Mixed‐mode membrane chromatography: mechanistic‐modeling‐based optimization and scale‐up of antibody charge variant separation using a novel membrane adsorber

This project studies how to evaluate, model, and scale up mixed‑mode membrane chromatography for separating charge variants of monoclonal antibodies (mAbs). It uses a new mixed‑mode membrane adsorber, Natrix® CH, that combines ion‑exchange and hydrophobic‑interaction sites. The goal is to overcome the drawbacks of traditional resin‑based chromatography in downstream bioprocessing. A systematic approach compares the selectivity of the mixed‑mode membrane with that of standard ion‑exchange membranes. The mixed‑mode membrane shows better resolution and stronger retention, especially when the salt concentration is high. To fine‑tune the separation, a stoichiometric displacement model is calibrated with low‑loading linear‑gradient elution experiments. In parallel, a steric mass‑action (SMA) model is improved by reverse fitting data

from high‑loading runs (up to 35 mg of protein per mL of membrane volume) to capture the non‑linear adsorption behavior. Together, these models give a reliable predictive tool for process optimization and scale‑up, enabling high‑throughput purification of complex biopharmaceuticals. The work also provides detailed guidance on how to implement and validate mechanistic chromatography models, supporting academic research in advanced downstream bioprocess engineering.

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