WO2000076534A1 - Manufacturing method for intravenous immune globulin and resultant product - Google Patents
Manufacturing method for intravenous immune globulin and resultant product Download PDFInfo
- Publication number
- WO2000076534A1 WO2000076534A1 PCT/US2000/011870 US0011870W WO0076534A1 WO 2000076534 A1 WO2000076534 A1 WO 2000076534A1 US 0011870 W US0011870 W US 0011870W WO 0076534 A1 WO0076534 A1 WO 0076534A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gamma globulin
- solution
- globulin solution
- detergent
- fraction
- Prior art date
Links
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
Definitions
- the present invention relates to an integral, multi-step commercial process for the production of intravenously administrable immune globulin containing IgG ( ⁇ -globulin) as the main ingredient.
- Usual starting materials for a ⁇ -globulin solution are Cohn Fraction II or Cohn Fraction II + III.
- 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 to any heat treatment.
- the liquid heat treatment can be carried out in the presence of a sugar, sugar alcohol or amino acid stabilizer.
- a sugar, sugar alcohol or amino acid stabilizer for example, a sugar, sugar alcohol or amino acid stabilizer.
- 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 ⁇ -globulin titre.
- PEG polystyrene glycol
- U.S. Patent 4,876,088 by Hirao et al describes the preparation of intravenously injectable ⁇ -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%/12%) which would remove heat denatured protein and then by other purification steps including DEAE- Sephadex ion exchange chromatography.
- An object of the present invention is to provide an integral, commercially useable process for producing a highly purified ⁇ -globulin solution from the Cohn fractionation process.
- a further object of the present invention is to provide a commercial ⁇ -globulin process enabling removal of any denatured protein produced during heat sterilization prior to a second stage viral inactivation.
- sorbitol is the heat stabilizer and trialkyl phosphate is the solvent.
- a single stage polyethylene glycol fractionation step is carried out without precipitation of the desired ⁇ -globulin.
- 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 globulin as a resultant product) without the intermediate recovery of partially purified gamma globulin solids.
- 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 globulin as a resultant product) without the intermediate recovery of partially purified gamma globulin solids.
- 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.
- 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%.
- temperature is gradually lowered to -5 ⁇ 1°C and ' p H i- s maintained or adjusted to 7.2+0.1, 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
- Fraction II + IIIw paste 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 to 15 volumes, of cold water at a temperature of about 0 to 5°C and with pH being adjusted to be between 4.5 to 6.0, preferably 5.0 to 5.5 using pH
- undissolved protein such as albumin and ⁇ -globulins can be removed by centrifugation and/or filtration.
- the immune globulin protein in the form of the aqueous mixture collected from the above-described partial 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% .
- 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.
- the solution pH is adjusted to 4.5 to 6.5, preferably 5.0 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.
- 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.
- 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 denatured prekallikrein activator, plasminogen, plasmin, IgA, IgM and aggregates.
- 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 .
- the final essential step of the present invention is to carry out a second viral inactivation procedure utilizing a solvent or solvent-detergent mixture.
- 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.
- a cationic exchange treatment is carried out after the solvent detergent viral inactivation.
- 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 virus being present within a large particle and thereby possibly avoiding exposure to the solvent-detergent .
- 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.
- trialkyl phosphate Today, the preferred solvent for inactivation of 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").
- TNBP tri (n-butyl) phosphate
- 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 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 .
- detergent examples include polyoxyethylene derivatives of a fatty acid, partial esters of anhydrous sorbitol such as Polysorbate 80
- Triton X100 Triton X100, etc.
- examples include other surfactants and detergents such as Zwitter ionic detergents and so on.
- the detergent 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%.
- the trialkyl phosphate treatment of the immune globulin containing composition is carried out at about 20 to 35°C,
- immune globulin is present at about a 5 to 10% protein solution in aqueous medium.
- an optional anionic exchange treatment can be carried out on the solvent detergent treated immune globulin.
- at least a cationic exchange treatment is carried out on the solvent-detergent treated product.
- the ionic exchange treatments are carried out on the immune globulin aqueous solution from solvent (or solvent detergent) processing, generally having a pH 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 of 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 comprises anion exchanging groups bonded to an insoluble carrier.
