GLP in Bioequivalence Studies

Role of GLP Compliance in Generating Accurate & Reproducible

BE Data

Dr. Bhaswat S. ChakrabortySr. VP & Chair, R&D Core Committee

Cadila Pharmaceuticals Ltd.

Presented at ACRO India WorkshopAMA, Ahmedabad, India, July 19-20, 2013

1

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

2

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.

Board and Dent 19963

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

Board and Dent 19964

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.

5

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.

6

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.

7

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.

8

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

9

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

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

11

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

12

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…

13

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.”

14

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. ……”

15

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.”

16

Bioanalytical GuidelinesEMEA/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”.

17

18

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

19

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

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

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

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

23

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

24

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

25

Thank You Very Much

26