EP0864071B1 - Procede et dispositif de lyophilisation, et systeme de remplissage - Google Patents

Procede et dispositif de lyophilisation, et systeme de remplissage Download PDF

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Publication number
EP0864071B1
EP0864071B1 EP96929123A EP96929123A EP0864071B1 EP 0864071 B1 EP0864071 B1 EP 0864071B1 EP 96929123 A EP96929123 A EP 96929123A EP 96929123 A EP96929123 A EP 96929123A EP 0864071 B1 EP0864071 B1 EP 0864071B1
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EP
European Patent Office
Prior art keywords
transport container
container
loading
condenser
lyophilized
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EP96929123A
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German (de)
English (en)
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EP0864071A1 (fr
Inventor
Manfred Granser
Helmut Eder
Helmut Holper
Peter Pfaffenbichler
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Baxter AG
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Baxter AG
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    • 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 lyophilizing biological or medical Materials under sterile conditions.
  • the invention relates to a device for lyophilizing biological or medical materials in a freeze dryer, with one that is to be lyophilized Material-receiving container, with a loading device for loading of the container with the material to be lyophilized, and with a part of the freeze dryer forming capacitor.
  • the invention also relates to a transport container for those to be lyophilized biological or medical materials in such a facility.
  • the invention relates to a filling system for loading a container lyophilizing biological or medical materials, with a e.g. one Sliding loading device for introducing the lyophilized Material in the container.
  • Lyophilization or freeze drying is used for the gentle drying and preservation of sensitive Materials, such as in particular from biological or medical (or in general pharmaceutical) materials (blood plasma, sera, viruses etc.), but also of food, used.
  • biological or medical materials blood plasma, sera, viruses etc.
  • sublimation drying this becomes deep-frozen material dried in a high vacuum, with liquid components or solvents frozen out and evaporated in the frozen state.
  • biological or medical materials is another requirement in addition to gentle treatment sterility. Accordingly, the lyophilization of such materials usually performed in sterile rooms.
  • sterile rooms are included a great deal of effort, which is not only due to the fact that large rooms, in where the necessary facilities can be accommodated, and in which the Personnel moved, kept sterile with appropriate suction, ventilation and filter systems must, but also because the people working in this room have a must wear appropriate protective clothing including gloves, masks, etc. to prevent contamination of the materials to be lyophilized.
  • the sterility must in the case of the material in question, from the beginning to the end, i.e. from filling these materials, e.g. by sterile filtration, in vessels such as bottles or the like, up to the closing of these vessels after freeze-drying or one or more subsequent steps, such as further filling processes (e.g. in the case multi-chamber syringes).
  • DE 20 45 887 A discloses a method and a device for freeze drying of powdery or small-sized goods, whereby no measures for keeping sterile of the goods are required or described.
  • the small-sized to powdery good is at Freezing temperature with the help of a funnel in a filling station in a pocket provided container, which is then transported to a freeze-drying station becomes.
  • US 5 129 162 A is the filling of a freeze dryer with the help of a transport device described in which the biological or medical to be lyophilized Materials are arranged on shelves that are horizontal on a frame are adjustably arranged, and of which the materials (i.e. material containing Vials) can be pushed into the freeze dryer chamber using a slide.
  • the aim of the invention is to reduce the effort required to maintain the sterility to reduce lyophilizing materials and especially by strictly separating the Operator materials to further minimize the risk of contamination. This should also make it easier for the operators become.
  • the invention provides a method with the features defined in claim 1 and also a device with the features specified in claim 20 in front.
  • the method according to the invention differs from the subject matter of DE 20 45 887 A especially in that the transport container is sterilized inside and inside a disinfected or sterilized loading insulator with the material and is closed and in the closed state with an insulated, internally sterile condenser is put together.
  • the device according to the invention differs in particular in that that the transport container and the condenser in the connected state the sterile room of the freeze dryer.
  • the invention expresses itself in particular in one specifically for the above mentioned technology designed transport device for the particular to be lyophilized biological or medical material compared to the transport device according to US 5 129 162 A characterized by the training as a container with a only designed for small pressure differences, low-mass housing, with a lockable loading opening and with a lockable coupling opening on the bottom to connect it to a condenser to make a freeze dryer form, this transport container set up for placement on the capacitor is.
