阅读说明：本技术 用于诸如色谱系统之类的分离系统的连接装置 (Connection device for a separation system, such as a chromatography system ) 是由 K·格鲍尔 A·伦丁 F·隆斯特罗姆 于 2019-08-20 设计创作，主要内容包括：一种连接装置(1；101)构造成用于使分离系统(3)与分离装置(5)连接,其中流体可从分离系统出口连接部(19)通过连接装置的旁通流体路径(27)流向分离系统入口连接部(15),同时绕过所连接的分离装置(5)。为了实现这样,设在连接装置中的入口阀(31)和出口阀(33)中的至少一个设在关闭状态中,且设在连接装置中的至少一个旁通阀(35；35a、35b)设在打开状态中。(A connection device (1; 101) is configured for connecting a separation system (3) with a separation device (5), wherein fluid can flow from a separation system outlet connection (19) to a separation system inlet connection (15) through a bypass fluid path (27) of the connection device, while bypassing the connected separation device (5). To achieve this, at least one of an inlet valve (31) and an outlet valve (33) provided in the connecting device is set in a closed state, and at least one bypass valve (35; 35a, 35b) provided in the connecting device is set in an open state.)

1. A connection device (1; 101) configured for connecting a separation system (3) with a separation device (5), the connection device comprising:

-a separation device inlet connection (7) configured for connection to a separation device inlet (9);

-a separating device outlet connection (11) configured for connection to a separating device outlet (13);

-a separation system inlet connection (15) configured for connection to a separation system inlet (17);

-a separation system outlet connection (19) configured for connection to a separation system outlet (21);

-a first fluid path (23) connecting the separation system inlet connection (15) with the separation device outlet connection (11);

-a second fluid path (25) connecting the separation system outlet connection (19) with the separation device inlet connection (7);

-a bypass fluid path (27) connecting the separation system inlet connection (19) with the separation system outlet connection (19);

-an inlet valve (31) provided in the second fluid path (25) in connection with the separation device inlet connection (7), the inlet valve (31) being operable to provide an open state allowing fluid flow through the separation device inlet connection (7) and a closed state preventing fluid flow through the separation device inlet connection (7);

-an outlet valve (33) provided in the first fluid path (23) in connection with the separating apparatus outlet connection (11), the outlet valve (33) being operable to provide an open state allowing fluid flow to exit through the separating apparatus outlet connection (11) and a closed state preventing fluid flow through the separating apparatus outlet connection (11); and

-at least one bypass valve (35; 35a, 35b) provided in the bypass fluid path (27), the at least one bypass valve (35; 35a, 35b) being operable to provide an on-off state allowing fluid flow through the bypass fluid path (27) and a closed state preventing fluid flow through the bypass fluid path (27),

wherein when at least one of the inlet valve (31) and the outlet valve (33) is set in a closed state and the at least one bypass valve (35; 35a, 35b) is set in an open state, fluid can flow from the separation system outlet connection (19) through the bypass fluid path (27) to the separation system inlet connection (15) while bypassing the connected separation device (5).

2. Connection device according to claim 1, characterized in that said at least one bypass valve (35; 35a, 35b) is of the diaphragm type.

3. The connecting device according to claim 1 or 2, characterized in that the bypass valve is positioned in the bypass fluid path (27) at a distance from the first fluid path (23) and/or the second fluid path (25) which is not more than 3 or 2 or 1 times the diameter of the first fluid path (23), the second fluid path (25) and/or the bypass fluid path (27).

4. Connection device according to claim 1 or 2, characterized in that said inlet valve (31) and said outlet valve (33) are of the diaphragm type.

5. The connecting device according to any one of the preceding claims, characterized in that the inlet valve (31) and the outlet valve (33) are positioned at a distance from a junction (81a, 81b) intermediate the first fluid path (23) and the second fluid path (25) and the bypass fluid path (27), which distance is not more than 3 or 2 or 1 times the diameter of the first fluid line (23), the second fluid line (25) and/or the bypass fluid line (27).

6. Connection device according to any of the preceding claims, characterized in that it is pre-sterilized and that the separation device inlet connection (7) and the separation device outlet connection (11) are provided with aseptic connectors.

7. Connection device according to any of the preceding claims, characterized in that it is pre-sterilized and that the separation system inlet connection (15) and the separation system outlet connection (19) are provided with aseptic connectors.

8. Connection device according to any of the preceding claims, characterized in that the inlet valve (31), the outlet valve (33) and the at least one bypass valve (35; 35a, 35b) are manually controllable into an open state and a closed state.

9. Connecting device according to any one of the preceding claims, characterized in that it comprises at least one monitoring device (51) which is connected to the inlet valve (31), the outlet valve (33) and/or the at least one bypass valve (35; 35a, 35b) and which shows the state of the inlet valve, the outlet valve and the at least one bypass valve.

10. The connecting device according to any one of the preceding claims, characterized in that it further comprises at least one sensor (53), said at least one sensor (53) being arranged in the connecting device (1; 101) for detecting an open state and/or a closed state of at least one of the inlet valve (31), the outlet valve (33) or the at least one bypass valve (35; 35a, 35 b).

