Method for transferring a package for processing in a process chamber of a containment system under aseptic conditions

Abstract

The present invention relates to a method for transferring a package (5) for processing in the process chamber (90) of a containment system (9) under aseptic conditions, in two embodiments. A single package (5) comprises a container (1) having an aseptic internal volume (10) and at least one first passage (12) that is covered. The container (1) is e.g. a tub-like tray having articles arranged therein such as phials, vials, or syringes. The problem addressed by the invention is that of ensuring that only a minimal, acceptable concentration of the contamination agent applied to the exterior of the package (5) during a necessary decontamination phase reaches the internal volume (10) of the container (1). To this end, in one method step, a substantially denser protective layer (4) is provided on an otherwise semi-permeable cover (2) which covers the at least one first passage (12) or a second passage (12') without gas-tight sealing. The method is carried out by means of a sequence comprising a cleanroom (6), the subsequent RABS (7), the following transfer device (8), and the containment system (9) connected thereto on the other side.

Description

[0001] Method for transferring a container for processing in a process chamber of a containment under aseptic conditions

[0002] Field of application of the invention

[0003] The present invention relates to a method for transferring a container for processing in the process chamber of a containment under aseptic conditions, in two embodiments. A single container comprises a receptacle with an aseptic internal volume and at least one first, sealed passage. The receptacle is, for example, a tub-shaped tub or tray with articles arranged therein, such as vials, phials, or syringes. The articles can be positioned in a nest inserted into the container.

[0004] State of the art

[0005] Figures 1A and 1B illustrate the prior art.

[0006] A single container 5 includes:

[0007] - a container 1 with an aseptic internal volume 10 and a first passage 12 closed by a cover 2;

[0008] - a nest 18 stored in the inner volume 10, in whose trough-shaped receiving contours the articles 19 are inserted, which are to be treated in the process chamber 90 of the containment 9 (see Figure 5) after opening the cover 2;

[0009] - optionally an intermediate layer 17 inserted between the cover 2 and the nest 18, above the articles 19; and

[0010] - usually a closed bag-like wrapping 15 surrounding the entire container 5 in the delivery state, which keeps the interior 50 sterile.

[0011] The container 1 is, for example, a tub-shaped tub. The articles 19 are, in particular, phials, vials, or syringes. At least portions of the cover 2 and the wrapping 15 preferably consist of a semi-permeable nonwoven fabric, such as Tyvek. The cover 2 is typically sealed, e.g., glued or welded, on the edge surface 11 surrounding the first opening 12 of the container 1 - forming a first adhesion 3 with the edge 30 - and thus keeps the internal volume 10 of the container 1 in a sterile state. After unpacking the container 5 from the wrapping 15 and before it can be transferred under aseptic conditions into the process chamber of a containment for processing, the container 5 must be externally decontaminated.The disadvantage here is that certain decontaminants acting on the container 5 penetrate the semi-permeable cover 2 to an undesirably high extent into the internal volume 10 of the container 1 and its contents, and flow out into the process chamber of the containment after the cover 2 is opened. This can still be critical, even though the escaping decontaminant residues are quickly diluted in the process chamber. However, it is very critical if residues of the gaseous decontaminant - e.g. H2O2 - remain within the articles 19, which can then alter the effect of the medication when it is filled into the articles 19. Furthermore, residues of the decontaminant can become embedded in the material of the articles 19 and / or in their closure elements (e.g. plugs) and thus flow into the medication after it has been filled.

[0012] Object of the invention

[0013] The object of the present invention is therefore to propose process-efficient measures based on the containers provided by the industry according to the prior art so that the decontaminant directed onto the exterior of the container during an essential decontamination phase only passes through the cover into the interior of the container in a minimal, acceptable concentration. The key objective is to ensure that, as far as possible, no decontaminant enters the substance being processed, especially medications, during the process.

