EP0343596A2 - Container for freeze drying under sterile conditions - Google Patents

Container for freeze drying under sterile conditions Download PDF

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Publication number
EP0343596A2
EP0343596A2 EP89109246A EP89109246A EP0343596A2 EP 0343596 A2 EP0343596 A2 EP 0343596A2 EP 89109246 A EP89109246 A EP 89109246A EP 89109246 A EP89109246 A EP 89109246A EP 0343596 A2 EP0343596 A2 EP 0343596A2
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EP
European Patent Office
Prior art keywords
membrane
container
dried
drying
freeze
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Granted
Application number
EP89109246A
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German (de)
French (fr)
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EP0343596A3 (en
EP0343596B1 (en
Inventor
Thomas Dr. Rer. Nat. Bergmann
Herbert Brustmann
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Roche Diagnostics GmbH
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Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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Priority to AT89109246T priority Critical patent/ATE73226T1/en
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Publication of EP0343596A3 publication Critical patent/EP0343596A3/en
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Publication of EP0343596B1 publication Critical patent/EP0343596B1/en
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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the invention relates to a method for freeze drying under sterile conditions and a container for carrying out the method.
  • the invention particularly relates to the drying of biological and / or pharmaceutical material.
  • Freeze-drying of biological and pharmaceutical substances is generally known (see also Ullmanns Enzyklopadie der Technischen Chemie, 3rd edition, Vol. I, p. 556 ff.). In order to avoid contamination of the dried goods with germs and other impurities, complex equipment and process engineering measures are taken.
  • the procedure is such that vials containing the frozen good are provided with a bacterial filter and the good in the vial is dried in a first drying step until sublimation of the frozen solvent is complete is.
  • the so-called post-drying or residual drying the goods remaining moisture removed. Since this second drying step is usually carried out in a special apparatus, the ampoules or vials must be removed from the first drying apparatus in a further contamination-sensitive operation and introduced into the second drying apparatus.
  • the bacterial filter is removed and replaced by an aluminum cap with a rubber diaphragm and a hollow needle.
  • the drying room is filled with an inert gas and with a slight overpressure and the diaphragm opening is sealed as vapor-tight as possible by a sealing compound.
  • freeze-drying of biological and pharmaceutical material is also carried out on plates under sterile conditions.
  • a solution of the material to be dried is first sterilized, for example by filtration through a sterile filter, then poured onto plates under sterile conditions and freeze-dried using known methods.
  • this method presupposes that the entire freeze dryer can be sterilized. It is also necessary to keep the area around the drying plant germ-free.
  • the aim of the invention is to overcome the disadvantages indicated above and to provide a simple method by means of which a sterile, freeze-dried material can be obtained without the complex sterility requirements for the drying system and the space surrounding it.
  • the material to be dried is introduced under sterile conditions into a germ-tight sealable container, the boundary wall surfaces of which at least partially consist of a germ-tight, porous, water-vapor-permeable hydrophobic membrane, that the container is sealed germ-tight and pressure-tight, in particular glued or welded, and the material is freeze-dried directly in the closed container under usual conditions.
  • the invention is based on the surprising finding that, contrary to expectations, the steam flow resulting from the sublimation of solvent molecules, in particular water molecules, which flows from the material to be dried to the condenser, is only hindered to a small extent by the membrane used in the process according to the invention.
  • the freeze-drying of material that is enclosed by the membrane takes place almost as quickly as the freeze-drying of the same open, non-packaged material.
  • the membranes used according to the invention are hydrophobic membranes, the pores contain, on the one hand permeable to water vapor, but on the other hand are so small that they can no longer be passed by microorganisms. Such pores preferably have a size of ⁇ 0.5 ⁇ m, in particular of ⁇ 0.2 ⁇ m.
  • membranes are preferably used which are still tear-resistant even under the respective process conditions when wet.
  • the method according to the invention can also be carried out with less stable membranes, provided that these are reinforced with a carrier material or are not subjected to excessive mechanical stress.
  • the proportion of the membrane on the wall surface of the container used in the method according to the invention depends on the respectively selected conditions and the drying time and can easily be found out by a person skilled in the art by simply trying it out.
  • the entire wall surface consists of the membrane film, in a further preferred embodiment approximately half.
  • the method according to the invention can also advantageously be carried out even if the wall surface consists of only 10% of the membrane film.
  • cellulose and conventional cellulose derivatives are particularly suitable.
  • membranes made of films of polymer compounds, such as polytetrafluoroethylene or polypropylene, are also preferably used.
  • Goretex and similar membranes are also available Usual film tubes used, such as those sold by Vihuri OY, Wipack, Finland, under the name "Mediplast".
  • any film membrane can be used regardless of its constituents, provided that it fulfills the requirements specified in DIN standard 58 953 with regard to germ density, air permeability and, in particular, strength.
  • the method according to the invention is carried out with a bag or tube, which preferably consists of two walls which are tightly and pressure-tightly connected at their edges, of which one wall consists of liquid-tight material and the other wall is formed by the membrane.
  • the membrane is preferably welded or glued to the vessel.
  • Troughs are particularly suitable as vessels according to the invention.
  • the trough consists of liquid-tight plastic and preferably has a wall thickness of 0.5 to 1 mm.
  • drying conditions such as pressure, temperature and quantity, depend on the material to be dried, the thickness of the membrane as well as the size and number of its pores and have to be determined for the respective material and the packaging by usual and simple trials.
  • the test of the germ density of a membrane was carried out in accordance with DIN 58 953 in such a way that microorganisms in water drops were placed on the test pieces and after the water drops had dried on it was examined whether microorganisms had passed through on the underside of the test pieces.
  • the membrane film to be tested was cut into squares with an edge length of approximately 50 mm.
  • the test pieces were sterilized and dried. Each test piece of the sterilized membrane was placed with the side that can be contaminated during use upwards on a sterilized surface and inoculated with 5 drops of 0.1 ml (corresponding to 107 to 107 germs).
  • the test pieces were stored at room temperature from 20 to 25 ° C under a relative humidity of 40 to 60%. The drops must be completely dry within 6 hours.
  • Each specimen was placed with the inoculated area up on the surface of a blood agar plate (1.5% agar) so that the entire film area came into contact with the agar. After 5 to 6 seconds the paper was removed.
  • the plates were incubated at 37 ° C for 16 to 25 h. If the agar plates treated with such film samples show no growth, the film is considered to be sufficiently germ-tight. Further information on testing the germ tightness of membranes, in particular the production of test microbial suspensions, can be found in part 6 of DIN standard 58 953.
  • a nutrient solution was prepared which consisted of 10 g peptone, 5 g glucose, 5 g NaCl, 0.084 g KH2PO4, 0.187 g Na2-HPO4x2H2O and pyrogen-free water ad 1.0 l existed and which was adjusted to pH 7.0. It was then sterilized in a closed vial.
  • a transparent sterile bag consisting of a transparent film and a suitable paper was prepared to hold the sterile nutrient solution to be lyophilized.
  • the commercially available transparent sterilization pouch film from Wipak Medical, type Steri-King R 47, which is tubular, i.e. welded on both sides, otherwise open, located on a roll (width of the roll 400 mm), cut off a piece with a length of 800 mm. This tube was sealed on the two open sides to a bag with a commercially available film device.
  • This bag was then sterilized in an autoclave with a filter program at 123 ° C and 2 bar steam pressure, the sterile bag with the transparent film facing downwards for better handling in an unsterile sheet tray (VA sheet, dimensions: length 800 mm, width 400 mm, height 30 mm) and opened in a laminar flow box under sterile conditions with disinfected scissors by cutting off a corner. Through this opening of approximately 30 mm between the film and paper, 1.5 l of the sterile nutrient solution were introduced via a sterile tube pushed into the opening. The bag filled in this way was sealed in the laminar flow box under sterile conditions by means of a commercially available film sealing device by corner sealing.
  • the entire arrangement (sheet tray, bag and sterile solution) was placed on a plate pre-cooled to -45 ° C in a commercially available, non-sterilizable freeze drying system from Edwards + Kniese a total floor space of 1.5 m2 and the solution frozen.
  • freeze-drying was carried out at a pressure of 10 ⁇ 1 torr and a plate temperature of 22 ° C and the product was dried at 10 ⁇ 3 torr, also under non-sterile conditions.
  • the total drying time was approx. 72 h.
  • the freeze-dried material thus obtained which was present as a light brown powder in the transparent sterilization bag, was placed in a laminar flow box including the bag and dissolved in 1.5 l of sterile water.
  • the intended puncture site on the paper side was disinfected with alcohol, a total of 1.5 l of sterile water was added to the bag using a sterile cannula and a suitable sterile syringe, the dried material was dissolved and the solution was transferred to a sterile bottle. This solution was incubated for 4 days at 37 ° C. and the germ count of the incubated solution was then determined using the membrane filter method.

