Quality Risk Management ICH Q9 History

1. QualityRisk ManagementICH Q9History Disclaimer: This presentation includes the authors views on quality risk management theory and practice. The presentation does not represent official guidance or policy of authorities or industry.

2. Purpose of this part is to: • Guide you throughthe historyof the development of the ICH Q9 document • Highlight some of the decisions and rationales for making them

3. The history of Q9 document OsakaNovember 2003 LondonMarch 2004 YokohamaNovember 2004 WashingtonJune 2004 2006 Draft for consultationMarch 2005 ChicagoNovember 2005 ICH Q92005

4. Concept ICH Steering Committee agrees to new document paper Step 1 Scientific discussions within the EWG Consensus of the 6 ICH partners and release for Step 2 pubic consultation within the 3 Regions Step 3 Consolidation of public comments Agreement of the 3 ICH regulators and Step 4 "Signed off" by ICH Steering Committee Not legally binding, unless incorporated in local law Step 5 Implementation within the 3 Regions ICH Q9 Milestones November 2003Osaka March 2004London June 2004Washington Nov. 2004Yokohama Sep. 2004Telecon March 2005Steering C. Feb. 2005Telecon May 2005Brussels Nov. 2005Chicago 2006ongoing

5. ICH Concept paper Osaka, November 2003 • Technology focus • Increase process capability • Focus on critical control points • Product • Stabilise manufacturing steps (decrease variability) • Guarantee shelf-life • People • Result in a superior performance of the Q-System • Customer • Reduce deviation • Reduce market complaint rate • Reduce technical related adverse events

6. Result of ICH Q9 EWG Meeting London, March 2004 • A draft table of contents, flow diagram, definitions were agreed • Assignments to produce first draftsof the full text for each section of the draft table of contents were agreed • Started the dialogue with the ICH Q8 EWG • Regulatory flexibility • The degree to which the final versions of both Q9 and Q8 could refer to 'regulatory relief' was a debate on principles. • Term changed to “regulatory flexibility” or “risk confidence”.

7. ICH Q9 Version 1 “Forget it” expressed what the EWG was thinking in terms of creating text on the agreed content

8. Result of ICH Q9 EWG Meeting Washington, June 2004 • Good agreement on overall content • No major disagreements between parties • Training and experience needed • The first official draft (No 2) was issued • All accept that wording is not perfect • Reaching ICH Step 2 in November was still the target • Highly dependent on the extent of comments received on draft

9. Result of ICH Q9 EWG Telecon September 2004 • Optional nature of ICH Q9 to be emphasized • All EWG parties want to push ICH Q9 forward • No support for delaying ICH Q9 • Appointments for redrafting in six groups • Subgroup decide on details of Chapter 5 / 6 as annex or not • One subgroup to deal with ICH Q8 relationships • Case studies: • Which ones are appropriate to use in ICH Q8, Q9 or Q10? • Everybody should decide, whether the case studies should be included as an annex in the ICH Q9 document or used as training material - Decision to be made in Yokohama

10. Result of ICH Q9 EWG Meeting November 2004 • Milestone: Draft 4 issued as “pre-step 2” document • Major concerns were addressed and resolved • Primary principle: link back to the potential harm to the patient • Integration of QRM into existing systems & regulatory processes will take time • For more details:Peter Gough and Stephan Roenninger, ICH Q9 : Quality Risk Management - an update Regulatory Affairs Journal, 16, 2005, 91-93

11. Result of ICH Q9 EWG Telecon February, 22 2005 • All EWG parties agreed to put Q9 forward to step 2 • Training slides will be provided • Slides to be discussed after step 4 • Next meeting of the EWG:ICH Meeting, November 2005, Chicago

12. Dr. Greg Guyer (Rapporteur) Mr. David Horowitz Merck &Co, Vice President, MMD QA Director, Office of Compliance, CDER Dr. Georgia Keresty Dr. H. Gregg Claycamp Centocor, Inc.,GlobalBiologicsSupply Director Scientific Support Staff Ms. Diana Kolaitis Vice President, Worldwide Quality District field inspector Mr. Jon Edward Clarke Ms. Emer Cooke FDA HFD (alternate: Q8) Dr. Yukio Hiyama Head of sector Inspections EMEA Chief, Third Section: Division of Drugs Dr. Jacques Morenas Mr. Ichiro Tsunoi Inspection and Companies Directorate Expert Working Compliance & Narcotic division AFSSAPS, FEMEA, PIC/S Dr. Yoshihiro Matzuda Mr. David Cockburn (alternate) Group ( EWG ) Principal Scientific Administrator EMEA MHLW, Registration Biol. Dr. Mayumi Shikano Review director Office of biologics Dr. Tamiji Nakanishi Reviewer, Office of new drugs I Dr. Yoshihiro Matsuda Reviewer, Office of new drugs I Mr. Etienne Ouimette Mr. Peter Gough Compliance and Enforcement Coordination division, Health prod. & Food Branch Inspectorate Health CDN Lilly, GB, Senior Quality Consultant, Corporate QS Ms. Christine Mundkur Dr. Stephan Rönninger F.Hoffmann-LaRoche, CH, Global Quality Manager International Generic Pharmaceutical Alliance Mr. Frederick Razzaghi Mr. Takayoshi Matsumura Consumer Health Product Association Dr. Sabine Kopp Eisai, Assistant Manager, Corporate QA Department Mr. Tetsuhito Takarada QA & Safety Medicines, WHO Dr. Urs Kopp Mochida Pharm.Deputy Director, Quality Control Mr. Hideo Sasaki (alternate) Head of Inspectorate, Swissmedic Nippon Shinyaka Co Ltd, Manager Anal.Chem.Sect. ICH Q9 Expert Working Group (EWG) as of ICH Step 2

