BENJAMIN F. HAEFNER*, MICHAEL NONNENMACHER, JOCHEN BECKER, DAVID VOIGTLAENDER, TIM POHLMANN
*Corresponding author
Evonik Nutrition & Care GmbH, Hanau-Wolfgang, Germany

Abstract

The shift from batch production towards continuous production in the pharmaceutical industry has been gaining momentum for many years. Main drivers are increasing requirements in product quality, plant safety and the need to enable novel process windows for innovative chemical transformations. Batch-to-conti switches need a paradigm shift in the approach towards process development and production. Proper design of continuous processes requires cross-functional and interdisciplinary teams covering areas of competency including organic chemistry, chemical engineering, process analytical technologies, quality assurance and mechanical engineering. We herein report the development of a multi-step flow process with organometallic reactions as case study to illustrate the cross-functional and interdisciplinary approach. Defined drivers to switch to flow processing are shown and an outlook is given on a modular continuous plant (MCP) allowing fast scale-up from lab to commercial production quantities.

INTRODUCTION

Advantages of continuous processing 

Main challenges of today’s and tomorrow’s fine chemistry and pharma production are growing demands for quality, reliability and flexibility. Furthermore, modern API syntheses are often very complex and frequently use hazardous chemicals. These challenges are increasingly difficult to meet by solely using batch processes. For certain reaction and workup steps, continuous processing allows for a high level of automation and greater control of chemical and thermodynamic parameters resulting in better selectivity, improved safety through small hold-up, as well as in economic benefits. Combining this with a modular plant approach, a multi-purpose pharmaceutical plant for synthesis of small molecule APIs can be realized on a small footprint.

The pharmaceutical industry sees an increasing demand of chemical transformations utilizing hazardous reactants, high pressure and strongly exothermic reactions as well as fast reaction kinetics. Such reactions require special attention to avoid loss over process control, runaway sc ...