CNJ-016, Vaccinia Immune Globulin Intravenous (Human) (VIGIV (vaccinia immune globulin intravenous) ), is a solvent/detergent-treated sterile solution of purified gamma globulin (IgG) fraction of human plasma containing antibodies to vaccinia virus. It is stabilized with 10% maltose and 0.03% polysorbate 80 (pH is between 5.0 and 6.5) and contains no preservative. This agent is manufactured from plasma collected from healthy, screened donors with high titres of anti-vaccinia antibody (meeting minimum potency specifications) that is purified by an anion-exchange column chromatography method.1,2 The plasma donors were boosted with vaccinia vaccine prior to donating plasma used in the production of the product. Each plasma donation used for the manufacture of VIGIV (vaccinia immune globulin intravenous) is tested for the presence of hepatitis B virus (HBV) surface antigen (HBsAg) and antibodies to human immunodeficiency viruses (HIV) ?, and hepatitis C virus (HCV) using FDA-licensed serological tests. In addition mini-pool testing of plasma used in the manufacture of this product was tested by FDA licensed Nucleic Acid testing (NAT) for HIV-1 and HCV and found to be negative. An investigational NAT for HBV was also performed on all Source Plasma used, and found to be negative; however, the significance of a negative result has not been established.

Several steps in the manufacturing process have been validated for their ability to remove/inactivate viruses that may not have been detected in the Source Plasma. The manufacturing process includes both a Planova 35 N virus filtration step and a solvent/detergent treatment step (using tri-n-butyl phosphate and Triton X-100) that have been validated for their capacity to remove and/or inactivate lipid-enveloped and non-enveloped viruses.3 Table 1 summarizes the viral reduction values obtained through validation studies. The viruses employed for the spiking studies were selected to represent those viruses that are potential contaminants for the product, and to represent a wide range of physio-chemical properties, in order to challenge the manufacturing process's ability for viral clearance in general.

Table 1 Virus reduction values obtained through validation studies.

Virus Used for Validation HIV-1 BVDV PRV
Envelope Yes Yes Yes
Size 80-100 nm 50-70 nm 120-200 nm
35N Nanofiltration Step ? 6.0 4.4 to ? 6.41 ? 6.8
S/D Step ? 4.7 ? 6.6 ? 5.0
Total Reduction (log10) > 10.7 ? 11.0 ? 11.8
1 The lower value was used for calculation of the total reduction factor. The range obtained was for the validation of the process robustness.
HIV-1: relevant virus for human immunodeficiency virus-1 and model for HIV-2
BVDV: bovine viral diarrhea virus; model virus for hepatitis C virus (HCV) and West Nile virus (WNV)
PRV: pseudorabies virus; model for large enveloped DNA viruses, including herpes and hepatitis B virus

In addition to the validated reduction values for lipid-enveloped viruses, two steps were identified as contributing to the overall viral clearance capacity for small, non-lipid enveloped viruses: 1) The anion-exchange chromatographic step yielded a clearance of 3.4 log10 of murine minute virus (MMV), which is a model for parvovirus B-19, and a clearance of 2.3 log10 for the relevant virus, hepatitis A virus (HAV). 2) The nanofiltration step yielded a clearance of 4.25 log10 of poliovirus, a model for hepatitis A virus.

The 35N nanofiltration step is expected to remove the vaccinia virus, based on the size of the virus (200-450 nm long x 140-460 nm wide), and on the results obtained for BVDV (50-70 nm). However, no validation studies were performed for the 35N nanofiltration step specifically using vaccinia virus. Further clearance is obtained by the solvent and detergent step, which was validated for the inactivation, and resulted in a 3.7 log10 reduction of the vaccinia virus. In addition, the presence of anti-vaccinia antibodies in the product is also predicted to inactivate the vaccinia virus.3

The product potency (as determined by a plaque reduction neutralization test) is expressed in arbitrary units (U) by comparison to the FDA reference standard. Each vial contains approximately 40-70 mg/mL total protein and greater than 50,000 units of vaccinia antibody neutralizing activity. The product contains 40 ?g/mL of Immunoglobulin A (IgA).

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