Development and implementation of a large-scale HPAPI manufacturing process

corresponding

IAN GRAYSON1*, JOCHEN BECKER1, TIM POHLMANN1, KAI BLUMBACH1, KENNY MCCLEARY2, MATTHEW VAN HOOSIER2
*Corresponding author
1. Evonik Nutrition & Care GmbH, Hanau-Wolfgang, Germany
2. Evonik Corporation, Indiana, USA

Abstract

The development and transfer of HPAPI manufacturing processes to full production scale presents particular challenges to a CMO. It is especially important to conduct a full risk analysis including setting of Occupational Exposure Limits (OELs) for each high potency chemical step. For this we need both reliable toxicity data and a high level of expertise in toxicology. The risk control strategy defines the equipment and procedures, at both laboratory and plant scale, in order to run the process safely. We show how this is achieved in practice with the example of a multi-step HPAPI process, taken from laboratory to routine large scale production. During scale-up and production, the high potency aspects of the process are continually reviewed in order to improve the safety and efficiency of the process.


INTRODUCTION

Highly Potent Active Pharmaceutical Ingredients (HPAPIs) today constitute a significant and increasing proportion of new drugs. It has been estimated that more than 25% of all new drugs in development, including antibody-drug conjugates (ADCs) are HPAPIs (1). A large number of pharmaceutical companies and contract manufacturing organisations (CMOs) have invested in manufacturing facilities for HPAPIs over the last ten years. Although some are well established, late entrants to the field still have to gain experience in large scale manufacturing and handling of HPAPIs. The manufacture of HPAPIs, especially at large scale, requires particular attention to safe handling and containment systems, to prevent exposure of the workforce, release of a HPAPI or pharmaceutically active intermediate, and cross-contamination with other products manufactured in the facility or on the site. The systems and methods chosen to achieve this by different manufacturers and recommended by consultants in the field have been presented previously in Chemistry Today (2-5). 

The containment system requirements for any particular process depend on the hazard assessment o ...