EP0864071A1 - Lyophilization method and device, containers and filling systems - Google Patents
Lyophilization method and device, containers and filling systemsInfo
- Publication number
- EP0864071A1 EP0864071A1 EP96929123A EP96929123A EP0864071A1 EP 0864071 A1 EP0864071 A1 EP 0864071A1 EP 96929123 A EP96929123 A EP 96929123A EP 96929123 A EP96929123 A EP 96929123A EP 0864071 A1 EP0864071 A1 EP 0864071A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- transport container
- container
- loading
- lyophilized
- condenser
- 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.)
- Granted
Links
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 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 a container holding the material to be lyophilized, with a loading device for loading the container with the material to be lyophilized, and with part of the freeze dryer Capacitor.
- the invention also relates to a container for holding biological or medical materials to be lyophilized.
- the invention relates to a filling system for loading a container with biological or medical materials to be lyophilized, with a e.g. a slider-loading device for introducing the material to be lyophilized into the container.
- Lyophilization or freeze drying is used for the gentle drying and preservation of sensitive materials, such as in particular biological or medical ( or generally pharmaceutical) materials (blood plasma, sera, viruses etc.), but also of food.
- biological or medical materials blood plasma, sera, viruses etc.
- sublimation drying the deep-frozen material is dried in a high vacuum, liquid constituents or solvents being frozen out and evaporated in the frozen state.
- sterility is another requirement in addition to the gentle treatment. Accordingly, the lyophilization of such materials is usually carried out in sterile rooms.
- sterile rooms are associated with a great deal of effort, which is not only due to the fact that large rooms, in which the necessary systems can be accommodated, and in which the personnel move, with corresponding Suction, ventilation and filter systems must be kept sterile, but also because the people working in this room must wear appropriate protective clothing, including gloves, masks, etc., in order to prevent contamination of the materials to be lyophilized.
- the sterility must be maintained from the beginning to the end, i.e. from the filling of these materials, for example by sterile filtration, into containers such as bottles or the like, to the closing of these containers after freeze-drying or one or more subsequent steps , such as further filling processes (e.g. in the case of multi-chamber syringes).
- the aim of the invention is therefore to reduce the effort required and, in particular, to further minimize the risk of contamination by strictly separating the product from operators. At the same time, this should make it easier for the operators.
- the inventive method of the type mentioned is characterized in that a closable, internally sterilized transport container within a disinfected or sterilized loading insulator is loaded and sealed with the material to be lyophilized, and then in the closed state with an insulated, internally sterile condenser , e.g. inside a freeze dryer housing, and that after establishing a sterile connection between the transport container and the condenser, the interior of the transport container is cooled and evacuated and heated in a lyophilization cycle.
- an insulated, internally sterile condenser e.g. inside a freeze dryer housing
- the device according to the invention of the type mentioned above is characterized in that the container is designed as a transport container with a closable loading opening and with a closable coupling opening for its connection to the condenser, preferably within a freeze dryer housing, the transport ⁇ container and the condenser in the connected state form the sterile space of the freeze dryer, and that the loading device is assigned to the transport container within a loading insulator.
- the invention expresses itself in particular in a container specially designed for the above-mentioned technology for holding the respective biological or medical material to be lyophilized, and this container is characterized in that it is used as a transport container with a closable loading opening and is formed with a coupling opening for its connection to a condenser to form a freeze dryer.
- a generic filling system for loading such a container with the biological or medical materials to be lyophilized is characterized in that the loading device is arranged within a tightly closable housing which forms a disinfectable loading insulator and for receiving it of the container is designed.
- the technique according to the invention is essentially based on the fact that for the individual operations loading and freeze-drying, separate, sterile conditions are provided in each case and transports in between can take place in non-sterile rooms, instead of carrying out all operations and steps in a single sterile room.
- the so-called isolator technology is used, that is to say the operations mentioned are each carried out in an externally insulated, sterile or aseptic environment, these environments being present in sealed housings which form sterile barriers.
- Such isolator technology is known per se and was developed for separating products from humans in order to protect operators from harmful influences from the respective product, such as when working with radioactive material which is inside an enclosed space, the isolator, is included, which can be used with the help of gloves, grippers, etc., which are hermetically inserted in openings, in order to be able to manipulate the material inside the insulator.
