Development of a new 10% liquid, triple virus reduced intravenous immune globulin product, new generation IGIV

Abstract

Rationale While immune globulin products after introduction of dedicated virus inactivation steps have an excellent safety record, patient concerns around transmission of particularly viruses still exist, and are fueled by newly emerging viruses. Methods To address these concerns, the manufacturing process of this new liquid IGIV contains three dedicated virus reduction steps: (1) a three component solvent-detergent (SD) treatment, (2) a 35 N nanofiltration step, and (3) a prolonged incubation period at low pH and elevated temperature. Results (1) SD treatment resulted in complete inactivation of all the lipid-enveloped viruses tested, already after only 1 minute of the 60 minutes treatment, and also at drastically reduced concentrations of the SD reagents. (2) Nanofiltration effectively removed lipid-enveloped viruses. Also, HAV and parvovirus B19, viruses which are smaller than the nominal pore size of the filter used, were reproducibly and robustly removed by antibody-enhanced nanofiltration which occurred at a wide range of HAV and B19 antibody concentrations. (3) Incubation at low pH and elevated temperature effectively inactivated lipid-enveloped viruses, and resulted in significant levels of inactivation for non-lipid enveloped viruses, including parvoviruses. Inactivation was shown to depend on a combination of low pH and elevated temperature. Conclusions The incorporation of three dedicated and mechanistically different virus reduction steps for this new liquid immunoglobulin product results in unprecedented safety margins.