ABSTRACT
As has been discussed elsewhere (1,2), for a novel drug candidate that progresses from discovery through pre-clinical 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-i.e., 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 polymorphic form) with similar solid characteristics (e.g., particle size, surface area, 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 final
marketed form, stress testing of early lots may not accurately reflect potential stability issues with new routes and processes. A significant factor in the design of stress testing studies at different stages is the reality that only a small percentage of novel drug candidates make it to the market-the vast majority fail at some point during the drug development process due to factors such as unexpected toxicity, poor absorption or bioavailability (or other biopharmaceutical or metabolism problems), or lack of efficacy (3,4). Since there is a high attrition rate (approximately 90% of compounds entering development will fail), it is not cost-effective to perform the kind of thorough research needed for a marketed product for every new drug candidate. Thus, it is worth discussing stress testing in the context of typical life cycles of a novel drug candidate: (1) drug discovery, (2) pre-clinical/ early phase, (3) ‘‘commercialization’’ or late phase, and (4) line-extensions and products on the market.
