Sterile connectors for the sterile transfer of a liquid medium

Abstract

Sterile connectors for the sterile transfer of a liquid, in particular biological, medium from a liquid container (2) into a bioprocess plant (3), in particular into a bioreactor, wherein the sterile connector (1) has two coupling devices (4a, 4b), characterized by that the coupling devices (4a, 4b) each have a housing (5a, 5b) with a housing interior (6a, 6b) and an actuating element (8a, 8b) adjustable in the housing interior (6a, 6b) forming a channel (7a, 7b), wherein the channel (7a, 7b) extends from an actuating element inlet opening (9a, 9b) to an actuating element outlet opening (10a, 10b) through the actuating element (8a, 8b), that the housing (5a) of one coupling device (4a) is mechanically connectable to the housing (5b) of the other coupling device (4b), that each housing (5a, 5b) has a fluid inlet (11a, 11b) and a fluid outlet (12a, 12b) that connect the housing interior (6a, 6b) to the environment, wherein, in the mechanically connected state of the housings (5a, 5b), the fluid outlet (12a) of one housing (5a) and the fluid inlet (11b) of the other housing (5b) are in overlapping positions, that in the mechanically connected state of the housings (5a, 5b) the actuating elements (8a, 8b) are each adjustable from a starting position in which a fluid connection between channel (7a, 7b) and actuating element inlet opening (9a, 9b) on the one hand and between channel (7a, 7b) and actuating element outlet opening (10a, 10b) on the other hand is blocked, to an operating position in which the actuating element inlet opening (9a, 9b) is in fluid communication with the fluid inlet (11a, 11b) and the actuating element outlet opening (10a, 10b) is in fluid communication with the fluid outlet (12a, 12b), that in the initial position a section of the respective actuating element (8a, 8b) hermetically seals the fluid inlet (11a, 11b) and a section of the respective actuating element (8a, 8b) seals the fluid outlet (12a, 12b) of the respective housing (5a, 5b).

Description

[0001] The invention relates to a sterile connector for the sterile transfer of a liquid, in particular biological, medium according to the preamble of claim 1, a coupling device of a sterile connector according to the preamble of claim 14, a packaging arrangement comprising a package and at least one such sterilely packaged coupling device or such a sterilely packaged sterile connector therein according to claim 15, and the use of such a sterilely packaged sterile connector, such a sterilely packaged coupling device and / or such a packaging arrangement according to claim 17.

[0002] In this context, a bioprocess plant is generally understood to be a facility used to carry out or support biotechnological processes. Bioreactors, in which microorganisms or tissue cells are cultivated under specific conditions, serve as just one example. Such a facility typically includes a container holding a biological reaction medium consisting of the substances intended for a biotechnological process, such as microorganisms or tissue cells, and a corresponding nutrient medium, in order to carry out the respective biotechnological process step, for example, fermentation or cultivation.

[0003] One example of such a bioreactor is a production bioreactor, a relatively large, production-scale bioreactor with a working volume of, for example, several hundred or several thousand liters, used for the industrial production of microbial or cellular products, particularly biopharmaceuticals. Such a bioreactor produces a fermentation broth, which is typically further processed in a downstream process to obtain a product from the cells or the culture supernatant. Another example is a laboratory bioreactor, a relatively small, laboratory-scale bioreactor with a working volume of, for example, less than 10 liters.Such a laboratory bioreactor is used, for example, to produce ATMPs (Advanced Therapy Medical Products) and / or to carry out cell expansion, thereby generating a sufficient number of cells, particularly tissue cells or microbial cells, for the respective application. One application is the proliferation of human cells, such as T cells (T lymphocytes), which are taken from the patient, then expanded ex vivo, and subsequently reinfused into the patient.

[0004] Especially in the production of ATMPs using a laboratory bioreactor, but also generally in production bioreactors, the sterile addition of individual liquid media, such as biological media, to the respective bioreactor is of paramount importance. Since many ATMPs cannot be sterilely filtered or sterilized, their production is carried out under sterile conditions in cleanrooms of appropriate cleanroom classes. The addition of a liquid medium to a bioreactor or the transfer of a liquid medium between two culture vessels and / or bioreactors inherently carries a risk of contamination, which is why such handling steps are typically performed in a cleanroom of cleanroom class A (GMP Guide Annex 1) or ISO 5 (ISO 14644-1). However, the production of pharmaceuticals in such cleanrooms is very costly due to stringent monitoring requirements, elaborate protective clothing procedures, etc.

[0005] For this reason, there is a demand for closed systems for cell cultivation and expansion, particularly in the field of ATMP manufacturing, which allows the use of lower cleanroom classes, such as cleanrooms of class D (GMP Guide Annex 1) or ISO 8 (ISO 14644-1). However, a challenge lies in adding a liquid medium to such a closed system in the simplest possible way. While various connection systems such as Luer connectors, Luer-lock connectors, etc., are known for connecting, for example, a small-volume liquid container like a syringe or vial to a closed system, these systems present a significant challenge.However, at the coupling point, where the two coupling devices of the connector – in the case of a Luer connector, the male Luer connector and the female Luer connector – are connected, there is a risk of contamination, which is why special attention must be paid to sterile conditions when making the connection.

[0006] Various designs of sterile connectors are known from the publications DE 10 2012 022 144 B4, US 2017 / 0 314 719 A1, DE 10 2011 106 852 A1 and US 2016 / 0 022 979 A1.

[0007] The invention is based on the problem of designing and further developing a sterile connector for the sterile transfer of a liquid medium from a liquid container to a bioprocess engineering plant in such a way that sterile conditions can be easily established during the transfer of the medium.

[0008] The above problem is solved in a sterile connector for the sterile transfer of a liquid, in particular biological, medium according to the preamble of claim 1 by the features of the characterizing part of claim 1.

[0009] The essential consideration is to create a sterile connector with two coupling devices for the transfer of liquid from a liquid container, which is for example a minimum quantity liquid container, into a bioprocess engineering plant, which is in particular a bioreactor, in which the coupling devices are initially provided in a state in which contamination of the parts relevant for the liquid transfer, preferably sterile, by the user is not readily possible, since in this state these are concealed in the coupling device and thus protected from contact.