- This isolator technology is now used in the technology for lyophilization according to the invention, but the materials to be lyophilized, to be kept sterile, are now kept protected against non-germ-free influences from the environment, in particular by the operators.
- the loading of the Container uses an insulator, the loading insulator; At the freeze-drying station, however, the transport container itself, together with the condenser tightly coupled with it, form a sterile barrier.
- a freeze dryer housing which accommodates the transport container and the condenser, is expediently provided if the transport container is light and therefore not pressure-resistant, as will be explained in more detail below, in which case the freeze dryer Housing is to be designed as a pressure housing.
- the materials to be kept sterile are transported in the closed transport container - within non-sterile rooms - without the sterility of the materials being impaired.
- An additional advantage of the technology according to the invention lies in the fact that the transport container also forms part of the actual freeze dryer, which not only reduces the outlay on equipment, but above all also simplifies the manipulations: whereas in the past when working in sterile rooms, multiple manipulations with the In the case of the present technique, it was only necessary to push the containers into a container after filling the material to be lyophilized and then transferring these containers from the container into the freeze dryer required, namely from the filling system into the transport container, in which the containers then remain even during the lyophilization process.
- the transport container must, of course, in order to be able to be used as part of the freeze dryer during lyophilization, have the corresponding coupling devices, for example in order to be able to supply and remove a suitable coolant for shock freezing, and in order to be able to evacuate the interior of the transport container.
- Appropriate valves and regulators can be provided outside the freeze dryer to control the flow rates or the pressures, as can the necessary storage containers. It is also possible without problems to bring the heat exchange medium outside the freeze dryer to the respective temperature, ie to cool or heat it. In particular, for many materials, such as blood plasma in particular, Plasma products etc. are advantageous if the interior of the transport container is heated to a temperature of 30 ° C.
- the interior of the transport container can preferably be cooled or heated with the aid of a coolant / heating medium, such as silicone oil, which is conducted through lines in the transport container; these lines can be present, for example, in the housing wall of the transport container.
- a coolant / heating medium such as silicone oil
- the transport container could be sterilized in the interior of the loading insulator before the material to be lyophilized was loaded.
- this would possibly entail additional expenditure with regard to the construction and connection device of the loading insulator, and for this reason and in order to be able to safely sterilize the transport container without problems, it has proven to be particularly advantageous if the interior of the transport container is sterilized before it is introduced into the loading insulator, the transport container being closed after sterilization. It is also favorable if the transport container is sterilized in an open autoclave and closed before being removed from the autoclave. It is also advantageous that suitable autoclaves are usually already present, so that additional equipment is avoided.
- the transport container is preferably sterilized in the autoclave with steam, in particular 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 The outside of the transport container cannot lead to contamination of the inside of the transport container, and for this purpose it is advantageous if the inside of the loading insulator, including the outside 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.
- a connection between the condenser and the transport container must be established that no germs or particles from the outside of the transport container into the interior of the transport container or capacitor.
- the transport container Prior to establishing the connection between the transport container and the condenser, the transport container is placed, for example, with a seal on the condenser, and then a connection passage between these two units must be opened in such a way that the sterility of the interior is maintained.
- openings can be provided in adjacent walls of the two units, which are closed with closure parts which are in direct and tight contact with one another in the closed state.
- these closure parts When the transport container is placed on the condenser, these closure parts can be connected to one another along their circumference using a technique known per se (cf., for example, US Pat. No. 5,421,626 A), in such a way that no particles from the then tightly enclosed surfaces of the closure parts or germs can enter the connection passage.
- a technique known per se cf., for example, US Pat. No. 5,421,626 A
- Another possibility which provides particular advantages with regard to the high level of safety that can be achieved thereby, is that after the transport container has been assembled with the condenser and before lyophilization, the area of the connection between the transport container and the condenser is sterilized, in particular sterilized with steam, becomes.
- 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 loading opening required and the coupling opening for coupling with the condenser being dimensioned accordingly. If such a transport container, in order to reliably prevent particles or germs from penetrating into the interior in the closed state, is to be suitably tightly sealable, 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 it has been loaded 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 is not too high. must be put.
- the space in the pressure-resistant freeze dryer housing outside the transport container is also evacuated, the interior of the transport container being under pressure relative to this space located outside of it is held.
- the transport container is expediently as light as possible - and thus not so pressure-resistant.
- a freeze dryer is usually designed as a pressure vessel, and this pressure-resistant design is provided separately for the freeze dryer housing in the present case.
