The US Food and Drug Administration (FDA) has issued draft guidance, Waiver of In Vivo Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. The guidance provides recommendations for sponsors of investigational new drug applications (INDs), and applicants that submit new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to these applications for immediate-release (IR) solid oral dosage forms, and who wish to request a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE) studies. These waivers are intended to apply to: (1) subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of IR dosage forms during the IND period, and (2) in vivo BE studies of IR dosage forms in ANDAs.
Regulations at 21 CFR part 320 address the requirements for BA and BE data for approval of drug applications and supplemental applications. Provision for waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR 320.22.2 This draft guidance updates the guidance for industry on Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, published in August 2000, and explains when biowaivers can be requested for IR solid oral dosage forms based on an approach termed the Biopharmaceutics Classification System (BCS). The guidance includes biowaiver extension to BCS Class 3 drug products, and additional modifications, such as criteria for high permeability and high solubility.
The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: (1) dissolution, (2) solubility, and (3) intestinal permeability. According to the BCS, drug substances are classified as follows: Class 1: High Solubility – High Permeability; Class 2: Low Solubility – High Permeability; Class 3: High Solubility – Low Permeability; and Class 4: Low Solubility – Low Permeability.
Observed in vivo differences in the rate and extent of absorption of a drug from two pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in vivo. However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal (GI) transit time. Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing Class 1 and Class 3 drug substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients. The BCS approach outlined in the draft guidance can be used to justify biowaivers for highly soluble and highly permeable drug substances (i.e., Class 1) as well as highly soluble and low permeable drug substances (i.e., Class 3) in IR solid oral dosage forms that exhibit rapid or very rapid in vitro dissolution using the recommended test methods. The recommended methods for determining solubility, permeability, and in vitro dissolution.