Data Integrity & compliance with

CGMP
FDA guidance (25591) April 2016
and December 2018

L.C.Clauss

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 Table of Content (1)
1. Definition and purpose
2. EU vs FDA requirements
3. FDA April 2016 and 2018 Guidance document
4. Data Integrity during development
5. Why Data Integrity Guidance from FDA?
6. FDA definition of Audit Trail
7. FDA definition of Back up
8. Computer and related system
9. FDA is concerned with the use of shared login accounts for computer systems
10. When does electronic data become a CGMP record?
11. How should blank forms be controlled?
12. Can electronic signatures be used instead of handwritten signatures for
master production and control record
13. The practice, also referred to as testing into compliance, is not consistent with
CGMP
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 Table of Content (2)
14. Typical issues with Password
15. Is it acceptable to only save the final results from reprocessed laboratory
chromatography?
16. Can an internal tip regarding a quality issue, such as potential data falsification,
be handled informally outside of the documented CGMP quality system?
17. FDA request that personnel should be trained in detecting data integrity issues
as part of a routine CGMP training program
18. FDA Warning letter Form 483

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 1.)Definition from FDA guidance

* For the purposes of this guidance, data integrity

refers to the completeness, consistency, and accuracy
of data. Complete, consistent, and accurate data
should be Attributable, Legible, Contemporaneously
Recorded, Original or a true copy, and Accurate
(ALCOA).

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 Data Integrity Definition

* Data integrity is the accuracy and consistency of stored

data, indicated by an absence of any alteration in data
between two updates of a data record.
* Data integrity is imposed within a system at its design
stage through the use of standard rules and procedures,
and is maintained through the use of error checking and
validation routines.

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Data integrity is critical throughout the CGMP data life cycle, including in the creation,
modification, processing, maintenance, archival, retrieval, transmission, and disposition of data
What is Metadata
after the record’s retention period ends. 6 System design and controls should enable easy
detection of errors, omissions, and aberrant results throughout the data’s life cycle.

b. What is “metadata”?

Metadata is the contextual information required to understand data. A data value is by itself
meaningless without additional information about the data. Metadata is often described as data
about data. Metadata is structured information that describes, explains, or otherwise makes it
easier to retrieve, use, or manage data. For example, the number “23” is meaningless without
metadata, such as an indication of the unit “mg.” Among other things, metadata for a particular
piece of data could include a date/time stamp documenting when the data were acquired, a user
ID of the person who conducted the test or analysis that generated the data, the instrument ID
used to acquire the data, material status data, the material identification number, and audit trails.

Data should be maintained throughout the record’s retention period with all associated metadata
required to reconstruct the CGMP activity (e.g., §§ 211.188 and 211.194). The relationships
between data and their metadata should be preserved in a secure and traceable manner.

c. What is an “audit trail”?

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 European Regulations

* Records retention requirements state that if the records are

supporting a Marketing Authorization (MA), then the records
have to be maintained, including the data integrity for as long as
the MA is in force. The recently published EU GMP Annex for
computerized systems 11, effective 30 June 2011, has several
sections dealing with data integrity. 5/15/2014 22Drug
Regulations : Online Resource for Latest Information

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 Data Integrity during
development
* FDA and other global regulatory agencies now oversee the
pharmaceutical product lifecycle from early development to
final product release more thoroughly
* Therefore R & D laboratories have come under increased
scrutiny within recent years
* Regulations have been in place since the 1970s, However
historically, FDA has concentrated its review process on the
manufacturing aspect of pharmaceutical products. This has
changed with the added scrutiny on data integrity 5/15/2014
31Drug Regulation

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 Why Data Integrity Guidance from
FDA?
* “The purpose of this guidance is to clarify the role of data integrity
in current good manufacturing practice (CGMP) for drugs, as
required in. Current Good Manufacturing Practice in
Manufacturing, Processing, Packing, or Holding of Drugs; General;
and Finished Pharmaceuticals (21 CFR/210/211/212).
* FDA expects that data be reliable and accurate, cGMP regulations
and guidance allow for flexible and risk based strategies to
prevent and detect integrity issues”

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 FDA expectations

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 FDA definition of Audit Trail
* “For purposes of this guidance, audit trail means a secure,
computer-generated, time-stamped electronic record that
allows for reconstruction of the course of events relating to the
creation, modification, or deletion of an electronic record. An
audit trail is a chronology of the “who, what, when, and why” of
a record.
* For example, the audit trail for a high performance liquid
chromatography (HPLC) run includes the user name, date/time
of the run, the integration parameters used, and details of a
reprocessing, if any, including change justification for the
reprocessing.”