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  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Drying Of Solid Materials (AREA)
  • Freezing, Cooling And Drying Of Foods (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

For the freeze-drying of, in particular, biological or pharmaceutical material under sterile conditions, the material to be dried is placed in a container whose sides are at least partly composed of a hydrophobic, porous, germproof membrane which is permeable to water vapour, the container is closed pressure-tight and then the material is freeze-dried in the closed container under usual conditions.

Description

Die Erfindung betrifft ein Verfahren zum Gefriertrock­nen unter sterilen Bedingungen sowie ein Behältnis zum Durchführen des Verfahrens. Die Erfindung betrifft ins­besondere das Trocknen von biologischem und/oder pharma­zeutischem Material.The invention relates to a method for freeze drying under sterile conditions and a container for carrying out the method. The invention particularly relates to the drying of biological and / or pharmaceutical material.

Bei biologischem und pharmazeutischem Material ist es häufig notwendig, die Substanzen bis zu ihrer Verwen­dung völlig trocken zu lagern. Meist sind diese empfind­lichen Substanzen nur durch Gefriertrocknung zugänglich. Zudem besteht in der Regel die Notwendigkeit, diese Substanzen völlig frei von mikrobiologischen Keimen zu halten, und zwar sowohl wegen der durch Mikroben verur­sachten Zersetzung von biologischen Substanzen als auch, um mögliche Infektionen bei ihrer Verwendung zu verhindern.With biological and pharmaceutical material, it is often necessary to store the substances completely dry until they are used. Most of these sensitive substances are only accessible by freeze drying. In addition, there is usually a need to keep these substances completely free of microbiological germs, both because of the decomposition of biological substances caused by microbes and in order to prevent possible infections when they are used.

