Any stability study must be conducted according to a written stability protocol designed to satisfy the developmental phase of the study. As per 21CFR312.23, data are required to support the stability of the drug substance during the pre-clinical toxicological studies, and in all phases of the IND to ensure that the drug substance is well within the acceptable chemical and physical limits for the planned duration of the proposed clinical investigation. The drug substance stability profile is usually developed early in the development process. The preliminary stability profile becomes very useful in the development of a stability protocol. It is important to note that there is no expiration dating required for a drug substance unless it is an antibiotic. The physiochemical changes of a drug substance on stability are quantitated using stability indicating chromatographic methods. These methods are used to determine the intrinsic stability of a new molecular entity by establishing degradation pathways to project the likely degradation products. Stability data from accelerated and long term testing is required for registration application. The laboratory scale drug substance batches placed on stability representing batches used in pre-clinical and clinical studies, are submitted as supportive stability data for registration.
Formal stability data are generated by placing batches of drug substance manufactured on a pilot scale using the final synthetic process. This is the formal stability data required in the new drug application. Post approval, three production size drug substance batches are placed on long term stability using the identical stability protocol as in the approved drug application.
Stability storage conditions for NDA registration should contain the following (USP <1196>):
• Long term testing 25° C ± 2° C/60% RH ± 5% with a minimum of 12 months data.
• Accelerated condition 40° C ± 2° C/75% RH ±. 5% with a minimum of 6 months storage.
When a "significant change" occurs during 6 months storage under accelerated conditions as listed above, additional testing at an intermediate condition (such as 30° C ± 2° C and 60% RH ± 5%) should be conducted for drug substance to be used in the manufacture of dosage forms and tested long term at 25° C 60% RH. This information is included in the registration application.
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