Comparison of Dissolution Similarity Assessment Methods for Products with Large Variations: f(2) Statistics and Model-Independent Multivariate Confidence Region Procedure for Dissolution Profiles of Multiple Oral Products

摘要

The current Japanese Ministry of Health Labour and Welfare (MHLW)'s Guideline for Bioequivalence Studies of Generic Products uses averaged dissolution rates for the assessment of dissolution similarity between test and reference formulations. This study clarifies how the application of model-independent multivariate confidence region procedure (Method B), described in the European Medical Agency and U.S. Food and Drug Administration guidelines, affects similarity outcomes obtained empirically from dissolution profiles with large variations in individual dissolution rates. Sixty-one datasets of dissolution profiles for immediate release, oral generic, and corresponding innovator products that showed large variation in individual dissolution rates in generic products were assessed on their similarity by using the f(2) statistics defined in the MHLW guidelines (MHLW f(2) method) and two different Method B procedures, including a bootstrap method applied with f(2) statistics (BS method) and a multivariate analysis method using the Mahalanobis distance (MV method). The MHLW f(2) and BS methods provided similar dissolution similarities between reference and generic products. Although a small difference in the similarity assessment may be due to the decrease in the lower confidence interval for expected f(2) values derived from the large variation in individual dissolution rates, the MV method provided results different from those obtained through MHLW f(2) and BS methods. Analysis of actual dissolution data for products with large individual variations would provide valuable information towards an enhanced understanding of these methods and their possible incorporation in the MHLW guidelines.