Human plasma provides a rich source of therapeutic medicines, including gamma globulins, coagulation factors, albumin, alpha anti-trypsin, and others. In 2001, sales of immuno gamma-globulin (IgG) were estimated at $2 billion with a production rate of 50 metric tons for the year.1 A number of new therapeutic products have recently been introduced including Gammimune from Bayer, RhoPhylac from ZLB Behring, and Octagam from Octapharma. Hyperimmunes (IgGs with high levels of antibodies targeted at a specific antigen such as a virus) are also under development for biodefense applications such as anthrax or smallpox. These can find usefulness as either therapeutics or preventative measures.
In the past, contamination of source plasma by enveloped viruses (HIV, HCV) has led to the contamination of plasma products and patient infection.2,3 In response, the industry adopted a multi-layered virus safety strategy that includes source plasma control (donor screening, plasma testing), product manufacturing (plasma pooling, clearance steps in plasma product manufacturing, cGMP), product testing, and pharmacovigilence (patient monitoring, recalls). The enveloped virus problem has been addressed by the adoption of virus clearance technologies such as solvent detergent, heat, low pH, caprylate, chromatography, and large virus filtration. Regulatory authorities have issued regulations describing requirements for marketing approval.4,5
Current plasma product safety concerns are focused on the smaller non-enveloped viruses (HAV, B9) and new agents (TSE, WNV, SARS). These small, non-enveloped viruses can be more difficult to inactivate or remove.6 The solvent detergent method, which is effective in preventing enveloped virus replication (through dissolution of their lipid envelope coating), is ineffective at inactivating non-enveloped viruses. The severe treatment conditions required for some non-enveloped virus inactivation (for example, 100B°C for PPV) can lead to significant product losses and potential formation of neo-antigens.
VIRUS FILTRATION SOLVES PROBLEMS
Virus filtration is a useful clearance method for non-enveloped viruses.7 Filters are inert and do not degrade the product or add any foreign substances requiring removal. They are also capable of providing high product yield, can be validated using scaledown models and in-process integrity tests, and can be conveniently integrated into manufacturing processes.
Figure 1. Magnified Image of Viresolve NFP Membrane
Virus filtration is a well-established unit operation in biopharmaceutical processes and has been implemented in a number of approved products dating back to the mid 1990s. Mononine, a Factor IX product developed by Armour Pharmaceutical Company, was approved in 1992 using an ultrafiltration process for viral reduction.8
The Millipore Viresolve NFP is a normal-flow parvovirus-removal filter with a patented membrane structure for strength and high flow. The NFP filter contains three layers of a highly asymmetric membrane as shown in Figure 1. The filter retains ≥4 logarithmic reduction value (LRV) of 20 nm diameter parvoviridae with high flows (75-150 L/m2/h at differential pressure of 30 psi [2.1 bar]) and high capacities (100-200 L per 0.5 m2 area filter). Features of the filter are listed in Table 1.
Table 1: Features of Viresolve NFP Filter