11. The connecting device according to any one of the preceding claims, characterized in that it comprises a combined control device (55), the combined control device (55) being connected to the inlet valve (31), the outlet valve (33) and the at least one bypass valve (35; 35a, 35b), and the combined control device (55) controlling the inlet valve and the outlet valve in an open state and the at least one bypass valve in a closed state in a first position, and the combined control device (55) controlling the inlet valve and the outlet valve in a closed state and the at least one bypass valve in an open state in a second position.

12. A connecting device according to any one of the preceding claims, characterised in that the connecting device comprises a bypass valve (35), and wherein the inlet valve (31), the outlet valve (33) and the bypass valve (35) are provided together in a valve assembly portion (42).

13. The connection arrangement according to any one of claims 1-11, wherein the connection arrangement (1) comprises a first bypass valve (35a) and a second bypass valve (35b), and wherein the connection arrangement comprises an inlet valve assembly portion (41) and an outlet valve assembly portion (43), the inlet valve assembly portion (41) comprising the inlet valve (31) and the second bypass valve (35b), the outlet valve assembly portion (43) comprising the outlet valve (33) and the first bypass valve (35a), wherein the bypass fluid path (27) is provided between the first bypass valve (35a) and the second bypass valve (35 b).

14. A separating device (5), the separating device (5) comprising a separating device inlet (9) and a separating device outlet (13) and a connecting device (1; 101) according to any one of the preceding claims connected to the separating device inlet and the separating device outlet.

15. The separation device of claim 14, wherein the separation device is a chromatography column, or a stack of chromatography units.

16. The separation device of claim 14 or 15, wherein the separation device is preloaded with a bed of chromatography media.

17. A separating device according to any one of claims 14-16, characterized in that the connecting device (1; 101) is connected to the separating device inlet and the separating device outlet by means of a barbed connection, a bar-block connection, a TC connection or a welded connection.

18. Separating device according to any of claims 14, 15 or 16, characterized in that the connecting device (1; 101) is integral with the separating device.

19. A separator device according to claim 18, wherein the bypass fluid path (27) is provided integral with an end unit (40) of the separator device, or in the form of at least one head (57, 59, 57') for the stack of units, the head comprising the valve.

20. Separation device according to any of claims 14-19, wherein the separation device is pre-sterilized and wherein the separation system inlet connection (15) and the separation system outlet connection (19) of the connection device (1; 101) are provided with aseptic connectors.

21. A separation system (3), the separation system (3) comprising a separation system inlet (17) and a separation system outlet (21) and a connection device (1; 101) according to any one of claims 1-13 connected to the separation system inlet and the separation system outlet.

22. A separation system according to claim 20, wherein the connection means (1; 101) is connected to the separation system inlet and the separation system outlet by a barbed connection, a bar block connection, a TC connection or a welded connection.

23. A separation system according to claim 20, characterized in that the connecting device (1; 101) is integral with the separation system.

Technical Field

The present invention relates to a connection device for connecting a separation device to a separation system, such as for example connecting a chromatography column to a chromatography system. It also relates to chromatography columns and separation systems, such as chromatography systems.

Background

The prepackaged chromatographic column is an important separation device in the production of biopharmaceuticals. They can be used to produce multiple drug products and therefore in different processes, however, they are preferably used to produce only a single biopharmaceutical drug product, avoiding the need for extensive cleaning and sterilization (due to the risk for cross-contamination when the same column is used to produce different drug products). Pre-packed columns are therefore typically used as single-use columns and are used with other single-use technical products, such as single-use flow paths and single-use fluid storage bags in chromatography systems, single-use tubes, etc.

As described, the advantages of fluid processing equipment using Single Use Technology (SUT) are primarily in that cross-contamination between production lots and production activities is reduced or completely eliminated when the SUT equipment is used for only a single drug product. The SUT devices are disposed of after use (which may be after a single run, batch, or activity that includes multiple runs and batches). When the SUT equipment is set to be pre-sterilized or bioburden controlled, initial cleaning and disinfection (e.g., by contacting the flow path with a sodium hydroxide solution) or sterilization can be avoided. Post-use cleaning may even be omitted when the SUT is used for only a single run or batch. With these features, the SUT device provides improved efficiency, safety, and convenience.

However, whether pre-packed columns are used for only a single drug product or for multiple drug products, it is typically necessary, primarily for cost reasons, to use the same column in multiple production runs, batches and production activities. Thus, it is typically necessary to disconnect and reconnect the column to the chromatography system or to a different SUT flow path of the chromatography system among the multiple production lots and/or production activities, which provides and controls fluid flow on the column, and the column may be stored prior to reconnecting the column to the same or a different chromatography system or a different flow path.

To allow columns to be used in multiple batches and production activities, these columns and/or separation systems are typically fitted with stainless steel valves at the interface of the column and the system to allow the column to be shut down during storage and later connected to the chromatography system and the use of the column for subsequent production runs. However, these stainless steel valves require cleaning and sterilization and are expensive when used only for a single column and biopharmaceutical products.

Disclosure of Invention

It is an object of the present invention to provide a connection device for connecting a separation device to a separation system, such as for example connecting a chromatography column to a chromatography system, or to provide a separation device or separation system comprising such a connection device, which facilitates easy connection, disconnection and/or reconnection of the device and system and improves the possibilities for sterilization.

It is a further object of the present invention to provide a connection device for connecting a separation device to a separation system, or to provide a separation device or separation system comprising such a connection device, which connection device facilitates connection, disconnection and/or reconnection of the separation device and the system, and facilitates removal of air in the connection between the separation device and the system without flushing air through the separation device, which improves the likelihood and efficiency of disinfection in using the separation device and the system.

