Viral Clearance Strategy Using a Three-Tier Orthogonal Technology Platform - How to implement a risk-based approach to eliminate viruses using orthogonal technologies. - BioPharm International

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Viral Clearance Strategy Using a Three-Tier Orthogonal Technology Platform
How to implement a risk-based approach to eliminate viruses using orthogonal technologies.


BioPharm International


VIRAL CLEARANCE CAPABILITIES OF MEMBRANE CHROMATOGRAPHY

Chromatography and filtration, on the other hand, are widely accepted methods for virus adsorption and removal respectively and act as orthogonal techniques in the viral-clearance platform. Membrane chromatography, a relatively newer technique gaining prominence in biomanufacturing, has proven to be efficient in removing small nonenveloped viruses.16 Ion-exchange membrane adsorbers, with ligand–virus-binding properties similar to those of anion-exchange (AEX) chromatography, have the disposable option as an added advantage. This not only reduces capital costs but also eliminates post-use cleaning, sterilization, validation, and risk of carry-over contamination, thereby simplifying adsorptive virus clearance.17,18


Table 1a. Process capacity and virus adsorption capability of Sartobind Q membrane adsorber16
Efficient clearance data between 4.41 log10 and 6.67 log10 for MVM has been determined for membrane chromatography.19 Additional studies have demonstrated that membrane chromatography meets and exceeds viral-clearance performance of Q resin chromatography.20 Clearance capabilities of Sartobind Q for nonenveloped viruses have been shown to be between 3.56 log10 for MVM and more than 6.92 log10 for PPV.21 It has been demonstrated that the platform tested membrane chromatography, has a process capacity greater than 3,000 g MAb/m2 or 10.7 kg MAb/L with a LRV >5 for four model viruses.17 Mass balance in viral-clearance study is another important parameter to demonstrate efficient virus removal by membrane adsorbers. A 100% recovery was demonstrated for PRV, Reo-3, and MVM, when the membrane was stripped with 1-M NaCl, illustrating efficient charge capture for the three model viruses while high salt treatment of the membrane showed 70% recovery for MuLV.16 The virus-clearance capability of such technology has been presented in Tables 1a and 1b.


Table 1b. Lower-range values (LRV) of different viruses demonstrating mass balance upon adsorption on Sartobind Q17

NANOFILTRATION


Table 2a. Virus retention capacity of Virosart CPV as demonstrated by TCID50 assay26
A second orthogonal technique in the virus-clearance platform is nanofiltration that has traditionally been accepted as a robust method for virus clearance.22 This is the most expensive downstream step, accounting for up to 40% of costs, and is the natural target for optimization.1 Initially, virus removal by filtration was found to be highly dependent on size of the virus, and less dependent on parameters like buffer composition, process time, protein type, and pressure.23 Earlier studies have shown the principal feasibility of PP7, a small nonenveloped 25 nm bacteriophage, to act as a model virus for small, nonenveloped viruses.24 The ability of commonly available nanofilters to retain bacteriophage has been clearly demonstrated in recent studies.25 Virus spiking trials using 20-nm retentive virus removal filters have also shown to clear both large and small viruses (Tables 2a and 2b).26,27


Table 2b. Virus retention capacity of Virosart CPV as demonstrated by Plaque assay27

EVALUATING A VIRUS FILTER


Figure 1
The evaluation of a virus filter should not be limited only to its capacity. An ideal virus filter should retain all viruses and allow high protein transmission while maintaining a high flow rate without significant virus breakthrough. Unexpected virus passage during a virus-clearance step is undesirable from a good manufacturing practice (GMP) and validation standpoint.28–30 Virus passage through the filter could occur for many reasons, including accumulation of aggregates, high spike concentrations, and other impurities that may block the filter or result in a breakthrough.31 This is a serious safety concern that must be minimized. Although contaminants and other various parameters may be the main cause of filter breakdown, some nanofilters still efficiently remove viruses at high LRVs even when experiencing high flow decay. Earlier, detailed analysis of the retention characteristics of PP7 by a PESU-based 20-nm nanofilter underlined the principal capability of nanofiltration to act as a robust and effective virus removal step independent of flow decay or the nature of product being filtered (Figure 1).31 Additionally, a recent report outlined the various titer reduction capabilities of virus retentive nanofilters.32 The study showed that not all filters tested for their LRVs versus flow decay profile experienced a significant loss of titer reduction with increasing flow decay. To ensure the highest level of viral safety of biopharmaceuticals, it is important to understand and predict the efficiency of virus removal steps while also realizing that small virus-retentive filters should not be viewed as absolute in their capacity to clear viruses.


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