  • a generic filling system for Loading such a container with the biological or medical to be lyophilized Materials characterized in that the loading device is sealed within a closable housing is arranged, which forms a disinfectable loading insulator and is designed to hold the container.
  • the technique according to the invention is essentially based on the fact that for the individual Working steps Loading and freeze-drying each have their own sterile conditions can be provided and in between transports can take place in non-sterile rooms instead perform all operations and steps in a single sterile room.
  • isolator technology is used, i.e. the operations mentioned are each performed in an externally isolated, sterile or aseptic environment, these environments being within sealed enclosures that are sterile barriers educational.
  • Such an isolator technology is known per se and has become Separation of products from humans designed to protect operators from harmful Protect influences from the respective product, such as when working with radioactive material contained within an enclosed space, the insulator in the gloves, grippers, etc., which are hermetically inserted in the openings can be intervened to manipulate the material inside the isolator to be able to.
  • This isolator technology is now used in the technology according to the invention applied for lyophilization, but now the ones to be lyophilized, to be kept sterile Materials against non-germ-free influences from the environment, especially through the operators are kept protected.
  • this is for loading the container uses an insulator, the loading insulator; at the freeze drying station on the other hand form the transport container itself, together with that with it tightly coupled capacitor, a sterile barrier.
  • a freeze dryer housing that Transport container and the condenser, is provided when the transport container - as is preferred with regard to the transport function - lightweight and so that it is not designed to be pressure-resistant, as will be explained in more detail below is, in which case the freeze dryer housing is to be designed as a pressure housing.
  • the materials to be kept sterile are stored in the closed transport container - within non-sterile rooms - transported without that the sterility of the materials is impaired.
  • An additional advantage of the technology according to the invention is that the Transport container also forms part of the actual freeze dryer, which is not only reduces the expenditure on equipment, but above all the manipulations significantly Simplified: Whereas in the past when working in sterile rooms, it was a multiple Manipulation with the materials filled into vessels was required, namely the insertion the vessels (e.g. by group transfer) into a container after the Filling the material to be lyophilized and then transferring these vessels the container in the freeze dryer is only a one-off in the present technique Pushing required, namely from the bottling plant in the transport container in which the vessels then remain even during the lyophilization process.
  • the transport container must, of course, be used in lyophilization as part of the freeze dryer to be able to have the corresponding coupling devices, for example in order to be able to supply and discharge a suitable coolant for shock freezing, and in order to be able to evacuate the inside of the transport container.
  • the heat exchange medium outside the freeze dryer on the bring the respective temperature, i.e. cool down or warm up. In particular it is for many materials, such as blood plasma in particular, Plasma products etc., inexpensive if during the lyophilization cycle the inside of the shipping container to a temperature from 30 ° C to 40 ° C, in particular to 37 ° C, is heated.
  • the inside of the transport container during the lyophilization cycle to a temperature of -20 ° C to -70 ° C, in particular about -50 ° C, is cooled.
  • the inside of the transport container can preferably with the help a coolant / heat medium conducted through lines in the transport container, like silicone oil, are cooled or heated; these lines can be, for example, in the housing wall of the transport container.
  • a coolant / heat medium conducted through lines in the transport container, like silicone oil, are cooled or heated; these lines can be, for example, in the housing wall of the transport container.
  • the coolant / heating agent also) through Lines in the shelf-like material carrying the material to be lyophilized Storage shelves of the transport container is directed.
  • the transport container could be loaded with the material to be lyophilized in the interior of the loading insulator be sterilized.
  • the transport container in one Autoclave sterilized in the open state and before Removed from the autoclave is closed. It is also advantageous that usually suitable autoclaves already are present, so that additional equipment is avoided.
  • the transport container is preferably in the Autoclaves are sterilized with steam, especially at 121 ° C.