Das Gefriertrocknen von biologischen und pharmazeuti­schen Substanzen ist allgemein bekannt (siehe auch Ullmanns Enzyklopädie der Technischen Chemie, 3. Aufl., Bd. I, S. 556 ff.). Dabei werden, um eine Kontamination des getrockneten Gutes mit Keimen und anderen Verunrei­nigungen zu vermeiden, aufwendige apparative und ver­fahrenstechnische Maßnahmen getroffen.Freeze-drying of biological and pharmaceutical substances is generally known (see also Ullmanns Enzyklopadie der Technischen Chemie, 3rd edition, Vol. I, p. 556 ff.). In order to avoid contamination of the dried goods with germs and other impurities, complex equipment and process engineering measures are taken.

Beim Trocknen von pharmazeutischen Präparaten in Ampul­len oder Fläschchen wird beispielsweise so vorgegangen, daß Fläschchen, die das gefrorene Gut enthalten, mit einem Bakterienfilter versehen werden und das Gut in den Fläschchen in einem ersten Trocknungsschritt so weit getrocknet wird, bis die Sublimation des gefrore­nen Lösungsmittels abgeschlossen ist.When drying pharmaceutical preparations in ampoules or vials, for example, the procedure is such that vials containing the frozen good are provided with a bacterial filter and the good in the vial is dried in a first drying step until sublimation of the frozen solvent is complete is.

Anschließend wird in einem zweiten Trocknungsabschnitt, der sogenannten Nach- oder Resttrocknung, dem Gut die noch verbliebene Restfeuchtigkeit entzogen. Da dieser zweite Trocknungsschritt meist in einer besonderen Ap­paratur durchgeführt wird, müssen die Ampullen oder Phiolen in einem weiteren kontaminationsempfindlichen Arbeitsgang der ersten Trocknungsapparatur entnommen und in die zweite Trocknungsapparatur eingebracht wer­den. Dazu werden die Bakterienfilter entfernt und durch eine mit einem Gummidiaphragma und einer Hohlnadel ver­sehenen Aluminiumkappe ersetzt. Nach einer je nach Art des zu trocknenden Gutes mehrtägigen Resttrocknung wird der Trockenraum mit einem Inertgas und mit leichtem Überdruck gefüllt und die Diaphragmaöffnung durch eine Vergußmasse möglichst dampfdicht verschlossen.Then, in a second drying section, the so-called post-drying or residual drying, the goods remaining moisture removed. Since this second drying step is usually carried out in a special apparatus, the ampoules or vials must be removed from the first drying apparatus in a further contamination-sensitive operation and introduced into the second drying apparatus. For this purpose, the bacterial filter is removed and replaced by an aluminum cap with a rubber diaphragm and a hollow needle. After a residual drying process lasting several days, depending on the type of material to be dried, the drying room is filled with an inert gas and with a slight overpressure and the diaphragm opening is sealed as vapor-tight as possible by a sealing compound.

Da die Sublimationsgeschwindigkeit bei dieser Art der Gefriertrocknung nur etwa halb so groß ist wie die­jenige von offen ausgebreitetem Material, wird die Gefriertrocknung von biologischem und pharmazeutischem Material auch auf Platten unter sterilen Bedingungen durchgeführt. Dabei wird eine Lösung des zu trocknen­den Gutes zuerst sterilisiert, beispielsweise durch Filtration über einen Sterilfilter, anschließend unter sterilen Bedingungen auf Platten gegossen und mittels bekannten Methoden gefriergetrocknet. Dieses Verfahren setzt jedoch voraus, daß die gesamte Gefriertrocknungs­anlage sterilisierbar ist. Zudem ist es erforderlich, auch die Umgebung der Trocknungsanlage keimfrei zu hal­ten.Since the rate of sublimation in this type of freeze-drying is only about half that of openly spread material, the freeze-drying of biological and pharmaceutical material is also carried out on plates under sterile conditions. A solution of the material to be dried is first sterilized, for example by filtration through a sterile filter, then poured onto plates under sterile conditions and freeze-dried using known methods. However, this method presupposes that the entire freeze dryer can be sterilized. It is also necessary to keep the area around the drying plant germ-free.

Nach erfolgter Trocknung ist es notwendig, das Gut in der Trocknungsanlage selbst oder in ihrer Umgebung mit mechanischen Verfahren von den Platten unter sterilen Bedingungen zu entfernen und in ebenfalls sterile Auf­bewahrungsbehältnisse zu füllen. Dieses Verfahren er­fordert aufwendige Anlagen und sterile Räume sowie ein besonders sorgfältiges Arbeiten mit dem zu trocknenden bzw. dem bereits getrockneten Gut bis zu seiner gebrauchs­fertigen Konfektionierung.After drying, it is necessary to remove the material from the plates in the drying system itself or in its surroundings by mechanical methods from the plates under sterile conditions and to fill them in sterile storage containers as well. This procedure requires complex facilities and sterile rooms as well particularly careful work with the goods to be dried or the goods that have already dried until they are ready for use.

Die Erfindung hat nun zum Ziel, die oben aufgezeigten Nachteile zu überwinden und ein einfaches Verfahren be­reitzustellen, mit dessen Hilfe ohne die oben angeführ­ten aufwendigen Sterilitätsanforderungen an die Trock­nungsanlage sowie an den diese umgebenden Raum ein ste­riles, gefriergetrocknetes Material gewonnen werden kann.The aim of the invention is to overcome the disadvantages indicated above and to provide a simple method by means of which a sterile, freeze-dried material can be obtained without the complex sterility requirements for the drying system and the space surrounding it.

