Effective clearance of large viruses:
The use of small retentive viral filters, also referred to as parvovirus
filters, are considered industry standard as a dedicated virus removal
unit operation. Removal of large viruses like murine retroviruses
(80-110 nm) by both large (35-50 nm) and small (~20 nm)
virus retentive filters has been shown to be highly robust and effective
(Lute, Brorson et al. 2005,
Lute, Riordan et al. 2008,
Chen 2014,
Lefkowitz, Dempsey et al. 2017). However,
for small virus retentive filtration, the pore size distribution can
pose a challenge for retaining parvoviruses with diameters of 20-30nm.
An FDA meta-analysis performed on the viral clearance data from
monoclonal antibody (mAb) regulatory submissions from 1990-2015
demonstrated robust and complete clearance for larger viruses in all 112
large virus retentive filter records and 469 out of 471 records related
to small virus retentive filters (Figure 1)
(Miesegaes, Lute et al. 2010,
Lute 2015). As noted in Figure 1, the two
instances of reported non-complete X-MuLV clearance values with small
virus retentive filters were determined to be study related.
Additionally, only very rare instances of retrovirus breakthrough of
small pore virus filters has been reported in the literature
(Chen 2014,
Stuckey, Strauss et al. 2014,
Stanley, Holmes et al. 2021), with no
clear explanation of whether the breakthrough was filter related or
study related. This highlights that during virus filtration studies,
care should be taken to avoid contaminating the filtrate samples which
are expected to contain little to no virus. A more recent multi-company
data review indicated parvovirus retentive filters provide effective
(i.e. >4 log10) or below detection limit
removal of a range of viruses beyond retroviruses
(Stanley, Holmes et al. 2021),
reinforcing the consensus that small virus filters provide robust
retrovirus clearance (Mattila, Clark et
al. 2016).
These studies provide a strong rationale for performing viral filtration
validation studies with small viruses, such as parvoviruses. The
parvovirus data could then represent worst-case to establish retention
claims for larger viruses, such as retroviruses, in regulatory
submissions (Mattila, Clark et al. 2016)
(Gefroh, Dehghani et al. 2014,
Stuckey, Strauss et al. 2014).