Statistical Methods for Quality Equivalence of Topical Products. 0.5 mg/g Betamethasone Ointment as a Case-Study.

Jordi Ocaña,Toni Monleón-Getino,Virginia Merino,Daniel Peris,Lluís Soler

doi:10.3390/pharmaceutics12040318

Abstract

This study examines the statistical implications, and their possible implementation, of the “Draft guideline on quality and equivalence of topical products” issued by the European Medicines Agency in 2018, with particular focus on the section devoted to quality equivalence of physical properties. A new confidence interval to conduct the quality equivalence test and a way to cope with the multiplicity of quality parameters are presented and discussed. As an example, the results and the statistical analysis of a study on betamethasone 0.5 mg/g ointment are presented. It is suggested that the equivalence limits proposed in the draft guideline are overly strict: It is as difficult to declare quality equivalence between two packaging formats of the same reference product as to declare quality equivalence between the reference and the test product.

Highlights

In October, 2018, the European Medicines Agency (EMA) issued a draft guideline on the quality and equivalence of topical products [1]
In this paper we present a quality equivalence study of physical properties, comparing a new topical product developed by Kern Pharma equivalent to the reference Leo Pharma Daivodet reference product
Presented first are the results of the equivalence analyses for the Kern Pharma generic product vs. the reference Leo Pharma Daivodet reference product. These analyses were performed separately for each one of the quantitative quality characteristics described in the Methods section, and summarizing the multivariate rheology characteristics by means of a reduced number of principal components

Summary

Introduction

In October, 2018, the European Medicines Agency (EMA) issued a draft guideline on the quality and equivalence of topical products [1]. On line 630 in Section 5.2.1, “Extended pharmaceutical equivalence acceptance criteria”, it is stated that: “For quantitative quality characteristics, the 90% confidence interval for the difference of means of the test and comparator products should be contained within the acceptance criteria of +/−10% of the comparator product mean, assuming normal distribution of data”. The main objectives of the study were: (i) To ascertain which experimental design is the most appropriate; (ii) to construct adequate testing procedures to prove quality equivalence between test and reference products; (iii) to elucidate how to manage the great multiplicity of available quality characteristics and (iv) to shed light on the chances of declaring equivalence under this regulatory proposal, even in an scenario of reasonably real equivalence. Some additional comments about these objectives are set forth below

Objectives

Methods

Results

Conclusion