Dieses Ziel wird erfindungsgemäß dadurch erreicht, daß das zu trocknende Material unter sterilen Bedingungen in ein keimdicht verschließbares Behältnis eingebracht wird, dessen begrenzende Wandflächen zumindest teilweise aus einer keimdichten, porigen, Wasser in Dampfform durchlässigen hydrophoben Membran bestehen, daß das Behältnis keimdicht und druckfest verschlossen, insbe­sondere verklebt oder verschweißt, und das Material di­rekt in dem verschlossenen Behältnis unter üblichen Be­dingungen gefriergetrocknet wird.This aim is achieved according to the invention in that the material to be dried is introduced under sterile conditions into a germ-tight sealable container, the boundary wall surfaces of which at least partially consist of a germ-tight, porous, water-vapor-permeable hydrophobic membrane, that the container is sealed germ-tight and pressure-tight, in particular glued or welded, and the material is freeze-dried directly in the closed container under usual conditions.

Die Erfindung beruht auf der überraschenden Erkenntnis, daß entgegen den Erwartungen der durch die Sublimation von Lösungsmittelmolekülen, insbesondere von Wassermo­lekülen, entstehende Dampfstrom, der vom zu trocknenden Gut hin zum Kondensator fließt, durch die im erfin­dungsgemäßen Verfahren verwendete Membran nur in gerin­gem Umfang behindert wird. Somit läuft überraschender­weise das Gefriertrocknen von Material, das von der Membran umschlossen ist, nahezu gleich schnell ab wie das Gefriertrocknen desselben offenen, nichtverpackten Materials. Bei den erfindungsgemäß verwendeten Membra­nen handelt es sich um hydrophobe Membranen, die Poren enthalten, die einerseits für Wasserdampf durchlässig, andererseits jedoch so klein sind, daß sie von Mikro­organismen nicht mehr passiert werden können. Solche Poren haben vorzugsweise eine Größe von ≦ 0,5 µm, ins­besondere von ≦ 0,2 µm. Vorzugsweise werden erfindungs­gemäß Membranen verwendet, die auch noch im nassen Zu­stand unter den jeweiligen Verfahrensbedingungen reiß­fest sind. Allerdings ist das erfindungsgemäße Verfah­ren auch mit weniger stabilen Membranen durchführbar, sofern diese mit einem Trägermaterial verstärkt sind oder nicht übermäßig mechanisch beansprucht werden.The invention is based on the surprising finding that, contrary to expectations, the steam flow resulting from the sublimation of solvent molecules, in particular water molecules, which flows from the material to be dried to the condenser, is only hindered to a small extent by the membrane used in the process according to the invention. Thus, surprisingly, the freeze-drying of material that is enclosed by the membrane takes place almost as quickly as the freeze-drying of the same open, non-packaged material. The membranes used according to the invention are hydrophobic membranes, the pores contain, on the one hand permeable to water vapor, but on the other hand are so small that they can no longer be passed by microorganisms. Such pores preferably have a size of ≦ 0.5 μm, in particular of ≦ 0.2 μm. According to the invention, membranes are preferably used which are still tear-resistant even under the respective process conditions when wet. However, the method according to the invention can also be carried out with less stable membranes, provided that these are reinforced with a carrier material or are not subjected to excessive mechanical stress.

Der im erfindungsgemäßen Verfahren jeweils gewählte An­teil der Membran an der Wandfläche des verwendeten Be­hältnisses hängt von den jeweils gewählten Bedingungen und der Trockungsdauer ab und kann vom Fachmann mittels einfachem Ausprobieren leicht herausgefunden werden. In einer erfindungsgemäß bevorzugten Ausführungsform besteht die gesamte Wandfläche aus der Membranfolie, in einer weiteren bevorzugten Ausführungsform etwa zur Hälfte. Überraschenderweise ist das erfindungsgemäße Verfahren auch noch dann vorteilhaft durchführbar, wenn die Wandfläche auch nur zu 10 % aus der Membranfolie besteht.The proportion of the membrane on the wall surface of the container used in the method according to the invention depends on the respectively selected conditions and the drying time and can easily be found out by a person skilled in the art by simply trying it out. In a preferred embodiment according to the invention, the entire wall surface consists of the membrane film, in a further preferred embodiment approximately half. Surprisingly, the method according to the invention can also advantageously be carried out even if the wall surface consists of only 10% of the membrane film.

Im besonderen eignen sich halbdurchlässige Papiere aus Cellulose und üblichen Cellulosederivaten, wie Cellulo­seacetat. Vorzugsweise finden erfindungsgemäß auch Mem­branen aus Folien von Polymerverbindungen, wie Poly­tetrafluorehtylen oder Polypropylen, Verwendung. Ganz besonders eignen sich als wasserdampfdurchlässige Mem­branen auch Folien aus Sterilisationspapier nach DIN 58 953, die somit als Teil der Beschreibung gilt. In weiteren bevorzugten Ausführungsformen der Erfindung werden Goretex- und ähnliche Membranen oder auch handels­ übliche Folienschläuche eingesetzt, wie sie von der Firma Vihuri OY, Wipack, Finnland, unter der Bezeich­nung "Mediplast" vertrieben werden. Im Prinzip ist jede Folienmembran unabhängig von ihren Bestandteilen ver­wendbar, sofern sie die in der DIN-Norm 58 953 angege­benen Anforderungen bezüglich Keimdichte, Luftdurchläs­sigkeit und insbesondere Festigkeit erfüllt.Semi-permeable papers made of cellulose and conventional cellulose derivatives, such as cellulose acetate, are particularly suitable. According to the invention, membranes made of films of polymer compounds, such as polytetrafluoroethylene or polypropylene, are also preferably used. Also particularly suitable as water vapor permeable membranes are films made of sterilization paper according to DIN 58 953, which is therefore part of the description. In further preferred embodiments of the invention, Goretex and similar membranes are also available Usual film tubes used, such as those sold by Vihuri OY, Wipack, Finland, under the name "Mediplast". In principle, any film membrane can be used regardless of its constituents, provided that it fulfills the requirements specified in DIN standard 58 953 with regard to germ density, air permeability and, in particular, strength.

