This blog post is Part 1 of the series and comes to us from Piero De Filippis, StabilityHub EU Regional Contributor, Verona (Italy).

Part 1: Stability Study Design for an Investigational Medicinal Product

European directive 2001/20/EC (Ref.1a) defines an Investigational Medicinal Product (IMP, also known in USA as ‘Investigational Drug Product’ (Ref.2&3)) as “a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form (…)”.

This blog reports points to consider when designing and evaluating data of a stability study on an IMP intended to support clinical studies in the European Union (EU); it includes both the EU regulatory perspective and some notes from the author’s experience. This is part 1 of a 2-part blog: the second part will cover IMP shelf-life assignment and extension for EU.

IMP use authorization for a clinical study in the EU

To run a clinical trial in the EU, a sponsor must request, among other things, an authorization to the competent authority of the Member State where the sponsor plans to conduct the clinical trial (Ref. 1b).

All the Chemistry, Manufacturing and Control information on the IMP for this authorization, including IMP stability data, are included in an Investigational Medicinal Product Dossier (IMPD) (Ref. 4), similar to the USA FDA Investigational New Drug Application (IND) (Ref. 2). The IMPD will be reviewed and approved by the EU Member state regulatory authority where the clinical trial will be run, as a prerequisite for the clinical study start.

However, as clinical trials are often designed as multi-center studies, potentially involving different EU Member States, EMA, (the well-known European Medicines Agency) (Ref.5), has prepared a guideline on IMPD contents to define harmonized requirements throughout the EU (Ref. 4). This guideline is the main basis for EU requirements and expectations for IMP stability testing reported in the present blog.

IMP Stability Batches & Packaging Selection for a Clinical Study

The selection of the right batches and packaging for the IMP stability study is a pre-requisite and key element for the overall success of the whole stability study in support of a product clinical development.

As far as number of batches to be placed on stability, the typical approach is to place on stability at least one batch of drug substance and one batch for each strength of the IMP to be used in the clinical study, as supported by EMA IMPD guideline wording interpretation (Ref. 4a & 4b) and author experience (i.e.; not at least three batches as for marketing authorization stability studies), unless the stability data shows variability.

A bracketing & matrixing design of stability studies (Ref.6) is expressly considered acceptable by the EMA guideline for IMP, if justified (Ref. 4b). This approach may be particularly useful when supporting clinical studies in which a wide range of doses will be used, to decrease resource efforts in supporting the IMP stability.

There is no EMA explicit requirement in the IMPD guideline that the stability batch(es) should be the actual clinical one(s); the only key indication is that batch(es) placed on stability to support a clinical study should be ‘representative’ of the clinical ones.

The representation of stability vs. clinical batches is defined in the EMA IMPD guideline for the drug substance stability batch(es) as ‘… batch(es) manufactured according to the representative process (the same/very similar synthesis, comparable batch size)’. (Ref. 4a). The term ‘representative’ is not further explained for drug product stability batches in the EMA IMPD guideline (Ref. 4b). However, in a previous section of the IMPD guideline for batch analysis for drug product (Ref. 4c) ‘representative batches’ are defined as having “…same manufacturing site, same manufacturing process, same composition, and comparable batch size, unless otherwise justified.” Although this is not clearly linked to stability batches, in the author’s view, this indication should be considered in assessing the degree of representation of stability vs. clinical batches.

If the clinical batches will not be placed on stability to support the clinical study, in the author’s experience, an in-depth assessment of potential differences of manufacturing characteristics of stability vs. clinical batches (e.g., input drug substance, comparable batch size, manufacturing equipment and site, etc.) should be performed to anticipate and assess any potential stability issues of the clinical batches.

Therefore, IMP stability batches may or may not be the clinical batches, provided they are representative of the clinical batches. Non-clinical batches can also be initially placed on stability to support an earlier shelf-life assignment, that is then confirmed and extended with subsequent clinical batches stability studies.

