Cation Exchange Chromatography (CEX) is well-established and commonly used to remove aggregates in the manufacture of monoclonal antibodies and other biotherapeutics. CEX can be operated in two different modes: Bind/Elute (B/E) and Flow-Through (FT).  Compared to the conventional B/E mode, FT CEX confers process intensification advantages in large-scale manufacturing, including substantial process efficiency and simplification gains. Operation in FT mode also streamlines application as a polishing step within an integrated and semi-continuous chromatography platform.<br/> <br/>In this work, a generalized process development approach and case study for FT CEX step design and optimization will be presented. Firstly, a commercially available CEX resin with low ligand density was identified and initial frontal chromatography experiments were conducted to select flow-through operating conditions and ranges using an IgG1 protein as a model system. More specifically, breakthrough studies were performed to fully characterize step performance and aggregate selectivity. Secondly, an IgG4 protein that had exhibited severe on-column aggregation behaviour when processed in B/E mode was selected and evaluated following a similar methodology. In this case, on-column aggregation was fully avoided in flow-through mode, while achieving an increase in overall efficiency and selectivity for aggregate removal. Finally, process scalability and manufacturing equipment feasibility for proposed FT CEX conditions were evaluated.

Flow through cation exchange chromatography: A development framework and case study for process intensification

ACS Spring 2022

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