EP2303700B1 - Method for filling dual-chamber systems in pre-sterilizable carrier systems and pre-sterilizable carrier system - Google Patents

Description

The invention relates to a method for filling dual-chamber systems in pre-sterilized carrier systems according to claim 1, a method for filling dual-chamber systems in pre-sterilized carrier systems according to claim 2, a pre-sterilizable carrier system according to claim 12, and a pre-sterilizable carrier system according to claim 13.

Pre-sterilizable carrier systems and methods for their filling are known. A known carrier system usually comprises washed, siliconized and sterilized syringes which are placed in a magazine after the washing and siliconizing step. The magazine - also called Nest - is then introduced into a container, which is then sealed with a closure element, preferably a gas-permeable membrane film, and sterilized by suitable sterilization processes. This is often an ethylene oxide fumigation used. The fact that the closure element is gas-permeable, the sterilization gas can penetrate into the interior of the container and also sterilize the contents of the container, so the washed and siliconized syringes and the magazine comprising them. The container does not have to be reopened after the sterilization step and can be delivered directly to a customer in the present form or fed to a filling line. Namely, the gas-permeable sealing element has a filtering effect such that it is permeable to a sterilizing gas, but closes the container in a sealed and sterile manner against germs, viruses and bacteria. As long as the container remains closed, is thus ensuring the sterility of its contents. At the customer, who typically operates a filling plant for filling the syringes or other hollow body with pharmaceutical content enclosed by the container, the container is opened, the hollow bodies are filled and closed, whereupon the container can also be resealed and transported to the end customer. Of course, the filled and closed hollow body can also be removed from the container and passed on in other packaging units to the end customer. It is essential in the case of the above-mentioned pre-sterilized carrier systems and the method for their filling that a standardized packaging form is used which can be used in connection with standardized filling lines. The hollow body to be filled therefore need not be removed from the container before filling, whereby a complex step is eliminated. Furthermore, it is advantageous that the hollow bodies can be sterilized together in already packaged form, after which a shipment or further processing can take place immediately, without elaborate intermediate steps such as repackaging in a pre-sterilized further packaging unit or repacking is necessary. On the part of a producing pharmaceutical company, which carries out the filling, a clean room or working step for the preparation of the hollow body can be omitted, since these are delivered ready for filling.

The production and / or preparation of the hollow body can also be done as an in-line process with the filling, when a hot air tunnel between the sterilization device and the clean room in which the filling takes place, is provided.

However, the known pre-sterilizable carrier systems and the methods for their filling are designed only for single-chamber systems, ie single-chamber syringes, single-chamber carpules or vials. In order to fill double-chamber systems such as dual-chamber syringes or cartridges, more complex processes and carrier devices are still necessary.

The object of the invention is therefore to provide a method for filling at least one dual-chamber system in a vorsterilisierbaren carrier system.

The object underlying the invention is achieved by a method having the features of claim 1.

This is characterized by the following steps: At least one sterilized dual-chamber system is provided which has a separating element separating the two chambers. A magazine accommodates the at least one dual chamber system, preferably a number of such systems, the magazine being disposed in a container sealed with a closure member. The container is introduced into a clean room. It is opened and the first chamber of the at least one dual-chamber system is filled. The container is closed with a gas-permeable closure element. This is followed by a process step in which the material contained in the first chamber of the at least one dual-chamber system is freeze-dried. In this case, the solvent vapor sublimes through the gas-permeable closure element of the container. After freeze-drying, the container is opened and the first chamber of the at least one dual-chamber system is closed. A second chamber of the at least one dual-chamber system is filled and closed. The at least one filled Doppelkammersystern is discharged from the clean room.

The object underlying the invention is also achieved by a method having the features of claim 2.

This is characterized by the following steps: There is provided at least one sterilized dual-chamber system, each with a separating the two chambers separating element in a magazine, which accommodates the at least one dual-chamber system, preferably a number of such systems, the magazine in one with a Closing element sealed container is arranged. The sealed container is introduced into a clean room. There it is opened, and it is filled a first chamber of the at least one dual-chamber system. This first chamber is closed. The magazine is inverted and a second chamber of the at least one dual chamber system is filled. It is also closed the second chamber, and the at least one filled dual-chamber system is discharged from the clean room. By using standardized pre-sterilisable carrier systems, a manufacturing pharmaceutical company is relieved of the time-consuming preparation of the hollow bodies and the use of standardized filling lines becomes possible.

