In vivo Bioavailability/Bioequivalence Waivers (2004)

Bioavailability (BA) is defined in 21 CFR 320.1 as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream [1], bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.” Bioequivalence (BE) is defined in 21 CFR 320.1 as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” As noted in the statutory definitions, both BE and product quality BA focus on the release of a drug substance from a drug product and subsequent absorption into the systemic circulation [1]. Over the last 30 years, dissolution testing has not only been recognized as a valuable quality control test but has also proved itself as a useful indicator of differences in bioavailability. This is due to the fact that drug absorption after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions and the permeability across the gastrointestinal tract. Whenever, a significant difference in bioavailability has been found among supposedly identical articles, the dissolution test most of the times has been able to discriminate among these articles. In fact, dissolution is so sensitive to formulation factors that bioequivalent formulations sometimes show differences in dissolution profiles. According to the regulations stated in CFR 320.24, bioavailability and bioequivalence could be assessed by several in vitro or in vivo methods depending on the purpose of the study, the availability of analytical methods, and the nature of the drug product. Specifically CFR 320.24 states that either an in vitro test that has been correlated with and is predictive of human bioavailability data or a currently available in vitro test acceptable to FDA that ensures that human in vivo bioavailability is acceptable [2]. This chapter starts with definitions followed by therelevant regulations governing in vivo bioavailability/bioequivalence waivers with a discussion on the various types of waivers based on comparability of dissolution profiles for both immediate-release (IR) dosage forms and modified-release (MR) dosage forms. Moreover, the types of scale up and postapproval changes that can be approved based on comparability of dissolution profiles are summarized for both IR and MR products. A brief description on how to compare dissolution profiles is given. The role of in vitro-in vivo correlations (IVIVC) for MR products as well as the biopharmaceutics classification system (BCS) for IR products in alleviating the regulatory burden is elucidated. Finally, an overview of the Japanese, European, and Canadian guidelines for instances where an in vivo BA/BE waiver can be granted based on comparability of dissolution profiles is provided.