Good Laboratory Practices for Pharmaceutical Quality Control Laboratories. GMP Requirement, Sample management, Reagents, calibration, Standard, Reserve samples, Analysis, Documentation, Data Integrity etc

1. Good Laboratory PracticesGood Laboratory PracticesGood Laboratory PracticesGood Laboratory Practices
Dr. A. Amsavel
1

2. Good Laboratory Practices
in Pharmaceutical
Quality Control Laboratory
Reference: GMP Guidelines
◦ ICH Q7: specifically Chapters 6, 7, 11, 12 &13
◦ 21CFR 210 & 211
◦ Schedule L1
2

3. ContentContent
 Definition
 Requirements
 QC Lab Management
 QC personal
 Sample Management
 Reagents & Reference standard Reagents & Reference standard
 Instruments and Calibration
 Computer System Validation
 Analysis, analytical data & Review
 Reserve sample
 Purposes of GMP Documentation
 Tips to good documentation practices
 Warning letters and observations
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4. Definition (WHO)Definition (WHO)
Analytical worksheet
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 .
Measurement uncertaintyMeasurement uncertainty
Non-negative parameter characterizing the dispersion of
quantity values being attributed to a measurand (analyte),
based on the information used
Metrological traceability
Property of a measurement result whereby the result can be
related to a reference through a documented, unbroken chain of
calibrations, each contributing to the measurement uncertainty.
4

5. Definition (WHO)Definition (WHO)
 Deviation:
Deviation from the prescribed procedure
 Out-Of-Specifi cation (OOS) result
All test results that fall outside the specifications or acceptance
criteria established in product dossiers, drug master files,criteria established in product dossiers, drug master files,
pharmacopoeias or by the manufacturer
 Reference substance (or standard)
An authenticated, uniform material that is intended for use in
specified chemical and physical tests, in which its properties are
compared with those of the product under examination, and which
possesses a degree of purity adequate for its intended use
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6. ICH Q7:RequirementICH Q7:Requirement
6.0 DOCUMENTATION AND RECORDS
6.1 Documentation System and Specifications
6.3 Records of Raw Materials, Intermediates, API.& Packaging Materials
6.6 Laboratory Control Records
7.0 MATERIALS MANAGEMENT
7.3 Sampling and Testing of Incoming Production Materials
11.0 LABORATORY CONTROLS
11.1 General Controls11.1 General Controls
11.2 Testing of Intermediates and APIs
11.3 Validation of Analytical Procedures - see Section 12
11.4 Certificates of Analysis
11.5 Stability Monitoring of APIs
11.6 Expiry and Retest Dating
12. 0 VALIDATION
12.8 Validation of Analytical Methods.
13.0 CHANGE CONTROL etc
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7. CFR ReferencesCFR References
21 CFR 58 GLP:
 All data generated during performing of a study, (except
automated data collection systems), shall be recorded directly,
promptly, and legibly in ink.
 All data entries shall be dated on the date of entry and signed or
initialed by the person entering the data.initialed by the person entering the data.
 Any change in entries shall be made so as not to obscure the
original entry, shall indicate the reason for such change, and shall
be dated and signed or identified at the time of the change.
21 CFR 211.194 (a)
Verification of laboratory test data for “Accuracy, Completeness
compliance with established standards”
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8. Laboratory ManagementLaboratory Management
 Organization and management
 Quality management systems
 Control of documentation and records
 Data processing equipment Data processing equipment
 Personnel
 Premises, equipment, instruments and other
devices
 Working procedures,
documents and safety
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9. Organization and ManagementOrganization and Management
 Function to meet Regulatory requirements
 Operate in accordance with GxP standards
 Personnel
◦ Adequately Qualified , experienced and competent
◦ Managerial and technical positions to ensure
operation in accordance with quality systems
◦ No conflict of interest
 Organizational chart and job descriptions
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10. Organization and ManagementOrganization and Management
 Adequate information flow
 Traceability of the samples (from receipt to
test report completion)
 Procedures (SOP), Work instruction & Procedures (SOP), Work instruction &
documents
 Current specifications & test method
 Safety procedures
 MSDS
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11. Documents in QCDocuments in QC
Documents & Procedures should ensure that:
 Specifications, sampling plans, and test procedures should
be scientifically sound
 Shall be current documents with Ref No. Version and Shall be current documents with Ref No. Version and
effective date
 Authorized SOPs are available near points of use
 Invalid documents are removed and replaced
 Revised documents refer to the previous document
 Documents are archived,
 Staff are trained for the new and revised SOPs
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12. RecordsRecords
 Procedure for the identification, collection,
indexing, retrieval, storage, maintenance and
disposal of documents/records.
