EP0674531A1 - Process for preparing a virus-safe biological composition - Google Patents
Process for preparing a virus-safe biological compositionInfo
- Publication number
- EP0674531A1 EP0674531A1 EP94901684A EP94901684A EP0674531A1 EP 0674531 A1 EP0674531 A1 EP 0674531A1 EP 94901684 A EP94901684 A EP 94901684A EP 94901684 A EP94901684 A EP 94901684A EP 0674531 A1 EP0674531 A1 EP 0674531A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- preparation
- surfactant
- virus
- weight
- biological
- Prior art date
- Legal status (The legal status 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 status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0088—Liquid substances
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
- Y10S530/83—Plasma; serum
Definitions
- the invention relates to a method for producing a virus-safe biological preparation by heating while maintaining at least 50% of the biological activity, and to the use of the method for increasing the virus safety of a biological preparation.
- Biological preparations are preparations of biological origin that can be obtained, for example, from body fluids, such as blood, or from cell cultures. Due to contact with potentially infectious material, there is a risk of contamination by infectious agents in such products.
- Blood products are understood to mean products from human or animal blood or plasma, which are intended for therapeutic, prophylactic or diagnostic use. Such products may contain enzymes, proenzymes including coagulation factors, enzyme inhibitors, immunoglobulins, albumin, plasminogen, fibrinogen, fibronectin or plasma.
- a method for the treatment of biological and pharmaceutical products by treatment with amphiphiles (surfactants) is at a temperature between 4 ° C and 37 ° C in the
- This treatment aims to inactivate hepatitis B viruses and non-A, non-B hepatitis viruses (membrane-covered).
- a nonionic detergent up to 2 g / 100 ml are added to aqueous protein solutions according to the process of EP-0 278 487 and then incubated at low temperature, for example 4 ° C., until a virus-inactivating effect has been achieved.
- this treatment with detergents has the disadvantage that it only targets membrane-enveloped viruses: if a surfactant is present in a concentration above the micelle-forming concentration (CMC), lipid-containing membranes are solubilized and the virus is inactivated.
- viruses that do not have a lipid-containing membrane as such e.g. Hepatitis A virus, which can, however, be enclosed in lipid vesicles, is released by a surfactant treatment and thus activated instead of inactivated (see also Manucci PM et al. (1992), The Lancet 339, 819 "Outbreak of hepatitis A among Italian patients with haemophilia ").
- surface-active agents are added in an amount of 0.01 to 0.5% by weight together with a polyol and a chelating agent to a fibronectin-containing solution which is heat-treated at a temperature of 50 to 70 ° C.
- the small amounts of surfactant protect fibronectin from denaturation by shear forces.
- Detergents are also used as solubilizers together with virus-inactivating agents (glycyrrhizin-triterpenoid compounds bond) added to blood plasma, which is kept at a temperature up to 60 ° C (US Pat. No. 5,186,945).
- virus-inactivating agents glycyrrhizin-triterpenoid compounds bond
- very small amounts of nonionic detergents are used, for example in a concentration of 0.001 to 5% by weight. The advantage of using these small amounts of detergent is that they do not have to be removed.
- EP 0 159 311 has proven itself as heat treatment of blood products in the solid state.
- Blood products are lyophilized, adjusted to a content of water, methanol or ethanol of more than 5% by weight and less than 70% by weight and heated in a closed container at a temperature in a range from 50 to 121 ° C.
- This process even kills resistant viruses such as vaccinia virus. In this case, the virus is inactivated very slowly, so that a very long heating period or a very high temperature must be used.
- a method for inactivating viruses in a product which is adsorbed on a solid phase is described in EP-0 197 554.
- the adsorbed product is brought into contact with a virus inactivating agent, after which the solid phase is separated off and washed. Finally, the product is desorbed again.
- An amphiphilic substance which can be anionic, cationic, zwitterionic and nonionic is described as a virus-inactivating agent. However, the treatment can only be carried out at a temperature of 0 to 50 ° C.
- the object of the invention is to provide a method for producing a virus-safe preparation containing a labile protein by heating, the effect of which is improved compared to the previously known heat treatments, the biological activity of the preparation being essentially retained.
- Resistant viruses such as vaccinia virus, should be inactivated as quickly and completely as possible so as not to unnecessarily reduce the biological activity of the preparation.