[0010] Specifically, the channel of each coupling device, and in one coupling device at least the outlet opening and in the other coupling device at least the corresponding inlet opening, are in a position protected from contamination, preferably sterile, in this state. After the two coupling devices are connected as intended, they can each be brought into a state in which the aforementioned parts relevant for the fluid transfer are moved out of the protected, preferably sterile, position and connected and aligned with each other so that the fluid transfer can take place.In this state, which enables the transfer, the previously protected and still sterile outlet opening of one coupling device and the previously protected and still sterile inlet opening of the other coupling device are arranged in such a way that the liquid medium can flow from one coupling device to the other. In this state, the liquid medium in the transition area between the two coupling devices only comes into contact with the previously protected and still sterile sections of the coupling devices. Areas that were previously unprotected and thus exposed to a potential risk of contamination are separated from the fluid flow area, so that no germs or other media can enter the liquid medium.

[0011] It is particularly preferred if, prior to connecting the two coupling devices, the liquid container from which the medium is to be dispensed and / or the bioprocessing plant into which the medium is to be added are sterilely connected to their respective coupling devices. This is particularly preferably done by the manufacturer. For example, the manufacturer of the liquid container could provide it already equipped with the associated coupling device of the sterile connector, preferably already filled at this point. The liquid container and the coupling device are then preferably provided to the user in their intended connected state, particularly as single-use components.The same applies to the bioprocess engineering plant, where it is also conceivable that the manufacturer of the plant already provides it with the associated coupling device of the sterile connector, possibly also with several such coupling devices, whereby the bioprocess engineering plant and the respective coupling device are preferably made available to the user in the intended connected state, in particular as single-use components.

[0012] In this way, the two coupling devices of the sterile connector cannot be contaminated at any point relevant to the fluid transfer, preferably a sterile one, before the connection is made, since a sterile connection already exists in the area where the medium flows from the fluid container into the coupling device connected to it, as well as in the area where the medium flows from the other coupling device into the bioprocessing plant. The sections of the coupling devices through which the medium is intended to flow from the coupling device associated with the fluid container to the respective other coupling device are only moved away from the protected, preferably sterile, area of ​​the respective coupling device and brought together after the two coupling devices have been connected.In particular, these two sections are brought together directly without coming into contact with other, potentially contaminated sections of the coupling devices or with the user during their movement from the protected area to their intended final position. Since the sterile parts of the coupling devices are only positioned and brought into contact with each other after they have been connected, and no contamination of the parts is possible during this movement, a sterile connection between a liquid container and a bioprocessing plant can be established in a particularly simple manner using the proposed sterile connector.

[0013] Specifically, it is now proposed that the coupling devices each comprise a housing with a, preferably sterile, interior and an actuating element, preferably sterile, which is adjustable within the interior and forms a channel, the channel extending through the actuating element from an inlet opening to an outlet opening; that the housing of one coupling device is mechanically connectable to the housing of the other coupling device; that each housing has a fluid inlet and a fluid outlet connecting the interior to the environment, wherein, in the mechanically connected state of the housings, the fluid outlet of one housing and the fluid inlet of the other housing are in overlapping position; that, in the mechanically connected state of the housings, the actuating elements each move from a starting position,in which a fluid connection between the channel and the actuator inlet opening on the one hand and between the channel and the actuator outlet opening on the other hand is blocked, are adjustable to an operating position in which the actuator inlet opening is in fluid communication with the fluid inlet and the actuator outlet opening is in fluid communication with the fluid outlet, such that in the initial position a section of the respective actuator hermetically seals the fluid inlet and a section of the respective actuator seals the fluid outlet of the respective housing.

[0014] In this context, the term "housing" is generally understood to mean a component that surrounds the actuating element at least partially, and preferably substantially completely, in at least one circumferential direction. If the actuating element, as will be explained further, is rotatably mounted, then this actuating element is surrounded by the housing at least partially or substantially completely in the radial direction, at least with respect to the axis of rotation. The latter is particularly preferred if the actuating element's inlet and outlet openings point radially outwards with respect to the axis of rotation. However, it is also conceivable that the actuating element's inlet and outlet openings point parallel to the axis of rotation, in which case the actuating element is preferably surrounded by the housing at least partially or substantially completely in the axial direction.In principle, the actuating element can also be linearly movable, in which case the housing preferably surrounds the actuating element at least partially or substantially completely on the sides parallel to the direction of movement, wherein in this case the actuating element inlet openings and the actuating element outlet openings of the actuating elements are directed in a direction transverse to the direction of movement.

[0015] “Essentially complete” means that the housing is completely closed in the respective direction except for the fluid inlet and fluid outlet.

[0016] The housing is designed in such a way that, in the initial position of the actuator, it protects the actuator inlet opening and the actuator outlet opening, thereby keeping them sterile, and in the operating position of the actuator, it allows the actuator outlet opening of one coupling device, which is particularly associated with the liquid container, and the actuator inlet opening of the other coupling device, which is particularly associated with the bioprocessing plant, to be brought into overlapping positions.

[0017] "Overlap" here means a partial or complete overlap of the two respective openings in a direction parallel to the central axes of the openings.

[0018] Claims 2 to 7 specify particularly preferred methods for optimally arranging the preferably sterile inlet and outlet openings of the actuator element within the housings in their initial position, protecting them from the environment and contamination, and for arranging them relative to each other in the operating position while maintaining sterility. For this purpose, a hermetically sealed area, preferably sterile in its delivered state, is provided within the respective housing. In the initial position of the actuator element, the channel extending through this area is located within this channel. Only by moving the actuator element from its initial position to its operating position would the channel, and consequently its inlet and outlet openings, enter a non-sterile area.However, when the sterile connector is used as intended, the two coupling devices are connected beforehand in such a way that the movement of the actuator from the starting position to the operating position cannot lead to any contact between the actuator inlet opening, the actuator outlet opening and the channel with the environment.

[0019] In this context, "hermetically sealed" or "hermetically sealed" means that a seal is provided that prevents the ingress of contaminants, especially germs. In another embodiment, "hermetically sealed" or "hermetically sealed" refers to a sterile and / or contamination-protected area of ​​the sterile connector. In a particularly preferred embodiment, the terms "hermetically sealed" or "hermetically sealed" also include the term "sterile" and are therefore interchangeable.

