Review of Quality Control Record and Analytical Data by Dr. A. Amsavel

Review of Quality Control Record
and Analytical Data
Dr. A. Amsavel,Dr. A. Amsavel, M.Sc.,B.EdM.Sc.,B.Ed., Ph.D.,., Ph.D.,

ContentContent
 Introduction
 Definition
 Requirement as per GMP
 Analytical documents to be reviewed
 Methodology of QC record review Methodology of QC record review
 Procedure and checklist for review of records/data
 Review of traceable /associated documents
 Review of Audit trail
 Role of Analyst & Reviewer
 Data Integrity & Good Record Practice
 FDA Citations.

Why GMP Documentation is Important?
“If it hasn't been documented, then it hasn't
done or happened!”
“If it is not documented, it is a rumour!”
Famous FDA statement:
The product considered as “Adulterated” if the
procedure not followed / not documented
properly.
3

Why QC Records have to be reviewed ?
 Good data demonstrate the standard and culture of the
company
 Review of documents is GMP requirement
 Documents & Data generated in QC are voluminous,
probability of error also high.
 Through review of record is required for the accuracy of data Through review of record is required for the accuracy of data
 Analysis result determines the approval/ rejection of product
 Accuracy of test result decide the safety of patient
 Correctness of QC data decide the fate of the company – DI
 QC is favorable area for regulatory inspectors
 Possibility for erroneous or alteration data
 There are several From 483/WL on data integrity from QC data
 Hence, QC data generation and Review is important

DefinitionDefinition
Data:
Information derived or obtained from raw data, (MHRA, 2015)
Facts, figures and statistics collected together for reference or
analysis. MHRA, 2018)
Raw data (Source data):
Raw data is defined as the original record (data) which can be
described as the first-capture of information, whether recorded on
paper or electronically. Information that is originally captured in a
dynamic state should remain available in that state.
1. Data can be ‘electronic’ or ‘paper based’ or ‘Hybrid’
2. From initial data generation and recording through processing (including transformation or
migration), use, retention, archiving, retrieval and destruction
3. Electronic information includes everything, such as emails, adverse events reports, complaints,
batch records, and quality control records—everything that’s stored electronically.

Verified by:
To ascertain the correctness of, as by examination, research, or
comparison of data /information, and to attest to the accuracy
of the data/information verified therein.
Reviewed by:
Process of evaluating or examining the contents of the reviewedProcess of evaluating or examining the contents of the reviewed
information/ data. Reviewer is attesting to the accuracy,
reliability, and completeness of data/information by evidence of
his/her signature and date.
Approved by:
Authoritative signatures allowed by documented procedures
demonstrating that the data/information, as presented in the
approved document, are accurate, reliable, and complete.

Meta data:
Data that describes the attributes of other data, and provides context
and meaning . Typically, these are data that describe the structure, data
elements, inter-relationships and other characteristics of data
Analytical worksheet (WHO):
A printed form, an analytical workbook or electronic means (e-records)
for recording information about the sample, as well as reagents and
solvents used, test procedure applied, calculations made, results and
any other relevant information or comments .

Audit trail (USFDA)
 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.modification, or deletion of an electronic record.
 An audit trail is a chronology of the “who, what, when, and why”
of a record.
 Electronic audit trails include those that track creation,
modification, or deletion of data (processing parameters and
results) and those that track actions at the record or system level
(such as attempts to access the system or rename or delete a file).

Objective of QC Records ReviewObjective of QC Records Review
 To meet the Regulatory requirements
 Batch released is based on the review and conclusion
 Conclusion made during review is critical and it could impact
Quality of product and safety of patients
 Review of data is as equal to regulator review in the absence of
regulatory agency
 All the records/ data generated in the QC shall be reviewed for
accuracy of result, adequacy, completeness of documents
 Review as per GxP requirements.

