WO1988008710A1 - Sequential improved method for treatment of human blood-clotting factor products - Google Patents
Sequential improved method for treatment of human blood-clotting factor products Download PDFInfo
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- WO1988008710A1 WO1988008710A1 PCT/US1988/001587 US8801587W WO8808710A1 WO 1988008710 A1 WO1988008710 A1 WO 1988008710A1 US 8801587 W US8801587 W US 8801587W WO 8808710 A1 WO8808710 A1 WO 8808710A1
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- time
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- heating
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- virus
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/647—Blood coagulation factors not provided for in a preceding group or according to more than one of the proceeding groups
-
- 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
- A61K39/12—Viral antigens
-
- 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
- A61K39/12—Viral antigens
- A61K39/29—Hepatitis virus
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/75—Fibrinogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
- C12N2770/24234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- This invention relates generally to preparation of blood products for therapeutic use; and more particularly to methods for reducing the infectivity of a virus in human blood-clotting factor products.
- the method is of particular interest in regard to viruses that cause various forms of hepatitis or that cause acquired immune deficiency syndrome ("AIDS"); and also cytomegalovirus.
- AIDS acquired immune deficiency syndrome
- viruses include (but are not limited to) hepatitis B virus, the virus known as "hepatitis non-A, non-B virus(es) ,” and hepatitis delta agent; and the viruses now believed to be causative agents of AIDS, denominated most commonly as HIV, but perhaps also including HIV-2, HIV-3 and HIV-4.
- AIDS virus AIDS virus
- Such products usually take the form of human coagulation-factor concentrates, but my invention is not limited to concentrates.
- concentrates are isolated from human blood plasma, by any of various processes called "plasma fractionatio .”
- plasma fractionatio A typical fractionation scheme is described in Seminars in Thrombosis and Hemostatis, volume VI number 1, page 4 (1979). This process yields cryoprecipitate and supernatant — the former fraction constituting a source of both Factor VIII concentrate and fibrinogen, and the latter fraction a source of Factor IX concentrate in addition to Factor II, VII and X concentrates.
- AIDS virus too can be transmitted by Factor VIII and IX concentrates which have not undergone viral inactivation. Cytomegalovirus also may be of concern. Considering hepatitis, AIDS and possibly cytomegalovirus, there is a clear risk of viral infection by coagulation-factor transfusion. This risk is a serious one. It is serious because a large number of plasma donors is required for commercial "pooled" production of clotting-factor concentrates. In absolute terms, if one donor is infected then possibly the entire supply may be infected, although for various reasons even this can be uncertain. It is further uncertain to me whether "dilution" of one infected donation in the pool of donations diminishes the risk of infection from that one donation.
- Heating the stable components at moderate temperatures and for moderate times suffices to substantially inactivate some of the most troublesome viruses.
- hepatitis transmission by albumin can be prevented by heating the albumin in solution at sixty degrees Centigrade for ten hours.
- Preliminary propositions for similarly inactivating hepatitis viruses in immune globulin by such pasteurization have also been reported — though, to the best of my knowledge, nowhere in the world is a product available from such a procedure, and nowhere have details of how to produce such a product appeared (Welch, A.G. et al., "Non-A, Non-B Hepatitis from Intravenous Immunoglobulin," 1983 Lancet page 1198).
- United States Patent 4,456,590 discloses a method for inactivating viruses present in Factor VIII and IX concentrates.
- the concentrates are lyophilized (freeze dried), then heated while they remain in the lyophilized state, and eventually reconstituted for therapeutic use.
- the lyophilized condition is believed to enhance stability of the concentrates during the heating step.
- the concentrates are heated for very extended periods of time, usually at moderate temperatures.
- one major United States manufacturer of clotting-factor concentrates heats the material, while it is lyophilized, at sixty degrees for thirty hours. Another manufacturer heats Factor IX at that temperature for approximately 144 hours.
- an incubator, water bath or oven is sometimes used for heat-treating a large number of discrete quantities of clotting-factor concentrate together, at the same time.
