(322e) Pharma 4.0: Advanced Control and Cyber-Physical Security of Continuous Pharmaceutical Manufacturing Pilot-Plant

Currently, Industry 4.0 concepts are being applied to pharma industry to achieve Pharma 4.0 paradigm. Pharma 4.0 reduces the time and resources needed for continuous pharmaceutical manufacturing and also improves the product quality and production consistency. It has many advantages but also have bigger challenges on the advanced process control and cyber-physical security side since the process and CQA’s are not only needed to controlled but also need to be protected from any vulnerability, in real time [1-4]. The quality of the pharmaceutical products can be improved significantly via implementing the advanced model predictive control (MPC) system coupled with an RTD based control system if an appropriate cyber-physical security defense is in place. However, much less attention has been paid to implement the integrated control and cyber-physical security system into the continuous pharmaceutical manufacturing plant.

In this work, an advanced model predictive control (MPC) system coupled with an RTD based control system has been implemented in the continuous pharmaceutical manufacturing (CPM) pilot-plant. The CPP’s and CQA’s are controlled in real time using advanced model predictive control (MPC) system while the none-confirming products are diverted in real time in waste to assure the final CQA’s of qualified tablet lots. This bi-layer coupled control strategy assures the final product quality, improves the production efficiency, minimizes the need of off line testing, and facilitated the real time release. The critical control variables that have been controlled in first layer using model predictive control (MPC) system are drug concertation, powder level before tablet press, main and pre compression forces, tablet weight and hardness. A novel control strategy for powder level control in a chute placed in between blender and tablet press unit operation of continuous tablet manufacturing process has been developed, implemented and evaluated. A noninvasive technique based on change in electric field concept has been used for real time monitoring of powder level in continuous manufacturing pilot-plant. The APC has been used to control feeder, blender and tablet press as well [1]. A systematic framework including the methods and tools for real time diversion of tablets have been developed and implemented into continuous pharmaceutical manufacturing process as a second layer assurance of product quality. 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. It is also providing a suitable platform to handle the pandemics such as Covid-19 via rapid production of suitable drugs and its real time release, with less time and resources.

A systematic framework including the methods and tools have been also developed for proactive identification and mitigation of potential cyber-physical attack risk on CPM. The cyber-physical security relevant software tools such as Snap 7, Wireshark, and Tripwire have been applied to CPM. A novel software tool named CPS (Cyber-Physical Security) has been developed for cyber-physical security of the continuous pharmaceutical manufacturing. The integrated commercially available and developed (in house) cyber-physical security tools have added an extra layer of security of our continuous pharmaceutical manufacturing pilot-plant for any unexpected attacks. All the relevant data generated during continuous manufacturing has been systematically collected, stored and organized in a data hub (OSI PI) and cloud system as per industry 4.0 standard.

The objective of this presentation is to demonstrate the performance of integrated MPC and RTD based bi-layer control strategy together with cyber-physical security system implemented into our continuous pharmaceutical manufacturing pilot-plant facility.

References

1. Bhaskar, A., Barros, F. N., Singh, R. (2017). Development and implementation of an advanced model predictive control system into continuous pharmaceutical tablet compaction process. International Journal of Pharmaceutics, 534 (1-2), 159-178.
2. Bhaskar, A., Singh, R. (2018). Residence time distribution (RTD) based control system for continuous pharmaceutical manufacturing process. Journal of Pharmaceutical Innovation. DOI: 10.1007/s12247-018-9356-7.
3. Singh, R. (2019). Systematic framework for implementation of RTD based control system into continuous pharmaceutical manufacturing pilot-plant. Pharma. Issue 34, 43-46.
4. Singh, R. (2020). The cyber-physical security of pharmaceutical manufacturing processes. Pharma., Issue 38, 53-57.