Global Testing Of A Consensus Solubility Assessment To Enhance Robustness Of The Who Biopharmaceutical Classification System

The WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to engage a global network of laboratories to experimentally quantify the pH-dependent solubility of the highest therapeutic dose of 16 APIs using a harmonized protocol. Intra-laboratory variability was <= 5 %, and no apparent association of inter-laboratory variability with API solubility was discovered. Final classification "low solubility" vs "high solubility" was consistent among laboratories. In comparison to the literature-based provisional 2006 WHO BCS classification, three compounds were reclassified from "high" to "low-solubility". To estimate the consequences of these experimental solubility results on BCS classification, dose-adjusted in silico predictions of the fraction absorbed in humans were performed using GastroPlus (R). Further expansion of these experimental efforts to qualified APIs from the WHO Essential Medicines List is anticipated to empower regulatory authorities across the globe to issue scientifically-supported guidance regarding the necessity of performing in vivo bioequivalence studies. Ultimately, this will improve access to affordable generic products, which is a critical prerequisite to reach Universal Health Coverage. (c) 2021 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).