GMP Requirement :QC Record& ReviewGMP Requirement :QC Record& Review
 21 CFR 211.22(a) :“There shall be a quality control unit that shall
have the responsibility and authority to approve or reject all
components, drug product containers, closures, in-process
materials, packaging material, labeling, and drug products, …….
 21CFR 211 Subpart I-Laboratory Controls (160, 165,& 170 etc) 21CFR 211 Subpart I-Laboratory Controls (160, 165,& 170 etc)
 21 CFR 211.194 : “Laboratory Records”.
 21 CFR 211.194(a) : “Laboratory records shall include complete
data derived from all tests necessary to assure compliance with
established specifications and standards, including examinations
and assays…”
 Note: 211.194. a(1-8), b, c, d, and e are similar to ICH Q7 6.60

ICH Q7 “Laboratory Control Records”. 6.60 & 6.61
 6.60: Laboratory control records should include complete data derived
from all tests conducted to ensure compliance with established
specifications and standards, including examinations and assays, as
follows:
 A description of samples received for testing, including the material A description of samples received for testing, including the material
name or source, batch number or other distinctive code, date sample
was taken, and, where appropriate, the quantity and date the sample
was received for testing; [ 211.194 (a)1]
 A statement of or reference to each test method used; [ 211.194 (a)2]
Use Standard is USP-NF).
 A statement of the weight or measure of sample used for each test as
described by the method; data on or cross-reference to the
preparation and testing of reference standards, reagents and standard
solutions; [ 211.194 (a)3]

ICH Q7 “Laboratory Control Records”. 6.60
 A complete record of all raw data generated during each test,
in addition to graphs, charts, and spectra from laboratory
instrumentation, properly identified to show the specific
material and batch tested; [211.194 (a)4]
 A record of all calculations performed in connection with the
test, including, for example, units of measure, conversion
factors, and equivalency factors; [211.194 (a)5]
 A statement of the test results and how they compare with
established acceptance criteria; [211.194 (a)6]
 The signature of the person who performed each test and
the date(s) the tests were performed; [211.194 (a)7]

ICH Q7 “Laboratory Control Records”. 6.60 (cont..)
 The date and signature of a second person showing that the
original records have been reviewed for accuracy, completeness,
and compliance with established standards. [ 211.194 (a)8].
Laboratory Control records” 6.61Laboratory Control records” 6.61
 Complete records should also be maintained for:
 Any modifications to an established analytical method; [211.194 (b)]
 Periodic calibration of laboratory instruments, apparatus, gauges,
and recording devices; [211.194 (d)]
 All stability testing performed on APIs; [ 211.194 (e)]
 Out-of-specification (OOS) investigations.

21 CFR 211.194 : Additional to ICH 6.61
 211.194 (b) Complete records shall be maintained of any
modification of an established method employed in testing. Such
records shall include the reason for the modification and data to
verify that the modification produced results that are at least asverify that the modification produced results that are at least as
accurate and reliable for the material being tested as the
established method.
 211.194 (c) Complete records shall be maintained of any testing
and standardization of laboratory reference standards, reagents,
and standard solutions.

ICH Q7 : Laboratory Control Records 6.70&6.71
 6.70: Written procedures should be established and followed for
the review and approval of batch production and laboratory
control records, including packaging and labeling, to determine
compliance of the intermediate or API with establishedcompliance of the intermediate or API with established
specifications before a batch is released.
 6.71: Batch production and laboratory control records of critical
process steps should be reviewed and approved by the quality
unit(s) before an API batch is released or distributed.
Production and laboratory control records of non-critical process
steps can be reviewed by qualified production personnel or other
units following procedures approved by the quality unit(s).”

Type of Records &Data
Analytical Records/ Raw data:
Review complete record of all raw data generated during each test,
including supporting data like Chromatograms, spectrum, graphs, charts,
weight prints etc
Calculation:
Verify all calculations performed as pert of testing , including units of
measure, conversion factors, and equivalency factors etc.measure, conversion factors, and equivalency factors etc.
Electronic Record :
Review the electronic data generated during analysis.
Cross reference / traceability:
Record related to test solution, volumetric solution,
standardization, standards used,
Conclusion with Standard:
Compare the obtained test results against specification as per
pharmacopeia or in-house and report on conclusion /statement.

