ZA200110168B - Manufacturing method for intravenous immune globulin and resultant product. - Google Patents
Manufacturing method for intravenous immune globulin and resultant product. Download PDFInfo
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- ZA200110168B ZA200110168B ZA200110168A ZA200110168A ZA200110168B ZA 200110168 B ZA200110168 B ZA 200110168B ZA 200110168 A ZA200110168 A ZA 200110168A ZA 200110168 A ZA200110168 A ZA 200110168A ZA 200110168 B ZA200110168 B ZA 200110168B
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- Prior art keywords
- solution
- gamma globulin
- globulin solution
- fraction
- detergent
- Prior art date
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- 108060003951 Immunoglobulin Proteins 0.000 title description 20
- 102000018358 immunoglobulin Human genes 0.000 title description 20
- 238000004519 manufacturing process Methods 0.000 title description 9
- 238000001990 intravenous administration Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims description 45
- 239000003599 detergent Substances 0.000 claims description 37
- 239000002202 Polyethylene glycol Substances 0.000 claims description 31
- 229920001223 polyethylene glycol Polymers 0.000 claims description 31
- 102000004169 proteins and genes Human genes 0.000 claims description 31
- 108090000623 proteins and genes Proteins 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 31
- 238000005194 fractionation Methods 0.000 claims description 22
- 108010074605 gamma-Globulins Proteins 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- 229910019142 PO4 Inorganic materials 0.000 claims description 14
- 108010032597 Cohn fraction II Proteins 0.000 claims description 13
- 241000700605 Viruses Species 0.000 claims description 13
- 239000010452 phosphate Substances 0.000 claims description 12
- 239000011347 resin Substances 0.000 claims description 12
- 229920005989 resin Polymers 0.000 claims description 12
- 125000002091 cationic group Chemical group 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 10
- 238000011084 recovery Methods 0.000 claims description 8
- 239000000440 bentonite Substances 0.000 claims description 7
- 229910000278 bentonite Inorganic materials 0.000 claims description 7
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 7
- 102000006395 Globulins Human genes 0.000 claims description 6
- 108010044091 Globulins Proteins 0.000 claims description 6
- 238000009295 crossflow filtration Methods 0.000 claims description 5
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical group CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 claims description 5
- -1 alkyl phosphate Chemical compound 0.000 claims description 4
- 239000003957 anion exchange resin Substances 0.000 claims description 3
- 238000010924 continuous production Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 230000000415 inactivating effect Effects 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 3
- 108010035369 Cohn fraction I Proteins 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000005352 clarification Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 47
- 230000003612 virological effect Effects 0.000 description 22
- 230000002779 inactivation Effects 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- 239000007858 starting material Substances 0.000 description 14
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 235000021317 phosphate Nutrition 0.000 description 12
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 11
- 229960002920 sorbitol Drugs 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229920005654 Sephadex Polymers 0.000 description 9
- 239000012507 Sephadex™ Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000600 sorbitol Substances 0.000 description 8
- 239000012760 heat stabilizer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000000539 dimer Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 108010088751 Albumins Proteins 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 4
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 4
- 125000000129 anionic group Chemical group 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 101150026046 iga gene Proteins 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010071241 Factor XIIa Proteins 0.000 description 3
- 108010088842 Fibrinolysin Proteins 0.000 description 3
- 102000013566 Plasminogen Human genes 0.000 description 3
- 108010051456 Plasminogen Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940012957 plasmin Drugs 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000012460 protein solution Substances 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 150000005846 sugar alcohols Chemical class 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000003171 anti-complementary effect Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010960 commercial process Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108090000113 Plasma Kallikrein Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- GTVWRXDRKAHEAD-UHFFFAOYSA-N Tris(2-ethylhexyl) phosphate Chemical compound CCCCC(CC)COP(=O)(OCC(CC)CCCC)OCC(CC)CCCC GTVWRXDRKAHEAD-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940099472 immunoglobulin a Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 108010058237 plasma protein fraction Proteins 0.000 description 1
- 229940081857 plasma protein fraction Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940124272 protein stabilizer Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- BGRJTUBHPOOWDU-UHFFFAOYSA-N sulpiride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- SFENPMLASUEABX-UHFFFAOYSA-N trihexyl phosphate Chemical compound CCCCCCOP(=O)(OCCCCCC)OCCCCCC SFENPMLASUEABX-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
- C07K16/065—Purification, fragmentation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Mycology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Description
MANUFACTURING METHOD FOR INTRAVENOUS IMMUNE
GLOBULIN AND RESULTANT PRODUCT
The present invention relates to an integral, multi-step commercial process for the production of intravenously administrable immune globulin containing IgG (y-globulin) as the main ingredient.
