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WO1992014360A1 - Procede de lyophilisation et de reconstitution de melanges de cellules non mammiferes non nuclees et de matiere sanguine - Google Patents

Procede de lyophilisation et de reconstitution de melanges de cellules non mammiferes non nuclees et de matiere sanguine Download PDF

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Publication number
WO1992014360A1
WO1992014360A1 PCT/US1992/000650 US9200650W WO9214360A1 WO 1992014360 A1 WO1992014360 A1 WO 1992014360A1 US 9200650 W US9200650 W US 9200650W WO 9214360 A1 WO9214360 A1 WO 9214360A1
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WIPO (PCT)
Prior art keywords
cells
process according
polymers
range
nucleated
Prior art date
Application number
PCT/US1992/000650
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English (en)
Inventor
Christine M. Williams
Raymond P. Goodrich, Jr.
Roger W. Hackett
Original Assignee
Cryopharm 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
Application filed by Cryopharm Corporation filed Critical Cryopharm Corporation
Priority to JP92506605A priority Critical patent/JPH05506457A/ja
Publication of WO1992014360A1 publication Critical patent/WO1992014360A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/125—Freeze protecting agents, e.g. cryoprotectants or osmolarity regulators
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/0233—Rickettsiales, e.g. Anaplasma
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the general field of biochemistry and medical sciences, and specifically to novel lyophilized and reconstituted cell compositions comprising non-mammalian nucleated cells.
  • Anaolasma mar ⁇ inale is a pathogen of considerable significance to the cattle industry.
  • Anaplasmosis is often endemic in the tropics and subtropics, notably in the Americas and Africa, but also is prevalent in Australia, the South Pacific Islands, and southern Asia. In the USA it has been reported from all the contiguous states, but is most prevalent in the southeast, the inter ountain west, and California.
  • the rickettsiae are small, spherical bodies without cytoplasm and are located in the stroma or cytoplasm of the RBC.
  • Anaplasma strip which is more centrally located in the RBC, is a relatively nonpathogenic variant found in cattle in some regions; another variant known as A. ovis occurs in sheep and goats and may cause disease in stressful situations. Anaplasma spp infections also occur in a variety of wild ungulates such as deer and antelope, and these can act as reservoirs of infection for cattle.
  • nucleated non-mammalian cells such as Anaplasma or Toxoplasma cells
  • the present invention provides a method for freeze- drying nucleated non-mammalian cells in the presence of red blood cells and platelets, in a manner which permits the reconstitution of the nucleated cells, as well as the red blood cells, platelets and white blood cells, with an intact cytoskeleton and with biologically-active hemoglobin, i.e. , useful red blood cells.
  • Useful RBC's can be characterized by one or more of the following: capability of synthesizing ATP; cell morphology; P 50 values; oxyhemoglobin, methemoglobin and hemichrome values; MCV, MCH, and MCHC values; cell enzyme activity; and in vivo survival.
  • RBC's have been lyophilized according to previous methods, for example in either an aqueous or phosphate-buffered saline (PBS) solution, the reconstituted cells are damaged to the extent that the cells are not capable of metabolizing or synthesizing ATP, and the cell hemoglobin cannot transport oxygen. Damaged red blood cells cannot support obligate parasites such as Anaplasma. hence it is important to preserve viable, intact red blood cells when using infected cells as a vaccine.
  • PBS phosphate-buffered saline
  • compositions provided by the present invention allow for storage of nucleated non-mammalian cells, particularly red blood cell parasites under normal conditions, while maintaining the structure and activity (viability) of the nucleated parasite cells and the host red blood cells.
  • the compositions are made by immersing a plurality of the nucleated non-mammalian cells and red blood cells (and platelets and white blood cells) in a physiologically buffered aqueous solution containing a carbohydrate, and a biologically compatible polymer, or mixture of polymers, preferably having amphipathic properties.
  • amphipathic it is meant there are hydrophobic and hydrophilic portions on a single molecule.
  • This immersion is followed by freezing the solution, and drying the frozen solution to yield novel freeze-dried cells containing less than 10%, and preferably about 3% or less by weight of moisture, which, when reconstituted, produce a significant percentage of viable, useful red blood cells and active nucleated cells. Methods of reconstitution of the cells are also provided.
  • the carbohydrate utilized in the method according to the invention is biologically compatible with the cells, that is, non-disruptive to the cell membranes, and one which permeates, or is capable of permeating, the membrane of the cells.
