Presentation Outline

1. ICH Q4BRegulatory Acceptance of Analytical Procedures and/or Acceptance Criteria(RAAPAC)Overview and UpdateRobert H. King, Sr.Office of Pharmaceutical Science, CDER, FDAAdvisory Committee for Pharmaceutical Science (ACPS)October 5, 2006

2. Presentation Outline • History and Overview • Q4B Process • Current Activities for the Q4B Expert Working Group (EWG) • Implementation Considerations

3. Background • The harmonization of specific compendial test chapters has been considered as critical by the ICH Steering Committee to attaining full utility of the ICH Q6A guideline. • Industry asks ICH SC to create an EWG to address regulatory acceptance (3 regions) of harmonized pharmacopeial methods from EP/JP/USP (PDG) – July 2003 • ICH SC establishes Q4 EWG with a scope to address 11 General Test Chapters discussed during development of ICH Q6A Guideline - November 2003 • SC approves Q4B Work Plan – April 2004

4. Background (Continued) • SC approves development of an ICH Guideline – June 2004 • Q4B EWG begins evaluating PDG harmonized text – November 2004 • Step 2 ICH Q4B Guideline approved by SC – June 2006 • 1st Annex (Residue on Ignition/Sulphated Ash) approved June 2006 • FDA Draft Guidances printed in FR August 2006 (60-day comment period)

5. Q6A-related General Chapters • Dissolution  Disintegration  • *Uniformity of Content *Uniformity of Mass • Extractable Volume  Particulate Matter  • Sterility  Microbiological Quality  • Bacterial Endotoxins  ROI/Sulphated Ash • Colour and Clarity (per ICH SC, work will just be on "Colour")  ______ * Harmonized to Uniformity of Dosage Units

6. What is PDG? • Pharmacopeial Discussion Group (PDG) comprised of representatives of the United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), and the European Pharmacopoeia (Ph.Eur. or EP) • Multi-step process to harmonize selected general test methods and monographs • May result in some residual or local differences that may pose issues for regulators – Q4B/PDG interaction to resolve issues

7. PDG Process Results in Harmonized Text Individual Pharmacopeial Approval & Official Printing Process JP Version ____________ ____________ ____________ ____________ ____________ ____________ ____________ ____________ ____________ ____________ USP Version ____________ ____________ ____________ ____________ ____________ ____________ EP Version ____________ ____________ ____________ ____________ ____________ ____________ ____________ ________________________ Do differences impact on the ability to achieve same result with same accept/reject capability?

8. Q4B Process Steps FOR EACH TOPIC: • PDG provides to Q4B Expert Working Group: • PDG-harmonized text • JP/EP/USP draft version of how harmonized text will be implemented in their compendia • Briefing note to delineate any local differences or potential issues • Printing timeline to move each pharmacopeia to official status • Q4B member parties bring the documents back to their constituents for independent evaluation

9. Q4B Process (continued) • Q4B EWG reviews the evaluations • Issues discussed within Q4B EWG for possible resolution • Evaluation results and possible resolution mechanisms conveyed back to and/or discussed with PDG • Once issues are resolved, Q4B EWG recommends approval (ICH Step 2) to the ICH SC – start of Annex process

10. PDG Document Submission Step 1: Q4B EWG assessment and annex development Step 2: ICH Sign off on draft Q4B annex Regional pharmacopoeial implementation Step 3: Regulatory Consultation on annex Step 4: Annex adopted by ICH Steering Committee Step 5: Regional regulatory implementation Inter-regional Acceptance Topic Specific Annex Process PDG Process ICH Process

11. What Q4B Activity Is • Effective way to raise and resolve issues that might impact both industry and regulators. • For FDA, interchangeability means the possible use of the harmonized methods of JP and EP, where deemed appropriate and based on our scientific review, to be considered as equivalent to the USP method. • A savings in time and effort: • More so to industry to globally unify testing strategies [for applications and other regulatory (compliance) needs] – one test rather than three • To possibly reduce or eliminate the need to go through a justification procedure as to the use of other compendial methods (done one time to eliminate repetitive justifications)

12. What Q4B Activity Is(continued) • Given the unified approach and strength of working directly with the three regulatory regions, it is an effective way to partner in the pharmacopeial process to effect change, where single, independent efforts might not be as successful. • Maintains FDA's review authority • In case of any question, the local regional method prevails. • Establishes a process for multi-center input into scientific review for determining the interchangeability.

13. What Q4B Activity Is Not • It will not be a mechanism to supplant FDA's CMC review processes and mandate. It will be up to the CMC reviewer and the sponsor to establish what are the best methods and acceptance criteria to ensure a safe and efficacious product • It will not reinvent the compendial revision cycle that resulted in the PDG harmonized text -- Industry and regulators have their input during the individual revision processes • It will not establish acceptance criteria outside of normal processes

14. Q4B Activity for Chicago Meeting • Work continuing to move Q4B Guideline and 1st Annex to ICH Step 4/5 • Finalize 2nd Annex for “Extractable Volume” to ICH Step 2 and move to regulatory consultant (ICH Step 3) • Work continuing on evaluation of other PDG harmonized text submissions: • Sterility Test • Particulate Matter • Dissolution • Other general test chapters to come

15. Implementation Considerations • Each completed topic moved to FDA Guidance for Industry • Transparency for industry and regulators • FDA stakeholder Work Group formed for awareness and training relative to the Q4B process. Representation from: • CDER (ONDQA, OGD, OBP, OTR, Office of Compliance) • CBER • CVM • ORA

16. Acknowledgements My thanks to: • Cindy Buhse • Jon Clark