Q&A Document on ANDA Stability Publishes as Draft Guidance – Gentlemen Start Your Engines or at Least Check to See if the Car Has a Full Tank of Gas!

Today the FDA issued the long awaited Guidance to Industry: ANDAs Stability of Drug Substances and Drug Products in draft answering questions the public submitted relative to the final ANDA stability guidance document issued September 25, 2012. Some of the most significant issues addressed in the guidance are outlined below.  The complete guidance can be viewed here.

The Agency clarified that the final stability guidance applies only to new ANDAs and DMFs and not to post approval changes.  In addition, there the Agency may have listened to GPhA and other commenters and has given a 6mont reprieve from its previously stated implementation date of January 1, 2014 by announcing a new implementation date of June 20, 2014.

FDA notes that after the implementations date ANDAs should be submitted with 6 months of room temperature and 6 months of accelerated stability data and recommends that ICH intermediate stability data be generated at the time of the original stability studies.  This will be necessary to avoid delay in review if the accelerated stability data shows a significant change.

FDA indicates that bracketing and matrixing according to the ICH guidance will be permitted without prior approval, but cautions to assure the tenants of that guidance are followed closely.

The Q&A document makes clear that the Office of Generic Drugs (OGD) will grant up to a 24 month date on an ANDA submitted with the requisite stability but noted that additional room temperature data (minimum at 12 months room temperature on all three exhibit batches) should be submitted during review of the ANDA.  There will be no relief from submission of the 2 pilot and one small scale batch at time of ANDA submission.  Remember, as FDA points out, the stability time clock is calculated in months not weeks thus 4 weeks does not equal one month.

DMF must also have the full complement of data at time of full scientific review, however for the purposes of the completeness and acceptability review of the DMF at time of initial reference or payment of the initial DMF fee, the DMF holder must demonstrate that the ICH stability studies have been started.  The initial and one additional time point for accelerated and long term stability should be submitted.  The DMF holder should amend the DMF when the additional data is generated.

In regard to drug product manufacturing and packaging FDA reminds firms that split lot packaging does not constitute discrete batches.  In addition FDA indicated that blow-fill-seal packaged products are expected to be final packaged into their secondary container for stability purposes and all exhibit bathce should be packaged in their proposed container closure system.  Stability data should be generated using at least 2 lots of API and different lots of container closures should be considered only when the container/closure ”could affect drug product performance and/or delivery.”

FDA also indicated that hand packaging should not occur and that even the small scale batch should be packaged with ‘systems the same or similar” to those intended for the commercial packaging.

OGD expects that completed batch records and all relevant CMC information be submitted for the three exhibit batches.  If multiple API sources are proposed, OGD expects qualification of one source using three exhibit batches and then one pilot scale lot using the second proposed source for qualification purposes (four batches altogether.

The guidance goes into detail relative to packaging requirements and batch size requirements for various dosage forms but appears to stop short of requiring full packaging of all exhibit lots.  (see response to question 13)

All batches to support the ANDA submission should be manufactured at the proposed production site. FDA also clarified that for amendments to pending ANDAs after the new guidance issues, the requirements in place at time of the original ANDA submission will apply.

The ANDA guidance departs from ICH traditional recommendations of three time points 0, 3 and 6 by requiring a fourth additional time point (thought to be 4 or 5 months). FDA also clarified the expected storage orientation of solution, suspension or semi-solid dosage forms to include inverted (or horizontal) and upright (vertical) positions during stability (and testing of products stored in both orientations) until the full expiration date is verified and worst case orientation for routine stability batches.