In einer bevorzugten Ausführungsform wird das erfin­dungsgemäße Verfahren mit einem Beutel oder Schlauch durchgeführt, der vorzugsweise aus zwei an ihren Rän­dern miteinander dicht und druckfest verbundenen Wänden besteht, wovon die eine Wand aus flüssigkeitsdichtem Material besteht und die andere Wand von der Membran gebildet wird.In a preferred embodiment, the method according to the invention is carried out with a bag or tube, which preferably consists of two walls which are tightly and pressure-tightly connected at their edges, of which one wall consists of liquid-tight material and the other wall is formed by the membrane.

Die Membran ist mit dem Gefäß vorzugsweise verschweißt oder verklebt. Als Gefäße eignen sich erfindungsgemäß besonders Wannen.The membrane is preferably welded or glued to the vessel. Troughs are particularly suitable as vessels according to the invention.

In einer weiteren bevorzugten Ausführungsform besteht die Wanne aus flüssigkeitsdichtem Kunststoff und hat vorzugsweise eine Wandstärke von 0,5 bis 1 mm.In a further preferred embodiment, the trough consists of liquid-tight plastic and preferably has a wall thickness of 0.5 to 1 mm.

Die günstigsten Trockungsbedingungen, wie Druck, Tempe­ratur und Menge, sind abhängig von dem jeweils zu trock­nenden Material, der Dicke der Membran sowie der Größe und Anzahl ihrer Poren und müssen durch übliches und einfaches Ausprobieren für das jeweilige Material und die Verpackung bestimmt werden.The most favorable drying conditions, such as pressure, temperature and quantity, depend on the material to be dried, the thickness of the membrane as well as the size and number of its pores and have to be determined for the respective material and the packaging by usual and simple trials.

Im folgenden wird die Erfindung anhand einiger Ausfüh­rungsbeispiele näher erläutert.The invention is explained in more detail below with the aid of a few exemplary embodiments.

Beispiel 1example 1

Die Prüfung der Keimdichte einer Membran wurde gemäß DIN 58 953 so durchgeführt, daß Mikroorganismen in Was­sertropfen auf die Probestücke gebracht wurden und nach dem Antrocknen der Wassertropfen untersucht wurde, ob Mikroorganismen auf die Unterseite der Probestücke durchgetreten sind.The test of the germ density of a membrane was carried out in accordance with DIN 58 953 in such a way that microorganisms in water drops were placed on the test pieces and after the water drops had dried on it was examined whether microorganisms had passed through on the underside of the test pieces.

Die zu prüfende Membranfolie wurde in Quadrate von etwa 50 mm Kantenlänge geschnitten. Die Probestücke wurden sterilisiert und getrocknet. Jedes Probestück der ste­rilisierten Membran wurde mit der Seite, die bei der An­wendung kontaminiert werden kann, nach oben auf eine sterilisierte Unterlage gelegt und mit 5 Tropfen zu je 0,1 ml (entsprechend 10⁶ bis 10⁷ Keimen) beimpft. Die Probestücke wurden bei Raumtemperatur von 20 bis 25 °C unter einer relativen Luftfeuchte von 40 bis 60 % ge­lagert. Die Tropfen müssen innerhalb von 6 h vollständig getrocknet sein. Jedes Probestück wurde mit der beimpf­ten Fläche nach oben auf die Oberfläche einer Blutagar­platte (1,5 % Agar) gelegt, so daß die ganze Folien­fläche mit dem Agar in Kontakt kam. Nach 5 bis 6 sec wurde das Papier entfernt. Die Platten wurden 16 bis 25 h bei 37 °C bebrütet. Weisen die mit solchen Folienproben behandelten Agarplatten kein Wachstum auf, gilt die Folie als ausreichend keimdicht. Weitere Angaben über die Prüfung der Keimdichtigkeit von Membranen, insbeson­dere die Herstellung von Testkeimsuspensionen, können dem Teil 6 der DIN-Norm 58 953 entnommen werden.The membrane film to be tested was cut into squares with an edge length of approximately 50 mm. The test pieces were sterilized and dried. Each test piece of the sterilized membrane was placed with the side that can be contaminated during use upwards on a sterilized surface and inoculated with 5 drops of 0.1 ml (corresponding to 10⁷ to 10⁷ germs). The test pieces were stored at room temperature from 20 to 25 ° C under a relative humidity of 40 to 60%. The drops must be completely dry within 6 hours. Each specimen was placed with the inoculated area up on the surface of a blood agar plate (1.5% agar) so that the entire film area came into contact with the agar. After 5 to 6 seconds the paper was removed. The plates were incubated at 37 ° C for 16 to 25 h. If the agar plates treated with such film samples show no growth, the film is considered to be sufficiently germ-tight. Further information on testing the germ tightness of membranes, in particular the production of test microbial suspensions, can be found in part 6 of DIN standard 58 953.