 All original observations, calculations and
derived data, calibration, validation andderived data, calibration, validation and
verification records, etc. and final results must
be retained on record for an appropriate
period of time, e.g.
 Records to contain sufficient information to
permit repetition of tests and traceability
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13. RecordsRecords
 Legible, readily retrievable, stored and
retained
 In a suitable environment that will prevent
modification, damage or deterioration and/or
lossloss
 Secure, confidential. Access restricted to
authorized personnel.
 Electronic storage and signatures allowed -
restricted access and in conformance with
requirements for electronic records
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14. QC personalQC personal
 Organization chart
 Personal shall have appropriate Qualification /education,
experience or trainings.
 Job description for each person
 Analyst qualification as per assigned work
Training & retraining to analyst, reviewer, validation & Training & retraining to analyst, reviewer, validation &
computer data evaluation
 Training on
◦ Quality system procedures
◦ Pharmacopeia General chapters
◦ Test methods
◦ Operation & calibration of Instruments
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15. General RequirementGeneral Requirement
 Water used in the Lab shall be suitable for indented
use.
 Washing of glassware shall be ensured and validated
 Separate area for sample preparation Separate area for sample preparation
 Separate oven for drying of glassware ( 60°C)
 SOPs are available
 Any deviation, OOS shll be reported and investigated.
CAPA shall be implemented and relevet reports
should be maintained
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16. Sample ManagementSample Management
 Written procedures for sampling methods for in-process
materials, intermediates, and APIs.
 Sampling plans and procedures should be based on scientifically
sound
 Samples should be representative of the batch of material
 Sampling methods should specify the number of containers to be
sampled, which part of the container to sample, and the amount
of material in each container.
 Sampling should be conducted at defined locations and to
prevent contamination
 Containers from which samples are withdrawn should be opened
carefully and subsequently re-closed.
 Containers should be marked to indicate that a sample
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17. Sample ManagementSample Management
 Label affixed to each container of the sample
 Procedure for preparation of representative samples
 Sampling activity shall be recorded and maintained
 Storage of sample and prevent mix-up or contamination Storage of sample and prevent mix-up or contamination
 Registration number allocated for every sample Eg.:
Registration number of the sample, date of receipt,
location of sample sent
 In-process sample shall be obtained from production with
request and appropriate tests will analysis before testing
starts
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18. ReagentsReagents
 Reagents, chemicals, solvents and materials used in
tests and assays shall be appropriate quality
 Reagents from reputed & approved suppliers
 Preparation of reagents:
◦ SOPs and as recommended in pharmacopoeia
◦ Clear responsibility in job descriptions
 Records for the preparation, and standardization of
volumetric solutions
 Storage & validity of based on established stability
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19. ReagentsReagents
 Reagents shall be clearly labelled:
◦ the contents, the manufacturer, the date received and
opened, concentration, storage conditions, expiry or re-
test date
◦ the name, date of preparation, initials of person, expiry
date, concentrationdate, concentration
 Volumetric solutions:
◦ the name, molarity or concentration, date of preparation,
the date of standardization and Normality/factor.
 Transportation in original containers
 When subdivided – into clean, fully labelled containers
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20. Reference standardReference standard
Reference substances and reference materials
 Assign a person responsible
 Primary reference standards obtained from an officially
recognized source like Pharmacopoeia reference substances
/ certified RS
 Use appropriate RS for testing, calibration, qualification Use appropriate RS for testing, calibration, qualification
of equipment, instruments or other devices
Registration and labelling
 Ref / Identification number
 Document the receipt & Label, batch number, etc
 Log or reconciliation
 Procurement evidence/ record
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21. Reference standardReference standard
Record for reference standard
 Ref No /identification No. of the material
 Description of the material
 Source & date of receipt
 batch designation or other identification code
 Potency , LOD any other details as appropriate
 Intended use of the material (e.g. as an infrared reference
material, as an impurity reference material for thin-layer
chromatography, etc.)
 location of storage in the laboratory, and any special
storage conditions
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22. InIn--house Reference standard /house Reference standard /
Working standardWorking standard
 Where a pharmacopeia RS is not available, in-house primary standard
should be established.
 Appropriate testing should be performed to establish fully the identity
and purity of the primary reference standard.
 Full characterization and assign potency or other quality attribute.
 Qualification , characterization recordshould be maintained. Qualification , characterization recordshould be maintained.
 Secondary reference standards (working standard) should be
appropriately prepared, identified, tested, approved, and stored.
