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사람 혈장으로부터 고순도 혈액응고 제 9인자의 산업적 생산
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 김용성 | - |
| dc.contributor.author | Cho, Yong Woon | - |
| dc.date.accessioned | 2018-11-08T07:59:34Z | - |
| dc.date.available | 2018-11-08T07:59:34Z | - |
| dc.date.issued | 2010-08 | - |
| dc.identifier.other | 10959 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/9514 | - |
| dc.description | 학위논문(박사)--아주대학교 일반대학원 :분자과학기술학과,2010. 8 | - |
| dc.description.tableofcontents | Contents i List of Tables iv List of Figures vi ABSTRACT vii Chapter I. General Introduction 1 1. Introduction to Factor IX 2 2. Hemophilia B 3 3. Factor IX Complex (Prothrombin Complex Concentrates) 8 3.1. Bebulin VH (by Baxter) 8 3.2. Profilnine SD (by GRIFOLS) 10 3.3. Proplex T (by Baxter) 11 4. High purity Factor IX 11 4.1. Alphanine SD (by GRIFOLS) 13 4.2. Mononine (by CSL Behring) 13 4.3. BeneFIX (Recombinant Factor IX by Genetics Institute) 14 5. Facnyne (Factor IX Complex by Green Cross Corp.) 14 5.1. Description 14 5.2. Indications 15 5.3. Dosage and administration 15 5.4. Adverse reactions 16 6. Aims of this study 18 Chapter II. Manufacturing Process Development of a High-purity Antihemophilic Factor IX from Human Plasma 19 1. Introduction 20 2. Materials and Methods 23 2.1. Factor IX Complex Manufacturing Process and Preparation of Process Samples 23 2.2 Development of Heparin-sepharose 6FF affinity column chromatography 23 2.3. Development of CM-sepharose cation-exchange column chromatography 24 2.4. Development of Viresolve NFP filtration 24 2.5. Physical and Biochemical Analysis 28 3. Results and Discussion 29 3.1. Development of Heparin-sepharose 6FF affinity column chromatography 29 3.2. Development of CM-sepharose cation-exchange column chromatography 32 3.3. Development of Viresolve NFP filtration 35 4. Summary 45 Chapter III. Removal and Inactivation of Viruses during the Manufacturing of a High-purity Antihemophilc Factor IX from Human Plasma 46 1. Introduction 47 2. Materials and Methods 49 2.1. High-purity Factor IX Manufacturing Process and Preparation of Process Samples 49 2.2. Validation of the Scale-down Process 52 2.3. Preparation and Titration of Viruses 53 2.4. Virus Spiking Studies 55 2.5. Calculation of Virus Reduction Factors 57 3. Results and Discussion 58 3.1. Validation of Scale-down Process 58 3.2. Inactivation of Envelped Viruses through S/D Treatment 58 3.3. Partitioning of Viruses through DEAE-Toyopearl 650M Anion-exchange Column Chromatography and Heparin-sepharose 6FF Affinity Column Chromatography 65 4. Summary 72 Chapter IV. Industrial-Scale Production of High-purity Antihemophilic Factor IX from Human Plasma 74 1. Introduction 75 2. Materials and Methods 78 2.1. Manufacturing Process of High-purity Factor IX (GreenNine VF) 78 2.2. Assay of Factor IX activity 79 2.3. Assay of Factor II, Factor VII, Factor X activity 80 2.4. Protein Concentration determination 80 2.5. Physico-chemical analysis of GreenNine VF 80 2.6. Abnormal toxicity and Pyrogen 82 2.7. Virus detection test 82 2.8. Sterility 82 3. Results and Discussion 83 3.1. Manufacturing Process of High-purity Factor IX (GreenNine VF) 83 3.2. Industrial Production Batch Analysis of GreenNine VF 85 3.3. Activity of Factor II, Factor VII and Factor X 88 3.4. Physico-chemical analysis of GreenNine VF 90 3.5. GreenNine VF Drug Product analysis 95 4. Summary 97 Overall Conclusion and Further Study 98 References 100 국문요약 110 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | 사람 혈장으로부터 고순도 혈액응고 제 9인자의 산업적 생산 | - |
| dc.title.alternative | Industrial-scale Production of High-purity Antihemophilic Factor IX from Human Plasma | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 일반대학원 | - |
| dc.contributor.alternativeName | Yong Woon Choi | - |
| dc.contributor.department | 일반대학원 분자과학기술학과 | - |
| dc.date.awarded | 2010. 8 | - |
| dc.description.degree | Master | - |
| dc.identifier.localId | 568877 | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000010959 | - |
| dc.subject.keyword | Factor IX | - |
| dc.description.alternativeAbstract | Human blood coagulation Factor IX is a glycoprotein that is indispensable for a coagulation cascade. The hemophilia B is caused by the absence or deficiency of the Factor IX due to a hereditary cause or a pathological cause. The hemophilia B is rare hereditary disease that primarily affects newborn male babies, affecting approximately one out of 30,000 ~ 50,000. The hemophilia B patient is treated by administering Factor IX concentrates purified from the human blood. Factor IX product is classified by purity; Factor IX complex (prothrombin complex concentrate containing vitamin K-dependent clotting factors) and high-purity Factor IX product. However, there were several findings reporting that administration of the Factor IX complex caused incidence of symptoms, such as venous thrombosis or disseminated intravascular coagulation (DIC). Such side reactions presumably result from hypercoagulable states caused by excessive amounts of coagulant proteins administered along with the Factor IX or unnecessary thrombogenic components in the concentrates. The most serious problem with blood-derived coagulation factors is the risk of viral infection due to plasma-derived viruses such as HIV, HAV, HBV, HCV and human parvovirus B19 contaminated in the blood. To ensure virus safety of the plasma-derived coagulation factors, virus inactivation and/or removal process is indispensable when we develop the manufacturing process. Green Cross Corp. has produced the Facnyne as a therapeutic product for hemophilia B patients since 1986. Also we introduced the solvent/detergent treatment which New York Blood Center developed as a virus inactivation method to manufacturing process of Factor IX complex in 1991. Because side effects of Factor IX complex may occur., higher purity and safer Factor IX product than Facnyne was required. Therefore, we developed the manufacturing process of GreenNine VF as a high-purity Factor IX product. To improve the purity of GreenNine VF, the purification processes such as heparin affinity column chromatography and cation exchange column chromatography were added to the manufacturing process of Facnyne. Also, to improve the virus safety of GreenNine VF, virus-retentive filtration process was introduced. All of the processes were optimized and scaled-up to industrial production scale. The GreenNine VF products obtained from industrial-scale production have shown to be of higher purity and viral safety. The specific activity of GreenNine VF was 190.8 IU/mg which exceeded that in Facnyne. GreenNine VF was shown to have the highest purity in comparison with commercially available high purity factor IX products; Mononine(CSL), Octanyne(Octapharma), Berinine HS(Behringwerke), and Immunine STIM plus 600 (Baxter). One lot size of the production was 2,400 vials of 250 IU drug product or 1,200 vials of 500 IU drug product from 1,600 L cryo-poor plasma. | - |
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