This study introduces an improved approach for determining the most suitable mobile phase maximizing repulsion between biomass and adsorbent to reduce biomass fouling in expanded bed adsorption (EBA) chromatography. Extended DLVO theory (xDLVO) has been utilized to comprehensively calculate optimal mobile phase compositions, thus increasing efficiency, improving hydrodynamics as well as product recovery. Biomass-adsorbent interaction energy surfaces were generated as a function of pH, ionic strength, and salt type, investigating the interactions of CHO cells with MabDirect (R) Protein-A beads. We have shown that mobile phases consisting of Na2SO4 were best suited at low ionic strength, whereas NaCl was more favorable at higher ionic strength. This was found to increase product recovery while maintaining a constant level of purity of monoclonal antibodies. Our method provides a tool for rapid method development of EBA purifications that can be dynamically adapted to operational requirements. In our case, the resulting optimized process was able to outperform the current protocol by up to 10% in terms of product recovery. (C) 2017 Elsevier B.V. All rights reserved.