- the overpressure in the interior of the transport container preventing the ingress of germs or particles can be dimensioned to be relatively low, and it has been shown to be sufficient if an overpressure of 10 Pa to 20 Pa, preferably 12 Pa to 13 Pa, in particular 12.7 Pa, is brought about.
- Such overpressures also correspond to usual recommendations which exist in connection with the sterile keeping of comparable products in closed containers in order to prevent the penetration of germs etc.
- the overpressure is continuously monitored and registered, for example with the help of a pen.
- continuous sterility can be demonstrated by demonstrating sufficient overpressure throughout the process;
- a security regarding continuous sterile maintenance would not be possible or would not be readily possible without the overpressure measure (sterility in each case would have to be carried out after an operation Transport container interior can be verified by appropriate measurements, which would, however, only be possible with comparatively great effort).
- other known recording devices such as in particular electronic or magnetic memories, can also be used for the continuous overpressure recording.
- the lyophilized material in the transport container is subjected to an aftertreatment with dry inert gas, such as nitrogen, while it is connected to the condenser.
- dry inert gas such as nitrogen
- the lockable coupling opening of the transport container is opened, and an opening of the capacitor is connected to it, so that the two interiors communicate with one another.
- the transport container has a bottom opening with an associated closure part that is adjustable relative to the bottom opening, and if the condenser has an upper opening that is flush with the bottom opening when the transport container is in place, with a corresponding adjustable closure part, the two Locking parts can be operated together.
- the two closure parts can be tightly connected to one another with their non-sterile, originally outer surfaces, so that only their sterile inner sides and edges are exposed to the sterile inner spaces of the drying container and condenser.
- a vertical adjustment movement is particularly expedient, and this opening movement or generally adjustment movement can be accomplished with the aid of a pressure medium cylinder.
- a seal which surrounds the opening and is arranged between it and the transport container, can be attached to the capacitor.
- the transport container is placed on this seal.
- the seal also facilitates the previously mentioned, preferred evacuation of the interior of the transport container and condenser and the exterior thereof, within the freeze dryer pressure housing, with various vacuum levels, so that the inside of the transport container and condenser has an overpressure with respect to the outside.
- the medical or biological material to be lyophilized is filled into bottles with sealing plugs, and these sealing plugs, as is known per se, have a through opening in a position placed on the bottle openings, which only opens when the bottle is completely pressed on or pushed in Stopper is closed in the bottles, and which allows the evacuation of the bottles in the merely attached state of the stopper.
- the transport container there are now expediently height-adjustable shelf-like shelves for bottles of this type with material to be lyophilized, and after the lyophilization process has ended, all shelves or shelves can be displaced vertically, whereby they are also moved closer together, as a result of which the sealing plugs are completely in the bottles are pushed in.
- the pressure medium cylinder together with the vertically adjustable locking parts, also forms a height adjustment device for the storage shelves.
- the transport container As already 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 be designed, for example, with a housing made of glass and / or stainless steel (stainless steel).
- Fig.l in a scheme a process flow when sterilizing and loading a transport container and when lyophilizing the contents of the transport container;
- FIG. 2 shows a schematic cross section of a freeze dryer station with a transport container placed tightly on a stationary condenser, which was previously loaded with the material to be lyophilized in the loading station;
- FIG. 3 shows a variant of the freeze dryer in a sectional view similar to FIG. 2, in which an intermediate space between the closure parts of the transport container opening and the condenser opening is sterilized before the two closure parts for connecting the transport container and the condenser together into the open position be moved;
- FIG. 4 shows a diagram to illustrate the temporal temperature profile during freeze-drying, the temperature of the shelves or storage shelves in the transport container being shown in full line and the temperature of the material to be lyophilized in the vials on the storage surfaces of the transport container in dashed lines.
- FIG. 1 which shows a process sequence as it is at least currently regarded as particularly favorable
- (a) schematically illustrates a transport container 1 which is cleaned in the open state and in an autoclave 2 with steam at excess pressure (saturated steam; for example approximately 1 bar overpressure and 121 ° C) is sterilized.
- the transport container 1 has a closable loading opening 3, for the closure of which a displaceable and / or pivotable door 4 is provided as a closure part.
- This door 4 is shown schematically in the open position in Fig.l at (a), since the cleaning should in particular capture the interior of the transport container 1.
