Part 1 of this blog (Ref. 1) has described at a high level the guidance provided by the European Medicines Agency (EMA) on in-use stability testing of multi-dose products for human use (Ref. 2 and 3).
The second of this 2-part blog series includes for completeness and reference, information on other world-wide (WW) regulatory guidance covering in-use stability studies for multi-dose products for human use.
WHO stability guideline
The World Health Organization (WHO) stability guideline contains a specific section on in-use stability studies, also applicable to multi-dose products (Ref. 4). This section combines the recommendations and text of both the ICH Q1A(R2) section (Ref. 5) and the EMA guideline (Ref. 2) on in-use stability studies. The WHO guideline derives from the EMA guideline the recommendation on the number of batches on which to perform the in-use stability study (i.e., two), with one batch chosen towards the end of its shelf-life.
A peculiarity of the WHO stability guideline vs. the other guidelines and regulations mentioned in this 2-part blog series, is that it normally considers an in-use period of 30 days to be acceptable without additional supporting data.
ANVISA stability regulation and guideline
ANVISA (Agência Nacional de Vigilância Sanitária), the Brazilian Human Health Regulatory Agency, has reported its requirements and expectations on in-use stability studies for multi-dose products after first opening of the container, in the stability regulation RDC 318/2019 (Ref. 6) and in the related stability guideline 28/2019 (Ref. 7). It may be interesting to note that the ANVISA definition of “multi-dose product” specifically includes, in addition to dosage forms in packaging such as bottles or tubes, also blister packs, when the dosage unit can be half of a scored tablet, and the unused half is returned to the blister pack (Ref. 7).
Key points to note in the sections of these two ANVISA documents on in-use studies for multi-dose products can be summarized as:
- The in-use stability study for multi-dose products should be designed to simulate the use of the product after opening the container at a long-term storage condition recommended by ANVISA (Ref. 6 – Art. 29 and 32), in the most critical in-use conditions of the product (Ref. 7).
- The in-use stability study must be performed on at least two batches, with at least one batch tested at end-of-shelf-life (Ref. 6 – Art. 31 and 32). If the long-term stability study is still in progress at the time of submission of the registration document, the in-use stability study must be performed at 12 months or at the last time point before submission (Ref. 6 – Art. 32).
- All tests planned in the long-term stability study should be performed at the test points planned in the in use stability study (Ref. 6 – Art. 35). In-use stability tests should be performed both immediately after container opening and at the end of the in-use shelf-life (Ref. 6 – Art. 30).
- For multi-dose products with a defined dosing regimen, the in-use study must demonstrate stability for the maximum duration of treatment (i.e., for the maximum possible period of use of the container), considering the lowest dosing regimen (Ref. 6 – Art. 33 and Ref. 7). An example is provided in the ANVISA stability guideline (Ref. 7) for an in-use study of a tablet presentation with a defined dosage regimen, packaged in a bottle, with two alternative fill counts, as summarized in table 1 in the Appendix.
- For multi-dose products with a non-defined dosing regimen or intended for sporadic use, the in-use stability study should alternatively be performed up to (Ref. 6 – Art. 34):
- the shelf life proposed for the closed product after closure breaching
- when there is a confirmed out-of-specification result in any test result in the in-use study
- the in-use expiry date after opening, if already defined in previous in-use studies
- The in-use study design for a product without a defined dosing regimen should consider, according to ANVISA, any situation in the actual in-use condition of the product, as e.g. by bracketing containers left nearly full or nearly empty after their first use. An example is provided in the ANVISA stability guideline (Ref. 7, Fig. 11 and 12) for a tablet presentation in a bottle, with a shelf-life of 24 months for the unopened container, for both a less stable and a more stable product option, once the container is opened. This example is summarized in table 2 in the Appendix below.
- In both cases (i.e. for both a less stable and a more stable product under in-use stability conditions) the in-use shelf-life after opening the packaging is the last time point at which all tests comply with specifications (Ref. 7).
- The ANVISA stability guideline also allows, as a possible option, to demonstrate the in-use stability of a product by means of positive stability data obtained after its direct exposure, outside its primary packaging, to storage conditions at elevated temperature and humidity for a time period corresponding to the in-use shelf-life period (Ref. 7). However, when applying this option, all the relevant requirements of the ANVISA RDC 318/2019 regulation (Ref. 6) must also be considered.
Other Guidelines and References
Other WW guidelines specifically mention and recommend in-use stability studies for multi-dose products for human use, such as e.g., the ASEAN (Association of Southeast Asian Nations) stability guideline, whose section text on in-use stability studies (Ref. 8) is superimposable to the corresponding sections in the WHO stability guideline and the Health Canada guidance on NDSs and ANDSs (Ref. 9).
A literature reference on in-use stability studies is also given in the ‘References’ section below (Ref. 10).