- the object is achieved according to the invention by a method for producing a virus-safe biological preparation by heating while maintaining at least 50% of the biological activity, which is characterized in that a surfactant is added to the preparation before the heating step and the heating is carried out in the presence of the same, whereupon preferably the surfactant is removed. It has been shown that the addition of a surfactant to the preparation before the heat treatment increases the effectiveness in a synergistic manner without significantly reducing the biological activity of the preparation. After the heat treatment, the surfactant is separated from the preparation.
- Biologically compatible anionic, cationic, non-ionic or zwitterionic amphiphiles are particularly suitable as surfactants.
- Surfactants are generally considered to be biologically ver inert if the concentration used does not lyse erythrocytes in a standardized in vitro test (see Pape et al., Arzneistoff.Forsch./Drug Res. 40, 498-502, 1990).
- surfactants from the following groups can be used:
- Alkyl glucosides e.g. Octyl- ⁇ -D-glucoside
- Acid amide derivatives e.g. Decanoyl-N-methylglucamide (MEGA-10), anionic surfactants such as e.g. Na deoxycholate,
- cationic surfactants such as Benzyltrimethylammonium chloride or benzyldimethyl-2-hydroxyethylammonium chloride, and
- zwitterionic surfactants such as N-Dodecyl-N ', N-dimethylammonio-3-propanesulfonate (sulfobetaine SB12).
- the surfactant is added in a high concentration corresponding to a ratio of surfactant to protein of at least 1: 100, preferably in the range from 2: 100 to 300: 100, if the treatment of the preparation is carried out in liquid or solid form. If the preparation has been adsorbed on a solid support and the heat treatment according to the invention is carried out on the solid support, the treatment can be carried out at even higher surfactant concentrations, for example up to 98% by weight.
- the invention likewise encompasses a method for increasing the virus safety of a biological preparation while maintaining at least 50%, preferably 80% of the biological activity, in particular the virus safety against membrane-enveloped and non-membrane-enveloped viruses, the preparation being present in the presence of a surfactant in a concentration of at least 1
- % By weight, preferably more than 10% by weight, is heated up to 98% by weight.
- the present method is also suitable for inactivating virus aggregates or vesicular structures that harbor viruses, for example hepatitis A viruses.
- the method according to the invention is therefore surprisingly also suitable for stabilizing a biological preparation which contains heat-labile proteins during a heat treatment.
- Measures to maintain biological activity during heat treatment are particularly important for heat-unstable proteins.
- Treatment of heat-stable preparations for example an albumin preparation, is, however, less critical.
- the invention therefore relates above all to a method for producing a preparation, with the exception of an albumin preparation which contains heat-labile proteins.
- preparations can also be produced which contain labile plasmatic proteins, such as factors of coagulation, fibrinolysis and thrombolysis or proenzymes and enzymes, or their inhibitors.
- the heat treatment of the preparation according to the invention is preferably carried out in the solid state, but can also be carried out in aqueous solution or in suspension.
- a preferred embodiment of the method is carried out so that the surfactant is added to the preparation in solution where is then lyophilized and heat-treated in the lyophilized state, the heat treatment then being possible at substantially higher temperatures.
- the heat treatment is advantageously carried out in a solid, wet state, for example in the lyophilized preparation with a water content of more than 5% by weight and less than 70% by weight in a closed container at a temperature of 50-121 ° C. for at least 10 minutes until the potential infectivity of the preparation is eliminated, preferably 1 to 30 h at 60 to 80 ° C.
- an aqueous solution containing blood coagulation factor XIII can also be heated according to the invention without using the usual stabilizers.
- the heat treatment in solution or suspension is carried out at a temperature of 55 to 65 ° C, preferably at about 60 ° C, and for a period of time sufficient to inactivate any viruses that may be present, preferably for 2 minutes to 100 hours. A treatment time of 30 minutes to 30 hours is most preferred.
- the time required for the method according to the invention can be determined using model viruses, such as HIV,
- Sindbis, polio, TBE and vaccinia viruses can be determined in a preliminary experiment. A virus added before heating must no longer be detectable after heating.
- the preparation obtained is distinguished by its low proportion of denaturing products, since despite heating at least 50%, preferably at least 80%, of the biological activity of the preparation is retained. It could be observed that the turbidity which occurs after heating highly concentrated preparations does not appear in a solution of the preparation.