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 Contains Nonbinding Recommendations

Who should review audit Trails ?

212.70(f)(1)(vi)). All data required to recreate a CGMP activity should be maintained as part of
the complete record.

7. Who should review audit trails?

Audit trail review is similar to assessing cross-outs on paper when reviewing data. Personnel
responsible for record review under CGMP should review the audit trails that capture changes to
data associated with the record as they review the rest of the record (e.g., §§ 211.22(a),
211.101(c) and (d), 211.103, 211.182, 211.186(a), 211.192, 211.194(a)(8), and 212.20(d)). For
example, all production and control records, which includes audit trails, must be reviewed and
approved by the quality unit (§ 211.192). The regulations provide flexibility to have some
activities reviewed by a person directly supervising or checking information (e.g., § 211.188).
FDA recommends a quality system approach to implementing oversight and review of CGMP
records. 12

8. How often should audit trails be reviewed?

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If the review frequency for the data is specified in CGMP regulations, adhere to that frequency
 211.101(c) and (d), 211.103, 211.182, 211.186(a), 211.192, 211.194(a)(8), and 212.20(d)). For
example, all production and control records, which includes audit trails, must be reviewed and
approved by the quality unit (§ 211.192). The regulations provide flexibility to have some
How often should audit trails be
activities reviewed by a person directly supervising or checking information (e.g., § 211.188).
FDA recommends a quality system approach to implementing oversight and review of CGMP
records. 12 reviewed?
8. How often should audit trails be reviewed?

If the review frequency for the data is specified in CGMP regulations, adhere to that frequency
for the audit trail review. For example, § 211.188(b) requires review after each significant step in
manufacture, processing, packing, or holding, and § 211.22 requires data review before batch
release. In these cases, you would apply the same review frequency for the audit trail.

If the review frequency for the data is not specified in CGMP regulations, you should determine
the review frequency for the audit trail using knowledge of your processes and risk assessment
tools. The risk assessment should include evaluation of data criticality, control mechanisms, and
impact on product quality. 13

Your approach to audit trail review and the frequency with which you conduct it should ensure
that CGMP requirements are met, appropriate controls are implemented, and the reliability of the
review is proven.

See the audit trail definition in 1.c. above for further information on audit trails.
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9. Can electronic copies be used as accurate reproductions of paper or electronic

 CGMP-compliant record-keeping practices prevent data from being lost or obscured and ensure
Howare does
that activities documentedFDA use
at the time the terms
of performance (see §§ “static”
211.68, 211.100,and
211.160(a),
“dynamic”
211.188, as they
and 211.194). Electronic relate
record-keeping to which
systems, recordinclude formats?
audit trails, can
support these CGMP requirements.

d. How does FDA use the terms “static” and “dynamic” as they relate to record formats?

For the purposes of this guidance, static is used to indicate a fixed-data record such as a paper
record or an electronic image, and dynamic means that the record format allows interaction
between the user and the record content. For example, a dynamic chromatographic record may
allow the user to change the baseline and reprocess chromatographic data so that the resulting
peaks may appear smaller or larger. It also may allow the user to modify formulas or entries in a
spreadsheet used to compute test results or other information such as calculated yield.

e. How does FDA use the term “backup” in § 211.68(b)?

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 records.

Is
Trueitcopies
acceptable to records
of dynamic electronic retain paper
may be made and printouts or static
maintained in the format of the
original records or in a format that allows for the content and meaning of the original records to
records
be preserved instead
if a suitable reader andof original
copying equipment electronic records
(e.g., software and hardware, including
media readers) are readily available (§§ 211.180(d) and 212.110).
from stand-alone computerized laboratory
10. Is it acceptable to retain paper printouts or static records instead of original
instruments
electronic records from such as an
stand-alone FTIR Instruments?
computerized laboratory instruments, (1)
such as
an FT-IR instrument?

A paper printout or static record may satisfy retention requirements if it is the original record or a
true copy of the original record (see §§ 211.68(b), 211.188, 211.194, and 212.60). During data
acquisition, for example, pH meters and balances may create a paper printout or static record as
the original record. In this case, the paper printout or static record, or a true copy, must be
retained (§ 211.180).

