The demonstration of drug substance (DS) or drug product (DP) stability over the shelf life is a regulatory requirement in the pharmaceutical industry. To fulfill this requirement, a stability-indicating method (SIM) must be developed and validated to separate and quantify both the active pharmaceutical ingredient (API) and its related compounds (process impurities and degradation products). This article discusses the characteristics and relevant considerations for the development and validation of a SIM.
Despite all of the requirements from the regulatory and governing entities, there is still not a clear consensus of what constitutes a stability-indicating method (SIM). The guidance documents also do not provide details about the scope and degradation study practices (1). Unfortunately, this leaves many in the industry with a requirement that must be achieved but without clear direction. This article will review existing literature and current best practices for a SIM. The objectives for a SIM, the process for development and validation, and the critical characteristics are also discussed.Defining Objectives of the Method
The method objectives should be defined early, so the development process can be clearly established. For example, the analytes that need to be separated should be established early in the process. Stress testing or forced degradation studies can be useful in defining degradation products and the major degradative pathways. In general, for Abbreviated New Drug Application (ANDA) development of generic drug products, only compounds that exceed the ICH threshold for reporting should be investigated unless special toxicology concerns (for example, genotoxic impurities) are known. After it is known which compounds are of interest, further objectives such as desired resolution, limit of quantitation (LOQ), precision and accuracy, analysis time, and adaptability for automation can be defined (2).
For biologics, a series of methods based on orthogonal approaches may be required to achieve a SIM (1). Biologics degrade in a much different manner than small molecules. To identify all of the degradation pathways requires a variety of biochemical, biophysical, and biological methods, which can lead to a lengthy process (3). While small molecules generally degrade following first order kinetics, biologics can follow secondary or higher order kinetics that may not fit to linear or exponential curves. Degradation of biologics can be both chemical (oxidation, de-amidation, disulfide bond rearrangement, hydrolysis) and physical (aggregation, adsorption, loss of three-dimensional structure) (4).