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Recently, continuous downstream processing has become a topic of discussion and analysis at conferences while no industrial applications of continuous downstream processing for biopharmaceutical manufacturing have been reported. There is significant potential to increase the productivity of a Protein A capture step by converting the operation to simulated moving bed (SMB) mode. In this mode, shorter columns are operated at higher process flow and corresponding short residence times. The ability to significantly shorten the product residence time during loading without appreciable capacity loss can dramatically increase productivity of the capture step and consequently reduce the amount of Protein A resin required in the process. Previous studies have not considered the physical limitations of how short columns can be packed and the flow rate limitations due to pressure drop of stacked columns. In this study, we are evaluating the process behavior of a continuous Protein A capture column cycling operation under the known pressure drop constraints of a compressible media. The results are compared to the same resin operated under traditional batch operating conditions. We analyze the optimum system design point for a range of feed concentrations, bed heights, and load residence times and determine achievable productivity for any feed concentration and any column bed height. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:938-948, 2016.

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The behavior of ion-exchange chromatography is well understood with respect to changes in ionic strength, pH, resin ligand density, bed height, elution flow rate, and gradient slope. Their relative importance for any specific chromatographic situation varies. When a chromatographic operation utilized to purify a human therapeutic protein is prepared for validation before commercial production, numerous tests have to be performed to establish the relative importance of each operating parameter to define its future role and importance in the framework of in-process controls. This prioritization process is usually performed using a purely empirical approach. In this work, we demonstrate the application of a rational approach based on chromatographic theory to prioritize operating parameters. Both methodologies, empirical and rational, were performed to evaluate a specific ion-exchange chromatography operation for the preparative separation of closely related protein species. We show that the application of the rational approach has the potential to accelerate the evaluation and significantly reduce the amount of analytical testing needed.

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