It is a further object of the present invention to provide a cost-effective connection device adapted to be adjusted to pre-packed chromatography columns and/or single-use chromatography columns as well as to single-use systems for only a limited number of pharmaceutical products and/or production runs.

This is achieved by a connecting device and a separating system according to the independent claims.

According to an aspect of the invention, there is provided a connection device configured for connecting a separation system with a separation device, the connection device comprising:

-a separation device inlet connection configured for connection to a separation device inlet;

-a separation device outlet connection configured for connection to a separation device outlet;

-a separation system inlet connection configured for connection to a separation system inlet;

-a separation system outlet connection configured for connection to a separation system outlet;

-a first fluid path connecting the separation system inlet connection with the separation device outlet connection;

-a second fluid path connecting the separation system outlet connection with the separation device inlet connection;

-a bypass fluid path connecting the separation system inlet connection with the separation system outlet connection;

-an inlet valve provided in the second fluid path in connection with the separation device inlet connection, the inlet valve being operable to provide an open state allowing fluid flow through the separation device inlet connection and a closed state preventing fluid flow through the separation device inlet connection;

-an outlet valve provided in the first fluid path in connection with the separating apparatus outlet connection, the outlet valve being operable to provide an open state allowing fluid flow to exit through the separating apparatus outlet connection and a closed state preventing fluid flow through the separating apparatus outlet connection; and

-at least one bypass valve provided in the bypass fluid path, the at least one bypass valve being operable to provide an open state allowing fluid flow through the bypass fluid path and a closed state preventing fluid flow through the bypass fluid path,

wherein when at least one of the inlet valve and the outlet valve is set in the closed state and at least one bypass valve is set in the open state, fluid can flow from the separation system outlet connection through the bypass fluid path to the separation system inlet connection while bypassing the connected separation device.

According to another aspect of the present invention there is provided a separating device comprising a separating device inlet and a separating device outlet and a connecting device according to the present invention connected to the separating device inlet and the separating device outlet.

According to another aspect of the present invention there is provided a separation system comprising a separation system inlet and a separation system outlet and a connection arrangement according to the present invention connected to the separation system inlet and the separation system outlet.

Thus, with a bypass fluid path connecting the separation system inlet connection with the separation system outlet connection and a valve controlling the fluid flow through the separation device and the bypass fluid (path), removal of air introduced into the fluid path when the connection is established and disinfection of the connection between the separation device and the separation system can be provided without the need for flushing through the separation device, such as for example a chromatography bed. The chromatography bed may have been sterilized after the last run, and the omission of a flush of air, additional sterilizing liquid, and a flush of potential contaminants from the inlet connection to the outlet connection increases the safety of the process and product, the efficiency of operation, and reduces the overall complexity and time requirements. Furthermore, between different production activities, the inlet and outlet valves may shut off the column for storage. Thereby providing an easy to handle separation device (such as a chromatography column) which can be stored, reused and sterilized in an efficient manner. Furthermore, air can be removed via the bypass fluid path without the need to pass air through the chromatography bed, which would be a time consuming operation, can compromise the integrity of the bed, and requires additional sterilization of the bed after the air is flushed out. The connection device may be provided with a sterile connector between the connection device and the separation system and/or between the connection device and the separation device to effectively prevent contamination during connection and to provide the possibility of removing air introduced during connection set-up by-passing without the need for flushing air through the bed.

The connection means may suitably be pre-sterilized, for example by gamma irradiation or autoclaving, to further reduce the risk with respect to contamination. When provided pre-sterilized and provided with sterile connectors, the connection device and/or the connection assembly of the connection device, the separation device and/or the separation system (and thus its flow path) may not need to be cleaned and sterilized at all before use.

In one embodiment of the invention, at least one bypass valve is of the diaphragm type.

In one embodiment of the invention, the bypass valve is positioned in the bypass fluid path at a distance from the first fluid path and/or the second fluid path that is no more than 3 or 2 or 1 times the diameter of the first fluid path, the second fluid path and/or the bypass fluid path.

In one embodiment of the invention, the inlet and outlet valves are of the diaphragm type.

In one embodiment of the invention, the inlet and outlet valves are positioned at a distance from the junction intermediate the first and second fluid paths and the bypass fluid path that is no greater than 3 or 2 or 1 times the diameter of the first, second and/or bypass fluid lines.

In one embodiment of the invention, the connection device is pre-sterilized and the separation device inlet and outlet connections are provided with sterile connectors.

In one embodiment of the invention it is pre-sterilized and the separation system inlet and outlet connections are provided with sterile connectors.

In one embodiment of the invention, the inlet valve, the outlet valve and the at least one bypass valve are manually controllable into an open state and a closed state.

In one embodiment of the invention it comprises at least one monitoring device which is connected to the inlet valve, the outlet valve and/or the at least one bypass valve and which shows the status of the inlet valve, the outlet valve and the at least one bypass valve.

In one embodiment of the invention, the connection device further comprises at least one sensor arranged in the connection device for detecting an open and/or closed state of at least one of the inlet valve, the outlet valve or the at least one bypass valve.

