Question and Answer: Stability Testing Study Design and Data Evaluation

Earlier this year, a 2-part blog series on this website – Stability Testing Study Design and Data Evaluation to Support a Clinical Study in the European Union – reported points to consider when designing a stability study and evaluating relevant data on an Investigational Medicinal Product (IMP) intended to support clinical studies in the European Union (EU) (Ref. 1).

This blog was mainly based on a European Medicines Agency (EMA) guideline covering the information to be included in the IMP regulatory dossier (IMPD) for the chemical and pharmaceutical parts (Ref. 2).

This follow-up blog post includes a pair of questions received by Piero De Filippis and his corresponding answers.

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 piero.df@outloook.com.

1. P. De Filippis. Stability Testing Study Design and Data Evaluation to Support a Clinical Study in the European Union. stabilityhub.com – a) Part 1, Published on 28 February 2021 – b) Part 2, Published on 15 March 2021
2. European Medicines Agency (EMA) guideline EMA/CHMP/QWP/545525/2017. Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials’ (20 September 2017) [Link: https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal – last accessed 25 September 2021]
3. European Medicines Agency (EMA) guideline EMA/CHMP/BWP/534898/2008 rev. 1 ‘Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials’ – a) Sect. S.7. Stability; b) Sect P.8. Stability; (September 2018) [Link: https://www.ema.europa.eu/en/requirements-quality-documentation-concerning-biological-investigational-medicinal-products-clinical – last accessed 25 September 2021]
4. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline Q5C. Quality of Biotechnological Products: Stability Testing of Biotechnological/ Biological Products (EMA Version CPMP/ICH/138/95: July 1996 – link: https://www.ema.europa.eu/en/ich-q5c-stability-testing-biotechnologicalbiological-products – last accessed 25 September 2021]
5. Food and Drug Administration Web Site ‘The drug development process – Step 3: Clinical Research’, [Link: https://www.fda.gov/patients/drug-development-process/step-3-clinical-research – last accessed 25 September 2021]