(373e) Moving Horizon Based Real Time Optimization and Hybrid Control of Continuous Pharmaceutical Manufacturing Process

Authors: 
Shah, A., Hovione
Singh, R., Rutgers, The State University of New Jersey
Ramachandran, R., Rutgers University
The pharmaceutical company is still largely a batch process industry. The different level of complexities involved with pharmaceutical processing has prevented the transition towards continuous manufacturing. However, Quality by Design (QbD), a novel initiative proposed by regulatory agencies, is a big leap in making this transition successful. QbD involves the use of process analytical technology (PAT) tools to monitor the process in real time and a feedback system to provide a control actions suitable for continuous manufacturing. Traditional control strategies such as proportional-integral-derivative (PID) and model predictive control (MPC) have been widely used in chemical and petrochemical industries in the past decades. However, pharmaceutical industries have been slow in adapting this technology in the traditional quality-by-testing (QbT) approach largely due to strict regulatory requirements and associated complexities.

In this work, a moving horizon based real time optimization (MH-RTO1) technique has been integrated with a hybrid model predictive control (MPC) system for a continuous downstream separation and purification process of Active Pharmaceutical Ingredients (API). The integrated process flowsheet consists of four continuous downstream unit operations (Crystallization, filtration, drying and mixing). In the proposed approach, the integrated MH-RTO provides the optimal operational set points for the total production rate in real time. The MH-RTO takes into consideration the capital and operating cost, the market fluctuations, the product inventory, the product quality assurance strategy, the regulatory constraints, and the product rejections. An advanced hybrid model predictive control system then ensures that required production rate with desired quality is met with minimum resources and time. A robust optimization strategy and an efficient control system have been integrated to achieve the maximum profit. The MH-RTO integrated with a hybrid control strategy ensures the maximum possible profit irrespective of the market demand fluctuations. The basic advantage of the MH-RTO framework is that it takes into consideration the future demand as well as past inventory and thus can lead to increased profit compared to a standard Real Time Optimization (RTO) or optimization free approaches.

The objective of this presentation is two-fold. First to highlight the moving horizon based real time optimization technique and MPC-PID hybrid control architecture, and second to demonstrate the real time optimization and control of continuous downstream API purification and separation process.

Reference

[1]. Singh, R., Sen, M., Ierapetritou, M., Ramachandran, R. (2015). Integrated moving horizon based dynamic real time optimization and hybrid MPC-PID control of a direct compaction continuous tablet manufacturing process. Journal of Pharmaceutical Innovation, 10 (3), 233-253.