  • the carbohydrate may be selected from the group consisting of monosaccharides, since disaccharides do not appear to permeate the membrane to any significant extent.
  • Monosaccharide pentoses and hexoses are preferred as is _a final concentration of from about 7.0 to 37.5 weight % in phosphate buffered saline (PBS) , preferably about 26%.
  • PBS phosphate buffered saline
  • Xylose, glucose, ribose, mannose and fructose are employed to particular advantage.
  • the invention will be hereafter described in connection with parasitic Anaplasma cells, as the nucleated non-mammalian cells, and red blood cells (host cells) , but it will be understood it is also applicable to other types of nucleated cells, such as Toxoplasma.
  • the lyophilization and reconstitution procedures according to the present invention maintain viable nucleated cells (the parasite) as well as viable host red blood cells which are critical for a viable parasite.
  • the reconstituted parasite cells can then be used for preparation of vaccines after extended storage in a dry state.
  • the reconstituted red blood cell and parasite mixture may also be injected directly as a vaccine formulation.
  • the polymer may be present in the solution in concentrations of from a final concentration of about 0.7 weight % up to saturation, and has a molecular weight in the range of from about IK to about 600K.
  • the polymer has a molecular weight in the range of from about 2.5K to about 36OK, most preferably from about 5K to 50K, and is present in a concentration of from about 3.6 weight % up to the limit of solubility of the polymer in the solution.
  • Polymers selected from the group consisting of polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone derivatives, and dextran and dextran derivatives provide significant advantages.
  • polyvinylpyrrolidone an amphipathic polymer of average molecular weight of in the range of 10-40K in an amount in the range of 12-20% weight to volume in the solution prior to lyophilization.
  • Amino acid based polymers i.e., proteins
  • dextrans or hydroxyethyl starch
  • Other amphipathic polymers may be used, such as poloxamers in any of their various forms.
  • the use of the carbohydrate-polymer solution in the lyophilization allows for the recovery of intact red blood cells, a significant percentage of which has normal morphologies, and exhibit viable cell metabolism as measured by synthesis of ATP.
  • amphipathic properties of the polymer allow them to bind to the cell membrane while protecting the membrane surface by extension of the hydrophilic portion into the aqueous environment. This may alleviate the damage to the cell membrane which causes other problems, such as cell aggregation.
  • lyophilization is broadly defined as freezing a substance and then reducing the concentration of the solvent, namely water, by sublimation and desorption, to levels which will no longer support biological or chemical reactions.
  • the drying step is accomplished in a high vacuum.
  • the extent of drying (the amount of residual moisture) is of critical importance in the ability of cells to withstand long-term storage at room temperature.
  • cells may be lyophilized to a residual water content of less than 10 weight %, preferably less than 3%, and still be reconstituted to useful cells.
  • the lyophilization solution will be buffered in the range of pH of 7.0 to 7.4 preferably by a phosphate- buffered saline solution.
  • a typical phosphate- buffered saline solution will comprise mono- and di ⁇ basic sodium phosphate (usually around 10 mM) , sodium chloride (usually about 150 mM) . This solution maintains the pH at around 7.2.
  • a preferred phosphate-buffered saline (PBS) solution to be used as the lyophilization buffer will comprise pyruvate, inosine, adenine, potassium chloride, sodium chloride, and dipotassium phosphate, all of which will serve as a basic salt buffer at a pH of about 7.2.
  • this lyophilization buffer will contain a final concentration of about 30% weight by volume of a monosaccharide, preferably 1.7 M glucose, and a final concentration of about 16% weight by volume of a polymer, preferably polyvinylpyrrolidone (average molecular weight of 24K) .
  • a mixture of polymers, preferably amphipathic polymers, may be used instead of a single polymer.
  • the mixture of polymers may be present in the buffered lyophilization solution in total concentrations of from 0.7% (by weight) up to saturation.
  • each of the polymer types in the mixture has a molecular weight in the range of from about IK to about 600K (number average molecular weight) .
  • at least one of the types of polymers of the mixture will have a molecular weight from about IK to 400K, and most preferably from 2.5K to 36OK.
  • Each of the polymer types may be present in a concentration of from about 3% (by weight) up to its limit of solubility in the buffered lyophilization solution.
  • one of the types of polymers of the mixture will have a molecular weight in the range of about 10OK to about 60OK, most preferably in the range of about 100-500K.
