In this work, a digital twin model of end-to-end continuous pharmaceutical manufacturing of liquid dosage forms has been developed. The continuous manufacturing and purification of drug substance is achieved in module 1 while the full finish final liquid dosage forms are produced continuously in module 2.
In module 1, a digital twin for continuous APIs manufacturing process using modular components has been developed and its applications have been demonstrated for dynamic optimization and control system design. The process flowsheet model is the heart of 'digital twin' and consists of mathematical representation of three sub-modules with the options of adding more as needed. The first sub-module is for feeding and dispensing. It consists of a refill unit, feed tank, pump, mixing, and preheater. The second sub-module is for performing the chemical reactions required to produce the target APIs. This module consists of tubular reactors placed inside a heating and cooling jacket. The third sub-module is focused on separation of API from impurities. A continuous chromatographic model is currently used for separation purposes that can be easily replaced with any other type of separation techniques such as continuous crystallization. Currently, the developed model library of module 1 consists of 32 units across 10 types that has been used to generate the integrated flowsheet model. The model has been validated using experimental data.
In module 2, 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 sub-modules. In sub-module 2a, all ingredients are pre-conditioned and pumped at controlled mass flow rates to module 2b. The module 2b consist of a static mixer, a homogenizer, and an ultrafiltration unit operation. The ultrafiltration membrane is used for purification and sterilization. In module 2c, 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 for module 2 consists of the mathematical model of unit operations involved in sub-modules 2a-c. In module 2a, the continuous feeding system model including feed tanks model, refill system model, and pump model have been developed. In module 2b, the mathematical model of static mixer to predict the mixing of different ingredients, a homogenizer model to predict the agglomerate size reduction, and an ultrafiltration model to predict the different critical process parameters (CPPs) including retentate and permeate fluxes have been developed. In module 2c, 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.
Learning Objectives:
Upon completion, participant will be able to understand the advantages and complexities of advanced continuous pharmaceutical manufacturing processes.
Upon completion, participant will be able to understand and develop the process model and digital twin of continuous pharmaceutical end-to-end injectable manufacturing processes.
Upon completion, participant will be able to demonstrate the applications of digital twin for optimization.
Upon completion, participant will be able to demonstrate the applications of digital twin for the design/tuning of control system.
Upon completion, participant will be able to understand different modelling approaches used in cintinuous injectable manufatcuirng.