Introduction and background
The ICH stability guideline Q1A(R2) recommends to assess the stability of a drug product to be constituted or diluted before administration (e.g., a powder for injection) as well as after its reconstitution or dilution, and throughout its entire period of use (Ref. 1).
This “in-use” stability study has the objective to provide information on the storage condition and the shelf-life to be assigned to the product once it is reconstituted or diluted, if applicable (Ref.1). The in-use study should be performed, according to ICH Q1A(R2), at initial and final time points of the stability study. If at the time of submission of the registration document, full shelf-life has not been reached, in-use stability data should be supplied for the 12 months point, or from the last time point for which data are available at submission (Ref. 1).
The European Medicines Agency (EMA) has integrated these ICH recommendations for in-use stability studies for products to be reconstituted or diluted, with a long-standing guideline, specifically covering the in-use stability testing of multi-dose products (Ref. 2). EMA has included a Questions & Answers segment on in-use stability studies on solid oral dosage forms in multi-dose containers (Ref. 3).
The target of this first in a 2-part series is to summarize in an easy schematic the main EMA recommended approaches for in-use stability studies for multi-dose products for human use.
Information from other world-wide regulatory guidances covering in-use stability studies for multi-dose products for human use will be provided for completeness and reference in Part 2 of this series.
In-use stability studies for multi-dose products according to EMA
The EMA main concern for the stability of a medicinal product in a multi-dose container after its first opening is that once the closure system has been breached, the repeated opening and closing of the container during product use could affect its physico-chemical or microbiological quality (Ref. 2).
Key points of the EMA In-use Stability Testing Guideline for Multi-dose Products for Human Use (Ref. 2) can be summarized as:
- In-use stability study design: the study should be set up, as far as possible, to simulate the use of the product in clinical practice, taking into consideration any needed dilution before final administration. Suitable quantities of the product, stored at the to-be-recommended in-use storage condition, should be removed from the container at appropriate time points. The chosen sampling time points, sample amount and withdrawal method should also be aligned with those to-be-recommended in the product leaflet. The product container-closure and any dosing device should be equivalent to those for marketing.
- Number of batches to be included: a minimum of two batches, at least at pilot scale, should be included in the study. At least one batch should be tested near its end-of-shelf life. If at the end-of-shelf life, in-use stability data are not available at time of submission of the registration dossier, one batch should be in-use tested at the final available time point before submission.
- Tests to be included: appropriate stability-indicating physical, chemical and microbiological tests should be performed during the in-use stability study, applying fully validated methods. The EMA guideline includes some examples of tests to be considered for the in-use study. Testing should also be performed, if possible, at intermediate time points in addition to the end of the proposed in-use shelf life.
- In-use information to be included in the registration dossier of a multi-dose product: tabulated in-use stability data with an assigned in-use shelf-life and related in-use storage condition or, a justification why an in-use shelf-life is not required (e.g. on the basis of experimental data) should be included in the registration document.
- In-use information to be included on the label of a multi-dose product: the applied in-use shelf life should be reported there. In addition, if feasible, a dedicated space should be present on the multi-dose product label to allow the user to record the date of first container opening or the in-use product expiry date
In-use stability studies for solid oral dosage forms in multi-dose containers according to EMA
EMA has also provided specific additional recommendations for in-use stability studies for solid oral dosage forms (e.g., tablets or capsules) in multi-dose containers within the Quality of Medicines Question & Answer (Q&A) area on the Agency website (Ref. 3).
Key points of these EMA recommendations from Q&A area (Ref. 3) can be summarized as:
- Need for In-use stability study on solid oral dosage forms in multi-dose containers: these studies should be performed only when stability or stress study data on the drug product show indications of possible product degradation under in-use conditions as noted in Ref. 3a, item 1.
- In-use stability study length: should be set according to patient treatment duration and number of multi-dose containers of the product needed for the entire treatment period. Table 1 below summarizes the EMA recommendations for in-use stability study duration (Ref. 3a, item 2). The in-use stability study does not need to be progressed beyond 6 months if no ‘relevant change’ (i.e. a significant change, as per ICH Q1A(R2) definition (Ref.1) or a change that is trending toward an OOS result) is observed. In such a case, no in-use shelf life needs to be defined for the product in its immediate packaging (Ref. 3a, item 2).
Table 1 – Summary of EMA recommended in-use stability study duration vs. treatment duration & number of multi-dose containers needed for the entire treatment for solid oral dosage forms
- Open dish stability studies (i.e. uncovered stability storage of drug product, without packaging protection, e.g. at 25°C/60%RH, as indicated as first choice by EMA): these studies can be used to assess in-use stability for solid oral dosage forms, as worst case scenario of an in-use study. If no ‘relevant changes’ are observed after 3 month open dish storage of a solid drug product, no in-use shelf life is considered needed by EMA. If any ‘relevant change’ is observed in open dish conditions, an in-use study, i.e. with suitable opening and sampling as in practical use, is required to establish any needed in-use shelf life (Ref. 3a, item 3).
- Assigning the in-use shelf life for solid oral dosage forms in multi-dose containers: indications are provided in the Q&A area in EMA website (Ref. 3b, item 1), as summarized in Table 2 below, with cases ranging from no degradation, to an Out-of-Specification (OOS) result observed in the in-use study.
Table 2 – Summary of EMA recommended assignment criteria of in-use shelf-life vs. in-use stability study results for solid oral dosage forms in multi-dose containers
- SUMMARY: An In-use shelf life date for solid oral dosage forms in multi-dose containers should only be applied when strictly necessary, based on in-use stability data, i.e. when a significant change as defined in ICH Q1A(R2) (Ref. 1) is observed (Ref. 3a, item 2 and 3b, item 1). This recommendation is due to the negative implications a restrictive in-use shelf life would have on patients, and on National Health Care Systems costs (Ref. 3b, item 2).
Piero De Filippis is the StabilityHub EU Regional Contributor, based in Italy. His e-mail address is firstname.lastname@example.org.
References (Part 1)
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline Q1A(R2). Stability Testing of New Drug Substances and Products – Section 2.2.7. Storage Conditions (6 February 2003)
- European Medicine Agency (EMA, formerly EMEA) Guideline CPMP/QWP/2934/99. Note for Guidance on In-Use Stability Testing of Human Medicinal Products (1 March 2001). Link: https://www.ema.europa.eu/en/use-stability-testing-human-medicinal-products. Accessed 03 August 2021
- EMA Quality of Medicines Questions and Answers: Part 2 – a) Section “Design of in-use shelf life for solid oral dosage forms in multi-dose containers” – b) Section “Claims for in-use shelf-life for solid oral dosage forms in multi-dose containers”. Links: a) https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/qa-quality/quality-medicines-questions-answers-part-2#design-of-in-use-shelf-life-for-solid-oral-dosage-forms-in-multi-dose-containers-section and b) https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/qa-quality/quality-medicines-questions-answers-part-2#claims-for-in-use-shelf-life-for-solid-oral-dosage-forms-in-multi-dose-containers-section. Accessed 03 August 2021