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.
Concerns over the inability of a drug product (DP) to meet quality standards over the course of its shelf life have been present
since the early 1970s. In 1975, the United States Pharmacopeia (USP) added a clause about the expiration dating of drug products. The US Food and Drug Administration (US FDA) provided the first
stability guideline in 1984. The US FDA took further steps in 1987 by issuing guidelines for the submission of stability information
and data for Investigational New Drugs (IND) and New Drug Applications (NDA). The International Conference on Harmonization
(ICH) created the Q1A guideline in 1993 to harmonize the requirements for international marketing in Japan, the United States,
and the European Union. Additional guidelines that followed from ICH included Q7A, GMP guide for active pharmaceutical ingredients
(API). More recently, the World Health Organization (WHO) has released guidelines on the stability of pharmaceuticals (1).
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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).