In one embodiment of the invention, it comprises a combination control device connected to the inlet valve, the outlet valve and the at least one bypass valve, and which in a first position controls the inlet valve and the outlet valve in an open state and controls the at least one bypass valve in a closed state, and which in a second position controls the inlet valve and the outlet valve in a closed state and controls the at least one bypass valve in an open state.

In one embodiment of the invention the connecting means comprises a bypass valve and wherein said inlet valve, said outlet valve and said bypass valve are provided together in one valve assembly part.

In one embodiment of the invention, the connection means comprises a first bypass valve and a second bypass valve, and wherein the connection means comprises an inlet valve assembly portion comprising the inlet valve and the second bypass valve and an outlet valve assembly portion comprising the outlet valve and the first bypass valve, wherein the bypass fluid path is provided between the first bypass valve and the second bypass valve.

In one embodiment of the invention, the separation device is a chromatography column.

In one embodiment of the invention, the separation device is pre-loaded with a bed of chromatographic medium.

In one embodiment of the invention, the connection means is connected to the separation means inlet and the separation means outlet by a barbed connection, a bar block connection, a TC connection or a welded connection.

In one embodiment of the invention, the connecting means is integral with the separating means.

In one embodiment of the invention, the bypass fluid path is provided integral with an end unit of the separation device.

In one embodiment of the invention, the separation device is pre-sterilized and wherein the separation system inlet and outlet connections of the connection device are provided with sterile connectors.

In one embodiment of the invention, the connection means is connected to the separation system inlet and the separation system outlet by a barbed connection, a bar block connection, a TC connection or a welded connection.

In one embodiment of the invention, the connecting means is integral with the separation system.

Drawings

Fig. 1a schematically shows a connection device according to one embodiment of the invention connecting a separation system with a separation device.

Fig. 1b schematically shows a connection device according to another embodiment of the invention connecting a separation system with a separation device.

Fig. 2a schematically shows a connecting device according to an embodiment of the invention connected to a separating device.

Fig. 2b is a perspective view of a portion of the same connection device as shown in fig. 2 a.

Fig. 2c is a cross-section of a portion of the same connection device as shown in fig. 2 a.

Fig. 3 schematically shows a connecting device according to an embodiment of the invention connected to a separating device.

Fig. 4a schematically shows a connection device according to an embodiment of the invention.

Fig. 4b schematically shows a connecting device according to an embodiment of the invention in cross-section.

Fig. 5a, 5b, 6a and 6b show further embodiments of combined connecting and disconnecting devices.

Detailed Description

Fig. 1a schematically shows a connection device 1 according to one embodiment of the invention connecting a separation system 3 with a separation device 5. The connection device 1 according to the invention may for example be used for connecting a chromatography system with a chromatography column, but may also be used for connecting another type of chromatography separation device (such as any type of fixed bed form that facilitates the chromatography separation capacity, such as a bed comprising a beaded porous structure, a membrane and/or membrane adsorber, a monolithic structure, a filter, a fiber based structure and/or a hybrid structure) to a separation system. However, in the remaining detailed description, reference is primarily made to examples relating to chromatography systems and chromatography columns. According to the invention, the connecting device 1 may be a separate part which is connected to the separation device 5 (also referred to as chromatography column 5) and the separation system 3 (also referred to as chromatography system 3), for example by a TC (Tri-Clamp) connection or a rod-and-block (St Gobain) connection ensuring effective disinfection. If the connection device is provided pre-sterilized and does not require subsequent sterilization, a conventional barbed connection, i.e. a connection for the interior of the connection device, may also be used.

However, according to another embodiment of the invention, the connecting device 1 or parts of the connecting device may instead be integrated parts of the separation device (chromatography column). In a further embodiment of the invention, the connecting device 1 or parts of the connecting device may instead be integrated parts of a separate system. In a further embodiment of the invention, the connection device 1 or parts of the connection device may be changed to integrated parts of the flow set. The degree and use of the features and improvements provided by the connection device according to the invention may vary depending on the embodiment.

The separation device 5 (chromatographic column) may comprise, for example, a bed of beads, a monolith or a modified membrane. The separation device 5 may be pre-loaded with a bed of chromatographic medium. The connecting device 1 according to the invention allows a separating device to be connected to a separating system 3. The connection device 1 comprises a separation device inlet connection 7 configured to be connected to a separation device inlet 9 of the separation device 5. Furthermore, the connecting device 1 comprises a separating device outlet connection 11 configured to be connected to a separating device outlet 13 of the separating device 5. These connections may be, for example, TC connections or bar block connections. However, in another embodiment, in which the connecting device 1 is integrated with the separating device 5, the separating device outlet connection 11 of the connecting device may instead be integrated with the separating device outlet 13 and the separating device inlet connection 7 of the connecting device may be integrated with the separating device inlet 9, whereby no specific connector is required. Different configurations are possible, for example the separation device outlet 13 may be positioned at the bottom side of the column and adjacent to the outlet side of the bed, respectively, and the separation device outlet connection 11 of the device may be integrated with 13 at the bottom or at the bed and the column, respectively. Other configurations are also possible for positioning other elements of the connection device or for connections connected and/or integrated between the column and the connection device, such as for example connections at the side of the column or at the side of the system.