Various processes are known for obtaining intravenously administrable y-globulin solutions from starting materials resulting from Cohn fractionation of human plasma. Certain of the Cohn fractions contain higher titres of y-globulin than others.
Usual starting materials for a y-globulin solution are Cohn Fraction II or Cohn Fraction II + III.
Although prior art processors employ various separation and sterilization techniques, process . modifications are constantly sought for improving final product purity and safety, and overall yield.
Many commercial processes employ either a solvent /detergent step for viral inactivation, or a heat treatment step for viral inactivation. To date,
the art has not provided a multi-step process beginning with Cohn Fraction II paste or II + III paste including two different viral inactivation procedures as part of an efficient, continuous high yield y-globulin manufacturing process.
U.S. Patent 5,151,499 by Kameyama et al. is directed to a process for producing viral inactivated protein compositions in which a protein composition is subjected to a viral inactivation for envelope viruses in a solvent/detergent treatment of the protein composition and a viral inactivation for non- envelope viruses in a heat treatment of the protein composition. The '499 patent teaches that preferably the solvent/detergent step occurs first and in the presence of a protease inhibitor, followed by a heat treatment. Where the heat treatment is carried out in the liquid state, the protein is first recovered } from the solvent/detergent by adsorption onto an ionic exchange column, prior toc any heat treatment.
The liquid heat treatment can be carried out in the presence of a sugar, sugar alcohol or amino acid stabilizer. Although the '499 patent lists many starting protein compositions including immunoglobulin, its production examples employ
Factor IX, thrombin, fibrinogen and fibronectin.
Removal of denatured protein produced in a heat treatment step through fractionation is not: considered.
U.S. Patent 5,371,196 by Yuki et al. is directed to purifying secretory immunoglobulin A. A liquid heat treatment or various combinations of liquid heat treatment and solvent treatment inactivation are described. A polyethylene glycol fractionation is employed following each step and always as a final step. This patent does not relate to immune globulin of high y-globulin titre.
Certain prior art processes for production of intravenously injectable y-globulin solutions describe the incorporation of a liquid heat treatment carried out in the presence of sorbitol heat stabilizer in a multi-step purification procedure . beginning with Cohn Fraction II + III paste. In
U.S. Patent 4,845,199 by Hirao et al., Cohn Fraction
II + III is subjected to polyethylene glycol (hereinafter "PEG") fractionation (8% w/v PEG followed by 12% w/v PEG), then ion exchange chromatography (DEAE-Sephadex) and removal of human blood group antibody prior to a liquid heat treatment in the presence of sorbitol as a protein stabilizer.
On the other hand, Example 1 of
U.S. Patent 4,876,088 by Hirao et al. describes the preparation of intravenously injectable y-globulin solution from Cohn Fraction II + III paste in which the paste is suspended in water, its pH adjusted to 5.5 and centrifuged, with the supernatant then being heat treated for viral inactivation in the presence of 33% w/v of sorbitol, followed by PEG fractionation (6%3/12%) which would remove heat denatured protein and then by other purification steps including DEAE-
Sephadex ion exchange chromatography. + — -—— SUMMARY -OF- THE -INVENTION-- - -—— — ~~ — — --—-
An. object of the present invention is to provide an integral, commercially useable process for producing a highly purified y-globulin solution from the Cohn fractionation process.
Another object of the present invention is to provide very pure intravenously administrable y- globulin solution free of both envelope and non- envelope viruses, including all heat sensitive viruses.
A further object of the present invention is to provide a commercial y-globulin process enabling removal of any denatured protein produced during heat sterilization prior to a second stage viral inactivation.
A further object of the present invention is to provide a continuous commercial y-globulin production process without the need for intermediate recovery of y-globulin protein through the carrying out, in order, of a heat sterilization, a PEG fractionation and a solvent detergent viral inactivation. 1S
The above and other objects which will be apparent to the skilled artisan are provided by the . present invention in which an alcoholic Cohn fraction, which may be partially purified, but is : rich in y-globulin, is heat treated in aqueous medium in the presence of a heat stabilizer for viral inactivation, the heat treated solution is thereafter first subjected to PEG fractionation, and then without intermediate y-globulin protein recovery to a second viral inactivation in the presence of a solvent, preferably a solvent-detergent mixture, for disruption of envelope viruses, followed by separation from the solvent or solvent-detergent mixture.
