Regulatory perspectives on in vitro (dissolution)/in vivo (bioavailability) correlations.

In vitro dissolution has been extensively used as a quality control tool for solid oral dosage forms. In several cases, however, it is not known whether one can predict the in vivo performance of these products from in vitro dissolution data. In an effort to minimize unnecessary human testing, investigations of in vitro/in vivo correlations (IVIVC) between in vitro dissolution and in vivo bioavailability are increasingly becoming an integral part of extended release (ER) drug product development. This increased activity in developing IVIVCs indicates the value of IVIVCs to the pharmaceutical industry. Because of the scientific interest and the associated utility of IVIVC as a valuable tool, the US Food and Drug Administration has published a Guidance in September 1997, entitled Extended Release Oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations. A predictive IVIVC enables in vitro dissolution to serve as a surrogate for in vivo bioequivalence testing. IVIVCs can be used in place of biostudies that may otherwise be required to demonstrate bioequivalence, when certain preapproval and postapproval changes are made in formulation, equipment, manufacturing process or in the manufacturing site. IVIVC development could lead to improved product quality (more meaningful dissolution specifications) and decreased regulatory burden (reduced biostudy requirements). This article will discuss in detail the FDA Guidance which deals with the development, evaluation methods and criteria, and applications of IVIVCs. From a regulatory point of view, the applications of IVIVC to grant biowaivers and to set dissolution specifications for ER oral dosage forms will be presented. Additionally, since the principles of IVIVC are considered to be similar for non-oral dosage forms, the guidance for oral extended release products may be applied for non-oral products as well. While the principles are likely to be the same, it is an interesting challenge to look at appropriate methods for dissolution testing and for development of in vitro/in vivo correlations for products such as injectable depot formulations.