HPE Drug stability: What do we need to know? | Page 14

It is essential to use validated stability-indicating assay methods that are able to separate degradation products being formed in the practical use of the drug salt effects, oxygen, shaking and shearing, and concentration. When studying chemical, physical and microbiological stabilities, the main aspects to be evaluated are: 1 Stability of the solution over time using one or more appropriate analytical techniques (HPLC (more commonly), mass spectrometry) 2 Identification of any degradation products and purity of product (Diode Array more commonly) 3 Simulation of the operating conditions of use and conservation 4 Compatibility with the primary packaging 5 Bibliographic references. A useful summary of the guidelines for the development of stability analysis methods has been presented by Bakshi and Singh, 18 who defined the fundamental steps for conducting these studies as: • Critical study of drug structure to define degradation patterns • Collection of information on chemical and physical properties • Forced degradation studies • Final development and optimisation of the method • Identification and characterisation of degradation products and standard preparations • Method validation. For in-use stability, the conditions of use cannot always be well standardised owing to the variability of the situations that the user might require. The EMA’s recommendations 4,5 for assessing in-use stability with the methods and limits of the tests to be performed detail important conditions, including: • Necessity to analyse at least two different production batches, of which at least one is numerically representative (pilot scale batches), based on the specific production • Desirable that one of the two lots be near the end of its shelf-life • That in the extraction of the samples for analysis, the conditions of use should be simulated, in terms of dilution for the administration of the product, and for the dose intervals, and suggested environmental and conservation conditions. 14 | 2019 | hospitalpharmacyeurope.com In practical stability studies, one batch might be acceptable but determinations should be performed in triplicate. The methods used by the pharmaceutical industry for analysing stability of a product are called ‘stability-indicating assays’. The ICH guidelines 6 recommend conducting forced degradation studies under a variety of conditions, such as pH, light, oxidation, dry heat, etc, and the separation of the drug from its degradation products; it is then recommended that the method allows the analysis of the individual degradation products. It is essential to use validated stability-indicating assay methods that are able to distinguish degradation products being formed in the practical use of the drug. A stability-indicating assay must therefore be able to identify drug substance and its degradation products; this usually occurs by stress testing/forced degradation, by varying: • pH: NaOH, HCl • temperature • heat: starting from 50°C • oxidative conditions: H 2 O 2 from 3% up to 30%. It is essential to degrade only a part of the drug present (ICH recommends no more than 40%); passing from mild conditions to conditions that become increasingly aggressive, in the eventuality of identifying different routes of degradation of the substance. A stability-indicating assay is a validated quantitative analytical method that can detect changes in the chemical, physical or microbiological properties of a drug substance over time, and which is specific enough to allow the active ingredients, degradation products and other components of interest to be separated, detected and quantified accurately. The practical stability study should first involve simplified stress assays performed in glass vials, testing for the intrinsic stability of the solution and to determine the relevant stability conditions to be used. After that, the drug should be tested in the solvent and the container used in clinical