- the anion exchanging groups include diethylaminoethyl (DEAE) , a quaternary aminoethyl (QAE) group, etc.
- 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.
- CM-Sephadex carboxy methyl Sephadex
- SP-Sephadex CM-cellulose
- CM- Sepharose CM- Sepharose
- SP-Sephadex CM- 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
- solvent or solvent detergent
- the IgG 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.
- the solvent (solvent detergent) treated solution is diafiltered" and concentrated by tangential flow filtration for removal of solvent detergent and PEG.
- a preferred processing is treatment with a cationic exchanger followed by tangential flow filtration.
- the IgG is clarified, diafiltered and concentrated to the extent needed.
- a stabilizer such as D- sorbitol can be added and final adjustments made to yield a solution of a composition containing about 50 to 100 mg/ml IgG, and 50 mg/ml D-sorbitol, with pH being at about 5.4.
- this solution may be filtered through 35 nanometers or less porosity filters. This stabilized and optionally nanofiltered solution is then sterile filtered through sterilized bacterial retentive filters and filled into vials.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Immunology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Genetics & Genomics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002375560A CA2375560A1 (en) | 1999-06-15 | 2000-06-06 | Manufacturing method for intravenous immune globulin and resultant product |
EP00942627A EP1185290A4 (en) | 1999-06-15 | 2000-06-06 | Manufacturing method for intravenous immune globulin and resultant product |
IL14643300A IL146433A0 (en) | 1999-06-15 | 2000-06-06 | A process for the preparation of an intravenously-administerable gamma globulin solution |
JP2001502867A JP2003501480A (en) | 1999-06-15 | 2000-06-06 | Production method and preparation of intravenous immunoglobulin |
BR0011648-3A BR0011648A (en) | 1999-06-15 | 2000-06-06 | Manufacturing method of intravenous immunoglobulin and resulting product |
AU57224/00A AU756071B2 (en) | 1999-06-15 | 2000-06-06 | Manufacturing method for intravenous immune globulin and resultant product |
KR1020017015561A KR20020010921A (en) | 1999-06-15 | 2000-06-06 | Manufacturing method for intravenous immune globulin and resultant product |
HK03100222.7A HK1048252A1 (en) | 1999-06-15 | 2003-01-09 | Manufacturing method for intravenous immune globulin and resultant product |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33328999A | 1999-06-15 | 1999-06-15 | |
US09/333,289 | 1999-06-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000076534A1 true WO2000076534A1 (en) | 2000-12-21 |
Family
ID=23302162
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/011870 WO2000076534A1 (en) | 1999-06-15 | 2000-06-06 | 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) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN106414476A (en) * | 2014-03-11 | 2017-02-15 | 株式会社绿十字控股 | Method for purifying immunoglobulin |
EP3118209A4 (en) * | 2014-03-11 | 2017-11-08 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
WO2018093049A1 (en) * | 2016-11-18 | 2018-05-24 | 주식회사 녹십자 | Method for removing fxi when purifying plasma proteins |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7932356B1 (en) * | 2010-06-23 | 2011-04-26 | Bing Lou Wong | Method for the preparation of a heat stable oxygen carrier-containing pharmaceutical composition |
Citations (7)
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 |
US4841023A (en) * | 1986-06-25 | 1989-06-20 | New York Blood Center, Inc. | Inactivation of viruses in labile protein-containing compositions using fatty acids |
US4874708A (en) * | 1985-05-30 | 1989-10-17 | Makula Marie France | Process for the preparation of intra-venously administered gamma-globulins and the gamma-globulins obtained |
US5110910A (en) * | 1991-03-25 | 1992-05-05 | Miles Inc. | Virucidal euglobulin precipitation |
