1. Role of GLP Compliance in
Generating Accurate & Reproducible
BE Data
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd.
Presented at ACRO India Workshop
AMA, Ahmedabad, India, July 19-20, 2013
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2. Contents
• GLP, its evolution
• Fundamentals of GLP
– Resources
– Rules & Characterization
– Documentation & QAU
• Regulatory BE studies
• GLP in BE
– USFDA, EU
• Legal & Excellence GLP
• GLP expectations in Bioanalytical
• Best BE Results
• Concluding remarks
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3. Good Laboratory Practices (GLP)
• Good Laboratory Practices or GLPs were initially invoked in a
reaction to malpractices in laboratories conducting safety
experiments of medicines.
• In early 1970s, research laboratories in the USA were found
doing work in unethical ways, like:
– data generation without conduct of study
– falsification of laboratory work
– replacement of dead animals and fabrication of test results etc.
• As a result, a series of guidelines were issued by US FDA,
Japan and finally by the whole group of OECD countries.
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4. Evolution of GLP
• 1976 – USA: FDA proposals
• 1978 – USA: FDA final rules
• 1980 – USA : FDA amendment to GLP
• 1981 – OECD: Guidelines for testing of chemicals – OECD Paris and
Guidelines for National GLP inspections – Paris
• 1982 – OECD: GLP in testing of chemicals - Paris
• 1984 – Japan: GLP proposals and notification to agricultural
production bureau
• 1987 – USA: FDA amendment final rule
• 1988 – OECD: Final report for working group on mutual
recognition of compliance with GLP
• 1989 – UK: GLP compliance program
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5. Fundamentals of GLP
1) Resources: organization, personnel, facilities
and equipment.
2) Rules: protocols and written procedures
(SOPs).
3) Characterization: test items and test systems.
4) Documentation: raw data, final report and
archives.
5) Quality assurance unit.
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6. Resources
• Organization and Personnel:
– structure of the research organization and responsibilities of the
research personnel should be clearly defined
– staffing levels must be sufficient to perform the tasks required
– qualifications and the training of staff must also be defined and
documented
• Facilities and Equipment:
– sufficient facilities and equipment must be existent in order to
perform the studies
– all equipment must be in working order.
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7. Rules & Characterization
• Protocols and Written Procedures:
– main steps of research studies must be described in the
study plan or protocol
– for repeatability of the studies and reproducibility of
results, routine procedures are described in SOPs
• Test item and the Test system
– essential to know as much as possible about the test item
and about the test system (often an animal or plant) to
which it is administered.
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8. Documentation & QAU
• Raw data must be accurately captured and organized to
reflect the procedures and conditions of the study
• Final report is the responsibility of the study director,
ensuring
– that the contents, results and interpretation thereof are accurate
• Archives should be safe for many years and equipped with
logical and prompt retrieval.
• Quality assurance (QA) is a team assuring GLP compliance
– organized independently of the operational and study program, and
function as witnesses to the whole pre-clinical research process.
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9. Critical GLP Violations
• Fabrication or falsification of data
• No Quality Assurance
• No study allotment
• No approved written study plans
• Failure to date, initial or sign data entries
• No training records and / or no job descriptions for
study personnel
• Absence of required information in final reports
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10. Critical GCP Violations
• Fabrication or falsification of data
• Evidence that formal procedure/systems were not in place or rather weak
• Lack of/inadequate Quality Certification.
• Importation and mfg. of investigational product without regulatory licence
• Inaccurate information about investigational product is supplied to
regulatory agency
• Use of expired/recalled/non GMP manufactured investigational product
• Poor/ineffective blinding system
• Poor accountability of investigational product
• Poorly documented/incorrect sponsorship/Legal Representative
arrangements
• Uncontrolled site to site transfer
• Failure to observe IND conditions
• Failure to report serious breaches of trial protocol/GCP
• Little or no oversight of pharmacovigilance requirements

