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%.