[0014] The aim is always to ensure that as little decontaminating agent as possible gets into the medication, so that the medication does not undergo undesirable changes. Overview of the invention

[0015] The method according to the invention for transferring a container for processing in a process chamber of a containment under aseptic conditions is characterized in a first embodiment by the sequence: a) providing the container at least comprising a receptacle with an aseptic internal volume and an uppermost passage closed with a partially permeable cover; b) applying a protective layer to the cover, wherein the protective layer: ba) is less permeable than the cover to the decontaminant introduced onto the container during a decontamination phase; bb) extends at least partially or entirely over the cover; and bc) is intended to ensure that the decontaminant introduced onto the container during the decontamination phase only passes through the cover into the internal volume in a minimal, acceptable concentration;c) carrying out a decontamination phase with the container provided with the cover and protective layer in a transfer device; d) transferring the container decontaminated with the cover and protective layer into the containment process chamber; and e) in the containment process chamber, removing the cover and protective layer from the container so that the passage to the interior volume of the container is open and further processing can take place.

[0016] Subordinate features of the method according to the invention in its first embodiment are defined below: The cover and the protective layer are removed together from the passage as a composite.

[0017] The protective layer is applied to the cover as a separate agent and / or is formed by exposure to the cover, resulting in a structural change that acts as a protective layer. Exposure to the cover to form the protective layer occurs, for example, thermally or by irradiation, preferably with UV radiation or ultrasound. The cover is a semipermeable film, e.g., Tyvek®, which is fixed to an edge surface of the container surrounding the passage by means of a first adhesive. The protective layer is in the form of a separate agent, a film, and is bonded flatly to the cover by means of a second adhesive. The extension of the protective layer ends before the outer edge of the cover.

[0018] During the decontamination phase, the decontaminant can penetrate through an outer edge of the cover, which is not shielded by the protective layer, to an edge of the first adhesion and onto a peripheral surface of the container. Hydrogen peroxide (H2O2) or nitrogen dioxide (NO2) or a fumigant in an appropriate concentration is used as the decontaminant.

[0019] During preparation, the container, with its aseptic interior volume and the cover sealing the passage, is placed in a bag-like wrapping. The container is prepared in a cleanroom, preferably with a cleanroom class C (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 7 (according to ISO standard 14644-1).

[0020] The container is transferred from the cleanroom to a RABS (Restricted Access Barrier System), where the surrounding enclosure is removed. The RABS preferably has a cleanroom class of Grade A for Supply (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 5 (according to ISO standard 14644-1). The transfer device is linked to the RABS on one side and to the containment on the other.

[0021] The method according to the invention for transferring a container for processing in a process chamber of a containment under aseptic conditions is characterized in a second embodiment by the sequence: a) providing the container at least comprising a container with an aseptic internal volume, wherein the container has: aa) a topmost first passage which is closed with an impermeable cover; and ab) a second passage located at the bottom or side of the container, which is closed with a partially permeable cover; b) applying a protective layer to the cover, wherein the protective layer: ba) is less permeable than the cover for the decontamination agent introduced onto the container during a decontamination phase; bb) extends at least partially or entirely over the cover;and bc) is intended so that the decontaminant introduced onto the container during the decontamination phase only passes through the cover into the internal volume in a minimal, acceptable concentration; c) carrying out a decontamination phase with the container provided with the cover and the protective layer in a transfer device; d) transferring the container decontaminated with the cover and the protective layer into the process chamber of the containment; and e) in the process chamber of the containment, removing the cover from the container so that the first passage to the internal volume of the container is open and further processing can take place.

[0022] Subordinate features of the inventive method in its second embodiment are defined below: The protective layer is applied to the cover as a separate agent and / or is formed by acting on the cover, resulting in a structural change that acts as a protective layer. The action on the cover to form the protective layer occurs, for example, thermally or by irradiation, preferably with UV radiation or ultrasound.

[0023] The cover is a semipermeable film, e.g., Tyvek®, which is affixed to an edge of the container surrounding the second passage by means of a first adhesive. The protective layer is in the form of a separate film and is bonded to the cover by means of a second adhesive. The extension of the protective layer ends before the outer edge of the cover.

[0024] During the decontamination phase, the decontaminant can penetrate through an outer edge zone of the cover, which is not shielded by the protective layer, to an edge of the first adhesion and onto the edge surface of the container surrounding the second opening. Hydrogen peroxide (H2O2) or nitrogen dioxide (NO2) or a fumigant in an appropriate concentration is used as the decontaminant.

