FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions. (Part-01)
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.
The forced degradation information provided in the abbreviated new drug application (ANDA) submissions is often incomplete and in those cases deficiencies are cited. 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 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.”