Dissolution Profiles of Generic Products in Dissolution Media Defined by Japanese Guidelines for Bioequivalence Studies.

Abstract

The International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use M9 Guidelines for Biopharmaceutics Classification System Biowaivers reached harmonization in November 2019. However, guidelines for bioequivalence studies are not internationally harmonized, and water as a dissolution medium is only required in Japanese guidelines, regardless of drug solubility. This study investigated the dissolution profiles of generic products in Japan that differ from those of original drugs in dissolution media defined in guidelines. Dissolution profiles disclosed on websites of generic manufacturers were investigated for 262 active ingredients listed in the bluebook (4638 oral solid products listed in the National Health Insurance drug price list) issued by the Ministry of Health, Labour and Welfare. 5% of all generic products were different from the original products in dissolution media, of which 20% was observed in water only. Among the active pharmaceutical ingredients that showed different dissolution profiles only in water, the ratio of original products that showed slower dissolution profiles to the generics was 73%. The ratio of products showing different dissolution in water only was higher than in other media investigated in this study; however, these do not reflect disintegration and dissolution of drug products in the gastrointestinal tract, since bioequivalence has been confirmed in human studies and the generic products were approved by Japanese authorities. Therefore, a discussion about the required use of water as a dissolution medium in the Japanese guidelines is needed among industry, academia, and regulatory authorities.