[0025] During preparation of the container, the container (1) with its aseptic interior volume and the cover that closes the second opening and the cover that closes the first opening is placed in a bag-like wrapping. The container is prepared in a cleanroom, preferably with cleanroom class C (according to GMP Annex 1: Good Manufacturing Practice), equivalent to class 7 (according to ISO standard 14644-1).

[0026] The container is transferred from the cleanroom to a RABS (Restricted Access Barrier System), where the surrounding enclosure is removed. The RABS preferably has a cleanroom class of Grade A for Supply (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 5 (according to ISO standard 14644-1). The transfer device is linked to the RABS on one side and to the containment on the other.

[0027] They show:

[0028] Figure 1A - a container with a closed wrapping to be processed by the first embodiment of the method according to the invention;

[0029] Figure 1B - the container according to Figure 1A without the wrapping in an exploded view; Figure 2A - the container from Figure 1A, without contents and with a cover over a first opening located at the top of the container, as a schematic representation;

[0030] Figure 2B - the container according to Figure 2A, additionally provided with a protective layer, in the first design;

[0031] Figure 2C - the container according to Figure 2A, additionally provided with a protective layer, in a second design;

[0032] Figure 3A - the arrangement from Figure 2B, with the edge surface of the container, the cover, adhesives and protective layer, as a detailed view;

[0033] Figure 3B - the arrangement from Figure 2C, with the edge surface of the container, the cover, adhesives and protective layer, as a detailed view;

[0034] Figure 4A - the container from Figure 1A with a cover over a second passage present at the bottom of the container, for the transfer method of the second embodiment, as a schematic representation;

[0035] Figure 4B - the container from Figure 1A with a cover over a second passage provided on the side of the container, for the transfer method of the second embodiment, as a schematic representation; and

[0036] Figure 5 - the interlinking of the clean room for the provision of the container, the subsequent RABS, the following transfer device and the containment connected thereto for carrying out the method according to the invention in the first embodiment.

[0037] Implementation example

[0038] With reference to the accompanying drawings, the method according to the invention for transferring a container for processing in a process chamber of a containment under aseptic conditions is described in detail below in two embodiments.

[0039] Figure 2A

[0040] At the start of the transfer process in its first embodiment, after removal of the usually present wrapping 15, the container 1 from Figure 1A is ready, with the partially permeable cover 2 over the first opening 12 located at the top of the container 1. In simplified form, the container 1 is shown with its internal volume 10 without contents. The cover 2 is a semipermeable film, e.g., Tyvek®, and is fixed to the edge surface 11 by means of a first attachment 3 as an adhesive or weld, wherein the outer edge 30 of the first attachment 3 extends to the outer edge of the edge surface 11 and the edge zone 20 of the cover 2 projects beyond the edge 30 of the first attachment 3 and the outer edge of the edge surface 11.

[0041] Figures 2B and 3A

[0042] In the next step of the transfer process, a protective layer 4 is applied to the cover 2. Compared to the cover 2, the protective layer 4 is less permeable to the decontaminant introduced onto the container 5 during a later decontamination phase, so that the decontaminant only passes through the cover 2 into the interior volume 10 in a minimal, acceptable concentration. In the first design shown, the protective layer 4 extends entirely over the cover 2, apart from its overhanging edge zone 20, and has the shape of a film as a separate means, which is bonded flatly to the cover 2 by means of the second adhesion 40. Alternatively, the protective layer 4 can be formed by a structure-changing effect on the cover 2, which then acts as a protective layer 4.The action on the cover 2 to form the protective layer 4 can be thermal or by means of irradiation, preferably with UV radiation or ultrasound.

[0043] Figures 2C and 3B

[0044] In contrast to Figure 2B, the protective layer 4 now, in the second design, ends before the overhanging edge zone 20 of the cover 2. This makes it possible for decontaminating agent to reach an edge 30 of the first adhesion 3 and an edge surface 11 of the container 1 through an outer edge zone 20 of the cover 2, which is not shielded by the protective layer 4, during the later decontamination phase.