  • the transport container is transported through a non-sterile space to the loading insulator, contamination of the outside of the transport container being possible. Accordingly, it must be ensured for the loading of the transport container in the loading insulator that such contamination of the outside of the transport container cannot lead to contamination of the interior of the transport container, and for this purpose it is advantageous if the interior of the loading insulator including the The inside of the still closed transport container is disinfected or, if necessary, sterilized before the transport container is loaded. Disinfection treatment is permitted if there is no contact with the material itself, and this is the case here.
  • the size of the transport container is preferably dimensioned according to a production batch, since then all vessels with material from one production batch can be subjected to lyophilization together, so that the batch numbers (for example bottles) are simplified. Accordingly, the transport container can have a size of, for example, approximately 1.5 ⁇ 1 ⁇ 1.5 m 3 , the required loading opening and the coupling opening for coupling with the capacitor having to be dimensioned correspondingly large. If such a transport container, in order to reliably prevent the penetration of particles or germs into the interior in the closed state, is to be sealed appropriately, a great deal of effort has to be accepted.
  • a comparatively simpler solution is obtained if the interior of the transport container is kept under overpressure in the closed state after it has been sterilized or after loading with the material to be lyophilized.
  • the overpressure in the interior of the transport container (compared to the ambient pressure, usually atmospheric pressure) reliably prevents the ingress of particles or germs, even if the transport container is not absolutely sealed.
  • the overpressure can be kept relatively low, so that the pressure resistance of the transport container does not have to be too high.
  • Overpressure inside the transport container can, as mentioned be dimensioned relatively small and it has proven to be sufficient shown when an overpressure of 10 Pa to 20 Pa, preferably 12 Pa to 13 Pa, in particular 12.7 Pa, brought about becomes.
  • Such pressures also correspond to usual recommendations, those related to the sterility of comparable Products in closed containers for prevention penetration of germs etc. exist.
  • the lyophilized material in the transport container is subjected to an aftertreatment with dry inert gas, such as nitrogen, while it is still connected to the condenser.
  • dry inert gas such as nitrogen
  • the lockable coupling opening of the transport container opened, and accordingly an opening of the capacitor connected so that the two interiors together communicate. It is advantageous if the transport container a bottom opening with an associated, relative to Has bottom opening adjustable closure part, and when the Condenser one in the attached state of the transport container with its bottom opening aligned upper opening with a has corresponding adjustable closure part, the two locking parts can be operated together. You can the two closure parts, as already mentioned, with their originally non-sterile outer surfaces are sealed be connected to each other so that only their - sterile - Inside and edges of the sterile interior of drying containers and capacitor are exposed.
  • the two closure parts are also hermetically sealed joint operation possible with the help of a single drive, whereby to move the closure parts from the closed position in the open position brings about, for example, a pivoting movement can be. From those to be explained in more detail below For reasons, however, a vertical adjustment movement is special expedient, and this opening movement or general adjustment movement can be accomplished with the help of a pressure medium cylinder become.
  • a sterile barrier For the secure sealing of the interior of transport containers and capacitor in the coupled state of these two units forming a sterile barrier can also be connected to the condenser one arranged between it and the transport container, seal surrounding the opening. On this seal the transport container is put on. The seal also relieves the previously mentioned preferred one Evacuation of the interior of the transport container and condenser as well as the outside of it, inside the freeze dryer pressure housing, with different vacuum levels so that the inside of the transport container and condenser towards the outside has an overpressure.
  • the transport container As stated above, it is not necessary to design the transport container as a pressure container, provided that a freeze dryer pressure housing is used.
  • the transport container can then, for example, with a made of glass and / or stainless steel (stainless steel) Housing be executed.
  • Fig.1 which shows a process flow, as it at least is currently regarded as particularly favorable, at (a) schematically illustrates a transport container 1, which in open state cleaned and in an autoclave 2 with steam at overpressure (saturated steam; e.g. about 1 bar overpressure and 121 ° C) is sterilized.
  • the transport container 1 has a lockable loading opening 3 for closing it a sliding and / or pivotable door 4 as a closure part is provided.
  • This door 4 is in Fig.1 at (a) shown schematically in the open position because the cleaning in particular to capture the interior of the transport container 1.