- temperature within a heating system is never perfectly uniform. As the equipment ages, subtle changes can perhaps compound the nonuniformity of temperature. As a result, those discrete quantities (in individual jars, watchglasses, or otherwise) of clotting-factor concentrate placed in certain parts of the heating system may not reach the same temperature as others.
- heating conditions are subject to slight variation from quantity to quantity. if the variation is between, say, one and three degrees, treatment of those particular quantities of clotting factor might be considered marginal. Therefore, to provide a natural opportunity for minimizing the effects of such uncontrolled variations would be desirable.
- My invention is a method of treating human blood- clotting factor concentrate to reduce the infectivity of a virus, such as hepatitis- or AIDS-causing virus or cytomegalovirus, if present.
- the method includes these steps:
- step (2) above I use the phrase "heating . . . for and at . . . different time-and-temperature combinations".
- the word “for” is associated with the word “time”; and the word “at” goes with "temperature.”
- the foregoing may be a definition of my invention in its broadest or most general form. For greatest enjoyment of its potential benefits and advantages, however, I prefer practice of the invention with a number of additional features or characteristics. For example, I prefer that the different time-and- temperature combinations occur in a sequence of progressively higher temperatures.
- I also prefer to provide the different time-and-temperature combinations in a sequence of progressively shorter times. Both these conditions can be satisfied in a single sequence. These characteristics are not necessary, however, and in some circumstances the opposite may be preferred — i. e., different time-and-temperature combinations occurring in a sequence of progressively longer times. That too is within the broad scope of my invention.
- the temperatures and times used in my procedure can be advantageously selected so that the aggregate of all times in the plurality of time-and-temperature combinations is no larger than the time accepted as adequate for disinfection of lyophilized concentrate in a single-heating-step procedure. In other words, the quality-assurance benefits of the invention can be obtained without using more time or more energy.
- At least one temperature is advantageously chosen no lower than a temperature accepted as nondamaging to lyophilized concentrate (and noninjurious to patients) in a single-heating-step procedure of adequate duration.
- a benefit of my present invention is the ability to make judicious and controlled use of at least one temperature that is considerably higher than, or at least near, the accepted temperatures. My invention also offers an incidental benefit which can be used if desired.
- each heating subcycle at a particular time-and-temperature combination can be used as a convenient stage for removal of the multiple quantities of clotting factor from the oven and in essence shuffling them for replacement in the oven.
- This removal, rearrangement and replacement is an additional step, performed between at least two of the time-and-temperature combinations.
- the step consists of decorrelating the discrete quantities of product, at least to some extent, with respect to any slight variation of conditions that may be occurring.
- the oven temperature is nonuniform, no one sample is likely to be treated at a low temperature for the entire multiple-heating procedure.
- This general principle applies to and may moderate the effects of other kinds of variations — even some that may not be recognized at all.
- the foregoing illustrates the important fact that the various time-and-temperature combinations need not all take place in continuous sequence. Any two time-and-temperature combinations may be separated, as - 11 -
- Such a step could be, for example, storing at room temperature, or refrigerating, or packaging, or reconstituting and redyhdrating, or shipping. I also mean to encompass any combination of such distinctly different procedural steps.
- ray drying methods perhaps can be substituted for lyophilization.
- spray drying and vacuum drying can possibly be used; however, care must be exercised to ensure that the amount of moisture removed from the plasma derivatives by these methods is sufficient to render them heat-stable. Also, care should be taken that the clotting-factor concentrate itself is not altered or damaged.
- Factor VIII is a large and relatively complex molecule, and may be unacceptably damaged by these techniques unless special precautions are taken. For this reason, lyophilization is the preferred mode of removing moisture from Factor VIII concentrate preparatory to heating.
- My present invention arises from the general recognition that improvement of the procedure introduced in my above-mentioned patent may be in order. More specifically, I believe that the procedure introduced in my earlier-mentioned patent perhaps can be refined in two regards: efficacy of viral disinfection, particularly for some viral strains or forms; and cost-effectiveness.
