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Open AccessFeature PaperArticle

Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route

1
Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
2
BIOMATH, Department of Data Analysis and Mathematical Modelling, Ghent University, B-9000 Ghent, Belgium
3
Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, B-9000 Ghent, Belgium
4
Discovery, Product Development & Supply, Janssen, Pharmaceutical Companies of Johnson & Johnson, 2340 Beerse, Belgium
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Processes 2019, 7(4), 234; https://doi.org/10.3390/pr7040234
Received: 12 March 2019 / Revised: 5 April 2019 / Accepted: 15 April 2019 / Published: 24 April 2019
(This article belongs to the Special Issue Model-Based Tools for Pharmaceutical Manufacturing Processes)
In view of growing interest and investment in continuous manufacturing, the development and utilization of mathematical model(s) of the manufacturing line is of prime importance. These models are essential for understanding the complex interplay between process-wide critical process parameters (CPPs) and critical quality attributes (CQAs) beyond the individual process operations. In this work, a flowsheet model that is an approximate representation of the ConsiGma TM -25 line for continuous tablet manufacturing, including wet granulation, is developed. The manufacturing line involves various unit operations, i.e., feeders, blenders, a twin-screw wet granulator, a fluidized bed dryer, a mill, and a tablet press. The unit operations are simulated using various modeling approaches such as data-driven models, semi-empirical models, population balance models, and mechanistic models. Intermediate feeders, blenders, and transfer lines between the units are also simulated. The continuous process is simulated using the flowsheet model thus developed and case studies are provided to demonstrate its application for dynamic simulation. Finally, the flowsheet model is used to systematically identify critical process parameters (CPPs) that affect process responses of interest using global sensitivity analysis methods. Liquid feed rate to the granulator, and air temperature and drying time in the dryer are identified as CPPs affecting the tablet properties. View Full-Text
Keywords: model integration; flowsheet modeling; sensitivity analysis; continuous manufacturing; wet granulation model integration; flowsheet modeling; sensitivity analysis; continuous manufacturing; wet granulation
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MDPI and ACS Style

Metta, N.; Ghijs, M.; Schäfer, E.; Kumar, A.; Cappuyns, P.; Van Assche, I.; Singh, R.; Ramachandran, R.; De Beer, T.; Ierapetritou, M.; Nopens, I. Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route. Processes 2019, 7, 234.

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