The connection device 1 further comprises a separation system inlet connection 15 and a separation system outlet connection 19 configured to be connected to a separation system inlet 17 and a separation system outlet 21, respectively, of the separation system 3. These connections may be, for example, TC connections or bar-block connections as described above. In one embodiment of the invention, the connection device 1 or parts of the connection device 1 are integrated with the separation system 3. In this embodiment, the separation system outlet connection 19 of the connection device may be integrated with the separation system outlet 21 and the separation system inlet connection 15 of the connection device may be integrated with the separation system inlet 17, whereby no special connector is required.

Furthermore, the connection device 1 comprises a first fluid path 23 connecting the separation system inlet connection 15 with the separation device outlet connection 11 and a second fluid path 25 connecting the separation system outlet connection 19 with the separation device inlet connection 7. The first and second fluid paths 23, 25 may be provided as separate flexible plastic tubes, as flexible plastic tubes comprised in a tube bundle or guiding device providing a high degree of order and rigidity, or as conduits integrated in a (semi-) rigid plastic block.

According to the invention, the connection device 1 further comprises a bypass fluid path 27 connecting the separation system inlet connection 19 with the separation system outlet connection 19 via portions of the first and second fluid paths 23, 25. That is, the bypass fluid path 27 is provided in this embodiment such that it connects the first fluid path 23 with the second fluid path 25 at a location of the first fluid path 23 and the second fluid path 25 intermediate the separation device inlet/outlet connection and the separation system inlet/outlet connection. The bypass fluid path 27 may be provided as a flexible plastic tube, as a flexible plastic tube comprised in a tube bundle or guiding device providing a high degree of order and rigidity, or as a conduit integrated in a (semi-) rigid plastic block. In an embodiment of the invention, the bypass fluid path 27 may also be integrated in the end unit 40 of the separation device 5.

Furthermore, an inlet valve 31 is provided in the second fluid path 25 in connection with the separating device inlet connection 7. The inlet valve 31 is operable to provide an open state allowing fluid flow through the separator inlet connection 7 and a closed state preventing fluid flow through the separator inlet connection 7. An outlet valve 33 is provided in the first fluid path 23 in connection with the separating apparatus outlet connection 11. The outlet valve 33 is operable to provide an open state allowing fluid flow to exit through the separation device outlet connection 11 and a closed state preventing fluid flow through the separation device outlet connection 11. The bypass fluid path 27 is connected to the first and second fluid paths 23, 25, respectively, at a location intermediate the separation system inlet/outlet connections 15, 19 and the inlet/outlet valves 31, 33. The inlet/outlet valves 31, 33 which allow the bed to be shut off are suitably positioned close to the junctions 81a, 81b intermediate the first and second fluid paths 23, 25 and the bypass fluid path 27 to avoid any dead space which could lead to difficulties in flushing the fluid effectively. The dead space between the inlet valve 31 and the outlet valve 33 and the fluid junctions 81a, 81b of the bypass line 27 is preferably less than 3 times the diameter of the fluid paths 23, 25 and/or 27, or less than 2 times the diameter, or less than 1 time the diameter.

According to the invention, at least one bypass valve is provided in the bypass fluid path 27. The at least one bypass valve is operable to provide an open state that allows fluid flow through the bypass fluid path 27 and a closed state that prevents fluid flow through the bypass fluid path 27. In the embodiment of the invention as shown in fig. 1a, two bypass valves 35a, 35b are provided in the bypass fluid path 27. The first bypass valve 35a is disposed close to the first fluid path 23, and the second bypass valve 35b is disposed close to the second fluid path 25. The closing may for example be a distance of less than 3 times the diameter of the fluid path 23, 25 and/or 27 or less than 2 times the diameter or less than 1 time the diameter.

Thereby, when at least one of the inlet valve 31 and the outlet valve 33 is set in the closed state and at least one bypass valve 35a, 35b is set in the open state, fluid may flow from the separation system outlet connection 19 through the bypass fluid path 27 to the separation system inlet connection 15 while bypassing the connected separation device 5. Thus, air can be removed via the bypass fluid path 27 without the need to pass air through the chromatography bed. Furthermore, the portions of the separation system inlet and outlet connections 15, 19 and the first and second fluid paths 23, 25 and the bypass fluid path 27 may be sterilized. By having the bypass valves 35a, 35b located close to the first and second flow paths 23, 25 and possibly also close to the inlet and outlet valves 31, 33, dead spaces are avoided in which fluid can become trapped such that it cannot be effectively flushed out. Thus, when applying a disinfectant (such as e.g. sodium hydroxide solution) for bio-burden reduction and control, a good disinfection of the connection device may also be provided between uses.

Fig. 1b schematically shows a connection device 101 according to another embodiment of the invention connecting a separation system 3 with a separation device 5, such as e.g. connecting a chromatography system 3 with a chromatography column 5. Many details are the same as in the embodiment described above in relation to fig. 1a and are also given the same reference numerals and will not be described again in detail. The difference in this embodiment is that only one bypass valve 35 is provided in the bypass fluid path 27.

For both embodiments as described in relation to fig. 1a and 1b, at least one bypass valve 35, 35a, 35b may be of the diaphragm type, for example. The inlet valve 31 and the outlet valve 33 may also be of the diaphragm type. In another embodiment, the bypass valves 35, 35a, 35b and/or the inlet valve 31 and the outlet valve 33 may be provided as rotary valves. In a rotary valve embodiment, multiple valve ports and functions may be integrated into one or more valve bodies. For example, rotation of the valve may open the bypass line 27 by opening the valve 35 and simultaneously close the bed by closing the valves 31, 33, and vice versa. Several other combinations of opening and/or closing the flow path by rotation of at least one rotary valve are possible.

