Characterization of Thrombate III®, a pasteurized and nanofiltered therapeutic human antithrombin concentrate.
Thrombate III(®) is a highly purified antithrombin concentrate that has been used by clinicians worldwide for more than two decades for the treatment of hereditary antithrombin deficiency. The manufacturing process is based on heparin-affinity chromatography and pasteurization. To modernize the process and to further enhance the pathogen safety profile of the final product, despite the absence of infectious disease transmission, a nanofiltration step was added. The biochemical characterization and pathogen safety evaluation of Thrombate III(®) manufactured using the modernized process are presented. Bioanalytical data demonstrate that the incorporation of nanofiltration has no impact on the antithrombin content, potency, and purity of the product. Scaledown models of the manufacturing process were used to assess virus and prion clearance under manufacturing setpoint conditions. Additionally, robustness of virus clearance was evaluated at or slightly outside the manufacturing operating limits. The results demonstrate that pasteurization inactivated both enveloped and non-enveloped viruses. The addition of nanofiltration substantially increased clearance capacities for both enveloped and non-enveloped viruses by approximately 4-6 log10. In addition, the process achieves 6.0 log10 ID50 prion infectivity clearance. Thus, the introduction of nanofiltration increased the pathogen safety margin of the manufacturing process without impacting the key biochemical characteristics of the product.
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: kang.cai@grifols.com.
Kang
K
Cai
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: wendy.osheroff@grifols.com.
Wendy P
WP
Osheroff
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: greg.buczynski@grifols.com.
Greg
G
Buczynski
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: joann.hotta@grifols.com.
JoAnn
J
Hotta
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: john.lang@grifols.com.
John
J
Lang
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: eelliott@cbbiologics.com.
Eric
E
Elliott
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: doug.lee@grifols.com.
Douglas C
DC
Lee
Research and Development, Biologics Industrial Group, Grifols, Research Triangle Park, NC, USA. Electronic address: nathan.roth@cslbehring.com.
Nathan J
NJ
Roth
D000991:Antithrombins / Q000737:chemistry* / Q000302:isolation & purification; D005374:Filtration / Q000379:methods*; D006801:Humans; D036103:Nanotechnology; D061352:Pasteurization
D000991:Antithrombins
Antithrombin; Biochemical characterization; Nanofiltration; Pathogen safety