SEVERINE THERESE F.C. MORTIER^1,2; INGMAR NOPENS¹, THOMAS DE BEER², KRIST V. GERNAEY³*
*Corresponding author
1. BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
2. Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, University of Ghent, Harelbekestraat 72, 9000 Ghent, Belgium
3. Department of Chemical and Biochemical Engineering, Technical University of Denmark, Building 229, 2800 Kgs. Lyngby, Denmark

Abstract

The intention to shift from batch to continuous production processes within the pharmaceutical industry enhances the need to monitor and control the process in-line and real-time to continuously guarantee the end-product quality. Mass and energy balances have been successfully applied to a drying process which is part of a continuous from-powder-to-tablet manufacturing line to calculate the residual moisture content of granules leaving the drying unit on the basis of continuously generated data from univariate sensors. Next to monitoring, the application of continuous processes demands also real-time adjustment of critical input variables to ensure that the process stays within the Design Space. Mechanistic models are very useful for this purpose as, once validated, several tools can be applied to gain further process knowledge, for example uncertainty and sensitivity analysis. In addition, several scenarios can be simulated, thus reducing the need to collect time-consuming, and often costly, experimental data.

INTRODUCTION: PHARMACEUTICAL REGULATION AND THE NEED FOR EFFICIENT CONTROL STRATEGIES

Traditionally, the pharmaceutical industry has mainly relied on batch processing in contrast to other industries, such as the bulk chemical industry and the food industry. However, currently the intention and opportunity exist to take a significant step forward in the pharmaceutical industry (5). The quality regulation for pharmaceuticals is for good reasons very strict, and as such, it was considered nearly impossible in the past to change something in the way of processing once a process was approved for production. However, the publication of the Process Analytical Technology (PAT) guidance has facilitated innovation and increased process efficiency, and as such, now the possibility exists to take the step towards continuous processes, both for Active Pharmaceutical Ingredient (API) production and for drug product formulation. To meet the PAT regulations, a thorough understanding of the process, and its subprocesses, is important to guarantee the production of end-products that meet the high quality standards.
A central concept introduced in the PAT guidance ...