13. Result of ICH Q9 EWG Meeting Chicago November, 6.-8. 2005 Points of discussion and changes to the step 2 document • Separate the “How to do?” (annex) from the “What to do?” (text) and move the tools examples to the annex • Modify original diagram in section 4 • Take an alternative proposal showing communication routes • Move “continuous improvement” to Annex II.1 (see ICH Q10) • Reduce complexity by combining and re-wording the individual sections • “formal” and “informal” risk management referenced • “detectability” as an element in several chapters

14. Dr. Georgia Keresty Dr. H. Gregg Claycamp (Rapporteur) Centocor, Inc.,GlobalBiologicsSupply Director Scientific Support Staff Vice President, Worldwide Quality Mr. A. D’Sa Mr. Tobias Massa Compliance Officer, CDER Bristol-Myers Squibb Ms. Diana Kolaitis Vice president Global Regulatory Sciences-CMC District field inspector Dr. Yukio Hiyama Ms. Emer Cooke Chief, Third Section: Division of Drugs Ichiro Tsunoi Head of sector Inspections EMEA Dr. Jacques Morenas Assistant Director, Office of Compliance, Pharm.& Food Safety Bureau, MHLW Inspection and Companies Directorate Expert Working Tamiji Nakanishi AFSSAPS, FEMEA, PIC/S Reviewer, Office of New Drugs I, PMDA Group ( EWG ) Mayumi Shikano Review Director, Office of Biologics, PMDA Yoshihiro Matsuda Reviewer, Office of New Drug I, PMDA Yukio Saito GMP Inspector, PMDA Takashi Nagashima Ms. Diana Dowthwaite GMP Expert, PMD A Compliance and Enforcement Coordination division, Mr. Malcolm Holmes Health prod. & Food Branch Inspectorate Health CDN GSK, UK, Global Quality Assurance, Director Ms. Christine Mundkur Dr. Stephan Rönninger International Generic Pharmaceutical Alliance F.Hoffmann-La Roche, CH, Global Quality Manager Mr. Frederick Razzaghi Consumer Health Product Association Dr. Sabine Kopp Mr. Takayoshi Matsumura QA & Safety Medicines, WHO Eisai, Assistant Manager, Corporate QA Department Dr. Markus-Peter Müller Mr. Tetsuhito Takarada Head of QM-Inspectorate, Swissmedic Mochida Pharm.Deputy Director, Quality Control Mr. Hideo Sasaki Nippon Shinyaka Co Ltd, Manager Anal.Chem.Sect. ICH Q9 Expert Working Group (EWG) as of ICH Step 4

15. Publication and implementation of ICH Q9 Legal position of ICH Q9 • US / FDA: - Guidance for Industry (June 2006)- By law, guidance documents are not enforceable or binding FDA will use the document internally in this spirit, as well • Japan / MHLW:- Product GMP Guideline “Annex”: ICH Guidelines • EU / EMEA:EUDRALEX Volume 4 - Medicinal Products for Human and Veterinary Use : Good Manufacturing Practice- EU-GMP Vol. 4, Annex 20- Teams established to update chapters of EU-GMP, NfG etc.

16. European legal position of ICH Q9 Publication of the document in EU for comments: • “It should be borne in mind that this guideline does not introduce new requirements or expectations but should be considered a resource document that can be used together with existing quality-related guidelines when a risk-based approach is appropriate.” • “Therefore, as well as complementing GMP guidelines, the document should be seen as also complementing and supporting existing and future guidelines published by CHMP and CVMP concerning the quality of medicinal products.” EU-Publication of Step 2 document

17. Authors Reviewers ICH Q9 Briefing Pack July 2006 • S. Rönninger, Roche (Chair) • G. Claycamp, FDA • P. Gough, former Lilly • M. Holmes, GSK • T. Matsumura, Eisai Co. • H. Sasaki, Nippon Shinyaku • T. Takarada, Mochida Pharm. • E. Cooke, EMEA • Y. Hiyama, MHLW • D. Horowitz, FDA • G. Keresty, Centocor • U. Kopp, Swissmedic • J. Morénas, AFSSAPS • C. Mundkur, Barr Laboratories • M.-P. Müller, Swissmedic • F. Razzaghi, CHPA Supported by EFPIA and JPMA ICH Q9 topic groups

18. ICH Q9 Briefing Pack ICH EWG members published a set of slides with more details on possible implementations • ICH homepage: www.ich.org -> -> scroll down to ICH Q9 • On the ICH Q9 Document • Background • History • Content • Tools • Applications • Additional features • Senior Management Training • Frequently Asked Questions (Q&A) Current direct link: http://www.ich.org/cache/html/3157-272-1.html

19. Optional but can benefit from its use!