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FDA GPHA CMC Workshop Post Implementation Update of the ANDA Stability Guidance(s) Radhika Rajagopalan, Ph.D. FDA/CDER/OPQ/OLDP May17-18, PDF

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FDA GPHA CMC Workshop Post Implementation Update of the ANDA Stability Guidance(s) Radhika Rajagopalan, Ph.D. FDA/CDER/OPQ/OLDP May17-18, Presentation today contains. Opinions expressed are those
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FDA GPHA CMC Workshop Post Implementation Update of the ANDA Stability Guidance(s) Radhika Rajagopalan, Ph.D. FDA/CDER/OPQ/OLDP May17-18, Presentation today contains. Opinions expressed are those of the presenter 2 Where Are We Today? Goal: Align stability expectations for ANDAs with ICH August 27, 2013: Published draft Q&A guidance with implementation date June 20, 2014: Implemented the Stability Guidance OLDP Continues to review & approve GDUFA ANDAS using the Guidances and supports activities 3 ANDA CMC Review in OLDP Infancy through maturity: Development planning, process planning, building in quality, BE/PK studies, site qualification should all be done ahead of time along with generation of three batches, 6 months stability data by ANDA applicant ANDA review in OLDP: Involvement will be at the final stages of DP selected for commercialization (market approval) Pathway to achieve GDUFA review time line goal and complete product quality assessment to make a recommendation 4 ANDA CMC Review GDUFA timelines for review are immensely helped by the three batch and longer duration stability data API lot variation is helpful in assessing product consistency Information Request process is mainly used by Product, Process, Biopharmaceutics, and other disciplines to communicate and conclude the review towards a recommendation Increased amount of quality data are very much helpful in decision making 5 What are repeating Questions? 6 Where are we today? What are repeating Q? Using at least two discrete batches/lots of DS to manufacture three batches of DP API Lot/batch 1 ANDA batch 1 API Lot/batch 2 ANDA batch 2 API Lot/batch 3 or 1 or 2 or a mix of 1 & 2 ANDA batch 3 Inhalation dosage forms to use three discrete lots for 3 batches of ANDA DP (addressed in footnotes) Certainly ties in with quality demonstration of product, process, and stability issues DMFs are complying with ICH stability requirements 7 Why 6 months of stability at submission? Harmonized expectations, and time periods across climatic zones Anda filing requirement: 3, and 6 months of accelerated and long-term data (6 months intermediate data if needed); 1 or 2 months data not needed (test at your discretion); GPHA request to file ANDA with 6 months data is honored Stability Q&A guidance, Section E, Q1: 0 (initial), 3 and 6 months 8 Question on the same topic. Should studies be continued to 6 months if the product fails at 3 months (40/75)? For semisolids ICH Q1A (R2) allows for appearance change; nonetheless our recommendation is not to stop, but continue to 6 months and report data [evaluate your product] If your plans are to file a submission of that product-formulapkg, then continue and do not stop the studies; report significant changes seen along with your assessment Option to consider: Wherein significant changes at 6 months accelerated, and intermediate conditions are seen, submit 12 months long-term data at the time of submission to avoid receiving a Major CR letter (i.e., generation of data per ICH requirement to aid in review timeline and regulatory decision) 9 Continued. If stability data are submitted that shows product failure (or significant change) at 6 months accelerated, and 6 months intermediate condition, the ANDA will receive a complete response letter Notice in the above case the applicant may consider submitting 12 months long-term data at the time of submission 10 When is day zero in stability studies? Product manufactured, tested (days 1 through 15), and release COA issued; product placed in stability ovens on day 21 in the following conditions Accelerated, Long-term, and Intermediate Day 21 now becomes day 0 for all three conditions in the stability oven COA Day (0) placed in ovens Day 90 Day Justification for Smaller Batch Size below ICH recommended threshold Orphan drug indications (RLD all indications on the label granted orphan status) Controlled DS requiring DEA allotment Commitment to submit PAS if scale is larger than exhibit scale 12 Justification for Smaller Batch Size Note the requirement for 2 API lots (or 3) still applies, and only the size of the ANDA DP batch is reduced Scale up for 1 & 2 is not impacted (follow SUPACbeyond 10 times) Item 3 requires a prior approval supplement to increase the scale, and for all other changes covered by Supac guidances please refer to them 13 Sample retention of Drug product 14 Retention Sample size Drug Product Samples from 3 (three) submission batches need to be retained Note: not the entire batch Enough samples to perform 4 times x 3 (batches) each test listed in your specification Reserve Samples 21 CFR (a) and (b) applies to both commercial and submission batches per GMPs makes sample retention a filing requirement for DP as it is under evaluation FDA lab testing, visual evaluation, consults across FDA offices 15 FDA OPQ, OLDP and GPhA Acknowledgements THANK YOU 16
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