FORCED DEGRADATION STUDIES: REGULATORY CONSIDERATIONS AND IMPLEMENTATIONS IN ANALYTICAL METHOD DEVELOPMENT AND VALIDATION

Prasad P. Talekar*, Chetan M. Bhalgat*, Zhang Wei, Huang Zhengyi, Yang Hai Yang, Chen FangFang, Kiran Pokharkar, Anil Nakade, Naresh Jambhale, Niket Gharat, Nitin Bhoir, Ramesh Ambule, Subodh Gambhir, Jayvant Harlikar and Manish Gangrade

ABSTRACT

This review discusses forced degradation methodology and validation as per regulatory aspects of investigations of degradation of active pharmaceutical ingredients. It also highlights the prediction of degradants of drug substances and degradation pathways and development of stability indicating analytical methods. Furthermore, review discusses analytical methodology of various conventional and hyphenated techniques for degradant separation and characterizations are summarized in detail. Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways of degradation products of the drug substance and helps in elucidation of the structure of the degradation products. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and selection of packaging material. In addition, the regulatory guidance is very general and does not explain about the actual performance of forced degradation studies. Thus, this review also discusses the comparative study in between International Conference on Harmonisation, Food and Drug Administration and World Health Organization’s guidelines which highlights the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method.

Keywords: Forced degradation study, High Performance Liquid Chromatography, Retro synthesis, Mass Spectrometry, Nuclear Magnetic Resonance Spectroscopy, Infra-red Spectroscopy.