[0045] Figure 4A

[0046] At the start of the transfer process in its second embodiment, after removal of the usually present wrapping 15, a container 1 modified to that shown in Figure 1A is ready. In simplified form, the container 1 with its aseptic interior volume 10 is again shown without contents. The first passage 12 provided at the top of the container 1 is closed with the impermeable cover 2'. The cover 2' is fixed to the edge surface 11 by means of adhesive or welding.

[0047] This container 1 has a second opening 12' located at the bottom, which is closed with a partially permeable cover 2. The cover 2 is a semipermeable film, e.g., Tyvek, and is fixed to the edge surface 1T by means of a first adhesion 3, either glued or welded, with the cover 2 projecting beyond the first adhesion 3. In the next step of the transfer process, a protective layer 4 is applied to the cover 2.

[0048] Analogous to Figure 2C, the protective layer 4 according to the second design ends before the outer edge zone 20 of the cover 2. This enables the decontamination agent to reach an edge 30 of the first adhesion 3 and the edge surface 1T of the container 1 through the outer edge zone 20 of the cover 2, which is not shielded by the protective layer 4, during the later decontamination phase. The protective layer 4 has the form of a film as a separate means, which is bonded flatly to the cover 2 by means of the second adhesion 40. With regard to the properties, nature, and alternative formation of the protective layer 4, reference is made to the above description of Figures 2B and 3A.

[0049] Figure 4B

[0050] As a variation to Figure 4A, the second passage 12', the cover 2 with the first attachment 3 for fixing to the edge surface 1T of the container 1, as well as the protective layer 4 with the associated second attachment 40 for connecting to the cover 2, are now all located on the side of the container 1. The above description of Figures 2B and 3A also applies here with regard to properties, nature and alternative formation of the protective layer 4. Figure 5

[0051] The sequence of the method according to the invention for transferring a container 5 for processing in a process chamber 90 of a containment 9 under aseptic conditions, in its first embodiment, is described below with reference to the illustrated interlinking of clean room 6, subsequent RABS 7, following transfer device 8 and, on the other hand, the containment 9 connected thereto.

[0052] Process section 1

[0053] The provision of the container 5 with the semi-permeable cover 2 closing the container 1, which is generally packaged as a unit in a sterile manner in the wrapping, takes place in the cleanroom 6, preferably with cleanroom class Grade C (according to GMP Annex 1: Good Manufacturing Practice), equivalent to class 7 (according to ISO standard 14644-1).

[0054] Yerfah renssch ritt 2

[0055] The container 5 is transferred from the cleanroom 6 to the process chamber 70 of the RABS 7, where the enclosure 15 surrounding the container 5 is removed. The RABS 7 preferably has a cleanroom class of Grade A for Supply (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 5 (according to ISO standard 14644-1). Depending on the size of the plenum of the RABS 7, several supply air fans 76 and supply air filters 77 are arranged to generate a purified unidirectional displacement flow 75 flowing through the process chamber 70.

[0056] Furthermore, in the RABS 7, the cover 2 on the now unpacked container 5 is provided with the protective layer 4, which is applied as a separate agent and / or produced by acting on the cover 2 with the resulting structural change, which acts as a protective layer 4.

[0057] Process step 3

[0058] From the RABS 7, the container 5, provided with the protective layer 4, is moved through an open exit gate 71 into a transfer device 8, where a decontamination phase is carried out. The transfer device 8 can, in particular, be in the form of a lock or a tunnel. Hydrogen peroxide (H2O2) or nitrogen dioxide (NO2) or a fumigant in an appropriate concentration have proven effective as decontamination agents.

[0059] Procedural step 4

[0060] From the transfer device 8, the externally decontaminated container 5, whose cover 2 is provided with the protective layer 4, is transferred through an entrance gate 91 into the process chamber 90 of the containment 9. Depending on the size of the containment 9, several supply air fans 96 and supply air filters 97 are arranged in the plenum of the containment 9 to generate a purified unidirectional displacement flow 95 flowing through the process chamber 90.

