WO1999033484A1 - Procede de production d'immunoglobuline serique a administration intraveineuse et produit resultant - Google Patents

Procede de production d'immunoglobuline serique a administration intraveineuse et produit resultant Download PDF

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Publication number
WO1999033484A1
WO1999033484A1 PCT/US1998/025208 US9825208W WO9933484A1 WO 1999033484 A1 WO1999033484 A1 WO 1999033484A1 US 9825208 W US9825208 W US 9825208W WO 9933484 A1 WO9933484 A1 WO 9933484A1
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WO
WIPO (PCT)
Prior art keywords
gamma globulin
solution
globulin solution
fraction
detergent
Prior art date
Application number
PCT/US1998/025208
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English (en)
Inventor
Raja R. Mamidi
Andranik Bagdasarian
Kazuo Takechi
Gorgonio Canaveral
Original Assignee
Alpha Therapeutic Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to UA99084781A priority Critical patent/UA64742C2/uk
Application filed by Alpha Therapeutic Corporation filed Critical Alpha Therapeutic Corporation
Priority to EP98961803A priority patent/EP0971727A4/fr
Priority to AU17038/99A priority patent/AU747893B2/en
Priority to CA002281938A priority patent/CA2281938A1/fr
Priority to BR9807598-5A priority patent/BR9807598A/pt
Priority to IL13147198A priority patent/IL131471A0/xx
Priority to JP53498599A priority patent/JP2001514672A/ja
Publication of WO1999033484A1 publication Critical patent/WO1999033484A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an integral, multi-step commercial process for the production of intravenously administrable immune serum globulin containing IgG ( ⁇ -globulin) as the main ingredient.
  • 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 '644 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.
  • 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.
  • Another object of the present invention is to provide very pure intravenously administrable ⁇ - 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 ⁇ -globulin process enabling removal of any denatured protein produced during heat sterilization prior to a second stage viral inactivation.
  • an alcoholic Cohn fraction which may be partially purified, but is rich in ⁇ - globulin, is heat treated in aqueous medium in the presence of a heat stabilizer for viral inactivation and is thereafter first subjected to PEG fractionation, and then 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.
  • a solvent preferably a solvent- detergent mixture
  • sorbitol is the heat stabilizer and trialkyl phosphate is the solvent.
  • 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 ⁇ - globulin.
  • any particulates present are removed prior to the solvent-detergent treatment.
  • a fraction containing immunoglobulin is used as the starting material. This fraction is not particularly limited in so far as it originates from human serum and contains an immunoglobulin fraction.
  • immunoglobulin-containing fraction examples 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 +
  • the starting material may contain impurities, such as human blood- group antibodies, plasminogen, plas in, kallikrein, prekallikrein activator, IgM, IgA, IgG polymers
  • aggregates (hereinafter “aggregates”) , etc.
  • Fraction II + IIIw is a disodium phosphate solution- washed Cohn Fraction II + III 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%.
  • temperature is gradually lowered to -5 ⁇ 1°C and pH is 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 more than 70% IgG
  • it can be suspended in 3 to 10 volumes, preferably 3 to 5 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 4.0 acetate buffer or hydrochloric acid.
  • the mixture is agitated for about 2 to 15 hours to allow all of the ⁇ -globulin to go into solution.
  • undissolved protein such as albumin and ⁇ - globulins can be removed by centrifugation and/or filtration.
  • 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.
  • 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 globulin aggregates present into immune globulin monomers and dimers, since aggregates are known to possess anti-complementary activity (ACA) .
  • 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.
  • the immune globulin protein is dissolved in water or, if in the form of an aqueous mixture such as the filtrate collected from the above-described partial purification of Fraction II + III, it can be used as is, 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 10 to 50 w/v%, up to saturation.
  • the aqueous solution of immune globulin contains sufficient water so that this solution contains about 1 to 6% total protein, a typical Fraction II + III starting material containing about 300 grams protein per kilogram paste.
  • the mixture is heated at about 50-70°C for about 10-100 hours, preferably at about 60°C, for about 10 to 20 hours, for viral inactivation of heat sensitive viruses.
