A Critical Overview of FDA and EMA Statistical Methods to Compare In Vitro Drug Dissolution Profiles of Pharmaceutical Products.

Jan Muselík,Kevin Matzick,Alena Komersová,Barbora Skalická,Kateřina Kubová

doi:10.3390/pharmaceutics13101703

Jan Muselík, Kevin Matzick + Show 3 more

Open Access

https://doi.org/10.3390/pharmaceutics13101703

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Journal: Pharmaceutics	Publication Date: Oct 15, 2021
Citations: 32	License type: CC BY 4.0

Affiliation: Masaryk University, University of Pardubice

Abstract

A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f2. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f2 based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f2 or CI derivation for the difference between reference and test samples was selected as the method of choice.

Highlights

If at least one prerequisite for the f 2 calculation is not met (e.g., coefficient of variation (CV) values at some time points are higher than the maximum acceptable value), the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines recommend using some alternative approach to evaluate the similarity of the dissolution profiles
Based on a statement in the EMA guidelines [12] that “( . . . ) similarity may be compared using ( . . . ) the percentage dissolved at different time points ( . . . )”, another simple approach in statistical comparison of dissolution profiles is to calculate the CI for the difference between the (T) and (R) sample with respect to mean percentage of the released drug at each time point separately
The release profiles evaluation very often involves the comparison of dissolution profiles

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The dissolution test is routinely used to provide critical in vitro drug release information in pharmaceutical development and the quality control process [2,3]. If a substantial variation from batch to batch exists, the use of the f 2 point estimate in comparing two drug dissolution profiles is not appropriate [14,15]. To circumvent this problem, the EMA and FDA guidelines allow other model-dependent or model-independent methods to be used for the dissolution profile comparison. This article aims to provide a detailed overview of the FDA and EMA mentioned methods used to compare the dissolution profiles, including their procedures and limitations

Dissolution Profile Comparison in the Context of the EMA and FDA Guidelines

Similarity Factor f2

CI Derivation for f2 Based on Bootstrap

CI Derivation for the Difference between Reference and Test Samples

Mahalanobis Distance

Findings

Conclusions