11. Regulatory Bioequivalence (BE)
Studies
• Clinical studies in healthy volunteers
– GCP compliance is a must
• Involves laboratory measurements of drug
concentrations in blood samples
– Logically GLP should be applicable
• They are not non-clinical, safety studies
– Thus may NOT have to CLAIM GLP compliance
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12. Scope Demarcation: GCP and GLP
• GCP: relate to clinical studies using human volunteers patients and
also relate to most of the clinical procedures that can be carried out
without a laboratory test
– Includes all clinical phase I-IV studies
• GLP apply to all analytical and testing process all safety studies for
human health market approval and include QC assays, clinical
chemistry and tests by instruments and certain bioanalytical
procedures
– Excludes validation studies, cosmetic safety, bioanalytical for
efficacy studies including animal efficacy studies
• Good QA is applicable to all biomedical research practices
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13. GLP in BE
• Common perceptions
– Confusing
– Only in the testing of non-clinical safety aspects
– Applies to bioanalytical? Or bioanalytical only?
– Wherever there is a lab
• Clinical pathology
• Serology
• Microbiology
• Bioanalytical…
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14. Guidance for Industry,
USFDA/CDER, May 2001
• “The analytical laboratory conducting
pharmacology/toxicology and other preclinical
studies for regulatory submissions should adhere to
FDA’s Good Laboratory Practices (GLPs) (21 CFR part
58) and to sound principles of quality assurance
throughout the testing process.
• The bioanalytical method for human BA, BE, PK, and
drug interaction studies must meet the criteria in 21
CFR 320.29.”
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15. 21 CFR 320.29
• “….shall be demonstrated to be accurate and
of sufficient sensitivity to measure, with
appropriate precision, the actual
concentration of the active drug ingredient or
therapeutic moiety, or its active metabolite(s),
achieved in the body. ……”
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16. EMEA CPMP/EWP/QWP/1401/98
• “The bioanalytical part of bioequivalence
trials should be performed in accordance
with the principles of Good Laboratory
Practice (GLP).
• However, as human bioanalytical studies fall
outside the scope of GLP, the sites conducting
the studies are not required to be monitored
as part of a national GLP compliance
programme.”
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17. Bioanalytical Guidelines
EMEA/CHMP/EWP/192217/2009
• “The validation of bioanalytical methods and the analysis of
study samples should be performed in accordance with the
principles of Good Laboratory Practice (GLP).
• However, as human bioanalytical studies fall outside of the
scope of GLP, as defined in Directive 2004/10/EC, the sites
conducting the human studies are not required to be
monitored as part of a national GLP compliance programme.
• In addition, for clinical trials in humans the principles of Good
Clinical Practice (GCP) should be followed”.
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18. 18

19. Excellence vs Legal GLP
• Legal GLP
– Accredited
– Monitored & certified by authorities
• Excellence in GLP
– Protocol & study director
– Proper sample collection, storage and processing
– Validated calibration and QC
– Successful analysis of batches
– High quality data (QC)
– Excellent QA
• Tracing, accountability & accuracy
– Proper reporting
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20. GLP expectations in Bioanalytical
• Pre-study method validation
– precision and accuracy – intra- and inter-batch across calibration
range, including LOQ
– selectivity – test for endogenous/exogenous interferences
– stability under study conditions – freeze/thaw, long-term frozen
storage, bench-top, auto-sampler (extract), stock solution
– recommend freshly prepared samples for comparison
– consider conditions of actual use – for example, increased batch size
during actual use
• Written, thorough documentation of the bioanalytical
method and results of validation
20Source: US FDA Guidelines & Presentations

21. GLP expectations in Bioanalytical..
• During incurred sample analysis
– select calibration range and QCs based on expected concentrations
for the study
– include a standard curve and quality control samples with each batch
of subject samples
– assure consistent integration of all chromatograms within a batch
• prepare complete study reports tabulate results for calibration standards,
QCs, subject samples
• list repeat results and the reason for the repeat
• list deviations and their impact
• description of failed runs
21Source: US FDA Guidelines & Presentations

22. GLP expectations in Bioanalytical...
• Reference standard – record identity, purity, expiration date,
lot number
• Document preparation – of stock solutions, and matrix-
based calibration standards and quality control (QC) samples
• Sample handling – store study samples under conditions that
maintain their integrity
• Document – storage condition, freezer removal/return
• Equipment – record instrumentation problems and
maintenance
22Source: US FDA Guidelines & Presentations

23. GLP expectations in Bioanalytical….
• Written procedures – establish a priori acceptance/rejection
criteria
– calibration standards, QCs, system suitability assessments
• e.g., at least 67% of all QCs in the batch, and at least 50% of the
QC replicates at each level, must be within 15% of intended
concentrations to accept a run
– chromatography acceptance
• define procedures for automatic and manual integrations,
handling interferences at the retention time of the analyte
– repeat analysis
• define basis for identifying samples for repeat analysis and
reporting the results of repeated samples
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24. For Best BE Results
• Effectively incorporate both GCP and GLP
• Follow the relevant regulations & guidelines in both areas
• Set up a QMS that follows the principles of total quality with
QA assuring traceability, integrity, accountability and
compliance of documents and standard procedures
• Be very open during internal & external audits and
inspections
• Address all problem areas (both GCP & GLP violations)
• Implement CAPA and improve systems
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25. Concluding Remarks
• Whether claimed or not, GLP compliance of bioanalytical and
clinical chemistry methods can help generate accurate and
precise data for BE studies
• Not all regulatory jurisdictions want it as a mandatory practice
• Many other authoritative regulations etc. (e.g., guidelines,
21CFR 32.9...) mirror the GLP expectations in essence
• Details of GLP expectations are a combination of GLP principles
and bioanalytical guidelines – if both are upheld, you will have
a first class BE data
• Ultimate common goal: integrity, accuracy and quality of
data
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26. Thank You Very Much
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