In a recent article, a U.K. group outlined their vision for downstream process analytic technology (PAT) and quality by design (QbD) within the context of batch vs. continuous chromatography. The authors, who discussed this topic with GEN, note that “limitations of conventional industrial fractionation control strategies using in-line UV and on-line HPLC” are slowing adoption of PAT in continuous purification, and as a consequence holding back continuous chromatography itself.
The study authors, Stephen Goldrick, PhD, Alexander Armstrong, PhD, and Kieran Horry, PhD, of University College, London, first discuss the limitations of conventional fractionation control for in-line UV and on-line HPLC monitoring. They then follow up novel monitoring and control methods that show promise in both process development and manufacturing. These new strategies combine rapid, in-line data capture from NIR, MALS, and UV with enhanced process understanding garnered through mechanistic and empirical modeling.
The issue here is the inherent complexity of continuous processing.
“Continuous chromatography control systems are more advanced due to the added operational complexity resulting from the use of multiple chromatography columns,” Armstrong explains. “These control systems require an additional column switching controller to maximize binding capacity and optimize column switch times.”
Unsurprisingly, while process analytic technologies (e.g., UV and HPLC) are interchangeable between batch and continuous processing, their successful deployments are much more advanced for batch processing.
“The control of batch processes is better understood and characterized and is the most common mode of operation,” Goldrick tells GEN. “And continuous processing offers the potential of higher yields and better economics, but we need to build more confidence in its benefits before industry fully adopts this mode of operation.”
Entry of advanced PAT into continuous processing might depend on identifying unit operations or processes that are accessible to this type of approach, or which are in the greatest need. Horry and Goldrick cite downstream unit operations such as membrane filtration and chromatography, “as these are less complex than upstream unit operations and also have fewer variables to control.”
But the most critical unmet need for control, for both upstream and downstream operations, is a lack of robust real-time process monitoring systems to inform the control unit, according to the scientists. “Great progress is being made here, especially for chromatography, as we highlighted in the paper,” Horry says. “Greater accessibility to chromatography mechanistic modeling software for industry, and the recent applications of multivariate data analysis to spectroscopy in academia, are showing real promise for advanced control.”
Bottom line question: Will advances in monitoring and controls change the current proportion of batch vs. continuous biomanufacturing processes? In other words, will advanced technologies make a difference?
Horry and Goldrick think so. “For chromatography systems, we believe that advances in process monitoring and control will further promote the transition from batch to continuous biologics manufacturing. Advanced process modeling can simplify the process design and development of the more complex continuous control systems, and real-time monitoring of the process will better inform column switching and pooling controls.”