US5132406A (en) * | 1986-05-19 | 1992-07-21 | The Green Cross Corporation | Method of producing immunoglobulin preparations for intravenous injection |
US5151499A (en) * | 1989-01-13 | 1992-09-29 | The Green Cross Corporation | Production method for protein-containing composition |
US5371196A (en) * | 1990-10-05 | 1994-12-06 | Jcr Pharmaceuticals Co., Ltd. | Process for producing secretory immunoglobulin A preparations |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 PL PL00352910A patent/PL352910A1/en not_active Application Discontinuation
- 2000-06-06 AU AU57224/00A patent/AU756071B2/en not_active Expired
- 2000-06-06 IL IL14643300A patent/IL146433A0/en unknown
- 2000-06-06 WO PCT/US2000/011870 patent/WO2000076534A1/en not_active Application Discontinuation
- 2000-06-06 CN CN00808372A patent/CN1358100A/en active Pending
- 2000-06-06 JP JP2001502867A patent/JP2003501480A/en active Pending
- 2000-06-06 KR KR1020017015561A patent/KR20020010921A/en not_active Application Discontinuation
- 2000-06-06 BR BR0011648-3A patent/BR0011648A/en not_active Application Discontinuation
- 2000-06-06 CZ CZ20014456A patent/CZ20014456A3/en unknown
- 2000-06-06 EP EP00942627A patent/EP1185290A4/en not_active Withdrawn
- 2000-06-06 CA CA002375560A patent/CA2375560A1/en not_active Abandoned
-
2001
- 2001-12-11 ZA ZA200110168A patent/ZA200110168B/en unknown
-
2003
- 2003-01-09 HK HK03100222.7A patent/HK1048252A1/en unknown
Patent Citations (7)
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 |
US4874708A (en) * | 1985-05-30 | 1989-10-17 | Makula Marie France | Process for the preparation of intra-venously administered gamma-globulins and the gamma-globulins obtained |
US5132406A (en) * | 1986-05-19 | 1992-07-21 | The Green Cross Corporation | Method of producing immunoglobulin preparations for intravenous injection |
US4841023A (en) * | 1986-06-25 | 1989-06-20 | New York Blood Center, Inc. | Inactivation of viruses in labile protein-containing compositions using fatty acids |
US5151499A (en) * | 1989-01-13 | 1992-09-29 | The Green Cross Corporation | Production method for protein-containing composition |
US5371196A (en) * | 1990-10-05 | 1994-12-06 | Jcr Pharmaceuticals Co., Ltd. | Process for producing secretory immunoglobulin A preparations |
US5110910A (en) * | 1991-03-25 | 1992-05-05 | Miles Inc. | Virucidal euglobulin precipitation |
Non-Patent Citations (1)
Title |
---|
See also references of EP1185290A4 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN106414476A (en) * | 2014-03-11 | 2017-02-15 | 株式会社绿十字控股 | Method for purifying immunoglobulin |
EP3118209A4 (en) * | 2014-03-11 | 2017-11-08 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
KR101917196B1 (en) * | 2014-03-11 | 2018-11-09 | 주식회사 녹십자홀딩스 | Method for purifying immunoglobulin |
KR101917197B1 (en) * | 2014-03-11 | 2018-11-09 | 주식회사 녹십자홀딩스 | Method for purifying immunoglobulin |
US10287315B2 (en) | 2014-03-11 | 2019-05-14 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
US10414816B2 (en) | 2014-03-11 | 2019-09-17 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
CN106414476B (en) * | 2014-03-11 | 2019-12-31 | 株式会社绿十字控股 | Method for purifying immunoglobulins |
WO2018093049A1 (en) * | 2016-11-18 | 2018-05-24 | 주식회사 녹십자 | Method for removing fxi when purifying plasma proteins |
Also Published As
Publication number | Publication date |
---|---|
AU5722400A (en) | 2001-01-02 |
IL146433A0 (en) | 2002-07-25 |
JP2003501480A (en) | 2003-01-14 |
AU756071B2 (en) | 2003-01-02 |
KR20020010921A (en) | 2002-02-06 |
CA2375560A1 (en) | 2000-12-21 |
PL352910A1 (en) | 2003-09-22 |
ZA200110168B (en) | 2002-08-26 |
EP1185290A4 (en) | 2005-08-31 |
CZ20014456A3 (en) | 2002-05-15 |
EP1185290A1 (en) | 2002-03-13 |
HK1048252A1 (en) | 2003-03-28 |
BR0011648A (en) | 2002-03-19 |
CN1358100A (en) | 2002-07-10 |
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