 The suitability should established by comparing against a primary
reference standard.
 Secondary reference standard should be periodically re-qualified
 Certificate of analysis with reference to PRS
 Store at recommended condition with expiry date or retest date
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23. Instrument & Testing devicesInstrument & Testing devices
Qualification, Calibration, validation and verification of
equipment, instruments and other devices
 Control, weighing, measuring, monitoring, and testing
equipment critical for ensuring the quality of product should
be calibrated according to written procedures and an
established schedule.established schedule.
 Calibration procedure can be used from Pharmacopiea
 Qualification / requalification DQ, IQ, OQ, PQ as necessary
 Performance verification at appropriate intervals
 Unique identification / code no for equipment, instruments,
devices used for testing, verification and/or calibration
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24. Instrument & Testing devicesInstrument & Testing devices
 Schedule /plan for regular calibration & execution and
record
 calibrations should be performed using standards
traceable to certified standards, if they exist.
 Diplay labels indicating status of calibration and due date Diplay labels indicating status of calibration and due date
 Records of these calibrations should be maintained.
 Instruments that do not meet calibration criteria should
not be used.
 Deviations from approved standards of calibration on
critical instruments should be investigated to determine if
these could have had an effect on the quality of the
intermediate(s)
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25. Records related to InstrumentsRecords related to Instruments
Records kept of each item of equipment/
instrument
 Dates, results and copies of reports, verifications and
certificates of all calibrations, adjustments, acceptance
criteria and the due date of the next qualification,
verification and/or calibrationverification and/or calibration
 Maintenance carried out, and the maintenance plan
 History of any damage, malfunction, modification or
repair
 Use and “remarks or observations” made at the time
the equipment, instruments or devices were used
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26. Analysis & RecordAnalysis & Record
Analytical worksheet
 Analyst shall record the information about the sample, the
test procedure, calculations and the results of testing
 Raw data shall ne controlled / issued by QA or as
appropriateappropriate
 Provides documentary evidence either:
◦ to confirm that the sample is tested as per requirements
◦ to support an OOS result and investigation
 A separate analytical worksheet for each numbered sample
 Keep all the test data (different analysts/units) together.
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27. Analytical worksheetAnalytical worksheet
 Dates (request, start of analysis, and completion), Time as
required
 Name and signature of the analyst
 Description of the sample
 Reference to the specifications and test methods and limits Reference to the specifications and test methods and limits
 Test equipment used
 Reference substance used
 Result of the system suitability test
 Reagents and solvents employed
 Interpretation of the results and the final conclusions
 Deviations and other remarks
 Reviewed / Approved and signed by the supervisor
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28. Analytical worksheetAnalytical worksheet
 Recording the data immediately on the analytical worksheet
 All graphical data attached or be traceable to an electronic record
◦ A complete record of all raw data generated during each test, in
addition to graphs, charts and spectra from laboratory
instrumentation,
Completed analytical worksheet signed by analyst(s), verified and Completed analytical worksheet signed by analyst(s), verified and
approved and signed by the supervisor
 Mistakes and amended results:
◦ old and new information available
◦ signed and dated by the person making the correction
◦ reason for the change given on the worksheet
 SOP for amending electronic worksheets and audit trail
 Follow ALCOA principles
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29. External testing LaboratoryExternal testing Laboratory
 When specific tests are to be done outside the laboratory –
test request and samples transferred.
 Ensure the external Lab is qualified and approved.
 Ensure the Lab id approved by regulatory authority,Ensure the Lab id approved by regulatory authority,
 Establish quality agreement
 Declaration on following the requirement
 Method validation, transfer as required.
 Ensure the sample and Test procedures detailed are
provided and followed
 Deviations/ OOS shall be investigated and documented
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30. Validation of Analytical MethodsValidation of Analytical Methods
 All analytical procedures used for testing should be
suitable for the intended use.