A method is also preferred, which is characterized in that the magazine, which accommodates the at least one dual-chamber system, comprises plastic, preferably made of plastic. This makes the magazine very light and therefore too easy to handle. It can also be designed as a product for single use, so that it can be disposed of after its use. It thus eliminates the usual in known carrier systems heavy metal magazines that are difficult to handle on the one hand and on the other hand consuming to autoclave in order to keep them sterile. In the case of the carrier systems according to the invention, on the other hand, a new plastic magazine is supplied with each new delivery, which is assigned to exactly one dual-chamber system or, in particular, to a batch of dual-chamber systems and disposed of after use. In addition to the elimination of complex work steps, this leads in particular to the fact that it is possible to handle double-chamber systems that are highly reproducible with respect to their sterility.

It is also preferred a method in which the container comprises plastic, preferably made of plastic. Again, it is preferably addressed that the container is used once and disposed of after use. Each batch of double-chamber systems is assigned a container so that the sterility of the batches with very good reproducibility is guaranteed.

Also, a method is preferred that is characterized in that the closure element for the container is gas-permeable. On the one hand, this responds to the closure element with which the container is delivered in the filling station. This closure element is preferably gas-permeable, so that the container can be pre-sterilized in the manufacturer's already closed state. The closure element should namely be designed to be permeable to sterilization gases, but no germs, viruses or bacteria On the other hand, the closure element is addressed, with which the container is closed, before possibly a freeze-drying step is stirred. This closure element is preferably gas-permeable so that the solvent vapor released during freeze-drying can sublimate through the closure element and thus leave the space enclosed by the container. It is preferred that both closure elements are designed as gas-permeable membrane films.

Also preferred is a method in which, after filling the first chamber of the at least one dual-chamber system and closing with a gas-permeable closure element, the container is first discharged from the clean room and introduced into a freeze-drying apparatus arranged outside the clean room. There, the freeze-drying takes place, after the end of the container removed from the device and in turn is introduced into a clean room. If the process is extended by this step, it is possible to completely separate the aseptic filling of the pharmaceutical contents from the freeze-drying, which does not have to be aseptic. This is possible because the container is provided with a gas-permeable closure member which, while permitting the sublimated solvent vapor to pass outwardly from the interior of the container during the freeze-drying process, but deters germs, viruses and bacteria from entering the container. The interior of the container thus remains aseptic, even if the environment in the freeze dryer is not sterile. In this way, elaborate cleaning and disinfecting steps for the freeze dryer can be omitted, and this need not be located within the clean room.

In this context, a method is preferred which is characterized in that the device for freeze-drying itself is not sterile and / or aseptic. As said, this is possible by closing the container with a gas-permeable but impermeable to viruses, bacteria and germs closure element.

Further advantageous embodiments with respect to the claimed method emerge from the subclaims.

The object of the invention is also to provide a vorsterilisierbares carrier system for at least one dual-chamber system.

This object is achieved by a vorsterilisierbares carrier system having the features of claim 12. It comprises at least one sterilized dual-chamber system, which has a separating element which separates the two chambers from each other. Furthermore, the pre-sterilisable carrier system comprises a magazine which serves to receive the at least one dual-chamber system. It also includes a container. The magazine accommodating the at least one dual-chamber system is disposed in the container, which is sealed with a closure member so that an active and / or adjuvant present in the first chamber is freeze-dried in the sealed container. The result is a closed container in which a magazine is arranged, which comprises at least one sterilized dual-chamber system. Particularly preferred is when the entire container is sterilized in its interior. As a result of the sealing, such pre-sterilisable carrier systems equipped with dual-chamber systems can be produced and stored in advance, the contents remaining sterile. It is also preferred a vorsterilisierbares carrier system, wherein the magazine comprises plastic, preferably made of plastic. In this case, the magazine is particularly lightweight and also disposable after the use of the pre-sterilizable carrier system, so that consuming cleaning or autoclaving omitted. In addition, each batch of dual-chamber systems is assigned to exactly one magazine, so that in terms of sterility very reproducible handling is possible.

