Achieving end-to-end continuous bioprocessing without introducing surges and pooling remains a goal for biomanufacturers. As they transition from vat to hybrid or continuous processing, biomanufacturers optimize individual steps but often overlook their interfaces, creating an imbalance in the system.
“The primary barrier to end-to-end continuous biomanufacturing is often not the lack of continuous unit operations themselves. The larger challenge is integrating technologies such as perfusion culture, multicolumn chromatography, continuous viral inactivation, and continuous filtration into a coordinated manufacturing train,” Moo Sun Hong, PhD, assistant professor, Seoul National University, tells GEN.
“Our review suggests that unresolved interface mismatches between unit operations, particularly between steady upstream harvest and cyclic downstream purification, remain the dominant obstacle to achieving true end-to-end continuity,” Hong says. Interface engineering is vital to manage throughput, residence times, process robustness, and product quality across interconnected units.
One part of the study compared batch and continuous biopharmaceutical manufacturing across 10 metrics, while another considered the various degrees of continuous processing. They concluded that the advantages of continuous processing result mainly from process intensification, which, in itself, introduces new vulnerabilities such as measurement latency and uncertainty around residence time distribution.
The challenge for manufacturers is that limited coordination between upstream and downstream processing results in flow-rate mismatches. “Unit operations operate with fundamentally different dynamics,” Hong acknowledges. “Upstream perfusion generates a relatively steady harvest stream, whereas many downstream operations operate cyclically. This creates flow-rate and residence-time mismatches that often require surge tanks or hold steps. Eliminating these interruptions requires careful interface engineering, synchronization of cycle times, real-time monitoring, and coordinated control across the entire process train.”
Take a systems approach
Hong and colleagues recommend evaluating batch-to-continuous processing transitions based upon “integrated techno-economic, sustainability, and operational performance metrics rather than isolated unit-operation productivity alone.” Therefore, process engineers can design the interfaces and control strategies in a way that enables a fully-connected, automated, continuous manufacturing platform that functions in a near steady-state without the need for holding tanks between units.
In a continuous processing environment, control strategies based on process analytical technology (PAT) and digital twin technology are vital. Hong calls them “the backbone of integrated continuous manufacturing.”
Specifically, PAT provides visibility and real-time monitoring for rapid responses to process variances, while digital twins provide enhanced predictive models, as well as fault detection, optimization, and analysis. Additional automation and control architectures also should be included “…that connect sensors and programmable logic controller/supervisory control and data acquisition (PLC/SCADA) systems, as well as process data repositories, control loops, and supervisory models across the integrated process train,” the scientists advise.
“In our view,” Hong concludes, “the challenge is not simply making individual operations continuous, but making the entire manufacturing platform function as an integrated system.”
