Harmonized Quality Requirements for Biotech Investigational Medicinal Products - A Regulator's View

Transcription

1 Harmonized Quality Requirements for Biotech Investigational Medicinal Products - A Regulator's View Brigitte Brake Pharmaceutical Biotechnology BfArM, Bonn

2 Evaluation Criteria National vs. EU Clinical Trial Applications National Authorities and Authorisation EU 27 Member States 23 Official Languages approx. 500 Mio Marketing Authorisation Application Centralised Procedure / EU BWP/CHMP Need for Harmonisation The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

3 Trial Statistics , Jan Feb März April Mai Juni Juli August Implementation of the European clinical trials directive (Directive 2001/20/EC) in August 2004

4 Trial Statistics Germany implemented the European clinical trials directive (Directive 2001/20/EC) in August Others Phase IV Phase III Phase II Phase I

5 6000 Clinical trials since 08/ Stand Germany Always the same countries ask questions

6 Evaluation Criteria National vs. EU Approval of clinical trials is the responsibility of individual EU Member States, who are evaluating the products used in clinical studies. Currently no common reference guidance on which to base the assessment of quality of biological clinical trial material National guidelines in effect in some MSs e.g. Germany (3. Bekanntmachung zur klinischen Prüfung) France UK (Mock application for a fictitious biotech product) others.. Difference in experience among sponsors and competent authorities

7 Existing Guidelines Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials. (CHMP/QWP/185401/2004) Guideline on the Requirements for First-In Human Clinical Trials for Potential High Risk Medicinal Products (EMEA/CHMP/SWP/28367/2007) EU GMP Guide, Annex 13: Manufacture of Investigational Medicinal Products Guideline on Virus Safety Evaluation of Biotechnological Investigational Medicinal Products (CHMP/BWP/398498/2005)

8 Internationale /EU Guidelines Currently no general guideline on the quality requirements for biotech/ biological investigational medicinal products General scientific considerations apply ICH Q5A: Viral Safety ICH Q5B: Genetic Stability ICH Q5C: Stability ICH Q5D Cell Substrates ICH Q6B Specifications ICH Q5E Comparability Other relevant CHMP/BWP Guidelines

9 Considerations Differentiation between the requirements for a dossier for a clinical trial application (IMPD) and a marketing authorisation application No pre-evaluation of MAA Requirements for clinical trial material should focus on risk/safety aspects and consider nature of product state of development/clinical phase patient population nature/severity of the illness type and duration of clinical trial The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

10 Consideration GMP for Clinical Trial Material Annex 13, EU GMP-Guidance 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.

11 Quality Considerations Safety of subjects participating in first in man studies but also in all other studies is the paramount consideration Quality requirements for high-risk medicinal products are not different to other medicinal products Concerns should not result from quality attributes Is it meaningful to have staged requirements for the different Phases (I-III)? If yes, for what sections of the IMPD How is the differentiation related to safety considerations/ assessment

12 more questions on: viral clearance studies adventitious agents cell bank characterisiation

13 Drafting group BWP Workplan 2009

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15 Main Scope of the Guideline Proteins and polypeptides, their derivatives, and products of which they are components (e.g., conjugates). These proteins and polypeptides are produced from recombinant or non-recombinant cell-culture expression systems and can be highly purified and characterized using an appropriate set of analytical procedures ( see ICH Q6B and ICH Q5C)

16 The guideline will address critical quality aspects Information needed about the structure of a molecule and the quality characteristics of the drug substance Information needed on cell banks Characterisation needed for process and product related impurities Information needed on the manufacturing process, the control of critical steps and in-process controls The development and/or validation of the manufacturing process that is required prior to and during clinical development. Comparability The qualification/validation required for the analytical procedures Setting and justification of preliminary specifications Batch data The requirements for stability data, shelf life extension Pharmaceutical development How much information/data is required??

17 Life Cycle Phases Knowledge on Process and Product adapted from S. Giess /PEI R&D Preclinical Phase I Phase II Phase III Post Marketing

18 Life Cycle Phases Knowledge on Process and Product Safety Impurities Characterisation GMP Critical process steps Stability Comparability exercise Analyt. Validation Consistency Process validation Sterility Viral safety Final characterisation adapted from S. Giess /PEI R&D Preclinical Phase I Phase II Phase III Post Marketing

19 IMPD Documentation follows module 3 format of CTD, as described in ICH M4. the explanatory text in the ICH document is sufficiently general to address MAA and IMPD approx pages No ASMF!!! Grade of detail depends on clinical phase IMPs based on innovative and/or complex technologies may need more detailed data to be submitted

20 Adequate Application?

21 Everything under control??