The object is also achieved by providing a vorsterilisierbares carrier system with the features of claim 13. It comprises at least one sterilized dual-chamber system which has a separating element which separates the two chambers from one another. Furthermore, the pre-sterilisable carrier system comprises a magazine which serves to receive the at least one dual-chamber system. It also includes a container. The magazine can be arranged in the container and comprises plastic, or preferably consists of plastic. It comprises the at least one dual-chamber system in such a way that it is held securely in the magazine regardless of the orientation of the magazine. The container is sealable with a closure element. Because the magazine comprises the at least one dual-chamber system in such a way that it is held securely in this regardless of the orientation of the magazine, it is ensured that the double-chamber system can not slip out of it even when the magazine is turned. Therefore, a filling of the second chamber of the dual-chamber system after filling and closing the first chamber to particularly easy catfish is possible by the magazine is turned.

It is also preferred a vorsterilisierbares carrier system, which is characterized in that the container comprises plastic, preferably made of plastic. Also in this case, the container is for single use so that each batch of dual chamber systems is associated with exactly one container. This also increases the reproducibility of the handling in terms of their sterility.

Furthermore, a vorsterilisierbares carrier system is preferred in which the closure element for the container is gas-permeable. In this case, the container already equipped with the magazine and the at least one dual-chamber system can be closed at the manufacturer and then sterilized by the gas intended for sterilization penetrating through the gas-permeable closure element into the interior of the container. After sterilization, it is no longer necessary to open the container, and it can be transported immediately, for example to a filling line. The fact that the container is already closed during the sterilization, can not penetrate by a subsequent opening or closing germ-containing material from the outside into the interior of the container. The word "gas-permeable" refers to the fact that the closure element allows gases and vapors to pass through but prevents germs, viruses or bacteria from penetrating into the interior of the container.

Figur 1

eine schematische Ansicht eines vorsterilisierbaren Trägersystems;

Figur 2

eine schematische Darstellung des Schritts der Befüllung einer ersten Kammer der Doppelkammersysteme in einem erfindungsgemäßen Verfahren;

Figur 3

eine schematische Ansicht des Verschließens der ersten Kammer der Doppelkammersysteme in dem Verfahren;

Figur 4

eine schematische Darstellung des Befüllens einer zweiten Kammer der Doppelkammersysteme in dem Verfahren; und

Figur 5

das Verschließen der zweiten Kammer der Doppelkammersysteme in dem Verfahren.

The invention will be explained in more detail below with reference to the drawings. Show it:

FIG. 1

a schematic view of a vorsterilisierbaren carrier system;

FIG. 2

a schematic representation of the step of filling a first chamber of the dual-chamber systems in a method according to the invention;

FIG. 3

a schematic view of the closing of the first chamber of the dual-chamber systems in the method;

FIG. 4

a schematic representation of the filling of a second chamber of the dual-chamber systems in the method; and

FIG. 5

closing the second chamber of the dual chamber systems in the process.

FIG. 1 schematically shows an embodiment of a vorsterilisierbaren carrier system. The vorsterilisierbare carrier system 1 comprises at least one sterilized and preferably washed and preferably siliconized dual chamber system 3 with two chambers 5, 5 ', which are separated by a separating element 7 from each other. The dual-chamber systems 3 are received by a magazine 9, which in turn can be arranged in a container 11. This is sealed with a closure element 13.

The container 11 may comprise plastic, preferably it consists of plastic. The magazine 9 may include plastic and is preferably made of plastic. Both elements are determinable for single use in this way, so that each batch of dual chamber systems 3 is assigned a magazine 9 and a container 11, respectively.

