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WO1999002169A1 - Procede pour produire du plasma sanguin ou du serum sanguin a virus inactives sous forme lyophilisee - Google Patents

Procede pour produire du plasma sanguin ou du serum sanguin a virus inactives sous forme lyophilisee Download PDF

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Publication number
WO1999002169A1
WO1999002169A1 PCT/EP1998/003389 EP9803389W WO9902169A1 WO 1999002169 A1 WO1999002169 A1 WO 1999002169A1 EP 9803389 W EP9803389 W EP 9803389W WO 9902169 A1 WO9902169 A1 WO 9902169A1
Authority
WO
WIPO (PCT)
Prior art keywords
virus
liquid
blood plasma
inactivated
blood
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.)
Ceased
Application number
PCT/EP1998/003389
Other languages
German (de)
English (en)
Inventor
Dieter Dickhörner
Heinz Hubert Mertens
Ulrich Grage
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Blutspendedienst Der Drk-Landesverbande Nordrhein und Westfalen-Lippe Gemeinnuetzige GmbH
Original Assignee
Blutspendedienst Der Drk-Landesverbande Nordrhein und Westfalen-Lippe Gemeinnuetzige GmbH
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 Blutspendedienst Der Drk-Landesverbande Nordrhein und Westfalen-Lippe Gemeinnuetzige GmbH filed Critical Blutspendedienst Der Drk-Landesverbande Nordrhein und Westfalen-Lippe Gemeinnuetzige GmbH
Publication of WO1999002169A1 publication Critical patent/WO1999002169A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K35/16—Blood plasma; Blood serum