  • the heat treatment step not only inactivates viruses, but also through the protein denaturization 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.
  • 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 di er, and unwanted denatured protein products produced by the heat treatment. These denatured protein products are denatured prekallikrein, plasminogen, plasmin, IgA, IgM and aggregates. Any of the PEG fractionation procedures documented in the prior art can be used. In general, two stages of PEG fractionation are carried out.
  • 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.
  • PEG concentration is increased with adjusting the pH to cause the desired IgG monomer and dimer to precipitate.
  • a first stage of PEG fractionation can be carried out at a pH of about 5.0 to 7.5, preferably within about 6.5 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 first stage of PEG fractionation can be carried out for about 1 to 8 hours, after which the precipitate is removed as above-described.
  • the filtrate will then have its pH adjusted to about 8.0 to 9.0, preferably about 8.5 to 8.9, and additional PEG added for final concentration of about 10 to 15%, preferably about 12%.
  • the precipitate formed, which is purified immunoglobulin, is removed by filtration and/or centrifugation.
  • 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.
  • a particularly advantageous procedure is to carry out an anionic exchange treatment prior to the solvent detergent viral inactivation and then a cationic exchange treatment after the solvent detergent viral inactivation.
  • certain undesirable protein materials such as prekallikrein activator, IgA, IgM and albumin
  • IgG prekallikrein activator, IgA, IgM, albumin and PEG
  • residual reagents used in the solvent-detergent treatment can be removed through the cationic exchange procedure.
  • 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.
  • 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, thetri(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/v)%, preferably about 0.1 to 3 (w/v)%.
  • 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 (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.)
  • nonionic oil bath rinsing agent such as oxyethylated alkylphenol
  • 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 ratios 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, preferably 25 to 30°C, for more than 1 hour, preferably about 5 to 8 hours, more preferably about 6 to 7 hours.
  • immune globulin is present at about a 3 to 8% protein solution in aqueous medium.
  • an 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 with immune globulin dissolved in an aqueous solvent, generally having a pH of about 5-8, 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, and either a batch or continuous system can be carried out.
  • anionic exchange batch-wise treatment can be carried out by mixing the immune globulin solution with the anionic exchanger in an amount from about 10 to 100 ml per ml of the pretreated anionic exchanger (for example, 1 gram of DEAE Sephadex A-50 resin swells to about 20 grams wet weight in 0.4% sodium chloride solution) , stirring the mixture at about 0-5°C for about 0.5 to 5 hours, and then filtering or centrifuging at 6,000 to 8,000 rpm for 10 to 30 minutes to recover the supernatant liquor.
  • Continuous treatment can be affected by passing immune globulin solution through a column of the anionic exchanger at a rate 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.
  • Usable cationic exchangers are carboxy methyl Sephadex (CM-Sephadex) CM-cellulose, SP-Sephadex, CM- Sepharose and S-Sepharose.
  • 1 ml of pretreated cationic exchanger (for example, 1 gram of CM-Sephadex C-50 resin swells to about 30-35 grams wet weight in 0.4% sodium chloride solution) is mixed with 0.5 ml to 5 ml of immune globulin solution and stirred at 0-5°C for 1-6 hours. The suspension is centrifuged or filtered to recover the IgG adsorbed resin. Also, a continuous process can be employed.
  • 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 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 100 mg/ml IgG, and 50 mg/ml D-sorbitol, with pH being at 5.4.
  • This solution is then sterile filtered through sterilized bacterial retentive filters and filled into vials.
  • immune globulin purification procedures can be appropriately combined with the processes described herein.
  • a bentonite clarification step useful for reducing the levels of kallikrein and pre-kallikrein activator can be employed. An illustration of this is set forth in Example 1, hereinbelow.
  • Fr II + IIIw paste Six hundred and eighty five grams of Fr II + IIIw paste was suspended in about 11.9 kg of cold water. Sodium acetate trihydrate solution was added to the suspension to a final concentration of approximately 0.04M to selectively solubilize IgG. After mixing for about 15 minutes, pH of the suspension was adjusted to 4.8 with pH 4.0 acetate buffer. Cold alcohol (95%) was added to the suspension to a final concentration of 17%. During the alcohol addition the temperature of the suspension was lowered gradually to about -6°C. Three hundred and three grams of acid washed Celite 535 available from Celite Corporation was added as a filter aid to the suspension to a final concentration of about 2.0%.