- the extinction E 600 of the preparation heated according to the invention in a solution with at least 5% by weight protein content is less than 0.1 (with a layer thickness of 1 cm, reference: water). The result is a product that is optically clear in solution and largely free of denaturing products.
- Arginine for example, can be added to a factor-XIII-containing solution in order to increase the effect of the surfactant effect on the reduction of the turbidity formation.
- the excellent virucidal effect of the highly concentrated surfactants means that there is no need to use organic solvents.
- the preparation treated according to the invention therefore contains no toxic traces of organic solvents.
- a further embodiment of the method according to the invention includes the addition of carbohydrates to the biological preparation, as a result of which the hydration of existing proteins is ensured even after lyophilization.
- carbohydrates for example, Sucrose or sorbitol can be added to the hydration of proteins in the preparation.
- the virus-inactivating heat treatment is carried out on a preparation adsorbed on a solid support, the adsorbed preparation being suspended in a solution of a surfactant when heated.
- the virus-inactivated preparation can be separated from the carrier in a known manner.
- Blood factors such as factors of the prothrombin complex, are adsorbed, for example, on an ion exchanger or on an affinity matrix and suspended and heated in an aqueous solution in the presence of high surfactant concentrations.
- the surfactant can preferably be separated from the preparation by means of suitable measures, such as dialysis, chromatographic purification methods (for example by ion-exchange chromatography) or protein precipitation.
- suitable measures such as dialysis, chromatographic purification methods (for example by ion-exchange chromatography) or protein precipitation.
- the treated preparation can adsorbed on a solid carrier and washed free of surfactants.
- the precipitation of the proteins to be prepared with precipitants such as ethanol, ammonium sulfate or polyethylene glycol
- the surfactant concentration in the preparation is preferably reduced to less than 0.1% by weight, most preferably less than 0.01% by weight.
- the improved effect of heat treatment can be shown if very small amounts of surfactant are used in an aqueous solution, which per se have a non-inactivating effect on viruses.
- a virus titer can therefore be set in the presence of surfactants, which is only eliminated by the heat treatment.
- the synergistic effect of the method according to the invention is evident when the kinetics of virus inactivation due to the heat treatment with and without surfactant content in the preparation are compared with one another.
- Model viruses such as vaccinia virus, Sindbis or SIV (Simian Immunodeficiency Virus) are described in Ge presence of ineffective amounts of surfactants during heat treatment of blood products in a solid, wet state is inactivated more quickly than during heat treatment of the preparation without surfactant content.
- Model viruses that are added to the preparation are killed under suitable conditions after only 10 minutes, but in any case after one hour of heat treatment according to the invention.
- Example 1 Heat treatment of a factor VIII preparation in the presence of octyl- ⁇ -D-glucoside.
- a factor VIII-containing preparation was produced in accordance with AT 391 808.
- the surfactant was removed by chromatographic purification of factor VIII using an anion exchanger.
- Example 2 Heat treatment of a factor VHI preparation in the presence of Triton ® X-100
- Triton® X-100 15 mg were added. The ratio of surfactant to protein was 19: 100.
- the solution was lyophilized and the water content adjusted to 20% by weight. Thereafter, heat treatment was carried out at 60 ° C.
- the virus titer was determined after 0, 1, 3 and 10 hours. The specific activity of factor VIII was also determined. The virus inactivation or residual activities are shown in Table 2.
- the surfactant was removed by chromatographic purification of factor VIII using an anion exchanger.
- Example 3 Heat treatment of a plasminogen preparation in the presence of Zwittergent ® 3-10
- Example 4 Heat treatment of a prothrombin complex preparation in the presence of Tween 80
- a prothrombin complex factor preparation was prepared by the method of Brummelhuis ("Methods of Plasma Protein Fractionation", J.M. Curling (ed.), S 117ff, Acad. Press, 1980).
- the virus titer was determined after 0, 1, 3 and 10 hours of heat treatment at 60 ° C, and after another hour of heat treatment at 80 ° C or in a further batch after 20, 40 and, 60 minutes at 80 ° C.
- the specific activity was determined before and after the heat treatment, the results are shown in Table 4.
- the surfactant was removed by chromatographic purification of the prothrombin complex using an anion exchanger.
