A new liquid intravenous immunoglobulin with three dedicated virus reduction steps: virus and prion reduction capacity.
OBJECTIVE
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.


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 (> or = 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.
Poelsler
G
G
Global Pathogen Safety.
Berting
A
A
Global Pathogen Safety.
Kindermann
J
J
Global Pathogen Safety.
Spruth
M
M
Global Pathogen Safety.
Hämmerle
T
T
Operations Central Europe.
Teschner
W
W
and Pre-clinical R&D, Baxter Bioscience, Vienna, Austria.
Schwarz
H P
HP
and Pre-clinical R&D, Baxter Bioscience, Vienna, Austria.
Kreil
T R
TR
Global Pathogen Safety.
D003588:Cytopathogenic Effect, Viral; D003902:Detergents; D004340:Drug Contamination / Q000517:prevention & control; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016756:Immunoglobulins, Intravenous / Q000302:isolation & purification*; D008851:Micropore Filters; D016133:Polymerase Chain Reaction; D011328:Prions / Q000302:isolation & purification*; D012449:Safety; D012997:Solvents; D013696:Temperature; D014462:Ultrafiltration; D038301:Virus Inactivation; D014780:Viruses / Q000235:genetics / Q000302:isolation & purification*
D003902:Detergents; D016756:Immunoglobulins, Intravenous; D011328:Prions; D012997:Solvents