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

  • Valeria Gigante World Health Organization, Geneva Switzerland
  • Giovanni M. Pauletti Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, Missouri, USA
  • Sabine Kopp Norms and Standards for Pharmaceuticals, World Health Organization, Geneva, Switzerland
  • Minghze Xu Institute for Chemical Drug Control, China National Institutes for Food and Drug Control, Beijing, China
  • Isabel Gonzalez-Alvarez Department of Engineering: Pharmacy section, Universidad Miguel Hernández de Elche, Alicante, Spain
  • Virginia Merino Department of Pharmaceutics and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain
  • Michelle P. McIntosh Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
  • Anita Wessels North_West University, School of Pharmacy, Potchefstroom, South Africa
  • Beom-Jin Lee College of Pharmacy and Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Republic of Korea
  • Kênnia Rocha Rezende Faculty of Pharmacy, Federal University of Goiás, Brazil
  • Gerhard K.E. Scriba Department of Pharmaceutical Chemistry, Friedrich Schiller-University, Jena, Germany
  • Gaurav P. S. Jadaun Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Govt. of India, Ghaziabad, India
  • Marival Bermejo Department of Engineering: Pharmacy section, Universidad Miguel Hernández de Elche, Alicante, Spain
Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system

Abstract

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.

 

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Published
07-10-2020
Section
Original Scientific Articles