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


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

BioPharm International Supplements

Methods for Viral Inactivation and Clearance

The robust and reliable capability to eliminate viruses must be demonstrated by a risk-based approach.10 Today's requirements demand a statistically independent combination of methods (orthogonal technologies) for removing enveloped and nonenveloped viruses based on the different physical principles of removal and inactivation, and yet are complementary to each other.11–12

Several methods can be used for virus clearance in bioprocessing. These include inactivation methods such as solvent and detergent (SD) or chemical treatments, low pH, microwave heating, adsorption by chromatography, and removal by mechanical or molecular sieving using normal and tangential-flow filtration methods. The first three of these, treatments with solvents and detergents, low pH, or microwave heating, all have significant limitations in their ability to inactivate small nonenveloped viruses. SD treatments were commonly used for plasma proteins and were considered the gold standard for inactivating enveloped viruses.13 It has been shown that SD treatments of a recombinant protein can completely and rapidly inactivate enveloped viruses like PI-3, XMuLV, IBR, and MCF.14 However, small nonenveloped viruses are not being eliminated substantially by this virus-clearance technology. Low pH inactivation of murine retroviruses is reported to be highly dependent on time, temperature, pH, and relatively independent of the recombinant protein type or conductivity conditions outlined.15 Heating is not considered one of the most reliable methods for virus inactivation because of the variation in stability of each viral genome to heat or temperature.

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

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.

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