EMA has issued a specific guideline covering the Agency’s expectations for the contents of an IMPD for a biological / biotechnology IMP (Ref. 3).
For a biological / biotechnology drug substance, the main EMA stability recommendations (Ref. 3a) can be summarized as:
- test intervals should normally follow the ICH stability guideline Q5C for biological products (Ref. 4)
- a re-test period (as defined in the ICH Q1A (R2) guideline) is not applicable to biological / biotechnology IMP’s, but rather a shelf life
- it may be acceptable for a biological IMP to assign a longer shelf-life than the period available for long-term, real-time stability data (having accelerated stability data available). This extension should not be more than twice, or more than twelve months longer than the available period of long-term stability data, with representative batch(es)
The same stability recommendations as for the active ingredient applies to the biological / biotechnology Investigational Medicinal Product (Ref. 3b). The stability protocol for IMP should consider the knowledge gained on the stability profile of the active substance.
Based on the author’s experience and on the text of the EMA guidelines on IMPD (Ref. 2 and 3), there is no explicit EMA requirement on the minimum period of stability data to be available at the time of IMPD submission in the EU. So, this period has to be decided on the basis of some additional (project) considerations.
The key point in this regard is that, progressing clinical studies from Phase I, to Phase II up to Phase III, there is a significant increase in the duration of the study (e.g., from several months for a Phase I, to several months-2 years for a Phase II, up to 12-48 months for a Phase III Clinical Trial, Ref. 5). This period increase is obviously linked to an increase in the necessary company resources and investment of money. In addition, there is a need to preferably adopt the final formulation for commercialization in Phase III clinical trials.
Thus, there is an increasing need, from initial Clinical Phase I through Phase III, to initiate the clinical study with a sufficiently stable IMP to avoid frequent IMP resupplies during the clinical study, due to its insufficient stability.
This point, also considering the EMA-recommended links between the available stability data period and the allowed shelf life (Ref. 1b), makes it important to have available, at initial phase-specific IMPD submission, sufficiently long stability data to support and predict a sufficiently long shelf life. This period, according to the author’s experience, can be taken indicatively for a need of stability data of 1-3 months for a Phase I IMPD submission, 3-6 months for a Phase II IMPD, up to 6-12 months for a Phase III IMPD.
Piero De Filippis is the StabilityHub EU Regional Contributor, based in Italy. His e-mail address is firstname.lastname@example.org.