[0020] Claim 8 relates to particularly preferred orientations of all fluid-flowing parts in the operating position of the respective actuating element. Particularly preferably, the two fluid inlets of the housings, the two fluid outlets of the housings, and the two channels of the actuating elements are arranged coaxially to each other. However, other orientations are also conceivable in principle.

[0021] The further preferred embodiments in claims 9 to 11 relate to the adjustment movement of the respective actuating element between the initial position and the operating position. In particular, the adjustment movement of one actuating element is accompanied by a corresponding adjustment movement of the other actuating element; that is, both actuating elements move synchronously and are simultaneously in their initial position and simultaneously in their operating position. This is preferably achieved by means of a transmission, in particular a gear transmission. The transmission can be actuated by the user from outside the housing, thereby effecting the adjustment movements of both actuating elements.

[0022] According to the particularly preferred embodiment of claim 12, the fluid inlet of one housing and the fluid outlet of the other housing can be connected or are connected by a hose or tube. As previously explained, it is particularly preferred if the liquid container is already connected by the manufacturer to the respective associated coupling device and the bioprocessing plant to the respective associated coupling device, which can also be done via a suitable hose or tube.

[0023] Claim 13 defines preferred methods for connecting the two housings to each other.

[0024] According to a further teaching as defined in claim 14, which has independent significance, a coupling device of a sterile connector, in particular of a proposed sterile connector, is claimed for the sterile transfer of a liquid, in particular biological, medium from a liquid container into a bioprocess plant, in particular into a bioreactor. Given that the proposed sterile connector has two coupling devices, reference may be made to all related explanations of the first-mentioned teaching.

[0025] According to a further teaching as described in claim 15, which also has independent significance, a packaging arrangement is claimed comprising a package and at least one, preferably exactly one, sterilely packaged, proposed coupling device or sterile connector therein. Given that the proposed packaging arrangement includes a sterile connector or coupling device, reference may be made to all related details concerning the first and second aforementioned teachings.

[0026] According to claim 16, the packaging can also contain either a liquid container or a bioprocess engineering plant in a sterile package, wherein the liquid container or the bioprocess engineering plant is already fluidically coupled to the coupling device in the packaging.

[0027] According to a further teaching as described in claim 17, which also has independent significance, the use of a sterilely packaged, proposed sterile connector, a sterilely packaged, proposed coupling device, and / or a proposed packaging arrangement for the sterile transfer of a liquid, in particular biological, medium from a liquid container into a bioprocessing plant, especially a bioreactor, is claimed. Given that the proposed use relates to the use of a proposed sterile connector, a proposed coupling device, and / or a proposed packaging arrangement, reference may be made to all related explanations of the aforementioned teachings.

[0028] With the proposed packaging arrangement and the proposed use, it has been recognized that a liquid medium can be supplied to a closed system, in particular a bioreactor, particularly easily and without any significant risk of contamination using the proposed sterile connector or coupling devices, by keeping the parts relevant for the liquid transfer in a sterile state, namely in the aforementioned initial position, until the liquid transfer actually takes place, namely in the aforementioned operating position.

[0029] In the particularly preferred embodiment according to claim 18, individual components of the aforementioned components, in particular the proposed coupling device, in particular both coupling devices, preferably also the liquid container and / or the bioprocessing plant and / or the hoses or tubes, are preferably designed as single-use components, wherein the components are preferably made of a plastic material.

[0030] The invention will now be explained in more detail with reference to a drawing that illustrates only one embodiment. The drawing shows Fig. 1 in a perspective view a proposed sterile connector when connecting its two coupling devices, Fig. 2 in a perspective view the two coupling devices in the connected state a) in the initial position of the two actuating elements and b) in the operating position of the two actuating elements, Fig. 3. In a sectional view, the two coupling devices in the connected state a) in the initial position of the two actuating elements and b) in the operating position of the two actuating elements and Fig. 4 in a perspective view a proposed packaging arrangement with a proposed coupling device and a liquid container connected thereto, and a proposed packaging arrangement with another proposed coupling device and a bioprocess engineering plant connected thereto.

[0031] The one in the Fig. 1, Fig. 2, Fig. 3 to Fig. The proposed sterile connector 1, as shown in Figure 4, serves for the sterile transfer of a liquid, particularly biological, medium from a liquid container 2, here a small-capacity liquid container (i.e., a liquid container with a small capacity of, for example, a maximum of 30 ml), to a bioprocessing plant 3, here a bioreactor. The proposed sterile connector 1 has two coupling devices 4a and 4b that can be mechanically and fluidically connected to each other. One coupling device 4a is associated with the liquid container 2, and the other coupling device 4b is associated with the bioprocessing plant 3. "Associated" means that the coupling device 4a can be connected to, or is connected to, the liquid container 2, and the coupling device 4b can be connected to, or is connected to, the bioprocessing plant 3.Particularly preferred is the manufacturer's own, sterile state, connection of the liquid container 2 with the coupling device 4a associated with it and the bioprocess engineering plant 3 with the coupling device 4b associated with it.

[0032] The bioprocess plant 3, in particular the bioreactor, forms a closed system or is integrated into a closed system. The bioreactor is designed, for example, as a laboratory bioreactor, meaning it has a relatively small working volume (maximum available filling volume) of no more than 10 liters, unlike a production bioreactor. Such a bioreactor serves to carry out a biotechnological process, which here, and preferably, is used for the production of an advanced therapy medicinal product (ATMP). For example, the biotechnological process could also be a cell expansion process for T cells. In any case, a biological reaction medium is provided in the bioreactor, which in particular contains tissue cells or microbial cells as well as a nutrient medium. It is necessary to add the liquid media to the closed system under sterile conditions.