 Analytical method shall be validated as appropriately
 If validation in other Lab, perform method transfer
 Pharmacopoeial methods to be confirmed as suitable
for use. If adapted for another use then to be validated
 In case of a major change in
analytical procedure , it
shall be revalidated
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31. System Suitability TestSystem Suitability Test
Ensure to follow System suitability test as appropriate
 SS is an integral part of many analytical procedures
 Shows that equipment, electronics, analytical operations
are appropriate/suitable for the samples to be analysed
 To be performed prior to the analysis
 In case of a large number of samples analyzed in sequence -
then appropriate system suitability tests are to be
performed throughout the sequence
 Verification not required for basic pharmacopoeial methods
– E.g. pH, loss on drying and wet chemical methods
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32. Review of Analytical ResultsReview of Analytical Results
Evaluation of test results
 All test results shall be reviewed and evaluated
 check that results are accurate , consistent and meeting
specifications
 Doubtful (atypical) and OOS results investigated Doubtful (atypical) and OOS results investigated
(supervisor with the analyst). Checks may include (not
limited to):
◦ Appropriate procedures applied and followed correctly
◦ Discrepancies in raw data; calculations correct
◦ Qualified, calibrated equipment used; system suitability tests were
done and acceptable
◦ Glassware, reagents, solvents and reference substances used
 Original sample kept until the investigation is complete
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33. Review of Analytical recordReview of Analytical record
 Proper review will prevent the Non-compliances/ observation;
 Sincere and effective review shall be done; not just signing as
reviewer;
 The following shall be reviewed but not limited to;
◦ Incomplete entries, signature
◦ missing records and out-prints
◦ Illegible entries / unacceptable corrections
◦ Traceability of relevant records /cross references
◦ Deviations, if any investigation the impact on the product
◦ Valid calibrations and service intervals of test equipment
◦ Compliance with specifications,
◦ Calculations
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34. Review of Analytical DataReview of Analytical Data
 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 + 2CEA◦ ALCOA and + 2CEA
 Good document practice
 Describe, How to review record s for accurate & completeness
 Define , what are the record to be reviewed
 Review of raw data /electronic data,
audit trail etc
 Access & Privileges as required
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35. Reserve sampleReserve sample
Pack & store the reserve samples is for the purpose of
potential future evaluation of the quality of batches of API
 Appropriately identified reserve samples of each API batch
should be retained for 1 year after the expiry date or for 3
years after distribution of the batch, whichever is longer.
The reserve sample should be stored in the same The reserve sample should be stored in the same
packaging system in which the API is stored or in one that
is equivalent to or more protective than the marketed
packaging system.
 Sufficient quantities should be retained to conduct at
least two full specification analyses
 Verify the reserve sample periodically and record for
physical attribute
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36. Computer System ValidationComputer System Validation
 GMP-related computerized systems should be validated.
 Appropriate installation and operational qualifications should
demonstrate the suitability of computer hardware and software to
perform assigned tasks.
 Commercially available software that has been qualified does not require
the same level of testing.
 Computerized systems should have sufficient controls to prevent
unauthorized access or changes to data. There should be controls to
prevent omissions in data (e.g., system turned off and data not
captured).
 There should be a record of any data change made, the previous entry,
who made the change, and when the change was made.
 SOP for the operation and maintenance of computerized systems.
 Any critical data is manual, ensure an additional check on the accuracy of
the entry.
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37. Computer System ValidationComputer System Validation
 Incidents related to computerized systems that could affect the
quality of product or test results should be recorded and
investigated.
 Changes to computerized systems should handled thorough
change procedure.
 Record all changes, modifications and enhancements made to
the hardware, software, and critical component of the system to
ensure that the system is maintained in a validated state.
 Records shall be a backed up. Ensure data protection all
computerized systems.
 Data can be recorded by a second means in addition to the
computer system.
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38. Good Document Practices
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39. Importance of GMP DocumentationImportance of GMP Documentation
“If it hasn't been documented, then it hasn't
done or happened!”
“If it is not documented, it is a rumour!”
Famous FDA statementFamous FDA statement
The product considered as “Adulterated” if
the procedure not followed/ not
documented properly.
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40. Data Integrity PrinciplesData Integrity Principles
ALCOA is an acronym representing the following
data integrity elements:
◦ Attributable – Who performed and when?
◦ Legible – Can it be read? Permanent Record◦ Legible – Can it be read? Permanent Record
◦ Contemporaneous – Recorded at the time the
activity was performed
◦ Original – Original record or certified
true copy
◦ Accurate – Error free
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41. ALCOA DescriptionALCOA Description
ALCOA Description/Explanation
A Attributable Who performed an action and when?
If a record is amended / changed, who did it and
why?
Why- reason & explain in detail
Traceable to the source data.Traceable to the source data.
L Legible Data shall be recorded permanently
Record shall be durable & readable.
C Contempora
neous
The data shall be recorded at the time the work is
performed. Signature / initial with date
O Original Is the information the original record or a certified
true copy?
A Accurate No errors or if editing, shall be amended properly
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42. ALCOA +ALCOA +
ALCOA + Description/Explanation
1 Complete All data including repeat or reanalysis
performed on the sample.
