Forced degradation studies conditions

TABLE 3 Suggested Conditions for Performing Forced Degradation Studies... 

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... 

Recent publications on the topic of stress testing/forced degradation studies reveal that there is still a tremendous variability in the conditions... 

A comprehensive literature search should be carried out before initiating any laboratory work related to forced degradation studies. Such a search may uncover the needed information if the API is a well-known entity or guide the choice of conditions to be used if information is available for related compounds. 

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. 

The desired outcome of forced degradation studies is the generation of not only degradation products that may be observed during normal storage of the API and the dosage form, but also degradation products that are not normally observed but could be formed under certain strenuous conditions. 

Some firms are satisfied when no degradation is observed under the chosen forced degradation conditions and consider this evidence that the API is inherently stable. It should be emphasized, however, that the main purpose of forced degradation studies is to generate degradation products, not to test the stability of the product, thus if the conditions initially chosen do not result in degradation, the severity of the conditions (i.e., time, temperature, and/or concentration) should be increased. If the substance does not react because it is insoluble, organic cosolvents should be used to solubilize the material. 

If degradants are not formed under initial forced degrations study conditions, repeat the studies using more stringent conditions. 

The temperature/humidity conditions used may be more severe than the typical accelerated stability testing conditions in order to generate potential degradation products in a reasonable time. The typical forced degradation conditions include thermolytic, hydrolytic, oxidative, photolytic (in excess of ICH conditions), high pH (alkaline conditions), and low pH (acidic conditions). Outlined in Table 9-25 and Table 9-26 are some solid-state and solution forced degradation studies, respectively, that could be conducted. In the following... 

Some approaches/examples for conducting forced degradation studies are given below For a forced degradation acid study for a particular API the API is exposed to acidic conditions. The API (at a known concentration) is usually prepared in the sample preparation solvent, which gives 0.1 M HCl concentration in the final solution. Once this solution is prepared, it is injected every half hour or hour to determine the loss of API over time. If the API is susceptible to degradation under acidic conditions, then peak(s) of degradation products would increase over time and the API should decrease over time... 

Equivalent stability evaluations have not been documented for the various alternatives under the two options or between the Option 1 and 2. Thoma and Kerker have compared several of these sources and obtained nonequivalent results (4,5). From a scientific viewpoint, the various alternatives are not equivalent assuming that experimental conditions are carefully controlled. Both the irradiance levels and the spectral power distributionsare different. For the purpose of a confirmatory study, the options could however, possibly be regarded as equivalent. The results are most likely to be combined with knowledge about the compound or product from previous tests e.g., by the time the ICH confirmatory test is carried out, product photostability is already known from the forced degradation studies. 

The choice of stress conditions should be consistent with product decomposition under normal manufacturing, storage, and use conditions. Recommended stress factors include high and low pH, elevated temperature, photolysis, and oxidation. The extent of the stress applied in forced degradation studies should ensure formation of the desired amount (usually 10-20%) of degradation. 

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