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.
Equilibrium solubility experiments were conducted by universities, official national control laboratories, pharmacopoeia laboratory, and WHO Collaborating Centres. The authors warmly thank: Liezl Badenhorst, North_West University, Potchefstroom, South Africa; Jeronimo R. de Oliveira Neto, Faculty of Pharmacy, Federal University of Goi\u00e1s, Goi\u00e2nia, Goi\u00e1s, Brazil; Elena Soler, Universidad Miguel Hern\u00e1ndez de Elche, Alicante, Spain; Matilde Merino-Sanju\u00e1n, University of Valencia, Valencia, Spain; Nilesh M. Meghani, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Republic of Korea; Tri-Hung Nguyen, Medicines Manufacturing Innovation Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; Raju Kanumuri, University of Cincinnati, Cincinnati, Ohio, USA; Satish Agrawal, St. Louis College of Pharmacy, St, Louis, Missouri, USA; Jing Xiong, National Institutes for Food and Drug Control (NIFDC), Beijing, China; Ramesh Kumar Jha, Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Govt. of India, Ghaziabad, India; for the precious collaboration in producing experimental data. All APIs studied in Cycles I and II were received as in-kind donations from pharmaceutical manufacturers supporting WHO in this scientific work: ACS Dobfar; Alcaliber S.A.U.; Aurobindo; Cipla Ltd; Guilin Pharmaceutical Co. Ltd; Ipca Laboratories Ltd; Laurus Labs Limited; Lupin Ltd.; Macleods Pharmaceuticals Ltd; Mangalam Drugs & Organics Ltd; Mylan Laboratories Ltd; Sandoz; Sanofi; Shanghai Desano Chemical Pharmaceutical Co. Ltd; Shenyang Antibiotic; Pfizer; Zhejiang Jiangbei Pharmaceutical Co. Ltd.