In one preferred embodiment of the present invention, bentonite is admixed with a collected PEG fractionation product for additional virus removal, prior to the solvent or solvent-detergent viral inactivation.
In a preferred embodiment of the present invention, sorbitol is the heat stabilizer and trialkyl phosphate is the solvent. lll de eee =
In another preferred embodiment of the present invention, denatured products of the heat treatment : viral inactivation are removed by the PEG fractionation prior to the second viral inactivation for providing an exceedingly pure heat treated y- globulin.
In another preferred embodiment of the present invention, any particulates present are removed prior to the solvent-detergent treatment.
In preferred embodiment of the Dresent invention, the y-globulin solution is treated with ar anion exchange resin.
In preferred embodiments of the present invention, a single stage polyethylene glycol fractionation step is carried out without precipitation of the desired y-globulin.
In yet another preferred embodiment of the present invention, the y-globulin solution is treated with a cationic exchange resin, or by diafiltration and/or tangential flow filtration, following the completion of viral inactivation.
In still another preferred embodiment of the } invention, there is provided a heat-sterilized and solvent -detergent sterilized y-globulin suitable for - intravenous administration.
The manufacturing method disclosed herein is a continuous process in the sense that once the process is started with a quantity of impure starting fraction containing immunoglobulin, such as Cohn
Fraction II + III paste, the process runs through until its completion (providing highly purified gamma
S globulin as a resultant product) without the intermediate recovery of partially purified gamma globulin solids. Of note, during the polyethylene glycol fractionation stage of the process disclosed herein, partially purified gamma globulin paste is not recovered as an intermediate product.
A fraction containing immunoglobulin is used as the starting material. This fraction is not particularly limited in so far as it originates from human plasma and contains an immunoglobulin fraction. —___
Specific examples of such an immunoglobulin- containing fraction include Fraction II + III and ’ Fraction II obtainable by ethanol fractionation of
Cohn, and paste of immunoglobulin-containing fractions equivalent thereto. Other starting materials are Fractions I + II + III, and Fraction II + IIIw and Fraction III paste. The starting material may contain impurities, such as human bloed-group antibodies, plasminogen, plasmin, kallikrein, prekallikrein activator, IgM, IgA, IgG polymers (hereinafter "aggregates"), etc.
The preferred starting materials are Cohn
Fraction II + III or Cohn Fraction II paste. Cchn
Fraction II + III paste can be used as is as a starting material or it can first be subjected to a preliminary washing procedure to form Fraction II +
ITIw, which is thereafter used in the process of this invention. "Fraction II + IIIw" is a disodium phosphate soluticon-washed Cohn Fraction II + IIT iG precipitate.
Fraction II + IIIw can be obtained by suspending
Fraction II + III precipitate in cold water for injection in a ratio of about 1 kilogram of II + III paste per about 20 volumes of water. A sodium phosphate solution is added to the final concentration of approximately 0.003M sodium phosphate for solubilizing lipids, lipoproteins and ) albumin. Cold ethanol is added to bring the final alcohol concentration to about 20%. During the alcohol addition, temperature is gradually lowered to -5:1°C and pH is maintained or adjusted to 7.210.1, for example by using acetate buffer or dilute sodium hydroxide. The Fraction II + IIIw precipitate which forms is recovered by centrifugation and/or filtration while maintaining the temperature at - 5+1°C.
Prior to the first viral inactivation step of the present invention, various preliminary purification and/or aggregate-reducing steps can be carried out. For example, when Fraction II + IIIw paste is used, typically containing about 20% alcohol and with more than 70% of the protein present as IgG, it can be suspended in 3 to 20 volumes, preferably 10 tc 15 volumes, of cold water at a temperature of about 0 to 65°C and with pH being adjusted to be between 4.5 to 6.0, preferably 5.0 to 5.5 using pH 4.0 acetate buffer or hydrochloric acid. The mixture is agitated for about "2° to ‘15 hours to allow all of" ~~ the y-globulin to go into solution. Thereafter, ) undissolved protein such as albumin and a-globulins can be removed by centrifugation and/or filtration.
With Fraction II + III paste starting material, each kilogram of Fraction II + III paste is suspended in 3 to 20 kg, preferably 13 to 17 kg, of cold water.
