Control of surge tanks for continuous manufacturing of monoclonal antibodies

Abstract

Surge tanks are critical but often overlooked enablers of continuous bioprocessing. They provide multiple benefits including dampening of concentration gradients and allowing process resumption efforts in case of equipment failure or unexpected deviations, which can occur during a continuous campaign of weeks or months. They are also useful in enabling steady‐state operation across a continuous train by facilitating mass balance between unit operations such as chromatography which have periodic loading and elution cycles. In this paper, we propose a design of a system of surge tanks for a monoclonal antibody (mAb) production process consisting of cell culture, clarification, capture chromatography, viral inactivation, polishing chromatography, and single‐pass ultrafiltration and diafiltration. A Python controller has been developed for robust control of the continuous train. The controller has four layers, namely data acquisition, process scheduling, deviation handling, and real‐time execution. A set of general guidelines for surge tank placement and sizing have been proposed together with process control strategies based on the design space of the individual unit operations, failure modes analysis of the different equipment, and expected variability in the process feed streams for both fed‐batch and perfusion bioreactors. The control system has been successfully demonstrated for several continuous runs of up to 36 h in duration and is able to leverage surge tanks for robust control of the continuous train in the face of product variability as well as process errors while maintaining critical quality attributes. The proposed set of strategies for surge tank control are adaptable to most continuous processing setups for mAbs, and together form the first framework that can fully realize the benefits of surge tanks in continuous bioprocessing.

Process design of a fully integrated continuous biopharmaceutical process using economic and ecological impact assessment

“…It should be noted that there are multiple surge tanks in the end‐to‐end integrated continuous process diagram, which are located before and after the multicolumn continuous chromatography operations to eliminate the cyclic discontinuity. The introduction of surge vessels adds safety, flexibility, and robustness to a fully continuous biomanufacturing line by providing a temporal buffer (Rathore et al, 2021; Thakur et al, 2021).…”

“…The structural similarities between different mAbs make this platform widely accepted and regarded as an industry benchmark. Thus, this platform is adopted in this study to construct the continuous process and the corresponding process line by providing a temporal buffer (Rathore et al, 2021;Thakur et al, 2021).…”

Converting a mAb downstream process from batch to continuous using process modeling and process analytical technology

“…Surge tanks were used in the continuous downstream process by many researchers to overcome operating constraints or mitigate risks. [ 43 ] As shown in Figure 1, each process step was connected through surge tanks. Although removing surge tanks can simplify the process, surge tanks can serve different purposes.…”

Recent advances in integrated process analytical techniques, modeling, and control strategies to enable continuous biomanufacturing of monoclonal antibodies

“…To tackle this issue, surge tanks can be introduced, where the ATF filtrate can be kept on hold for a limited time; however, the impact of surge tank hold time on product quality is needed to support such operations. 12 Another hurdle is the limited process optimization for continuous perfusion operations due to time and resource constraints. 16 To this end, there is a critical need for the development of scale-down equipment 17 and associated process models to better enable exploration of the design space of perfusion technology and to enable more efficient integration with downstream steps.…”

“…Based on both upstream and downstream operations, in silico integrated process models that capture each unit operation can be built 118, 119 . The size and locations of surge tanks can also be designed by coupling mechanistic models with control systems that are critical to dealing with equipment failures and unexpected deviations during continuous operations 12 . However, due to the high computational costs of mechanistic models, which can cause difficulty with process analysis and optimization, the final integrated process models are usually simplified by using empirical equations, 118 hybrid models, and regression models or developed based on process simulators that use inbuilt input–output relations 120–126 .…”