Manufacturing complex biopharmaceuticals with higher efficiency and simultaneously reducing costs sets pressure on downstream processing and encourages the development of novel techniques. Membrane chromatography, a relatively new technique, holds excellent potential in the purification of proteins. Its primary purpose of being operated at very high flow rates has been combined with functionality that rivals particle-based materials in efficiency and flexibility. Usually operated in flowthrough mode, the applications of membrane chromatography in industrial processes range from the removal of contaminants like DNA and HCPs to the purification of large biomolecules like viruses, VLPs, and protein complexes. This study aims to demonstrate the usability of cation-exchange membrane chromatography in a bind and elute mode. As an example, a high-resolution separation of monoclonal antibody charge variants was used. After calibration of a mechanistic membrane chromatography model, an in-silico simulation strategy was applied to optimize the separation of mAb charge variants. Additional data from high loading studies (up to 35 mg/mLMV) was included to enable simulations at far higher loadings. Membrane volume and flow rates were successfully scaled up from 0.87 ml to 10 ml membrane volume and from 10 mL/min to 240 mL/min, respectively. For a cost-effective approach, in silico simulations were used to improve and optimize the separation of charge variants using a combination of flowthrough and step elution. At similar conditions, the novel membrane prototype has a DBC10% of 90 mg/mL, comparable to its resin-based counterpart. The resolutions achieved using the membrane devices are close to those obtained through column chromatography. However, much higher flow rates are possible using the latter. The flow rate's influence is significantly different from that of column chromatography, indicating distinctive mass transfer behaviors.

Mechanistic modelling-based optimization and scale-up of ion-exchange membrane chromatography

ACS Fall 2021

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