compliance with the Federal Food, Drug, and
Cosmetic Act (the Act). The firm manufactures and distributes hotel amenity products,
including shower gels, shampoos, lotions, and conditioners, to retail and charitable
organizations. These products are intended to be applied to the human body for
cleansing, beautifying, promoting attractiveness, or altering the appearance, and as
such, are cosmetic products within the meaning of section 201(i) of the Act [21 U.S.C.
§321(i)].
The FDA collected a sample of their “Gilchrist & Soames Spa Therapy Conditioning
Shampoo” product during the inspection, and “(b)(4) Shower Gel,” “Pelican Hill Shower
Gel,” and “Essential Elements Shampoo” products post-inspection. Their analysis of
these products, manufactured at their facility, found significant microbial contamination. 
The microbial contamination of the “Gilchrist & Soames Spa Therapy Conditioning
Shampoo,” “(b)(4) Shower Gel,” “Pelican Hill Shower Gel,” and “Essential Elements
Shampoo” products causes these products to be adulterated.
Observations included:
1. FDA analysis of your “Gilchrist & Soames Spa Therapy Conditioning Shampoo”
and “(b)(4)Shower Gel” products determined that of the five subsamples analyzed
for each product, all contained the pathogen Pseudomonas aeruginosa.  P.
aeruginosa is opportunistically pathogenic to humans and highly resistant to
antibacterial agents such as quaternary ammonium compounds, penicillin, and
many broad-spectrum antibiotics. It is among the most virulent opportunistic
pathogens and can cause severe and life-threatening infections (especially in
immunocompromised patients, burn patients, patients suffering from respiratory
disease, cancer, chemotherapy patients, etc.).  P. aeruginosa can survive in
topical and eye-area cosmetics and has been implicated in significant eye
infections which may lead to corneal ulcers and blindness.
Cosmetic products are not expected to be aseptic; however, they must be free of high-
virulence microbial pathogens and the total number of aerobic microorganisms per gram
must be low.
Comment: 
USP Chapters that one should review include USP<1111> and USP<62> which
discuss the numbers of microorganisms recommended within non-sterile
products as well as ‘objectionable” microorganisms.  Within USP<62> P.
aeruginosa is viewed as both “specified” and “objectionable”. 
2. FDA analysis of your “Gilchrist & Soames Spa Therapy Conditioning Shampoo,”
“(b)(4) Shower Gel,” “Pelican Hill Shower Gel,” and “Essential Elements
Shampoo” products determined that the subsamples of the products contained an
excessive level of microorganisms as evidenced by high Aerobic Plate Counts
(APC), which may render them injurious to users because the presence of such
microorganisms in these finished products can increase the users’ risk of infection.
APC measures the level of microorganisms in a product and can indicate the
quality of the product.  FDA’s guideline is that the APC should not be greater than
500 CFU/g for eye area cosmetics and 1,000 CFU/g for all other products. These
guidelines can be found in the BAM (Click Here). Specifically, your products
 contained APC of up to 210,000,000 CFU/gm. Of particular concern, the high
counts of Enterobacter gergoviae.  Enterobacter gergoviae are part of the normal
intestinal flora and may be considered an opportunistic pathogen.  Individuals with
weakened immune systems, who suffer from a serious pre-existing condition, who
have been treated surgically or belong to another sensitive group of persons are
at particular risk of infection.
Comment:
Microbial counts as high as 2.1 x 108      per gram can be hazardous to one’s health
(if healthy) and particularly hazardous with individuals who have weakened
immune systems.  The high aerobic plate counts also illustrate how readily
bacteria may thrive within conditioning shampoos and shower gels.  
The FDA further found that:
Their investigators also observed the following insanitary practices that could cause
their products to be adulterated under section 601(c) of the Act in that these practices
may lead to insanitary conditions and may cause the products manufactured in their
facility to become contaminated with filth or rendered injurious to health.  Specifically,
the FDA observed that:
1. The microbiological safety of starting materials and/or raw ingredients is not
routinely evaluated by your firm.  Materials are not sampled and tested for
conformance with specifications and to ensure the absence of filth,
microorganisms, and other adulterants prior to processing or usage. Your firm
does not perform any microbial testing on any incoming raw materials, nor have
you validated your suppliers’ quality testing through independent verification.
Comment: 
No mention of preservatives was noted as being present within the raw materials,
in-process materials or finished product.  I find this somewhat surprising since
almost all shampoos, conditioners and gels commercially available contain one
or more preservatives.  Perhaps because the products are provided for hotel
guests and are assumed to be “single use only”, the manufacturers believe the
products to not require any preservative systems.
We acknowledge receipt of your firm’s October 14, 2015, October 27, 2015, December
8, 2015, December 21, 2015, and January 19, 2016, letters sent in response to the FDA
483 issued to your firm at the close of the inspection.  In your letters you stated that you
are currently evaluating raw material inventory and determining which raw materials are
micro-sensitive.  We also note that you state that you send micro-sensitive raw
materials to be tested for microbiological content at an external laboratory.  We cannot
evaluate the adequacy of your corrective actions without the supporting documentation.
2. The equipment used to manufacture your products is not maintained in a clean
and orderly condition, or sanitized at appropriate times.  Your firm was also
unable to document clean out procedures for (b)(4)gallon bulk raw material tanks
and (b)(4) gallon tank (b)(4) water tank use for manufacturing and equipment
cleaning.  As suggested in FDA’s Draft Guidance for Industry: Cosmetic Good
Manufacturing Practice (Click Here), FDA expects cosmetic firms to document
equipment cleaning and procedures and assure that the processes are adequate
to prevent adulteration.
In your firm’s response letters you provided a date of February 29, 2016, for your
cleaning validation studies to be completed.  We also note that you state water samples
are being collected and analyzed by your third-party lab. We cannot evaluate the
adequacy of these corrective actions without the supporting documentation.
3. Raw materials, in-process samples and finished products should be tested or
examined to verify their identity and determine their compliance with
specifications for physical and chemical properties, microbial contamination, and
hazardous or other unwanted chemical contaminants. However, your products
continue to be contaminated with microorganisms. Specifically, P. aeruginosa
was isolated by FDA from a sample of 1.5 oz bottles of “Thymes naia Body
Wash” lot 1308, collected by an FDA investigator on December 17, 2014. The
analytical results for this sample were sent to you on March 6, 2015. Yet, P.
aeruginosa was isolated from FDA samples of “Gilchrist & Soames Spa Therapy
Conditioning Shampoo,” packaged in June, 2015, and ” (b)(4)Shower Gel,”
“Pelican Hill Shower Gel,” and “Essential Elements Shampoo,” all packaged in
September, 2015.
Comment:
Where was the microbiologist? I remain quite surprised that the FDA did not
strongly suggest to this vendor that they should have a microbiologist on the
staff that would be examining raw materials, in-process materials and finished
products to assure the absence of both “objectionable” and “specified”
microorganisms. While the FDA expects cosmetic firms to document equipment
cleaning and procedures and assure that the processes are adequate to prevent
adulteration, they also expect that all tankage be evaluated for microbial content.