Application of flowsheet modeling for scheduling and debottlenecking analysis to support the development and scale-up of a plasma-derived therapeutic protein purification process

Abstract

Plasma fractionation stands as a pivotal process for the production of therapeutic and diagnostic proteins, such as albumin and immunoglobulin G. Besides these two primary proteins in human plasma, numerous other proteins can be purified for therapeutic purposes. To support process development, a flowsheet modeling-based approach is utilized to improve production efficiency and productivity while minimizing the resource investments. The flowsheet model is first built to represent the baseline drug substance production process at pilot-scale, with operating parameters extrapolated from lab-scale experiments conducted at CSL Behring. To improve operational efficiency and save costs, throughput analysis is applied to enhance the batch throughput through new process design, scheduling, and bottleneck identification. Through implementing the strategies, the batch throughput could be increased by 47.2 % by introducing one additional operator and one buffer preparation tank into the process. Furthermore, after applying a new strategy involving multiple extractions of the initial material (paste), the batch throughput was doubled, with operating cost of goods reduced by 36.1 %. To assess the performance of the modified design and validate the model results, the pilot-scale experiments with two extractions were performed by CSL Behring and compared with model predictions, resulting in good agreement. This work demonstrates the potential of flowsheet modeling in facilitating process development from lab-scale to pilot-scale, fostering cost-effective and efficient production with limited resource investment.