However, electronic records from certain types of laboratory instruments—whether stand-alone

or networked—are dynamic, and a printout or a static record does not preserve the dynamic
record format that is part of the complete original record. For example, the spectral file created
by FT-IR (Fourier transform infrared spectroscopy) is dynamic and can be reprocessed.
However, a static record or printout is fixed and would not satisfy CGMP requirements to retain
original records or true copies (§ 211.180(d)). Also, if the full spectrum is not displayed in the
printout, contaminants may be excluded.

You must ensure that original laboratory records,

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including paper and electronic records, are06/12/2023
subject to second-person review (§ 211.194(a)(8)) to make certain that all test results and
 Is it acceptable to retain paper
However, electronic records from certain types of laboratory instruments—whether stand-alone
or networked—are dynamic, and a printout or a static record does not preserve the dynamic
printouts
record format that is partor static
of the records
complete original instead
record. For example, theof original
spectral file created
electronic
by FT-IR (Fourier records
transform infrared spectroscopy)from
is dynamicstand-alone
and can be reprocessed.
However, a static record or printout is fixed and would not satisfy CGMP requirements to retain
computerized
original records or true copies (§laboratory instruments
211.180(d)). Also, if the suchin theas
full spectrum is not displayed
printout, contaminants mayanbe FTIR
excluded. Instruments? (2)

You must ensure that original laboratory records, including paper and electronic records, are
subject to second-person review (§ 211.194(a)(8)) to make certain that all test results and
associated information are appropriately reported. Similarly, in microbiology, a
contemporaneous written record is maintained of the colony counts of a petri dish, and the record
is then subject to second-person review.

Document control requirements in § 211.180 pertain only to CGMP records.

For more information on static and dynamic records, see 1.d. in this guidance. For PET drugs,
see the guidance for industry PET Drugs—Current Good Manufacturing Practice (CGMP) for
discussion of equipment and laboratory controls, including regulatory requirements for records.

11. Can electronic signatures be used instead

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production and control records?

 FDA definition of Back up

* FDA uses the term backup to refer to a true copy of the

original data that is maintained securely throughout the
records retention period. The backup file should contain
the data (which includes associated metadata) and
should be in the original format or in a format
compatible with the original format.
( 21CFR§ 211.68(b) and § 211.180)

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 Computer and related system
* Computer or related systems can refer to:
* computer hardware,
* software,
* peripheral devices,
* networks,
* cloud infrastructure,
* operators, and associated documents
* (e.g., user manuals and standard operating
procedures).
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 FDA is concerned with the use of shared
login accounts for computer systems
* Companies must exercise appropriate controls to
assure that changes to computerized MPCRs*, or other
records, or input of laboratory data into computerized
records, can be made only by authorized personnel
(CFR § 211.68(b)).
* FDA recommends to restrict the ability to alter
specifications, process parameters, or manufacturing
or testing methods by technical means where possible
(for example, by limiting permissions to change
settings or data).
* *MPCS= Master Production and Control Record
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212.71(b) and the guidance for industry Investigating Out-of-Specification (OOS) Test Results
for Pharmaceutical Production. Even if test results are legitimately invalidated on the basis of a
scientifically sound investigation, the full CGMP batch record provided to the quality unit would
include the original (invalidated) data, along with the investigation report that justifies
Does each CGMP workflow on a
invalidating the result. The requirements for record retention and review do not differ depending
on the data format; paper-based and electronic data record-keeping systems are subject to the
computer system need to be validated?
same requirements.

3. Does each CGMP workflow on a computer system need to be validated?

Yes, a CGMP workflow, such as creation of an electronic master production and control record
(MPCR), is an intended use of a computer system to be checked through validation (see
§§ 211.63, 211.68(b), and 211.110(a)). The extent of validation studies should be commensurate
with the risk posed by the automated system. When the same system is used to perform both
CGMP and non-CGMP functions, the potential for non-CGMP functions to affect CGMP
operations should be assessed and mitigated appropriately. 10