The closure element 13 for the container 11 is preferably gas-permeable, so that the fully loaded and sealed container 11 can be sterilized in the closed state by placing it in an atmosphere comprising a sterilization-specific gas or steam intended for sterilization. The gas or steam can penetrate through the closure element 13 into the interior of the container 11, and thus in particular also sterilize the interior of the container 11 and the double-chamber systems 3 and the magazine 9 contained therein.

The different methods are now based on the FIGS. 2 to 5 explained in more detail.

First, the pre-sterilizable carrier system 1 is provided, and introduced into a clean room. Then, the closure element 13 is removed, so that the dual-chamber systems 3 are accessible.

FIG. 2 shows the step of filling a first chamber 5 of the dual-chamber systems 3. The same and functionally identical elements are provided with the same reference numerals, so that reference is made to the preceding description. A dispensing device 15 is provided, through which a first solution L1 of a heat and / or auxiliary substance can be introduced into a first chamber 5 of the dual chamber systems 3

After filling the first chamber 5 of the dual-chamber systems 3, the first chamber can be closed, as shown in FIG FIG. 3 is shown. Identical and functionally identical elements are provided with the same reference numerals, so that in this respect to the preceding Description is referenced. A first closing device 17 is provided, with which the first chamber 5 of the dual-chamber systems 3 can be closed, each with a closure 19. The closure 19 may be a crimp cap, tamper-evident closure, attachable needle closure, or needle-fitted closure. In principle, other types of closures can be used, it is only essential that the first chamber 5 of the dual-chamber systems 3 is sealed by a closure 19.

Instead of closing the first chamber 5 of the dual-chamber systems 3 directly after filling, it is also possible to interpose a freeze-drying step for the active ingredient and / or auxiliary present in the solution L1. For this purpose, the container 11 is closed after filling the first chamber 5 of the dual-chamber systems 3 with a gas-permeable closure element, preferably a gas-permeable membrane film. The container 11 sealed in this manner may be introduced into a freeze-drying apparatus where the solvent contained in the first chamber 5 is sublimated through the gas-permeable sealing member, so that the active and / or auxiliary substance present in the dual-chamber systems 3 is freeze-dried. Since the container 11 is hygienically sealed by the gas-permeable closure member 13, it is possible to provide the apparatus for freeze-drying outside the clean room. The container 11 can thus be discharged from the clean room and introduced into an external freeze-drying device. This does not have to be sterile and / or aseptic itself, since no germs, viruses or bacteria can pass through the closure element 13 into the interior of the container 11. This is how the double-chamber systems in particular remain 3 sterile or aseptic, even if the freeze-drying is carried out in a non-sterile and / or aseptic environment. After freeze-drying, the container 11 can again be introduced into a clean room in which the further method steps take place.

Of course, it is also possible to arrange the apparatus for freeze-drying in the clean room itself, so that a discharging and re-slipping of the container 1 is eliminated. It is obvious that in this case also the apparatus for freeze drying itself has to be sterile and / or aseptic.

During freeze-drying, the dual-chamber systems 3 are embedded in the container 11 and safely protected against interference or other interference.

If such a freeze drying step is interposed between the filling of the first chamber 5 of the dual chamber systems 3 and the closing of this first chamber, then it is obvious that the container 11 must be reopened, possibly after re-entrainment into a clean room, so that the dual chamber systems 3 are accessible are. After closing the first chamber 5 of the dual-chamber systems, a second chamber 5 'is filled. This is possible in a particularly simple manner when the magazine 9 is turned. It is provided in this case that the magazine 9, the dual-chamber systems 3 includes such that they are held regardless of the orientation of the magazine 9 securely in this. This ensures that the double-chamber systems 3 do not slip out of the magazine 9 even when turning the magazine. After turning the magazine 9 this is preferably again introduced into the container 11, wherein now through the opening of the container 11, a second chamber 5 'of the dual-chamber systems 3 is accessible.

FIG. 4 schematically shows the filling of the second chamber 5 'of the at least one dual-chamber system 3. The same and functionally identical elements are provided with the same reference numerals, so that reference can be made to the preceding description. Again, a dispensing device 15 is provided, through which a second medium L2 in the second chamber 5 'of the dual-chamber systems 3 can be introduced. The second medium L2 may be the solution of another active and / or auxiliary substance, but it may also be a - preferably pure - solvent or a solvent mixture.