In another embodiment, the valves 31, 33 and/or 35, 35a, 35b may be of the pinch valve type, wherein the flexible tube is closed by pinching the flexible wall section and sealing off the interior of the tube.

The entire connection device 1 may be made of a suitable disposable material suitable for pre-sterilization (e.g. by gamma radiation) and thus adapted to the Single Use Technique (SUT).

The connection device 1, 101 according to the invention may suitably be provided with an aseptic connector for connection to the separation device 5 and possibly also with an aseptic connector for connection to the separation system 3. If the connection device 1, 101 is an integrated part of the separation device 5, it may suitably be provided with a sterile connector for connection to the separation system 3. The connecting device 1, 101 may suitably be pre-sterilized and the pre-assembled separating device 5 to which it is connected is suitably further provided with a sterile connector for connecting to the connecting device 1, 101. The separation device may be pre-sterilized or subject to bioburden control. Thus, for example, the chromatographic bed of the separation device need not be sterilized prior to first use.

If the connection device 1, 101 further comprises a sterile connector for connection to a separation system, the removal of air may be performed after connection to the system via the bypass fluid path, and furthermore the chromatography bed or the connector to the system does not need to be further sterilized before use.

The sterile connection between the connection device 1, 101 and the system may be, for example, by a sterile connector (e.g., ReadyMate), a sterile Multi-connector (e.g., Lynx Multi-connector from Millipore), or by welding. Thermoplastic pipes can also be connected (fused) by a welder (fusion splicer) and thereby provide a sterile connection. Weldable pipes can also be closed (sealed) and broken by a sealer (heat sealer). However, joining two tubes by welding and/or disconnecting the tubes by sealing typically requires the use of unreinforced (non-woven reinforced) thermoplastic tubes. The use of non-reinforced tubing may limit the operating pressure range and the use of columns, connection devices and systems, as non-reinforced tubing is typically not capable of withstanding operating pressures greater than 1 bar (bar), and typical operating pressures for pre-packed chromatography columns in biopharmaceutical production may range up to 4 to 6 bar. To allow for operating pressures of a few bars, the weldable unreinforced tube may thus be supported by a rigid exoskeleton or shell that may be fitted to the welded tube for withstanding high pressures after the welding operation has been performed. Thereby, a shell is provided around the tube, which can withstand the desired operating pressure. Such shells may be adjustable in length, for example by a telescoping function or by segments that may be engaged and applied to variable lengths to adjust to differences in tube length (which may be caused by repeated welding operations in disconnecting and reconnecting the tubes and columns). Thereby, the welding position of the connection between the two pipes can be provided with a skeleton, and thus a high fluid pressure can be withstood even if an unreinforced pipe is used for the portion of the pipe in which the connection is provided.

The inlet valve 31, the outlet valve 33 and the at least one bypass valve 35, 35a, 35b can be manually controlled into an open state and a closed state. If the valve is, for example, a diaphragm valve, the actuator may be controlled manually, for example by means of a screw having an open state and a closed state. Diaphragm valves include a flexible diaphragm (or diaphragm) that is displaced between open and closed valve positions, the latter typically being complied by moving the diaphragm (or diaphragm) to a valve seat and thereby closing fluid flow. In one embodiment of the invention, the connection device 1 comprises at least one monitoring device 51 (only shown in fig. 1a, but applicable also in fig. 1b), which monitoring device 51 is connected to the inlet valve 31, the outlet valve 33 and/or the at least one bypass valve 35, 35a, 35b, and which monitoring device 51 shows the status of the inlet valve, the outlet valve and the at least one bypass valve. Thereby, it will be easy to see from the outside whether the separating apparatus is connected or bypassed. The connection device 1 may further comprise at least one sensor 53 (only shown in fig. 1a, but applicable also in fig. 1b), which at least one sensor 53 is arranged in the connection device for detecting an open and/or closed state of at least one of the inlet valve 31, the outlet valve 33 or the at least one bypass valve 35, 35a, 35 b.

In another embodiment, the monitoring device 51 may provide visual, audible or tactile feedback to the operator.

In one embodiment of the invention, the connecting device 1 comprises a combination control device 55 (shown only in fig. 1a, but applicable also in fig. 1b), which combination control device 55 is connected to the inlet valve 31, the outlet valve 33 and the at least one bypass valve 35, 35a, 35b, and which combination control device 55 in a first position controls the inlet valve 31 and the outlet valve 33 in an open state and controls the at least one bypass valve 35, 35a, 35b in a closed state, and which combination control device 55 in a second position controls the inlet valve 31 and the outlet valve 33 in a closed state and controls the at least one bypass valve 35, 35a, 35b in an open state. Thereby, a connection device which is easy to control is achieved.

The control device 55 may be provided as a mechanical, electronic or other solution that provides for a dependency between valve positions, accommodating simultaneous actuation of multiple valves by combined actuation with little operator or control system action (such as turning a lever, turning a knob, or engaging a system control element).

The control device 55 may also or only provide features for monitoring valve position, actuation and operator interaction (monitoring device 51). The sensing capability may output a read signal to a control system interfaced with the separation system or a higher level control and/or monitoring system via a wired or wireless connection.