Beispiel 2Example 2

Es wurde eine Nährlösung hergestellt, die aus 10 g Pepton, 5 g Glucose, 5 g NaCl, 0,084 g KH₂PO₄, 0,187 g Na₂-HPO₄x2H₂O und pyrogenfreiem Wasser ad 1,0 l bestand und die auf pH 7,0 eingestellt wurde. Anschlie­ßend wurde sie in einer verschlossenen Durchstichflasche endsterilisiert.A nutrient solution was prepared which consisted of 10 g peptone, 5 g glucose, 5 g NaCl, 0.084 g KH₂PO₄, 0.187 g Na₂-HPO₄x2H₂O and pyrogen-free water ad 1.0 l existed and which was adjusted to pH 7.0. It was then sterilized in a closed vial.

Zur Aufnahme der sterilen, zu lyophilisierenden Nährlö­sung wurde ein Klarsichtsterilbeutel, bestehend aus einer Klarsichtfolie und einem geeigneten Papier, angefertigt. Hierzu wurde von der handelsüblichen Klarsichtsterili­sierungsbeutelfolie der Firma Wipak Medical, Typ Steri-­King R 47, die sich schlauchförmig, d.h. beiderseits verschweißt, sonst offen, auf einer Rolle (Breite der Rolle 400 mm) befindet, ein Stück von einer Länge von 800 mm abgeschnitten. Dieser Schlauch wurde an den bei­den offenen Seiten zu einem Beutel mit einem handelsüb­lichen Foliengerät verschweißt. Anschließend wurde die­ser Beutel in einem Autoklaven mit Filterprogramm bei 123 °C und 2 bar Dampfdruck sterilisiert, der sterile Beutel mit der Klarsichtfolie nach unten zur besseren Handhabung in eine unsterile Blechwanne (VA-Blech, Ab­messungen: Länge 800 mm, Breite 400 mm, Höhe 30 mm) gelegt und in einer Laminar-Flowbox unter sterilen Be­dingungen mit einer desinfizierten Schere durch Ab­schneiden einer Ecke geöffnet. Durch diese Öffnung von etwa 30 mm zwischen Folie und Papier wurden 1,5 l der sterilen Nährlösung über einen in die Öffnung gescho­benen sterilen Schlauch eingefüllt. Der so gefüllte Beutel wurde noch in der Laminar-Flowbox unter sterilen Bedingungen mittels eines handelsüblichen Folienschweiß­geräts durch Verschweißen über Eck verschlossen.A transparent sterile bag consisting of a transparent film and a suitable paper was prepared to hold the sterile nutrient solution to be lyophilized. For this purpose, the commercially available transparent sterilization pouch film from Wipak Medical, type Steri-King R 47, which is tubular, i.e. welded on both sides, otherwise open, located on a roll (width of the roll 400 mm), cut off a piece with a length of 800 mm. This tube was sealed on the two open sides to a bag with a commercially available film device. This bag was then sterilized in an autoclave with a filter program at 123 ° C and 2 bar steam pressure, the sterile bag with the transparent film facing downwards for better handling in an unsterile sheet tray (VA sheet, dimensions: length 800 mm, width 400 mm, height 30 mm) and opened in a laminar flow box under sterile conditions with disinfected scissors by cutting off a corner. Through this opening of approximately 30 mm between the film and paper, 1.5 l of the sterile nutrient solution were introduced via a sterile tube pushed into the opening. The bag filled in this way was sealed in the laminar flow box under sterile conditions by means of a commercially available film sealing device by corner sealing.

Die gesamte Anordnung (Blechwanne, Beutel und sterile Näherlösung) wurde auf eine auf -45 °C vorgekühlte Platte einer handelsüblichen, nicht sterilisierbaren Gefriertrocknungsanlage der Firma Edwards + Kniese mit einer Gesamtstellfläche von 1,5 m² verbracht und die Lösung eingefroren. Nach vollständigem Einfrieren der Lösung unter nichtsterilen Bedingungen wurde bei einem Druck von 10⁻¹ torr und einer Plattentemperatur von 22 °C gefriergetrocknet und das Produkt bei 10⁻³ torr, ebenfalls unter nichtsterilen Bedingungen, nachgetrock­net. Die Gesamttrocknungsdauer betrug ca. 72 h.The entire arrangement (sheet tray, bag and sterile solution) was placed on a plate pre-cooled to -45 ° C in a commercially available, non-sterilizable freeze drying system from Edwards + Kniese a total floor space of 1.5 m² and the solution frozen. After completely freezing the solution under non-sterile conditions, freeze-drying was carried out at a pressure of 10⁻¹ torr and a plate temperature of 22 ° C and the product was dried at 10⁻³ torr, also under non-sterile conditions. The total drying time was approx. 72 h.

Das so erhaltene, als hellbraunes Pulver im Klarsicht­sterilisierbeutel vorliegende gefriergetrocknete Gut wurde einschließlich Beutel in eine Laminar-Flowbox verbracht und in 1,5 l sterilem Wasser gelöst. Hierzu wurde auf der Papierseite die vorgesehene Einstichstelle mit Alkohol desinfiziert, mittels einer sterilen Kanüle und geeigneten sterilen Spritze insgesamt 1,5 l steri­les Wasser in den Beutel gegeben, das getrocknete Gut gelöst und die Lösung in eine sterile Flasche überführt. Diese Lösung wurde 4 Tage bei 37 °C bebrütet und an­schließend die Keimzahl der bebrüteten Lösung nach der Membranfiltermethode bestimmt.The freeze-dried material thus obtained, which was present as a light brown powder in the transparent sterilization bag, was placed in a laminar flow box including the bag and dissolved in 1.5 l of sterile water. For this purpose, the intended puncture site on the paper side was disinfected with alcohol, a total of 1.5 l of sterile water was added to the bag using a sterile cannula and a suitable sterile syringe, the dried material was dissolved and the solution was transferred to a sterile bottle. This solution was incubated for 4 days at 37 ° C. and the germ count of the incubated solution was then determined using the membrane filter method.

