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A new manufacturing process to remove thrombogenic factors (II, VII, IX, X, and XI) from intravenous immunoglobulin gamma preparations.
Biologicals. 2017 Jan; 45:1-8.B

Abstract

Coagulation factors (II, VII, IX, X, and particularly XIa) remaining in high concentrations in intravenous immunoglobulin (IVIG) preparations can form thrombi, causing thromboembolic events, and in serious cases, result in death. Therefore, manufacturers of biological products must investigate the ability of their production processes to remove procoagulant activities. Previously, we were able to remove coagulation factors II, VII, IX, and X from our IVIG preparation through ethanol precipitation, but factor XIa, which plays an important role in thrombosis, remained in the intermediate products. Here, we used a chromatographic process using a new resin that binds with high capacity to IgG and removes procoagulant activities. The procoagulant activities were reduced to low levels as determined by the thrombin generation assay: <1.56 mIU/mL, chromogenic FXIa assay: <0.16 mIU/mL, non-activated partial thromboplastin time (NaPTT): >250 s, FXI/FXIa ELISA: <0.31 ng/mL. Even after spiking with FXIa at a concentration 32.5 times higher than the concentration in normal specimens, the procoagulant activities were below the detection limit (<0.31 ng/mL). These results demonstrate the ability of our manufacturing process to remove procoagulant activities to below the detection limit (except by NaPTT), suggesting a reduced risk of thromboembolic events that maybe potentially caused by our IVIG preparation.

Authors+Show Affiliations

Green Cross Corp., Ihyeon-ro 30 beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.Green Cross Corp., Ihyeon-ro 30 beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.Green Cross Corp., Ihyeon-ro 30 beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.Green Cross Corp., Ihyeon-ro 30 beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.Green Cross Corp., Ihyeon-ro 30 beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea. Electronic address: kimky@greencross.com.Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: jhhan551@skku.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27876270

Citation

Park, Dong Hwarn, et al. "A New Manufacturing Process to Remove Thrombogenic Factors (II, VII, IX, X, and XI) From Intravenous Immunoglobulin Gamma Preparations." Biologicals : Journal of the International Association of Biological Standardization, vol. 45, 2017, pp. 1-8.
Park DH, Kang GB, Kang DE, et al. A new manufacturing process to remove thrombogenic factors (II, VII, IX, X, and XI) from intravenous immunoglobulin gamma preparations. Biologicals. 2017;45:1-8.
Park, D. H., Kang, G. B., Kang, D. E., Hong, J. W., Lee, M. G., Kim, K. Y., & Han, J. W. (2017). A new manufacturing process to remove thrombogenic factors (II, VII, IX, X, and XI) from intravenous immunoglobulin gamma preparations. Biologicals : Journal of the International Association of Biological Standardization, 45, 1-8. https://doi.org/10.1016/j.biologicals.2016.11.002
Park DH, et al. A New Manufacturing Process to Remove Thrombogenic Factors (II, VII, IX, X, and XI) From Intravenous Immunoglobulin Gamma Preparations. Biologicals. 2017;45:1-8. PubMed PMID: 27876270.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A new manufacturing process to remove thrombogenic factors (II, VII, IX, X, and XI) from intravenous immunoglobulin gamma preparations. AU - Park,Dong Hwarn, AU - Kang,Gil Bu, AU - Kang,Dae Eun, AU - Hong,Jeung Woon, AU - Lee,Min Gyu, AU - Kim,Ki Yong, AU - Han,Jeung Whan, Y1 - 2016/11/18/ PY - 2016/06/18/received PY - 2016/10/24/revised PY - 2016/11/07/accepted PY - 2016/11/24/pubmed PY - 2017/1/24/medline PY - 2016/11/24/entrez KW - Coagulation factor XIa KW - Intravenous immunoglobulin G KW - Procoagulant activity KW - Thromboembolic events SP - 1 EP - 8 JF - Biologicals : journal of the International Association of Biological Standardization JO - Biologicals VL - 45 N2 - Coagulation factors (II, VII, IX, X, and particularly XIa) remaining in high concentrations in intravenous immunoglobulin (IVIG) preparations can form thrombi, causing thromboembolic events, and in serious cases, result in death. Therefore, manufacturers of biological products must investigate the ability of their production processes to remove procoagulant activities. Previously, we were able to remove coagulation factors II, VII, IX, and X from our IVIG preparation through ethanol precipitation, but factor XIa, which plays an important role in thrombosis, remained in the intermediate products. Here, we used a chromatographic process using a new resin that binds with high capacity to IgG and removes procoagulant activities. The procoagulant activities were reduced to low levels as determined by the thrombin generation assay: <1.56 mIU/mL, chromogenic FXIa assay: <0.16 mIU/mL, non-activated partial thromboplastin time (NaPTT): >250 s, FXI/FXIa ELISA: <0.31 ng/mL. Even after spiking with FXIa at a concentration 32.5 times higher than the concentration in normal specimens, the procoagulant activities were below the detection limit (<0.31 ng/mL). These results demonstrate the ability of our manufacturing process to remove procoagulant activities to below the detection limit (except by NaPTT), suggesting a reduced risk of thromboembolic events that maybe potentially caused by our IVIG preparation. SN - 1095-8320 UR - https://www.unboundmedicine.com/medline/citation/27876270/A_new_manufacturing_process_to_remove_thrombogenic_factors__II_VII_IX_X_and_XI__from_intravenous_immunoglobulin_gamma_preparations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1045-1056(16)30144-0 DB - PRIME DP - Unbound Medicine ER -