If you validate the computer system but you do not validate it for its intended use, you cannot
know if your workflow runs correctly. 11 For example, qualifying the Manufacturing Execution
System (MES) platform, a computer system, ensures that it meets its relevant requirements and
specifications; however, it does not demonstrate that a given MPCR generated by the MES
contains the correct calculations. In this example, validating the workflow ensures that the
intended steps, requirements, and calculations in the MPCR are accurate and perform properly.
This is similar to reviewing a paper MPCR and ensuring all supporting procedures are in place
before the MPCR is implemented in production (see §§ 211.100, 211.186, and 212.50(b) and the
guidance for industry PET Drugs—Current Good Manufacturing Practice (CGMP)).
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MPCR Master production and control record

 FDA is concerned with the use of shared
login accounts for computer systems (2)

* FDA suggests that the system administrator role, including any

rights to alter files and settings, be assigned to personnel
independent from those responsible for the record content.
* To assist in controlling access, FDA recommends maintaining a
list of authorized individuals and their access privileges for each
CGMP computer system in use

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 When does electronic data
become a CGMP record?
* When generated to satisfy a CGMP requirement, all data
become a CGMP record. Data should be documented, or saved,
at the time of performance to create a record in compliance
with CGMP requirements, including, but not limited to.
CFR §§ 211.100(b) and 308 211.160(a).
* FDA expects processes to be designed so that quality data
required to be created and maintained cannot be modified.
* For example, chromatograms should be sent to long-term
storage (archiving or a permanent record) upon run completion
instead of at the end of a day’s runs.
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 When is it permissible to invalidate
Contains Nonbinding Recommendations
a CGMP
result and exclude it from the determination
2. When is it permissible
of to invalidate
batch a CGMP result and exclude it from the
conformance?
determination of batch conformance?

Data created as part of a CGMP record must be evaluated by the quality unit as part of release
criteria (see §§ 211.22 and 212.70) and maintained for CGMP purposes (e.g., § 211.180). 9
Electronic data generated to fulfill CGMP requirements include relevant metadata required to
reconstruct the CGMP activity captured in the record. Invalidating test results to exclude them
from quality unit decisions about conformance to a specification requires a valid, documented,
scientifically sound justification. See, for example, §§ 211.160(b), 211.188, 211.192, and
212.71(b) and the guidance for industry Investigating Out-of-Specification (OOS) Test Results
for Pharmaceutical Production. Even if test results are legitimately invalidated on the basis of a
scientifically sound investigation, the full CGMP batch record provided to the quality unit would
include the original (invalidated) data, along with the investigation report that justifies
invalidating the result. The requirements for record retention and review do not differ depending
on the data format; paper-based and electronic data record-keeping systems are subject to the
same requirements.
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3. Does each CGMP workflow on a computer system need to be validated?

 How should blank forms be controlled?

* There must be document controls in place to assure

product quality
(21CFR§§ 211.100, 212 211.160(a), 211.186, 212.20(d), and 212.60(g)).

* FDA recommends that, if used, blank forms (including,

but not limited to, worksheets, laboratory notebooks,
and MPCRs*) be controlled by the quality unit or by
another document control method.
* For example, numbered sets of blank forms may be
issued as appropriate and should be reconciled upon
completion of all issued forms.
*MPCS = Master Production and Control Record
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 How should blank forms be controlled?
(2)

* Incomplete or erroneous forms should be kept as part of the

permanent record along with written justification for their
replacement
* bound paginated notebooks, stamped for official use by a
document control group, allow detection of unofficial
notebooks as well as of any gaps in notebook pages.

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 Can electronic signatures be used instead
of handwritten signatures for master
production and control records?
* Electronic signatures with the appropriate controls can
be used instead of handwritten signatures or initials in
any CGMP required record.
* Requirement is to be able to clearly identify the
individual responsible for signing the record. An
electronic signature with the appropriate controls to
securely link the signature with the associated record
fulfills this requirement.

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 The practice, also referred to as testing into
compliance, is not consistent with CGMP (1)

* The use of actual samples to perform system suitability testing

as a means of testing into compliance is not acceptable.
* It is considered as a violative practice to use an actual sample in
test, prep, or equilibration runs as a means of disguising testing
into compliance.
* According to the United States Pharmacopeia (USP), system
suitability tests should include replicate injections of a standard
preparation or other standard solutions to determine if
requirements for precision are satisfied (see USP General
Chapter <621> Chromatography).

