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PAT as key-enabling technology for QbD in pharmaceutical manufacturing – A conceptual review on upstream and downstream processing

corresponding

M. KORNECKI, A. SCHMIDT, J. STRUBE*
*Corresponding author
Clausthal University of Technology, Institute for Separation and Process Technology, Clausthal-Zellerfeld, Germany

Abstract

The transition from batch to continuous bioprocesses in regulated industries has been and will continue to be one of the biggest technological changes of the last decades. Necessary technologies to enable continuous biomanufacturing are Process Analytical Technology (PAT) and Quality-by-Design (QbD), which are closely associated with process automatization and control to obtain key process information in real-time. This article provides some insight into the fundamentals and shows a way for PAT as key-enabling technology for a QbD derived process development and control strategy on the example of a monoclonal antibody derived from cell cultivation and harvest by aqueous two-phase extraction (ATPE).


INTRODUCTION

Production of biopharmaceuticals in regulated industries is still predominantly based on batch processes, although continuous processes offer decisive advantages regarding agility, flexibility, quality, cost, and societal benefits (1). 

For those categories, FDA (U.S. Food and Drug Administration) and CDER (Center for Drug Evaluation and Research) give specific examples of achievable improvements, e.g. continuous manufacturing (CM) enables expansion of production volumes without the current problems related to batch scale-up (agility). CM also tackles the challenge to rapidly increase production in case of shortages or emergencies (flexibility). Currently, production supply chains are spread globally and therefore vulnerable in many ways. Furthermore, CM enables regional and intranational manufacturing (geography). Switching to CM also allows for introduction of highly meaningful statistical process control (quality) and a decreased initial investment (cost). The environmental impact is generally lower, it triggers the demand for highly trained staff and freed resources can be invested in new product ...