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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, 2016

Presentation today contains…….

• Opinions expressed are those of the presenter…

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Where Are We Today?

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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

ANDA CMC Review in OLDP

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• 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

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

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What are repeating Questions?

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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

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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

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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-formula-pkg, 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)

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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

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When is day one 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 1 for all three conditions

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COA Day 90 Day 1 in

ovens

Day 180

Justification for Smaller Batch Size below ICH recommended threshold

• 1. Orphan drug indications (RLD all indications on the label granted orphan status)

• 2. Controlled DS requiring DEA allotment

• 3. Commitment to submit PAS if scale is larger than exhibit scale

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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 SUPAC- beyond 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

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Sample ‘retention’ of Drug product

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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 211.170 (a) and (b) – applies to both commercial and submission batches per GMPs

• 314.50 makes sample retention a filing requirement for DP as it is under evaluation

– FDA lab testing, visual evaluation, consults across FDA offices

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Acknowledgements

• FDA OPQ, OLDP and GPhA

• THANK YOU

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