Good Laboratory Practices- Pharma QC Lab_Dr.Amsavel

1
Good Practices for QC Laboratories in Pharma
Industries

• Dr. A. Amsavel

2
The Overview

• Definition
• Requirements
• QC Lab Management
• Documents Records
• QC personal
• Sample Management
• Reagents Reference standard
• Instruments and Calibration
• Computer System Validation
• Analytical method
• Analysis, analytical data Review
• Reserve sample
• Purposes of GMP Documentation
• Tips to good documentation practices
• Warning letters and observations

3
Definition (WHO)

• Quality ControlAll measures taken, including
  the setting of specifications, sampling,
  testingand analytical clearance, to ensure that
  raw materials, intermediates, packaging materials
  and finished pharmaceutical products conform with
  established specifications for identity,
  strength, purity and other characteristics
• Quality Management SystemAn appropriate
  infrastructure, encompassing the organizational
  structure,procedures, processes and resources,
  and systematic actions necessary toensure
  adequate confidence that a product or service
  will satisfy givenrequirements for quality.
• Analytical test reportAn analytical test report
  usually includes a description of the test
  procedure(s) employed, results of the analysis,
  discussion and conclusions and/or recommendations
  for one or more samples submitted for testing

4
Definition (WHO)

• Analytical worksheetA 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 uncertaintyNon-negative parameter
  characterizing the dispersion of quantity values
  being attributed to a measurand (analyte), based
  on the information usedMetrological
  traceabilityProperty 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.

5
Definition (WHO)

• Deviation
• Deviation from the prescribed procedure
• Out-Of-Specifi cation (OOS) resultAll test
  results that fall outside the specifications or
  acceptance criteriaestablished 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

6
GDP 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.
• 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.

7
GDP references

• 21 CFR 211.194 (a)
• Verification of laboratory test data for
  Accuracy, Completeness compliance with
  established standards
• ICH Q7 Chapter6 other GMP guidelines
• Documentation and Records

8
Why 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 statement
• The product considered as Adulterated if the
  procedure not followed/ not documented properly.

9
QC Lab Management

• Organization and management
• Quality management systems
• Control of documentation and records
• Data processing equipment
• Personnel
• Premises, equipment, instruments and other
  devices
• Working procedures, documents and safety

10
Organization and Management

• Function to meet Regulatory requirements
• Operate in accordance with Good Practice
  standards
• Good Manufacturing Practices and Good Practices
  in Quality control
• 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
• Supervision and training

11
Organization and Management

• Adequate information flow
• Traceability of the samples (from receipt to test
  report completion)
• Procedures (SOP), Work instruction documents
• Current specifications test method
• MSDS
• Safety procedures

12
Documents in QC

• Procedures should ensure that
• All specifications, sampling plans, and test
  procedures should be scientifically sound
• 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

13
Records

• Procedure for the identification, collection,
  indexing, retrieval, storage, maintenance and
  disposal of documents/records.
• All original observations, calculations and
  derived 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

14
Records

• Legible, readily retrievable, stored and retained
• In a suitable environment that will prevent
  modification, damage or deterioration and/or loss
• Secure, confidential. Access restricted to
  authorized personnel.
• Electronic storage and signatures allowed -
  restricted access and in conformance with
  requirements for electronic records

15
QC personal

• Organization chart
• Assess and ensure QC has sufficient people
• 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 computer data evaluation
• Training on
• Quality system procedures
• Pharmacopeia General chapters
• Test methods
• Operation calibration of Instruments

16
General 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 oven for drying of glassware ( 60C)
• 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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Work plan

• Forwarding to testing / work allocation
• Sample for testing allocated to analyst or unit
• Should have competence, expertise, training
• Use specification and test procedure
• Verbal requests for testing followed up by
  written request
• Ensure the resources reagents are available

18
Sample 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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Sample 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
• 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 sent
• In-process sample shall be obtained from
  production with request and appropriate tests
  will analysis before testing starts

20
Reagents

• Reagents, chemicals, solvents and materials used
  in tests and assays shall be appropriate quality
  with COA
• From reputable, 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

21
Reagents

• 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, 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

22
Reference standard

• Reference substances and reference materials
• Assign a person responsible
• Primary reference standards obtained from an
  officially recognized source
• Pharmacopoeia reference substances / certified RS
• Used for testing, calibration, qualification of
  equipment, instruments or other devices
• Registration and labelling
• Ref / Identification number
• number marked on each vial and quoted on the
  analytical worksheet at every use (batch number)
• Log or reconciliation
• Procumbent evidence/ record

23
Reference 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 apprppriate
• 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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In-house Reference standard / Working 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.
• 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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Instrument 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.
• 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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Instrument Testing devices

• Schedule /plan for regular calibration
  execution and record
• calibrations should be performed using standards
  traceable to certified standards, if they exist.
• Display 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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Records 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 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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Analysis 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 appropriate
• 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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Analytical 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
• Test equipment used
• Reference substance used
• Results of the system suitability test
• Reagents and solvents employed
• Results obtained
• Interpretation of the results and the final
  conclusions
• Deviations and other remarks
• Reviewed / Approved and signed by the supervisor

30
Analytical 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 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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External 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,
• 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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Validation of analytical procedures

• Validation of analytical procedures
• 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

33
System Suitability testing

• 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

34
Review 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
  (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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Review 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

36
Reserve 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
  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

37
Computer 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.

38
Computer 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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• Good Document practice

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Good Document practiceData Integrity

• ALCOA is an acronym representing the
  following data integrity elements
• Attributable Who performed and when?
• 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

41
ALCOA Description
ALCOA 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.
L Legible Data shall be recorded permanently Record shall be durable readable.
C Contemporaneous 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
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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Tips to Good 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 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 (Dont 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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Tips to Good 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. Dont use pens like gel
pens, ink pens for making entries. Dont use pens
like red, green color ink.

• Pencil writing is not acceptable,

45
Tips to Good 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 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

46
Tips to Good 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.

47
Observations on poor documentation practices

• Document error correction not signed/dated, and
  didnt 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 didnt
  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.

48
I swear to follow the good documentation
practice and document the actual information
and on line..
49
Data integrity issues

• Backdating/Postdating/Missing Signatures
• Fabricating/faking data
• Copying existing data as new data
• Releasing failing product
• 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

50
Data integrity issues

• Re-running samples / Test until release/ No
  /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
• 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.

51
Typical 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 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

52
Typical 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

53

• Thank You
• QA