The control device 55 may be embodied as a stand-alone device or integrated with a control and/or monitoring system at the unit operation level (e.g., chromatography system) or plant level (e.g., production execution system, MES).

Fig. 2a schematically shows a connection device 1 according to one embodiment of the invention connected to a separation device 5, which separation device 5 in this example is a chromatography column 5. In this example, the inlet 9 of the separating apparatus is provided at the upper end unit of the separating apparatus and the outlet 13 is provided at the lower end unit of the separating apparatus. The flow from the inlet through the column to the outlet is referred to as a downflow mode. However, the separation device can also be used in upflow mode, and the nomenclature for the inlets and outlets at the column, the connection devices and the system, and the flow direction in the respective elements and the bypass lines will be adjusted accordingly. In this case, the inlet serves as the outlet, and the outlet serves as the inlet. Most of the details are the same as in the embodiment shown in fig. 1a and are also given the same reference numerals and will not be described again. In this embodiment, the connection device 1 comprises an inlet valve assembly portion 41 and an outlet valve assembly portion 43, the inlet valve assembly portion 41 comprising the inlet valve 31 and the second bypass valve 35b, the outlet valve assembly portion 43 comprising the outlet valve 33 and the first bypass valve 35b, wherein the bypass fluid path 27 is provided between the first and second bypass valves 35a, 35 b. In this embodiment, TC connection 45 is used to connect inlet valve assembly portion 41 and outlet valve assembly portion 43 to first fluid path 23, second fluid path 25 and bypass fluid path 27 in connection 1. However, other types of connections, such as bar-type connections, may be used instead. The inlet valve assembly portion 41 and the outlet valve assembly portion 43 are described in more detail with reference to fig. 2b and 2 c. In fig. 2a, the inlet valve assembly portion 41 is shown in cross-section, while the outlet valve assembly portion 43 is not. The two portions 41, 43 may be identical.

Figure 2b is a perspective view of the inlet valve assembly portion 41 or the outlet valve assembly portion 43 of the connection device 1 as shown in figure 2 a. As described above, the inlet valve assembly portion 41 or the outlet valve assembly portion 43 is connected to the bypass fluid path 27 by the TC connection 45 in this embodiment. The inlet valve assembly portion 41 or the outlet valve assembly portion 43 is further connected in the first fluid path 23 or the second fluid path 25 by two TC connectors 45. The inlet valve assembly portion 41 or the outlet valve assembly portion 43 includes the inlet valve 31 or the outlet valve 33 and the first or second bypass valve 35a, 35 b. In this embodiment all valves 31, 33, 35a, 35b are diaphragm valves, wherein the diaphragm will close or open the valve. An actuator 47 is provided for controlling the position of the diaphragm of each valve 31, 33, 35a, 35 b. The actuator 47 is in this embodiment controlled by the screw 46. However, other control means than a screw may be provided for controlling the actuator 47.

Fig. 2c is a cross-section of the same inlet valve assembly portion 41 or outlet valve assembly portion 43 of the connection device 1 as shown in fig. 2a and 2 b. An inlet valve seat 48a or an outlet valve seat 48b is provided in the inlet valve 31 or the outlet valve 33, and an inlet diaphragm 49a or an outlet diaphragm 49b is provided for fluid flow for closing or opening the inlet valve seat 48a or the outlet valve seat 48 b. Furthermore, a first bypass valve seat 48c or a second bypass valve seat 48d is provided in the first or second bypass valve 35a, 35b, and a bypass diaphragm 49c, 49d is provided for the fluid flow for closing or opening the first or second bypass valve seat 48c, 48 d. As described above, the positions of the inlet, outlet and bypass diaphragms 49a, 49b, 49c, 49d are controlled by the actuator 47.

According to the present invention, the inlet valve seat 48a and the second bypass valve seat 48c in the inlet valve assembly portion 41 (and in the same way the outlet valve seat 48b and the first bypass valve seat 48d in the outlet valve assembly portion 43) are disposed close to each other for preventing dead space, i.e. fluid from being trapped in the portion of the connecting device 1 not used at that time. Closed may mean, for example, a distance less than three times the diameter of one of the fluid paths of the system (e.g., bypass fluid path 27 as discussed above). In one embodiment of the invention, the distance between the inlet valve seat 48a and the second bypass valve seat 48c (and the distance between the outlet valve seat and the first bypass valve seat in the outlet valve assembly portion 43) is less than twice the diameter of the fluid path in the connection device 1 or even less than one time the diameter.

Fig. 3 schematically shows a connecting device 1' according to an embodiment of the invention connected to a separating device 5. Many of the details of this embodiment are the same as described above with respect to the embodiment shown in fig. 1a and 2a, and these details are given the same reference numerals and will not be described again. In this embodiment the connecting device 1' is integrated with the separating device 5, i.e. mounted to the column during production at the factory.

Fig. 4a schematically shows a connecting device 101 according to an embodiment of the invention. The connecting device 101 is of the type as described above in relation to fig. 1b, i.e. only one bypass valve 35 is provided. In this embodiment, the valve assembly portion 42 is configured to include all of the inlet valve 31, the outlet valve 33, and the bypass valve 35. Thus, the bypass fluid path 27 is provided only within the valve assembly portion 42 itself.

