1. 1 ACPS November 15, 2000 314.70 Update Nancy B. Sager, Associate Director Office of Pharmaceutical Science Center for Drug Evaluation & Research Food and Drug Administration

2. 2 Regulatory Approach CDER’s regulatory approach to post approval CMC changes is evolving 21 CFR 314.70 (1985 rewrite) SU/PACs (early 90’s to present) FDAMA (1997) Implementation of FDAMA §116 (now) Next ?

3. 3 21 CFR 314.70: Supplements and Other Changes to an Approved Application (1985 rewrite) “The applicant shall notify FDA about each change in each condition established in an approved application beyond variations provided for in the application” Provides a general listing of changes with reporting mechanisms

4. 4 Scale Up/Post Approval Change - Guidance Documents Level of Changes Minor change Moderate change Major change Application / Compendial Tests In Vitro Dissolution / Release In Vivo Annual Report Changes Being Effected Supplement Prior Approval Supplement Tests Filing

5. 5 FDA Modernization Act Section 116 (November 1997) Recognized the importance of the SU/PAC approach Amended the Food, Drug, and Cosmetic Act by adding Section 506A Required revision of 314.70 Guidance was developed to document FDA’s current thinking on how to apply Section 506A

6. 6 FDAMA Section 116 Reporting categories are based on the potential for the change to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the drug product.

7. 7 FDAMA Section 116: Reporting Categories Substantial potential –Prior approval supplements Moderate potential: –Supplement — changes being effected in 30 days (CBE-30) –Supplement — changes being effected (CBE-0) Minimal potential –Annual reports

8. 8 FDAMA 116 Implementation Status Draft guidance published for public comment on June 28, 1999; comment period closed on Aug. 27, 1999; final guidance published Nov. 1999 (30 comment letters, 1200 individual comments) Proposed regulation published for public comment on June 28, 1999; comment period closed on Sept. 13, 1999 (30 comment letters, 300 individual comments)

9. 9 Changes to an Approved NDA or ANDA (Nov. 1999 guidance) Modeled on SU/PACs Recommends reporting categories only Covers all dosage forms No recommendations on specific information that should be developed by the applicant to assess the effect of the change

10. 10 FDAMA 116 Implementation Status The November 1999 guidance on Changes to an Approved NDA or ANDA represents FDA’s current thinking on how it will apply the requirements of section 506A of the Act for NDA and ANDA products.

11. 11 FDAMA 116 Implementation Status (cont’d) Until the final regulation for § 314.70 publishes, section 506A is the sole basis for FDA’s regulation of postapproval manufacturing changes for products approved in NDAs or ANDAs

12. 12 FDAMA 116 Implementation Status (cont’d) The final rule for § 314.70 has been drafted and is in the beginning stages of the clearance process (ETA = winter/spring) The guidance on Changes to an Approved NDA or ANDA is being revised to conform to § 314.70 and will publish at the same time as the final rule.