The impact of the EMA change in definition of "dose" on the BCS dose-solubility ratio: a review of the biowaiver monographs.

The Biopharmaceutics Classification System (BCS) defines the solubility characteristics of an active pharmaceutical substance based on its dose-solubility ratio: for highly soluble drugs this ratio is less than 250 mL over a defined pH range. Prior to the revision of the European Medicines Agency (EMA, formerly EMEA) guideline in 2010, the "dose" in this ratio was consistently defined by the US FDA, the EMA, and the WHO biowaiver guidelines as the highest dosage strength. However, in the revised EMA guideline, the dose is defined as the highest single dose administered according to the Summary of Product Characteristics. The new EMA criterion for highly soluble may be closer to the actual conditions of use, but it is not in line with the dose that would be used in the in vivo bioequivalence study. This paper evaluates the impact on the BCS classification of the active pharmaceutical ingredients of the published biowaiver monographs and discusses the consequences of the possible change in classification on biowaiver recommendations. Using the current definition of dose by the EMA, the biowaiver recommendations for metoclopramide hydrochloride and verapamil hydrochloride are no longer valid according to EMA criteria. For prednisolone and prednisone, a reevaluation of the biowaiver recommendation, taking into account the usual dosing levels, seems appropriate.