- Example 5 Heat treatment of a fibrinogen preparation in the presence of MEGA-10
- Plasma was fractionated according to Cohn and the Cohn I fraction containing fibrinogen was prepared. 1.8 ml of a solution of this fraction was mixed with 0.2 ml of a vaccinia virus suspension and decanoyl-N-methylglucamide (MEGA-10) was added to the solution so that its concentration in solution was 0.2% by weight. The ratio of surfactant to protein was 2.5: 100. The mixture was lyophilized and the water content adjusted to 10% by weight. The lyophilisate was heated at 60 ° C. for 10 hours and then at 80 ° C. for 3 hours or in a further batch at 80 ° C. for 3 hours.
- MEGA-10 decanoyl-N-methylglucamide
- the virus titer was determined after 0, 1, 3 and 10 hours of heating (60 ° C) and after a further 3 hours (80 ° C). The virus titer was also determined after 1, 2 and 3 hours of heating (80 ° C). The specific activity of the fibrinogen was determined as a clottable material per unit volume determined before and after the heat treatment. The results are shown in Table 5.
- the surfactant was removed by precipitation of the fibrinogen with glycine.
- Example 6 Heat treatment of a thrombin preparation in the presence of 0.5% octyl- ⁇ -D-glucoside
- a thrombin preparation was produced according to the procedure of the Austrian application A 2183/91.
- the surfactant was removed by chromatographic purification of the thrombin on an anion exchanger.
- Example 7 Heat treatment of a Cl-esterase inhibitor preparation in the presence of 0.5% octyl- ⁇ -D-glycoside
- a Cl-esterase inhibitor preparation was made according to the method of Vogelaar et al (1973) Vox Sang. 26, 118-127.
- 1.8 ml of a solution of this preparation were mixed with 0.2 ml of a vaccinia virus suspension and 10 mg of octylglucoside were added to the solution (0.5% by weight).
- the ratio of surfactant to protein was 12.5: 100.
- the mixture was lyophilized, a water content of 15% by weight was established and the mixture was heated to 60.degree.
- the virus titer was determined after 0, 1, 3, 6 and 10 hours
- the C1-esterase inhibitor was adsorbed on DEAE-Sephadex and washed with a buffer until it was free of surfactant.
- the different detection limit of the virus titer in the process comparison results from the choice of the detection method, which is due to the presence of surfactants. This different detection limit is not relevant in this context.
- Example 8 Heat treatment of activated prothrombin complex (FEIBA) bound to ion exchangers in the presence of Tween-80 (inactivation of vaccinia virus)
- FEIBA activated prothrombin complex
- the buffer-moist gel-protein complex was then suspended with 1 ml of undiluted Tween-80 for 10 min at 60 ° C., 0.1 ml of a vaccinia virus suspension being added beforehand. The virus titer was determined after 2, 4, 6, 8 and 10 min.
- the suspension of the gel-protein complex in Tween-80 was then diluted 1:10 with a solution of 30 g / 1 NaCl in water. The active ingredient was eluted from the gel.
- the surfactant was removed from this solution in a known manner by adsorption with Extracti-Gel TM D Detergent Removing Gel (Pierce). The solution was then dialyzed against distilled water, frozen and lyophilized. After reconstitution of the lyophilizate, the FEIB activity was determined in accordance with AT-350726.
- a preparation of FEIBA which was also produced, mixed with virus, but without treatment with hot surfactant, and a preparation without surfactant and heat treatment served as a control.
- Example 9 Heat treatment of activated prothrombin complex (FEIBA) bound to ion exchangers in the presence of Tween-80 (inactivation of TBE viruses)
- FEIBA activated prothrombin complex
- FEIBA was produced analogously to Example 8. However, 0.1 ml of a TBE virus suspension was added to treat the buffer-moist gel-protein complex with undiluted Tween-80. The virus titer was determined after 0.5, 1, 1.5, 2, 3, 4, 7 and 10 min. The FEIB activity in the eluate was determined as described in Example 8.
- Example 10 Heat Treatment of Prothrombin Complex Bound to Ion Exchangers in the Presence of Tween-80 (Inactivation of Vaccinia Viruses)
- the washed gel was then suspended with 1 ml of Tween-80 for 10 min at 60 ° C. to inactivate the virus.
- 0.1 ml of a vaccinia virus suspension was added to the surfactant solution.
- the virus titer was determined after 2, 4, 6, 8 and 10 min.
- the suspension of the gel-protein complex in Tween-80 was then diluted with a solution of 1 g / l Na 3 citrate .2H 2 O, 30 g / l NaCl, 1000 IU heparin / l, pH 7.0, 1:10.
