CMC Strategy Forum, Paris 2008

Transcription

1 Assay Validation Studies in Clinical Development: Regulatory Perspective CMC Strategy Forum, Paris 2008,, Germany 1

2 Scope Biologicals PEI Analytical Validation Not: Process Validation Investigational products Not: licensed products GCP Quality Assessor 2

3 After the TGN 1412 Tragedy What risks are acceptable during phase I clinical trials for healthy volunteers who can not expect a clinical benefit? Is the ratio between safety risks for volunteers and the benefit from clinical trials still well-balanced? How much can be done beforehand to minimise safety risks for volunteers? 3

4 Guidance GMP Annex 13: Manufacture of investigational medicinal products GMP Annex 18: Good manufacturing practice for active pharmaceutical ingredients CHMP/QWP/185401/2004: Guideline on the Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products CHMP/BWP/466097/2007: Concept paper on a guideline on the chemical and pharmaceutical quality documentation concerning biological investigational medicinal products in clinical trials CHMP/ICH/5721/03: Comparability of Biotechnological/Biological Products CHMP/BWP/49348: Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues German Procedural Guideline on clinical trials : 3. Notification on the clinical trial of medicinal products for human use (3. Bekanntmachung zur klinischen Prüfung von Arzneimitteln am Menschen) 4

5 GMP Annex 13 Manufacture of IMP PRINCIPLE Investigational medicinal products should be produced in accordance with the principles and the detailed guidelines of Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in The European Community, Volume IV). Other guidelines published by the European Commission should be taken into account where relevant and as appropriate to the stage of development of the product. Procedures need to be flexible to provide for changes as knowledge of the process increases, and appropriate to the stage of development of the product. In clinical trials there may be added risk to participating subjects compared to patients treated with marketed products. The application of GMP to the manufacture of investigational medicinal products is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. Equally, it is intended to ensure that there is consistency between batches of the same investigational medicinal product used in the same or different clinical trials, and that changes during the development of an investigational medicinal product are adequately documented and justified. The production of investigational medicinal products involves added complexity in. 5

6 Potential Risks for the Volunteer Mode of Action of the AI Expected Features Unexpected Features Other Risks.... Quality Defects Impurities Sterility Stability Conformational Variants Microheterogeneity Potency Undefined Dose 6

7 The Volunteer's Perspective I am prepared to take the risk of a new active ingredient in the hope of a potentially much bigger benefit. The risks should arise only from the (at least partially) unknown properties of the new API. I rely on that the manufacturer takes every care that there are no additional risks which could be prevented by state of the art production and quality control. 7

8 The Perspective of a Seriously ill Patient Although new APIs should be as safe as possible, do not let regulatory pressure slow down the process of bringing effective new API into clinical trials and with that (hopefully) to the market. 8

9 GMP Annex 18: Good Manufacturing Practice for Active Pharmaceutical Ingredients Chapter 19: API for clinical trials 19.8 Laboratory Controls While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials. 9

10 What Makes a Method Scientifically Sound? A publication in a (peer-reviewed) journal? A detailed description in a Pharmacopoeia? A validation according to ICH Q2R? A generic validation? Is there anything in between? 10

11 The Gold Standard : Method Validation Method Development Evaluation and Optimisation Validation Plan Validation Study Validation Report Implementation into Routine QC 11

12 Implementation without Validation Method Development Evaluation and Optimisation Implementation into Routine QC 12

13 Approach 1: Method Qualification Method Development Evaluation and Optimisation X Validation Plan Validation Study Validation Report Implementation into Routine QC 13

14 Approach 2: Ongoing Method Validation Method Development Evaluation and Optimisation Validation Plan Validation Study Validation Report Implementation into Routine QC 14

15 Approach 3: Method validation depending on its importance Method I Development Method II Development Evaluation and Optimisation Evaluation and Optimisation Validation Plan Validation Plan Validation Study Validation Study Validation Report Validation Report Implementation into Routine QC Implementation into Routine QC 15

16 What is absolutely necessary even during the early clinical study phases? All safety aspects: e.g. impurities, sterility, pyrogens, virus safety Content of the active ingredient Biologicals: potency 16

17 What do we gain by using test methods which are not completely validated? Method Development Time (?) Resources (?) Evaluation and Optimisation Validation Plan Validation Study Validation Report Implementation into Routine QC 17

18 German Procedural Guideline on Clinical Trials Annex III/1: General Requirements on the chem. pharm. & biol. Documentation Phase 1 Phase 2 Phase 3 Drug substance Description of the suitability of the test Proposed validation parameters and their acceptance criteria have to be presented in tabulated form Suitability of the test should be demonstrated Validation Results should be presented in tabulated form Complete validation report is not necessary Complete validation report should exist and presented when requested Drug product Description of the suitability of the test Proposed validation parameters and their acceptance criteria have to be presented in tabulated form Suitability of the test should be demonstrated Validation Results should be presented in tabulated form Complete validation report is not necessary Complete validation report should exist and presented when requested Biologics: Val. Report must be presented 18

19 German Procedural Guideline on Clinical Trials Annex III/2: Requirements for Gen. Bioequivalence Studies Drug Substance and Drug Product: Suitability of the test should be demonstrated Validation results should be presented in tabulated form Complete validation report should exist and presented when requested 19

20 German Procedural Guideline on Clinical Trials Annex III/3: Requirements for licensed, modified Reference preparations Suitability of the test should be demonstrated Validation results should be presented in tabulated form Complete validation report should exist and presented when requested 20

21 Conclusions Even in early clinical phases the risks for volunteers should be minimised. This is only possible with drugs of high pharmaceutical quality. High quality can only be ensured by scientifically sound analytical procedures. True validation remains the gold standard for the assessment of analytical test methods and is required for phase III test methods. Only minor reduction of the requirements seem to be possible during phase I and II. 21

22 Thank you for your attention!, CMC Forum Paris