Fig. 4b schematically shows a connecting device 101 according to an embodiment of the invention in cross-section. This may be the same connection device 101 as described in relation to fig. 4a, however in this embodiment the valve assembly portion 42 is not connected to the first and second fluid paths 23, 25 by a TC connection 45 as shown in fig. 4a, but instead by another type of integrated connector (which may be of the welded type). In this cross section, the inlet valve seat 48a, the outlet valve seat 48b and the bypass valve seat 48c are visible. An inlet diaphragm 49a is provided for fluid flow through the inlet valve seat 48a for closing or opening, an outlet diaphragm 49b is provided for fluid flow through the outlet valve seat 48b for closing or opening, and a bypass diaphragm 49c is provided for fluid flow through the bypass valve seat 48c for closing or opening. As described above with respect to other embodiments, the diaphragm may be controlled by an actuator controlled by a suitable control device, such as the screw 46 as shown in fig. 4 a.

The valve assembly portion 42 of the embodiment shown in fig. 4a and 4b and the inlet valve assembly portion 41 and the outlet valve assembly portion 43 of the embodiment shown in fig. 2a-c and 3 may be connected, for example, with a stem block type connector (as shown in fig. 2 a-b) or a TC connector (as shown in fig. 2a and in some connections in fig. 2 c), or integrated with the separating apparatus 5 instead. The bypass fluid path 27, the inlet and outlet valves 31, 33 and the bypass valves 35, 35a, 35b may also be integrated in the separation device 5, for example in the end unit of the column, or possibly in a separate unit mounted to the end unit of the column. The connector suitably may be a sterile connector. Alternatively, the sterile connection may be provided by welding as described above.

The connecting device shown in the figures and shown above has particular utility for single use pre-loaded separating devices which are in essence required to be compact. In this case it is possible to combine the connecting means into separate means, for example as described below.

Fig. 5a and 5b and fig. 6a and 6b each show a separation device (150, 105') that incorporates a connection device (102, 102'), which connection device (102, 102') is similar to the devices 1 and 101 mentioned above except in these figures, with inlet and outlet valves and fluid connections (such as bypasses) being combined into the separation device shown.

In more detail, fig. 5a shows a separation device 150 formed by stacking similar separation units 50 and an integrated connection device 102 formed by opposing headers 57 and 59. Fig. 5b shows a cross section through the apparatus 150 shown in fig. 5a, wherein each separation unit 50 has an inlet 52, an outlet 54 and a separation material 56 in-between the fluid distribution and collection fluid path 58 between the inlet 52 and the outlet 54. The inlets and outlets are arranged to be co-terminal (co-terminal) with each other to form a common inlet path 53 and a common outlet path 55.

The connecting means 102 is formed by the two heads 57 and 59. The headers 57 and 59 are fluidly connected to the stacked separation units 50 via the common inlet and common outlet, and are thus configured for connection to a separation system, such as the system 3 described above. The connection means further comprises a three-way inlet valve 131 and a three-way outlet valve 133, each of which is operable as described above, such that the function of the valves is the same as the function of the valves 31 and 33 described above. In this case, the valves may be rotated by means of knobs on the outside of the respective heads, but other valve types may be used.

Thus, it can be seen that the connection device 102 has: a separation device inlet connection 107 configured for connection to the separation device common inlet 53; a separation device outlet connection 111 configured for connection to the separation device common outlet 55; a separation system inlet connection 115 configured for connection to a separation system inlet (not shown); a separation system outlet connection 119 configured for connection to a separation system outlet (not shown); and a bypass fluid path 123 for connecting the separation system inlet connection 115 with the separation device outlet connection 111. By integrating the bypass fluid path 123 into the separation unit 50, a compact design with an optimal hold-up volume is achieved when the length of the bypass fluid path 123 is varied in proportion to the number of separation units installed in the separation device.

Fig. 6a and 6b show a combined separating and connecting device 150 'similar to the arrangement of fig. 5a and 5b, respectively, wherein as a result the connecting device 102' can be made as a head and a leg 59 'is used to close the lower end of the stack of units 50' and introduce fluid to the bottom of the stack, which avoids entrainment of air. Fig. 6b shows the separating device and the separating unit, which are arranged in a vertical position to show that the separating device can be used in different orientations. In addition, the inlet and outlet connections of the separation device may be positioned in various alternative locations at the head (not shown), and the fluid conduits may be drawn differently than shown by the schematic drawings. In practice, the inlet and outlet connections and the fluid conduits will be positioned such that the fluid hold-up volume can be minimised and/or that the purging of air from the separation device will be facilitated in an optimal manner.

In the embodiments of fig. 5a and 6a, an integral bypass is employed, but in practice it is possible to use two-way valves as described above and to use an external bypass. For external bypassing, the use of flexible tubing will allow the separation device to be adjusted for different numbers of separation units and thus variations in the height of the stacked separation units. For each embodiment, a clamping force may be used to hold the stack of units together, and removal of the force allows the units to be removed, leaving the heads 57, 59 or head 57 'and leg 59' in place (if desired). A sealing arrangement, such as an O-ring or a sealing surface provided by over-molding (over-mold), is not shown here but is suitably applied to the sealing connection between the head, the separation unit and the separation system.

The connecting device according to the invention may also be employed with other types of separation systems than chromatography systems, such as, for example, filtration systems, fluidized bed systems or the like.