  • Polymers selected from the group consisting of polyvinylpyrrolidone (PVP) , polyvinylpyrrolidone derivatives, dextran, dextran derivatives, amino acid based polymers (i.e., proteins) and hydroxyethyl starch (HES) may be employed.
  • Other amphipathic polymers may be used, such as poloxamers in any of their various forms.
  • 3% PVP molecular weight of about 360K
  • HES molecular weight in the range of about 100K-500K
  • the host red blood cells and the parasitic nucleated cells will preferably be prepared from whole blood centrifugation of blood containing the red blood cells infected with the parasite, mutation of the parasite, or attenuated parasite strain, with the lyophilization buffer described above so that the final diluted concentration of carbohydrate and polymer are maintained in the necessary ranges.
  • packed red blood cell concentrates containing the parasite, parasite mutant or attenuated parasite strain may be used, prepared in CPDA (commercial solution containing citrate, phosphate, dextrose and adenine) .
  • the lyophilized cells may be maintained under vacuum in vacuum-tight containers, or under nitrogen or other inert gas, at room temperatures for extended periods of time in absence of or without significant degradation of their desirable properties when reconstituted for use. It is a particular advantage of the present invention that the lyophilized cells may be stored at room temperature or refrigerated for extended periods of time.
  • the lyophilized cells may be reconstituted at normal temperatures, i.e. greater than about 17 ⁇ C up to about 37 ⁇ C, which corresponds to normal human body temperature, and preferably at room temperature (about 22 ⁇ C) .
  • the reconstitution medium is preferably a solution comprising a polymer or mixture of polymers having a molecular weight of from about IK to 360 K, preferably 5K to about 360K, present in a concentration in the range of about 10 to 30% weight by volume. This polymer may be the same polymer utilized to lyophilize the red blood cells as described above.
  • polymers polyvinylpyrrolidone, hydroxyethyl starch, and dextran are particularly preferred and most preferred is polyvinylpyrrolidone present in a concentration of about 19% weight by volume in the reconstitution solution.
  • the reconstitution solution will be buffered again typically by phosphate-buffered saline as described hereinabove to maintain a pH within the range of about 7.0 to 7.4.
  • the most particularly preferred polymer is polyvinylpyrrolidone of an average molecular weight of about 10K.
  • the most preferred reconstitution buffer will be a solution comprising potassium chloride, sodium chloride and sodium phosphate and potassium dihydrogen phosphate, all of which form a basic salt buffer at a pH of about 7.2, which also contains about 19% weight by volume of polyvinylpyrrolidone (average molecular weight about 10K) .
  • the reconstitution solution may also optionally contain a monosaccharide, preferably present in the concentration range of about 7.0 to 37.5% weight to volume.
  • the preferred monosaccharides are xylose, glucose, ribose, mannose and fructose.
  • the lyophilized cells can be reconstituted by mixing with an equal volume of the reconstitution buffer at a temperature of about 37 ⁇ C and mixed until fully hydrated.
  • the solution is preferably diluted 1:1 with dextrose-saline solution, at pH 7 and 290 mOsm.
  • the rehydrated cells be washed according to the following procedure. It is realized, however, that once the cells are reconstituted with reconstitution buffer they are in a useful form, but the combination of washings described hereinafter are preferred, specifically to optimize retention of intact cells.
  • the resulting packed cells are preferably resuspended in (approximately the volume used in the reconstitution) a buffer comprising the basic salt buffer at pH 7.2, described above, further containing about 10% weight by volume polyvinylpyrrolidone (molecular weight about 2.5K) . Separation by centrifugation completes the first post-rehydration step, a washing step.
  • the cells can be used as is or stored refigerated prior to injection.
  • the lyophilized nucleated cells and their host cells are advantageously storable at ambient atmospheric temperatures (i.e., room temperatures 20-30 ⁇ C) and can be reconstituted to viable states. This allows for the preparation and storage of viable parasite cells or attenuated viable parasite cells which are useful to prepare vaccines to the parasite. Although vaccines comprising non-viable parasite cells or particles may also be useful, it is preferred that viable parasites be recovered since viable attenuated parasites in some instances are the preferred vaccine.
  • Samples were reconstituted by mixing a volume equal to the original volume of the following reconstitution buffer with the dried material at 37°c.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
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  • Medicinal Chemistry (AREA)
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  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Abstract