Definitions

  • the invention relates to a method for producing 5 virus-inactivated blood plasma or serum in lyophilized form.
  • Blood plasma and blood serum, as well as other protein-containing solutions of components obtained from blood plasma or blood serum) are mainly used in the therapy of various diseases, as well as for emergency substitution. Since blood plasma and serum can only be obtained from blood donations, virus inactivation of liquids is necessary to prevent the transmission of viruses to the recipient of the liquid.
  • Virus-inactivated blood plasma is generally used to treat volume reductions in blood volume during bleeding. It continues to be used in the therapy of
  • Tri-n-butyl phosphate as a solvent and an alkylphenyl polyethylene glycol as a detergent. Then be
  • EP 0 050 061 A2 describes a method for virus inactivation of biological and pharmaceutical products, in particular plasma protein products by adding Akylphenylpolyethylenglykolen (Triton-X-
  • EP 0 239 859 describes, as a further development thereof, the virus inactivation of blood plasma and other biological fluids with the aid of a solvent / detergent mixture of tri-n-butyl phosphate (TNBP) and Triton-X-100 ® .
  • TNBP tri-n-butyl phosphate
  • Triton-X-100 ® Triton-X-100 ®
  • the substances are removed by extraction with vegetable oils. Soybean oil, castor oil, cottonseed oil, corn oil, peanut oil, olive oil and other vegetable oils are used in particular for this purpose.
  • WO 91/14439 also describes a method for producing non-infectious blood plasma, in which the above-mentioned methods are used.
  • the virus is inactivated by adding tri-n-butyl phosphate and
  • Triton-X-100 ® The virus-inactivating substances are then separated off by adding biologically compatible lipids such as soybean oil or castor oil. This is followed by chromatographic purification on a column with C-18 adsorbent.
  • the virus-inactivated liquids can also be manufactured, stored and sold as lyophilized products.
  • lyophilized biological fluids for example lyophilized blood plasma
  • lyophilized blood plasma can be stored at cow's cabinet temperatures of 2 to 8 ° C for 2 years while maintaining the activity.
  • lyophilization of blood plasma or blood serum has not yet been implemented.
  • Most of the blood plasma is generally produced in plastic bags and deep-frozen and accordingly has to be thawed in a complex manner before use.
  • the conventional procedure in which the liquid product is filled into bottles, the bottles are subsequently deep-frozen to at least minus 30 ° C. and then subjected to the freeze-drying process, often has problems since the lyophilisate obtained shows only poor solubility when solving. Furthermore, the lyophilized preparation has a lower stability, since a proportion of residual water is present in the lyophilisate, which freeze drying process can not be removed. In the freeze-drying process, too, it often happens that the frozen product migrates out of the bottle when the water is drawn off due to the migration of the solvent crystals in the frozen solution. This must be prevented by expensive measures.
  • WO 96/29556 describes a device and a method for the lyophilization of biological fluids, the containers rotating about a horizontal axis of rotation and being filled with the biological fluid. The liquid is then frozen by injecting a liquid or gaseous coolant into the liquid.
  • this method has the disadvantage that the horizontal rotation of the containers can lead to the leakage of the liquid or to contamination of the outer wall of the container. Furthermore, there is also the risk of introducing pollutants by injecting the coolant into the liquid.
  • the technical object of the invention is therefore to provide a process for the production of blood plasma or serum in lyophilized form, in which the above-mentioned disadvantages of the freeze-drying processes do not occur, a more soluble lyophilisate is obtained and because of a smaller amount of residual water a height ⁇ re stability.
  • This technical problem is solved by a method for producing virus-inactivated blood plasma or serum in lyophilized form by treating the blood plasma or blood serum with virus-inactivating substances, removing the virus-inactivating substances, the virus-inactivated biological fluid being filled into containers, which are then filled filling at 600 to 1000 rpm as long can rotate until the liquid in the container has taken the form of a hollow cylinder, immersing the rotating container in a cooling medium so that the liquid therein freezes, removing the container with the frozen liquid and lyophilizing the frozen liquid.
  • a solvent / detergent mixture is used as the virus-inactivating substance, which preferably contains TNBP (tri-n-butyl phosphate) as the solvent and Triton-X- 100® (alkylphenylpolyethylene glycols) as the detergent.
  • TNBP tri-n-butyl phosphate
  • Triton-X- 100® alkylphenylpolyethylene glycols
  • the virus-inactivated biological liquid is subjected to sterile filtration before it is filled.
  • Round containers are preferably used, with glass bottles being particularly preferred.
  • the containers are immersed in the cooling medium for 1 to 40 minutes, depending on the cooling medium used.
  • the cooling medium is particularly preferably selected from the group consisting of ethanol, liquid nitrogen or other liquid gases or gas mixtures.
  • liquid nitrogen or other liquid gases or gas mixtures as the cooling medium is particularly preferred. Immersion times of 1 to 10 minutes, preferably 1 to 5 minutes, are achieved here.
  • the virus-inactivated blood plasma is produced separately according to blood groups 0. A, B and AB. It is free of cells and cell components, but contains, for example, the coagulation factors and their inhibitors, among other components.
  • Frozen fresh plasma from medically controlled donors is used for the production, which was obtained, tested, certified and released according to the applicable guidelines.
  • the blood plasma is processed on a production scale of approximately 100-300 kg to lyophilized blood plasma. This is done in designated rooms of cleanliness classes 100 and 10,000 (US Federal Standard 209 E).
  • the blood plasma is produced under defined conditions using the solvent / detergent method. The process of starting raw material, frozen fresh plasma, goes through the following stages.
  • the frozen fresh plasma is first thawed at 10 to 15 ° C.
  • the plasma is pooled and then conditioned by adjusting the temperature, pH and adding predetermined amounts of sodium dihydrogen phosphate and glycine.
  • the plasma is then clarified.
  • Tri-n-butyl phosphate as a solvent and Triton-X-100 ® as a detergent are added to the blood plasma at 26 to 28 ° C. and pH 7, so that a final concentration of 1% is achieved in each case.
  • Virus inactivation takes place at 29 ° C for four hours.