After filling the second chamber 5 'of the dual-chamber systems 3, these can also be closed.

FIG. 5 shows schematically the step of closing the second chamber 5 'of the dual-chamber systems 3. The same and functionally identical elements are provided with the same reference numerals, so that reference is made to the preceding description. The second chamber 5 'is closed with the aid of a second closing device 21 with a closure element, which here for example is designed as a stopper 23. This is preferably displaceable in the dual-chamber system 3, so that pressure forces in the second chamber 5 'and ultimately in the separating element 7 can be introduced via it, which lead to an activation of the dual-chamber system 3. It is preferred that the plug 23 is formed as a threaded plug. He can act as a piston element, with a not shown Piston rod by means of an external thread with the internal thread of the threaded plug 23 can be brought into engagement. Thus, pressure forces in the second chamber 5 'and thus indirectly in the separating element 7 can be introduced in a very simple manner, which lead to an activation of the dual-chamber systems 3.

After closing the second chamber 5 ', the container 11 can be closed again and discharged from the clean room. It is also possible to omit the closing of the container 11, and optionally to eject the container 11 openly out of the clean room, or to eject only the magazine 9 or even the individual dual-chamber systems 3 from the clean room. Since both chambers 5, 5 'of the dual chamber systems 3 are sealed, it is not necessary to keep the dual chamber systems 3 in a sterile and / or aseptic environment.

After all, it has been found that the production methods according to the invention and the presterilizable carrier system according to the invention are advantageous over known methods and devices for filling dual-chamber systems. According to the invention, it is possible for a manufacturing pharmaceutical company to use standardized packaging directly on standardized filling lines. Here, products intended for freeze-drying can be filled on systems designed for pre-sterilisable systems. In known processes, especially for filling dual chamber systems in connection with materials intended to be subjected to freeze-drying, heavy and expensive metallic magazines are used which are reused and therefore autoclaved at high cost have to. In the present case, a standardized packaging form is used instead of such magazines during the entire filling process, which is preferably fed to a single use and then disposed of. Since the carrier system according to the invention can be gas-permeable, but impermeable to germs, viruses or bacteria, it is possible to arrange the filling and the freeze-drying decentralized to each other, which also makes it possible to carry out the freeze-drying in a non-sterile environment. The content of the carrier system according to the invention therefore remains sterile at all times. In known methods, moreover, it is necessary to close each individual chamber 5, 5 'of the dual-chamber systems 3 with a so-called lyo-closure prior to the step of freeze-drying, which limits the choice of the closure of the first chamber 5. In the present method, however, it is possible to choose any locking system. This is achieved by the fact that the container 11 itself is closed by a gas-permeable closure element 13, so that a single closing of the first chamber 5 of the dual-chamber systems 3 is unnecessary for the freeze-drying step. Since only semi-automatic, automatic or manual loading and unloading of the freeze-dryer only hygienically sealed containers are handled, falls here also a much lower Kontiminationsrisiko than is the case with known methods.

Claims (16)

1. Method for filling dual-chamber systems (3) in pre-sterilized carrier systems (1), characterized by the following steps:

   - providing at least one sterilized dual-chamber system (3) in a magazine (9), the dual-chamber system comprising respective separating elements (7) separating the two chambers (5, 5') from each other, the magazine (9) accommodating the at least one dual-chamber system (3) and being arranged in a container (11) which is sealed with a closure element (13);

   - introducing the container (11) into a clean room;

   - opening the container (11) and filling a first chamber (5) of the at least one dual-chamber system (3);

   - closing the container (11) with a gas-permeable closure element (13);

   - lyophilizing the solution (L1) contained in the first chamber (5) of the at least one dual-chamber system (3);

   - opening the container (11) and closing the first chamber (5) of the at least one dual-chamber system (3);

   - filling a second chamber (5') of the at least one dual-chamber system (3);

   - closing the second chamber (5') of the at least one dual-chamber system (3);

