HPE Drug stability: What do we need to know? | Page 13

in-use stability, because they are based mainly on microbiological stability data and not on the physico-chemical stability of the medicinal product. Pharmaceutical companies perform stability studies as an integral part of the information provided to regulatory authorities in support of the marketing authorisation of a drug. The manufacturers adopt the guidelines of the EMA, which generally recommend, for sterile not preserved products, a limit of 24 h at 2°–8°C. There is an exception in cases in which the reconstitution or dilution are carried out under validated aseptic conditions, in which it could be assumed that in-use expiry dates would be extended. These precautionary provisions refer mainly to the preparation of sterile medicines in areas having variable storage conditions, such as hospital wards. By contrast, pharmacy compounding units can guarantee the microbiological quality of the compounded product. Guidance for compounding in pharmacies describes the characteristics that the premises, equipment and personnel must have in order to ensure the appropriate standards for sterile and non-sterile preparations. 17 The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) gives recommendations for validation of analytical methods and stability studies: particularly ICH Q1A (evaluation for stability data), ICH Q1A(R2) (stability testing of new drug substances and products), ICH Q2A (test on validation of analytical procedures), ICH Q1B (stability testing: photostability testing of new drug substances and products), Q3B (impurities in new drug products), and Q5C (stability testing of biotechnological/biological products). 6 However, ICH guidelines are dedicated to stability but are written for industry and not for hospitals. Thus, specific recommendations for stability studies in hospital pharmacies have been produced by various expert societies to adapt the ICH guidelines, European Pharmacopoeia and the most relevant literature for the clinical environment, thereby identifying methodologies for stability studies for hospitals and compounding pharmacy units. 1,2 In addition, specific guidelines of good compounding practice are provided by the PIC/S Guide to Good Manufacturing Practice of Preparation of Medicinal Products in Healthcare Establishments (PE 010-4). 17 These standards take into consideration the hospital situation and reduced-scale production, which is not comparable to the industrial situation, where compliance with GMP standards is mandatory. Another essential reference for the production of medicines in hospital pharmacy is Chapter 797 United States Pharmacopoeia (USP) Establishing a standard practice for sterile compounding preparation in pharmacy. 16 These guidelines describe the acceptable microbiological stability date, given storage conditions and risk of contamination. Because the SPCs of medicinal products do not offer sufficient data to determine the in-use chemical, physical and biological stabilities, one can try to evaluate these by referring to the current legislation, the accredited scientific literature, and the various European and international guidelines (EMA, ICH, US Food and Drug Administration). Because these sources are often not exhaustive, and sometimes contradictory, the resulting determination is approximate and therefore inapplicable from a practical point of view. In order to validate a production process, specific experimental studies might be required, conducted in compliance with guidelines and simulating the real conditions of use on-site, in order to obtain reliable data on the in-use stability of a drug and to identify the best methods for its determination. Proven stability enables advance preparation, elimination of the peak moments in workload, greater efficiency and reduced working costs, the application ‘dose banding’, reduced drug wastage, batch preparation, use of returned preparations, reduced interruptions of therapy and drug shortages, outsourcing to external compounding units or commercial partners, and development of ready-to-administer drugs. The stability study should include testing of all variables that are likely to influence quality, safety and efficacy, clearly justified by relevant literature, and include well- designed stability- indicating assays Stability study design When designing the practical stability study, it should reflect the clinical needs and real storage conditions of the studied product brand, evaluating loss of efficiency and the presence of degradation products over time. Specific routes of administration must be also considered. The stability study should include testing of all variables that are likely to influence quality, safety and efficacy, clearly justified by relevant literature, and include well-designed stability-indicating assays. According to the EU Pharmacopoeia, stability is defined as the time during which a drug maintains its essential chemical and physical properties, or in which a change occurs within tolerable limits, with a degradation of the drug not exceeding 10% of the initial value, without the formation of toxic degradation products, or a significant decrease in pharmacological activity. The permissible level of any degradation product will depend on the dose and type of toxicity; however, for most drugs, the permitted levels of a single impurity (without there being explicit toxicological tests) is generally less than 1% of the drug (although this can vary according to the maximum daily dose). The ICH specifies the amount of impurities that can form during storage, based on the total daily intake of the drug. The parameters that usually need to be studied in order to determine the in-use stability of a preparation are: • Physical: colour, transparency, integrity of the closure, assessment of particulate matter • Chemical: content of active ingredient and any degradation products, levels of degradation products of antimicrobial and antioxidant preservatives, pH of the solution • Microbiological: sterility, possible microbial count (total viable count), pyrogenicity. For physical stability, an appropriate sub-visual evaluation, in addition to a visual inspection, should be performed over time; this is particularly important for biological products in order to evaluate any aggregation. pH should also be evaluated over time. The packaged drug must be weighed at all sample times to determine any water loss to correctly calculate the concentration of the drug and degradation products. Sequential temperature designs should be encouraged to replicate problems seen in daily practice, for example, rupture of the cold chain, returned preparation to the pharmacy, etc. Specific aspects concerning the stability of biological medicinal products should be considered because these can undergo more complex degradation pathways during the various manipulation steps than chemical drugs. The main causes of instability include temperature fluctuations, formulation pH, adsorption, hospitalpharmacyeurope.com | 2019 | 13