  • Coupling opening 5 which is generally plate-shaped or disc-shaped closure part 6 can be closed tightly.
  • This - not shown in Fig.1 - is located closure part 6 during cleaning and steam sterilization the open position. With steam sterilization, it is preferred just keep the bottom clutch opening 5 open and the To have door 4 in the closed position because there is less space is required, thus a smaller autoclave 2 for steam sterilization is sufficient.
  • the transport container 1 can be made of glass and / or stainless steel, for example, and its dimensions (width x depth x height) can be, for example, 1.5 x 1 x 1.5 m 3 .
  • Such dimensions mean on the one hand that the transport container 1 in the case of, for example, the production of blood and plasma products and the like is suitable for accommodating entire production batches, and on the other hand a transport container of this size easily fits to the dimensions of one as far as the other parts are concerned , conventional freeze dryer system 7 (Fig.2 or schematically at (e) in Fig.1).
  • the transport container 1 After steam sterilization, the transport container 1 still closed within the autoclave 2, previously the Pressure in the autoclave 2 to a value slightly above the ambient pressure (Atmospheric pressure) is lowered, for example to an overpressure of 12.7 Pa compared to the ambient pressure. Then the closed transport container 1 from the Sterile room of the autoclave 2 for example transports unsterile space, which is shown schematically at (b) in Fig.1 is shown, during which transport by a non-sterile space inside the transport container 1 existing overpressure of 12.7 Pa continuously with the help of itself known and suitable pressure sensors monitored and with the help a registration device, also known per se, such as a pen or an electronic or magnetic one Storage medium (also not shown), ongoing is registered.
  • a registration device also known per se, such as a pen or an electronic or magnetic one Storage medium (also not shown), ongoing is registered.
  • This overpressure monitoring and registration results if it is performed whenever the Transport container 1 is in a non-sterile room, complete proof that - due to the overpressure - no germs or particles from the environment to the inside of the Transport container 1 may have penetrated.
  • this overpressure technology is also cheaper than using a construction "absolutely" tightly closable doors or locking parts without Monitoring the internal pressure, since it is never really absolute It can be excluded that there is no germ on the seals can get past the inside of the transport container. Apart from that, it would be an extraordinarily high one Effort for an absolutely tight seal of the Transport container required.
  • Transport container 1 passes through the non-sterile room, step (b) in Fig.1, to a filling and insulator technology Loading system, step (c) in Fig. 1, where the transport container 1 should be loaded with the product to be lyophilized. Therefor the transport container 1 must be opened, but what conditioned that previously the outside of the transport container 1 - the yes according to step (b) in Fig. 1 through an unsterile room was transported - and its surroundings were sterilized again or at least be disinfected to prevent contamination of the Inside the transport container 1 or the bottles 9, etc. prevent.
  • Loading insulator 10 For this purpose, as already indicated in Insulator technology in the area of the filling and loading system provided, with a housing isolating from the environment as Loading insulator 10 is present.
  • this loading insulator 10 are the transport container 1 to be loaded on the one hand and on the other hand, only a schematically illustrated one Filling device 11 and a loading device 12.
  • two isolators instead, one for the transport container 1 and one for the filling device 11, as well as one indicated in dashed lines in FIG. 1 (c) Provide connection between these two insulators so that ultimately in this case also a unified one, one of the Sterilization or disinfection accessible interior created becomes.
  • the product to be lyophilized is in the conventional filling device 11 is filled into bottles 9, where the bottled product - according to, for example Sterile filtration - just like the bottle 9 is sterile.
  • the Bottles 9 are then attached, but not completely indented plug 13 using only the general loading device 12 shown in the transport container 1 transferred, for example with a slide plate 14 and one Slider 15, each of a transverse row of bottles 9 on the respective shelf 8 within the transport container 1 pushes; there are the slide 15 and the slide plate 14 for alignment with the respective shelves 8 in Transport container 1 adjustable in height.
  • the filling and loading step described may vary Production batch e.g. 5 to 6 hours, but only half a hour Hour, long. It is also preferred during loading the laminar displacement flow with sterile air inside the loading insulator 10 maintained.
