An integrated continuous downstream process with real-time control: A case study with periodic countercurrent chromatography and continuous virus inactivation

Abstract

Integrated continuous downstream processes with process analytical technology offer a promising opportunity to reduce production costs and increase process flexibility and adaptability. In this case study, an integrated continuous process was used to purify a recombinant protein on laboratory scale in a two-system setup that can be used as a general downstream setup offering multi-product and multi-purpose manufacturing capabilities. The process consisted of continuous solvent/detergent virus inactivation followed by periodic countercurrent chromatography in the capture step, and a final chromatographic polishing step. A real-time controller was implemented to ensure stable operation by adapting the downstream process to external changes. A concentration disturbance was introduced to test the controller. After the disturbance was applied, the product output recovered within 6 hours, showing the effectiveness of the controller. In a comparison of the process with and without the controller, the product output per cycle increased by 27%, the resin utilization increased from 71.4% to 87.9%, and the specific buffer consumption was decreased by 21% with the controller, while maintaining a similar yield and purity as in the process without the disturbance. In addition, the integrated continuous process outperformed the batch process, increasing the productivity by 95% and the yield by 28%.

Integrated continuous biomanufacturing on pilot scale for acid‐sensitive monoclonal antibodies

“…As the figure shows the UV in relation to time, and not volume, the area under the peak from the UV2 signal is roughly half of that from the UV1 signal during this phase. The start and end of the pooling phases, from both columns, were automated using a pooling control strategy, which has been implemented in previous work (Löfgren et al, 2021). With this pooling control strategy, the pooling started at a predefined threshold UV value.…”

“…Orbit is not limited to one setup but can communicate with multiple systems and other additional equipment, such as the balance used to monitor the weight of the harvest tank. Examples of previous implementations of Orbit for real‐time control of multiple systems can be found elsewhere (Gomis‐Fons, Schwarz, et al, 2020; Löfgren et al, 2021). In a multi‐machine setup, each system is controlled by its own Orbit program, and they communicate with each other via handshaking.…”

An integrated and continuous downstream process for microbial virus‐like particle vaccine biomanufacture

“…The collected flowthrough from the previous Capto™ Q chromatography run, which was collected in a stirred vessel (50 ml bottle on ice, 50 rpm, 20 mm stirring bar), was used without any further adjustment for bind‐elute processing. To determine the design space, breakthrough curves at flowrates of 1 ml min −1 (1 min contact time), 0.5 ml min −1 (2 min contact time), and 0.25 ml min −1 (4 min contact time) were measured at a VP1‐J8 concentration of 0.71 mg ml −1 and the maximum possible overloading calculated, according to the area under the breakthrough curve method (Godawat et al, 2012; Löfgren et al, 2021). The maximum overloading can be defined as being when the integral of the breakthrough curve equals the dynamic binding capacity.…”