Guidances related to bioavailability and bioequivalence: European industryperspective

The investigations of bioavailability and bioequivalence can be classified according to three separate areas of information. Firstly, estimation of bi oavailability judged on a drug substance's in vivo characteristics taking i nto account solubility, polymorphism, stability (especially under the condi tions of the GI tract), gut wall permeability and first pass metabolism. Se condly, evaluation of formulation properties including dissolution profile in the GI tract and its contribution to exposure variability with respect t o the desired absorption characteristics. Finally, maintaining quality duri ng the market phase with respect to equivalence to the clinical trial formu lations. While in the first two areas, the range of the estimated mean values and th e intra- and inter-subject variabilities contain the desired information fo r proper medical decisions, in the third area the mean values and their con fidence limits describe the quality with regard to the formulations of prov en efficacy. Guidelines should clearly distinguish between the different areas in their recommendations regarding the intended information, e.g. mean values and/or ranges and confidence intervals. New approaches of granting limited waiver s for BE studies (e.g. Biopharmaceutical Classification System (BCS)) shoul d be expanded to consideration of pharmacokinetic properties of drugs (e.g. gastrointestinal metabolism, evidence for an absorption window, magnitude of first-pass effect; half-life) as already partly implemented in the Germa n waiver concept, and further (scientifically) validated to achieve world-w ide harmonisation (e.g. via ICH).