  • freeze dryer system For lyophilization is the one already mentioned, generally with 7 designated freeze dryer system provided, also here an insulator technique is used; there is a outer freeze dryer pressure housing 16 present, which in Fig.1 in (e) is only indicated schematically, and this also from Fig.2 and Fig. 3 can be seen.
  • This freeze dryer pressure housing In contrast to the transport container 1, 16 is sufficiently pressure-resistant carried out in the case of a previous steam sterilization (Autoclave treatment) as well as freeze drying positive existing between its inside and its outside or negative pressure difference (in the order of 1 bar). It will, as below It should be explained in more detail, not just the inside of a sterile barrier educational, i.e.
  • the condenser contained in the freeze dryer pressure housing 16 17 contains in the drawing, cf. especially Fig.2, schematically indicated cooling coils 19, on which the sublimed Solvent (water) condenses.
  • the capacitor 17th has an upper opening 20 defining at its top Flange 21 on which the transport container 1 with an intermediate layer a seal 22 can be placed tightly.
  • the top opening 20 forms a coupling opening to the transport container 1, if this was put on, as shown in Fig.2, and she is by a generally disc-shaped closure part 23 - similar to the closure part 6 - normally tightly closed. As shown in Fig.2, cf.
  • the temperature is first inside the transport container 1, more precisely the temperature of the contained in the bottles or vessels 9 in general lyophilizing materials, from the original temperature, e.g. Room temperature (+ 20 ° C), to a suitable freezing temperature, e.g. -30 ° C or -50 ° C, lowered.
  • a suitable freezing temperature e.g. -30 ° C or -50 ° C
  • Coupling systems on the outside of the transport container 1 be provided to the lines in the storage shelves 8 with and discharge lines through the freeze dryer pressure housing 16 through with appropriate supply and cooling facilities to connect on the outside.
  • supply, feed and coupling devices are known per se and require no further explanation.
  • the actual freeze drying includes in usually four sections, namely freezing the material, the main drying, the post-drying and, if necessary, a Aftercare. These sections are in Figure 4 at I, II, III and IV illustrates.
  • Freezing process I in Fig. 4
  • the main drying phase II in Fig. 4
  • Solvents mostly water
  • freeze dryer pressure housing 16 keeps the pressure differences (outside: Ambient pressure; inside: about -1 bar vacuum in the ratio pressure) due to its pressure-resistant design.
  • the sublimed solvent condenses during the drying process as mentioned on the cooling coils 19, and the one carried out
  • the main drying process is a post-drying process (III in Fig.4) above, in which the still existing Solvent (water) is no longer present as ice, but from the dry matter is absorbed.
  • the duration of the post-drying is low pressures are decisive.
  • Fig. 4 in which the individual phases: freezing (I), Haupttrocknung- (II), Nachrockrock- (III) and aftertreatment with Inert gas (IV) is illustrated with a fully extended Curve A is the temperature of the shelves or the these shelves or shelves 8 passed through Silicone oil and with a dashed curve B die Temperature of the product contained in the bottles 9 illustrated.
  • the entire freeze drying process beginning of the Phase I until the end of phase IV can last several hours, e.g. 6 Hours, but also 120 hours.
  • Freeze-drying required for evacuation Suction ports can be stationary in the area of the condenser 17 be provided alone, the interior of the transport container 1 is evacuated via the condenser 17, it can however, also when inserting the transport container 1 in the Freeze dryer pressure housing 16 connectable connections on the Outside of the transport container 1 or inside of the freeze dryer pressure housing 16 to be present so just above these couplings or connections the inside of the transport container 1 evacuate. In a corresponding manner are also Provide evacuation connections on the freeze dryer pressure housing 16. Because these are inherently conventional techniques is from a representation in the drawing of the better overview because of.