[0033] It is essential that the coupling devices 4a, 4b each have a housing 5a, 5b with a preferably sterile interior 6a, 6b and an actuating element 8a, 8b, preferably sterile, which is adjustably mounted in the interior 6a, 6b and forms a channel 7a, 7b, wherein the channel 7a, 7b extends from an actuating element inlet opening 9a, 9b to an actuating element outlet opening 10a, 10b through the actuating element 8a, 8b. Furthermore, it is essential that the housing 5a of one coupling device 4a is mechanically connectable to the housing 5b of the other coupling device 4b.It is also essential that each housing 5a, 5b has a fluid inlet 11a, 11b and a fluid outlet 12a, 12b, which connect the housing interior 6a, 6b with the environment of the respective housing 5a, 5b, wherein, in the mechanically connected state of the housings 5a, 5b, the fluid outlet 12a of one housing 5a and the fluid inlet 11b of the other housing 5b are in overlapping positions. Finally, it is also essential that, in the mechanically connected state of the housings 5a, 5b, the actuating elements 8a, 8b each move from a starting position ( ). Fig. 2a), Fig. 3a)), in which a fluid connection between channel 7a, 7b and actuator inlet opening 9a, 9b on the one hand and between channel 7a, 7b and actuator outlet opening 10a, 10b on the other hand is blocked, into an operating position ( Fig. 2b), Fig. 3b)), in which the actuator inlet opening 9a, 9b is in fluid inlet 11a, 11b and the actuator outlet opening 10a, 10b is in fluid outlet 12a, 12b, in particular completely, in fluid connection, are adjustable.

[0034] In the proposed sterile connector 1 and the proposed coupling devices 4a, 4b to be connected to each other, it is provided that the actuating elements 8a, 8b can be moved from a starting position to an operating position, wherein in the starting position the parts relevant for fluid transfer, namely the channel 7a, 7b, the actuating element inlet opening 9a, 9b and / or the actuating element outlet opening 10a, 10b, are in a sterile state. The sterile state is ensured by the fact that the parts relevant for fluid transfer are preferably sterile in the starting position of the actuating element 8a, 8b and are covered from the surroundings of the housing 5a, 5b and thus protected from contamination. Once the two coupling devices 4a, 4b are connected to each other as intended, the actuating elements 8a, 8b can be moved into the operating position, in which the transfer of the liquid medium can then take place.In the operating position, the aforementioned parts relevant for fluid transfer remain sterile, since the two coupling devices 4a, 4b and the two housings 5a, 5b were connected to each other beforehand, i.e., before the movement from the initial position to the operating position, in such a way that the parts relevant for fluid transfer could not come into contact with the environment at any time.

[0035] In the embodiment shown here, which is preferred in this respect, the respective channel 7a, 7b extends in the initial position into an area of ​​the housing interior 6a, 6b that is hermetically sealed from the surroundings of the housing 5a, 5b and is preferably sterile in the delivered state. Furthermore, preferably, in the initial position the actuator inlet opening 9a, 9b and the actuator outlet opening 10a, 10b each point towards the inner wall 13a, 13b of the respective housing 5a, 5b.

[0036] The respective actuating element 8a, 8b is here preferably one that is rotatably mounted and, as Fig. Figure 3 shows that it has a substantially circular cross-section. Accordingly, the respective actuating element 8a, 8b has a shape about the axis of rotation x. a , x b the actuating element 8a, 8b circumferential, substantially cylindrical circumference, wherein the respective actuating element inlet opening 9a, 9b and the respective actuating element outlet opening 10a, 10b are here and preferably arranged on the circumference and in a radial direction with respect to the axes of rotation x a , x b The channel 7a, 7b connecting the respective actuator inlet opening 9a, 9b with the respective actuator outlet opening 10a, 10b has a straight course here, preferably. The channel runs centrally through the respective actuator 8a, 8b, and thus also through the axis of rotation x. a , x bof the respective actuating element 8a, 8b. The actuating element inlet opening 9a, 9b and the actuating element outlet opening 10a, 10b of the respective actuating element 8a, 8b are located here, and preferably diametrically opposite each other. In an alternative embodiment, not shown here, it is also conceivable that the actuating element inlet opening and / or actuating element outlet opening of the actuating element 8a, 8b are located laterally, i.e., parallel to the axis of rotation x. a , x b , can be directed. Additionally or alternatively, in a further embodiment not shown here, it is also conceivable to provide a linearly movable actuating element instead of a rotatable actuating element 8a, 8b. The descriptions of the actuating elements 8a, 8b, which are rotatable here and preferably, apply accordingly to differently designed or adjustable actuating elements, in particular also to linearly adjustable actuating elements.

[0037] The fluid inlet 11a of one housing 5a and the fluid outlet 12b of the other housing 5b are designed as channels, i.e., as inlet and outlet channels leading from the outside into the housing interior 6a, 6b, respectively. In contrast, the fluid outlet 12a of one housing 5a and the fluid inlet 11b of the other housing 5b are designed as openings that directly connect the housing interior 6a, 6b to the environment. In an exemplary embodiment, the cross-section of the fluid inlet 11a of one housing 5a and the fluid outlet 12b of the other housing 5b is smaller than the cross-section of the fluid outlet 12a of one housing 5a and the fluid inlet 11b of the other housing 5b. The "cross-section" always refers to a section perpendicular to the flow direction.The longitudinal extent of the fluid inlet 11a of one housing 5a and the fluid outlet 12b of the other housing 5b is also greater than the longitudinal extent of the fluid outlet 12a of one housing 5a and the fluid inlet 11b of the other housing 5b. The latter is almost zero. The "longitudinal extent" is always relative to the flow direction.

[0038] Here, and preferably, it is further provided that in the initial position, a section, in particular a circumferential section Ua1, Ub1, of the respective actuating element 8a, 8b hermetically seals the fluid inlet 11a, 11b of the respective housing 5a, 5b. Additionally or alternatively, it is further provided that in the initial position, another section, in particular another circumferential section Ua2, Ub2, of the respective actuating element 8a, 8b hermetically seals the fluid outlet 12a, 12b of the respective housing 5a, 5b.

[0039] Furthermore, and preferably, in the initial position, a section extending around the actuator inlet opening 9a, 9b, in particular a circumferential section Ua3, Ub3, of the respective actuator 8a, 8b, hermetically seals against the inner wall 13a, 13b of the respective housing 5a, 5b. Additionally or alternatively, and preferably, in the initial position, a section extending around the actuator outlet opening 10a, 10b, in particular a circumferential section Ua4, Ub4, of the respective actuator 8a, 8b, hermetically seals against the inner wall 13a, 13b of the respective housing 5a, 5b.