The pH of the suspension is adjusted to 4.5 to 6.0, preferably 4.8 to 5.4. The suspension is mixed for 1 to 20 hours, preferably 2 to 10 hours, at 0 to 25°C,
preferably 0 to 10°C. The insoluble material is then removed by filtration using depth filters cor centrifugation. If filtration is used, about 1 to 5 w/w% filter aid may be added before separation. The centrifugate or the filtrate may be further clarified by a membrane filter. The clarified solution may be concentrated to about 1 to 12%, preferably 4 to 8%, protein by ultrafiltration using 10,000 to 100,000 molecular weight cut off (MWCO) membranes.
Where a different starting Cohn fraction is employed, the initial step or steps of the process can be appropriately selected where desired for carrying out a preliminary purification for obtaining a fraction of high IgG content to be further processed. For example, where Cohn Fraction II (contains over 95% IgG) has been separated from Cohn
Fraction III, with Fraction II to be further : processed, the initial processing can be at an acid
PH of 3.2 to 5.0, preferably 3.8 to 4.2, as described ’ by Uemura et al. U.S. Patent 4,371,520, in order to break down immune glcbulin aggregates present into immune globulin monomers and dimers, since aggregates are known to possess anti-complementary activity © 25 (ACA) . As another alternative, with Cohn Fraction
IT + III starting material, the Uemura, et al. patent low pH treatment can be carried out as an additional step following an initial purification step as above described and prior to the viral inactivating heat treatment step.
For the heat sterilization step, the immune globulin protein in the form of the aqueous mixture collected from the above-described partial purification, such as the filtrate from Fraction II +
III paste purification, can be used as is or concentrated to about 1 to 12%, preferably 4 to 8%, protein by ultrafiltration, and a sugar, sugar alcohol and/or amino acid heat stabilizer is added thereto. The heat stabilizer is preferably sucrose, maltose,._ sorbitol. ..or...mannitol,. . most. -preferably--- --- sorbitol. The sugar or sugar alcohol is added to the immune globulin solution as a powder or first mixed ’ with a small volume of water and then added, to provide a final concentration of about 25 to 50 w/w%, up to saturation, preferably 30 to 40 w/w%. At this point, the aqueous solution of immune globulin contains sufficient water so that this solution contains about 1 to 8% total protein, a typical
Fraction II + III starting material containing about 300 grams protein per kilogram paste.
Following addition of the heat stabilizer, the solution pH is adjusted to 4.5 to 6.5, preferakly 5.C to 6.0 and the mixture is heated at about 50-70°C for about 1-20 hours, preferably for 10 to 11 hours at about 60°C, for viral inactivation of heat sensitive viruses. The heat treatment step not only inactivates viruses, but also through the protein denaturation effect thereof, can preferentially reduce the amount of certain undesirable proteins normally associated with Cohn Fractions II + III, such as prekallikrein, plasmin, plasminogen and IgA.
After the heat treatment, the solution is either processed directly or diluted with cold water up to 5 times the volume of the heat treated solution. The solution is then cooled to 0-10°C, preferably 0 to 5°C. )
Next, PEG fractionation is carried out on the . heat treated solution. PEG fractionation is a well known procedure in the art of purification of immune globulin in order to separate the desired IgG monomer and dimer from IgG aggregate and from other impurities naturally occurring in the starting plasma protein fraction. However, in the present process,
the PEG fractionation also accomplishes a separation between the desired IgG monomer and dimer, and unwanted denatured protein products produced by the heat treatment. These denatured protein products are
S denatured prekallikrein activator, plasminogen, plasmin, IgA, IgM and aggregates.
Any of the PEG fractionation procedures documented in the prior art can be used as long as
PEG concentration and pH are selected so that the desired IgG monomer and dimer remain in solution while undesired proteins such as aggregate are precipitated out of solution. The PEG is added as a powder, flakes or as a. 50% solution. directly to_the _. __ heat treated solution for providing the desired PEG concentration. N
For example, the PEG fractionation can be carried out at a pH of about 5.0 to 7.5, preferably within about 6.0 to 7.5 pH when Fraction II + IIIw paste is used as starting material, and preferably within about 5.5 to 6.0 pH when Fraction II + III paste is used as starting material, with a PEG concentration ranging from about 4 to 8%, preferably either 4 to 6% when Fraction II + IIIw paste is used as starting material, or 6 to 8% when
Fraction II + III paste is used as starting material.
While maintaining cold temperatures of about 0-2°C, the PEG fractionation can be carried out for about 1 to 8 hours, after which the precipitate is removed by ’ either centrifugation or filtration.
As an optional viral removal step, bentonite is added to the centrifugate or filtrate to a final 1¢ concentration cf abouts 0.05 to 2.0 w/w%, preferably 0.1 to 1.0 w/w%, and the mixture is mixed for 1 to 5 hours, and then the bentonite paste is removed by filtration.
