NIMA YAZDANPANAH
Procegence LLC, Washington DC, USA

Abstract

Mechanistic modelling and process simulation, based on first principle analysis, is a well-practiced tool in the chemical industry. A mechanistic model is a knowledge-based description of a system designed to help an observer understand how the system works and predict its behaviour. Mechanistic models can be used for process design, process scale-up, technology transfer, knowledge management, and risk analysis for forward decision-making. Model-based scale-up and optimisation is a powerful technique for achieving the desired product quality and for reducing the cost of experimentation and the time to market.

This paper aims to provide a short summary of the fundamentals, applications, benefits, and limitations of the use of mechanistic modelling for process scale-up and technology transfer for the development and manufacturing of active pharmaceutical ingredients. Two case studies of reactor and crystallisation process scale-up are provided here. Detailed mathematical equations and technical discussions of numerical methods are avoided for the sake of the general audience.

INTRODUCTION

Efficient process development for achieving high-quality active pharmaceutical ingredients (APIs) at high yield and low manufacturing cost is the prime goal for development studies and scale-up to manufacturing scale. Process development criteria and process development and scale-up practices are based on classic chemical engineering knowledge and can be carried out by expensive and lengthy trial-and-error or by fast and efficient mechanistic modelling. A mechanistic model (based on first-principle knowledge) is a predictive tool that through proper development, validation, and implementation enables applicants to reduce cost, time, and resources for scale-up and technology transfer. It helps by significantly reducing the DoE effort on a manufacturing scale and by finding optimal conditions for equipment sizing and process parameters.

The aim of this paper is to provide an overview of mechanistic modelling and simulation in the pharmaceutical manufacturing industry for equipment characterisation and scale-up. Deep technical discussions and mathematical expressions are beyond the scope of this work. Interested readers a ...