- FIG. 1 which shows a process sequence as it is at least currently regarded as particularly favorable
- the transport container 1 has in its bottom a coupling opening 5 which will be explained in more detail below and which can be closed tightly with the aid of a generally plate-shaped or disc-shaped closure part 6.
- This - in Fig.l not visible - closure part 6 is in the open position during cleaning and during steam sterilization. In steam sterilization, it is preferred to keep only the bottom coupling opening 5 open and the To have door 4 in the closed position, since less space is then required, so a smaller autoclave 2 is sufficient for steam sterilization.
- seals of known type can be provided in a conventional manner for the door 4 and for the closure part 6, even if this is not shown in the drawing, in order to seal the loading opening 3 or the coupling opening 5 as hermetically as possible Ensure door 4 or the locking part 6.
- An absolutely tight closing of the transport container 1 is not necessary in the present exemplary embodiment, however, because whenever the closed transport container 1 is in a non-sterile environment, an internal overpressure is provided in the transport container 1 compared to the surroundings.
- 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 receiving 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.l).
- the sterilization is effected through the bottom coupling opening 5 (hereinafter referred to as bottom opening) of the transport container 1 on all surfaces, in particular also at the edge of the opening 5 and at the edge of the closure part 6.
- bottom opening Such sterilization is also brought about on the shelves or shelves 8 present in the interior of the transport container 1, with shelves 8, cf. also FIG. 2, in a later process step (namely at (c) in FIG. 1) the products to be lyophilized - here bottled in bottles 9 not yet tightly closed - are accommodated.
- the transport container 1 After steam sterilization, the transport container 1 is still closed within the autoclave 2, the previously Pressure in the autoclave 2 is reduced to a value slightly above the ambient pressure (atmospheric pressure), for example to an excess pressure of 12.7 Pa compared to the ambient pressure.
- the closed transport container 1 is then transported from the sterile room of the autoclave 2 through, for example, a non-sterile room, which is shown schematically at (b) in FIG. 1, the excess pressure of 12 present in the interior of the transport container 1 during this transport through an unsterile room , 7 Pa continuously monitored with the help of known and suitable pressure sensors and continuously registered with the aid of a registration device, also known per se, such as a pen or an electronic or magnetic storage medium (also not shown).
- a registration device also known per se, such as a pen or an electronic or magnetic storage medium (also not shown).
- This overpressure monitoring and registration if it is carried out whenever the transport container 1 is in a non-sterile room, provides complete proof that - due to the overpressure - no germs or particles from the environment into the interior of the transport container 1 may have penetrated.
- this overpressure technique is also cheaper than a construction with "absolutely" tightly closable doors or locking parts without monitoring the internal pressure, since it can never really be ruled out that germs cannot get past the seals into the interior of the transport container. Apart from that, an extraordinarily high effort would be required to seal the transport container as tightly as possible.
- step (b) in FIG. 1 The inside of the transport container 1, which has the excess pressure, passes through the non-sterile space, step (b) in FIG. 1, to a filling and loading system designed in isolator technology, step (c) in FIG. 1, where the transport container 1 should be loaded with the product to be lyophilized.
- the transport container 1 must be opened, but this requires that the outside of the transport container 1 - which was transported through an unsterile space according to step (b) in Fig.l - and its surroundings are sterilized or at least disinfected again to prevent contamination of the interior of the transport container 1 or the bottles 9 etc.
- a housing which isolates itself from the environment being provided as the loading insulator 10.
- this loading insulator 10 there are on the one hand the transport container 1 to be loaded and on the other hand a filling device 11, only schematically illustrated, and a loading device 12.
- a filling device 11 only schematically illustrated, and a loading device 12.
- two insulators one for the transport container 1 and one for the filling unit Direction 11, as well as a connection shown in dashed lines in Fig.l (c) between these two insulators, so that ultimately in this case, too, a uniform interior which is accessible for sterilization or disinfection is also created.
- the product to be lyophilized is filled into the bottles 9 in the conventional filling device 11, the filled product - for example according to sterile filtration - being sterile just like the bottles 9.
- the bottles 9 are then transferred to the transport container 1 with the plugs 13 placed but not fully pressed in using the loading device 12, which is only shown generally, for example with a slide plate 14 and a slide 15, each of which has a transverse row of bottles 9 on the respective one Storage shelf 8 within the transport container 1 pushes; the slide 15 and the slide plate 14 are adjustable in height for the purpose of alignment with the respective shelves 8 in the transport container 1.
