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Biotechnology and bioprocess engineering v.14 no.6, 2009년, pp.716 - 724   피인용횟수: 1

Removal and Inactivation of Viruses during the Manufacture of a High-purity Antihemophilic Factor IX from Human Plasma

Kim, In-Seop    (Department of Biological Sciences and Center for Biopharmaceuticals Safety Validation, Hannam University   ); Bae, Jung-Eun    (Department of Biological Sciences and Center for Biopharmaceuticals Safety Validation, Hannam University   ); Sung, Hark-Mo    (Graduate Program in BT-NT Fusion Science and Technology, Hannam University   ); Kang, Yong    (Green Cross Corp.   ); Choi, Yong-Woon    (Green Cross Corp.  );
  • 초록

    The purpose of this study was to evaluate the efficacy and mechanisms of the solvent/detergent (S/D) treatment, DEAE-toyopearl 650M anion-exchange column chromatography, heparin-sepharose 6FF affinity column chromatography, and Viresolve NFP filtration steps employed in the manufacture of high-purity antihemophilic factor IX (Green-Nine VF) from human plasma, with regard to removal and/or inactivation of blood-borne viruses. A variety of experimental model viruses for human pathogenic viruses, including human immunodeficiency virus (HIV), bovine herpes virus (BHV), bovine viral diarrhoea virus (BVDV), hepatitis A virus (HAV), murine encephalomyocarditis virus (EMCV), and porcine parvovirus (PPV), were all selected for this study. Samples from relevant stages of the production process were spiked with each virus and subjected to scale-down processes mimicking the manufacture of high-purity factor IX. Samples were collected at each step, immediately titrated using a 50% tissue culture infectious dose ( $TCID_{50}$ ), and virus reduction factors were evaluated. S/D treatment using the organic solvent, tri (n-butyl) phosphate (TNBP), and the detergent, Tween 80, was a robust and effective step in inactivation of enveloped viruses. Titers of HIV, BHV, and BVDV were reduced from the initial titer of 6.06, 7.72, and 6.92 $log_{10}$ $TCID_{50}$ , respectively, reaching undetectable levels within 1 min of S/D treatment. DEAE-toyopearl 650M anion-exchange column chromatography was found to be a moderately effective step in the removal of HAV, EMCV, and PPV with log reduction factors of 1.12, 2.67, and 1.38, respectively. Heparin-sepharose 6FF affinity column chromatography was also moderately effective for partitioning BHV, BVDV, HAV, EMCV, and PPV with log reduction factors of 1.55, 1.35, 1.08, 1.19, and 1.61, respectively. The Viresolve NFP filtration step was a robust and effective step in removing all viruses tested, since HIV, BHV, BVDV, HAV, EMCV, and PPV were completely removed during the filtration step with log reduction factors of $\geq$ 5.51, $\geq$ 5.76, $\geq$ 5.18, $\geq$ 5.34, $\geq$ 6.13, and $\geq$ 4.28, respectively. Cumulative log reduction factors of HIV, BHV, BVDV, HAV, EMCV, and PPV were $\geq$ 10.52, $\geq$ 12.07, $\geq$ 10.49, $\geq$ 7.54, $\geq$ 9.99, and $\geq$ 7.24, respectively. These results indicate that the production process for GreenNine VF has a sufficient virus reduction capacity for achievement of a high margin of virus safety.


  • 주제어

    antihemophilic factor IX .   viral inactivation and/or removal .   log reduction factor .   virus safety.  

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  • 이 논문을 인용한 문헌 (1)

    1. Bae, Jung-Eun ; Kim, Jin-Young ; Ahn, Jae-Hyoung ; Choi, Da-Mi ; Jeong, Hyo-Sun ; Lee, Dong-Hyuck ; Kim, In-Seop 2010. "Virus Inactivation Processes for the Manufacture of Human Acellular Dermal Matrix" 한국미생물·생명공학회지 = Korean journal of microbiology and biotechnology, 38(2): 168~176     

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