• blood-borne;
  • immunoglobulin;
  • pathogen;
  • prion;
  • TSE;
  • viral safety

Background and Objectives  A new 10% liquid human intravenous immunoglobulin (US trade name: Gammagard Liquid; European trade name: KIOVIG) manufactured by a process with three dedicated pathogen inactivation/removal steps (solvent/detergent treatment, 35-nm nanofiltration and low pH/elevated temperature incubation) was developed. The ability of the manufacturing process to inactivate/remove viruses and prions was investigated.

Materials and Methods  Virus and prion removal capacities were assessed with down-scale spiking experiments, validated for equivalence to the large-scale process.

Results  Lipid-enveloped viruses were completely inactivated/removed by each of the three dedicated virus clearance steps, and for human immunodeficiency virus 1 (HIV-1) and pseudorabies virus (PRV), also by the upstream cold ethanol fractionation step. Relevant non-enveloped viruses [i.e. hepatitis A virus (HAV) and parvovirus B19 (B19V)] were effectively removed by nanofiltration and the cold ethanol fractionation step, and partial inactivation of non-enveloped viruses was achieved by low pH incubation. Overall log reduction factors were > 20·0 for HIV-1, > 18·1 for bovine viral diarrhoea virus, > 16·3 for West Nile virus, > 10·0 for influenza A virus subtype H5N1, > 21·8 for PRV, 12·0 for HAV, > 12·1 for encephalomyocarditis virus, 10·6 for B19V and 10·3 for mice minute virus. Prions (Western blot assay) were completely removed (≥ 3·2 mean log reduction) by a step of the cold ethanol fractionation process.

Conclusions  Introducing three dedicated virus-clearance steps in the manufacturing process of immunoglobulins from human plasma provides high margins of safety.