The final essential step of the present invention is to carry out a second viral inactivation procedure utilizing a solvent or solvent-detergent mixture. As described below, further purification ’ procedures, specifically those involving the use of ionic exchange resins, can be carried out prior to and/or following the solvent-detergent treatment.
One option’ is to carry out an anionic exchange treatment prior to the solvent detergent viral inactivation for further removal of albumin, transferrin and prekallikrrein activator. In a preferred embodiment, a cationic exchange treatment is carried out after the solvent detergent viral inactivation. By this procedure, certain undesirable protein materials (such as IgA, IgM and albumin) found within human plasma and PEG can be removed from the IgG through the cationic exchange procedure along with the residual reagents used in the solvent- detergent treatment.
If not otherwise accomplished during the overall process the solution to be subjected to the solvent- detergent should be treated for removal of all particulate matter, which can include denatured protein. Therefore, it is preferred to filter the solution with a 1 micron or finer filter prior to solvent -detergent addition. This will also reduce the likelihood of wvirus being present within a large . particle and thereby possibly avoiding exposure to the solvent-detergent. : 20
The filtrate may be diafiltered and/or concentrated up to about 12% protein, preferably 5- 10% protein, and then subjected to the solvent, or solvent -detergent treatment.
Today, the preferred solvent for inactivation of le envelope viruses is trialkyl phosphate. The trialkyl phosphate used in the present invention is not subject to particular limitation, but it is preferable to use tri(n-butyl)phosphate (hereinafter "TNBP") . Other usable trialkyl phosphates are the tri (ter-butyl) phosphate, the tri (n-hexyl)phosphate, the tri(2-ethylhexyl)phosphate, and so on. It is possible to use a mixture of 2 or more different trialkyl phosphates.
The trialkyl phosphate is used in an amount of between 0.01 to 10 (w/w)$%, preferably about 0.1 to 3 (w/w)%.
The trialkyl phosphate may be used in the presence or absence of a detergent or surfactant. It is preferable to use trialkyl phosphate in combination with the detergent. The detergent : functions to enhance the contact of the viruses in the immune globulin composition with the trialkyl phosphate.
Examples of the detergent include polyoxyethylene derivatives of a fatty acid, partial esters of anhydrous sorbitol such as Polysorbate 80 (Tradename: Tween 80, etc.) and Polysorbate 20
(Tradename: Tween 20, etc.); and nonionic oil bath rinsing agent such as oxyethylated alkylphenol (Tradename: Triton X100, etc.) Examples include other surfactants and detergents such as 2Zwitter ionic detergents and so on.
When using the detergent, it is not added in a critical amount; for example, it may be used at concentrations between about 0.001% and: about 10%, preferably between about 0.01% and 3%.
In the present invention, the trialkyl phosphate treatment of the immune globulin containing composition is carried out at about 20 to 35°C, preferably ~ 25 "to 30°C, for “more than 1 hour, preferably about 5 to 8 hours.
During the trialkyl phosphate treatment, immune . globulin is present at about a 5 to 10% protein solution in aqueous medium.
If not carried out prior to the solvent- detergent treatment, an optional anionic exchange treatment can be carried out on the solvent detergent treated immune globulin. Preferably, at least a cationic exchange treatment 1s carried out on the solvent -detergent treated produce. The ionic exchange treatments are carried out on the immune globulin aqueous solution from solvent (or solvent detergent) processing, generally having a pd of about 4.5 to 6.5, with where desired low ionic strength for maximum adsorption of IgG. The protein concentration generally is within the range of about 1-15 w/v%, more preferably from about 3 to 10 w/v%. The ionic exchanger is equilibrated with the same aqueous solvent as used.
A continuous system is carried out by passing immune globulin solution through a column cf the anionic exchanger at a ratio from about 10 to 100 ml per ml of the ionic exchanger and recovering the non- adsorbed fraction.
The anionic exchanger to be used, for example, comprises anion exchanging groups bonded to an ’ insoluble carrier. The anion exchanging groups include | diethylaminoethyl (DEAE) , a guaternary aminoethyl (QAE) group, etc., and the insoluble carrier includes agarose, cellulose, dextran, polyacrylamide, etc. 1 gram of DEAE Sephadex A-50 resin swells to about 20 to 30 grams wet weight in
0.4% sodium chloride solution.
