小中大How ‘‘hard’’ should a drug substance be stressed?
This is one of the most frequently asked questions related to stresstesting
studies, probably because there are no official regulatory guidances
that deal with such specifics. The primary question is whether the drug must
be forced to degrade (regardless of how harsh the conditions or how long
the exposure) or simply exposed to conditions of ‘‘reasonable harshness’’
with the understanding that if the drug does not degrade under this set of
conditions then it can be regarded as ‘‘stable’’ to the particular stress condition.
We assert that there should be realistic limits to stress-testing studies，and these limits are discussed in detail in Chapter 2. Additional guidance and discussion can be found in the PhRMA ‘‘Available Guidance and Best
Practices’’ article (3), in Chapter 1, and elsewhere (4). As discussed in the
PhRMA article, the target of stress testing is the ‘‘lesser of 10% degradation
of the active ingredient or exposure to energy in slight excess of accelerated
storage . . . ’’. The approach discussed in the PhRMA article acknowledges
that a compound may not degrade under a given stress condition after a reasonable
amount of time, and that no further stressing is advised in these
cases. Increasing stress conditions to force degradation (without regard to
whether or not the stressing is excessive) can lead to degradation pathways
that are not representative of ‘‘real world’’ degradation. Such degradation
will cause unnecessary method development for separation of components
that will never be observed under realistic conditions, e.g., upon storage
according to ICH guidelines (4) or under reasonable shipping or distribution
excursions or patient use.
