FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions - Pharmaceutical Technology

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FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions
The author outlines the scientific aspects of forced degradation studies that should be considered in relation to ANDA submissions.


Pharmaceutical Technology
Volume 36, Issue 5, pp. 73-80

Termination of study

Stress testing could be terminated after ensuring adequate exposure to stress conditions. Typical activation energy of drug substance molecules varies from 1224 kcal/mol (18). A compound may not necessarily degrade under every single stress condition, and general guideline on exposure limit is cited in a review article (10). In circumstances where some stable drugs do not show any degradation under any of the stress conditions, specificity of an analytical method can be established by spiking the drug substance or placebo with known impurities and establishing adequate separation.

Other considerations

Stress testing may not be necessary for drug substances and drug products that have pharmacopeial methods and are used within the limitations outlined in USP <621>. In the case where a generic drug product uses a different polymorphic form from the RLD, the drug substance should be subjected to stress testing to evaluate the physiochemical changes of the polymorphic form because different polymorphic forms may exhibit different stability characteristics.

Forced degradation in QbD paradigm

A systematic process of manufacturing quality drug products that meet the predefined targets for the critical quality attributes (CQA) necessitates the use of knowledge obtained in forced degradation studies.

A well-designed, forced degradation study is indispensable for analytical method development in a QbD paradigm. It helps to establish the specificity of a stability indicating method and to predict potential degradation products that could form during formal stability studies. Incorporating all potential impurities in the analytical method and establishing the peak purity of the peaks of interest helps to avoid unnecessary method re-development and revalidation.

Knowledge of chemical behavior of drug substances under various stress conditions can also provide useful information regarding the selection of excipients for formulation development. Excipient compatibility is an integral part of understanding potential formulation interactions during product development and is a key part of product understanding. Degradation products due to drug-excipient interaction or drug-drug interaction in combination products can be examined by stressing samples of drug substance, drug product, and placebo separately and comparing the impurity profiles. Information obtained regarding drug-related peaks and non-drug-related peaks can be used in the selection and development of more stable formulations. For instance, if a drug substance is labile to oxidation, addition of an antioxidant may be considered for the formulation. For drug substances that are labile to acid or undergo stereochemical conversion in acidic medium, delayed-release formulations may be necessary. Acid/base hydrolysis testing can also provide useful insight in the formulation of drug products that are liquids or suspensions.

Knowledge gained in forced degradation studies can facilitate improvements in the manufacturing process. If a photostability study shows a drug substance to be photolabile, caution should be taken during the manufacturing process of the drug product. Useful information regarding process development (e.g., wet versus dry processing, temperature selection) can be obtained from thermal stress testing of drug substance and drug product.

Additionally, increased scientific understanding of degradation products and mechanisms may help to determine the factors that could contribute to stability failures such as ambient temperature, humidity, and light. Appropriate selection of packaging materials can be made to protect against such factors.


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