Usable cationic exchangers are carboxy methyl
Sephadex (CM-Sephadex) CM-cellulose, SP-Sephadex, CM-
Sepharose and SP-Sepharose. Pretreated cationic exchanger (for example, 1 gram of CM-Sephadex C-50 resin swells to about 25-35 grams wet weight in 0.4% sodium chloride solution) is used as a column bed through which the immune globulin solution from solvent (or solvent detergent) processing is passed in a continuous process. at about 0-5°C.
When the above-described conditions are used with the «cationic exchanger, the IgG will be adsorbed, and thereafter following washing of the protein-adsorbed cationic exchange resin, IgG can be eluted, for example by about a 1.4 N sodium chloride ’ solution.
When ionic exchange treatments are not employed, the solvent (solvent detergent) treated solution is : diafiltered and concentrated by tangential flow filtration for removal of solvent detergent and PEG.
Where very low levels of solvent detergent and PEG are desired in the final product, a preferred processing is treatment with a cationic exchanger followed by tangential flow filtration.
Following the steps of the above process, the
IgG is clarified, diafiltered and concentrated to the extent needed. If desired, a stabilizer such as D- sorbitol can be added and final adjustments made to vield a solution of a composition containing about 50 to 100 mg/ml IgG, and S50 mg/ml D-sorbitol, with pH being at about 5.4. For additional . removal of viruses, this scluticn may ke filtered through 2E nanometers or less porosity filters. This stabilized and optionally nancfiltered solution is then sterile filtered through sterilized bacterial retentive filters and filled into vials.
The following example is set forth to illustrate the invention but is non-limiting.
Manufacturing Method for Intravenous
Immune Globulin and Resultant Product
One thousand eight hundred grams of Fr II+III paste was suspended in 15 kg of cold water. After mixing for one hour at 0 to 5°C, pH of the suspension was adjusted to about 5.0 with dilute acetic acid.
After mixing the suspension for 3 hours,
approximately 900 grams of filter aid (acid washed celite) was added and mixed for 45 minutes. The insoluble material along with the celite was removed by filtration. The filtrate was clarified and then concentrated by ultrafiltration, using 100,000 molecular weight cut off (MWCO) membranes, to an approximate protein concentration of 6%.
D-sorbitol was added to the concentrated protein solution to a final concentration of 33 w/w% and mixed at pH 5.0 until all the sorbitol was dissolved.
The solution was then heated at 60°C for 10 hours.
The heated solution was cooled to less than 10°C and diluted with equal weight of cold water. The pH of the. diluted. solution--was adjusted- te 5.7 with -dilute- - = sodium hydroxide solution and then a sclution of 50% polyethylene glycol (PEG) 3350 was added to a final concentration of 6 w/w%. After mixing for : approximately 2 hours at pH 5.7, the precipitate so formed was removed by filtration with acid washed celite filter aid added to 3% w/w. Approximately 3.5 kg of the 6% PEG filtrate was set aside for other experiments. After adjusting pH of the remaining 6%
PEG filtrate to 4.9, bentonite was added in the amount of 1 g per kg of filtrate and the pH was allowed to go up to about 5.1. After mixing for 2 hours, the suspension was filtered to remove bentonite. The filtrate was then concentrated and diafiltered by ultrafiltration, using 100,000 MWCO membranes.
The pH of the solution was adjusted to about 6.5 with dilute sodium hydroxide and then about 0.4 kg pre-swollen DEAE Sephadex A-50 resin was added to the solution. After mixing the protein solution with
PRY . resin, the resin was removed by filtration. 2 solvent detergent (SD) solution containing a mixture of tri-n-butyl phosphate (TNBP) and polysorbate 80 was added to the filtrate to a final concentration of 0.3 w/w and 1.0 w/w%, respectively. After incubating the solution containing SD at 27°C for 6 hours, the solution was cooled to 0 to °C, the conductivity was adjusted to approximately 7mS/cm with sodium chloride solution and the pH was adjusted : to 5.8. About 2.7 kg of pre-treated Cm Sephadex C-50 resin was added to the solution, mixed and then filtered to retain the resin. The resin containing the adsorbed IgG was washed with 0.3% sodium chloride solution and then the adsorbed IgG was eluted with 1.4M sodium chloride solution. The eluate was clarified, concentrated and diafiltered with cold water, D-sorbitol was added and final adjustments were made to yield a solution of a composition containing about 100 mg/ml IgG and 50 mg/ml D- sorbitol with pH being at about 5.4. After final adjustments, the solution was sterile filtered and filled into glass vials. Test results of the resultant product are presented in the following
Table.
