Submitted: 26 April 2024; Revised: 9 May 2024; Accepted: 15 May 2024; Published online first: 29 May 2024

During the last decades, anticancer therapy has changed significantly regarding the types and mechanisms of medicinal products used. Monoclonal antibodies and cell therapies play an increasingly important role. However, small molecules with non-specific antineoplastic activity remain an indispensable part of combination chemotherapy. Modern anticancer therapies comprise non-specific antineoplastic agents, targeted anticancer medication, and advanced therapy medicinal products.

Anticancer therapy is still predominantly administered via the parenteral route. Infusion therapy takes place in outpatient and inpatient settings, either in hospitals, private offices, or even at the patient’s home. Pharmacy-based centralised cytotoxic preparation units provide ready-to-administer (RTA) parenteral preparations just in time, utilizing licensed medicinal products as starting material. The quality and safety of the preparations are ensured by following pharmacy regulations, such as Ph.Eur. 2619 ‘Pharmaceutical preparations’ [1]. The pharmacopeia monograph covers unlicensed pharmaceutical preparations made for specific patients’ needs.

Preparations fall into two main categories: first extemporaneous preparations, i.e. pharmaceutical preparations individually prepared for a specific patient or patient group and supplied after preparation; and second, stock preparations, i.e. pharmaceutical preparations prepared in advance and stored until a request for supply.

Stability requirements of preparations are dependent on their intended use and desired storage time [1]. The pharmacist responsible for the preparation must ensure, with a suitable level of assurance, that the pharmaceutical preparation maintains appropriate quality and is suitable and fit for its purpose throughout its shelf-life [1]. Extended stability is especially important in ambulatory care settings, home infusion, and for achieving efficient processing of dose-banded and standardized dose products for stock.

Each preparation must be labelled with an adequate shelf life, assigned empirically by the responsible pharmacist based on a risk assessment. Therefore, both the physicochemical and microbiological stability of the preparations are taken into consideration. Notably, decisions must be justified based on analytical data or professional judgement, which may be supported by literature references [1]. The quality of a stability study and the reliability of its results are relevant for making a proper decision. Stability testing of RTA preparations must follow ‘Good Stability Testing Practice’, which is the focus of several guidelines established by professional associations [2–5]. Assignment of shelf-life beyond the recommendations in the Summary of Product Characteristics (SmPC) should be based on at least one full publication in a peer-reviewed journal. Results of in-use stability studies are published in pharmaceutical journals and compiled in specialised databases [6, 7]. The ‘Stabilis’ database comprises useful information on the level of evidence of stability studies, and the ‘NHS Standard protocol for deriving and assessing stability’ [3] encompasses a checklist for the assessment of stability data. The responsible pharmacist should match the internal and external stability-determining factors used in the stability study with the stability-determining factors of the preparation in question.

Although many studies on the extended stability of small molecule RTA preparations have been published, not all combinations of licensed medicinal products used as starting materials and stability-determining factors in clinical practice are covered. Different dosages and concentrations, new types of containers, formulation changes of the starting material, and advanced administration technologies continuously require additional in-use stability studies. In some cases, more recent studies following the ‘Good Stability Testing Practice’ guidelines are necessary. There will always be room for improvement, and new, reliable information on in-use stability will be needed.

We are happy to provide some of this information in the following articles. Experimental tests were performed in external laboratories, and the articles are based on elaborated protocols that were provided as data on file by the manufacturer.

Funding sources

This study was funded by Accord Healthcare.

Competing interests: The authors Irene Krämer and Judith Thiesen have no competing interests to declare.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Professor Irene Krämer, PhD
Judith Thiesen, PhD

Department of Pharmacy, University Medical Center of the Johannes Gutenberg University Mainz, 1 Langenbeckstraße, DE-55131 Mainz, Germany

References
1. Council of Europe. Monograph 2619 Pharmaceutical Preparations. European Pharmacopoeia 11th edition. Strasbourg, France, European Medicines Agency.
2. Bardin C, Astier A, Vulto A, Sewell G, Vigneron J, Trittler R, et al. Guidelines for the practical stability studies of anticancer drugs: a European consensus conference. Ann Pharm Franc. 2011;69(4):221-31.
3. Sautou V, Bossard D, Chedru-Legros V, Crauste-Manciet S, Fleury-Souverain S, Lagarce F, et al. Methodological guidelines for stability studies of hospital pharmaceutical preparations. 1st edition. GERPAC and SFPC 2013. Available from: https://www.gerpac.eu/IMG/pdf/guide_stabilite_anglais.pdf
4. NHS Pharmaceutical Quality Assurance Committee. A Standard Protocol for Deriving and Assessment of Stability. Part 1 – Aseptic Preparations (Small Molecules) 5th edition. 2019. Available: https://www.sps.nhs.uk/wp-content/uploads/2013/12/Stability-part-1-small-molecules-5th-Ed-Sept-19.pdf
5. NHS Pharmaceutical Quality Assurance Committee. A Standard Protocol for Deriving and Assessment of Stability. Part 2 – Aseptic Preparations (Biopharmaceuticals) 5th edition. 2021. Available: https://www.sps.nhs.uk/wp-content/uploads/2017/03/Stability-Part-2-Biopharmaceuticals-v5.pdf
6. Stabilis® database. Available: https://stabilis.org
7. ADKA Service GmbH. ADKA STABIL database. Available: https://aminfo.adka.de/adka-datenbanken/adka-stabil-datenbank

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