Es zeigte sich, daß durch die Gefriertrockung keine Keime eingeschleppt werden.It was shown that no germs were introduced by freeze-drying.

Claims (10)

1. Verfahren zum Gefriertrocknen von insbesondere biologischem oder pharmazeutischem Material unter sterilen Bedingungen, dadurch gekennzeichnet, daß das zu trock­nende Material in ein Behältnis, dessen Seiten zumindest teilweise aus einer hydrophoben, pori­gen, keimdichten, wasserdampfdurchlässigen Membran besteht, eingebracht, das Behältnis druckfest verschlossen und das Material anschließend in dem verschlossenen Behältnis unter üblichen Bedingungen gefriergetrocknet wird.1. A method for freeze-drying in particular biological or pharmaceutical material under sterile conditions, characterized in that the material to be dried is introduced into a container, the sides of which at least partially consist of a hydrophobic, porous, germ-tight, water-vapor-permeable membrane, the container is pressure-tightly closed and the material is then freeze-dried in the closed container under normal conditions. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß eine Membran verwendet wird, deren Poren eine Größe von ≦ 0,5 µm aufweisen.2. The method according to claim 1, characterized in that a membrane is used, the pores of which have a size of ≦ 0.5 µm. 3. Verfahren nach Anspruch 1 bis 2, dadurch gekennzeichnet, daß eine Membran verwendet wird, deren Poren eine Größe von ≦ 0,2 µm aufweisen.3. The method according to claim 1 to 2, characterized in that a membrane is used whose pores have a size of ≦ 0.2 microns. 4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet,
daß als Membran eine Folie mit den Eigenschaften gemäß DIN 58 953 verwendet wird.4. The method according to any one of claims 1 to 3, characterized in
that a film with the properties according to DIN 58 953 is used as the membrane. 5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet,
daß eine Membran aus halbdurchlässigem Papier, vorzugsweise aus Cellulose und Cellulosederivaten, verwendet wird.5. The method according to any one of claims 1 to 4, characterized in
that a membrane made of semipermeable paper, preferably of cellulose and cellulose derivatives, is used. 6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß eine Membran aus Celluloseacetat verwendet wird.6. The method according to claim 5, characterized in that a membrane made of cellulose acetate is used. 7. Verfahren nach Anspruch 1 bis 4, dadurch gekennzeichnet, daß als Membran eine Folie aus einer Polymerverbindung, vorzugswei­se aus Polytetrafluorethylen oder Polypropylen ver­wendet wird.7. The method according to claim 1 to 4, characterized in that a film made of a polymer compound, preferably made of polytetrafluoroethylene or polypropylene is used as the membrane. 8. Verfahren nach Anspruch 1 bis 7, dadurch gekennzeichnet, daß als Behältnis ein Schlauch oder Beutel verwendet wird, der vor­zugsweise eine wasserundurchlässige Wand aufweist, die mit einer weiteren von der Membran gebildeten Wand druckfest verbunden ist.8. The method according to claim 1 to 7, characterized in that a tube or bag is used as a container, which preferably has a water-impermeable wall which is pressure-tightly connected to another wall formed by the membrane. 9. Verfahren nach Anspruch 1 bis 7, dadurch gekennzeichnet, daß als Behältnis eine Flasche, Ampulle oder Phiole verwendet wird, die mit der Membran verschlossen ist.9. The method according to claim 1 to 7, characterized in that a bottle, ampoule or vial is used as a container, which is closed with the membrane. 10. Verfahren nach Anspruch 1 bis 7, dadurch gekennzeichnet, daß als Behältnis eine Wanne verwendet wird, die mit der Membran als Abdeckung druckfest verbunden ist.10. The method according to claim 1 to 7, characterized in that a trough is used as the container, which is pressure-tightly connected to the membrane as a cover.
EP89109246A 1988-05-26 1989-05-23 Container for freeze drying under sterile conditions Expired - Lifetime EP0343596B1 (en)

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AT89109246T ATE73226T1 (en) 1988-05-26 1989-05-23 CONTAINERS FOR FREEZE DRYING IN STERILE CONDITIONS.