- test Conditions and Procedures I obtained paired samples of lyophilized Factor VIII and IX concentrates, which had previously been heat-treated at approximately sixty degrees in the lyophilized state by the manufacturer. Within each pair, the two samples had identical lot numbers and were considered to be duplicates. The samples generally weighed less than one hundred grams each, and were packaged in vials of volume ranging from fifty to ninety milliliters. One sample in each pair was heated, by placing the sample vial in a dry oven at a first predetermined temperature at ambient room pressure for a first predetermined period of time.
- This temperature was seventy or seventy-three degrees for Factor VIII, and eighty degrees for Factor IX.
- the remaining sample in each pair served as a control. It was refrigerated at four to six degrees during the heating of its duplicate. After the heat treatment, some of the samples were again heated, but at a second predetermined temperature. This temperature was eighty or eighty-two degrees for Factor VIII, and eighty or ninety-two degrees for Factor IX. Both the control and heat-treated samples were then reconstituted with sterile water. (In these tests, reconstitution was generally carried out according to manufacturer's specifications.
- Von Willebrand Antigen kits (marketed by American BioProducts) .
- the Factor IX assay was a one-stage standard assay.
- the lot appearing in Table 1 coded with prefix "A” was manufactured by Alpha Therapeutics. All the other lots were obtained from Cutter Laboratories.
- Table 3 establishes for Factor IX activity a like conclusion — namely, that following multiple heat treatment in the lyophilized state there was significant recovery.
- plasma fractions such as Factor VIII and IX concentrates of varying purity can be repeatedly heat-treated in lyophilized form, at different elevated temperatures and for extended periods of time, without significantly impairing clotting activity.
- time-and-temperature combinations can be established for effective and safe heat-sterilization of plasma fractions.
- visual observations confirm that the solubility of lyophilized Factor VIII and IX concentrates is not deleteriously affected by the high-temperature heat-treatment of the present invention.
- the amount of diluent added in reconstitution can be increased until complete solubility is achieved.
- the latter observation is important from a practical standpoint.
- bulk manufacturers of lyophilized clotting-factor concentrates and other plasma derivatives instruct end-users to carry out resolubilization of the lyophilized .concentrtes with specified amounts of diluent — e. g., sterile water, saline solutions or the like.
- the specified amounts have been empirically determined to ensure adequate solubility of the concentrates upon reconstitution. If, however, an attempt to resolubilize a heat-treated lyophilized concentrate according to manufacturer's specifications yields a solution of unacceptable viscosity, more diluent can be added.
- the method of this invention can be performed at essentially any point during the plasma fractionation process. That is, at any point along the fractionation where a plasma or plasma derivative can be lyophilized, heat treatment can be performed — and the plasma or derivative resolubilized or reconstituted before continuing the fractionation.
- heat treatment can be performed at any point along the fractionation where a plasma or plasma derivative can be lyophilized.
- the plasma or derivative resolubilized or reconstituted before continuing the fractionation.
- initial heating even at low temperatures has the effect of "priming" some viruses that are not completely inactivated at the lower temperatures, so that they are more susceptible to destruction at higher temperatures.
- This general process of priming might take the form of, say, a sort of embrittlement.
- a short exposure to the higher temperature simply completes inactivation of the "embrittled” viruses, possibly much more rapidly than with continued exposure to the lower temperature.
- Another possibility is that some viruses are in a sense embedded and sheathed within structures formed by others. In this model, denaturing those other structures breaks down the protective sheathing. Breakdown of the sheathing makes the embedded viruses more accessible to bombardment by fast-moving molecules of water or other small species (e.
- applying one or more high-temperature treatments, for a short time — in addition to applying a lower-temperature treatment for a relatively long time — may be expected to invoke the steep initial part of the inactivation functions at both temperatures. This will both hasten the entire process of inactivation and provide superior overall reduction of infectivity. Still another possibility is that two or more of these models are correct, operating in combination with one another and possibly in combination with still others. In this case the observed and expected behavior could occur as the result of two or more such groups of effects together. Once again, this discussion is of theories or hypotheses, and their truth has not been prove . Chemists and biologists use various rules of thumb to compare the relative rapidity of chemical or life processes at different temperatures.
- the assay at the beginning of this second heating interval corresponds presumably to the concentration, of the remaining viruses — whether less heat-sensitive viral forms, or embrittled viruses, or unsheathed viruses, or otherwise.