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  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Drying Of Solid Materials (AREA)

Claims (31)

  1. Procédé de lyophilisation de substances biologiques et médicinales dans des conditions stériles, dans lequel une cuve de transport, dont l'intérieur est stérilisé et susceptible d'être fermé, est introduite avec les substances à lyophiliser à l'intérieur d'un isolateur de chargement désinfecté ou stérilisé, est fermée, puis, à l'état fermé, est ensuite assemblée avec un condenseur isolé, stérile à l'intérieur, monté par exemple à l'intérieur du caisson d'un lyophilisateur, dans lequel procédé, après la réalisation de l'assemblage stérile entre la cuve de transport et le condenseur et au cours d'un cycle de lyophilisation, l'intérieur de la cuve de transport est refroidi et mis sous vide, puis réchauffé.
  2. Procédé selon la revendication 1, caractérisé en ce que l'intérieur de la cuve de transport est refroidi pendant le cycle de lyophilisation jusqu'à une température de -20°C à -70°C, de préférence environ -50°C.
  3. Procédé selon la revendication 1 ou 2, caractérisé en ce que, pendant le cycle de lyophilisation, l'intérieur de la cuve de transport est chauffé à une température de 30°C à 40°C, de préférence 37°C.
  4. Procédé selon l'une quelconque des revendications 1 à 3, caractérisé en ce que, pendant le cycle de lyophilisation, l'intérieur de la cuve de transport est refroidi ou chauffé au moyen d'un agent de refroidissement ou de chauffage qui circule dans des canalisations à l'intérieur de la cuve de transport.
  5. Procédé selon la revendication 4, caractérisé en ce que l'agent de refroidissement ou de chauffage est acheminé à travers des canalisations vers des plateaux de réception, formant des étagères dans la cuve de transport, sur lesquelles reposent les substances à lyophiliser.
  6. Procédé selon la revendication 4 ou 5, caractérisé en ce que l'agent de refroidissement ou de chauffage utilisé est de l'huile de silicones.
  7. Procédé selon l'une quelconque des revendications 1 à 6, caractérisé en ce que l'intérieur de la cuve de transport est stérilisé avant que celle-ci ne soit introduite dans l'isolateur de chargement, la fermeture de la cuve de transport étant réalisée encore dans l'environnement stérile après le processus de stérilisation.
  8. Procédé selon la revendication 7, caractérisé en ce que la cuve de transport est stérilisée à l'état ouvert dans un autoclave et est fermée avant d'être retirée de l'autoclave.
  9. Procédé selon la revendication 8, caractérisé en ce que la cuve de transport est soumise dans l'autoclave à un processus de stérilisation à la vapeur, de préférence à +121°C.
  10. Procédé selon l'une quelconque des revendications 7 à 9, caractérisé en ce que l'intérieur de l'isolateur de chargement, y compris la paroi extérieure de la cuve de transport encore fermée et posée dans ledit isolateur de chargement, est désinfecté ou, le cas échéant, stérilisé, avant le remplissage de la cuve de transport.
  11. Procédé selon la revendication 10, caractérisé en ce que la paroi extérieure de la cuve de transport est désinfectée avec du peroxyde d'hydrogène (H2O2), qui est ensuite évacué par l'intermédiaire d'un catalyseur hors de l'intérieur de l'isolateur de chargement.
  12. Procédé selon la revendication 10 ou 11, caractérisé en ce que, avant le processus de désinfection, des particules éventuellement présentes à l'extérieur de la cuve de transport posée dans l'isolateur de chargement sont éliminées à l'aide d'un jet d'air.
  13. Procédé selon l'une quelconque des revendications 1 à 12, caractérisé en ce qu'un flux de rinçage laminaire contenant de l'air stérile est maintenu à l'intérieur de l'isolateur de chargement pendant le remplissage de la cuve de transport.
  14. Procédé selon l'une quelconque des revendications 1 à 13, caractérisé en ce que, après l'assemblage de la cuve de transport avec le condenseur et avant la lyophilisation, la zone de l'assemblage entre la cuve de transport et le condenseur est stérilisée, de préférence à la vapeur.
  15. Procédé selon l'une quelconque des revendications 1 à 14, caractérisé en ce que l'intérieur de la cuve de transport, à l'état fermé, est maintenu en surpression après la stérilisation ou après le chargement des substances à lyophiliser.