Procedure for ReviewProcedure for Review
 SOP should be available to verify the accuracy, reliability, and
completeness of the Analytical data
 Role & Responsibility : Define the Analysts, Reviewers, and various level
/lab managers
 SOP Shall cover the data integrity principles: ALCOA and + CCEA
 Good document practice Good document practice
 Describe- how records are reviewed for accuracy & completeness
 Define- what are the record to be reviewed
 Define the Access & Privileges as required
 How and when to review of raw data /electronic data, audit trail etc
 Defined time period for data review ie No of days/ week/ month.
◦ Earliest review period is prepared , since it is easier for corrections if any &
easier to identify “root cause” in the investigation

Requirement : Reviewer
 Review shall be performed by Trained & Qualified person
 Reviewer shall posses the following;
◦ Appropriate qualification and experience
◦ Trained on Analytical Review & QMS
◦ Familiar about the system and procedure in the QC lab
◦ Knowledge on analytical method/ technique
◦ Skill to identify the mistakes ie third eye
◦ Define the responsibility and include in the Job description
◦ Reviewer must be dedicated; preferably person is not
involve in routine analysis

Records/ Data In the QC LabRecords/ Data In the QC Lab
 Routine QC Release Testing: Data generated during testing of
RM, PM, in-process & final product testing for release
 Stability test data
 Experimental /Special Studies
 Process Validation Process Validation
 Cleaning Validation
 Analytical method validation/ Verification or method transfer
 Instrument Qualification & Calibration
 Laboratory Investigation: OOS /Deviation / Incident
 Reports from external Lab

How to Review
 Purpose of data review is to ensure that the data are:
◦ Accurate , Complete, Reliable & Trustworthy
 Use Check list for review and it is a document as evidence of
review
 Review Checklist should cover all the elements of review
 Review and document chronologically.
 Recheck all the calculations 100%
 Individual test details are recoded in sequential order
 Analyst’s initials and date
 Test results / value should be numerical value and proper rounding
off and with reporting with significant figures
 Consolidated report with conclusion / status

What are to be Reviewed
 Review each & every analysis of hardcopy of raw data and
electronic data
 Ensure that all the data are reviewed thoroughly and
technically
 Verify the Test Method and spec is recorded correctly Verify the Test Method and spec is recorded correctly
 Verify that the following are recorded in the raw data
 Instrument id / code, calibration details, test condition like
column, temperature, wave length, mobile phase, System
suitability parameters etc
 All printouts are match with the Test Method.
 Verify the instrument logbooks entries are correct

Records & Data to be Reviewed
 Verify the weighing record / weight print are available.
 Check the weights used is within the range specified in the procedure
 Is dilution prepared as per procedure and recorded
 Confirm solution prepared as per procedure (where required freshly
prepared) and used are within valid period.prepared) and used are within valid period.
 Verify the chemicals, reagents, buffer solutions, mobile phase, test
solutions, volumetric solutions, reference standards, sample, etc., used
are correct
 Confirm material and reagents are stored as per recommended condition
 Verify the solution preparation details of and standardization records
 Ensure that sensitive reagents are not opened multiple times and used
eg. OPA. TEA etc

Review of Sampling Report
 Written procedures for sampling methods for in-process materials,
intermediates, and APIs.
 Samples should be representative of the batch
 Sampling plan and procedure should be based on rational &
scientific basis
 Specify the quantity of sample drawn from each containers, Specify the quantity of sample drawn from each containers,
number of containers to be sampled, how & where to collect
sample.
 Verify the environment while sampling and area should be
protected to prevent contamination
 Containers should be opened carefully and closed properly.
 Containers should be identified that are sampled
 Record all the above details and report has to be reviewed