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 The practice, also referred to as testing into
compliance, is not consistent with CGMP (2)

* System suitability tests, including the identity of the

preparation to be injected and the rationale for its selection,
should be performed according to the firm’s established
written procedures and the approved application or applicable
compendial monograph
(21CFR§§ 211.160 and 212.60).

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 Typical issues with Password
* “Common passwords Analysts share passwords, it is not
possible to identify who creates or changes records.
* User privileges The system configuration for the software does
not adequately define or segregate user levels and users have
access to inappropriate software privileges such as modification
of methods and integration.
* Computer system control Laboratories have failed to implement
adequate controls over data, and unauthorized access to
modify, delete, or not save electronic files is not prevented; the
file, therefore, may not be original, accurate, or complete”.
5/15/2014 17Drug Regulations”
21CFR §11
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 Is it acceptable to only save the final results
from reprocessed laboratory chromatography?

* NO, FDA considered that Analytical methods should be capable

and stable. For most lab analyses, reprocessing data should not
be regularly needed. If chromatography is reprocessed, written
procedures must be established and followed and each result
retained for review

* FDA requires complete data in laboratory records, which

includes raw data, graphs, charts, and spectra from laboratory
instruments

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 Can an internal tip regarding a quality issue, such
as potential data falsification, be handled
informally outside of the documented CGMP
quality system?

* Suspected or known falsification or alteration of records

required must be fully investigated under the CGMP quality
system to determine the effect of the event on patient safety,
product quality, and data reliability; to determine the under
root cause; and to ensure the necessary corrective actions are
taken
(see 21§§ 211.22(a), 378 211.125(c), 211.192, 211.198, 211.204, and
212.100). parts 210, 375 211, and 212

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 FDA request that personnel should be trained
in detecting data integrity issues as part of a
routine CGMP training program
* Training personnel to detect data integrity issues is consistent with
the personnel requirements according to cGMP, which state that
personnel must have the education, training, and experience, or
any combination thereof, to perform their assigned duties.
( 21CFR§§ 211.25 and 212.10)
* Is the FDA investigator allowed to look at my electronic
records?
* Yes. All records required under CGMP are subject to FDA
inspection. Authorized inspection should be able to review, and
copying of records, which includes copying of electronic data
(21CFR§§ 211.180(c) and 212.110(a) and (b)).
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 FDA Warning letter Form 483

* How does FDA recommend data integrity problems identified

during inspections, in warning letters, or in other regulatory
actions be addressed?
* FDA encourages you to demonstrate that you have effectively
remedied your problems by: hiring a third party auditor,
determining the scope of the problem, implementing a
corrective action plan (globally), and removing at all levels
individuals responsible for problems from CGMP positions.
* FDA may conduct an inspection to decide whether CGMP
violations involving data integrity have been remedied.

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 QUESTIONS ?
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 CFR211.188 (1)

* SUBCHAPTER C--DRUGS: GENERALPART 211 -- CURRENT GOOD

MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS
* Subpart J--Records and Reports
* Sec. 211.188 Batch production and control records. Batch
production and control records shall be prepared for each
batch of drug product produced and shall include complete
information relating to the production and control of each
batch. These records shall include:
* (a) An accurate reproduction of the appropriate master
production or control record, checked for accuracy, dated, and
signed;
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 CFR211.188 (2)
* (b) Documentation that each significant step in the
manufacture, processing, packing, or holding of the batch was
accomplished, including:
* (1) Dates;
* (2) Identity of individual major equipment and lines used;
* (3) Specific identification of each batch of component or in-
process material used;
* (4) Weights and measures of components used in the course of
processing;
* (5) In-process and laboratory control results;
* (6) Inspection of the packaging and labeling area before and
after use;
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 CFR211.188 (3)
* (7) A statement of the actual yield and a statement of the
percentage of theoretical yield at appropriate phases of
processing;
* (8) Complete labeling control records, including specimens or
copies of all labeling used;
* (9) Description of drug product containers and closures;
* (10) Any sampling performed;
* (11) Identification of the persons performing and directly
supervising or checking each significant step in the operation,
or if a significant step in the operation is performed by
automated equipment under 211.68, the identification of the
person checking the significant step performed by the
automated equipment.
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 CFR211.188 (5)

* (12) Any investigation made according to 211.192.

* (13) Results of examinations made in accordance with 211.134.
* [43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51933, Sept. 8,
2008]

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