HPE Drug stability: What do we need to know?

STUDY DESIGN Recommendations and design quality for stability studies Specific recommendations for stability studies have been written by various expert societies, and identify methodology requirements for these studies for hospitals and compounding pharmacy units Marta Trojniak PharmD MPH IRCCS Ospedale Infantile Burlo Garofolo, Trieste, Italy Stability studies refer to two specific conditions, that is, ‘before’ (shelf-life) and ‘after’ opening of the primary package (in-use stability). Specific regulations and guidelines for conducting shelf-life studies are available from regulatory authorities. The stability of drugs for hospital needs is a topic of increasing interest for hospital pharmacy. Manufacturers perform stability studies in support of a medicinal product’s marketing authorisation. The stability data in the Summary of Product Characteristics (SPCs) related to clinical practice are often insufficient to assign the appropriate in-use expiry date. Stability data in the SPCs are frequently limited to 12–24 hours in-use stability. Hospital-compounded drugs require well- documented data on the chemical, physical, and biological stabilities of the drugs in practical storage conditions used after reconstitution and after further dilution with different diluents, different concentrations, mixtures of drugs, and compatibilities in different packages. Hence there is a need to search for alternative scientific sources that can integrate information into SPCs, and therefore extend stability beyond 24 hours. Therefore, reviewing available evidence on practical stabilities in the clinical environment in the shared databases, 3 as well as hospital pharmacy teams conducting good quality stability studies and research, is necessary. 1,2 Centralised drug preparation units offer innumerable advantages in terms of organisational efficiencies and pharmacoeconomics, as well as important benefits for patients. The drug production can be realised through traditional extemporaneous preparation, where the times between the preparation and the administration are short and the stability data are usually described in the SPCs. For both hospital needs and compounding pharmacy units, the compounding unit might prepare the standardised, ready-to-use preparations with or without dose banding, and intermediate solutions, ready for dilution, which can then be set up in advance, thereby organising the storage of medicines for varying times according to clinical needs and practical storage conditions. In this scenario, stability of the compounded products in varying clinical environments, reconstituted or diluted, and the compatibilities of the products with medical devices, take on a particular relevance. 3 The concept of stability refers to two specific conditions: those adopted by the manufacturer to define the shelf-life; and those adopted by the user who, after the package has been opened, prepares the preparations for personalised use starting from 12 | 2019 | hospitalpharmacyeurope.com the medicinal products (in-use stability). According to the European Medicines Agency (EMA), specific storage needs of the user must be taken into account by the manufacturer in order to conduct appropriate physico-chemical studies to update the technical information already available (Pharmacopoeia monographs, SPCs). 4,5 However, this information is usually incomplete and therefore does not always meet the needs of clinical practice and formulation in hospital pharmacy. Hospital pharmacists mainly prepare sterile products, including anticancer drugs, antibiotics, eye drops, medications for use in intensive care, and parenteral nutrition. Hospital pharmacists might need to prepare alternative oral formulations beyond the commercially available ones, to confer the full benefit of the therapy to the patient. Regulatory aspects Ensuring an acceptable stability during the development of a pharmaceutical formulation at industrial level is a challenge. Whereas classically the stability refers to the loss of chemical or biological stability due to degradation, in clinical practice, the term stability refers mostly to the admissible conservation time before any degradation product in the formulation reaches a sufficient quantity to pose a risk to the patient. 6,7 Preparation processes for medicinal products in pharmacies must meet specified requirements of safety, efficacy and quality. The pharmacist is responsible for the quality, safety and efficacy of the preparation of medicinal products and the required quality standards are similar in many countries. 3,8–14 The European Pharmacopoeia, 15 the EC GMP 7 and US Pharmacopeia (USP) 16 require pharmaceutical processes that affect product quality to be validated, and that the necessary premises, materials and equipment are qualified. The validation provides documented evidence that the processes satisfy quality assurance systems in practice. In this context, for evaluation of the stability of a drug, it is essential to consider critical requirements such as the chemical, physical and biological stabilities and sterility of the preparation, which make it possible to determine its period of validity. There is then a fundamental requirement for well-documented data on the stability of drugs after opening of the primary package; this type of stability is defined by the EMA as in-use stability. 5 The in-use expiry date of a medicinal product is the time during which a product maintains, within defined limits, the same properties and characteristics that it possessed at the time of production. As mentioned, SPCs give insufficient information in relation to

HPE Drug stability: What do we need to know? | Page 12