  16. Procédé selon l'une quelconque des revendications 1 à 15, caractérisé en ce que pendant la lyophilisation, l'espace intérieur du caisson du lyophilisateur qui est réalisé de façon étanche à la pression, compris en dehors de la cuve de transport, est aussi mis sous vide, le volume intérieur de la cuve de transport étant maintenu en surpression par rapport à cet espace à l'extérieur de ladite cuve.
  17. Procédé selon la revendication 15 ou 16, caractérisé en ce que l'on fait régner une surpression de 10 Pa à 20 Pa, de préférence de 12 Pa à 13 Pa, en particulier de 12,7 Pa.
  18. Procédé selon l'une quelconque des revendications 15 à 17, caractérisé en ce que la surpression est surveillée en permanence et est enregistrée à l'aide d'un traceur, par exemple.
  19. Procédé selon l'une quelconque des revendications 1 à 18, caractérisé en ce que les substances lyophilisées dans la cuve de transport, encore en position assemblée avec le condenseur, sont soumises à un traitement consécutif avec un gaz inerte sec, tel l'azote.
  20. Dispositif destiné à la lyophilisation de substances biologiques ou médicinales dans un lyophilisateur (18), comprenant une cuve (1) destinée à recevoir les substances à lyophiliser, un dispositif de chargement (12) destiné à charger les substances à lyophiliser dans la cuve (1), et un condenseur (17) formant une partie du lyophilisateur (18), la cuve étant conçue sous forme de cuve de transport (1) munie d'une embouchure de chargement (3), susceptible d'être fermée, et d'un orifice d'assemblage (5), susceptible d'être fermé et destiné à l'assemblage avec le condenseur (17), de préférence à l'intérieur du caisson d'un lyophilisateur (16), dans lequel dispositif la cuve de transport (1) et le condenseur (17) forment en position assemblée l'enceinte stérile du lyophilisateur (18), et dans lequel le dispositif de chargement (12) est associé à la cuve de transport (1) à l'intérieur d'un isolateur de chargement (10).
  21. Dispositif selon la revendication 20, caractérisé en ce que la cuve de transport (1) comporte un orifice inférieur (5) associé à un organe de bouchage (6) réglable par rapport à l'orifice inférieur (5), et le condenseur (17) comporte un orifice supérieur (20) aligné avec l'orifice inférieur (5) de la cuve de transport (6) en position assemblée et muni d'un organe de bouchage (23) réglable de manière correspondante, les deux organes de bouchage (6, 23) pouvant être actionnés ensemble.
  22. Dispositif selon la revendication 20 ou 21, caractérisé en ce qu'un joint d'étanchéité (22), entourant l'orifice (20), est posé sur le condenseur (17), entre celui-ci et la cuve de transport (1).
  23. Dispositif selon l'une quelconque des revendications 20 à 22, caractérisé en ce que la cuve de transport (1) est munie de plateaux de réception (8) à hauteur réglable, destinés à recevoir les substances à lyophiliser.
  24. Dispositif selon l'une quelconque des revendications 20 à 22, caractérisé en ce qu'un vérin pneumatique (24) est monté dans le condenseur (17) pour déplacer vers le haut les deux organes de bouchage (6, 23).
  25. Dispositif selon les revendications 23 et 24, caractérisé en ce que le vérin pneumatique (24), conjointement avec les organes de bouchage (6, 23) réglables dans le sens vertical, forme en même temps un dispositif de réglage de la hauteur des plateaux de réception (8).
  26. Dispositif selon l'une quelconque des revendications 20 à 24, caractérisé en ce que le caisson du lyophilisateur (16) est conçu sous forme de caisson de pression.
  27. Cuve destinée à la lyophilisation de substances biologiques ou médicinales (9) dans un dispositif selon l'une quelconque des revendications 20 à 26, caractérisée par sa conception en forme de cuve de transport (1) comprenant des parois présentant un faible poids et conçues uniquement pour de faibles différences de pression, comprenant par ailleurs des plateaux de réception (8) disposés les uns au-dessus des autres et destinés à recevoir les substances à lyophiliser, comprenant une embouchure de chargement (3), susceptible d'être fermée, et un orifice d'assemblage (5), susceptible d'être fermé et destiné à l'assemblage de la cuve avec un condenseur (17), afin de former un lyophilisateur (18), ladite cuve de transport (1) étant réalisée pour être posée sur le condenseur (17).
