467352 Advanced Flexible Control System Implementation into Direct Compaction Continuous Pharmaceutical Manufacturing Pilot-Plant

Thursday, November 17, 2016: 3:59 PM
Continental 4 (Hilton San Francisco Union Square)
Ravendra Singh1, Fernando J. Muzzio2, Rohit Ramachandran1 and Marianthi Ierapetritou1, (1)Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, (2)Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ

Currently, pharmaceutical companies are going under paradigm shift from batch to continuous manufacturing. Real time monitoring and supervisory control system are necessary part of efficient continuous manufacturing. However, the minimum level of control necessary to produce the product with desired critical quality attributes depends on several factors including drug content (low dose, high dose), formulation properties (e.g. flowability, segregation), and product properties. Nevertheless, different control strategies such as feedforward (FF), feedback (FB), or combined FF/FB1as well as different control algorithms such as PID, MPC, or hybrid MPC-PID can be potentially used. Selection of a right control strategy and algorithm is mandatory task both for efficient manufacturing as well as regulatory point of view. However, because of different levels of complexities and unavailability of systematic method and tools, the identification of required level of control, type of control strategy and control algorithm are still a challenging task.

In this work, a flexible control system has been implemented into a direct compaction continuous tablet manufacturing pilot-plant. The flexible control system consists of three control strategies (FF, FB, combined FF/FB1) and three control algorithms (PID, MPC, hybrid MPC-PID) giving options for multiple control schemes. The flexible control system is designed in such a way that any control scheme can be easily selected. The control system is also modular in nature that can be easily transferred to any other control platform and manufacturing plant. The continuous tablet manufacturing pilot-plant runs under each control scheme and their performance are evaluated using standardized performance indicators. Based on the results obtained, a systematic methodology is proposed to assist the selection of control strategy and algorithm for continuous pharmaceutical manufacturing process.

Direct compaction continuous tablet manufacturing process is considered to demonstrate the implementation of flexible control strategy. The flexible control strategy consist of the five supervisory feedback control loops and three supervisory forward control loops among which the required number of control loops can be selected. Feedback loops are for drug concentration, powder level in chute, main compression force, tablet weight and hardenss control while the feedforward loops are for proactively mitigate the effects of process and raw materials variabilities. For example, measured powder bulk density is considered in real time in tablet press to proactively mitigate the effect of powder bulk density on tablet weight and hardness via changing the fill depth. Similarly, the feed forward loop to mitigate the effects of lubricant concentration variability on tablet hardness and thereby on tablet dissolution is added. As well as a feed forward control loop to mitigate the effects variation on blend composition on tablet potency. All feedforward control loops can not be used simultaneously because of limitations of number of actuators and therefore the methodology plays an important role to identify the appropriate control loops for a particular pharmaceutical product. The flexible control system are implemented using industry standard control platform (e.g. DeltaV), PAT data management tool (synTQ), OPC communication protocol, fieldbus devises, chemometric tools and real time monitoring tools.



  1. Singh, R., Muzzio, F., Ierapetritou, M., Ramachandran, R. (2015). A combined feed-forward/feed-back control system for a QbD based continuous tablet manufacturing process. PROCESSES Journal, 3, 339-356.

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