(448g) A Novel Modular Plant and Digital Twin Model of Continuous Pharmaceutical Manufacturing of Liquid Dosage Forms

Advanced continuous manufacturing (CM) is emerging as a preferred platform to produce active pharmaceutical ingredients (APIs) as well as full finished injectable liquid dosage forms [1]. The future continuous pharmaceutical manufacturing is desired to be based on modular plug and play concept. In this approach, mobile modules consisting of a group of unit operations have been developed that can be easily reconfigured to assemble a scalable pharmaceutical manufacturing process for different products. It is also suitable for on-demand manufacturing such as in the case of pandemic. However, because of different levels of complexity, the development and adaptation of flexible and modular CM plant for injectable manufacturing 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 process development [2].

In this work, a novel plant and digital twin model of continuous manufacturing of full finish final liquid dosage forms has been developed. The developed continuous injectable manufacturing process takes the API synthesized and purified via a continuous API manufacturing process, either in powder form or as a solution in the final liquid ingredient of the formulation and turns it into a finished liquid product. This process is composed of three modules. In module 1, the API is conditioned in a preconditioning tank. This involves either dissolving powder API, or diluting an API liquid feedstock, to generate a solution with the desired concentration. Solutions of all remaining formulation ingredients are dispensed from additional refillable tanks. All ingredients are pumped at controlled mass flow rates to module 2. The module 2 consist of a static mixer, a homogenizer, and an ultrafiltration unit operation. The ultrafiltration membrane is used for purification and sterilization. In module 3, the outlet stream from ultrafiltration unit is pumped into a reservoir tank (surge capacity), from where it is metered-fed into vial filling machine. The filled vials are then transferred to a capping station.

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, a homogenizer model to predict the agglomerate size reduction, and a 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 model is predictive in nature and has been verified using the experimental data generated from our injectable CM pilot-plant.

The objective of this presentation is two-fold; first to highlight the developed unit operation model library for the continuous pharmaceutical manufacturing of liquid dosage forms and then demonstrate its application for integrated flowsheet model generation, dynamic optimization, and design 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-m....

[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.

Acknowledgements

This work is supported by the US Food and Drug Administration (FDA) under contract number 75F40122C00122.