Table
Test Results of Example Product
Protein (mg/ml
I5G purity (3
Molecular distribution: (by HPLC)
Monomer (%) 89
Dimer (%) 11
Prekallikrein activator <2.5 ($ CBER Ref. Lot No. 3)
Anticomplementary activity 0.2 (CHsp U/mg IgG) | oo
Variations of the invention will be apparent to the skilled artisan.
Claims (21)
1. A continuous process for preparing an "intravenously administrable gamma globulin solution +» which comprises: (a) heat treating an impure gamma globulin solution under time and temperature conditions : sufficient for inactivating heat sensitive viruses; (b) without recovery thereof, subjecting the heat treated gamma globulin solution to polyethylene glycol fractionation, without causing precipitation . of the desired gamma globulin, for obtaining a - purified gamma globulin solution; and (c) without recovery thereof, treating the purified--gamma.. globulin _solution with _ an organic = _ solvent for inactivating envelope viruses.
2. The process of claim 1 wherein the impure gamma globulin solution contains Cohn Fraction I + IT + III, Cohn Fraction II + III paste, Cohn Fraction II + IIIw, or Cohn Fraction II.
3. The process of claim 1 wherein the impure gamma globulin solution contains proteins from Cohn Fraction II+III paste.
4. The process of claim 1 wherein the impure gamma globulin solution is subjected to at least one step of purification prior to the heat treating step (a) and the partially purified solution is subjected to the heat treatment step (a) without its intermediate recovery.
5. The process of claim 1 wherein the heat treating step (a) is carried out at about 50 to 70°C for about 10 to 20 hours.
6. The process of claim 5 wherein the heat treating step (a) is carried out for about 10 to 11 hours at about 60°C. 1s VO PUI SEE
7. The process of claim 1 wherein the polyethylene glycol fractionation is carried out in a single stage comprising at least one step in which impurities are removed as a precipitant and the desired gamma globulin remains in solution.
8. The process of claim 6 wherein the impure gamma globulin solution contains proteins from Cohn Fraction II+III paste.
9. The process of claim 1 wherein the organic solvent used in step {(c) is an alkyl phcosphate.
10. The process of claim 7 wherein the organic solvent used in step (c) is an alkyl phosphate.
11. The process of claim 10 wherein the alkyl phosphate is tri-n-butyl phosphate.
12. The process of claim I wherein tho crganic solvent contains a detergent.
13. The process of claim 11 wherein the organic solvent contains a detergent.
14. The process of claim 1 wherein after step (c) the gamma globulin solution without recovery thereof is treated with a cationic exchange resin.
15. The process of claim 7 wherein a bentonite clarification step is «carried out on the gamma globulin sblution obtained after the polyethylene glycol fractionation.
16. The process of claim 15 wherein the bentonite treated solution is treated with an anionic exchange resin.
17. The process of claim 1 wherein after step (b) the gamma globulin solution is treated with an anionic exchange resin.
18. The process of claim 14 wherein after the cationic exchange treatment, the gamma globulin solution is concentrated by tangential flow filtration.
19. The process of claim 1 wherein after step (c), the gamma globulin solution without recovery thereof is concentrated by tangential flow filtration. le Ce me