Review of Sampling Report
 Ensure Labels are available on each container, supplier label,
quarantine. Verify name, lot no etc are correct
 Follow sampling procedure & prepare representative samples
 Record for detailed sampling activity with purpose
 Store the sample properly & prevent mix-up/contamination Store the sample properly & prevent mix-up/contamination
 Registration number allocated for every sample
 Information recorded in a register and include e.g.: Registration
number of the sample, date of receipt, location of sample
 In-process sample shall be obtained from production with request
and appropriate tests will analysis before testing starts

Review of Sample Information
 Ensure that storage of sample as per recommended condition and
protect from contamination or degradation. eg temperature
sensitive, hygroscopic, etc
 There should not be any additional / extra sample are tested.
 Review the record including log books to confirm that any testReview the record including log books to confirm that any test
performed without documentation.
 Reconciliation of each Sample used for routine test or additional
test or stability sample
 Destruction of leftover sample

Data Review: Reference Standard
Reference Standard:
Record of receipt & source shall be documented
◦ Record the Lot no, potency, water content or LOD value from
the certificate
◦ Indicate the usage : eg “as is” or apply potency or dry basis
◦ Periodic verification for Pharmacopeia Standard for current lot◦ Periodic verification for Pharmacopeia Standard for current lot
Working standard:
 Record on source (Selection / purification), Qualification/
Characterization record with raw data.
◦ Confirm potency/ moisture or LOD values are established
◦ COA & validity and supporting document for expiry.

Data Review: Reference Standard
Reference Standard / Working standard:
Review and ensure the following;
 Verify the Storage & handling conditions
 Usage instructions “as is” or e.g, “dry before use”, etc . Is followed
 Verify the correct potency is applied in the calculation Verify the correct potency is applied in the calculation
 Reference standard / Working standard usage log
 Reconciliation of use of standard- regulator may suspect that
standards are used as sample. Ensure Standard is has not expired

Data Review : Primary Standard
 Primary Standard for standardization of VS
 Calibration standards with NIST traceable
 Reference Standard: Record of receipt detail and document
 COA & validity and supporting document for expiry
 Verify lot no, potency, water content, LOD value are recorded
and applied for calculation as in the certificate
 Usage instructions “as is” or e.g, “dry before use”, etc.)
followed and recorded
 Reconciliation of use of standard

Review of Reagents usedReview of Reagents used
 Chemicals and reagent used for analysis shall be recorded in raw data.
 Ensure reagent used are within the validity period and recorded
 Record shall have make, grade, lot number and validity.
 Documentation of all Chemical and Reagent usage information for both Documentation of all Chemical and Reagent usage information for both
release and in-process testing
 Standard Record of Analysis with spaces provided for recording
purposes
 Chemicals and reagent shall be labeled of opening and validity
properly and stored as per recommended condition.
 Establish the solution stability for volumetric solution & test solutions

Review of Calibration ReportsReview of Calibration Reports
Review the calibration record, for the following;
 Calibration performed as per schedule,
 Calibration parameter & procedure is as per pharmacopeia or other
standard method
Calibration performed as per procedure Calibration performed as per procedure
 Values are meeting the acceptance criteria
 Conclusion on calibration with next due is recorded
 Standard used is traceable eg NIST
 Is Label affixed on the analytical equipment
 Out of calibration (OOC) if any is reported, investigated & assessed
for impact on the test result of previously approved material.

Review of Reserve Sample RecordReview of Reserve Sample Record
Review the reserve /retain sample records for the following;
 Review the reserve/ retain samples are packaging, identified and stored
 Should be retained for one year after the retest/ expiry date of the batches
for three years after distribution of the batch, whichever is the longer.
 Stored in the same packaging system in which the API is stored or
equivalent or more protective than the marketed packaging system.
 Quantities should be at least two full compendial /in-house specification
analyses
 Reserve samples from representative sample lots or batches selected by
acceptable statistical procedures shall be examined visually at least once a
year
 Any evidence of reserve sample deterioration shall be investigated
 Record for all of the above activities documented and maintained