  • the solvent / detergent reagents are then separated from the virus-inactivated plasma by means of castor oil extraction at 15 to 18 ° C. There is a phase separation.
  • the blood plasma is filtered through filters, e.g. B. the sizes 0.45 - 1.0 ⁇ m.
  • the remaining solvent / detergent reagents and the residues of the castor oil are then removed from the virus-inactivated blood plasma by chromatographic purification using C-18 column materials.
  • the pH from 6 to 7 is adjusted by adding citric acid.
  • sterile filtration is carried out over 0.45 and 0.2 ⁇ m filters.
  • the virus-inactivated sterile-filtered blood plasma is either filled into transfer bags or bottled for lyophilization.
  • the transfer bags are then frozen. There is an intermediate storage until the final packaging at at least minus 30 ° C.
  • the bottles intended for lyophilization are provided with GT stoppers.
  • the filled glass bottles with their liquid contents are set in rotation in an apparatus around their longitudinal axis at 600 to 1000 rpm.
  • the axis of rotation is vertical.
  • the liquid in the container rises on the walls and releases the bottom of the container.
  • the liquid takes the form of a hollow cylinder in the container.
  • This change in the ratio of surface to thickness is important for the subsequent freeze drying, in which solid solvent crystals have to migrate through the entire frozen column of ice in the container in order to be removed from the frozen solution.
  • the container can be rotated before the freezing process outside or inside the cooling medium. It only has to be ensured that the freezing process does not start until the liquid is evenly distributed on the vertical walls of the container and has taken the form of a hollow cylinder.
  • ethanol, liquid nitrogen or other liquid gases or gas mixtures can serve as the cooling medium for the temperatures, which must be minus 35 ° C or lower. It is important that the cooling medium can be removed without residue or evaporates independently to prevent the user from coming into contact with the container Side effects are caused.
  • the freezing process is complete when the entire contents of the container are frozen. The time required for this is between 1 and 40 minutes, depending on the cooling medium.
  • liquid nitrogen as the cooling medium is particularly preferred.
  • the low temperatures result in considerable advantages over the use of ethanol. This means that the contents of the bottle freeze faster after only 1 to 5 minutes. This has numerous advantages over the ethanol previously used as a cooling medium.
  • Ethanol had to be kept at temperatures of around minus 40 ° C. When several containers were immersed, it took about 30 minutes to freeze the liquids contained in the container. Furthermore, it was often not possible to freeze several batches in a row, since the ethanol heated up too much and therefore breaks had to be taken between the individual batches.
  • the bottles are transported through the tunnel on a conveyor belt, simultaneously sterilized at an air temperature of 360 to 370 ° C and then cooled to room temperature by sterile-filtered cold air. After leaving the hot air tunnel, the bottles are transported to the bottle filling machine via a turntable, where they are kept ready for subsequent filling.
  • the sterile filter output is z. B. directly connected to the bottle filling machine via a milk pipe thread. Due to the nitrogen overpressure present on the vessel with the virus-inactivated plasma, the virus-inactivated blood plasma is conveyed to the bottle filling machine after opening the bottom valve and the nitrogen overpressure line through the sterile filter. The bottle filling stops automatically as soon as the desired amount of blood plasma has passed the flow pulse generator and the flow pulse generator closes the flow valve.
  • the filled bottles are sealed under clean room conditions with a siliconized, autoclaved rubber stopper (GT stopper) and then frozen in an apparatus with rotation. After freezing, the bottles are removed from the freezer, placed in transport containers and stored at minus 30 ° C until freeze-drying. The filled glass bottles are only removed from the minus 30 ° C intermediate storage immediately before freeze-drying. The glass bottles are made under clean room conditions opened by lifting the freeze-drying plug and the freeze-drying program, which lasts several days, is started.
  • GT stopper siliconized, autoclaved rubber
  • the bottles are automatically closed under vacuum in the freeze-drying chamber by lifting the chamber panels and pressing the rubber stoppers into the glass bottles.
  • the lyophilization chamber is automatically slowly ventilated, the bottles with the freeze-dried blood plasma are removed and a test device is used to check whether there is negative pressure in the bottles. The bottles are then bound and assembled.
  • a 250 ml glass bottle which is filled with 200 ml of liquid virus-activated blood plasma, is closed with a rubber stopper and rotated at room temperature at 800 U / mm.
  • the rotating bottle is then immersed in an ethanol bath set at a temperature of minus 40 ° C.
  • the mixture is rotated for 30 minutes.
  • the bottle is temporarily stored in a deep-freeze store at at least minus 30 ° C and then subjected to freeze-drying.
  • Example 2 The procedure is carried out as in Example 1, but with the difference that the bottles rotate at 800 U / mm before being immersed in a cooling medium. This process is continued until the liquid in the bottle takes the form of a hollow cylinder. Only then is it immersed in the cooling medium of liquid nitrogen. The process is finished in less than 5 minutes. The bottles are removed and stored at least minus 30 ° C until freeze-drying.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un procédé pour produire du plasma sanguin ou du sérum sanguin à virus inactivés, sous forme lyophilisée. Ledit procédé consiste à traiter le plasma sanguin ou le sérum sanguin avec des substances inactivant les virus, puis à éliminer les substances inactivant les virus. L'introduction du plasma sanguin ou du sérum sanguin à virus inactivés s'effectue dans des contenants que l'on fait tourner ensuite à des vitesses de 600 à 1000 tours/minute jusqu'à ce que le liquide dans le contenant prenne la forme d'un cylindre creux. Ledit procédé consiste ensuite à plonger les contenants en rotation dans un agent réfrigérant de façon à congeler le liquide se trouvant à l'intérieur, puis à retirer le contenant avec le liquide congelé et à lyophiliser ledit liquide.
PCT/EP1998/003389 1997-07-11 1998-06-05 Procede pour produire du plasma sanguin ou du serum sanguin a virus inactives sous forme lyophilisee Ceased WO1999002169A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19729778.1 1997-07-11
DE19729778A DE19729778A1 (de) 1997-07-11 1997-07-11 Verfahren zur Herstellung von virusinaktivierten biologischen Flüssigkeiten