Procédé de lyophilisation d'un mélange de cellules nucléés et de matière sanguine consistant à utiliser des solutions comprenant des hexoses et des pentoses monosaccharidiques, ainsi qu'un mélange d'au moins deux polymères amphipathiques biocompatibles. On peut récupérer à l'état viable les cellules nuclées, telles que des parasites cellulaires, ainsi que la matière sanguine (érythrocytes, plaquettes et globules blancs).
PCT/US1992/000650 1991-02-15 1992-02-05 Procede de lyophilisation et de reconstitution de melanges de cellules non mammiferes non nuclees et de matiere sanguine WO1992014360A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP92506605A JPH05506457A (ja) 1991-02-15 1992-02-05 非哺乳類の有核細胞と血液物質の混合物の凍結乾燥及び再構成法

Applications Claiming Priority (2)

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US65655391A 1991-02-15 1991-02-15
US656,553 1991-02-15

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WO1992014360A1 true WO1992014360A1 (fr) 1992-09-03

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JP (1) JPH05506457A (fr)
AU (1) AU1415992A (fr)
CA (1) CA2078004A1 (fr)
IL (1) IL100954A0 (fr)
WO (1) WO1992014360A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0483329A1 (fr) * 1990-05-17 1992-05-06 Cryopharm Corp Nouvelles compositions de cellules reconstituees et lyophilisees.
EP0484519A1 (fr) * 1990-05-25 1992-05-13 COBE Laboratories, Inc. Procede de lyophilisation de cellules, de matieres analogues a des cellules et de plaquettes dans un melange de polymeres amphipathiques biocompatibles
US5340592A (en) * 1988-05-18 1994-08-23 Cobe Laboratories, Inc. Lyophilization of erythrocytes
US5425951A (en) * 1988-05-18 1995-06-20 Cryopharm Corporation Method of reconstituting lyophilized cells
EP0668013A2 (fr) * 1994-02-22 1995-08-23 Nippon Telegraph And Telephone Corporation Globules sanguines, cellules souches et plaquettes lyophilisées et procédé de leur préparation
US7112576B1 (en) 1999-12-10 2006-09-26 Regents Of The University Of Minnesota Compositions and methods for cryopreservation of peripheral blood lymphocytes
EP1950283A1 (fr) * 2005-11-17 2008-07-30 Nippon Zenyaku Kogyo Co., Ltd. Solution aqueuse pour la conservation de cellules
WO2011101796A1 (fr) 2010-02-19 2011-08-25 Cadila Pharmaceuticals Limited Composition pharmaceutique de cellules tuées avec immunogénicité substantiellement conservée
WO2012098358A1 (fr) * 2011-01-20 2012-07-26 Biopharma Technology Ltd Procédé de lyophilisation
GB2502016A (en) * 2011-01-20 2013-11-13 Biopharma Technology Ltd Freeze drying method
US8871434B2 (en) 2008-03-21 2014-10-28 Fenwal, Inc. Red blood cell storage medium for extended storage
US8968992B2 (en) 2008-03-21 2015-03-03 Fenwal, Inc. Red blood cell storage medium for extended storage
WO2015175672A1 (fr) 2014-05-14 2015-11-19 Merial, Inc. Procédés de lyophilisation et de réhydratation de produits biologiques
US9409128B2 (en) 2009-10-23 2016-08-09 Fenwal, Inc. Methods for storing red blood cell products
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4874690A (en) * 1988-08-26 1989-10-17 Cryopharm Corporation Lyophilization of red blood cells

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4874690A (en) * 1988-08-26 1989-10-17 Cryopharm Corporation Lyophilization of red blood cells