Review of Chromatographic data:
 Verify the Chromatograms are printed with proper scale to identify all
the peaks eg. Print lower level scale (zoom) for related substances test to
visually see the small impurities
 Test data and test results are accurately transcribed from the
instrument printout to the Laboratory notebook.
 Report the incident / deviation any of the following is observed Report the incident / deviation any of the following is observed
◦ System Suitability Failures
◦ Out of limit before or after sample injection
◦ Instrument malfunction during analysis or any other assignable cause
◦ Justification for the incident if failure is before sample injection
◦ Investigated the failure if any after sample injection
◦ Corrective actions to prevent the reoccurrence of failure

Review of Chromatograms:
Verify the following in Chromatographic data;
 All are tested as per approved test method.
 Instrument set conditions, Injection sequence are as per STP/SOP.
 System suitability, Retention time etc are meeting the acceptance criteria
 All the chromatograms / sequence /method are printed and signed with date
 Injection date and time are in order and in sequence
 Ensure integration is default and integration parameters are same in the
entire sequences processed.
 Reprocessing or manual integration if any shall be authorized, verified and
justified by QA
 Check the hard copy is matching with softcopy
 Calculation of all the related substance & assay from raw data
 If any time gap found, it shall be justified and documented.

Review of Audit Trail
Review of Audit trail:
 Use check list for audit trail verification and Record the same.
 Changes in the test method, sequence, addition or deletion of
sequence
 Any change shall be recorded with reason and justification
 Verify that here is no re-processing, re-testing, no unprocessed
injections. peak /base line correction or extraneous peak
 Avoid the manual integration; if required , get approved by QA.
 Ensure that there is no trial injection, additional test/data that was
not documented.
 Changes to the standard / sample weight or dilution or any other
data that may compromise the reported results.

Audit Trail Reviewer
 Reviewer of audit trail should have adequate knowledgeable
and specially trained on Part-11 requirement.
 Experience and competent in chromatographic analysis,
application software, Instrumentation, computer etc
 Knowledgeable in chromatographic data processing technique: Knowledgeable in chromatographic data processing technique:
◦ Integration parameters and its impact on the variation of result
◦ Manual Integration
◦ Selective peak inhibition
◦ Error message in the application software

Role of AnalystRole of Analyst
 Analyst: Perform all tests as per approved specifications and method
and record the same and follow GxP.
 Record the reagents, reference standard used , cross reference,
update the relevant register/records
 Record measurement, calculations with units of measurement
 Attach all supporting data eg. Printouts, Graphs, charts, spectra etc
 Document all the activities contemporaneously and sign with date
 Report the test results, compare with Specification and conclusion.
 Report the assignable cause if found, also report the deviation /
failure result immediately to Lab manager
 Correction if any can be done as per procedure

Role of Reviewer
 Review the OOS, Deviation/Incident &Investigation reports for
completeness. Verify the problem statement, timely initiation , root cause,
remedial action and CAPA.
 Verify all are documented chronologically and as per procedure.
 Ensure copy of supporting data is attached, indexed as applicable.
 Verify & track the action are implemented as per target time.
 Report to QC/QA immediately failure / deviations are not reported and Report to QC/QA immediately failure / deviations are not reported and
identified during review and initiate the investigation
 Complete review of records in time / as per timeline in the SOP.
 Document the review by filling the checklist. Record the observation if
found during review.
 Analyze / trend the observations periodically an take action eg training
change of procedure/ instruments etc
 Classify the major and critical observations eg lack of training, lack of
procedure / instruction, deviation from SOP, GDP etc

Good Document Practice
&
Data IntegrityData Integrity

Data IntegrityData Integrity
Data integrity is critical to regulatory compliance, and the
fundamental reason for 21 CFR Part 11.
A - Attributable
L – Legible
C – ContemporaneousC – Contemporaneous
O – Original
A - Accurate
+ Complete
+ Consistent
+ Enduring
+ Available

ALCOA DescriptionALCOA Description
ALCOA Description/Explanation Comments
AA Attributable Who performed an action and when? If a
record is changed, who did it and why?
Link to the source data.
Who did it?
Source data
LL Legible Data must be recorded permanently in a
durable medium and be readable.
Can you read it?
Permanent record
CC Contempora
neous
The data should be recorded at the time
the work is performed and date/time
stamps should follow in order.
Was it done in
“real time”?
OO Original Is the information the original record or a
certified true copy?
Is it original or
true copy?
AA Accurate No errors or editing performed without
documented amendments.
Is it accurate?

