ABSTRACT
As has been discussed elsewhere ( 1 , 2 ), for a novel drug candidate that progresses from discovery through preclinical and clinical stages of development and eventually to the market, stress testing is not a “one-time” event. Instead, stress testing is typically performed at several stages in the “life cycle” of a novel drug candidate with different goals (and therefore often different strategies and levels of thoroughness) depending on the stage of development. For example, stress testing of a solid drug substance requires the testing of material that is representative, that is, the material that will be used during clinical trials or the material that will be marketed. Thus, the drug substance should be the same solid form (e.g., same salt, solvation state, and polymorphic form) with similar solid characteristics (e.g., particle size, surface area, crystallinity, etc.). Since early lots of a drug candidate are generally obtained from synthetic routes and processes that will not be the same as that used for the fi nal marketed form, solidstate stress testing of early lots may not accurately refl ect potential active pharmaceutical ingredient (API) stability issues with new routes and processes. Therefore, API stability needs to be evaluated over the course of development. This is especially critical to reassess solid-state stress testing as a result of API process changes (i.e., synthetic steps, crystallization solvents, milling/ micronization, etc.) and changes in polymorph/salt form.
