(272d) Integrated Flowsheet Model of Continuous API Manufacturing Process and Its Applications for Dynamic Optimization and Control

Advanced continuous manufacturing (CM) is emerging as a preferred platform to produce active pharmaceutical ingredients (APIs). The future continuous pharmaceutical manufacturing is desired to be based on modular plug and play concept. In this approach, mobile modules consisting of a group of unit operations have been developed that can be easily reconfigured to assemble a scalable pharmaceutical manufacturing process for different products. It is also suitable for on-demand manufacturing such as in the case of COVID-19. However, because of different levels of complexity, the development and adaptation of flexible and modular CM plant is still an open area of research. Therefore, a systematic framework of methods and tools are needed to develop, adapt and evaluate the flexible modular CM plant for API manufacturing with reduced time and resources. In particular, a digital twin is critical for quick design, adaptation, optimization, scale up, and control of continuous APIs manufacturing process, allowing for virtual modeling of operations without extensive process development.

In this work, a digital twin for continuous APIs manufacturing process using modular components has been developed and its applications have been demonstrated for dynamic optimization and control system design. The process flowsheet model is the heart of 'digital twin' and consists of mathematical representation of three modules with the options of adding more as needed. The first module is for feeding and dispensing. It consists of a refill unit, feed tank, pump, mixing, and preheater. The second module is for performing the chemical reactions required to produce the target APIs. This module consists of tubular reactors placed inside a heating and cooling jacket. The third module is focused on separation of API from impurities. A continuous chromatographic model is currently used for separation purposes that can be easily replaced with any other type of separation techniques such as continuous crystallization. Currently, the developed model library consists of 32 units across 10 types that has been used to generate the integrated flowsheet model. The model has been validated using experimental data.

The applications of the digital twin have been demonstrated for dynamic optimization as well as design and development of suitable control architecture for a continuous APIs manufacturing process. The dynamic optimization provides the optimum operating conditions for the manufacturing process that improves the critical quality attributes (CQAs). A suitable control architecture then has been developed using digital twin to track the optimum set points for the key control variables. The developed control architecture is also modular in nature and can be easily adapted for different manufacturing processes of APIs that may have different material and information flows, dead time variations, and tuning parameters. The proposed digital twin can save the time and resources needed for continuous APIs manufacturing and improve the product quality significantly.

The objective of this presentation is two-fold; first to highlight the developed unit operation model library and integrated flowsheet model and then demonstrate its application for dynamic optimization and design of control architecture of continuous API manufacturing processes.