Abstract
A multi-connector port provides an air connection for sterile air, at least one access arranged on a connecting piece, and at least one line arranged on the connecting piece. The access comprises a self-closing diaphragm.
Claims
1.-17. (canceled)
18. A multi-connector port comprising an air connection for sterile air, at least one access arranged on a connecting piece, and at least one line arranged on the connecting piece, wherein the access comprises a first self-closing diaphragm.
19. The multi-connector port as claimed in claim 18, wherein the air connection comprises a second self-closing diaphragm and a sterile filter.
20. The multi-connector port as claimed in claim 19, wherein the sterile filter has a pore diameter of less than or equal to 0.22 μm.
21. The multi-connector port as claimed in claim 19, wherein a side of the sterile filter facing away from the second self-closing diaphragm is in contact with the outside air.
22. The multi-connector port as claimed in claim 18, wherein the air connection is configured such that sterile air can be drawn through it into a tip.
23. The multi-connector port as claimed in claim 18, wherein the at least one access, the air connection and the at least one line are fluidically connected to one another via the at least one connecting piece.
24. The multi-connector port as claimed in claim 18, further comprising exactly two accesses, in which a first access is configured for an addition of media and a second access is configured for a withdrawal of media.
25. The multi-connector port as claimed in claim 18, further comprising a fixing device adapted for connection to a handling system.
26. The multi-connector port as claimed in claim 18, wherein the handling system comprises a handling robot.
27. The multi-connector port as claimed in claim 18, wherein the multi-connector port is adapted to be sterilizable, and wherein the sterilization is performed by autoclaving, irradiation, or with ethylene oxide.
28. The multi-connector port as claimed in claim 18, further comprising a cap for covering the at least one access or the air connection.
29. The multi-connector port as claimed in claim 18, wherein the first self-closing diaphragm is configured as a pierceable septum or wherein the access is configured as a needle-free diaphragm valve comprising the first self-closing diaphragm.
30. A method for filling or withdrawal via a multi-connector port as claimed in claim 18, the method comprising the steps: connecting the at least one line of the multi-connector port to a vessel; cleaning an outer surface of the at least one access or an outer surface of the air connection by wiping or rinsing with a cleaning agent comprising isopropanol; penetrating the first self-closing diaphragm of the at least one access with a first tip in the form of a hollow needle, a pipette tip, or a male connecting piece; adding a medium into the vessel or drawing a medium out of the vessel via the first tip; withdrawing the first tip; and applying sterile air.
31. The method as claimed in claim 30, wherein the vessel is a bioreactor.
32. The method as claimed in claim 30, wherein the application of sterile air comprises the following steps: penetrating a second self-closing diaphragm of the air connection with a second tip; drawing in ambient air through a sterile filter via the second tip into a reservoir that is connected to the second tip; withdrawing the second tip from the second self-closing diaphragm; penetrating the first self-closing diaphragm of the at least one access of the multi-connector port with the second tip; and applying air from the reservoir into the access.
33. The method as claimed in claim 30, wherein after the application of sterile air, a final cleaning of the outer surface of the at least one access or of the outer surface of the air connection is performed.
34. The method as claimed in claim 33, wherein the multi-connector port comprises at least one cap and wherein the at least one cap is removed before the cleaning operation or is mounted after the final cleaning operation.
35. The method as claimed in claim 30, wherein the first tip is part of a handling system and the connecting piece has a fixing device and wherein the multi-connector port is exactly positioned in relation to the handling system by means of the fixing device before the cleaning operation.
36. A system comprising a multi-connector port as claimed in claim 18 and a handling system with at least one tip in the form of a hollow needle, a pipette tip, or a male connecting piece.
37. The system as claimed in claim 36, further comprising an encapsulating device for encapsulating the tip with respect to ambient air or a self-closing casing.
