1. CDER/Office of Generic Drugs1 Regulatory Issues Related to Crystal Habits - Polymorphism 1:45 - 2:00Polymorphs - What’s the Problem? Gary Buehler, R. Ph., Director, OGD, FDA 2:00 - 2:30Scientific Considerations of Polymorphism in ANDAs. Lawrence X. Yu, Ph. D., Director for Science, OGD, FDA 2:30 - 3:00Expert Comments, 30 minutes Kenneth R. Morris, Ph. D., Purdue University Harry G. Brittain, Ph. D., Center for Pharmaceutical Physics Leslie Benet, Ph. D., University of California 3:30 - 4:45Q & A

2. Polymorphs - What’s the problem? Gary J. Buehler, R.Ph. Director, Office of Generic Drugs Advisory Committee for Pharmaceutical Science October 21, 2002

3. CDER/Office of Generic Drugs3 Polymorphs The same...but...maybe different

4. CDER/Office of Generic Drugs4 n Same active ingredient: Carbon n Coal cannot be generically substituted for a diamond unless ANDA applicants show that n Coal is bioequivalent to a diamond n Coal exhibits the same identity, strength, purity, quality, and stability

5. CDER/Office of Generic Drugs5 Polymorphs/Formulations Intestinal Membrane Crystalline Sugar Powdered Sugar Bioequivalent Not Bioequivalent

6. CDER/Office of Generic Drugs6 “Same” Requirement n 314.94(a)(5) states, …the active ingredient is the same as that of the reference listed drug…

7. CDER/Office of Generic Drugs7 “Same” Requirement n Regulation Preamble clarifies the definition of “same” n Meets the same standards for identity as described in USP n In some cases, however, FDA may prescribe additional standards, i.e., crystalline structure or stereoisomeric mixture n Questions should be directed to OGD

8. CDER/Office of Generic Drugs8 What is Polymorphism? n Different physical forms of the same chemical structure n Different polymorphs may exhibit different properties, including stability and bioavailability

9. CDER/Office of Generic Drugs9 Polymorph Proliferation n With modern technology, the identification of multiple polymorphs has become easier n Because of their unacceptable properties however, the majority of these polymorphs have little utility and cannot be developed into quality products

10. CDER/Office of Generic Drugs10 History n Cefuroxime Axetil n Sept 29, 2000 Citizen Petition filed on behalf of GlaxoSmithKline (GSK) n Requested that FDA deny approval of any ANDA for a Cefuroxime Axetil product whose active ingredient is wholly or partially in crystalline form n Or, require stringent drug substance and drug product specifications for solid-state form (including content of individual polymorphs)

11. CDER/Office of Generic Drugs11 History n Cefuroxime Axetil n Involved USP monograph petition n Result was a 37-page response that detailed our own scientific position on polymorphs n Response is in the public record - Petition Number: 00P-1550/CP1 & PSA1 Petition Number: 00P-1550/CP1 & PSA1 01P-0428/CP1 & PSA1 01P-0428/CP1 & PSA1

12. CDER/Office of Generic Drugs12 History n Omeprazole n About 4 months before the pediatric exclusivity for Prilosec  was due to expire, we were informed of a possible polymorph issue n After significant review of the available data, the issue was addressed

13. CDER/Office of Generic Drugs13 History n Fluoxetine n On July 18, 2001, about two weeks before the pediatric exclusivity for Prozac  was due to expire, we were informed that aaiPharma held a patent on one polymorphic form of fluoxetine n They asserted that their patent claimed the drug product or method of using Prozac  and should be listed in the Orange Book n Only the NDA sponsor however, is authorized to request a patent listing

14. CDER/Office of Generic Drugs14 History n Fluoxetine n Eli Lilly, the NDA applicant for Prozac, informed aaiPharma that they did not plan on listing the patent in the Orange Book n aaiPharma appealed to FDA n FDA contacted Eli Lilly and asked for a confirmation of their decision n Lilly replied to FDA that it was not listing the patent n aaiPharma then asked FDA to list the patent

15. CDER/Office of Generic Drugs15 History n Fluoxetine n FDA replied that only the NDA applicant can list patents for its product in the Orange Book n aaiPharma sued the FDA n aaiPharma lost the lawsuit and the appeal

16. CDER/Office of Generic Drugs16 Summary n An ANDA applicant is required to demonstrate that their proposed product meets the standards for identity, exhibits acceptable stability, and is bioequivalent to the reference listed drug.