   - discharging from the clean room.
2. Method for filling dual chamber systems (3) in pre-sterilized carrier systems (1), characterized by the following steps:

   - providing at least one sterilized dual-chamber system (3) in a magazine (9), the dual-chamber system comprising respective separating elements (7) separating the two chambers (5, 5') from each other, the magazine (9) comprising plastic, preferably consisting of plastic, and accommodating the at least one dual-chamber system (3) such that the at least one dual-chamber system (3) is securely retained in the magazine (9) independently of the magazine's orientation, the magazine being arranged in a container (11) which is sealed with a closure element (13);

   - introducing the container (11) into a clean room;

   - opening the container (11) and filling a first chamber (5) of the at least one dual-chamber system (3);

   - closing the first chamber (5) of the at least one dual-chamber system (3);

   - turning over the magazine (9);

   - filling a second chamber (5') of the at least one dual-chamber system (3);

   - closing the second chamber (5') of the at least one dual-chamber system (3);

   - discharging from the clean room.
3. Method according to the claim 1, characterized in that the magazine (9) comprises plastic and preferably consists of plastic.
4. Method according to any one of the preceding claims, characterized in that the container (11) comprises plastic and preferably consists of plastic.
5. Method according to any one of the preceding claims 2 to 4, characterized in that the closure element (13) for the container (11) is gas-permeable.
6. Method according to claim 1 or according to any of claims 3 to 5, characterized in that after filling the first chamber (5) of the at least one dual-chamber system (3) and closing with a gas-permeable closure element (13), the container (11) is discharged from the clean room and introduced into a lyophilization device within which lyophilization takes place and which is arranged outside of the clean room, and that the container (11) is removed from the device after lyophilization and is re-introduced into the clean room.
7. Method according to claim 6, characterized in that the lyophilization device itself is not sterile and/or aseptic.
8. Method according to claim 1 or according to any one of claims 3 to 7, characterized in that the magazine (9) is turned over after closing the first chamber (5) and before filling the second chamber (5') of the at least one dual-chamber system (3).
9. Method according to any one of the preceding claims, characterized in that the first chamber (5) of the at least one dual-chamber system (3) can be closed with a flanged cap, a tamper-proof closure, a closure with attachable needle or a closure with attached needle.
10. Method according to any one of the preceding claims, characterized in that the second chamber (5') of the at least one dual-chamber system (3) can be closed with a plug (23).
11. Method according to claim 10, characterized in that the second chamber (5') of the at least one dual-chamber system can be closed with a threaded plug (23).
12. Pre-sterilizable carrier system, with

    - at least one sterilized dual-chamber system (3) comprising a separating element (7) separating a first chamber (5) and a second chamber (5') from each other;

    - a magazine (9) accommodating the at least one dual-chamber system (3);

    - a container (11),
    the magazine (9) comprising the at least one dual-chamber system (3) being arranged in the container (11) and the container (11) being sealed with a gas-permeable closure element (13) so that an active agent and/or an adjuvant being present in the first chamber (5) is lyophilizable in the sealed container (11).
13. Pre-sterilizable carrier system, with

    - at least one sterilized dual-chamber system (3) comprising a separating element (7) separating a first chamber (5) and a second chamber (5') from each other;

    - a magazine (9) accommodating the at least one dual-chamber system (3);

    - a container (11),
    wherein the magazine (9) comprising the at least one dual-chamber system (3) can be arranged in the container (11), wherein the magazine (9) comprises plastic, preferably consists of plastic, and comprises the at least one dual-chamber system (3) such that the at least one dual-chamber system (3) is securely retained in the magazine (9) independently of the magazine's orientation, and wherein the container (11) can be sealed with a closure element (13).
14. Pre-sterilizable carrier system according to claim 12, characterized in that the magazine (9) comprises plastic and preferably consists of plastic.
15. Pre-sterilizable carrier system according to any one of the claims 12 to 14, characterized in that the container (11) comprises plastic and preferably consists of plastic.
16. Pre-sterilizable carrier system according to any one of the claims 13 to 15, characterized in that the closure element (13) for the container (11) is gas-permeable.

Images