Demonstration of an end-to-end integrated and continuous bench-scale mAb production process

Much of the biologics industry’s future lies with integrated and continuous manufacturing (CM). Continuous processes can offer higher throughputs, tighter process control, and reduced material usage, all in a smaller plant footprint. While CM offers unique challenges to various biologic modalities, there are several difficulties that are relevant across the industry. Within unit operations, there is the question of conversion from batch to continuous. This necessitates device sizing, which can be challenging given an industry filled with products foremost designed for batch processing. With CM, the reaction time for a given process shortens dramatically. Hence, changes to the process monitoring and control strategies are vital for success. Additionally, the testing needed to describe process dynamics will necessarily be unique to CM.
In this work, we executed a fully continuous process using a 15L perfusion production integrated with multicolumn capture chromatography, in-line viral inactivation, flow-through polishing and continuous diafiltration and single-pass tangential flow filtration. We maintained steady-state operation for three full days. We explored challenges in the areas of unit operation connectivity and the necessary surge vessel control strategy. Hotswaps were performed on the bioburden reducing filtration units. A steady process was preserved by adjusting the train’s operating parameters to account for natural changes in mass flow. We also deployed a novel digital monitoring strategy. Finally, any other pain points resultant from the continuous process were investigated.
Over five days of operation, including three contiguous days at steady-state, more than 75 gAb in bulk drug substance were produced at concentrations greater than 170 g/L. Targets for product quality (less than 1% HMW) and removal of process related impurities (below LOQ of 3 ng/mL for residual HCP) were achieved. Overall, the demonstration was highly informative as to where efforts should be directed in the areas of process development and control/monitoring strategies.