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The US FDA has issued draft guidelines on waiver of in-vivo bioavailability (BA) and bioequivalence(BE) studies for immediate release solid oral dosage forms based on a bio-pharmaceutics classification system (BCS).

The guidance provides recommendations to sponsors of investigational new drug applications (INDs) and applicants that submit new drug applications (NDAs). It would also cover abbreviated new drug applications (ANDAs) and applications for immediate release (IR) solid oral dosage forms which are looking for a waiver of in-vivo BA and BE studies.

These waivers are intended to apply to subsequent in-vivo BA or BE studies of formulations during the IND period, said the regulatory authority.

“This guidance updates the norms for the industry that was earlier published in August 2000. It includes bio waiver extension to BCS Class 3 drug products and additional modifications, such as criteria for high permeability and high solubility. But, the big advantage for the companies is that save on cost and time,” said Prema Desai, consultant auditor for pharma plants.

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 of three major factors that govern the rate and extent of drug absorption from IR solid oral 48 dosage forms. These are dissolution, solubility and intestinal permeability. According to the BCS, drug substances are classified as Class 1 for high solubility and high permeability. Class 2 as low solubility and high permeability. Class 3 as high solubility and low permeability. Class 4 as low solubility and low permeability.

In addition, some IR solid oral dosage forms are categorized as having rapid or very rapid dissolution. Within this framework, when certain criteria are met, the BCS can be used as a drug development tool to help sponsors/applicants justify requests for bio-waivers.

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 in relation to gastric emptying, the drug is known to have high solubility. The rate and extent of drug absorption is unlikely to be dependent on drug dissolution in the 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 if the inactive ingredients used in the dosage form do not significantly affect its absorption, said the regulator.

The BCS approach outlined in this guidance can be used to justify bio-waivers for highly soluble and highly permeable drug substances which is categorized under Class 1. It be waived for highly soluble and low permeable drug substances under Class 3 in IR solid oral dosage forms.

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