(342f) Improved Monoclonal Antibody Ultrafiltration Process Development and Optimization Based On the Determination of Concentration Dependent Biophysical Solution Properties

Ultrafiltration (UF) is the preferred process-scale method to concentrate and formulate therapeutic monoclonal antibodies. The increased use of high concentration formulations required for its sub-cutaneous delivery has resulted in new challenges to the development of UF processes. Very high protein concentrations at the membrane surface due to polarization effects limit the maximum achievable process flux and protein concentration. Optimization of mass transfer coefficients as influenced by buffer conditions is thus important for a high-concentration UF step. A common approach to UF process development and diafiltration buffer screening is to determine mass transfer coefficients from flux excursions, which allows determination of process time, buffer consumption and maximum achievable concentration. This methodology is not only time and feedstock consuming for screening of a large set of buffer conditions but also limited in the prediction of maximum achievable concentrations. We have developed an improved methodology for optimization of UF buffer conditions based on the determination of diffusion coefficients, osmotic pressures and solution viscosities as a function of monoclonal antibody concentration. Using a model accounting for the variation in these solution biophysical properties with concentration, has enabled a framework to more accurately predict flux, process time, buffer consumption and better estimate the maximum achievable protein concentration.