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Simplified Model-Dependent and Model-Independent Approaches for Dissolution Profile Comparison for Oral Products: Regulatory Perspective for Generic Product Development

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Abstract

Dissolution profile comparison among different formulations plays a critical role during new drug as well as generic product development. In the generic product development, dissolution profile comparison is a mandate for biowaivers (BCS-based, for lower strengths and IVIVC-based biowaivers) and also from quality control perspective. Even though traditionally similarity factor or f2 is used as a metric for dissolution profile comparison, it comes with multiple limitations and requirements (e.g., number of time points and variability). To overcome this, regulatory agencies suggested model-independent (e.g., MSD) and model-dependent (e.g., zero order, Weibull) dissolution profile comparison methods. Although most of regulatory guidance documents mention about such approaches, their usage in reality is limited probably due to lack of clear, detailed, and step-wise procedure. In this context, the present article describes simplistic yet detailed procedures of dissolution profile comparison with case studies covering generic product development scenario’s from a regulatory perspective. Detailed review of regulatory guidances from various agencies was made along with examples of such approaches in regulatory submissions. Data from three formulations—Formulations A, B, and C—were utilized to perform dissolution profile comparison using MSD, zero-order, and Weibull release profile–based comparisons. Dissolution profile comparisons were made using all of these three approaches complying with regulatory requirements. These examples demonstrated value and utility of these approaches and the simplified and detailed procedure explained in this manuscript can be adapted for generic product applications.

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Abbreviations

API:

active pharmaceutical ingredient

BCS:

biopharmaceutics classification system

IVIVC:

in vitro and in vivo correlation

MSD:

multivariate statistical distance

T2EQ:

T^2test for equivalence

USFDA:

United States Food and Drug Administration

EMA:

European Medicines Agency

ANVISA:

Agencia Nacional de Vigilancia Sanitaria

MOH:

Ministry of Health

RSD:

relative standard deviation

RLD:

reference listed drug

QC:

quality control

CR:

controlled release

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Acknowledgements

Authors would like to thank Dr. Reddy’s Laboratory for providing an opportunity to publish this work. We would like to thank statistician Daka Krishna Reddy for inputs in the manuscript.

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Authors and Affiliations

  1. Biopharmaceutics Group, Global Clinical Management, Dr. Reddy’s Laboratories Ltd., Integrated Product Development Organization (IPDO), Bachupally, Medchal Malkajgiri District, Hyderabad, Telangana, 500 090, India

    Sivacharan Kollipara, Rajkumar Boddu, Tausif Ahmed & Siddharth Chachad

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  1. Sivacharan Kollipara
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Contributions

Sivacharan Kollipara—concept and design, writing manuscript; Rajkumar Boddu—concept and design, writing manuscript; Tausif Ahmed—concept and design, manuscript review, approval for version to be published; Siddharth Chachad—manuscript review, approval for version to be published

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Correspondence to Tausif Ahmed.

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All the authors are employees of Dr. Reddy’s laboratory and report no conflicts interest. The authors alone are responsible for the content and writing of this article.

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Kollipara, S., Boddu, R., Ahmed, T. et al. Simplified Model-Dependent and Model-Independent Approaches for Dissolution Profile Comparison for Oral Products: Regulatory Perspective for Generic Product Development. AAPS PharmSciTech 23, 53 (2022). https://doi.org/10.1208/s12249-021-02203-7

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