- the prothrombin complex was eluted.
- the surfactant from this solution was removed in a known manner by adsorption with Extracti-Gel TM D Detergent Removing Gel (Pierce).
- the solution containing prothrombin complex was buffered against a buffer containing 4 g / l Na 3 citrate.2H 2 O and 8 g / l NaCl, pH 7.0 and lyophilized.
- the protein content and the coagulation factors II, VII, IX and X were determined in the reconstituted prothrombin complex.
- a prothrombin complex prepared as described above, but without surfactant treatment, and a preparation without surfactant and heat treatment served as controls.
- Example 11 Heat treatment of prothrombin complex bound to ion exchangers in the presence of Tween-80 (inactivation of TBE viruses)
- Prothrombin complex was prepared analogously to Example 10. However, 0.1 ml of a TBE virus suspension was added to treat the buffer-moist gel protein complex with undiluted Tween-80. The virus titer was determined after 0.5, 1, 1.5, 2, 3, 4, 7 and 10 min. The protein content and the coagulation factors II, VII, IX and X were determined in the reconstituted prothrombin complex.
- a prothrombin complex prepared as described above, but without surfactant treatment, and a preparation without surfactant and heat treatment served as controls.
- Example 12 Stability of factor XIII when heated in solution (without stabilizers) in the presence of a surfactant
- a plasma fraction (Cohn I precipitate) was mixed with 10 times the amount of a citrate-containing buffer solution, pH 7.0 (13.4 g / l Na 3 citrate. 2H 2 O, 29 g / l NaCl, 20,000 KIE aprotinin / 1) solved. After adding ammonium sulfate to 16% saturation (at room temperature), the mixture was cooled to 4 ° C. and the mixture was stirred for a further 2 h. The resulting precipitate was dissolved with the buffer solution and the precipitation with ammonium sulfate was repeated once.
- a citrate-containing buffer solution pH 7.0 (13.4 g / l Na 3 citrate. 2H 2 O, 29 g / l NaCl, 20,000 KIE aprotinin / 1
- the precipitate was dissolved in a citrate-containing buffer solution, pH 7.0 (5.9 g / l Na 3 citrate. 2H 2 O, 7 g / l NaCl, 100 KIE aprotinin / l) and heated to 56 ° C. for 10 min.
- the resulting precipitate from denatured fibrinogen was centrifuged off.
- the heat precipitation supernatant was freed from accompanying proteins by precipitation with 3.5% by weight of PEG 4000 at 4 ° C.
- the factor XIII was then precipitated by adding PEG 4000 to a concentration of 10% by weight at 4 ° C., separated by centrifugation and in 1/25 of the original volume of a 0.1% by weight sodium citrate buffer (pH 7.0 ) solved.
- the specific activity was 21 U factor XHI / mg protein.
- the solution was divided and 1 part by weight of Tween 80 was added. Both solutions were heated to 60 ° C for 6 hours.
- the factor XIII residual activities after heating for 6 hours were 82% without added surfactant and 84% with added surfactant.
- Example 12 was repeated with different surfactants in different concentrations (heating: 4 h, 60 ° C.). TABLE 12
- Examples 12 and 13 show that heat treatment of factor XIII can be carried out in the presence of surfactants without having to accept major losses in factor XIII activity.
- example 14 illustrates the surprisingly improved inactivation kinetics of a model virus by heat treatment in the presence of a surfactant compared to heat treatment without the addition of surfactant:
- Example 14 Inactivation of a model virus (Sindbis) in a factor XIII-containing solution in the presence or absence of a surfactant
- a factor XIII-containing solution according to Example 12 was divided and 0.3% by weight of n-octylglucoside was added to part.
- Sindbis virus suspension is added (start of virus inactivation reaction) and incubated further at 60 ° C. Samples were taken at certain intervals and the virus titer was determined.