  • the Celite and the Fraction III paste containing unwanted protein such as plasmin, plasminogen, IgA and IgM were then removed by filtration utilizing a filter press.
  • the filtrate was further clarified by 0.45 ⁇ m and 0.2 ⁇ m filters.
  • the pH of the Fraction II + III w clarified solution was adjusted to 4.0 with 1.0 N hydrochloric acid and then concentrated by ultrafiltration to about 3.4 liters (l/5th the original volume).
  • Cold water equal to the amount removed by the 1st ultrafiltration was added to the concentrated solution and it was again concentrated by ultrafiltration to about l/5th the original volume.
  • protein concentration of the solution was about 2%.
  • the solution was further concentrated to about 4% and diafiltered against cold water until the conductivity of the solution was below 300 ⁇ S/cm to help avoid protein aggregation and denaturation during heat treatment.
  • the solution was further concentrated to about 8.8% protein.
  • D-sorbitol was added to the solution to a final concentration of about 33%.
  • pH of the sorbitol containing solution was adjusted to 5.5 with 0.5 N sodium hydroxide.
  • the solution was then heated for 10 hours at 60°C. After the heat treatment, cold water equal to 3 times the volume of the heat treated solution was added and the diluted solution was cooled to 0-2 °C.
  • the pH of the solution was adjusted to 6.9 with
  • CM-Sephadex C-50 with 0.4% sodium chloride at pH 5.8
  • pH of the solution was adjusted to 5.8 and about 860 grams of previously equilibrated CM-Sephadex C-50 (with 0.4% sodium chloride at pH 5.8), was added.
  • the suspension was filtered.
  • adsorbed IgG was eluted with 1.4 N sodium chloride.
  • the eluate was clarified, diafiltered and concentrated. D-sorbitol was added and final adjustments were made to yield a solution with composition of about 100 mg/mL IgG, 50 mg/mL D- sorbitol at pH 5.4.
  • the solution was then sterile filtered through sterilized bacterial retentive filter and filled into vials.
  • the intermediate bentonite step in this Example is useful for further reducing the presence of hypotensive enzymes such as kallikrein and prekallikrein activator.
  • Fr II + III paste was suspended in 4.5 kg of cold water at 0-2°C. After mixing for 1 hour, pH of the suspension was adjusted to 5.0 with 1 N hydrochloric acid. After mixing for 3 hours at pH 5.0, the precipitate was removed by centrifugation. D-sorbitol was added to the centrifugate to a final concentration of 33% and mixed for 1 hour. The pH of the suspension was adjusted to 5.5 and then it was heated for 10 hours at 60°C. After the heat treatment, cold water equal to 3 times the volume of the heat treated solution was added and the diluted solution was cooled to 0-2 °C. Fifty percent polyethylene glycol (PEG) 3350 solution was added to a final concentration of 6% PEG.
  • PEG polyethylene glycol
  • the pH of the 6% PEG suspension was adjusted to 5.7 with 0.5 N sodium hydroxide and the suspension was mixed for 2 hours.
  • Acid wash Celite 535 was added to a final concentration of 1.5% and the suspension was mixed for 1 hour.
  • the precipitate along with the Celite was removed by filtration.
  • the pH of the filtrate was adjusted to 8.8 with 0.5 N sodium hydroxide, and the PEG concentration adjusted to 12% with the addition of 50% PEG solution.
  • the pH of the 12% PEG suspension was readjusted to 8.8, the suspension being mixed for 1 hour and filtered to collect the purified immune globulin paste. About 251 g of purified immune globulin paste was recovered.
  • Tri-n-butyl phosphate (TNBP) and Polysorbate 80 mixture was added to the solution to give a final concentration of 0.3% TNBP and 1.0% Polysorbate 80.
  • the solution was then incubated for 1 hour at 27 °C and left overnight in a cold box at 4°C. Next day, pH of the solution was adjusted to 5.8 and 1.8 kg of CM-Sephadex C-50 resin previously equilibrated with 0.4% sodium chloride at pH 5.8, was added. After mixing for 2 hours , the resin was separated by filtration. After washing the CM-Sephadex resin 3 times with 0.3% sodium chloride, adsorbed IgG was eluted with 1.4 N sodium chloride. The eluate was clarified, diafiltered and concentrated.
  • D-sorbitol was added and final adjustments were made to yield a solution with composition of about 100 mg/mL of IgG and about 50 mg/mL D-sorbitol.
  • the solution was split into 2 parts, part A and part B.
  • the pH of part A was adjusted to 5.4 and part B was adjusted to pH 4.3.
  • the solutions of part A and part B were then individually sterile filtered through sterilized bacterial retentive filters and filled into vials.