[0040] Furthermore, it is preferably the case here that in the initial position a section Aa1 of the housing 5a of the coupling device 4a, which here is assigned to the liquid container 2 and / or a section Ab2 of the housing 5b of the coupling device 4b, which here is assigned to the bioprocess plant 3 and which runs around the fluid outlet 12b, is hermetically sealed against the respective actuating element 8a, 8b, namely the section Aa1 against the actuating element 8a and the section Ab2 against the actuating element 8b. Here, and preferably, it is further provided that in the initial position, a section Aa2 of the housing 5a of the coupling device 4a, which here is assigned to the liquid container 2, and / or a section Ab1 of the housing 5b of the coupling device 4b, which here is assigned to the bioprocess plant 3, which runs around the fluid outlet 12a, is hermetically sealed against the respective actuating element 8a, 8b.

[0041] How in particular the Fig. As shown in Figures 3a) and b), the actuating element 8a of one housing 5a and the actuating element 8b of the other housing 5b are in a preloaded position when the housings 5a, 5b are mechanically connected, at least when both actuating elements 8a, 8b are in their operating position, and preferably also when both actuating elements 8a, 8b are in their initial position. Here, and preferably, the two actuating elements 8a, 8b are constantly in a preloaded position. This is achieved in particular by making the actuating elements 8a, 8b either entirely or at least only in the area of ​​their mutual contact from a comparatively soft plastic, especially an elastomer. In this way, the actuating elements 8a, 8b can deform elastically in the area of ​​mutual contact. Fig. As shown in Figure 3, it is here and preferably such that in the mechanically connected state of the housings 5a, 5b, when both actuating elements 8a, 8b are in their operating position, a section extending around the actuating element outlet opening 10a, in particular circumferential section Ua4, of one actuating element 8a and a section extending around the actuating element inlet opening 9b, in particular circumferential section Ub3, of the other actuating element 8b hermetically seal the respective channel 7a, 7b to the respective housing 5a, 5b.

[0042] For the purpose of hermetic sealing, as mentioned above, an elastomer is particularly suitable. The actuating element 8a, 8b is particularly preferably made partially or completely of such an elastomer. The respective housing 5a, 5b can also be made, at least partially, of an elastomer, although it is preferred that the housing 5a, 5b be made of a plastic with as little elasticity as possible, preferably a plastic with lower elasticity, in particular a thermoplastic.According to a particularly preferred embodiment, the respective actuating element 8a, 8b is made of an elastomer section by section or completely, in particular in the section, here circumferential section Ua1, Ub1, which hermetically seals the fluid inlet 11a, 11b, and / or in the section, here circumferential section Ua2, Ub2, which hermetically seals the fluid outlet 12a, 12b, and / or in the section running around the actuating element inlet opening 9a, 9b, here circumferential section Ua3, Ub3, and / or in the section running around the actuating element outlet opening 10a, 10b, here circumferential section Ua4, Ub4.Additionally or alternatively, it may be provided that the respective housing 5a, 5b is designed section by section, in particular in the section Aa1, Ab1 extending around the fluid inlet 11a, 11b and / or in the section Aa2, Ab2 extending around the fluid outlet 12a, 12b, from an elastomer and preferably otherwise from a plastic with a lower elasticity, in particular a thermoplastic.

[0043] How Fig. 3b) further illustrated, in the mechanically connected state of the housings 5a, 5b, when both actuating elements 8a, 8b are in their operating position, the fluid inlet 11a, 11b and the actuating element inlet opening 9a, 9b of the coupling devices 4a, 4b are in overlapping positions, and / or the fluid outlet 12a, 12b and the actuating element outlet opening 10a, 10b are in overlapping positions. In particular, these are aligned coaxially with each other. Simultaneously, the fluid outlet 12a of one housing 5a and the fluid inlet 11b of the other housing 5b are also in overlapping positions. These, too, are preferably aligned coaxially with each other. Particularly preferred here are, as shown, Fig. 3b) shows the two fluid inlets 11a, 11b, the two fluid outlets 12a, 12b and the two channels 7a, 7b aligned coaxially to each other.

[0044] The in Fig. 3a) The adjustment movement of one actuating element 8a between its initial position and its operating position, represented by a circumferential arrow, is here and preferably accompanied by a corresponding adjustment movement of the other actuating element 8b. This applies here and preferably exclusively to the mechanically connected state of the housings 5a, 5b, as shown in the Fig. 2 and Fig. Figure 3. For this purpose, a gearbox 14 is preferably provided here, which, as shown in Fig. Figure 2 shows a gear transmission, which is particularly preferably a gear transmission. The transmission 14 has at least two transmission components, preferably each in the form of a gear and / or gear segment 14a, 14b. For example, a toothed circumferential section of a circular disk is provided as a gear segment 14a, 14b, wherein, instead of a completely circumferential disk as shown here, it can also have only the form of a circular segment, with the toothing then extending along the circular arc. Here, and preferably, two gear segments 14a, 14b are provided as transmission components. In the mechanically connected state of the housings 5a, 5b, the transmission 14 causes a synchronous adjustment of the two actuating elements 8a, 8b between their initial position and their operating position.Here, and preferably, a transmission component of the transmission 14, in particular a gear or gear segment 14b of the transmission 14, is connected or connectable in a rotationally fixed manner to an actuating element 15 for manual actuation of the transmission 14. The actuating element 15 can be a lever, a crank, or the like.

[0045] The adjustment movement of the respective actuating element 8a, 8b between the initial position and the operating position is, as previously indicated, preferably a rotary movement; that is, the actuating element 8a, 8b is a rotatable actuating element. The respective actuating element 8a, 8b is adjusted between the initial position and the operating position at an angle of less than 45 degrees, preferably less than 40 degrees, more preferably less than 35 degrees, and more preferably less than 30 degrees. In principle, as mentioned, a linear movement of the respective actuating element is also conceivable as the adjustment movement in an alternative embodiment not shown here.

[0046] The adjustment movement of the respective actuating element 8a, 8b can be limited in one or both directions, i.e., towards the initial position and / or towards the operating position. Here, and preferably, this is ensured in both directions by the fact that at least one gear component, here both gear components, is / are a gear segment 14a, 14b, so that an adjustment movement is only possible in the toothed circumferential section, i.e., for example, only in an angular range of less than 45 degrees, preferably less than 40 degrees, more preferably less than 35 degrees, and more preferably less than 30 degrees. Additionally or alternatively, as in the Fig. As shown in Figures 3a) and b) only by way of example, the adjustment movement in the starting position may be limited by a stop 16a, 16b and / or in the operating position by a stop 17a, 17b. The respective stop 16a, 16b and / or the respective stop 17a, 17b may be located inside the housing 5a, 5b, as shown here, or outside the housing 5a, 5b.