[0061] Containment 9 must meet cleanroom class Grade A (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 5, i.e. the strict requirements regarding the purity of particles and germs in the air and on the surfaces, which is why Containment 9 is decontaminated, usually with H2O2.

[0062] Decay renssch ritt 5

[0063] In the process chamber 90 of the containment 9, the protective layer 4 and the cover 2 are removed from the container 5, preferably together as a composite, so that the first passage 12 to the inner volume 10 of the container 1 is opened and further processing can take place.

[0064] Transfer process .in.two.exe

[0065] The container 5 according to Figures 4A and 4B has the modified structure with a second passage 12' provided at the bottom or side of the container 1, which is closed with the partially permeable cover 2 and associated protective layer 4. Furthermore, the uppermost first passage 12 is closed with an impermeable cover 2'. Therefore, the cover 2' must be removed from the container 1 in the process chamber 90 of the containment 9 in order to access the interior volume 10 of the container 1 for further processing through the then opened first passage 12. Cover 2 and protective layer 4, however, can remain on the container 1, be disposed of together, or be recycled.

Claims

P a t e n t a n s p r ü c h e 1. A method for transferring a container (5) for processing in a process chamber (90) of a containment (9) under aseptic conditions, in a first embodiment, is characterized by the sequence: a) providing the container (5) at least comprising a receptacle (1) with an aseptic internal volume (10) and an uppermost passage (12) which is closed with a partially permeable cover (2); b) applying a protective layer (4) to the cover (2), wherein the protective layer (4): ba) is less permeable than the cover (2) for the decontamination agent introduced onto the container (5) during a decontamination phase; bb) extends at least partially or entirely over the cover (2);and bc) is intended so that the decontaminating agent introduced onto the container (5) during the decontamination phase only passes through the cover (2) into the internal volume (10) in a minimal, acceptable concentration; c) carrying out a decontamination phase with the container (5) provided with the cover (2) and the protective layer (4) in a transfer device (8); d) transferring the container (5) decontaminated with the cover (2) and the protective layer (4) into the process chamber (90) of the containment (9); and e) in the process chamber (90) of the containment (9), removing the cover (2) and the protective layer (4) from the container (5) so that the passage (12) to the internal volume (10) of the container (1) is opened and further processing can take place.; 2. Method according to claim 1, characterized in that the cover (2) and the protective layer (4) are removed together as a composite from the passage (12).

3. Method according to at least one of claims 1 and 2, characterized in that the protective layer (4): a) is applied as a separate agent to the cover (2); and / or b) by acting on the cover (2) a structural change is formed thereon, which acts as a protective layer (4).

4. Method according to claim 3, characterized in that the action on the cover (2) to form the protective layer (4) takes place thermally or by means of irradiation, preferably with UV radiation or ultrasound.

5. Method according to at least one of claims 1 to 3, characterized in that a) the cover (2) is a semi-permeable film, e.g. Tyvek, which is fixed to an edge surface (11) of the container (1) surrounding the passage (12) by means of a first adhesive (3); and b) the protective layer (4) is in the form of a separate means as a film and is connected flatly to the cover (2) by means of a second adhesive (40).

6. Method according to at least one of claims 1 to 5, characterized in that the extension of the protective layer (4) ends before the outer edge of the cover (2).

7. Method according to at least one of claims 5 and 6, characterized in that during the decontamination phase, decontamination agent can reach an edge (30) of the first adhesion (3) and an edge surface (11) of the container (1) through an outer edge zone (20) of the cover (2), which is not shielded by the protective layer (4).

8. Method according to at least one of claims 1 to 7, characterized in that hydrogen peroxide (H2O2) or nitrogen dioxide (NO2) or a fumigant in a suitable concentration is used as the decontaminant.

9. Method according to at least one of claims 1 to 8, characterized in that during the provision of the container (5), the container (1) with its aseptic internal volume (10) and the cover (2) which closes the passage (12) lies in a bag-like wrapping (15).

10. Method according to at least one of claims 1 to 9, characterized in that the provision of the container (5) takes place in a clean room (6), preferably with clean room class Grade C (according to GMP Annex 1: Good Manufacturing Practice), equivalent to class 7 (according to ISO standard 14644-1).