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Abstract

L'invention concerne un procédé de production d'une solution de gammaglobuline à administration intraveineuse sensiblement exempte de contamination virale. Ce procédé consiste à soumettre à un traitement d'inactivation virale et à fractionner une solution de gammaglobuline impure puis à traiter la gammaglobuline purifiée avec un mélange solvant-détergent pour une inactivation virale complémentaire.
PCT/US1998/025208 1997-12-24 1998-12-07 Procede de production d'immunoglobuline serique a administration intraveineuse et produit resultant WO1999033484A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
UA99084781A UA64742C2 (uk) 1997-12-24 1998-07-12 СПОСІБ ОДЕРЖАННЯ РОЗЧИНУ <font face="Symbol">g</font>-ГЛОБУЛІНУ, ПРИЗНАЧЕНОГО ДЛЯ ВНУТРІШНЬОВЕННОГО ВВЕДЕННЯ, І ПРОДУКТ, ЩО ОДЕРЖУЄТЬСЯ У ЦЕЙ СПОСІБ (ВАРІАНТИ)
EP98961803A EP0971727A4 (fr) 1997-12-24 1998-12-07 Procede de production d'immunoglobuline serique a administration intraveineuse et produit resultant
AU17038/99A AU747893B2 (en) 1997-12-24 1998-12-07 Production process for intravenous immune serum globulin and resultant product
CA002281938A CA2281938A1 (fr) 1997-12-24 1998-12-07 Procede de production d'immunoglobuline serique a administration intraveineuse et produit resultant
BR9807598-5A BR9807598A (pt) 1997-12-24 1998-12-07 Processo de produção para globulina de soro imunológico intravenoso e produto resultante
IL13147198A IL131471A0 (en) 1997-12-24 1998-12-07 Production process for intravenous immune serum globulin and resultant product
JP53498599A JP2001514672A (ja) 1997-12-24 1998-12-07 静脈投与用ガンマグロブリンの製造方法とその生産物

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Application Number Priority Date Filing Date Title
US99795297A 1997-12-24 1997-12-24
US08/997,952 1997-12-24

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WO1999033484A1 true WO1999033484A1 (fr) 1999-07-08

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JP (1) JP2001514672A (fr)
KR (1) KR20000075562A (fr)
CN (1) CN1214042C (fr)
AR (1) AR018260A1 (fr)
AU (1) AU747893B2 (fr)
BR (1) BR9807598A (fr)
CA (1) CA2281938A1 (fr)
CO (1) CO4970799A1 (fr)
IL (1) IL131471A0 (fr)
MY (1) MY117328A (fr)
RU (1) RU2198668C2 (fr)
TW (1) TW546144B (fr)
UA (1) UA64742C2 (fr)
WO (1) WO1999033484A1 (fr)

Cited By (9)

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Publication number Priority date Publication date Assignee Title
EP1185290A1 (fr) * 1999-06-15 2002-03-13 Alpha Therapeutic Corporation Procede de fabrication d'immunoglobuline intraveineuse et produit resultant
WO2002026258A2 (fr) * 2000-09-28 2002-04-04 Research Corporation Technologies, Inc. Traitement des maladies d'origine immunologique au moyen de l'administration par voie orale de fractions de plasma enrichies en immunoglobuline g
EP1225180A2 (fr) * 2001-01-17 2002-07-24 Probitas Pharma, S.A. Procédé de production de gammaglobuline G humaine à virus inactivé
WO2003034982A2 (fr) * 2001-10-19 2003-05-01 Hemacare Corporation Procede de purification a rendement eleve d'immuno-globulines a partir de plasma sanguin et d'intermediaires de plasma sanguin
US7138120B2 (en) * 1998-06-09 2006-11-21 Statens Serum Institut Process for producing immunoglobulins for intravenous administration and other immunoglobulin products
US20120294847A1 (en) * 2011-05-16 2012-11-22 Omrix Biopharmaceuticals Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
EP1561756B1 (fr) 2002-09-11 2015-12-23 Chugai Seiyaku Kabushiki Kaisha Methode de purification d'une proteine
CN106459140A (zh) * 2014-03-11 2017-02-22 株式会社绿十字控股 用于纯化免疫球蛋白的方法
US9631007B2 (en) 2005-05-25 2017-04-25 Hoffmann-La-Roche Inc. Method for the purification of antibodies

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Publication number Priority date Publication date Assignee Title
KR100791502B1 (ko) * 2006-09-29 2008-01-03 한스바이오메드 주식회사 바이러스 불활화된 무세포 인체 이식재 생산방법
DK2350271T3 (en) * 2008-11-20 2016-04-04 Biogen Ma Inc ARGININ INACTIVATION OF ENVIRONMENT VIRA
ES2381828B1 (es) * 2012-03-20 2012-11-16 Grifols, S.A. PROCEDIMIENTO PARA OBTENER UNA COMPOSICION DE IgG MEDIANTE TRATAMIENTO TERMICO
CN107880116B (zh) * 2016-09-30 2023-02-03 盖立复集团公司 用于制备免疫球蛋白的方法

