(665e) A Novel Digital Twin and Its Applications for the Control of Advanced Continuous Pharmaceutical Injectable Manufacturing Process

Currently, advanced modular continuous pharmaceutical manufacturing (CM) is emerging as a preferred platform to produce the full finished injectable liquid dosage forms [1-2]. Such a process should be easily reconfigurable to assemble a pharmaceutical manufacturing process for various products. However, because of different levels of complexity, the development and adaptation of flexible and modular CM plant is still an open area of research. Therefore, a systematic framework of methods and tools are needed to develop, adapt, and evaluate the flexible modular CM plant for pharmaceutical manufacturing of liquid dosage forms with reduced time and resources. In particular, a digital twin is critical for quick design, adaptation, optimization, and control of manufacturing process, allowing for virtual modeling of operations without extensive experimentation.

In this work, a digital twin of continuous manufacturing of full finish final liquid dosage forms has been developed. The heart of digital twin is the unit operation model library. The developed digital twin model library consists of the mathematical model of unit operations involved in modules 1-3. In module 1, the continuous feeding system model including feed tanks model, refill system model, and pump model have been developed. In module 2, the mathematical model of static mixer to predict the mixing of different ingredients, and an ultrafiltration model to predict the different critical process parameters (CPPs) including retentate and permeate fluxes have been developed. In module 3, the surge tank model has been developed to make the balance between modules 2 and 3. The vial filling model has been developed to predict the final critical quality attributes (CQAs) of the injectable drug product. The unit operation models have been integrated to develop the integrated flowsheet model which is a digital representation of the injectable manufacturing pilot-plant. The integrated digital twin model has been used to design and evaluate the control system of the continuous injectable manufacturing process. A bilayer control system has been developed. In first layer, the critical process parameters (CPPs) and critical quality attributes (CQAs) have been controlled using feedback control system while in second layer the out of specification product stream has been diverted in real time.

The feedback control architecture has been developed and evaluated for drug concentration control, excipient concentration control, and pH control to assure CQAs in real time. The liquid level in surge tank has been controlled to assure the continuous manufacturing operation without interruption. The diversion strategy of out of specification product has been developed. The diversion at three locations of the pilot plant namely before surge tank, after surge tank, and after vial filling have been compared using the digital twin model. A Python-based software tool has been developed to divert the waste product in real time.

The objective of this presentation is two-fold; first to highlight the developed digital twin of the continuous pharmaceutical manufacturing of liquid dosage forms and then demonstrate its application for design and evaluation of control system.

References

(1). O’Connor, T. (2020). FDA Grand Rounds: Modernization of Pharmaceutical Manufacturing through the Adoption of Advanced Technology. https://www.fda.gov/science-research/fda-grand-rounds/fda-grand-rounds-….

(2). Singh, R., Sahay, A., Fernando Muzzio, Ierapetritou, M., Ramachandran, R. (2014). A systematic framework for onsite design and implementation of the control system in continuous tablet manufacturing process. Computers & Chemical Engineering Journal, 66, 186-200.