2 Consistent Consistent application of data time
stamps in the expected sequence
3 Enduring & Recorded on controlled worksheets,
laboratory notebooks, or electronic
media.
4 Available Available/accessible for review/audit for
the lifetime of the record.
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43. Good Documentation PracticesGood Documentation Practices
 All entries must be clear and legible
 Never make erasures or write overs.
 Do not scribble out or "white out" entries;
Thus, the integrity of the record will not be in question.
 Any written error must be crossed out in such a manner that the 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
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44. 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.
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Pencil writing is not acceptable,
and able to be photocopied.
Don’t use pens like gel pens, ink pens
for making entries. Don’t use pens
like red, green color ink.

45. Good Documentation PracticesGood Documentation Practices
 When portions of a page or a complete page remain unused, a
single line must be drawn angularly across the unused portion.
Sign and date the crossed out section and provide an explanation
Eg- Not applicable; Remining pages not used refer new note
book
 Ensure the pagination (all pages to be numbered; could be page X Ensure the pagination (all pages to be numbered; could be page X
of Y for loose sheets and page x.. For bound books)
 Make the required entries on the record as the work is
performed.
Do not record information on a
separate piece of paper /temporary
entry and enter on the record later
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46. Good Documentation PracticesGood Documentation Practices
 Use correct rounding off procedures and significant figures
 When a comment or explanation is required, make all
statements objective. Avoid personal comments and opinions.
 When dating a signature, use the actual day the signature was
signed.
 If the activity being recorded occurs on more than one day,
the record must clearly indicate where the "break" occurred.
This can be accomplished by drawing a horizontal line
through the procedure at the break" and indicating the new
date or making entries that are initiated and dated
appropriately.
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47. Poor Documentation PracticesPoor Documentation Practices
 Document error correction not signed/dated, and didn’t include
a reason for the correction
 Write-overs, multiple line-through and use of "White-out" or
other masking device
 Sample sequence table and audit trail not documented (if its not
documented, it didn’t happen)documented, it didn’t happen)
 SOP related to production, calibration, storage and maintenance
not authorized by the QA head
 The delegation for the batch release, in case of absence of the QA
manager, not recorded / documented
 Out-of-specification (OOS) procedure not detailed enough; flow
chart and /or check-list not available.
47

48. 48
“ I swear to follow the good documentation
practice and document the actual
information at the time of performed …..”

49. Data integrityData integrity issuesissues
 Backdating/Postdating/Missing Signatures
• Fabricating/faking data
• Copying existing data as new data
• Releasing failing product
• Hiding/obscuring SOP or protocol deviations• Hiding/obscuring SOP or protocol deviations
• Not saving electronic or hard copy data
• Inadequate reporting of failure and deviation
• Use of non-validated software
• Mismatch between reported data and actual data
• No links/traceability to source documents or original data
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50. Data integrity issuesData integrity issues
 Re-running samples / Test until release
 No or Inappropriate Audit Trail
 Inadequate Access Authorization/ Privileges
 Discarding Deleting of data/ omitting negative data (like OOS or
eliminating outliers)
 Not reporting failing results /stability failures Not reporting failing results /stability failures
 Conducting unofficial analysis
 Disabling audit trails in electronic data capture systems
 Fabricating training data
 Having unofficial batch sheets and analytical reports
This is not related to training or understanding a particular
technical or quality concept but mainly related to honesty and
ethical issues.
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51. Typical content in WLTypical content in WL
 Firm did not identify, report, or investigate the out-of-
specification (OOS) results.
 Firm did not retain any raw data related to sample weights
and sample solution preparations for the HPLC assays….
 Repeated the analysis next day using a new set of sample Repeated the analysis next day using a new set of sample
solutions, and reported the retest results in COA
 Firm deleted /disregarded OOS data without
investigations, and selectively reported only passing
results.
 During inspection, QC Chemist admitted that, under the
direction of a senior colleague, he had recorded false data
in the logbooks for reserve samples
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52. Typical content in WLTypical content in WL
 QC analyst label sample “trial” injections as standard rather than
by the actual sample batch numbers”
 Creating passing test results without performing the test
 Access control is not implemented in GC, FTIR and HPLC to
prevent unauthorized access and control
 Lack of records demonstrating who performed analysis
 Raw data not recorded contemporaneously nor by the
performing analyst
 Failed injections of QC standards (SS) deleted, repeated and
inserted into the analytical sequence without explanation.
 Falsification of batch records (re-writing clean records) Non-
contemporaneous recording of lab data Recording of sample
weights on scraps of paper Missing raw data 52

53. Follow GLP
Thank You
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