ICH-M9-Biopharmaceutics classification system based biowaivers

Background and Objective

Two drug products containing the same drug substance(s) are considered bioequivalent if their bioavailabilities (rate and extent of drug absorption) after administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e., similarity in terms of safety and efficacy. In in vivo bioequivalence studies, the pivotal pharmacokinetic parameters AUC (area under the concentration time curve) and Cmax (maximum concentration), are generally used to assess the rate and extent of drug absorption.

The BCS (Biopharmaceutics Classification System)-based biowaiver approach is intended to reduce the need for in vivo bioequivalence studies i.e., it can provide a surrogate for in vivo bioequivalence. In vivo bioequivalence studies may be exempted if an assumption of equivalence in in vivo performance can be justified by satisfactory in vitro data. The BCS is a scientific approach based on the aqueous solubility and intestinal permeability characteristics of the drug substance(s). The BCS categorizes drug substances into one of four BCS classes as follows:

Class I: high solubility, high permeability

Class II: low solubility, high permeability

Class III: high solubility, low permeability

Class IV: low solubility, low permeability

This guidance provides recommendations to support the biopharmaceutics classification of drug substances and the BCS-based biowaiver of bioequivalence studies for drug products. The BCS-based biowaiver principles may be applied to bioequivalence purposes not explicitly specified in the guideline, provided they can be supported by a thorough scientific rationale.

Scope

BCS-based biowaivers may be used to substantiate in vivo bioequivalence. Examples include comparison between products used during clinical development through commercialization, post-approval changes, and applications for generic drug products in accordance with regional regulations.

The BCS-based biowaiver is only applicable to immediate release, solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation. Drug products having a narrow therapeutic index are excluded from consideration for a BCS-based biowaiver in this guidance. Fixed-dose combination (FDC) products are eligible for a BCS-based biowaiver when all drug substances contained in the combination drug product meet the criteria as defined in sections 2 and 3 of this guidance.

BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE

BCS-based biowaivers are applicable to drug products where the drug substance(s) exhibit high solubility and, either high permeability (BCS Class I) or low permeability (BCS Class III).

A biowaiver is applicable when the drug substance(s) in test and reference products are identical. A biowaiver may also be applicable if test and reference products contain different salts provided that both belong to BCS Class I (high solubility and high permeability). A biowaiver is not applicable when the test product contains a different ester, ether, isomer, mixture of isomers, complex or derivative of a drug substance from that of the reference product, since these differences may lead to different bioavailabilities not deducible by means of experiments used in the BCS-based biowaiver concept. Pro-drugs may be considered for a BCS-based biowaiver when absorbed as the pro-drug.

Question and answers