WO1997020181A1

WO1997020181A1 - Lyophilization method and device, containers and filling systems

Info

Publication number: WO1997020181A1
Application number: PCT/AT1996/000160
Authority: WO
Inventors: Manfred Granser; Helmut Eder; Helmut Holper; Peter Pfaffenbichler
Original assignee: Immuno Aktiengesellschaft
Priority date: 1995-11-29
Filing date: 1996-09-12
Publication date: 1997-06-05
Also published as: ATE198662T1; DE59606323D1; EP0864071A1; EP0864071B1; AT1399U1

Abstract

In order to lyophilize biological and medical materials under sterile conditions, a closable, internally sterilized conveying container (1) is charged with the material to be lyophilized and is sealed inside a disinfected or sterilized charge isolator (10). The closed transport container (1) is then introduced into a freeze-drying pressurized housing (16) which is equipped with a condenser (17) and in which the interior of the conveying container (1) is cooled, evacuated and heated in a lyophilization cycle when a sterile connection has been produced between the conveying container (1) and the condenser (17).

Description

METHOD AND DEVICE FOR LYOPHILIZING AND CONTAINER AND FILLING PLANT

The invention relates to a method for lyophilizing biological or medical materials under sterile conditions.

Furthermore, 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.

Finally, 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 (see, for example, EP 278 039 A, EP 343 596 A, DE 40 06 015 A or US 5 129 162 A) 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. In this technique, also called 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. In the case of biological or medical materials, sterility is another requirement in addition to the gentle treatment. Accordingly, the lyophilization of such materials is usually carried out in sterile rooms. However, working in sterile rooms is 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. In the case of the materials in question, 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.

Accordingly, 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.

Correspondingly, 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.

According to a further aspect of the invention, 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. In detail, 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.

Between the individual stations, 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. to 40 ° C., in particular 37 ° C., during the lyophilization cycle. For said blood products other hand it is also advantageous if the interior of the transport container during the lyophilised sierungszyklusses to a temperature of -20 ° C to -70 ° C, about -50 ins¬ particular ^β C, is cooled.

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. For a rapid heat transfer to the material to be frozen or heated, however, it is particularly advantageous if the coolant / heat medium is (also) led through lines into the shelf-like storage shelves of the transport container carrying the material to be lyophilized.

As such, the transport container could be sterilized in the interior of the loading insulator before the material to be lyophilized was loaded. However, 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.

As a rule, after such a previous sterilization, 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. It has also been shown that a gas disinfection treatment, which can be carried out relatively simply in comparison to steam sterilization, is quite sufficient, and it is accordingly also advantageous if the outside of the transport container is disinfected with H ₂ O ₂ is, which is then removed from the inside of the filling insulator via a catalyst. Metal salts can be used as catalysts in a manner known per se. It is also advantageous if any particles outside the transport container are removed using an air shower before disinfection. A laminar displacement flow with sterile air can be provided as the air shower, for example, which is directed over the outside of the still closed transport container. Such a laminar displacement flow is preferably also maintained during the loading of the transport container.

After loading and closing the transport container, if it is again brought to the freeze drying station through a non-sterile space, such 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. 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. For this purpose, 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. 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. Of course, there must be a seal between the transport container and the condenser immediately adjacent to these closure parts, so that no contamination can occur from the surroundings. 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.

In this context, it has also proven to be advantageous if, during the lyophilization, 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. As a result, even when evacuating to a pressure of approximately -1 bar compared to the ambient pressure during the lyophilization, it is reliably avoided that the transport container is compressed by the atmospheric pressure which is otherwise present within the freeze dryer pressure housing if it is not correspondingly pressure-resistant would be executed. With regard to its suitability as a means of transport, on the other hand, the transport container is expediently as light as possible - and thus not so pressure-resistant. On the other hand, 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.

As mentioned, 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.

