(496a) Modeling the Ultrafiltration Behavior of Highly Concentrated Monoclonal Antibodies

Monoclonal antibodies are used extensively in the treatment of diseases and sometimes need to be delivered at very high concentrations to achieve the desired therapeutic effect. This creates unique challenges in the development and implementation of ultrafiltration processes for the concentration and final formulation of these antibody products. The objective of this study was to develop a new theoretical framework for describing the filtrate flux during the ultrafiltration of highly concentrated protein solutions.

Experiments were performed with a highly purified monoclonal antibody provided by Amgen Inc.  Data were obtained for the protein osmotic pressure (using membrane osmometry), the second virial coefficient (using self-interaction chromatography), the solution viscosity (using a RFS-II viscometer), and the filtrate flux over a wide range of antibody concentrations.  The filtrate flux attained a pressure-independent value at high transmembrane pressures, consistent with the concentration polarization model.  However, plots of the filtrate flux versus the logarithm of the bulk protein concentration showed a distinct curvature, in contrast to predictions of the classical stagnant film model.  The complex behavior at very high protein concentrations is due to the corresponding increase in the protein osmotic pressure and solution viscosity.

The filtrate flux data were analyzed using a theoretical framework that accounts for the effects of intermolecular interactions and the enhanced solution viscosity on protein transport in the concentration polarization boundary layer.  Calculations were also performed to evaluate the effect of the increased axial pressure drop in the highly concentrated protein solutions on the local variation in the filtrate flux.  These results provide important insights into the factors controlling the ultrafiltration behavior of highly concentrated protein solutions encountered in bioprocessing applications.