- the above-mentioned overpressure of 12.7 Pa relative to the environment (outside the loading insulator 10) is used, and this overpressure remains inside the transport container 1 when the container 4 is at its loading opening with the door 4 3 is closed again.
- This excess pressure is then in turn continuously monitored and registered, in particular while, in accordance with step (d) in FIG. 1, the transport container 1 loaded in this way is in turn transported through an unsterile space, etc. to a point where the product filled into bottles 9 is lyophilized, see Fig. 1, step (e).
- the filling and loading step described can, depending on the production batch, e.g. Take 5 to 6 hours, but only half an hour.
- the laminar displacement flow with sterile air inside the loading insulator 10 is also preferably maintained.
- freeze dryer system For lyophilization, the freeze dryer system already mentioned, generally designated 7, is provided, an isolator technology also being used here; there is an outer freeze dryer pressure housing 16, which is indicated only schematically in (e) in Fig.l, and which can also be seen from Fig.2 and Fig.3. In contrast to the transport container 1, this freeze dryer pressure housing 16 is designed to be sufficiently pressure-resistant to withstand the positive or negative pressure difference (in the order of magnitude) between its interior and exterior during a previous steam sterilization (autoclave treatment) as well as during freeze drying 1 bar).
- autoclave treatment autoclave treatment
- Capacitor 17 is formed and thus defines the sterile space, but also outside this actual freeze dryer 18, inside the freeze dryer pressure housing 16, evacuated so as to transport container 1 (and according to FIG. 2 also a capacitor 17) with a relatively thin housing wall. This is particularly important with regard to the transport function of the transport container 1, for which a low-mass design is expedient.
- the capacitor 17 contained in the freeze dryer pressure housing 16 contains in the drawing, cf. 2, in particular, schematically indicated cooling coils 19, on which the sublimed solvent (water) condenses.
- the condenser 17 has on its upper side a flange 21 defining an upper opening 20, on which the transport container 1 can be placed tightly with the interposition of a seal 22.
- the upper opening 20 forms a coupling opening to the transport container 1 when it has been put on, as shown in FIG. 2, and it is normally sealed by a generally disk-shaped closure part 23 - similar to the closure part 6. As shown in Fig.2, cf.
- the closure part 23 closes flush with the top or end face of the flange 21 of the capacitor 17 in the closed state, so that when the transport container 1 is closed, the closure part 6 closing the bottom opening 5 can be placed tightly on the closure part 23.
- the two closure parts 6, 23 can be actuated together while ensuring a tight connection between them, etc. for example with the aid of a pressure medium cylinder 24 which is arranged in the condenser 17 and whose piston rod 25 can be moved vertically up and down in order to adjust the two closure parts 6, 23 vertically.
- Such a mutual, hermetic sealing of the closure parts 6, 23 (as well as the opening edges) when the transport container 1 is placed on the condenser 17 has the advantage that a connection of the two sterile interior spaces, namely the interior of the transport container 1 on the one hand and the interior of the Capacitor 17, on the other hand, is possible without further measures, although previously the transport container 1 - in the closed state - was transported through an unsterile space, so that its outside has been contaminated. The outside of the transport container 1 does not come into contact with the interior due to the tight placement on the capacitor 17 according to FIG. According to FIG. 3, in a modification of FIG.
- the condenser 17 is simply formed by a compartment of the freeze dryer pressure housing 16, so that the walls of the condenser 17 - optionally except for the partition wall 17a serving to delimit the compartment which the coupling opening 20 is provided - are designed to be “pressure-resistant” in the sense described above.
- 3 there is an intermediate space between the closure parts 6 and 23 (the latter not being tightly connected to the bottom closure part 6 of the transport container 1), which is sterilized before opening the connection between the transport container 1 and the condenser 17, for example by introduction of saturated steam (for example at 121 ° C. and with overpressure of approx. 1 bar) via a connection 26.
- saturated steam for example at 121 ° C. and with overpressure of approx. 1 bar
- the actual freeze drying generally comprises four sections, namely the freezing of the material, the main drying, the post-drying and, if appropriate, an aftertreatment. These sections are illustrated in Figure 4 at I, II, III and IV.