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US5257983A (en) * 1991-04-12 1993-11-02 Cryopharm Corporation Blood bag for lyophilization
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
WO1995027180A1 (en) * 1994-04-04 1995-10-12 W.L. Gore & Associates, Inc. Improved method for minimizing contamination of freeze-dried products
US5596814A (en) * 1995-11-06 1997-01-28 W. L. Gore & Associates, Inc. Vented vial stopper for processing freeze-dried products
FR2738057A1 (en) * 1995-08-22 1997-02-28 Lab Francais Du Fractionnement Sealed packaging assembly for drying e.g. vaccines and antibiotics
WO1997008503A1 (en) * 1995-08-22 1997-03-06 Laboratoire Français Du Fractionnement Et Des Biotechnologies Sealed packaging assembly useful for drying, particularly freeze-drying, and drying, particularly freeze-drying method using same
WO1997020181A1 (en) 1995-11-29 1997-06-05 Immuno Aktiengesellschaft Lyophilization method and device, containers and filling systems
US5732837A (en) * 1994-08-19 1998-03-31 W. L. Gore & Associates, Inc. Vented vial closure member for freeze-drying which minimizes contamination of freeze-dried products
US5958778A (en) * 1995-09-22 1999-09-28 The United States Of America As Represented By The Department Of Health And Human Services Container for drying biological samples, method of making such container, and method of using same
US6312648B1 (en) 1998-01-12 2001-11-06 The United States Of America As Represented By The Department Of Health And Human Services Applicator system
EP1958618A1 (en) * 2007-02-15 2008-08-20 Octapharma AG Method for freeze-drying with optimum reconstitution of biopolymers
EP2386399B1 (en) * 2010-04-23 2015-06-10 MC Beteiligungs-GmbH Method for making openings in a waterproof coating and base body with such coating
WO2015162273A1 (en) 2014-04-25 2015-10-29 Merck Sharp & Dohme Bv A method to dry multiple individual frozen bodies and a system for applying this method
US11609043B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same

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DE19751031A1 (en) * 1997-11-19 1999-06-24 Ingo Dipl Ing Heschel Process for the production of porous structures
DE19815993C2 (en) * 1998-04-09 2003-03-06 Schott Glas Freeze-drying containers and storage for medical products
JP2010124931A (en) * 2008-11-26 2010-06-10 Kanae Co Ltd Method for manufacturing package of freeze-dried medicine
JP2019090596A (en) * 2017-11-10 2019-06-13 エイブル株式会社 Method for producing freeze-dried product, freeze-drying bag, and freeze-drying device

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Cited By (24)

* 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
US5257983A (en) * 1991-04-12 1993-11-02 Cryopharm Corporation Blood bag for lyophilization
WO1995027180A1 (en) * 1994-04-04 1995-10-12 W.L. Gore & Associates, Inc. Improved method for minimizing contamination of freeze-dried products
US5732837A (en) * 1994-08-19 1998-03-31 W. L. Gore & Associates, Inc. Vented vial closure member for freeze-drying which minimizes contamination of freeze-dried products
FR2738057A1 (en) * 1995-08-22 1997-02-28 Lab Francais Du Fractionnement Sealed packaging assembly for drying e.g. vaccines and antibiotics
WO1997008503A1 (en) * 1995-08-22 1997-03-06 Laboratoire Français Du Fractionnement Et Des Biotechnologies Sealed packaging assembly useful for drying, particularly freeze-drying, and drying, particularly freeze-drying method using same
FR2740108A1 (en) * 1995-08-22 1997-04-25 Lab Francais Du Fractionnement WATERPROOF PACKAGING FOR DRYING, IN PARTICULAR LYOPHILIZATION, AND PROCESS FOR DRYING, IN PARTICULAR LYOPHILIZATION, USING SUCH PACKAGING
US6503455B1 (en) 1995-09-22 2003-01-07 The United States Of America As Represented By The Department Of Health And Human Services Container for dying biological samples, method of making such container, and method of using same
US5958778A (en) * 1995-09-22 1999-09-28 The United States Of America As Represented By The Department Of Health And Human Services Container for drying biological samples, method of making such container, and method of using same
US5596814A (en) * 1995-11-06 1997-01-28 W. L. Gore & Associates, Inc. Vented vial stopper for processing freeze-dried products
WO1997020181A1 (en) 1995-11-29 1997-06-05 Immuno Aktiengesellschaft Lyophilization method and device, containers and filling systems
US6312648B1 (en) 1998-01-12 2001-11-06 The United States Of America As Represented By The Department Of Health And Human Services Applicator system
US8518452B2 (en) 2007-02-15 2013-08-27 Octapharma Ag Method for stabilizing blood plasma components in a lyophilizate using carbon dioxide and phosphoric acid
EP2431024A1 (en) 2007-02-15 2012-03-21 Octapharma AG Method for stabilising blood plasma contents in a lyophilisate
EP1958618A1 (en) * 2007-02-15 2008-08-20 Octapharma AG Method for freeze-drying with optimum reconstitution of biopolymers
EP2386399B1 (en) * 2010-04-23 2015-06-10 MC Beteiligungs-GmbH Method for making openings in a waterproof coating and base body with such coating
WO2015162273A1 (en) 2014-04-25 2015-10-29 Merck Sharp & Dohme Bv A method to dry multiple individual frozen bodies and a system for applying this method
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same
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

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IE891541L (en) 1989-11-26
PL159938B1 (en) 1993-01-29
IE61012B1 (en) 1994-09-07
DK252589D0 (en) 1989-05-24
DD283864A5 (en) 1990-10-24
HUT52617A (en) 1990-07-28
PL279609A1 (en) 1990-01-22
JPH0450830B2 (en) 1992-08-17
CA1337974C (en) 1996-01-23
DE58900902D1 (en) 1992-04-09
FI91442C (en) 1994-06-27
GR3004584T3 (en) 1993-04-28
EP0343596A3 (en) 1990-02-28
ATE73226T1 (en) 1992-03-15
EP0343596B1 (en) 1992-03-04
FI892563A0 (en) 1989-05-25
DE3817906A1 (en) 1989-11-30
DK173643B1 (en) 2001-05-14
ES2030556T3 (en) 1992-11-01
DK252589A (en) 1989-11-27
FI91442B (en) 1994-03-15
JPH0229256A (en) 1990-01-31
FI892563A (en) 1989-11-27
HU204126B (en) 1991-11-28

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