Status of the ICH Q11 Guideline on Development and Manufacture of the Active Substance. Riccardo Luigetti Prague, 9 December 2009

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1 European Medicines Agency Status of the ICH Q11 Guideline on Development and Manufacture of the Active Substance Riccardo Luigetti Prague, 9 December 2009 The views presented in these slides are those of the author and should not be understood or quoted as being made on behalf of the EMEA and/or its scientific committees 1 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 2 1

2 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 3 ICH Q8/9/10/(11) A new vision Develop a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science Brussels,

3 Regulatory framework - ICH ICH Q8 Pharmacutical Development (implemented) ICH Q8 annex (Implemented) ICH Q9 Quality Risk Management (implemented) ICH Q10 Pharmaceutical Quality System (step 5 regional implementation) Q/As from the ICH Q Implementation working Group clarifying concepts in the guidelines e.g. Pharmaceutical Quality Systems, Knowledge Management, Design Space, Real Time Release Testing, Control Strategy (published on the ICH and EMEA websites) 5 Quality by Design Quality: The suitability of either the drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity (from ICH Q6A and ICH Q8) Quality by Design: A systematic approach to development that begins with predefined objectives and emphasises process and product understanding and process control, based on sound science and quality risk management (from ICH Q8 annex) Process Analytical Technology (PAT): A system for designing, analysing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality (from ICH Q8) 6 3

4 Regulatory framework EU guidelines Chemical products Chemistry of Active Substances (1987) Chemistry of New Active Substances (rev ) Biological products Development Pharmaceutics for Biotechnological and Biological Products (2000) Several guidelines published on Manufacture, Characterisation and Control of the Drug Substance, mainly related to specific kind of products and/or tests e.g. Production and Quality Control of Monoclonal Antibodies and Related Substances; Potency Testing of Cell Based Immunotherapy Medicinal Products for the Treatment of Cancer 7 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 8 4

5 Q11 Problem statement From the Concept Paper (April 2008) Limited guidance regarding the description and justification of development and manufacturing processes for drug substances and the type and extent of information to be submitted in regulatory dossiers Many of the principles and concepts that have been addressed in ICH guidelines Q8, Q9, and Q10 are also applicable to the development and manufacture of drug substances Biotechnological/biological drug substances present a number of unique manufacturing and quality challenges therefore it will be important to identify what is common and what is different between the development and manufacturing of biotechnological/biological and chemical entities Variability in the content and level of detail requested by the various regions for evaluating the concisely described meaningful scientific knowledge gained during development 9 Q11 Scope (1) From the Concept Paper (April 2008) Harmonisation of scientific and technical principles for the development and manufacturing process of Drug Substances Including both chemical entities and biotechnological/biological entities Take into consideration concepts included in ICH guidelines (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality Systems (Q10) 10 5

6 Q11 Scope (2) Biological and chemical entities Development and manufacturing process Traditional and enhanced approaches to development 11 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 12 6

7 Development status After St Louis ICH meeting (October 2009) progress made but not ready for public consultation 4 working groups are working on 4 main areas to be covered by the guideline Control strategy (including starting materials) Pharmaceutical development Process validation Description of Manufacturing Process (including lifecycle management) Good guideline is more important than completion time 13 Issues to be addressed (1) Starting materials Defined chemical structure Significant structural fragment Commercial availability Specification for SM SM for semi-synthetic substances SM in the dossier defines the point from which GMP is applicable 14 7

8 Issues to be addressed (2) Process validation Traditional approach (3 batches) vs continuous monitoring What to file pre-approval vs before commercial distribution (results of PV studies in MA dossier should be submitted pre-approval for sterile NCE and biotech) Approaches to PV for biotech Manufacturing platform concept Use of models and scaling PV data when a design space is proposed in the application 15 Issues to be addressed (3) Development Drug Substance Quality Attributes (linkage of CQA to proposed CPP) Delineation of traditional & enhanced approaches for the active substance 16 8

9 Issues to be addressed (4) Manufacturing process Lifecycle management Information required for description of the Design Space Controls of critical steps and intermediates 17 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 18 9

10 Progress in St. Louis (October 2009) Control strategy (starting materials) Major content for control strategy agreed Discussion ongoing on definition of starting materials Issue still open is definition of starting materials for semi-synthetic products Development section Agreed on major content, some issues identified for further discussion Process validation Need further discussion in particular on validation approaches for biologicals and on alternative approaches to validation Manufacturing process description Major content agreed Section on lifecycle management under development 19 Next steps Working groups to continue to work separately on the main areas to be covered by the guideline between ICH meetings Interim meeting of the EWG in March 2010, following ICH October 2009 meeting in St. Louis Next ICH meeting in June 2010 in Brussels Target for finalisation of the guideline for public consultation 4Q

11 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 21 Guideline on NIR Revision of the GL started to take into account advance in science and technique (e.g. PAT) Public consultation phase ended in August 2009 Next step: finalisation of the guideline by 3Q

12 GL on Parametric Release Revision of the GL started to introduce Real Time Release Testing concept Concept paper published in December 2008 Next step: publication for external consultation by 1Q GL on Process Validation Revision of the GL started in order to take into account new concepts (e.g. continuous process monitoring) Included in the QWP work program for 2010 Next step: publication of the concept paper by 3Q

13 Content of the presentation The regulatory framework ICH Q11 Scope Development status Next steps Other ongoing g related regulatory activities Conclusions 25 Conclusions (1) Q11 will extend the new quality paradigm (Q8-9-10) to active substances, this will be particularly relevant for biotechnological/biological products The scope of the document is broad (chemical/biological products; development/manufacture; traditional/enhanced approach to pharmaceutical development) Due to the complexity of the topic and to the ambitious scope, some difficulties still to be overcome and further discussion needed at ICH and regional level before public consultation 26 13

14 Conclusions (2) It will be a very important document which will help the introduction ti of QbD concepts and techniques, in particular for what concerns biotech/biological medicinal products In addition, some fundamental gaps currently present in the available guidance (for both traditional and enhanced/qbd approaches) will be filled 27 Acknowledgment Thanks to Keith McDonald (MHRA) member of the ICH Q11 Expert Group as EU regulator, for kindly reviewing the presentation 28 14

15 Thank you for your attention! ti Any question? europa eu