ANDA Stability Guidance(s)

1 ANDA Stability guidance (s) Radhika Rajagopalan , Quality Assessment Lead OLDP-OPQ-CDER GPhA June 2015 1 Agenda Highlights Q1D Matrixing while considering an ANDA Q1 E Other items 2 ANDA Stability guidance 3 Improve ANDA quality and eliminate differences between NDA and ANDA CMC expectations Decrease Stability related failures Follow ICH Stability Guidances Capitalize on considerable awareness Highlights Q&A guidance Companion guidance Small scale batch size defined for many dosage forms Listed exemptions for pilot scale batch size Clarified multiple lots to 2 discrete lots of API for most dosage forms Expectation for the addition of second source for API included Miscellaneous questions on Stability studies answered 4 Highlights 5 Clarify misunderstandings such that RTR can be avoided at the time of ANDA submission 2. At the time of submission, provide 6 months of data that include accelerated and long-term conditions. FDA recommend following ICH with respect to intermediate conditions to support shelf-life.

2 5. Provide one fully packaged primary batch. Intermediate data submission Captured in ANDA Submissions RTR Standards ( guidance 2015) Follow definition of significant change per Q1A(R2) Required for all three batches, when significant change is experienced Time points are 0, 6, 9, and 12 with 0, and 6 months included at the time of ANDA submission Does not apply to drug products intended for storage in refrigerator 6 Small scale and Packaging OGD filing requirement of 100,000 units from 3 batches is acceptable when a small scale batch of (the three submission batch) is made and completely packaged If ANDA comes in with three commercial scale batches then one of three batches should be completely packaged 7 Other findings .. Commercial scales batches (as primary submission batches) Still needs to package one batch completely Two (or three) discrete lots of API should be used in the production of primary batches ---------------------------------------- ------------------ Process validation has begun not completed (2011 FDA guidance : Process Validation: General Principles and Practices) PAS needed for scale up 8 Q1 D - Matrix design Reduction in testing via Matrixing is applicable When 3 batches of each strength is made Applicable for long-term testing Stability protocol While matrixing time points.

3 Initial, 3 months and 6 months at long-term conditions are ANDA filing requirements 12, 24 months are anniversary points and we recommend testing to facilitate approval/ data analysis Testing to include all test attributes 9 Packaging Stability guidance recommends one primary batch to be fully packaged Use of bulk (for solid dosage forms) containers, HDPE, blisters for solid dosage forms Partial packaging from the other two primary batches is acceptable for most dosages (use the same configurations as batch one) 10 Matrix TD systems RTR guidance (2015) Consult for details Different lots of API, adhesives, backing and other critical elements/excipients be utilized Batch size defined in the Stability Q & A guidance 11 Q1E Stability data and written summary is expected Assay, impurities (plots to be updated as more data comes in) Stability commitment to test first commercial lots is expected when Small scale/pilot scale is proposed followed by larger scale Satisfactory 24 months full long-term data is not present in the ANDA at the time of approval Intermediate condition Stability data when accelerated data experiences significant change 12 Other items 21 CFR (e)(1) Sample requirements apply to all three primary submission batches oMethods verification at the FDA labs oVisual evaluation during review oConsults between Center Offices 13 Acknowledgement CDER- OPQ, and OGD OPQ Management, and Stability WG GPhA 14