In order to obtain evidence of the continuous sterile maintenance of the materials, it is also advantageous if the overpressure is continuously monitored and registered, for example with the help of a pen. In this way, continuous sterility can be demonstrated by demonstrating sufficient overpressure throughout the process; In the case of a closed transport container which is considered to be tight, such 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). Of course, other known recording devices, such as in particular electronic or magnetic memories, can also be used for the continuous overpressure recording.

In the case of critical products that are sensitive to moisture, such as blood products in particular, it is also advantageous if 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. In such post-drying, for example with N ₂ , the residual moisture is reduced further.

As already mentioned, when the transport container is coupled to the condenser, in order to form the actual freeze dryer, 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. It is advantageous if 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. As already mentioned, 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. With such a hermetic connection of the two closure parts, their joint actuation is also possible with the aid of a single drive, wherein, for example, a pivoting movement can be brought about to move the closure parts from the closed position into the open position. For reasons to be explained in more detail below, however, 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. For the secure sealing of the interiors of the transport container and the condenser when these two units, which form a sterile barrier, are coupled to one another, 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.

Frequently, 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. In 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. In this case, it is also advantageous if the pressure medium cylinder, together with the vertically adjustable locking parts, also forms a height adjustment device for the storage shelves.

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).

The invention will be further elucidated below on the basis of preferred exemplary embodiments, to which, however, it should not be limited, and with reference to the drawing. purifies. Show it:

Fig.l in a scheme a process flow when sterilizing and loading a transport container and when lyophilizing the contents of the transport container;

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;

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; and

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.

In 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. As is shown schematically in FIG. 2, 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.

Of course, 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).

During steam sterilization in the autoclave 2, 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. 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.

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). 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. In this respect, 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.

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. For this, 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. For this purpose, as already indicated in An isolator technology is provided in the area of the filling and loading system, a housing which isolates itself from the environment being provided as the loading insulator 10. In 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. Of course, it would also be conceivable to instead have 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.

It is thus initially to sterilize or disinfect the inside of the loading insulator 10 or the transport container 1 while the door 4 is still closed, and for this purpose, for example, a laminar displacement flow with sterile air is passed through the for 5 to 10 minutes Loading insulator 10 and passed over the transport container 1 so as to remove all existing particles through this "air shower". A steam disinfection step is then carried out using hydrogen peroxide (H, 0 ₂ ), the H _? 0 is then removed again in a manner known per se via a catalyst, for example metal salts. Thus, following this disinfection step, there is a disinfected interior of the loading insulator 10 and a disinfected outside of the transport container 1, so that the transport container 1 can now be opened for loading, as is shown schematically in (c) in FIG. 1.

Specifically, 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.

During the filling and loading, 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. During the loading, the laminar displacement flow with sterile air inside the loading insulator 10 is also preferably maintained.

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). As will be explained in more detail below, it is not only the interior of the actual freeze dryer 18 that forms a sterile barrier, that is to say isolates, that is located through the transport container 1 in connection with a fixedly arranged inside the freeze dryer pressure housing 16, for example 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 dashed lines, 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. As a result, 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. 2, it is provided that 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. Following this, similarly as in the embodiment according to FIG. 2, the two closure parts 6, 23 together in height with the aid of the pressure medium cylinder 24 adjusted so as to connect the interior of the transport container 1 or the condenser 17 via the coupling openings 5 or 20.

It should also be mentioned that during freeze drying the door 4 of the transport container 1 is continuously in the closed position, and that this door 4 has been omitted in the illustration according to FIGS. 2 and 3 in order to illustrate the interior of the transport container 1 . During the lyophilization process, access to the interior of the transport container 1 is only possible via the bottom opening 5.

When Lyophilisiervorgang even the temperature of the interior of the transport container 1 is first, more precisely the temperature of the bottles or generally containers 9 contained structure to be lyophilized materials from the original Tempera¬, eg room temperature (+20 ^β C), to a suitable freezer ¬ temperature, e.g. -30 ° C or -50 ° C, lowered. For this purpose, channels or lines (not illustrated in any more detail in the shelves or shelves 8) are supplied with appropriately cooled silicone oil; For this purpose, coupling systems, not shown in more detail, can be provided on the outside of the transport container 1 in order to connect the lines in the storage shelves 8 with supply and discharge lines through the freeze dryer pressure housing 16 with corresponding supply and cooling devices on the outside. Such supply, feed and coupling devices are known per se and require no further explanation.