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AMERICAN JOURNAL OF VETERNARY RESEARCH, Volume 33, No. 12, issued December 1972, LOVE, "Crogenic Preservation of Anaplasma marginale with Dimethyl Sulfoxide", pages 2557-2560. *
CRYOBIOLOGY, Volume 9, 1972, ASHWOOD-SMITH et al., "Low-Temperature preservation of Mammalian Cells in Tissue Culture with polyvinylprolidone (PVP), Dextrans, and Hydroxyethyl Starch (HES)", pages 441-449. *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5340592A (en) * 1988-05-18 1994-08-23 Cobe Laboratories, Inc. Lyophilization of erythrocytes
US5425951A (en) * 1988-05-18 1995-06-20 Cryopharm Corporation Method of reconstituting lyophilized cells
US5648206A (en) * 1988-08-26 1997-07-15 Cobe Laboratories, Inc. Lyophilization of cells
EP0483329A1 (fr) * 1990-05-17 1992-05-06 Cryopharm Corp Nouvelles compositions de cellules reconstituees et lyophilisees.
EP0483329A4 (en) * 1990-05-17 1993-08-11 Cryopharm Corporation Novel lyophilized and reconstituted cell compositions
EP0484519A1 (fr) * 1990-05-25 1992-05-13 COBE Laboratories, Inc. Procede de lyophilisation de cellules, de matieres analogues a des cellules et de plaquettes dans un melange de polymeres amphipathiques biocompatibles
EP0484519A4 (en) * 1990-05-25 1993-12-29 Cryopharm Corporation Process for lyophilizing cells, cell-like materials and platelets in a mixture of biocompatible amphipathic polymers
EP0668013A2 (fr) * 1994-02-22 1995-08-23 Nippon Telegraph And Telephone Corporation Globules sanguines, cellules souches et plaquettes lyophilisées et procédé de leur préparation
EP0668013A3 (fr) * 1994-02-22 1997-07-30 Nippon Telegraph & Telephone Globules sanguines, cellules souches et plaquettes lyophilisées et procédé de leur préparation.
US7112576B1 (en) 1999-12-10 2006-09-26 Regents Of The University Of Minnesota Compositions and methods for cryopreservation of peripheral blood lymphocytes
KR101368924B1 (ko) 2005-11-17 2014-03-04 니뽄젠야쿠코교 가부시키가이샤 세포 보존용 수용액
EP1950283A4 (fr) * 2005-11-17 2013-04-24 Nippon Zenyaku Kogyo Co Ltd Solution aqueuse pour la conservation de cellules
US8460926B2 (en) 2005-11-17 2013-06-11 Nippon Zenyaku Kogyo Co., Ltd Aqueous solution for cell preservation
EP1950283A1 (fr) * 2005-11-17 2008-07-30 Nippon Zenyaku Kogyo Co., Ltd. Solution aqueuse pour la conservation de cellules
US8871434B2 (en) 2008-03-21 2014-10-28 Fenwal, Inc. Red blood cell storage medium for extended storage
US8968992B2 (en) 2008-03-21 2015-03-03 Fenwal, Inc. Red blood cell storage medium for extended storage
US9409128B2 (en) 2009-10-23 2016-08-09 Fenwal, Inc. Methods for storing red blood cell products
US11864553B2 (en) 2009-10-23 2024-01-09 Fenwal, Inc. Methods and systems for providing red blood cell products with reduced plasma
US9943077B2 (en) 2009-10-23 2018-04-17 Fenwal, Inc. Methods for storing red blood cell products
WO2011101796A1 (fr) 2010-02-19 2011-08-25 Cadila Pharmaceuticals Limited Composition pharmaceutique de cellules tuées avec immunogénicité substantiellement conservée
GB2502016B (en) * 2011-01-20 2018-01-31 Biopharma Tech Ltd Method of freeze drying and reconstituting biological material
GB2502016A (en) * 2011-01-20 2013-11-13 Biopharma Technology Ltd Freeze drying method
WO2012098358A1 (fr) * 2011-01-20 2012-07-26 Biopharma Technology Ltd Procédé de lyophilisation
WO2015175672A1 (fr) 2014-05-14 2015-11-19 Merial, Inc. Procédés de lyophilisation et de réhydratation de produits biologiques
US10632182B2 (en) 2014-05-14 2020-04-28 Boehringer Ingelheim Animal Health USA Inc. Methods for freeze-drying and rehydrating biologics
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11609042B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11609043B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11740019B2 (en) 2019-03-14 2023-08-29 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11747082B2 (en) 2019-03-14 2023-09-05 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11815311B2 (en) 2019-03-14 2023-11-14 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11994343B2 (en) 2019-03-14 2024-05-28 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use

Also Published As

Publication number Publication date
CA2078004A1 (fr) 1992-08-16
AU1415992A (en) 1992-09-15
IL100954A0 (en) 1992-11-15
JPH05506457A (ja) 1993-09-22

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