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US7138120B2 (en) * 1998-06-09 2006-11-21 Statens Serum Institut Process for producing immunoglobulins for intravenous administration and other immunoglobulin products
EP1185290A4 (fr) * 1999-06-15 2005-08-31 Alpha Therapeutic Corp Procede de fabrication d'immunoglobuline intraveineuse et produit resultant
EP1185290A1 (fr) * 1999-06-15 2002-03-13 Alpha Therapeutic Corporation Procede de fabrication d'immunoglobuline intraveineuse et produit resultant
WO2002026258A2 (fr) * 2000-09-28 2002-04-04 Research Corporation Technologies, Inc. Traitement des maladies d'origine immunologique au moyen de l'administration par voie orale de fractions de plasma enrichies en immunoglobuline g
WO2002026258A3 (fr) * 2000-09-28 2002-10-24 Res Corp Technologies Inc Traitement des maladies d'origine immunologique au moyen de l'administration par voie orale de fractions de plasma enrichies en immunoglobuline g
CZ300413B6 (cs) * 2001-01-17 2009-05-13 Grifols, S.A. Zpusob výroby humánního gama-globulinu G a viry inaktivovaný humánní gama-globulin G
US6875848B2 (en) 2001-01-17 2005-04-05 Probitas Pharma, S.A. Process for the production of virus-inactivated human gammaglobulin G
EP1225180A2 (fr) * 2001-01-17 2002-07-24 Probitas Pharma, S.A. Procédé de production de gammaglobuline G humaine à virus inactivé
EP1225180A3 (fr) * 2001-01-17 2004-01-28 Probitas Pharma, S.A. Procédé de production de gammaglobuline G humaine à virus inactivé
US6893639B2 (en) 2001-10-19 2005-05-17 Hemacare Corporation Method for high yield purification of immune globulins from blood plasma and blood plasma intermediates
WO2003034982A3 (fr) * 2001-10-19 2003-11-06 Hemacare Corp Procede de purification a rendement eleve d'immuno-globulines a partir de plasma sanguin et d'intermediaires de plasma sanguin
US7125552B2 (en) 2001-10-19 2006-10-24 Hemacare Corporation Method for high yield purification of immune globulins from blood plasma and blood plasma intermediates
WO2003034982A2 (fr) * 2001-10-19 2003-05-01 Hemacare Corporation Procede de purification a rendement eleve d'immuno-globulines a partir de plasma sanguin et d'intermediaires de plasma sanguin
EP1561756B1 (fr) 2002-09-11 2015-12-23 Chugai Seiyaku Kabushiki Kaisha Methode de purification d'une proteine
US10654888B2 (en) 2002-09-11 2020-05-19 Chugai Seiyaku Kabushiki Kaisha Method for removing viruses in a physiologically-active protein-containing sample
US9631007B2 (en) 2005-05-25 2017-04-25 Hoffmann-La-Roche Inc. Method for the purification of antibodies
US11034754B2 (en) 2005-05-25 2021-06-15 Hoffmann-La Roche Inc. Method for the purification of antibodies
US9023994B2 (en) * 2011-05-16 2015-05-05 Omrix Biopharmaceuticals, Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
US9796770B2 (en) 2011-05-16 2017-10-24 Omrix Biopharmaceuticals Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
US20120294847A1 (en) * 2011-05-16 2012-11-22 Omrix Biopharmaceuticals Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
EP3118209A4 (fr) * 2014-03-11 2017-11-08 Green Cross Holdings Corporation Procédé de purification d'immunoglobuline
US10287315B2 (en) 2014-03-11 2019-05-14 Green Cross Holdings Corporation Method for purifying immunoglobulin
CN106459140B (zh) * 2014-03-11 2019-12-10 株式会社绿十字控股 用于纯化免疫球蛋白的方法
CN106459140A (zh) * 2014-03-11 2017-02-22 株式会社绿十字控股 用于纯化免疫球蛋白的方法

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BR9807598A (pt) 2000-02-22
MY117328A (en) 2004-06-30
AU747893B2 (en) 2002-05-30
KR20000075562A (ko) 2000-12-15
EP0971727A4 (fr) 2005-01-19
JP2001514672A (ja) 2001-09-11
TW546144B (en) 2003-08-11
EP0971727A1 (fr) 2000-01-19
UA64742C2 (uk) 2004-03-15
AU1703899A (en) 1999-07-19
CO4970799A1 (es) 2000-11-07
CA2281938A1 (fr) 1999-07-08
CN1214042C (zh) 2005-08-10
IL131471A0 (en) 2001-01-28
AR018260A1 (es) 2001-11-14
CN1252729A (zh) 2000-05-10
RU2198668C2 (ru) 2003-02-20

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