1. ACPS Advisory Committee Meeting October 21 - 22, 2002 ACPS Advisory Committee Meeting October 21 - 22, 2002 Scientific Considerations of Polymorphism in ANDAs Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration

2. 2 Presentation Outline l What is polymorphism? l How does polymorphism affect pharmaceutical properties of drugs? l l To what extent should scientific considerations be given to polymorphism in ANDAs? l What is polymorphism? l How does polymorphism affect pharmaceutical properties of drugs? l l To what extent should scientific considerations be given to polymorphism in ANDAs?

3. 3 What is Polymorphism? Haleblian JK. J. Pharm. Sci. 64:1269-88 (1975) Ordered arrangement Disordered arrangement ICH Definition on Polymorphism

4. 4 Characterization l l Crystallography; x-ray diffraction pattern u u Nonequivalent crystal structure l l Microscopy l l Thermal analysis; DSC and TGA l l Apparent solubility studies l l Intrinsic dissolution rate l l Infrared absorption, and Raman spectroscopy l l Solid-state nuclear magnetic resonance l l Crystallography; x-ray diffraction pattern u u Nonequivalent crystal structure l l Microscopy l l Thermal analysis; DSC and TGA l l Apparent solubility studies l l Intrinsic dissolution rate l l Infrared absorption, and Raman spectroscopy l l Solid-state nuclear magnetic resonance

5. 5 Pharm. Properties Exhibited by Different Polymorphs l Melting Point l Hygroscopicity l Chemical and Physical Stability l Apparent Solubility and Dissolution l Bioavailability and Bioequivalence l Manufacturability l Melting Point l Hygroscopicity l Chemical and Physical Stability l Apparent Solubility and Dissolution l Bioavailability and Bioequivalence l Manufacturability

6. 6 Effect of Polymorphism on Melting Point DSC profiles of the fluoroquinolone (US Patent 5,985,893) Temperature ( o C) Watts/g

7. 7 Effect of Polymorphism on Hygroscopicity Moisture sorption of the fluoroquinolone (US Patent 5,985,893) Form III Form I Relative Humidity Weight Gain % w/w

8. 8 Effect of Polymorphism on Apparent Solubility Solubility of the fluoroquinolone (US Patent 5,985,893)

9. 9 Effect of Polymorphism on Intrinsic Dissolution Form I Form II Dihydrate Kabayashi et al. Int. J. Pharm. 193:137-146 (2000)

10. 10 Effect of Polymorphism on Bioavailability : Low Solubility Drugs Kabayashi et al. Int. J. Pharm. 193:137-146 (2000) Dihydrate Form I Solution

11. 11 Polymorphic Form Conversion During Manufacturing l l Milling/micronization l l Wet granulation u u Inter-conversions between anhydrates and hydrates, or between different hydrates l l Spray-drying u u Amorphous form l l Milling/micronization l l Wet granulation u u Inter-conversions between anhydrates and hydrates, or between different hydrates l l Spray-drying u u Amorphous form

12. 12 Decision Tree Development on Polymorphism in ANDAs l Process for evaluating when and how polymorphs of drug substances in ANDAs should be monitored and controlled u Based on the ICH Guidance Q6A decision trees on polymorphism u Biopharmaceutics Classification System (BCS) l Process for evaluating when and how polymorphs of drug substances in ANDAs should be monitored and controlled u Based on the ICH Guidance Q6A decision trees on polymorphism u Biopharmaceutics Classification System (BCS)

13. 13 ICH Q6A: Decision Tree #4 Investigating the Need to Set Acceptance Criteria for Polymorphism in DS and DP for NDAs l Part 1 u Do multiple polymorphic forms exist? l Part 2 u Is routine polymorph testing of DS valuable? l Part 3 u Is routine polymorph testing of DP valuable? l Part 1 u Do multiple polymorphic forms exist? l Part 2 u Is routine polymorph testing of DS valuable? l Part 3 u Is routine polymorph testing of DP valuable?

14. 14 Limits to Oral Drug Absorption Gastric Emptying Transit Absorption Dissolution Metabolism l Dissolution Rate = D *S/h (C s - C l ) v D - diffusion coefficient v S - dissolution surface area v h - Aqueous boundary thickness v Cs - Solubility v Cl - Concentration in dissolution media l Absorption: Permeability l Dissolution Rate = D *S/h (C s - C l ) v D - diffusion coefficient v S - dissolution surface area v h - Aqueous boundary thickness v Cs - Solubility v Cl - Concentration in dissolution media l Absorption: Permeability

15. 15 What is the BCS? l The BCS is a scientific framework for classifying drugs based on their aqueous solubility and intestinal permeability.

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17. 17 Decision Trees on Polymorphism in ANDAs l l Decision Tree #1. Investigating the need to set acceptance criteria of polymorphs l l Decision Tree #2. Investigating the need to set acceptance criteria of polymorphs for drug substance l l Decision Tree #3. Investigating the need to set acceptance criteria of polymorphs for drug product l l Decision Tree #1. Investigating the need to set acceptance criteria of polymorphs l l Decision Tree #2. Investigating the need to set acceptance criteria of polymorphs for drug substance l l Decision Tree #3. Investigating the need to set acceptance criteria of polymorphs for drug product

18. 18 Decision Tree #1. Investigating the Need to Set Acceptance Criteria of Polymorphs Decision Tree # 2 START Are there known polymorphs with different apparent solubility? NO YES END No further test or poly- morphic acceptance criteria for drug substance and drug product Are all known polymorphs highly soluble? NO YES Adequate knowledge of drug substance polymorphs is available by the time an ANDA is filed

