1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Implementation of ICH Q8, Q9, Q10 Q-IWG Status update Georges France

2. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 2 Q-IWG Status update © ICH, November 2010 Disclaimer The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG members for the purposes of a training workshop.

3. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 3 Q-IWG Status update © ICH, November 2010 ICH Q8, Q9 & Q10 A real opportunity Benefit of a New Paradigm - A life cycle approach: A focus investment during the development with the benefit at the manufacturing - Process Understanding - Process Capability and Robustness - Increase confidence between industry and regulators - Continuous improvement changes - Facilitate innovation and new technology (RMM, PAT,…) - Increased flexibility to implement

4. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 4 Q-IWG Status update © ICH, November 2010 ScenarioPotential Opportunity 1.Comply with GMPsCompliance – status quo 2. Demonstrate effective pharmaceutical quality system, including effective use of quality risk management principles (e.g., ICH Q9 and ICH Q10). Opportunity to: o increase use of risk based approaches for regulatory inspections. 3. Demonstrate product and process understanding, including effective use of quality risk management principles (e.g., ICH Q8 and ICH Q9). Opportunity to: o facilitate science based pharmaceutical quality assessment; o enable innovative approaches to process validation; o establish real-time release mechanisms. 4. Demonstrate effective pharmaceutical quality system and product and process understanding, including the use of quality risk management principles (e.g., ICH Q8, ICH Q9 and ICH Q10). Opportunity to: o increase use of risk based approaches for regulatory inspections; o facilitate science based pharmaceutical quality assessment; o optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement; o enable innovative approaches to process validation; o establish real-time release mechanisms. ICH Q10, Annex I

5. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 5 Q-IWG Status update © ICH, November 2010 ScenarioPotential Opportunity 2. Demonstrate effective pharmaceutical quality system, including effective use of quality risk management principles (e.g., ICH Q9 and ICH Q10). Opportunity to: o increase use of risk based approaches for regulatory inspections. ICH Q10, Annex I

6. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 6 Q-IWG Status update © ICH, November 2010 ScenarioPotential Opportunity 3. Demonstrate product and process understanding, including effective use of quality risk management principles (e.g., ICH Q8 and ICH Q9). Opportunity to: o facilitate science based pharmaceutical quality assessment; o enable innovative approaches to process validation; o establish real-time release mechanisms. ICH Q10, Annex I

7. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 7 Q-IWG Status update © ICH, November 2010 ScenarioPotential Opportunity 4. Demonstrate effective pharmaceutical quality system and product and process understanding, including the use of quality risk management principles (e.g., ICH Q8, ICH Q9 and ICH Q10). Opportunity to: o increase use of risk based approaches for regulatory inspections; o facilitate science based pharmaceutical quality assessment; o optimise science and risk based post- approval change processes to maximise benefits from innovation and continual improvement; o enable innovative approaches to process validation; o establish real-time release mechanisms. ICH Q10, Annex I

8. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 8 Q-IWG Status update © ICH, November 2010 ICH Q8, Q9 & Q10: A real opportunity QbD, a reality: - Application including elements of a QbD - In EU (Tallinn update) - 14 centralised approved product application - In US (Washington update) - In CMC pilot 10 NDAs & 3 sNDAs - Outside pilot 22 INDs, 22 NDAs, 5 sNDAs Quality by design : A cultural change Global Harmonisation within and outside ICH region

9. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 9 Q-IWG Status update © ICH, November 2010 A cultural change challenged by globalisation outside ICH region Step by step approach: Learning by doing Support of the implementation is required - From the theory to the practical aspect - Clarifying in Q&A - Training / workshop Role and value of Quality-Implementation Working Group (Q-IWG)

10. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 10 Q-IWG Status update © ICH, November 2010 ICH Q-IWG: Achievements Q&A 45 already done Cooperation outside the 3 ICH Regions facilitated by the Global Cooperation Group (GCG) in ICH Working on External Collaboration with other not-for-profit organisation e.g. PIC/S, PDA (PCMO), ISPE (PQLI),… Major and unique Training/Workshop

11. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 11 Q-IWG Status update © ICH, November 2010 Q-IWG Achievements: Q&A This Questions and Answers document (Q&A) are there to support the harmonised implementation the guidelines of ICH Q8, Q9 and Q10 - Brussels Oct 08First Q&A ICH SC approval: April 2009 - Yokohama June 09New Q&A ICH SC approval: June 2009 - St Louis Oct 09New Q&A ICH SC approval: October 2009

12. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 12 Q-IWG Status update © ICH, November 2010 Q-IWG: Q&A Status currentlyopen For general clarification3 Quality by Design (QbD) topics1+ 3 - Design Space8+ 3 - Real Time Release Testing11+ 8 - Control Strategy5 Pharmaceutical Quality System8+ 1 GMP Inspection practice3 Knowledge Management5 Software solution1 Total45+15

13. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 13 Q-IWG Status update © ICH, November 2010 This ICH Q-IWG Training / Workshop: What is the difference? Only 3 workshops endorsed and operated by the ICH Q-IWG A story based on a case study, on the life cycle aspect. Development assessment manufacturing and inspection The same workshop will be offered by the same faculty in each of the three ICH regions. All attendees to participate in the breakouts on each life Report back for future Q-IWG Q&A development Workshop materials will be published by ICH and can be used for internal training by authorities (assessors and inspectors) and industry The idea behind: to illustrate the concept of enhanced approach, which can be apply from simple to complex molecule Complexity of the scheme …

14. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 14 Q-IWG Status update © ICH, November 2010 Product/Process Development Key Steps for a product under Quality by Design (QbD) Pharmaceutical Development PQS & GMP Local Environment Commercial Manufacturing Quality Unit (QP,..) level support by PQS Manage product lifecycle, including continual improvement Design Space (DS), RTR testing Link raw material attributes and process parameters to CQAs and perform Risk Assessment Methodology Potential CQA (Critical Quality Attribute) identified & CPP (Critical Process Parameters) determined QTPP : Definition of intended use & product Quality Target Product Profile CPP : Critical Process Parameter CQA : Critical Quality Attribute Risk Management Opportunities Design to meet CQA using Risk Management & experimental studies (e.g. DOE) DOE : Design of Experiment Control Strategy Technology Transfer Batch Release Strategy Prior Knowledge (science, GMP, regulations,..) Continual improvement Product/Process Understanding QRM principle apply at any stage Marketing Authorisation Quality System PQS

15. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 15 Q-IWG Status update © ICH, November 2010 ICH Q-IWG: Future actions Evaluate training outcome from Tallinn, Washington & Tokyo Additional Q&A if needed Cooperation outside the 3 ICH Regions facilitated by the Global Cooperation Group (GCG) in ICH Potential collaboration with other not-for-profit organisation e.g. PIC/S, PDA (PCMO), ISPE (PQLI),… Consider possible gap/barrier on existing ICH Q guidelines with the new paradigm: Review & proposed actions

16. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 16 Q-IWG Status update © ICH, November 2010 Q-IWG Goals and Achievements: Outcome of the training Take away for you and for Q-IWG Key messages: clear or not Practical concerns of implementation Clarification required and addressed to Q-IWG

17. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 17 Q-IWG Status update © ICH, November 2010 Q-IWG Goals and Achievements: Outcome of the Tallinn training Key messages: clear or not - Critical / Non Critical Practical concerns of implementation - DS:Design Space supports life cycle management - CS:Relationship between RTRT and specification - QRM:Outline relative risk and how to present it - PQS:Flexibility to allow Continual Improvement Clarification required - CTD:How and where to present QbD,…..

18. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 18 Q-IWG Status update © ICH, November 2010 THANK YOU

19. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop slide 19 Q-IWG Status update © ICH, November 2010 Acknowledgement This presentation has been developed by members of the ICH Quality Implementation Working Group (IWG) Jean-Louis Robert (rapporteur) Diana Amador-Toro Robert G. Baum Nicholas Cappuccino David Cockburn Georges France Richard L. Friedman Nigel Hamilton Hirotada Nagai Yukio Hiyama Fusashi Ishikawa Takao Kiyohara Urs Kopp Akira Kusai Yoshihiro Matsuda Motoaki Mitsuki Elaine Morefield Jacques Morénas Masatoshi Morisue Markus-Peter Müller Tamiji Nakanishi Moheb Nasr Kazuhiro Okochi Anthony Ridgway Rachael Roehrig Stephan Rönninger Swroop Sahota Hideki Sasaki Tetsuhito Takarada Shigeki Tamura Krishnan Tirunellai Mats Welin Jean M. Wyvratt A J van Zyl