11. Method according to at least one of claims 9 and 10, characterized in that a) the container (5) is transferred from the clean room (6) to a RABS (7) and the wrapping (15) surrounding the container (5) is removed there; wherein b) the RABS (7) preferably has clean room class Grade A for Supply (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 5 (according to ISO standard 14644-1).

12. Method according to claim 11, characterized in that the transfer device (8) is linked on the one hand to the RABS (7) and on the other hand to the containment (9).

13. A method for transferring a container (5) for processing in a process chamber (90) of a containment (9) under aseptic conditions, in a second embodiment, is characterized by the sequence: a) providing the container (5) at least comprising a container (1) with an aseptic internal volume (10), wherein the container (1) has: aa) a topmost first passage (12) which is closed with an impermeable cover (2'); and ab) a second passage (12') located at the bottom or side of the container (1) which is closed with a partially permeable cover (2); b) applying a protective layer (4) to the cover (2), wherein the protective layer (4): ba) is less permeable to the decontamination agent introduced onto the container (5) during a decontamination phase compared to the cover (2); bb) extends at least partially or entirely over the cover (2); and bc) is intended so that the decontamination agent introduced onto the container (5) during the decontamination phase only passes through the cover (2) into the internal volume (10) in a minimal, acceptable concentration; c) carrying out a decontamination phase with the container (5) provided with the cover (2) and the protective layer (4) in a transfer device (8); d) transferring the container (5) decontaminated with the cover (2) and the protective layer (4) into the process chamber (90) of the containment (9);and e) in the process chamber (90) of the containment (9), removing the cover (2') from the container (5) so that the first passage (12) to the inner volume (10) of the container (1) is opened and further processing can take place.; 14. The method according to claim 13, characterized in that the protective layer (4): a) is applied as a separate agent to the cover (2); and / or b) by acting on the cover (2), a structural change is formed thereon, which acts as a protective layer (4).

15. The method according to claim 14, characterized in that the action on the cover (2) to form the protective layer (4) takes place thermally or by means of irradiation, preferably with UV radiation or ultrasound.

16. Method according to at least one of claims 13 to 15, characterized in that a) the cover (2) is a semipermeable film, e.g. Tyvek®, which is fixed to an edge surface (11') of the container (1) surrounding the second passage (12') by means of a first adhesive (3); and b) the protective layer (4) is in the form of a separate means as a film and is connected flatly to the cover (2) by means of a second adhesive (40).

17. Method according to at least one of claims 13 to 16, characterized in that the extension of the protective layer (4) ends before the outer edge of the cover (2).

18. Method according to at least one of claims 16 and 17, characterized in that during the decontamination phase, decontamination agent can reach an edge (30) of the first adhesion (3) and the edge surface (1 T) of the container (1) surrounding the second passage (12') through an outer edge zone (20) of the cover (2), which is not shielded by the protective layer (4).

19. Method according to at least one of claims 13 to 18, characterized in that hydrogen peroxide (H2O2) or nitrogen dioxide (NO2) or a fumigant in a suitable concentration is used as the decontamination agent.

20. Method according to at least one of claims 13 to 19, characterized in that during the provision of the container (5), the container (1) with its aseptic internal volume (10) and the cover (2) which closes the second passage (12') and the cover (2') which closes the first passage (12) lies in a bag-like wrapping (15).

21. Method according to at least one of claims 13 to 20, characterized in that the provision of the container (5) takes place in a clean room (6), preferably with clean room class Grade C (according to GMP Annex 1: Good Manufacturing Practice), equivalent to class 7 (according to ISO standard 14644-1).

22. Method according to at least one of claims 20 and 21, characterized in that a) the container (5) is transferred from the clean room (6) to a RABS (7) and the wrapping (15) surrounding the container (5) is removed there; wherein b) the RABS (7) preferably has clean room class Grade A for Supply (according to GMP Annex 1: Good Manufacturing Practice), equivalent to Class 5 (according to ISO standard 14644-1).

23. Method according to claim 22, characterized in that the transfer device (8) is linked on the one hand to the RABS (7) and on the other hand to the containment (9).

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