  28. Cuve selon la revendication 27, caractérisée en ce que l'orifice d'assemblage (5), réalisé dans le fond, est associé à un organe de bouchage (6) réglable par rapport à celui-ci, dans le sens vertical, par exemple.
  29. Cuve selon la revendication 27 ou 28, caractérisée en ce que les plateaux de réception (8) sont réglables en hauteur.
  30. Cuve selon l'une quelconque des revendications 27 à 29, caractérisée en ce que la cuve de transport (1) est formée par des parois en verre et/ou en acier inoxydable.
  31. Unité de remplissage destinée à charger les substances biologiques ou médicinales à lyophiliser dans une cuve, comprenant un dispositif de chargement (12), muni d'un tiroir par exemple, et destiné à charger les substances à lyophiliser dans la cuve (1), caractérisée en ce que le dispositif de chargement (12) est monté à l'intérieur d'un caisson susceptible d'être fermé de façon étanche, qui forme un isolateur de chargement (10) qui peut être désinfecté et est conçu pour recevoir la cuve (1).
EP96929123A 1995-11-29 1996-09-12 Procede et dispositif de lyophilisation, et systeme de remplissage Expired - Lifetime EP0864071B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AT0064895U AT1399U1 (de) 1995-11-29 1995-11-29 Verfahren und einrichtung zum lyophilisieren
AT64895 1995-11-29
AT648/95 1995-11-29
PCT/AT1996/000160 WO1997020181A1 (fr) 1995-11-29 1996-09-12 Procede et dispositif de lyophilisation, conteneurs et systeme de remplissage

Publications (2)

Publication Number Publication Date
EP0864071A1 EP0864071A1 (fr) 1998-09-16
EP0864071B1 true EP0864071B1 (fr) 2001-01-10

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AT (2) AT1399U1 (fr)
DE (1) DE59606323D1 (fr)
WO (1) WO1997020181A1 (fr)

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DE10136498A1 (de) * 2001-07-27 2003-02-06 Steris Gmbh Kammer für eine Gefriertrocknungseinrichtung
DE10218007A1 (de) * 2002-04-23 2003-11-06 Bayer Ag Gefriertrockenvorrichtung
WO2004029529A1 (fr) 2002-09-18 2004-04-08 Sueverkruep Richard Procede de production d'une preparation d'une matiere pharmaceutique sous forme de lyophilisat et installation adaptee a cet effet
US7077176B2 (en) 2003-04-28 2006-07-18 Medical Instill Technologies, Inc. Container with valve assembly for filling and dispensing substances, and apparatus and method for filling
US8196416B2 (en) * 2004-02-02 2012-06-12 Core Dynamics Limited Device for directional cooling of biological matter
US20070022622A1 (en) * 2005-07-26 2007-02-01 Lanaway Ivan H Freeze drying apparatus
US9222728B2 (en) 2006-04-24 2015-12-29 Medinstill Development Llc Penetrable and resealable lyophilization device
CN101196366B (zh) * 2006-12-07 2010-05-12 上海理工大学 一种实验用低温冻干机
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
US20090107001A1 (en) * 2007-03-19 2009-04-30 Hemcon Medical Technologies, Inc. Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma
DE102008017461B4 (de) 2008-04-03 2010-04-15 Süverkrüp, Richard, Prof. Dr. Vorrichtung und Verfahren zur Herstellung eines pulverförmigen lyophilisierten Materials, bestehend aus annähernd gleich großen kugelförmigen Teilchen

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Publication number Publication date
EP0864071A1 (fr) 1998-09-16
ATE198662T1 (de) 2001-01-15
DE59606323D1 (de) 2001-02-15
AT1399U1 (de) 1997-04-25
WO1997020181A1 (fr) 1997-06-05

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