As is generally known, 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. As already mentioned, during the freezing process (I in FIG. 4), the temperature is reduced from the ambient temperature to a freezing temperature, generally for example between -20.degree. C. and -70 ° C. In the main drying phase (II in FIG .4) the frozen solvent (mostly water) 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. ”Simultaneously with the evacuation of the interior of the transport container 1 and condenser 17, 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. As mentioned, 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.

During the drying process, 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. In order to reduce the remaining water content as much as is necessary for the respective material, the duration of the post-drying at low pressures is decisive.

During the aftertreatment (IV in FIG. 4), which is carried out on critical products, such as blood or blood plasma products, which are sensitive to moisture, a dry gas purge with inert gas, usually nitrogen (N ₂ ), is carried out in order to further increase the residual moisture Reduce.

In FIG. 4, in which the individual phases: freezing (I), main drying (II), post-drying (III) and aftertreatment with inert gas (IV) are illustrated, 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) can take several hours, e.g. 6 hours, but also 120 hours.

Following this freeze-drying process, 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.

As an alternative to pushing out the piston rod 25, pressure can also be exerted from above, the support bases being moved vertically downward against a lower abutment.

Thereafter, 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. Then 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.

The 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.

Claims

Claims:

1. A method for lyophilizing biological or medical materials under sterile conditions, characterized in that a closable, internally sterilized transport container within a disinfected or sterilized loading insulator is loaded with the material to be lyophilized and sealed, and then in the closed state with an insulated, sterile inside condenser, e.g. within a freeze dryer housing, and that after establishing a sterile connection between the transport container and the condenser, the inside of the transport container is cooled and evacuated and heated in a lyophilization cycle.

2. The method according to claim 1, characterized in that the interior of the transport container is cooled to a temperature of -20 ° C to -70 ° C, preferably about -50 ° C, during the lyophilization cycle.

3. The method according to claim 1 or 2, characterized in that the interior of the transport container is heated to a temperature of 30 ° C to 40 ° C, preferably to 37 ° C, during the lyophilization cycle.

4. The method according to any one of claims 1 to 3, characterized gekenn¬ characterized in that the interior of the transport container is cooled or heated during the lyophilization cycle with the aid of a coolant / heating medium conducted through lines in the transport container.

5. The method according to claim 4, characterized in that the coolant / heating medium is passed through lines in the shelf-like shelves of the transport container to be lyophilized.

6. The method according to claim 4 or 5, characterized in that silicone oil is used as the cooling / heating agent.

7. The method according to any one of claims 1 to 6, characterized gekenn¬ characterized in that the interior of the transport container is sterilized before its introduction into the loading insulator, the transport container being closed after sterilization in the sterile environment.

8. The method according to claim 7, characterized in that the Transport container in an autoclave is sterilized in the open state and sealed before removal from the autoclave.

9. The method according to claim 8, characterized in that the transport container is subjected to steam sterilization in the autoclave, preferably at +121 "C.

10. The method according to any one of claims 7 to 9, characterized gekenn¬ characterized in that the inside of the loading insulator including the outside of the still closed transport container introduced into it is disinfected or sterilized before the transport container is loaded.

11. The method according to claim 10, characterized in that the outside of the transport container with hydrogen peroxide (H ₂ 0 ₂ ) is disinfected, which is then removed from the interior of the loading insulator via a catalyst.

12. The method according to claim 10 or 11, characterized in that prior to disinfection, any particles outside the transport container located in the loading insulator are removed with the aid of an air shower.

13. The method according to any one of claims 1 to 12, characterized gekenn¬ characterized in that a laminar displacement flow with sterile air is maintained during loading of the transport container inside the loading insulator.

