The BCS (Biopharmaceutics Classification System)-based biowaiver approach is meant to reduce in vivo bioequivalence studies, i.e., it may represent 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.

　　Applying for a BCS-based biowaiver is restricted to highly soluble drug substances with known human absorption and considered not to have a narrow therapeutic index (see section 4.1.9). The concept is applicable to immediate release, solid pharmaceutical products for oral administration and systemic action having the same pharmaceutical form. However, it is not applicable for sublingual,buccal, and modified release formulations. For orodispersible formulations the BCS-based biowaiver approach may only be applicable when absorption in the oral cavity can be excluded.

　　BCS-based biowaivers are intended to address the question of bioequivalence between specific test and reference products. The principles may be used to establish bioequivalence in applications for generic medicinal products, extensions of innovator products, variations that require bioequivalence testing,and between early clinical trial products and to-be-marketed products.

　　II. Summary Requirements

　　BCS-based biowaiver are applicable for an immediate release drug product if the drug substance has been proven to exhibit high solubility and complete absorption (BCSclass I; for details see section III) and either very rapid (> 85 % within 15 min) or similarly rapid (85 % within 30 min ) in vitro dissolution characteristics of the test and reference product has been demonstrated considering specific requirements (see section IV.1) and excipients that might affect bioavailability are qualitatively and quantitatively the same. In general, the use of the same excipients in similar amounts is preferred.

　　BCS-based biowaiver are also applicable for an immediate release drug product if the drug substance has been proven to exhibit high solubility and limited absorption (BCSclass III; for details see section III) and very rapid (> 85 % within 15 min) in vitro dissolution of the test and reference product has been demonstrated considering specific requirements and excipients that might affect bioavailability are qualitatively and quantitatively the same and other excipients are qualitatively the same and quantitatively very similar.

　　Generally the risks of an inappropriate biowaiver decision should be more critically reviewed (e.g.site-specific absorption, risk for transport protein interactions at the absorption site, excipient composition and therapeutic risks) for products containing BCS class III than for BCS class I drug substances.

　　III. Drug Substance

　　Generally, sound peer-reviewed literature may be acceptable for known compounds to describe the drug substance characteristics of importance for the biowaiver concept.Biowaiver may be applicable when the active substance(s) in test and reference products are identical.Biowaiver may also be applicable if test and reference contain different salts provided that both belong to BCS-class I (high solubility and complete absorption; see sections III.1 and III.2). Biowaiver is not applicable when the test product contains a different ester, ether, isomer, mixture of isomers, complex or derivative of an active 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.

　　The drug substance should not belong to the group of ‘narrow therapeutic index’drugs.

　　III.1 Solubility

　　The pH-solubility profile of the drug substance should be determined and discussed. The drug substance is considered highly soluble if the highest single dose administered as immediate release formulation(s) is completely dissolved in 250 ml of buffers within the range of pH 1-6.8 at 37±1℃.This demonstration requires the investigation in at least three buffers within this range (preferably at pH 1.2, 4.5 and 6.8) and in addition at the pKa, if it is within the specified pH range. Replicate determinations at each pH condition may be necessary to achieve an unequivocal solubility classification (e.g. shake-flask method or other justified method). Solution pH should be verified prior and after addition of the drug substance to a buffer.

　　III.2 Absorption

　　The demonstration of complete absorption in humans is preferred for BCS-based biowaiver applications. For this purpose complete absorption is considered to be established where measured extent of absorption is ≥ 85 %. Complete absorption is generally related to high permeability.

　　Complete drug absorption should be justified based on reliable investigations in human.

　　Data from absolute bioavailability or

　　mass-balance studies could be used to support this claim.

　　When data from mass balance studies are used to support complete absorption, it must be ensured that the metabolites taken into account in determination of fraction absorbed are formed after absorption.Hence, when referring to total radioactivity excreted in urine, it should be ensured that there is no degradation or metabolism of the unchanged drug substance in the gastric or intestinal fluid. Phase 1 oxidative and Phase 2 conjugative metabolism can only occur after absorption (i.e. cannot occur in the gastric or intestinal fluid). Hence, data from mass balance studies support complete absorption if the sum of urinary recovery of parent compound and urinary and faecal recovery of Phase 1 oxidative and Phase 2 conjugative drug metabolites account for ≥ 85 % of the dose.

　　In addition highly soluble drug substances with incomplete absorption, i.e. BCS-class III compounds,could be eligible for a biowaiver provided certain prerequisites are fulfilled regarding product composition and in vitro dissolution (see also sect. IV.2 Excipients). The more restrictive requirements will also apply for compounds proposed to be BCS class I but where complete absorption could not convincingly be demonstrated.

　　Reported bioequivalence between aqueous and solid formulations of a particular compound administered via the oral route may be supportive as it indicates that absorption limitations due to (immediate release) formulation characteristics may be considered negligible. Well performed in vitro permeability investigations including reference standards may also be considered supportive to in vivo data.