There are no explicit requirements in the IMPD guideline as far as IMP stability packaging, however it should be considered as falling in the same full ‘representative’ requirement of the stability batches.

The EMA IMPD guideline also specifically indicates that, if a solid drug product is stored in a bulk pack for a “significant time period”, stability data and relevant shelf-life of product in bulk pack should be included in the IMPD (Ref. 4b). This situation may take place during clinical development for a product with different packaging configurations (i.e., different solid dosage form fill counts in the same packaging) with supplies prepared at different times for different clinical studies of the product.

Storage conditions and test points

There are no explicit requirements on this topic in the IMPD guideline apart from a mention of the need to supply long term and accelerated condition data for drug product (Ref. 4b). A typical choice in the author’s experience in this area is to adopt ICH stability storage conditions and test points as reported in the ICH Q1A(R2) and Q1B stability guidelines (Ref.7a & 8). The typical approach is to include, in addition to ICH indications, one or two time points between the initial and the 3-month time points (e.g., 1 or 1 & 2 or 1.5 months) at both long term and accelerated conditions to allow an earlier initial assignment of shelf-life to the IMP.

An easy to avoid regulatory deficiency is to ensure that the stability protocol covers at least the assigned extrapolated shelf-life (Ref. 4b). It may be convenient to state in the IMPD that the stability study may be stopped when the time point that covers the actual product administration period in a clinical study has been reached. This may be useful e.g., when an IMP project with a long shelf-life assigned is terminated well in advance of the clinical lot expiry.

Tests to be performed in the stability study

There are no explicit indications in the IMPD guideline for this topic, so criteria outlined in the ICH Q1A (R2) (Ref. 7b) are typically followed for test selection in the IMP stability study.

The EMA IMPD guideline specifically indicates the need to generate in-use stability data, assigning an in-use shelf-life when applicable, for non-oral solid preparations intended to be administered after reconstitution, dilution or mixing and for products in multi-dose containers (Ref. 4b). In-use stability studies should mimic the practice described in the clinical protocol. Specific tests are recommended in the guideline for these in-use stability studies. No in-use data are required for product to be administered immediately after opening or reconstitution. This type of studies can also be applied for extemporaneously prepared IMP at the clinical site in early clinical phases.

Extractables & leachables studies may be required for phase III clinical studies according to the EMA IMPD guideline for dosage forms that have a higher potential for interaction between filling and container closure systems (e.g., parenteral and ophthalmic products, oral solutions) (Ref. 4d).
Suitability of the applied analytical methods in the stability study should be demonstrated (Ref. 4e).

Comparator products

Comparator products are defined in a European Commission guideline on GMP for IMP as ‘investigational or marketed product (i.e., active control) or placebo used as a reference in a clinical trial’ (Ref. 9).

Stability data are required for comparator products by the EMA IMPD guideline only if a modification applied to a marketed product employed as comparator in a clinical trial (i.e., to allow a blind design of the clinical study) has a likely significant impact on product stability (e.g., over-encapsulation or tablet grinding) (Ref. 4f). In the author’s experience, the choice of storage conditions, test points and tests applied in this stability study heavily depends on several factors (e.g., degree of marketed product modification, the need to extrapolate the shelf-life, etc.). In any case, it is always convenient to place on stability in parallel (also as optional testing only) the unmodified comparator, to be able to better assess stability data of the modified comparator, in case of changes in storage of the stability testing parameters.

In case of only minor modifications, a justification of the stability over the intended trial period may be acceptable according to the EMA IMPD guideline (Ref. 4f).

The assigned shelf-life to a modified comparator product may not exceed the shelf-life originally assigned to the specific authorized product (Ref. 4f). Therefore, the expiry date assigned to each batch of a modified comparator product going to clinical studies, based on the assigned shelf-life, should not exceed the expiry date of the original batch of the unmodified authorized product.

