Continuous manufacturing of monoclonal antibodies: Dynamic control of multiple integrated polishing chromatography steps using BioSMB

We propose a strategy for automation and control of multi-step polishing chromatography in integrated continuous manufacturing of monoclonal antibodies. The strategy is demonstrated for a multi-step pol-ishing process consisting of cation exchange chromatography in bind-and-elute mode followed by mixed-mode chromatography in flowthrough mode. A BioSMB system with a customized Python control layer is used for automation and scheduling of both the chromatography steps. Further, the BioSMB valve mani-fold is leveraged for in-line conditioning between the two steps, as tight control of pH and conductivity is essential when operating with multimodal resins because even slight fluctuations in load conditions adversely affect the chromatography performance. The pH and conductivity of the load to the multi-modal chromatography columns is consistent, despite the elution gradient of the preceding cation ex-change chromatography step. Inputs from the BioSMB pH and conductivity sensors are used for real-time control of the 7 pumps and 240 valves to achieve in-line conditioning inside the BioSMB manifold in a fully automated manner. This is confirmed by showcasing different elution strategies in cation exchange chromatography, including linear gradient, step gradient and process deviations like tubing leakage. In all the above cases, the model was able to maintain the pH and conductivity of multimodal chromatography load within the range of 6 +/- 0.1 pH and 7 +/- 0.3 mS/cm conductivity. The strategy eliminates the need for using multiple BioSMB units or integrating external pumps, valves, mixers, surge tanks, or sensors between the two steps as is currently the standard approach, thus offering a simple and robust structure for integrating multiple polishing chromatography steps in continuous downstream monoclonal antibody purification trains.(c) 2023 Elsevier B.V. All rights reserved.

Automated summary

This article proposes a strategy for automating and controlling multi-step polishing chromatography in the continuous manufacturing of monoclonal antibodies. The strategy utilizes a BioSMB system with a customized Python control layer and leverages the BioSMB valve manifold for in-line conditioning. Real-time monitoring of pH and conductivity, along with control of pumps and valves, allows for automated in-line conditioning inside the BioSMB manifold. The strategy eliminates the need for multiple BioSMB units or external equipment, offering a simple and robust structure for integrating multiple polishing chromatography steps.