Publications (1)

Publication Number Publication Date
WO1999002169A1 true WO1999002169A1 (fr) 1999-01-21

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PCT/EP1998/003389 Ceased WO1999002169A1 (fr) 1997-07-11 1998-06-05 Procede pour produire du plasma sanguin ou du serum sanguin a virus inactives sous forme lyophilisee

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Country Link
DE (1) DE19729778A1 (fr)
WO (1) WO1999002169A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2362571C2 (ru) * 2003-12-19 2009-07-27 Октафарма Аг Вирус-инактивированная плазма крови универсального применения, полученная из порций плазмы индивидуумов, не относящихся к европеоидной расе
US8449520B2 (en) 2007-03-19 2013-05-28 HemCon Medical Technologies Inc. Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006517938A (ja) * 2003-02-13 2006-08-03 オクタファルマ アクチェン ゲゼルシャフト アルブミン溶液およびその調製のための製法
WO2005027320A1 (fr) 2003-09-10 2005-03-24 Aisin Aw Co., Ltd. Dispositif et procede de fabrication d'une machine electrique rotative
CN106461327B (zh) 2014-06-09 2019-12-13 泰尔茂比司特公司 冻干法
CN111295094A (zh) 2017-10-09 2020-06-16 泰尔茂比司特生物技术有限公司 冻干容器及使用冻干容器的方法
EP3938741B1 (fr) 2019-03-14 2024-05-01 Terumo BCT Biotechnologies, LLC Agencement de remplissage de contenant de lyophilisation, système et procédé d'utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3195547A (en) * 1962-10-23 1965-07-20 Usifroid Device for the freezing of a product to be lyophilized and other products
WO1991014439A1 (fr) * 1990-03-20 1991-10-03 Octapharma Ag Procede pour la fabrication de plasma sanguin non-infectieux

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2732225A1 (de) * 1977-07-16 1979-01-25 Bayer Ag Sterile hexobarbital natrium arzneizubereitungen
GB9505523D0 (en) * 1995-03-18 1995-05-03 Wellcome Found Lyophilization process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3195547A (en) * 1962-10-23 1965-07-20 Usifroid Device for the freezing of a product to be lyophilized and other products
WO1991014439A1 (fr) * 1990-03-20 1991-10-03 Octapharma Ag Procede pour la fabrication de plasma sanguin non-infectieux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XP002900254 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2362571C2 (ru) * 2003-12-19 2009-07-27 Октафарма Аг Вирус-инактивированная плазма крови универсального применения, полученная из порций плазмы индивидуумов, не относящихся к европеоидной расе
US8449520B2 (en) 2007-03-19 2013-05-28 HemCon Medical Technologies Inc. Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma

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Publication number Publication date
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