Final Conclusions and Overall Summary
In-use stability testing studies should be considered for multi-dose products, taking into account such points as:
- Preliminary definitions of: [in agreement as far as possible, with the interested internal departments (e.g. Medical and Commercial)]
- Product daily dosing schedule, i.e. assumed number and frequency of doses (e.g. number of tablets or volume of a liquid to be administered within all possible frequencies and dosing variations)
- Pack size, i.e. number of doses included in the packaging(s) planned for marketing
- Pack type and any dosing device present in the pack or recommended in the leaflet
- Simulate in the in-use stability study, the worst case conditions for opening the container & dose sampling by the patient or user according to the recommended dosing regimen, as per product leaflet.
- A minimum of two batches should be tested for the in-use stability study, with at least one tested at end-of-shelf life plus at the last time point before registration document submission.
- For oral solid dosage forms in multi-dose containers, according to EMA, in-use stability studies should be considered (only) when available stability data indicate possible product degradation in the conditions of container opening & closing in clinical practice. The in-use stability study length should be defined in this case, on the basis of the treatment duration and number of multi-dose containers needed for the entire treatment for these products, applying a worst-case scenario approach for sampling the dosage forms from container(s) throughout the maximum treatment length.
- Open dish’ stability studies (i.e., studies with the dosage form exposed outside its packaging) may be used to waive or supplement in-use stability studies for solid oral dosage forms. The EMA Guidance (Q&A Page) specifies the exposure conditions as 25°C/60%RH. ANVISA’s open dish exposure recommendations are more vaguely described as “stress conditions with elevated T/RH%.” When making any open dish study design decisions, consider the information available in the stability profile of the product at high %RH and the countries in which the relevant registration application will be submitted. Always consult with your Regulatory specialist before proceeding.
The information included in this two-part blog is intended to supply only high-level coverage of world-wide regulatory expectations for in-use stability studies for multi-dose products to the StabilityHub community. The author therefore recommends personnel directly involved in these studies, to review detailed contents of original and relevant documents mentioned in the ‘Reference’ sections of Parts 1 and 2, within the context of the information of the product under development.
Piero De Filippis is the StabilityHub EU Regional Contributor, based in Italy. His e-mail address is firstname.lastname@example.org.
References (Part 2)
- P. De Filippis, In-use stability studies for multi-dose dosage forms: guidance by EMA and by other world-wide Authorities (Part 1: EMA). stabilityhub.com. Published 10 August 2021
- European Medicine Agency (EMA, former EMEA) “Note for Guidance on In-Use Stability Testing of Human Medicinal Products” CPMP/QWP/2934/99 (1 March 2001). https://www.ema.europa.eu/en/use-stability-testing-human-medicinal-products . Accessed 20 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”. 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 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 20 August 2021
- World Health Organization (WHO) Technical Report Series, No. 1010 – Annex 10 ‘Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products – Section 2.2.11 In-use and hold time stability (2018)
- 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)
- ANVISA Resolução de Diretoria Colegiada (Collegiate Board of Directors Resolution) RDC No. 318/2019. ‘Estabelece os critérios para a realização de Estudos de Estabilidade de insumos farmacêuticos ativos e medicamentos, exceto biológicos, e dá outras providências’ [‘Establishes the criteria for conducting Stability Studies for active pharmaceutical ingredients and drug products, except for biological, and provides other arrangements’] (7 November 2019 – in Portuguese). https://www.in.gov.br/web/dou/-/resolucao-rdc-n-318-de-6-de-novembro-de-2019-226513805 . Accessed 20 August 2021
- ANVISA Guia [Guideline] Nº28/2019 – Vers. 1 ‘Guia de Estudos de Estabilidade’ [Stability Study Guideline] – Sect. XI ‘Estudos de estabilidade em uso’ [In-use stability studies], pages 27-29 (11 November 2019 – in Portuguese). http://antigo.anvisa.gov.br/legislacao#/visualizar/409543 . . Accessed 20 August 2021
- ASEAN Guideline on Stability Study of Drug Product– Sect. 4.8. ‘In-use Stability’ (2018). https://asean.org/wp-content/uploads/2018/01/25PPWG-ANNEX-7-iv-Final-ASEAN-Guideline-on-Stability-Study-Drug-Product-R2.pdf . Accessed 20 August 2021
- Health Canada Quality Guidance ‘New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)’ – Sections P.2 ‘Pharmaceutical Development’ and P.8.1 ‘Stability Summary and Conclusions’ (Effective Date 30 January 2018). https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/chemical-entity-products-quality/guidance-document-quality-chemistry-manufacturing-guidance-new-drug-submissions-ndss-abbreviated-new-drug-submissions.html. Accessed 20 August 2021
- Bawazir AS. et al. Shelf Life Assessment of Drug Product after opening Container for the first time. International Journal of Scientific Development and Research. 2018; 3(8): 88-91.
Table 1 – Summary of an ANVISA example of an in-use stability study for a tablet presentation in a bottle with a defined dosing regimen of one tablet, minimum every 12 hours for 10 days (Ref. 7)
Table 2 – Summary of an ANVISA example of an in-use stability study for a tablet presentation without a defined dosing regimen (Ref. 7, Fig. 11 and 12)