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Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT250092A AT402892B (en) | 1992-12-16 | 1992-12-16 | Process for the production of a virus-safe biological product |
AT2500/92 | 1992-12-16 | ||
AT154793A AT402151B (en) | 1993-08-03 | 1993-08-03 | Process for the production of a virus-safe biological product |
AT1547/93 | 1993-08-03 | ||
PCT/AT1993/000191 WO1994013329A1 (en) | 1992-12-16 | 1993-12-10 | Process for preparing a virus-safe biological composition |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0674531A1 true EP0674531A1 (en) | 1995-10-04 |
Family
ID=25596141
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94901684A Ceased EP0674531A1 (en) | 1992-12-16 | 1993-12-10 | Process for preparing a virus-safe biological composition |
Country Status (7)
Country | Link |
---|---|
US (2) | US5639730A (en) |
EP (1) | EP0674531A1 (en) |
JP (1) | JP3133338B2 (en) |
AU (1) | AU6653094A (en) |
HR (1) | HRP931496B1 (en) |
SI (1) | SI9300659A (en) |
WO (1) | WO1994013329A1 (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0674531A1 (en) * | 1992-12-16 | 1995-10-04 | IMMUNO Aktiengesellschaft | Process for preparing a virus-safe biological composition |
DE4435485C1 (en) * | 1994-10-04 | 1996-03-21 | Immuno Ag | Process for obtaining high-purity von Willebrand factor |
SE503424C2 (en) * | 1994-11-14 | 1996-06-10 | Pharmacia Ab | Process for purification of recombinant coagulation factor VIII |
DE19528221C2 (en) * | 1995-08-01 | 1998-10-22 | Blutspendedienst Der Drk Lande | Process for the production of a virus-safe, therapeutic preparation from human plasma |
GB9604921D0 (en) * | 1996-03-08 | 1996-05-08 | Nat Blood Authority | Purification method |
US6068838A (en) * | 1996-04-29 | 2000-05-30 | Baxter Aktiengesellschaft | Purified multimerase |
AT405135B (en) | 1997-01-17 | 1999-05-25 | Immuno Ag | PREPARATION COMPREHENSIVE THIOL GROUP-PROTEINS |
AT404358B (en) | 1997-02-04 | 1998-11-25 | Immuno Ag | METHOD FOR CHROMATOGRAPHIC CLEANING OR FRACTIONATION OF VON WILLEBRAND FACTOR FROM A VWF-CONTAINING MATERIAL |
AT405485B (en) | 1997-05-28 | 1999-08-25 | Immuno Ag | A PHARMACEUTICAL PREPARATION CONTAINING THE VWF PROPEPTIDE |
AT406120B (en) | 1997-08-28 | 2000-02-25 | Immuno Ag | TISSUE ADHESIVE |
AT405739B (en) | 1997-09-19 | 1999-11-25 | Immuno Ag | METHOD FOR PURIFYING ANTITHROMBIN III |
DE60027695T2 (en) * | 1999-02-12 | 2007-04-26 | Baxter Ag | PROCESS FOR THE PRODUCTION OF FIBRINOGEN AND FIBRONECTIN AND PROTEIN COMPOSITIONS THEREFORE MANUFACTURED |
AT410218B (en) | 1999-08-20 | 2003-03-25 | Baxter Ag | METHOD FOR PRODUCING A QUALITY-ASSURED POOL OF BIOLOGICAL SAMPLES |
EP1148063A1 (en) * | 2000-04-18 | 2001-10-24 | Octapharma AG | Composition containing hemostatic activ vWF and process for its preparation |
US7347967B2 (en) * | 2001-03-02 | 2008-03-25 | Isan Biotech Co. | Plastic system and method of porous bioimplant having a unified connector |
DE102004037805B3 (en) * | 2004-08-03 | 2006-03-23 | Zlb Behring Gmbh | Process for the heat treatment of fibrinogen-containing pharmaceutical preparations |
AU2005229674B2 (en) * | 2004-11-18 | 2010-11-04 | Kedrion Melville Inc. | Low concentration solvent/detergent process of immuneglobulin with pre-treatment |
JP4248537B2 (en) * | 2005-09-29 | 2009-04-02 | 日本航空電子工業株式会社 | connector |
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- 1993-12-10 JP JP06513548A patent/JP3133338B2/en not_active Expired - Fee Related
- 1993-12-14 US US08/165,906 patent/US5639730A/en not_active Expired - Lifetime
- 1993-12-15 HR HR931496A patent/HRP931496B1/en not_active IP Right Cessation
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US5639730A (en) | 1997-06-17 |
HRP931496A2 (en) | 1996-10-31 |
SI9300659A (en) | 1994-06-30 |
US5733885A (en) | 1998-03-31 |
WO1994013329A1 (en) | 1994-06-23 |
JPH08504407A (en) | 1996-05-14 |
JP3133338B2 (en) | 2001-02-05 |
AU6653094A (en) | 1994-07-04 |
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