Placebo products

Placebo products used in clinical trials are considered IMP and must be therefore described in the IMPD. The EMA IMPD guideline specifically requires stability studies on placebo product only when there is a rational basis to anticipate that it could undergo physical or microbiological changes in its characteristics on storage. For example; appearance, tablet hardness or microbial purity of multi-dose placebo product containers (Ref. 4g). In all other cases, a short justification of the assigned shelf-life will suffice. In general, it is the author’s experience that a minimal stability study (e.g.; appearance only) for internal use only and when not strictly required, may be beneficial for placebo products if historical data are not available. This approach will help to better manage any unexpected issue that can affect any aspect of blind design of the clinical study, such as apparent discoloration of the active during the study.

Do you have any information or a request for clarification for this blog author or any experience in this area that you wish to share with the StabilityHub community? Please send your question or comment to the author at piero.df@outlook.com with the subject ‘Comment on blog on stability study for an IMP in EU – Part 1.’ Or you may click the button below. Questions & Answers and comments will be collected by this blog author in a document that will be posted after this blog.

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References (Part 1)

  1. European Parliament and Council Directive 2001/20/EC. (..) implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use’ – a) Article 2(d) Definitions; b) Article 9(2) Commencement of a clinical trial. (2009) [Link: https://ec.europa.eu/health/human-use/clinical-trials/directive_en – last accessed 12nd February 2021]
  2. U.S. Food & Drug Administration (FDA). Guidance for Industry INDs for Phase 2 and Phase 3 Studies – Chemistry, Manufacturing, and Controls Information. (2003) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/inds-phase-2-and-phase-3-studies-chemistry-manufacturing-and-controls-information – last accessed 12nd February 2021]
  3. United States Pharmacopeia (USP). Chapter 〈1079.1〉 Storage and Transportation of Investigational Drug Products. USP 43 – NF 38, United States Pharmacopeia Convention, Rockville, MD., USA (2019)
  4. 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’ – a) Sect. 2.2.1.S.7 ‘Stability’; b) Sect 2.2.1.P.8 ‘Stability’; c) Sect. 2.2.1.P.5.4 ‘Batch analyses’ ; d) Sect. 2.2.1.P.7 ‘Container closure system’; e) Sect. 2.2.1.S.4.3 and 2.2.1.P.5.3 ‘Validation of analytical procedures’; f) 4.2.1.P.8 ‘Stability’; g) 6.2.1.P.8 ‘Stability’ (20 September 2017) [Link: https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal – last accessed 12nd February 2021]
  5. European Medicines Agency web site at https://www.ema.europa.eu/en (last accessed 12nd February 2021]
  6. International Council for Harmonisation (ICH) guideline ICH Q1D. Bracketing and matrixing designs for stability testing of new drug substances and products (2002) [link: https://www.ema.europa.eu/en/ich-q1d-bracketing-matrixing-designs-stability-testing-drug-substances-drug-products – last accessed 12nd February 2021]
  7. International Council for Harmonisation (ICH) guideline Q1A(R2). Stability Testing of New Drug Substances and Products’ – a) Sections 2.1.7. and 2.2.7 ‘Storage Conditions’; b) 2.1.5. and 2.2.5. ‘Specification’ (2003) [Link: https://www.ema.europa.eu/en/ich-q1a-r2-stability-testing-new-drug-substances-drug-products – last accessed 12nd February 2021]
  8. International Council for Harmonisation (ICH) guideline Q1B. Photostability Testing of New Active Substances and Medicinal Products (1998) [Link: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-1-b-photostability-testing-new-active-substances-medicinal-products-step-5_en.pdf – last accessed 12nd February 2021]
  9. European Commission EU Guidelines to Good Manufacturing Practice – Medicinal Products for Human and Veterinary Use – EudraLex, Volume 4 Annex 13 ‘Investigational Medicinal Products’. Glossary (February 2010) [link: https://ec.europa.eu/health/documents/eudralex/vol-4_en – last accessed 12nd February 2021]

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