Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system

Valeria Gigante, Giovanni M. Pauletti, Sabine Kopp, Minghze Xu, Isabel Gonzalez-Alvarez, Virginia Merino, Michelle P. McIntosh, Anita Wessels, Beom Jin Lee, Kênnia Rocha Rezende, Gerhard K.E. Scriba, Gaurav P.S.Jadaun, Marival Bermejo

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7 Citations (Scopus)


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 re-classified 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®. 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.

Original languageEnglish
Pages (from-to)23-39
Number of pages17
JournalADMET and DMPK
Issue number1
Publication statusPublished - 1 Jan 2021


  • biowaiver
  • essential medicines
  • multisource products
  • permeability
  • regulatory guidance

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