- the temperature is reduced from the ambient temperature to a freezing temperature, generally for example between -20.degree. C. and -70 ° C.
- the frozen solvent mostly water
- the frozen solvent is removed by sublimation, and for this purpose there is a gradual heating - with the help of the silicone oil passed through the channels in the shelves 8 - to over 30 ° C, for example 37 ° C at the end of A corresponding vacuum, in the order of magnitude of 1 mbar, for example 0.5 to 1.5 mbar absolute, is generated in parallel with this.
- the intermediate space 27 between these two units also becomes 1, 17 on the one hand and the freeze dryer pressure housing 16 surrounding them on the other hand, so as to reduce the pressure difference between the interior of the E to keep units 1, 17 and their surroundings - intermediate space 27 - practically the same, only a slight overpressure in the interior of units 1, 17 (e.g. of 12.7 Pa) is maintained compared to the pressure in the intermediate space 27, in order to prevent, as already explained above, the penetration of germs etc. from the intermediate space 27 into the interior of the transport container 1 and the condenser 17. In this way, prior disinfection or sterilization of the interior or intermediate space 27 within the freeze dryer pressure housing 16 is unnecessary.
- the freeze dryer pressure housing 16 in turn holds the pressure differences (outside: ambient pressure; inside: approximately - 1 bar negative pressure in relation to the ambient pressure) due to its pressure-resistant design.
- the sublimed solvent condenses on the cooling coils 19, as mentioned, and the main drying process carried out in this way passes into a post-drying process (III in FIG. 4) in which the still present Solvent (water) is no longer present as ice, but is absorbed by the dry substance.
- the duration of the post-drying at low pressures is decisive.
- the curve A shows the temperature with a full curve of the shelves or of the silicone oil passed through these shelves or storage shelves 8 and with a dashed curve B illustrates the temperature of the product contained in the bottles 9.
- the entire freeze drying process beginning of phase I to end of phase IV
- the piston rod 25 of the pressure medium cylinder 24 is pushed out further, the vertically adjustable support bases 8 being moved vertically upward one after the other; by pressing against an upper abutment 28 and against each other, the plugs 13 previously inserted only over part of their length into the vessels or bottles 9 - which thus allow the sublimation of the frozen-out liquid constituents via known passages in a manner known per se - Completely pressed into the vessels 9 to seal them hermetically.
- pressure can also be exerted from above, the support bases being moved vertically downward against a lower abutment.
- the bottom opening 5 is closed again by lowering the piston rod 25 with the aid of the closure part 6, after (before the containers 9 have been closed) a corresponding pressure equalization for raising to the ambient pressure (if necessary again to an overpressure compared to the ambient pressure of 12.7 Pa) has been carried out.
- the freezer dryer pressure housing 16 can be opened, and the transport container 1 with the contained, sealed, lyophilized material-containing bottles 9 can be transported away again, for example for the purpose of carrying out further processing operations, cf. Fig.l, step (f).
- An overpressure inside the transport container 1 is only necessary here if further sterile operations are to be carried out; however, if, as in the present example, there are already bottles 9 which have been treated with sterility and are now tightly sealed, such overpressure and further handling while observing sterile conditions can be dispensed with.
- suction connections required for freeze-drying for the evacuation can be provided stationary in the area of the condenser 17 alone, the interior of the transport container 1 being evacuated via the condenser 17, but it can also be coupled when the transport container 1 is inserted into the freeze dryer pressure housing 16 Connections may be provided on the outside of the transport container 1 or on the inside of the freeze dryer pressure housing 16 in order to evacuate the inside of the transport container 1 directly via these couplings or connections. In a corresponding manner, evacuation connections are also to be provided on the freeze dryer pressure housing 16. Since these are conventional techniques per se, they have not been shown in the drawing for the sake of clarity.
