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

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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


Nanofiltration


Table2
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

Evaluating a Virus Filter


Figure 1. Log-reduction value (LRV) versus flow decay using monoclonal antibodies (MAbs) at 8 mg/mL in 20 mM Tris, 25 mM NaCl, at 7.2 pH, 2 bar, and upstream titer of 7.3 x 107/mL. All samples prefiltered through 0.1 mm membrane.31
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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