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WHO “Biowaiver List”: proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms
1. Introduction and background:
The World Health Organization (WHO) recognizes the possibility to waive in vivo bioequivalence studies for immediate-release, solid oral dosage forms with active pharmaceutical ingredients (APIs) belonging to classes I and III according to the Biopharmaceutical Classification System (BCS), using comparative dissolution studies as surrogate proof of bioequivalence (1).
The WHO solubility classification, also referred to as the “WHO Biowaiver List”, is a tool for national regulatory authorities (NRAs) and pharmaceutical manufacturing companies, suggesting medical products that are eligible for a waiver from in vivo bioequivalence studies, which are usually necessary to establish the therapeutic equivalence with the originator (comparator). For exemption from an in vivo bioequivalence study, an immediate-release, multisource (generic) product should exhibit very rapid or rapid in vitro dissolution characteristics that are comparable to those of the reference product. A risk-based evaluation should also account for the excipients used in the formulation of the finished pharmaceutical product.
In addition, the present list replaces the existing literature-based compilation published in 2006 that is reported in the Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (3) based on data extracted from the public domain (i.e. solubility data published by different authors using inconsistent experimental conditions).
The WHO Biowaiver Project is organized into study cycles. Previous and current cycles are summarized below in order to provide an overview of the project development:
■ 2018: cycle I; also referred to as the pilot phase.
■ 2019: cycle II.
■ 2020: cycle III. The new results presented in this updated document come from cycle III.
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WHO TRS (Technical Report Series) 1033, 2021 Annex 8:
