(682f) Challenges of UF Optimization for High Concentration Therapeutic Proteins

High concentration monoclonal antibodies (mabs) are being increasingly used in therapeutic products for injection. Product concentrations greater than 100mg/ml often result in higher viscosity solutions and pose a challenge to the ultrafiltration process. The recovery and stability of the molecule becomes challenging at high concentrations due to several reasons; most importantly viscosity increase and absorption onto the membrane. An optimized and well designed ultrafiltration/diafiltration (UF/DF) process is warranted for these processes, which can yield greater than ninety five percent recovery.

In this study UF/DF process was optimized for two mabs at concentrations between 100 to 200g/L. Several process parameters were studied which includes different membrane types, feed flow rate, transmembrane pressure, control of retentate vs. permeate flow and shear effect by different pumps. The stability of the product was monitored using various analytical tools including Size exclusion chromatography, DLS and DSC. Critical observations from this study include (a) at concentrations higher than 100mg/mL the stability of the molecule was highly molecule specific compared to processing impact (b)The viscosity of the solution impacted flux rate and  mass transfer coefficient however the bulk concentration and concentration at the membrane remained same (c) SEC was the best indicator for stability and DLS also provided a relative difference.