1. Introduction
Virus filtration is widely used as a necessary virus removal step for biotherapeutics and protein drug products derived by plasma fractionation.[1] The multi-layered membranes of virus filters allow for separating viruses from proteins, despite the small size difference.[2] While virus removal from proteins is possible due to the sensitive separation membrane, larger sized proteins and aggregates in particular have been confirmed to cause clogging in virus filters.[3] To improve the capacity of the virus filtration step, processing the feed solution through one of several commercially available prefilters has been confirmed to be effective in removing substances that cause clogging and has been widely implemented.[4] Column chromatography has also been shown to effectively remove aggregates.[5]
Based on the differences and changes in filtration behavior of solutions with aggregates and following various upstream processing, the impact of protein solution characteristics on filtration capacity can be estimated. The theoretical relationship between filtration volume and filtration throughput for a given feed solution can be fitted to one of four established clogging models for filter membranes:[6] cake filtration, intermediate blocking filtration, standard blocking filtration and complete blocking filtration. Model analysis can inform process development, such as applying the maximum filtration volume (Vmax) that was theoretically determined using the standard blocking model based on filtrations conducted with a microfilter at constant pressure to facility scale-up recommendations.[7] Following this same strategy, the standard blocking model has been applied in nanofiltration to determine Vmax of virus filters under constant pressure suggesting that the standard blocking model is the appropriate model for filtration with a virus filter.[8] In more recent studies, there have been attempts to combine several clogging models into a theoretical equation that can be used not only to estimate Vmax but also to match complex filtration behavior results to theoretical values.[9]
In this report, we demonstrate the improvement in filterability that can be achieved by processing monoclonal antibody (mAb) and plasma IgG, each spiked with aggregates prepared from the respective solution, with various chromatography resins in flow through mode or through a prefilter. Using the filtration volume (throughput) and flow rate (flux) results obtained for constant pressure filtration with Planova BioEX filters, we determine the best fit clogging model and discuss the impact of solution characteristics on clogging behavior. These findings provide a framework for further application of clogging models in process development.