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

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

doi:10.5599/admet.850

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.

Highlights

In a world where one third of the population lacks access to essential medicines [1] and medicines represent the largest family expenditure after food, generic competition and differential pricing are major drivers to sustain a healthy population, especially in low-income countries [2]
A distinct feature of the World Health Organization (WHO) Biopharmaceutical Classification System (BCS) when compared to other BCS classification systems as defined by various regional regulatory authorities is that the WHO classification centers on the highest single oral therapeutic dose of each active pharmaceutical ingredients (APIs) to estimate the dose/solubility volume (DSV)
The rationale for this definition is that BCS classification is mimicking more closely real life conditions and corresponds to the “worst case scenario” when patients are taking the therapeutic oral dose prescribed

Summary

Introduction

In a world where one third of the population lacks access to essential medicines [1] and medicines represent the largest family expenditure after food, generic competition and differential pricing are major drivers to sustain a healthy population, especially in low-income countries [2]. The World Health Organization (WHO) has identified access to essential medicines as one of its key priorities to meet the millennium Sustainable Development Goals and reach Universal Health Coverage. Regulatory agencies carry the public health responsibility to carefully balance access to and safety of medicines within their respective authorities. Successful accomplishment of this objective requires risk management strategies that are based on scientifically valid data. Various regulatory agencies around the world have adopted guidances specifying the use of the BCS as a scientific framework to grant a waiver of mandatory human in vivo bioequivalence studies for immediate-release solid oral dosage. Qualifications defined for a biowaiver directly impact access to and affordability of a finished pharmaceutical product while assuring the quality of the medicine

Objectives

Results

Conclusion