Pivotal stability programs that are used to generate stability data for NDA submissions are different than research stability programs used to design the drug product, explore packaging configurations, etc. This is common sense, but we have seen instances of pivotal stability programs that have been performed for clients with no defined specifications. A stability protocol with no defined specifications means that all data are acceptable and, there are no out of specification results. A stability study without pre-defined specifications will not be acceptable to FDA for ANDA/NDA approval.
When a development program is initiated there are many unknowns. The sponsor may not know how to define the critical release specifications or the key stability specifications. Many research batches of a new drug product will be manufactured and used to support the definition of the specifications. Often the early research batch will be subjected to stress conditions to understand what parameters are impacted by these stresses, such as accelerated stability. Do not confuse research material with clinical trial material.
Once a program has advanced to the stage of preparing clinical trial material, specifications should be proposed and any data collected should be scrutinized against those proposed specifications. Clinical trial material should be viewed as pivotal. These are the data that will form the basis for the development history of this new drug product. Attention should be paid to changes that occur, investigations and rationale should be provided for any aberrant data. Investigations should be performed for all out-of-specification data including those generated on stability.
Often these stability studies are performed at a contract research facility. The occasions where a Sponsors’ contractor has performed stability studies on clinical trial material with the specifications for all tests are “report result” do not support the requirements of a new drug application per the ICH Q1A (R2) guidelines for stability studies.
Sponsors should be actively involved in their programs that are being conducted at contract sites. Timely follow-up on issues with out-of-specification results can be critical to identifying the root cause of the problem and enforcing corrective action as well as providing a coherent understanding of the properties of the drug product under development.