14. The method according to any one of claims 1 to 13, characterized gekenn¬ characterized in that after the assembly of the transport container with the capacitor and before the lyophilization, the area of the connection between the transport container and the capacitor is sterilized, preferably sterilized with steam.

15. The method according to any one of claims 1 to 14, characterized gekenn¬ characterized in that the interior of the transport container is kept in the closed state after its sterilization or after loading with the material to be lyophilized under excess pressure.

16. The method according to any one of claims 1 to 15, characterized gekenn¬ characterized in that when lyophilizing the space in the pressure-resistant freeze dryer housing is evacuated outside the transport container, the interior of the transport container relative to this outside space Over¬ pressure is kept.

17. The method according to claim 15 or 16, characterized in that an excess pressure of 10 Pa to 20 Pa, preferably 12 Pa to 13 Pa, in particular 12.7 Pa, is brought about.

18. The method according to any one of claims 15 to 17, characterized in that the overpressure is continuously monitored and registered, for example with the aid of a pen.

19. The method according to any one of claims 1 to 18, characterized gekenn¬ characterized in that the lyophilized material in the transport container still in the state connected to the condenser of a post-treatment with dry inert gas, such as. Nitrogen.

20. Device for lyophilizing biological or medical materials in a freeze dryer (18), with a container (1) receiving the material to be lyophilized, with a loading device (12) for loading the container with the material to be lyophilized, and with one Part of the freeze dryer (18) forming condenser (17), characterized in that the container as a transport container (1) with a closable loading opening (3) and with a closable coupling opening (5) for its connection to the condenser (17), is preferably formed within a freeze dryer housing (16), the transport container (1) and the condenser (17) forming the sterile space of the freeze dryer (18) in the connected state, and the loading device (12) of the transport container (1) inside is assigned to a loading insulator (10).

21. The device according to claim 20, characterized in that the transport container (1) has a bottom opening (5) with an associated, relative to the bottom opening (5) adjustable Ver¬ closure part (6), and the capacitor (17) one in the attached state of the transport container (1) with its bottom opening (5) is aligned with the upper opening (20) with a corresponding adjustable closure part (23), the two closure parts (23) being operable together.

22. Device according to claim 20 or 21, characterized in that on the capacitor (17) between it and the transport container (1) arranged, the opening (20) surrounding seal (22) is attached.

23. Device according to one of claims 20 to 22, indicates that the transport container (1) has height-adjustable shelves (8) for the material to be lyophilized.

24. Device according to one of claims 20 to 22, characterized in that a pressure medium cylinder (24) for lifting the two closure parts (6, 23) is arranged in the condenser (17).

25. Device according to claim 23 and 24, characterized in that the pressure medium cylinder (24) together with the vertically adjustable closure parts (6, 23) also forms a height adjustment device for the shelves (8).

26. Device according to one of claims 19 to 24, characterized ge indicates that the freeze dryer housing (16) is designed as a Druck¬ housing.

27. Container for receiving biological or medical materials to be lyophilized, characterized in that it is used as a transport container (1) with a closable loading opening (3) and with a coupling opening (5) for its connection to a capacitor (17) Freeze dryer (18) is formed.

28. Container according to claim 27, characterized in that the transport container (1) has a bottom opening (5) with an associated, relatively, e.g. vertical, to the bottom opening (5) adjustable closure part (6).

29. A container according to claim 27 or 28, characterized in that the transport container (1) has height-adjustable shelves (8) for the material to be lyophilized.

30. Container according to one of claims 27 to 29, characterized gekenn¬ characterized in that the transport container (1) has a housing made of glass and / or stainless steel.

31. Filling system for loading a container with biological or medical materials to be lyophilized, with a e.g. a slider-loading device (12) for introducing the material to be lyophilized into the container (1), characterized in that the loading device (12) is arranged within a sealable housing which forms a disinfectable loading insulator (10) and is designed to accommodate the container (1).