20. An intravenously-administrable gamma globulin solution produced by the process of claim 1.
21. An intravenously-administrable gamma globulin solution produced by the process of claim 18.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33328999A | 1999-06-15 | 1999-06-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200110168B true ZA200110168B (en) | 2002-08-26 |
Family
ID=23302162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200110168A ZA200110168B (en) | 1999-06-15 | 2001-12-11 | Manufacturing method for intravenous immune globulin and resultant product. |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1185290A4 (en) |
| JP (1) | JP2003501480A (en) |
| KR (1) | KR20020010921A (en) |
| CN (1) | CN1358100A (en) |
| AU (1) | AU756071B2 (en) |
| BR (1) | BR0011648A (en) |
| CA (1) | CA2375560A1 (en) |
| CZ (1) | CZ20014456A3 (en) |
| HK (1) | HK1048252A1 (en) |
| IL (1) | IL146433A0 (en) |
| PL (1) | PL352910A1 (en) |
| WO (1) | WO2000076534A1 (en) |
| ZA (1) | ZA200110168B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2437518A (en) * | 2006-04-26 | 2007-10-31 | Noel Kavanagh | Antiserum preparation |
| WO2007136327A1 (en) * | 2006-05-22 | 2007-11-29 | Ge Healthcare Bio-Sciences Ab | A method of producing igg |
| US7932356B1 (en) * | 2010-06-23 | 2011-04-26 | Bing Lou Wong | Method for the preparation of a heat stable oxygen carrier-containing pharmaceutical composition |
| CN106414476B (en) * | 2014-03-11 | 2019-12-31 | 株式会社绿十字控股 | Method for purifying immunoglobulins |
| US10287315B2 (en) | 2014-03-11 | 2019-05-14 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
| KR101941974B1 (en) * | 2016-11-18 | 2019-01-24 | 주식회사 녹십자 | Methods for Eliminating Factor XI during Plasma Protein Purification |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4820805A (en) * | 1983-07-14 | 1989-04-11 | New York Blood Center, Inc. | Undenatured virus-free trialkyl phosphate treated biologically active protein derivatives |
| FR2582515B1 (en) * | 1985-05-30 | 1988-11-04 | Merieux Inst | PROCESS FOR THE PREPARATION OF GAMMA-GOBULINS ADMINISTRABLE BY THE INTRAVENOUS ROUTE AND GAMMA-GLOBULINS OBTAINED |
| JPH0662436B2 (en) * | 1986-05-19 | 1994-08-17 | 株式会社ミドリ十字 | Method for producing intravenous immunoglobulin preparation |
| US4841023A (en) * | 1986-06-25 | 1989-06-20 | New York Blood Center, Inc. | Inactivation of viruses in labile protein-containing compositions using fatty acids |
| DE69011136T3 (en) * | 1989-01-13 | 2003-10-23 | Mitsubishi Pharma Corp | Process for the preparation of a protein-containing composition. |
| DE3927111C3 (en) * | 1989-08-17 | 1994-09-01 | Biotest Pharma Gmbh | Process for the preparation of unmodified intravenous IgM and / or IgA-containing immunoglobulin preparations |
| JP3145696B2 (en) * | 1990-10-05 | 2001-03-12 | 日本ケミカルリサーチ株式会社 | Method for producing secretory immunoglobulin A preparation |
| US5110910A (en) * | 1991-03-25 | 1992-05-05 | Miles Inc. | Virucidal euglobulin precipitation |
| DE4431833C1 (en) * | 1994-09-07 | 1995-05-18 | Blutspendedienst Der Drk Lande | Prepn. of an anti-haemophilic factor from a cryo-precipitate |
| UA64742C2 (en) * | 1997-12-24 | 2004-03-15 | Альфа Терапевтик Корпорейшн | Process for producing intravenously-administrable gamma globulin solution and product manufactured by this process |
-
2000
- 2000-06-06 BR BR0011648-3A patent/BR0011648A/en not_active Application Discontinuation
- 2000-06-06 WO PCT/US2000/011870 patent/WO2000076534A1/en not_active Application Discontinuation
- 2000-06-06 CA CA002375560A patent/CA2375560A1/en not_active Abandoned
- 2000-06-06 CN CN00808372A patent/CN1358100A/en active Pending
- 2000-06-06 PL PL00352910A patent/PL352910A1/en not_active Application Discontinuation
- 2000-06-06 JP JP2001502867A patent/JP2003501480A/en active Pending
- 2000-06-06 CZ CZ20014456A patent/CZ20014456A3/en unknown
- 2000-06-06 AU AU57224/00A patent/AU756071B2/en not_active Expired
- 2000-06-06 IL IL14643300A patent/IL146433A0/en unknown
- 2000-06-06 EP EP00942627A patent/EP1185290A4/en not_active Withdrawn
- 2000-06-06 KR KR1020017015561A patent/KR20020010921A/en not_active Application Discontinuation
-
2001
- 2001-12-11 ZA ZA200110168A patent/ZA200110168B/en unknown
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- 2003-01-09 HK HK03100222.7A patent/HK1048252A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CZ20014456A3 (en) | 2002-05-15 |
| BR0011648A (en) | 2002-03-19 |
| IL146433A0 (en) | 2002-07-25 |
| EP1185290A1 (en) | 2002-03-13 |
| CN1358100A (en) | 2002-07-10 |
| WO2000076534A1 (en) | 2000-12-21 |
| AU5722400A (en) | 2001-01-02 |
| KR20020010921A (en) | 2002-02-06 |
| PL352910A1 (en) | 2003-09-22 |
| JP2003501480A (en) | 2003-01-14 |
| CA2375560A1 (en) | 2000-12-21 |
| AU756071B2 (en) | 2003-01-02 |
| HK1048252A1 (en) | 2003-03-28 |
| EP1185290A4 (en) | 2005-08-31 |
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