Landscapes
- 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)
Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT64895 | 1995-11-29 | ||
AT648/95 | 1995-11-29 | ||
AT0064895U AT1399U1 (en) | 1995-11-29 | 1995-11-29 | METHOD AND DEVICE FOR LYOPHILIZING |
PCT/AT1996/000160 WO1997020181A1 (en) | 1995-11-29 | 1996-09-12 | Lyophilization method and device, containers and filling systems |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0864071A1 true EP0864071A1 (en) | 1998-09-16 |
EP0864071B1 EP0864071B1 (en) | 2001-01-10 |
Family
ID=3496143
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96929123A Expired - Lifetime EP0864071B1 (en) | 1995-11-29 | 1996-09-12 | Lyophilization method and device, and filling system |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0864071B1 (en) |
AT (2) | AT1399U1 (en) |
DE (1) | DE59606323D1 (en) |
WO (1) | WO1997020181A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007012797A1 (en) * | 2005-07-26 | 2007-02-01 | The Boc Group Plc | Freeze drying apparatus |
CN101196366B (en) * | 2006-12-07 | 2010-05-12 | 上海理工大学 | Low-temperature freeze dryer for experiment |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10136498A1 (en) * | 2001-07-27 | 2003-02-06 | Steris Gmbh | Chamber for a freeze dryer |
DE10218007A1 (en) | 2002-04-23 | 2003-11-06 | Bayer Ag | Freeze dryer |
WO2004029529A1 (en) | 2002-09-18 | 2004-04-08 | Sueverkruep Richard | Method for production of a preparation of a pharmaceutical material as a lyophilisate and plant for the same |
EP1631496B1 (en) | 2003-04-28 | 2014-02-26 | Medical Instill Technologies, Inc. | Container with valve assembly for filling and dispensing substances, and apparatus and method for filling |
WO2005072790A1 (en) * | 2004-02-02 | 2005-08-11 | I.M.T. Interface Multigrad Technology Ltd. | Device for directional cooling of biological matter |
ES2683919T3 (en) | 2006-04-24 | 2018-09-28 | Medical Instill Technologies, Inc. | Freeze-drying device that can be pierced with a needle and resealed, and related method |
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 (en) | 2008-04-03 | 2010-04-15 | Süverkrüp, Richard, Prof. Dr. | Apparatus and method for producing a powdery lyophilized material consisting of approximately equal sized spherical particles |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1406556A (en) * | 1964-06-08 | 1965-07-23 | Thomson Houston Comp Francaise | Improvements made to freeze-drying facilities |
US3397462A (en) * | 1965-02-20 | 1968-08-20 | Edwards High Vacuum Int Ltd | Apparatus for lyophilization of substances containing an aqueous phase |
US3537189A (en) * | 1968-10-14 | 1970-11-03 | Virtis Co Inc | Removable tray and cover lift assembly |
DE2045887C3 (en) | 1970-09-17 | 1975-11-13 | General Foods Corp., White Plains, N.Y. (V.St.A.) | Elongated mobile container for freeze-drying of powdery or small pieces |
EP0278039B1 (en) | 1987-02-13 | 1991-12-11 | FINN-AQUA SANTASALO-SOHLBERG GmbH | Freeze-drying apparatus |
DE3806299A1 (en) * | 1988-02-27 | 1989-09-07 | Martin Christ Gefriertrocknung | PLANT FOR SUBLIMATION DRYING OF SUBSTANCES |
DE3812485A1 (en) * | 1988-04-15 | 1989-10-26 | Suwelack Nachf Dr Otto | METHOD AND DEVICE FOR FREEZING DRYING |
DE3817906A1 (en) | 1988-05-26 | 1989-11-30 | Boehringer Mannheim Gmbh | METHOD AND CONTAINER FOR FREEZING DRYING UNDER STERILE CONDITIONS |
DE9001612U1 (en) * | 1989-04-07 | 1990-04-19 | Finn-Aqua Santasalo-Sohlberg GmbH, 50354 Hürth | Device for loading and unloading a freeze-drying device |
US4993171B1 (en) * | 1989-11-22 | 1996-07-02 | Boc Group Inc | Covering for a hydraulic ram of a freeze dryer |
DE4006015A1 (en) | 1990-02-26 | 1991-09-05 | Leybold Ag | FREEZER DRYING DEVICE |
-
1995
- 1995-11-29 AT AT0064895U patent/AT1399U1/en not_active IP Right Cessation
-
1996
- 1996-09-12 AT AT96929123T patent/ATE198662T1/en not_active IP Right Cessation
- 1996-09-12 WO PCT/AT1996/000160 patent/WO1997020181A1/en active IP Right Grant
- 1996-09-12 DE DE59606323T patent/DE59606323D1/en not_active Expired - Fee Related
- 1996-09-12 EP EP96929123A patent/EP0864071B1/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
See references of WO9720181A1 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007012797A1 (en) * | 2005-07-26 | 2007-02-01 | The Boc Group Plc | Freeze drying apparatus |
CN101196366B (en) * | 2006-12-07 | 2010-05-12 | 上海理工大学 | Low-temperature freeze dryer for experiment |
Also Published As
Publication number | Publication date |
---|---|
EP0864071B1 (en) | 2001-01-10 |
AT1399U1 (en) | 1997-04-25 |
DE59606323D1 (en) | 2001-02-15 |
