New Era in Bioequivalence Global Harmonization through ICH M13 Initiative: Critical Review on New Concepts, Alternative Approaches for High-Risk Products.

Abstract

Bioequivalence (BE) studies have made significant advancements, particularly with the introduction of the ICH M13 guidances. This review examines the historical aspects leading to the harmonization efforts of the latest ICH M13A, the draft of ICH M13B, and the anticipated ICH M13C.The primary focus of this article is on ICH M13A, highlighting the significant changes over previous guidelines of USFDA and EMA. It outlines the stringent requirements for high-risk products as per ICH M13A and emphasizes the necessity for both fasting and fed studies. This review highlights the high-risk complex formulations, such as amorphous solid dispersions, microemulsions, and nanotechnology-based formulations, which often exhibit different food effects compared to conventional formulations.Additionally, the role of PBPK/PBBM modeling in predicting food effects and fed bioequivalence for high-risk products is discussed. Further, the potential of modeling based methodologies as "alternative BE" approaches for securing waivers for fed BE studies is discussed in depth.Furthermore, the latest ICH M13B guidance is reviewed, focusing on differences from previous guidelines on dissolution similarity and bracketing approaches. The review also discusses the anticipated directions for ICH M13C and its potential impact on future BE studies for HVDs, NTIs, and complex designs.