BEBAC   Ing. Helmut Schütz

Concept Paper on BCS-based Biowaiver


On 24 May 2007 a Concept Paper on BCS-based Biowaiver was published by the Efficacy Working Party (EWP).

An overview of the document is given below:

  1. Introduction

    The concept underlying the Biopharmaceutics Classification System (BCS) lead to introducing the possibility of waiving in vivo BE studies in favour of specific comparative in vitro testing in order to conclude BE of oral immediate release products with systemic actions. This approach is meant to reduce unnecessary in vivo BE studies however, is restricted to non-critical drug substances in terms of solubility, permeability, and therapeutic range, and to non-critical pharmaceutical forms. Although frequently discussed, BCS-based biowaivers are still rarely used probably attributed to uncertainties on both, pharmaceutical companies and regulatory authorities. Substantial differences of biowaiver dossiers and respective assessments contribute to the impression that a common understanding is lacking on a successful use of the BCS concept to support biowaivers. It is intended to reach an optimal and harmonised application of biowaiver principles within the European community by means of preparing an annex to the guideline on BA/BE (CPMP/EWP/QWP/1401/98).

  2. Problem Statement

    Section 5.1.1 of the NfG on the Investigation of BA/BE describes basic criteria to be met by active pharmaceutical ingredients and drug products as prerequisites to use the biowaiver approach. With respect to the active substance the guideline paragraph addresses e.g. the risk of therapeutic failure and the possible evidence of BA problems which is considered an unspecific request and difficult to be appropriately addressed in respective dossiers. Although high permeability is mentioned as referred to the BCS concept; linear and complete absorption is stated to be a favourable pharmacokinetic property. However, at the same time biowaiver extensions are frequently discussed and applied for focusing on substance solubility only. In addition, guideline recommendations are fairly arbitrary regarding drug product investigations, i.e., in vitro dissolution and evaluation of excipients. EU guideline limitations lead applicants to follow the FDA guideline on BCS-based biowaiver which may result e.g. in unnecessary cell culture investigations. On the other hand, there is no harmonised assessment of BCS-based biowaiver applications within the EU from the regulatory perspective even resulting in general rejection of respective applications.

  3. Discussion Points
    • Which characteristics are deemed indispensable to prove a drug substance eligible for the BCS-based biowaiver approach and what kind of data (literature and/or experimental) are acceptable, for instance (in addition to known guideline requirements):
    • Recommendations on BE in the current guidance will be updated with regard to:
      • Discuss ‘risk of bioinequivalence’.
      • Define dose to be investigated in terms of solubility.
      • Discuss whether BCS-based biowaiver may be acceptable within a restricted dose range due to solubility limitations, i.e., biowaiver for lower strengths and in vivo BE study for higher dose strengths.
      • Define permeability and/or absorption requirements.
      • Discuss/clarify acceptance or exclusion of biowaiver extensions, e.g., BCS-based biowaiver for BCS class II and/or III drugs.
    • Drug product considerations
    • Comprehensive description of in vitro dissolution requirements.
      • Experimental setting; method validation.
      • Evaluation of absence of product differences (or product ‘similarity’).
      • Delimitation from in vitro/in vivo correlations and quality control.
      • Specify number of batches to be investigated.
      • Specify evaluation of excipients.
      • Clarification regarding fixed dose combinations and pro-drugs.
      • Clarification on the applicability of the BCS-based biowaiver approach (generic applications, drug development, variations).

It is proposed to complement the current Note for Guidance on the Investigation of BA/BE (CHMP/EWP/QWP/1401/98) with an annex to address the issue of BCS-based biowaiver.

It is anticipated that a draft CHMP document may be released 6 months after adoption of the Concept Paper. It will be later released for 6 months of external consultation and finalised within 3 months. The preparation of this document will involve the EWP Therapeutic Subgroup on Pharmacokinetics and members of the QWP.

End of consultation (deadline for comments) by interested parties (international scientific societies related to BA/BE/PK and in vitro dissolution) was 31 August 2007.
Comments should by provided to
Fax: +44 20 74 18 86 13

This document is superseded by the new Guideline on the Investigation of Bioequivalence with 01 August 2010.