High concentration tangential flow ultrafiltration of stable monoclonal antibody solutions with low viscosities

During production of concentrated monoclonal antibody formulations by tangential flow ultrafiltration (TFF), high viscosities and aggregation often cause extensive membrane fouling, flux decay and low product yields. To address these challenges, the co-solutes histidine or imidazole were added at high concentrations from 250 to 320mM to reduce the viscosity by up to ten-fold relative to conventional low co-solute formulations, to as low as 40cP at 250mg/mL. At high mAb concentrations of up to 280mg/mL, the transmembrane flux was increased threefold by adding high concentrations of co-solutes that also lowered the viscosity. Furthermore, the co-solutes also increased the mAb gel point concentration cg by up to 100mg/mL mAb and thus enhanced concentration polarization-driven back-diffusion of the mAb at the membrane wall, which led to increased fluxes. The low viscosity and hollow fiber filter modules with straight flow paths enabled more uniform TMP and wall shear stress τw profiles, which mitigated the reversible flux decay that results from an axial decline in the local TMP. The concentrated mAb was stable by SEC before and after extended storage at 4°C and 37°C. [Display omitted] •300mM histidine/imidazole caused up to 10x viscosity reduction at 250mg/mL mAb.•300mM histidine/imidazole with trehalose increased cg by up to 100mg/mL mAb.•Low viscosity minimizes total permeation resistance at high mAb concentration.•High co-solute flux was 3x higher than the low co-solute flux at 250mg/mL mAb.•Hollow fiber geometry and low viscosity minimized axial variation in local TMP.