WO1997020181A1 (en) | 1997-06-05 |
ATE198662T1 (en) | 2001-01-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE102008030268B3 (en) | Method for filling dual-chamber systems in pre-sterilizable carrier systems and pre-sterilisable carrier system | |
EP0584484B1 (en) | Method and apparatus for disinfecting bone transplants, especially human spongiosa transplants | |
EP2359870B1 (en) | Sterilisation method for air-conditioning chambers | |
EP1673609B1 (en) | Device and method for handling a probe | |
DE69632191T2 (en) | STEAM Vapor Plasma Sterilization Device And Method. | |
EP0864071B1 (en) | Lyophilization method and device, and filling system | |
DE102016103404A1 (en) | A method for transferring a plurality of containers for storing substances for medical, pharmaceutical or cosmetic purposes in a clean room, transport and packaging containers and packaging structures therefor, and use | |
EP2252331A1 (en) | Transfer container fr pharmaceutical recipients | |
EP1412686B1 (en) | Chamber for a freeze-drying device | |
DE202010018582U1 (en) | Plant for the production of containers with retractable transfer wheel | |
EP2303700B1 (en) | Method for filling dual-chamber systems in pre-sterilizable carrier systems and pre-sterilizable carrier system | |
DE2260911A1 (en) | SUBLIMATOR WITH MODULAR DEPARTMENTS | |
WO2019053186A1 (en) | Transportable clean room, method for producing a transportable clean room, and method for filling a medicine container in a transportable clean room | |
EP0301117A1 (en) | Freeze-drying apparatus | |
EP0734734B1 (en) | Method and apparatus for desinfection or sterilisation of infectious waste | |
EP0278039B1 (en) | Freeze-drying apparatus | |
DE3311525A1 (en) | Process and apparatus for freeze-drying a product in a vessel with a narrow opening | |
DE102012200331A1 (en) | Container for medical or dental instruments for mounting in an autoclave and method for instrument preparation | |
DE4235512C2 (en) | Method and motor vehicle for disinfecting, in particular medical or the like, waste | |
DE4407311C1 (en) | Sealed plastic bags or plastic containers contg. infected hospital refuse | |
DE19755688A1 (en) | Process for generating a disinfecting hot atmosphere and device | |
WO2004029529A1 (en) | Method for production of a preparation of a pharmaceutical material as a lyophilisate and plant for the same | |
WO2022128420A1 (en) | Thermally insulated transport container | |
WO2018202826A1 (en) | Method for contamination-free freeze drying | |
DE10045295A1 (en) | Apparatus for lyophilizing aqueous solutions and suspensions of substances, in particular, medicaments under sterile conditions comprises a drying chamber with a heater and a gas cooled condenser |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19980505 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE LI |
|
17Q | First examination report despatched |
Effective date: 19990125 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BAXTER AKTIENGESELLSCHAFT |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BAXTER AKTIENGESELLSCHAFT |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
RTI1 | Title (correction) |
Free format text: LYOPHILIZATION METHOD AND DEVICE, AND FILLING SYSTEM |
|
RTI1 | Title (correction) |
Free format text: LYOPHILIZATION METHOD AND DEVICE, AND FILLING SYSTEM |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE LI |
|
REF | Corresponds to: |
Ref document number: 198662 Country of ref document: AT Date of ref document: 20010115 Kind code of ref document: T |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REF | Corresponds to: |
Ref document number: 59606323 Country of ref document: DE Date of ref document: 20010215 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: KIRKER & CIE SA |
|
EN | Fr: translation not filed | ||
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20010820 Year of fee payment: 6 Ref country code: CH Payment date: 20010820 Year of fee payment: 6 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: AT Payment date: 20010821 Year of fee payment: 6 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20010914 Year of fee payment: 6 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020912 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020930 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020930 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020930 |
|
BERE | Be: lapsed |
Owner name: *BAXTER A.G. Effective date: 20020930 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20030401 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |