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

Abstract

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.

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

“…Metta et al (2019) performed design and dynamic simulation of a continuous tableting line (composed of feeders, blenders, wet granulation, fluidized bed drying, milling + tablet press). The authors elucidated the critical process parameters affecting product quality that needed to be ensured in order to facilitate robust process design [35].…”

Change of Data-Driven Drug Design Trends Through Patent Analysis

“…The manufacturing system can be made more productive and efficient through the adoption of data science analysis methods. In the recent years, the continuous tablet manufacturing system is one of the most notable applications of data science-driven innovation [11]. The genomic data analysis-based development of drugs is used in clinical practice to reduce the cost of gathering the three billion human DNA [24].…”

“…In the last 10 years, rapid changes in innovation have occurred as a result of improvements in data availability and computational ability. This innovation is a part of the "fourth industrial revolution," which combines technologies and blends advanced services based on data science [6][7][8][9][10][11][12][13][14]. In detail, data science shows many possibilities of improving productivity and adopting new business models with promising technologies, such as wireless sensor networking, big data, artificial intelligence, cloud-based services, and so forth.…”

Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing

“…Several authors have covered the entire manufacturing process. Flowsheet models have been developed to predict dynamics for processes based on direct compression [16], dry granulation [17], and wet granulation [18]. Singh et al developed a control strategy for dry granulation and implemented it into a process-wide flowsheet based on firstprinciples models [19].…”