Optimization of Single-Column Batch and Multicolumn Continuous Protein A Chromatography and Performance Comparison Based on Mechanistic Model.

Expensive Protein A chromatography resins drive the need to maximize process productivity as well as resin capacity utilization. To this end, two strategies are explored. The first one is termed "super-batch," which utilizes a single short-bed-height column with rapid cycling to increase productivity, combined with variable load flow rates to enhance resin capacity utilization. The second one is multicolumn continuous chromatography, which utilizes multiple columns in the load zone to achieve high resin capacity utilization. The general rate model is used to simulate and optimize single-column super-batch and multicolumn continuous chromatography. Compared to conventional long-bed-height chromatography, both strategies yield productivity enhancements of 2.5-fold at 1, threefold at 5, and fourfold at 15 g L of feed titer. Using the mechanistic model, the performances of conventional batch, single-column super-batch, and multicolumn continuous Protein A chromatography are investigated at a 2000 L scale considering perfusion and fed-batch cell culture processes. Multicolumn continuous chromatography achieves resin capacity utilization >90%, 16% higher than that of the super-batch process for a 15 g L cell culture process, and it does not show any meaningful performance improvement compared to the single-column super-batch process in a low-titer perfusion cell culture process.