First-Principles and Empirical Approaches to Predicting In Vitro Dissolution for Pharmaceutical Formulation and Process Development and for Product Release Testing

Nikolay Zaborenko,Md Anik Alam,Brian M Zacour,Andre Hermans,Brandye M Smith-Goettler,Zhenqi Shi,Leah Xiong,Michael J Cohen,Limin Zhang,Claudia C Corredor,Xujin Lu,Colleen M Neu

doi:10.1208/s12248-019-0297-y

Abstract

This manuscript represents the perspective of the Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) and of two focus groups of the American Association of Pharmaceutical Scientists (AAPS): Process Analytical Technology (PAT) and In Vitro Release and Dissolution Testing (IVRDT). The intent of this manuscript is to show recent progress in the field of in vitro predictive dissolution modeling and to provide recommended general approaches to developing in vitro predictive dissolution models for both early- and late-stage formulation/process development and batch release. Different modeling approaches should be used at different stages of drug development based on product and process understanding available at those stages. Two industry case studies of current approaches used for modeling tablet dissolution are presented. These include examples of predictive model use for product development within the space explored during formulation and process optimization, as well as of dissolution models as surrogate tests in a regulatory filing. A review of an industry example of developing a dissolution model for real-time release testing (RTRt) and of academic case studies of enabling dissolution RTRt by near-infrared spectroscopy (NIRS) is also provided. These demonstrate multiple approaches for developing data-rich empirical models in the context of science- and risk-based process development to predict in vitro dissolution. Recommendations of modeling best practices are made, focused primarily on immediate-release (IR) oral delivery products for new drug applications. A general roadmap is presented for implementation of dissolution modeling for enhanced product understanding, robust control strategy, batch release testing, and flexibility toward post-approval changes.

Highlights

IntroductionTechnology Center North, B302, Drop 3210, Indianapolis, Indiana 46285, USA. 2 Drug Product Science and Technology, Bristol-Myers Squibb, NewBrunswick, New Jersey 08903, USA. 3 Merck & Co., Inc., Kenilworth, New Jersey 07033, USA. 4 Analytical Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. 5 Global Chemistry and Manufacturing Controls, Pfizer Inc., Groton, Connecticut 06340, USA. 6 To whom correspondence should be addressed. (e–mail: Orally administered solid dosage forms (tablets and capsules) constitute a large fraction of pharmaceutical products
Technology Center North, B302, Drop 3210, Indianapolis, Indiana 46285, USA. 2 Drug Product Science and Technology, Bristol-Myers Squibb, NewBrunswick, New Jersey 08903, USA. 3 Merck & Co., Inc., Kenilworth, New Jersey 07033, USA. 4 Analytical Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. 5 Global Chemistry and Manufacturing Controls, Pfizer Inc., Groton, Connecticut 06340, USA. 6 To whom correspondence should be addressed
The purpose of this paper is to show recent progress in the field of in vitro predictive dissolution modeling, as well as to provide recommended general approaches to developing in vitro predictive dissolution models for both early- and latestage formulation/process development and batch release

Summary

Introduction

Technology Center North, B302, Drop 3210, Indianapolis, Indiana 46285, USA. 2 Drug Product Science and Technology, Bristol-Myers Squibb, NewBrunswick, New Jersey 08903, USA. 3 Merck & Co., Inc., Kenilworth, New Jersey 07033, USA. 4 Analytical Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. 5 Global Chemistry and Manufacturing Controls, Pfizer Inc., Groton, Connecticut 06340, USA. 6 To whom correspondence should be addressed. (e–mail: Orally administered solid dosage forms (tablets and capsules) constitute a large fraction of pharmaceutical products. 2 Drug Product Science and Technology, Bristol-Myers Squibb, New. Brunswick, New Jersey 08903, USA. (e–mail: Orally administered solid dosage forms (tablets and capsules) constitute a large fraction of pharmaceutical products. 4 Analytical Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. These formulations are designed to release the active pharmaceutical ingredient (API) through the patient’s gastrointestinal (GI) tract in a prescribed manner. Understanding the in vivo mechanism of API release and absorption is a key objective to streamline and optimize the development of orally administered drug products. Dissolution profiles have been used to understand the impact of formulation composition and process parameters on the in vitro release of API. Dissolution testing plays an important role in the context of scienceand risk-based process development, validation, evaluation of

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Conclusion