[0047] In this way, the initial position can first be set as a defined position, particularly by the manufacturer, thus ensuring that the parts relevant for fluid transfer are located in a protected and, in particular, sterile area. Subsequently, the operating position can be set as a defined position, particularly by the user, thus ensuring that the respective actuator inlet opening 9a, 9b is aligned with its respective fluid inlet 11a, 11b and the respective actuator outlet opening 10a, 10b is aligned with its respective fluid outlet 12a, 12b.

[0048] The Fig. 1 and Fig. Figure 2 further shows that here, and preferably, the fluid inlet 11a of one housing 5a and the fluid outlet 12b of the other housing 5b are each connectable or connected to a hose 18a, 18b or tube, particularly via a push-fit connection. Here, and preferably, the fluid inlet 11a of one housing 5a is coupled to the fluid reservoir 2 via a hose 18a or a tube. Additionally or alternatively, as shown in the Fig. 1 and Fig. Figure 2 also shows that the fluid outlet 12b of the other housing 5b is fluidically coupled to the bioprocess engineering system 3, here the bioreactor, via a hose 18b or a tube.

[0049] Furthermore, the Fig. 1, Fig. 2 to Fig. 3. It is evident that the housings 5a, 5b can be positively connected to one another. Here, they are merely shown as examples of a plug-in connection, for instance, via a dovetail joint or the like. However, it is also conceivable that the housings 5a, 5b can be latched together. The essential point is that the housings 5a, 5b are held securely together during the adjustment movement of the actuating elements 8a, 8b. Since the actuating elements, at least in the operating position, preferably bear against each other under preload, the positive connection preferably also exists in the direction of the preload. Here, and preferably, the positive connection between the housings 5a, 5b exists in the flow direction of the liquid medium during its transfer.

[0050] According to a further teaching, which has independent significance, the respective coupling device 4a, 4b, i.e., here the coupling device 4a assigned to the liquid container 2 and / or the coupling device 4b assigned to the bioprocessing plant 3, is claimed as such. In particular, the coupling device 4a, 4b is a coupling device of the proposed sterile connector 1.

[0051] Such a coupling device 4a comprises a housing 5a with an interior 6a and an actuating element 8a, which is adjustably mounted in the interior 6a and forms a channel 7a. The channel 7a extends through the actuating element 8a from an inlet opening 9a of the actuating element to an outlet opening 10a of the actuating element. The housing 5a of the coupling device 4a is mechanically connectable to the housing 5b of a further coupling device 4b. For the design of the further coupling device 4b, reference may be made to the descriptions of the first coupling device 4a as proposed.Housing 5a has a fluid inlet 11a and a fluid outlet 12a that connect the housing interior 6a to the environment. In the mechanically connected state of housings 5a and 5b, the fluid outlet 12a of housing 5a of the proposed coupling device 4a and the fluid inlet 11b of housing 5b of the further coupling device 4b can be brought into contact with each other. In the mechanically connected state of housings 5a and 5b, the actuator 8a is adjustable from a starting position in which a fluid connection between channel 7a and actuator inlet opening 9a on the one hand, and between channel 7a and actuator outlet opening 10a on the other hand, is blocked, to an operating position in which the actuator inlet opening 9a is in fluid communication with the fluid inlet 11a and the actuator outlet opening 10a is in fluid communication with the fluid outlet 12a. Reference may be made to all statements concerning the proposed sterile connector 1.

[0052] According to a further teaching, which is also of independent significance, a packaging arrangement 19, 21 is claimed, comprising a packaging 20, 22 and at least one, preferably exactly one, sterilely packaged coupling device 4a, 4b or a sterilely packaged sterile connector 1 therein. Reference may be made to all embodiments of the sterile connector 1 and the coupling device 4a.

[0053] According to one embodiment, a packaging arrangement 19, as shown in Fig. Figure 4 above shows a package 20 containing a sterilely packaged, proposed coupling device 4a and a sterilely packaged, in particular filled, liquid container 2, which is already filled by the manufacturer. The liquid container 2 is fluidically coupled to the proposed coupling device 4a of the sterile connector 1, i.e., already in its packaged state, and the control element 8a of the coupling device 4a is in its initial position.

[0054] According to a further embodiment, a packaging arrangement 21, as described in Fig. Figure 4 below shows a package 22 containing a sterilely packaged, proposed coupling device 4b and a sterilely packaged bioprocessing plant 3, in this case a bioreactor. The bioprocessing plant 3, or bioreactor, is fluidically coupled to the proposed coupling device 4b of the sterile connector 1 in its packaged state, and the actuating element 8b of the coupling device 4b is in its initial position. Here, and preferably, the package 21 also includes an actuating element 15, which, when the sterile connector 1 is assembled (i.e., when the housings 5a and 5b are connected as described), serves to manually actuate the gearbox 14 and, accordingly, to adjust the actuating elements 8a and 8b from their initial position to their operating position.

[0055] In an alternative embodiment, not shown here, a packaging arrangement is also conceivable in which only a sterile connector 1 of the proposed design, comprising the two coupling devices 4a, 4b, is sterilely packaged. It is also conceivable, in principle, to provide a packaging arrangement in which only the respective coupling device 4a, 4b is sterilely packaged.

[0056] According to a further teaching, which is also of independent significance, the use of a sterilely packaged, proposed sterile connector 1, a sterilely packaged proposed coupling device 4a, 4b and / or a proposed packaging arrangement 19, 21 for the sterile transfer of a liquid, in particular biological, medium from a liquid container 2 into a bioprocess plant 3, in particular into a bioreactor, is claimed as such. Reference may also be made to all descriptions of the proposed sterile connector 1, the proposed coupling device 4a, 4b and the proposed packaging arrangement 19, 21 with regard to the claimed use.