19. 19 Drug Substance Polymorphism: Knowledge versus Process l l FDA receives many ANDA applications for the same drug substance l l Each applicant needs to have adequate knowledge on drug substance polymorphism to make appropriate decisions u u Each applicant has a unique approach to address polymorphic issues u u Polymorphic information may come from literature, patents, compendia, experience, or others l l The Decision Tree # 1 emphasizes knowledge on polymorphism; not approaches used l l FDA receives many ANDA applications for the same drug substance l l Each applicant needs to have adequate knowledge on drug substance polymorphism to make appropriate decisions u u Each applicant has a unique approach to address polymorphic issues u u Polymorphic information may come from literature, patents, compendia, experience, or others l l The Decision Tree # 1 emphasizes knowledge on polymorphism; not approaches used

20. 20 Polymorph Appearing and Disappearing l Benzylidine-dl-piperitone l Polymorph    l M. P. ( o C) 59-60 63-64 69-70 l 1921  and  in Australia,    l 1936  in Scotland,  or    l 1987  in India no ,  not mentioned l Benzylidine-dl-piperitone l Polymorph    l M. P. ( o C) 59-60 63-64 69-70 l 1921  and  in Australia,    l 1936  in Scotland,  or    l 1987  in India no ,  not mentioned From David Grant

21. 21 BACPAC I Guidance (2001) Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Controls Documentation l “Generally, only two physical properties of the drug substance, morphic form and particle size, are considered critical for evaluation of equivalence.” l Equivalence of Physical Properties u “ Conformance to established acceptance criteria for morphic form or, where acceptance criteria do not exist, the isolation of the same form or mixture within the range of historical data,…” l “Generally, only two physical properties of the drug substance, morphic form and particle size, are considered critical for evaluation of equivalence.” l Equivalence of Physical Properties u “ Conformance to established acceptance criteria for morphic form or, where acceptance criteria do not exist, the isolation of the same form or mixture within the range of historical data,…”

22. 22 Decision Tree #1. Investigating the Need to Set Acceptance Criteria of Polymorphs Decision Tree # 2 START Are there known polymorphs with different apparent solubility? NO YES Initial scientific characterization of the form(s): e. g., X-ray Powder Diffraction, DSC / Thermoanalysis, Microscopy, and/or Spectroscopy END No further test or poly- morphic acceptance criteria for drug substance and drug product Are all known polymorphs highly soluble? NO YES

23. 23 Decision Tree #2. Investigating the Need to Set Acceptance Criteria of Polymorphs for DS Decision Tree # 1 Is there a polymorphic specification in the USP? (e.g., melting point) Set new polymorphic acceptance criteria for drug substance Is the USP polymorphic specification adequate? NO YES NO YES Set the same polymorphic acceptance criteria for drug substance as the USP Decision Tree # 3 1) Different polymorphic form 2) Allow to establish tight specification

24. 24 Decision Tree #3. Investigating the Need to Set Acceptance Criteria of Polymorphs for DP Decision Tree # 2 Is there sufficient concern that polymorphic acceptance criteria for drug product should be established? YES No need to set polymorphic acceptance criteria for drug product END NO Next Slide In general, there should not be a concern if 1) The most stable polymorphic form is used or 2) The form is used in a previously commercialized product

25. 25 Decision Tree #3. Investigating the Need to Set Acceptance Criteria of Polymorphs for DP (Continued) Dissolution testing can frequently detect potential conversion of polymorphs. In rare cases, solid characterization methods have to be used. Does the drug product dissolution testing provide adequate controls if the polymorphic ratio changes? NO Set acceptance criteria for the drug product dissolution testing as a surrogate for polymorph control in the drug product END YES Previous Slide Set acceptance criteria for the drug product using other approaches, such as solid characterization method END FDA BA/BE Guidance: “It is recommended that the sponsor select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available in vitro and in vivo data.”

26. 26 Presentation Outline l What is polymorphism? l How does polymorphism affect pharmaceutical properties of drugs? l l To what extent should scientific considerations be given to polymorphism in ANDAs? l What is polymorphism? l How does polymorphism affect pharmaceutical properties of drugs? l l To what extent should scientific considerations be given to polymorphism in ANDAs?

27. 27 Questions l Do the proposed decision trees adequately address the key polymorph issues (stability and bioavailability) that should be considered in FDA's regulatory assessment on an ANDA? u Decision Tree#1. Are there other issues with respect to characterization of polymorphic forms that FDA should consider? u Decision Tree #3 addresses the necessity of having a polymorph spec for drug product when using the most stable or previously used form: v Please comment on methods, approaches, and challenges for establishing specification for polymorphs in drug products. Also, in your experience, how often would you anticipate that such a specification necessary? l Do the proposed decision trees adequately address the key polymorph issues (stability and bioavailability) that should be considered in FDA's regulatory assessment on an ANDA? u Decision Tree#1. Are there other issues with respect to characterization of polymorphic forms that FDA should consider? u Decision Tree #3 addresses the necessity of having a polymorph spec for drug product when using the most stable or previously used form: v Please comment on methods, approaches, and challenges for establishing specification for polymorphs in drug products. Also, in your experience, how often would you anticipate that such a specification necessary?

28. 28 Questions l What additional considerations, if any, should be addressed on the issue of manufacture-ability or "process-ability" when different polymorph forms are present?