ALCOA & CCALCOA & CCEAEA
ALCOA + Description/Explanation Comments
+1 Complete All data including repeat or reanalysis
performed on the sample.
21 CFR 211.194
+2 Consistent Consistent application of data time
stamps in the expected sequence
Date time
stamps
+3 Enduring & Recorded on controlled worksheets,
laboratory notebooks, orelectronic
media.
Medium -to
record data
+4 Available Available/accessible for review/audit
for the lifetime of the record.
For the lifetime
of the record

Good Documentation PracticesGood Documentation Practices
Use only black or blue permanent ink.
The ink should not run or smear if the
record is splashed with liquid. All entries
must be permanent and able to be
photocopied.
42
• Pencil writing is not
acceptable,
photocopied.
Don’t use pens like gel pens, ink pens
for making entries. Don’t use pens like
red, green color ink.

 Ensure correct rounding off & significant figures
 All entries must be clear and legible
 Never make erasures or write overs.
 Do not scribble out or "white out" entries;
 Any written error must be crossed out in such a manner that the original
information is still legible.
 The crossed out section must be initialed and dated by originator.
Corrections must be made adjacent to the deleted entry. Write reason for
correction eg Transposition, Illegible entry, Scale zero error
 DO NOT USE “write-overs” (Don’t turn a “6” or “9” into an “8”.)
 Never vary your initials or signature
 Eg. Weight of material - 14.5 kg 14.75 kg Ams 13/12/07
43

 Ditto marks or continuation lines are not acceptable.
 Blank or unused spaces has to be crossed /slash mark.
signature and date.
 Document shall be free from error.
 Tape to secure data in notebooks – Do not apply tape
over any data, and ensure initials and date are signedover any data, and ensure initials and date are signed
overlapping both the notebook page, and the data
being secured.
 If space/ column for entry of data is constraint. Write
separately with footnote.
 Don’t try to squeeze to avoid unclear/unreadable entry.
44

Typical FDA ObservationsTypical FDA Observations
 During the review of QC Batch Records and supporting documents, it was
observed that the analysts occasionally applied inhibit integration time
events to regions of the chromatogram, where peaks of interest were not
detected during visual checking of the sample chromatograms on an expanded
scale. As such, manual detection practice is subjected to human error, and
could lead to the unintended under-reporting of impurities, and results,
especially when minute impurities escaped detection by naked eyes. Thisespecially when minute impurities escaped detection by naked eyes. This
incident report is initiated as a concern of manual detection of peaks, versus
leaving the integration to the capability of the Waters Empower
Chromatography Software.
 Inhibit integration time events have been observed in the processing
methods for the detection, and integration of impurities in Related Substances
by GC and HPLC. This incident report intends to delineate whether all peaks of
interest have been accurately detected and integrated during the application
of inhibit integration time events to the product batches A, B and C.

Typical FDA ObservationsTypical FDA Observations
 Audit Trails - Consideration should be given, based on a risk assessment, to
building into the system the creation of a record of all GMP-relevant changes
and deletions (a system generated "audit trail").
 For change or deletion of GMP-relevant data the reason should be
documented. Audit trails need to be available and convertible to a generally
intelligible form and regularly reviewed.intelligible form and regularly reviewed.
 Each software has its own audit trail formats. Need to be familiar with the
individual system audit trail features in order to create the data review
procedures that include the instructions for reviewing the relevant audit
trail reports.
 Altered Sample Sets (changes to injection sequences including sample
identifiers) are identified and Audit trail includes rationale for “alteration”.
 Modification associated with “Altered Sample Set” should be approved prior
to data acquisition.

Review of Quality Control Record and Analytical Data by Dr. A. Amsavel

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