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.
May 02, 2012
Volume 36, Issue 5

Forced degradation is synonymous with stress testing and purposeful degradation. Purposeful degradation can be a useful tool to predict the stability of a drug substance or a drug product with effects on purity, potency, and safety. It is imperative to know the impurity profile and behavior of a drug substance under various stress conditions. Forced degradation also plays an important role in the development of analytical methods, setting specifications, and design of formulations under the quality-by-design (QbD) paradigm. The nature of the stress testing depends on the individual drug substance and the type of drug product (e.g., solid oral dosage, lyophilized powders, and liquid formulations) involved (1).

The International Conference on Harmonization (ICH) Q1B guideline provides guidance for performing photostability stress testing; however, there are no additional stress study recommendations in the ICH stability or validation guidelines (2). There is also limited information on the details about the study of oxidation and hydrolysis. The drug substance monographs of Analytical Profiles of Drug Substances and Excipients provide some information with respect to different stress conditions of various drug substances (3).

The forced degradation information provided in the abbreviated new drug application (ANDA) submissions is often incomplete and in those cases deficiencies are cited. An overview of common deficiencies cited throughout the chemistry, manufacturing, and controls (CMC) section of the ANDAs has been published (46). Some examples of commonly cited deficiencies related to forced degradation studies include the following:

  • Your drug substance does not show any degradation under any of the stress conditions. Please repeat stress studies to obtain adequate degradation. If degradation is not achievable, please provide your rationale.
  • Please note that the conditions employed for stress study are too harsh and that most of your drug substance has degraded. Please repeat your stress studies using milder conditions or shorter exposure time to generate relevant degradation products.
  • It is noted that you have analyzed your stressed samples as per the assay method conditions. For the related substances method to be stability indicating, the stressed samples should be analyzed using related substances method conditions.
  • Please state the attempts you have made to ensure that all the impurities including the degradation products of the unstressed and the stressed samples are captured by your analytical method.
  • Please provide a list summarizing the amount of degradation products (known and unknown) in your stressed samples.
  • Please verify the peak height requirement of your software for the peak purity determination.
  • Please explain the mass imbalance of the stressed samples.
  • Please identify the degradation products that are formed due to drug-excipient interactions.
  • Your photostability study shows that the drug product is very sensitive to light. Please explain how this is reflected in the analytical method, manufacturing process, product handling, etc.

In an attempt to minimize deficiencies in the ANDA submissions, some general recommendations to conduct forced degradation studies, to report relevant information in the submission, and to utilize the knowledge of forced degradation in developing stability indicating analytical methods, manufacturing process, product handling, and storage are provided in this article.

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