FDA published its long awaited draft guidance for industry, ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers, in the Federal Register August. 27, 2013. The document provides answers to questions submitted during the public comment period on the draft stability guidance that was published on September 25, 2012. The final guidance for industry was published on June 20, 2013. The question-and-answer draft guidance document is open for comment for the next 60 days.
FDA’s stability guidance for generic drugs recommends that the generic-drug industry follow ICH stability-related guidance. The question-and-answer guidance clarifies the effect of the stability guidance on drug master file (DMF) holders, discusses questions related to manufacturing and packaging, offers recommendations for amendments to pending abbreviated new drug applications, and answers other questions about stability studies. A number of most significant issues addressed in the guidance are outlined below.
The Agency clarified that the final stability guidance applies only to new ANDAs and DMFs and not to post approval changes. In addition, responding to comments received from the Generic Pharmaceutical Association and others, the FDA has given a 6 month reprieve from its previously stated implementation date of January 1, 2014 by announcing a new implementation date of June 20, 2014.
The Agency notes that after the implementations date ANDAs should be submitted with 6 months of room temperature and 6 months of accelerated stability data, whiles’ also recommending that ICH intermediate stability data be generated at the same time as 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 that specifics of the ICH guidance must followed closely.
The Draft Guidance document makes clear that the Office of Generic Drugs (OGD) will grant up to a 24 month date on an ANDA submitted with the requisite stability but noted that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. Keep in mind, as FDA points out, the stability time clock is calculated in months not weeks, hence 4 weeks does not equal one month. In addition, there will be no relief from submission of the 2 pilot and one small scale batch at time of the ANDA submission.
The Drug Master File (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, the DMF holder must demonstrate that the ICH stability studies have been started at time of initial reference or payment of the initial DMF fee. The document notes that initial and one additional time point for accelerated and long term stability should be submitted. And, the DMF holder should amend the DMF when the additional data is generated.
With regards to drug product manufacturing and packaging, FDA reminds firms that split lot packaging does not constitute discrete batches. The Agency indicated that blow-fill-seal packaged products are expected to be final packaged into their secondary container for stability purposes and all exhibit batches 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.”
The draft guidance 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.
The Office of Generic Drugs (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 becomes effective, the requirements in place at time of the original ANDA submission will apply.
The ANDA guidance does depart from the ICH Guidelines of three time points 0, 3 and 6 by requiring a fourth additional time point. 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 identified.