- This concentration is generally one or two logs lower than the initial assay at the beginning of the first heating interval. Consequently the number of logs' reduction required in this second heating interval — to reach a given target level of infectivity — may be smaller.
- the clock can be reset again, so to speak, for inactivation of this third viral form or group of forms — or, under any model, this third target population of viruses — by raising the temperature to a still higher value.
- the length of time required for effective reduction of this third group is possibly shorter because of its initially lower concentration. Therefore the clock once reset need not run as long.
- At least one treatment temperature that is very-generally over sixty degrees and at least one other that is significantly higher than sixty-five, would satisfy the relatively conservative requirement for basing the procedure on similarly-accepted treatments. The same is true for providing one treatment time significantly longer than twenty hours, and another significantly shorter than seventy-two hours.
- At directed to the near-terra use of the invention is one combination of sixty to seventy degrees for twenty to seventy-two hours, together with another combination of over seventy degrees for fewer than thirty hours.
- heating at a very high temperature e. g. , greater than eighty-five degrees — for less than one hour can be applied as one of the treatments.
- time-and-temperature combination generally in the range of seventy to eighty degrees and three to thirty hours;
- time-and-temperature combination generally in the range of over eighty degrees and fewer than ten hours.
- This set of specifications, using lower temperatures and longer times of each combination, will be seen to correspond to a treatment regimen based more closely on currently accepted single-heating treatment, with moderate "add on” processing. (I refer to sixty degrees for perhaps thirty to seventy-two hours, seventy for ten to thirty, and eighty for six to ten.) Its low-temperature and long-tirae range liraits thus express a critically useful combination for commercialization relatively soon.
- the same set, but using higher temperatures and shorter times also enumerated, corresponds to a more cost-effective and sophisticated application of the principles of my invention.
- the method of my present invention will significantly reduce the infectivity of a virus, such as hepatitis- or AIDS-causing virus or cytomegalovirus, if present. It is also my professional opinion that the method of this invention will increase the inactivation beyond the level obtained by any currently accepted heat-treating procedure involving a single time-and-temperature combination heat treatment of a clotting-factor product while lyophilized. The method of my present invention will do so, in ray further professional opinion, without significantly reducing patient safety or the therapeutic value of the products. Finally, there is some potential for using my invention to manufacture vaccine against, e. g. , certain hepatitis- and AIDS-causing agents.
- a virus such as hepatitis- or AIDS-causing virus or cytomegalovirus
- hepatitis B virus and probably non-A, non-B hepatitis are distributed in the clotting-factor derivatives — particularly Factor VIII and IX concentrates.
- Heat treatment of clotting-factor fractions in lyophilized or dried form at suitable temperatures for suitable periods of time can render any hepatitis virus that is ' present in the concentrates noninfectious.
- Such treatment can perhaps be optimized so as to leave that virus still iramunogenic. Consequently, reconstituted heat-treated lyophilized coagulation-factor concentrates perhaps can function as hepatitis vaccines — while simultaneously providing the therapeutic benefits normally associated with clotting-factor fractions.
