2. Arthur Fabian, PhD February 7, 2007 FDA Public Meeting Rockville MD

3. SST Business Model Represent numerous API & Intermediate Manufacturers worldwide. Represent numerous API & Intermediate Manufacturers worldwide. Market and Sell APIs & Intermediates to both the Brand and Generic Industries in the US. Market and Sell APIs & Intermediates to both the Brand and Generic Industries in the US. Provides a unique Regulatory vantage-point. Provides a unique Regulatory vantage-point.

4. SST Regulatory Model Type II DMF Holder SST (A)NDA Sponsor API Manufacturers/Suppliers Customers

5. Industry Regulatory Model Type II DMF Holder (A)NDA Sponsor Historical Model for Generic Industry Historical Model for Generic Industry Widespread model (40%) for the Brand Industry due to Outsourcing Widespread model (40%) for the Brand Industry due to Outsourcing

6. SST’s Business Interest Maintain Supplier competitiveness. Maintain Supplier competitiveness. Introduce new synthetic methods, equipment, alternate sites, specifications, PAT techniques. Introduce new synthetic methods, equipment, alternate sites, specifications, PAT techniques. Encourage Change / Innovation. Encourage Change / Innovation. Same goal as Agency’s Quality Initiative. Same goal as Agency’s Quality Initiative.

7. Presentation Perspective Drug Substance & DMF Holder Drug Substance & DMF Holder rather than rather than Drug Product & (A)NDA Sponsor Drug Product & (A)NDA Sponsor

8. Presentation Topics Five Points to Consider in the revision Five Points to Consider in the revision Relevance of the Risk-Based Paradigm Relevance of the Risk-Based Paradigm “Outside the Box” Ideas “Outside the Box” Ideas

9. Point # 1

10. Point # 2

11. Separate Sections Requires authors to adopt a presently absent Drug Substance mindset. Requires authors to adopt a presently absent Drug Substance mindset. Filing recommendations for scale and equipment changes for small molecule APIs would be present. Filing recommendations for scale and equipment changes for small molecule APIs would be present. Change from Centrifugation to Filtration would not be a PAS.* Change from Centrifugation to Filtration would not be a PAS.* *Particle Design of APIs Through Crystallization, W.Beckmann, Schering AG, American Pharmaceutical Review, Vol 9, Issue 6, pg 110 & ff, Sept. ‘06

12. Point # 3

13. DMF Holders Filing mechanism format: Sponsor/DMF Holder Filing mechanism format: Sponsor/DMF Holder PAS/AM, CBE-0/AM, AR/AM. PAS/AM, CBE-0/AM, AR/AM. Expand the use of DMF Annual Update Expand the use of DMF Annual Update Minor Changes via AR/AU.Minor Changes via AR/AU. No additional documentation to FDA.No additional documentation to FDA.

14. Point # 4

15. Present Guidance All Process Changes after the Final Intermediate (FI) require a Pre-Approval Supplement !!

16. Final Step: Changes Guidance FI API FI API Last Step

17. Final Step: Science-Based Final Step: Science-Based FI CAPI PAPI FAPI FI CAPI PAPI FAPI ChemicalPurification Post Post Synthetic Operations* Synthetic Operations* * Drying, Milling, Micronization, Blending, Packaging CAPI: Crude API PAPI: Purified API FAPI: Final API

18. Final Step: Science-Based A FI Crude PAPI Change here Equivalence here steps PAS should not be necessary ! FAPI

19. Phased Approach Phased Approach FI CAPI PAPI Chemical Purification FAPI YesNoNo YesNoYes NoYesNo NoYesYes NoNoYes YesYesNo YesYesYes NoNo No, ie different FI No, ie different FI Post synthetic Operations

20. Chemical Phase Only Chemical Phase Only FI CAPI PAPI Yes No No Yes No No Chemical Purification Post synthesis FAPI Yes CBE/AM No Equivalent PAPI? PAPI? Yes CBE-30/AM PAS/AM Equivalent CAPI? CAPI? No

21. Purification Phase Only Purification Phase Only FI CAPI PAPI FAPI Chemical Purification Post Post synthesis synthesis EquivalentPAPI? CBE-30/AMPAS/AM YesNo No Yes No No Yes No

22. Post Synthesis Phase Only FI CAPI PAPI FAPI FI CAPI PAPI FAPI ChemicalPurification Post Post synthesis synthesis EquivalentFAPI? CBE-30/AM PAS/AM Yes No No No Yes No No Yes

23. Chemical & Purification Phases FI CAPI PAPI FAPI FI CAPI PAPI FAPI ChemicalPurification Post Post synthesis synthesis EquivalentPAPI? CBE-30/AM PAS/AM Yes No Yes Yes No Yes Yes No Yes/No EquivalentCAPI?

24. Chemical & Post synthesis Phases FI CAPI PAPI FAPI FI CAPI PAPI FAPI ChemicalPurification Post Post synthesis synthesis EquivalentPAPI? CBE-30/AM PAS/AM YesNo Yes No Yes Yes No Yes EquivalentCAPI? Yes/No Yes/No EquivalentFAPI?

25. Change in all Three Phases FI CAPI PAPI FAPI FI CAPI PAPI FAPI ChemicalPurification Post Post synthesis synthesis Equivalent PAPI? PAPI? CBE-30/AM PAS/AM Yes No Yes Yes Yes Yes Yes Yes EquivalentCAPI? Yes/No Yes/No EquivalentFAPI?

26. Change in no Phases: new FI FI’ CAPI PAPI FAPI FI’ CAPI PAPI FAPI Chemical Purification Post Post synthesis synthesis Equivalent PAPI? PAPI? CBE-30/AM PAS/AM Yes No No No No No No No EquivalentCAPI? No Yes Yes CBE-30/AM

27. Point # 5

28. Proposed Redefinition Major Process Changes Major Process Changes Must impact the API, not an upstream IntermediateMust impact the API, not an upstream Intermediate Proof of Equivalence needs supporting data beyond a specification comparison.Proof of Equivalence needs supporting data beyond a specification comparison. This definition amenable to Scale and Equipment Changes, but other factors need consideration. This definition amenable to Scale and Equipment Changes, but other factors need consideration. Site and Specification Changes need a different analysis. Site and Specification Changes need a different analysis.

30. Risk-Based Paradigm Risk-Based Paradigm FDA only pre-approves Changes affecting the API and requiring more complex equivalence data, ie, Major. FDA only pre-approves Changes affecting the API and requiring more complex equivalence data, ie, Major. Totally analogous to the Risk-Based Inspection Model. Totally analogous to the Risk-Based Inspection Model. Does not offer select companies reduction of filing mechanism; not needed. Does not offer select companies reduction of filing mechanism; not needed.

32. Outside the Box Ideas CBE 60/90 as Bridge to reducing PAS. CBE 60/90 as Bridge to reducing PAS. Special DMF Amendment for Changes; no link to (A)NDA Sponsor filing. Special DMF Amendment for Changes; no link to (A)NDA Sponsor filing. High Quality CMC Information, not high volume. High Quality CMC Information, not high volume.