(506f) Model-Based Control of An Integrated Continuous Pharmaceutical Manufacturing Process

The pharmaceutical industry is a tightly regulated industry where all production must comply with good manufacturing practices (GMP) and quality requirements should be strictly satisfied. Historically, manufacturing in the pharmaceutical industry has been carried out in batch configuration which potentially results in expensive, inefficient and poorly controlled processes. Recently, both pharmaceutical industries and regulatory authorities have recognized that continuous manufacturing has significant potential to improve product quality. The shift from batch to continuous processing would necessitate the simulation of a complex process plant with interconnected unit operations, recycle and bypass streams and heat integration. This significantly alters the plant-wide process dynamics and increase the overall complexity of the integrated process. The interactions between process units may lead to poor performance of the decentralized unit-operation level control systems which are currently studied and found in the literature. Therefore a robust control strategy of the integrated process is required to support the overall plant-wide control strategy that needs to be adopted. The lack of an efficient control strategy for the integrated process remains a bottleneck in the overall implementation of a developing an efficient process control framework for the pharmaceutical manufacturing process.

The overall objective of this study is to develop a robust regulatory and advanced control framework to maintain critical quality attributes (CQA) of tablets (or intermediate products) at specified set-points given process disturbances, for the integrated pharmaceutical process consisting of several inter-connected unit operations. The focus will be on the manufacturing of oral solid dosage drugs which consist of approximately 85% of the entire pharmaceutical production. A typical manufacturing process for a powder based product (e.g., tablets and most capsules) is via continuous direct compaction and involves multiple processing steps, which are powder feeding, powder blending and tablet compaction. Tablet dissolution is also considered as a product model to relate tablet properties to the final dissolution rate which is required by the regulatory authorities to be tightly controlled. Simulations show that that at very mild interactions, a regulatory control strategy is able to maintain set-points at desired values. However, at moderate to high process interactions, oscillatory behavior of controlled variables is seen. Advanced control strategies (e.g. decouplers and model predictive control) were able to mitigate these deviations from set-point.