(557d) RTD Based Control System for Continuous Pharmaceutical Manufacturing Process

Currently, the pharmaceutical companies are going through a paradigm shift from conventional batch to continuous manufacturing (CM) process integrated with advanced automation and control system [1-2]. In CM, Real Time Release Testing (RTRT) can be facilitated by the development of a highly efficient control system that can monitor and correct process variables in real time when a fault is detected. But, there may be some out of specification tablets that need to be diverted in real time, in order to ensure the quality of final products. Specifically, the drug concertation of each tablet must be guaranteed before it can be released to the market. However, currently no methods and tools are available that can assure the drug concentration and divert the non-confirming products in real time. Therefore, the systematic methods and tools are needed for real time assurance of tablet drug concentration and diversion of non-confirming products.

In this work, a systematic framework including the methods and tools have been developed for design and implementation of control system to assure the drug concertation of final pharmaceutical tablet. The framework is based on the residence time distribution (RTD) model and a novel tablet diversion system. The work has been performed in two phases. In first phase, a mathematical model based Insilco study has been performed to identify the best strategy that can be employed to divert the non-confirming tablets in real time. In CM, the drug concentration is measured in real time before the tablet compaction (chute &/or feed frame) using PAT sensor. The proposed control strategy then uses this inlet concentration to determine a signal for the diversion strategy that can accurately be used to reject tablets that are out of tolerance limits at the outlet of the tablet press. Two strategies, i.e. ‘fixed window based strategy’ and RTD based strategy have been developed, compared and evaluated. In fixed window approach, the tablet diversion is facilitated through knowledge of time delays from the point of detection to the point of the affect (tablet press outlet gate) in the system. The sensor that detects the concentration is connected to a comparator block which decides if the said concentration is within the specifications. If it is not within specification, the experimentally derived time delay is applied and post this the diversion begins. The diversion stops when a concentration within spec is detected and the another time delay is applied. In RTD based approach, the RTD is used to predict the outlet concentration from the inlet concentration. The predicted signal is then used to initiate the diversion. The first approach is simpler to implement but may lead to lower production efficiency. The second approach is based on more advanced technique and will ensure more efficiency but is relatively complex to implement. In second phase of this work, the proposed strategies have been implemented into our pilot-plant facility for experimental demonstration.

The objective of this presentation is two-fold; first to highlight the Insilco studies for the development and evaluation of strategies for drug concertation assurance and diversion of non-confirming tablets and then demonstrate the performance of best strategies into our continuous pharmaceutical manufacturing pilot-plant facility

Reference
1. Singh, R. (2018). System engineering for a novel continuous pharmaceutical manufacturing process. Pharma. Issue 30. https://www.pharmafocusasia.com/manufacturing/system-engineering-pharmac....
2. Barros, F. N., Bhaskar, A., Singh, R. (2017). A validated model for design and evaluation of control architectures for continuous tablet compaction process. Processes Journal, 5(4), 76. doi:10.3390/pr5040076