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.