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5015387A | 1987-05-15 | 1987-05-15 | |
US050,153 | 1987-05-15 | ||
US193,449 | 1988-05-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1988008710A1 true WO1988008710A1 (en) | 1988-11-17 |
Family
ID=21963642
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1988/001587 WO1988008710A1 (en) | 1987-05-15 | 1988-05-13 | Sequential improved method for treatment of human blood-clotting factor products |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0413687A1 (en) |
AU (1) | AU2251288A (en) |
WO (1) | WO1988008710A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5410022A (en) * | 1992-04-24 | 1995-04-25 | Immuno Aktiengesellschaft | Method of producing a factor VIII preparation |
WO1996017631A1 (en) * | 1994-12-08 | 1996-06-13 | Common Services Agency | Heat treated blood plasma proteins |
US5614493A (en) * | 1993-06-18 | 1997-03-25 | Immuno Ag | Use of human protein C for prevention and treatment of depositions of thrombocytes |
US5614405A (en) * | 1991-06-20 | 1997-03-25 | Immuno Aktiengesellschaft | Method of determining the virus inactivation capacity of an inactivation treatment |
US5639730A (en) * | 1992-12-16 | 1997-06-17 | Immuno Aktiengesellschaft | Method of producing a virus-safe biological preparation |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2120254A (en) * | 1982-05-13 | 1983-11-30 | Cedars Sinai Medical Center | Heat treatment of factor viii compositions |
US4446134A (en) * | 1981-10-28 | 1984-05-01 | The Green Cross Corporation | Process for heat treatment of aqueous solution containing human blood coagulation factor VIII |
US4486410A (en) * | 1984-02-09 | 1984-12-04 | Armour Pharmaceutical Company | Heat defibrinogenation of AHF preparation |
US4640834A (en) * | 1984-03-09 | 1987-02-03 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Method of inactivating reproducible filterable pathogens in blood products as well as a method of producing blood products |
US4721777A (en) * | 1984-09-25 | 1988-01-26 | The Green Cross Corporation | Process for the virus-inactivation of immunoglobulin |
JPH01155332A (en) * | 1987-12-14 | 1989-06-19 | Fuji Photo Film Co Ltd | Production of photographic silver halide emulsion |
-
1988
- 1988-05-13 EP EP88906718A patent/EP0413687A1/en not_active Ceased
- 1988-05-13 WO PCT/US1988/001587 patent/WO1988008710A1/en not_active Application Discontinuation
- 1988-05-13 AU AU22512/88A patent/AU2251288A/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4446134A (en) * | 1981-10-28 | 1984-05-01 | The Green Cross Corporation | Process for heat treatment of aqueous solution containing human blood coagulation factor VIII |
GB2120254A (en) * | 1982-05-13 | 1983-11-30 | Cedars Sinai Medical Center | Heat treatment of factor viii compositions |
US4486410A (en) * | 1984-02-09 | 1984-12-04 | Armour Pharmaceutical Company | Heat defibrinogenation of AHF preparation |
US4640834A (en) * | 1984-03-09 | 1987-02-03 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Method of inactivating reproducible filterable pathogens in blood products as well as a method of producing blood products |
US4721777A (en) * | 1984-09-25 | 1988-01-26 | The Green Cross Corporation | Process for the virus-inactivation of immunoglobulin |
JPH01155332A (en) * | 1987-12-14 | 1989-06-19 | Fuji Photo Film Co Ltd | Production of photographic silver halide emulsion |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5614405A (en) * | 1991-06-20 | 1997-03-25 | Immuno Aktiengesellschaft | Method of determining the virus inactivation capacity of an inactivation treatment |
US5864016A (en) * | 1991-06-20 | 1999-01-26 | Immuno Aktiengesellschaft | Blood product, a method of producing the same and a method of determining the virus inactivation capacity of an inactivation treatment |
US5410022A (en) * | 1992-04-24 | 1995-04-25 | Immuno Aktiengesellschaft | Method of producing a factor VIII preparation |
US5639730A (en) * | 1992-12-16 | 1997-06-17 | Immuno Aktiengesellschaft | Method of producing a virus-safe biological preparation |
US5733885A (en) * | 1992-12-16 | 1998-03-31 | Immuno Aktiengesellschaft | Method of producing a virus-safe biological preparation |
US5614493A (en) * | 1993-06-18 | 1997-03-25 | Immuno Ag | Use of human protein C for prevention and treatment of depositions of thrombocytes |
WO1996017631A1 (en) * | 1994-12-08 | 1996-06-13 | Common Services Agency | Heat treated blood plasma proteins |
AU692018B2 (en) * | 1994-12-08 | 1998-05-28 | Bio Products Laboratory Limited | Heat treated blood plasma proteins |
US5831027A (en) * | 1994-12-08 | 1998-11-03 | Common Services Agency | Heat treated blood plasma proteins |
Also Published As
Publication number | Publication date |
---|---|
EP0413687A4 (en) | 1990-05-14 |
EP0413687A1 (en) | 1991-02-27 |
AU2251288A (en) | 1988-12-06 |
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