[0057] According to the in Fig.In the embodiment shown in Figure 4, after unpacking the unit consisting of coupling device 4a and liquid container 2 on the one hand, and after unpacking the unit consisting of coupling device 4b and bioprocessing plant 3 on the other, the coupling devices 4a and 4b are connected to each other using the connecting hoses 18a and 18b, respectively, as described. Subsequently, the actuating elements 8a and 8b are moved, particularly synchronously, from their initial position to their operating position, so that the transfer of the liquid medium from the liquid container 2 via the coupling device 4a and the coupling device 4b into the bioprocessing plant 3 can then take place.

[0058] In a particularly preferred embodiment, at least the proposed coupling device 4a or the proposed coupling device 4b, and in particular both coupling devices 4a, 4b, and preferably also the liquid container 2 and / or the bioprocessing plant 3 and / or the hose(s) 18a, 18b or tube(s), are each single-use components. The respective component, i.e., the respective coupling device 4a, 4b, the liquid container 2, the bioprocessing plant 3 and / or the respective hose 18a, 18b or tube, is made at least partially, preferably at least predominantly, of a plastic material. Suitable plastics for the individual components include, in particular, a silicone material and / or a polymer material, especially an elastomer and / or thermoplastic.Examples include PE (polyethylene), PP (polypropylene), PTFE (polytetrafluoroethylene), PBT (polybutylene terephthalate), PSU (polysulfone), PESU (polyethersulfone), PC (polycarbonate).

