Integrated Continuous USP Platform for Maximum Productivity and Closed-Loop Controlled CQA

Development of a entirely closed cell culture perfusion system that (1) reduces media consumption, (2) provides higher cell & biologic yields, and (3) automates control methods of productivity and Critical Quality Attributes.

Industry Need

Biotherapeutic manufacturing has been improved significantly in terms of productivity and controllability of Critical Quality Attributes (CQA), but fully controllable, scalable, and intensified biomanufacturing is still a distance target.

Perfusion-based continuous manufacturing has been demonstrated as a new platform but still poses a few challenges:
Excessive usage of media
Lack of fully automated control methods for CQA and productivity
Suboptimal scale-up and operation
Because of these challenges, perfusion-based production has been limitedly applied, and mostly in N-1 bioreactors with VCD as a controlled variable.
Perfusion cell-culture has been explored for decades, but its potential has been unrealized due to issues with practical implementation and cost.

Approach

The team is developing and validating a mammalian cell culture system with an integrated continuous USP platform for maximum productivity and closed-loop control of CQA. The new intensified biomanufacturing platform will deliver:

Scalable perfusion-based continuous production
Optimal media usage through economically optimized perfusion operation
Automated control methods of productivity and CQA during specific stages of continuous operation

Impacts

The development of a closed design cell culture perfusion system will provide the industry with a fully controllable, scalable, and intensified solution that enables continuous biomanufacturing.

Create a prototype perfusion system for future cGMP implementation.

Demonstrate advanced control of productivity and CQA during specific stages of continuous operation.

Produce an economically-optimized perfusion operation in a production bioreactor.

Implement an intensified continuous biomanufacturing platform.

Value Statement/Outcomes

This project integrated a continuous upstream cell culture platform that increases productivity for drug companies, resulting in cost benefits across mammalian cell culture.

Outputs/Deliverables

Microfluidic cell retention device building

Integration of hardware and software system

Perfusion system with media recycle

Utilize EK filter for separating lactate and product while retaining most media components

Demonstration of CHO productivity and CQA control implementation

Publications

Lee, J., Song, S., Park, Do., Wynne, E., Rajendran, A., Han, J., Yoon, S., & Yamanaka, H., (2025), Continuous Nonoclonal Antibody Production Using Media Recycle in Perfusion, Biotechnology and Bioengineering

Wynne, E., Yoon, J., Park, D., Cui, M., Morris, C., Lee, J., Wang, Z., Yoon, S., & Han, J. (2024). Regeneration of Spent Culture Media for Sustainable and Continuous mAb Production via Ion Concentration Polarization. Biotechnology and Bioengineering. https://doi.org/10.1002/bit.28888

Posters

Lee, J., Yoon, S., Participant, Tuscon, AZ, ECI Cell Culture Engineering, April 27, 2025.

Park, D., Wynne, E., Lee, J., Bertalan, T., Han, J., Yoon, S., Wang, Z., Song, S., Yamanaka, H., & Rajendran, A., Integrated Continuous USP Platform for Maximum Productivity and Closed-loop Controlled CQA, NIIMBL National Meeting, Washington, DC, June 24, 2024.

Presentations

Lee, J., Yoon, S., Speakers, Bioprocess International Boston 2025, Boston, MA September 15, 2025.

Lee, J., Yoon, S., Speakers, Boston, MA American Institute of Chemical Engineering (AIChE) Annual Meeting, November 3, 2025

Lee, J., Yoon, S., Speakers, Integrated Continuous Bioprocessing VII, Croatia, October 6, 2025.

Park, D., Bevacqua, A., Lee, J., Wang, Z., Yoon, S., & Han, J., High-throughput microfluidic cell retention device for perfusion culture, 2023 Bioprocess International, Boston, MA, September 21, 2023.

Wynne, E., Park, D., Yoon, J., Cui, M., & Han, J., High-throughput Electrokinetic Filter for CHO media Regeneration, MicroTAS 2023, Katowice, Poland, November 14, 2023.

Yoon, S., Integrated USP Platform Process, NIIMBL National Meeting 2023, Washington, DC, June 26, 2023.