Drug products forced degradation

In case study A.ll, a degradant was observed in drug product-forced degradation (thermal/humidity) studies of the drug substance salt. This compound was at a later stage of development and proactive efforts were... 

Extractables and Leachables — Materials or components derived from the container and closure that have been transferred into the contained drag substance or drug product. Forced Degradation Testing Studies [ICH Q1B] — Studies undertaken to degrade the sample deliberately. These studies, which may be undertaken in the development phase normally on the drug substances, are used to evaluate the overall photosensitivity of the material for method development purposes or degradation pathway elucidation. 

Even if the same drug substance HPLC method is used for the drug product, forced decomposition studies must be performed again for the drug product to confirm the resolution of potential degradation products from the API. In addition, forced decomposition studies must also be performed for different dosage forms (capsule, tablet, suspension, injectable, etc.) of the same drug substance. 

It is common practice to utilize forced degradation studies to accelerate degradation of the drug substance or drug product to get an understanding of its degradation profile. Potential environmental conditions that can be used include 40°C and 75% relative humidity (RH), 50°C and 75% RH, 70°C and 75% RH, or 80°C and 75% RH. Oxidation, reduction, and pH-related degradations are... 

Table 1 shows a general outline for degradation studies of new drug substances and drug products that was endorsed at the PhRMA Acceptable Analytical Practices for Forced Degradation workshop (3). 

Table 1 General Protocol for Forced Degradation Studies (Stress Testing) of Drug Substance and Drug Products...

The sponsor should consider evaluating forced degradation products in animal studies to determine if they present a toxicity issue, and, if so, an appropriate limit to ensure safety. Failure to identify toxic degradation products early in the development program can be costly mistake if the drug has to be abandoned later because of potential toxicity concerns. 

To determine product protection requirements. Forced degradation studies provide valuable information related to the type of protection (i.e., container-closure system and storage conditions) that will be necessary, not just for the API, but also for the drug product. These studies also help to determine whether or not special precautions are required during shipping. 

Forced degradation studies on the drug product are carried out on a single batch of the formulation to be marketed to determine if there are any additional degradation pathways and degradants formed due to interactions between or among the API and the excipients. 

The FDA IND Phase 2/3 Guidance recommends that these studies be carried out in phase 3. The timing of forced degradation studies on the drug product is a trade-olf. On the one hand, the sponsor would prefer to carry out... 

Forced Degradation Studies (Solid State and Solution)—Drug Substance and Drug Product... 

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