Claims

[1] Sterile connectors for the sterile transfer of a liquid, in particular biological, medium from a liquid container (2) into a bioprocess plant (3), in particular into a bioreactor, wherein the sterile connector (1) has two coupling devices (4a, 4b), characterized by , that the coupling devices (4a, 4b) each have a housing (5a, 5b) with a housing interior (6a, 6b) and an actuating element (8a, 8b) adjustable in the housing interior (6a, 6b) forming a channel (7a, 7b), wherein the channel (7a, 7b) extends from an actuating element inlet opening (9a, 9b) to an actuating element outlet opening (10a, 10b) through the actuating element (8a, 8b), that the housing (5a) of one coupling device (4a) is mechanically connectable to the housing (5b) of the other coupling device (4b), that each housing (5a, 5b) has a fluid inlet (11a, 11b) and a fluid outlet (12a, 12b) that connect the housing interior (6a, 6b) to the environment, wherein, in the mechanically connected state of the housings (5a, 5b), the fluid outlet (12a) of one housing (5a) and the fluid inlet (11b) of the other housing (5b) are in overlapping positions, that in the mechanically connected state of the housings (5a, 5b) the actuating elements (8a, 8b) are each adjustable from a starting position in which a fluid connection between channel (7a, 7b) and actuating element inlet opening (9a, 9b) on the one hand and between channel (7a, 7b) and actuating element outlet opening (10a, 10b) on the other hand is blocked, to an operating position in which the actuating element inlet opening (9a, 9b) is in fluid communication with the fluid inlet (11a, 11b) and the actuating element outlet opening (10a, 10b) is in fluid communication with the fluid outlet (12a, 12b), that in the initial position a section of the respective actuating element (8a, 8b) hermetically seals the fluid inlet (11a, 11b) and a section of the respective actuating element (8a, 8b) seals the fluid outlet (12a, 12b) of the respective housing (5a, 5b). [2] Sterile connector according to claim 1, characterized by , that in the initial position the respective channel (7a, 7b) extends in an area of ​​the housing interior (6a, 6b) that is hermetically sealed from the surroundings of the housing (5a, 5b), preferably that in the initial position the actuator inlet opening (9a, 9b) and the actuator outlet opening (10a, 10b) each point towards the inner wall (13a, 13b) of the respective housing (5a, 5b). [3] Sterile connectors according to claim 1 or 2, characterized by, that in the initial position a section extending around the actuator inlet opening (9a, 9b), in particular a circumferential section (Ua3, Ub3), of the respective actuator (8a, 8b) and / or a section extending around the actuator outlet opening (10a, 10b), in particular a circumferential section (Ua4, Ub4), of the respective actuator (8a, 8b) hermetically seals against the inner wall (13a, 13b) of the respective housing (5a, 5b), and / or that in the initial position a section (Aa1, Ab1) extending around the fluid inlet (11a, 11b) of the respective housing (5a, 5b) and / or a section (Aa2, Ab2) extending around the fluid outlet (12a, 12b) of the respective housing (5a, 5b) hermetically seals against the respective actuator (8a, 8b) is attached. [4] Sterile connectors according to any one of the preceding claims, characterized by, that the actuating element (8a) of one housing (5a) protrudes from the housing interior (6a) through the fluid outlet (12a) of the housing (5a), and / or that the actuating element (8b) of the other housing (5b) protrudes from the housing interior (6b) through the fluid inlet (11b) of the housing (5b). [5] Sterile connectors according to any one of the preceding claims, characterized by , that the actuating element (8a) of one housing (5a) and the actuating element (8b) of the other housing (5b) are in mechanically connected state of the housings (5a, 5b) at least when both actuating elements (8a, 8b) are in their operating position, preferably also when both actuating elements (8a, 8b) are in their initial position, further preferably continuously, in contact with each other under preload, preferably that the actuating elements (8a, 8b) deform elastically in the area of ​​mutual contact. [6] Sterile connectors according to any one of the preceding claims, characterized by, that in the mechanically connected state of the housings (5a, 5b) when both actuating elements (8a, 8b) are in their operating position, a section extending around the actuating element outlet opening (10a), in particular circumferential section (Ua4), of one actuating element (8a) and a section extending around the actuating element inlet opening (9b), in particular circumferential section (Ub3), of the other actuating element (8b), hermetically sealing the respective channel (7a, 7b) to the respective housing (5a, 5b), are in contact with each other. [7] Sterile connectors according to any one of the preceding claims, characterized bythat the respective actuating element (8a, 8b) is made section by section or completely, in particular in the section that hermetically seals the fluid inlet (11a, 11b), and / or in the section that hermetically seals the fluid outlet (12a, 12b), and / or in the section extending around the actuating element inlet opening (9a, 9b) and / or in the section extending around the actuating element outlet opening (10a, 10b), of an elastomer, in particular of a silicone material, and / or that the respective housing (5a, 5b) is made section by section, in particular in the section extending around the fluid inlet (11a, 11b) and / or in the section extending around the fluid outlet (12a, 12b), of an elastomer, in particular of a silicone material, and preferably otherwise of a plastic with lower elasticity, in particular a thermoplastic, is designed. [8] Sterile connectors according to any one of the preceding claims, characterized by , that in the mechanically connected state of the housings (5a, 5b), when both actuating elements (8a, 8b) are in their operating position, the fluid inlet (11a, 11b) and actuating element inlet opening (9a, 9b) and / or fluid outlet (12a, 12b) and actuating element outlet opening (10a, 10b) of both coupling devices (4a, 4b) are in overlapping positions, in particular aligned coaxially with each other, and the fluid outlet (12a) of one housing (5a) and the fluid inlet (11b) of the other housing (5b) are in overlapping positions, in particular aligned coaxially with each other, preferably that in the mechanically connected state of the housings (5a, 5b), when both actuating elements (8a, 8b) are in their operating position, the two fluid inlets (11a, 11b) and the two fluid outlets (12a, 12b) and the two channels (7a, 7b) are aligned coaxially to each other. [9] Sterile connectors according to any one of the preceding claims, characterized by , that in the mechanically connected state of the housings (5a, 5b) an adjustment movement of one actuating element (8a, 8b) between its initial position and its operating position is accompanied by a corresponding adjustment movement of the other actuating element (8b, 8a), preferably that a transmission (14), in particular a gear transmission, is provided which, in the mechanically connected state of the housings (5a, 5b), causes a synchronous adjustment of the two actuating elements (8a, 8b) between their initial position and their operating position, further preferably that a transmission component of the transmission (14), in particular a gear or gear segment of the transmission (14), is rotationally fixedly connected or connectable to an actuating element (15). [10] Sterile connectors according to any one of the preceding claims, characterized by, that the adjustment movement of the respective actuating element (8a, 8b) between its initial position and its operating position is a rotary movement or a linear movement. [11] Sterile connectors according to any one of the preceding claims, characterized by , that the adjustment movement of the respective actuating element (8a, 8b) between its initial position and its operating position is limited in the initial position and / or operating position by a stop (16a, 16b, 17a, 17b). [12] Sterile connectors according to any one of the preceding claims, characterized by, that the fluid inlet (11a) of one housing (5a) and the fluid outlet (12b) of the other housing (5b) can be connected or is connected, in particular via a plug connection, to a hose (18a, 18b) or tube, preferably that the fluid inlet (11a) of one housing (5a) is fluidically coupled via the hose (18a) or the tube to a liquid container (2), in particular to a small quantity liquid container, for the dispensing of a liquid, in particular biological, medium, and / or that the fluid outlet (12b) of the other housing (5b) is fluidically coupled via the hose (18b) or the tube to a bioprocess engineering plant (3), in particular a bioreactor. [13] Sterile connectors according to any one of the preceding claims, characterized by , that the two housings (5a, 5b) can be positively connected to each other, in particular plugged together or locked together. [14] Coupling device of a sterile connector (1) for the sterile transfer of a liquid, in particular biological, medium from a liquid container (2) into a bioprocess plant (3), in particular into a bioreactor, in particular sterile connector (1) according to one of the preceding claims, characterized by , that the coupling device (4a, 4b) has a housing (5a, 5b) with a housing interior (6a, 6b) and an actuating element (8a, 8b) adjustable in the housing interior (6a, 6b) forming a channel (7a, 7b), wherein the channel (7a, 7b) extends from an actuating element inlet opening (9a, 9b) to an actuating element outlet opening (10a, 10b) through the actuating element (8a, 8b), that the housing (5a, 5b) of the coupling device (4a, 4b) can be mechanically connected to the housing (5b, 5a) of another coupling device (4b, 4a) of the sterile connector (1), that the housing (5a, 5b) has a fluid inlet (11a, 11b) and a fluid outlet (12a, 12b) that connect the housing interior (6a, 6b) to the environment, wherein, in the mechanically connected state of the housings (5a, 5b), the fluid outlet (12a, 12b) of the housing (5a, 5b) of the coupling device (4a, 4b) and the fluid inlet (11b, 11a) of the housing (5b, 5a) of the further coupling device (4b, 4a) can be brought into overlap with each other, that in the mechanically connected state of the housings (5a, 5b) the actuating element (8a, 8b) is adjustable from a starting position in which a fluid connection between channel (7a, 7b) and actuating element inlet opening (9a, 9b) on the one hand and between channel (7a, 7b) and actuating element outlet opening (10a, 10b) on the other hand is blocked, to an operating position in which the actuating element inlet opening (9a, 9b) is in fluid communication with the fluid inlet (11a, 11b) and the actuating element outlet opening (10a, 10b) is in fluid communication with the fluid outlet (12a, 12b), that in the initial position a section of the respective actuating element (8a, 8b) hermetically seals the fluid inlet (11a, 11b) and a section of the respective actuating element (8a, 8b) seals the fluid outlet (12a, 12b) of the respective housing (5a, 5b). [15] Packaging arrangement comprising a packaging (20, 22) and comprising at least one, preferably exactly one, sterilely packaged coupling device (4a, 4b) therein according to claim 14 or a sterilely packaged sterile connector (1) therein according to any one of claims 1 to 13. [16] Packaging arrangement according to claim 15, characterized by , that the actuating element (8a, 8b) of the coupling device (4a, 4b) which is sterilely packaged in the packaging (20, 22) is in its initial position and that the packaging (20, 22) also contains a liquid container (2), in particular a filled one, which is fluidly coupled to the coupling device (4a), or a bioprocess plant (3) which is sterilely packaged and which is fluidly coupled to the coupling device (4b). [17] Use of a sterile packaged sterile connector (1) according to any one of claims 1 to 13, a sterile packaged coupling device (4a, 4b) according to claim 14 and / or a packaging arrangement (19, 21) according to claim 15 or 16 for the sterile transfer of a liquid, in particular biological, medium from a liquid container (2) into a bioprocessing plant (3), in particular into a bioreactor. [18] Use according to claim 17, characterized by , that at least one coupling device, in particular both coupling devices (4a, 4b), preferably also the liquid container (2) and / or the bioprocessing plant (3) and / or the hose(s) (18a, 18b) or tube(s), in particular as a single-use component, are designed at least partially, preferably at least predominantly, from a plastic material.

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