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Regulatory Issues Related to Crystal Habits - Polymorphism

Regulatory Issues Related to Crystal Habits - Polymorphism. 1:45 - 2:00 Polymorphs - What’s the Problem? Gary Buehler, R. Ph., Director, OGD, FDA 2:00 - 2:30 Scientific Considerations of Polymorphism in ANDAs. Lawrence X. Yu, Ph. D., Director for Science, OGD, FDA

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Regulatory Issues Related to Crystal Habits - Polymorphism

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  1. Regulatory Issues Related to Crystal Habits - Polymorphism 1:45 - 2:00 Polymorphs - What’s the Problem? Gary Buehler, R. Ph., Director, OGD, FDA 2:00 - 2:30 Scientific Considerations of Polymorphism in ANDAs. Lawrence X. Yu, Ph. D., Director for Science, OGD, FDA 2:30 - 3:00 Expert 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 - 4:45 Q & A CDER/Office of Generic Drugs

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

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

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

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

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

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

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

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

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

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

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

  13. History • Fluoxetine • 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 • They asserted that their patent claimed the drug product or method of using Prozac and should be listed in the Orange Book • Only the NDA sponsor however, is authorized to request a patent listing CDER/Office of Generic Drugs

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

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

  16. Summary • 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. CDER/Office of Generic Drugs

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