38. The system as claimed in claim 37, wherein the encapsulating device comprises a nozzle device for causing sterile air to flow around the tip.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] Further embodiments will be discussed below by way of example on the basis of the accompanying Figures, in which:
[0039] FIG. 1 shows an embodiment of a multi-connector port according to the first aspect of the invention;
[0040] FIG. 2 shows a further embodiment of a multi-connector port according to the first aspect of the invention;
[0041] FIG. 3a shows a further embodiment of a multi-connector port according to the first aspect of the invention;
[0042] FIG. 3b shows a further embodiment of a multi-connector port according to the first aspect of the invention;
[0043] FIG. 4 shows a further embodiment of a multi-connector port according to the first aspect of the invention;
[0044] FIG. 5 shows an embodiment of a method according to the second aspect of the invention;
[0045] FIG. 6 shows an embodiment of a system according to the third aspect of the invention;
[0046] FIG. 7 shows a detail view of parts of an embodiment of a system according to the third aspect of the invention; and
[0047] FIG. 8 shows a detail view of parts of an embodiment of a system according to the third aspect of the invention in two states.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0048] FIG. 1 shows an embodiment of a multi-connector port 100 according to the first aspect of the invention. In the embodiment shown, the multi-connector port 100 has two accesses 110, 120. Each of these accesses 110, 120 is arranged on a connecting piece 111, 121. Furthermore, in each case, one line 112, 122 is arranged on the respective connecting piece 111, 121. Each of the accesses 110, 120 has a self-closing diaphragm 115, 125. In the embodiment shown here, the self-closing diaphragm 115, 125 of each access 110, 120 is configured as a pierceable septum. The septum may, for example, be a commercially available silicone septum; this can be penetrated by a tip, for example, in the form of a hollow needle or a pipette tip, and yet seals off in leak-tight fashion with respect to the outside. In preferred embodiments, the pierceable septum is configured with a slot, in particular, a cross-shaped slot, through which the tip can penetrate, such that the walls of the slot lie tightly against the tip and thus close off the lumen under the septum in leak-tight fashion with respect to the outside. In alternative embodiments that are not shown here, the accesses 110, 120 may also be configured as needle-free diaphragm valves. Aside from the accesses 110, 120, the multi-connector port 100 has an air connection 130 which, in the embodiment shown, likewise comprises a further self-closing diaphragm 135 and a sterile filter 140. In the embodiment shown, the sterile filter has a pore diameter of less than or equal to 0.22 μm. In the embodiment shown, the air connection 130 is fluidically connected to the lines 112, 122 and the accesses 110, 120 via the connecting pieces 111, 121. With this embodiment of the air connection, purging of the connecting pieces 111, 121 and of the lines 112, 122 with sterile air is easy to realize by virtue of air being introduced via a tip through the further self-closing diaphragm and being filtered by the sterile filter 140. There is thus no need for sterile air to be kept available with corresponding connection pieces for the storage thereof, which can then be connected to the multi-connector port. Alternatively, it is also possible to provide standardized air connections for sterile air on the multi-connector port. The lines 112, 122 lead here to the head plate 155 of a bioreactor 150, for the filling and withdrawal of which the multi-connector port 100 is used here. The multi-connector port 100 may, however, also be used for a large number of other vessels and connection possibilities. It can be flexibly combined with other systems. For this purpose, special connections for connecting in leak-tight fashion to the respective vessel may be provided on the lines 112, 122. The line 112, 122 may, however, also be configured in the form of simple hoses which are inserted into, for example, existing septa on head plates.
[0049] The multi-connector port 100 allows simple and reliable filling and withdrawal for a large number of vessels by virtue of the addition and withdrawal points being decoupled from the vessel itself. The addition or removal takes place via the accesses 110, 120. In the embodiment shown here, it is particularly advantageous if one of the accesses, in this case the access 110, is only used for additions and the other access, in this case access 120, is only used for withdrawals. It can thus be ensured that samples taken from the vessel are not contaminated by media previously added via the access 110 and its connecting piece 111 and the line 112. The access 120 and its connecting piece 121 and the line 122 are fluidically separated from the access 110. The two parts of the multi-connector port are connected to one another only via the air connection, through which no liquids are exchanged. As already mentioned, the air connection 130 serves for the purging of the connecting pieces and lines such that any media present in the connecting pieces 111, 121 or lines 112, 122 are forced into the reactor by the addition of sterile air. Previously added media are thus transferred fully to the reactor and scarcely any dead volumes, or no dead volumes, remain within the connecting piece or the line. It can be ensured in this way that the previously set quantity of medium also actually reaches the bioreactor or the other vessel. In the case of the access for withdrawal, the medium withdrawn by way of the purging with sterile air is forced back into the bioreactor or the respective vessel such that no medium remains in the withdrawal line, which medium would over time be exposed there to conditions different than those in the reactor itself. It is thus ensured even for later withdrawals of samples that the samples originate entirely from the interior space of the bioreactor or of the other vessel, and are not contaminated by sample residues that have remained in the line or the connecting piece for a relatively long period of time. The entire multi-connector port 100 is preferably designed to be sterilizable. It is furthermore advantageous if all of the outer surfaces of the multi-connector port, in particular, the diaphragm, can be easily sterilized for example by wiping with a cleaning liquid such as isopropanol or else merely spraying or rinsing with such a cleaning liquid. By means of these cleaning and sterilization steps, it can be ensured that the filling of vessels is possible in a sterile manner even outside sterile working environments by means of the multi-connector port 100. This lowers the costs for the working steps and at the same time facilitates the work involved in the withdrawal or addition of samples, which can, therefore, also be performed flexibly in terms of location. As a further protective measure that is not shown here, the multi-connector port 100 may comprise one or more caps for the accesses 110, 120 and the air connection 130, which caps are firstly removed before an addition or withdrawal of media and are mounted again after the completion thereof, such that the accesses and the air connection are protected against contamination while they are not in use.
[0050] FIG. 2 shows a further embodiment of a multi-connector port 200 according to the first aspect of the invention. The multi-connector port 200 is of substantially identical construction to the multi-connector port 100 from FIG. 1. Therefore, the further features, in particular, will be discussed below, and reference is otherwise made to the description relating to FIG. 1. Components of the multi-connector port 200 that are identical to those of the multi-connector port 100 are denoted by the same reference designations. On the multi-connector port 200 is connected to the head plate 255 of a bioreactor 250. In the embodiment shown, however, said head plate is arranged in a liquid-handling system, by means of which automated additions and withdrawals can be realized. In the embodiment shown, the multi-connector port 200, therefore, has a fixing device 260 which, here, is connected and fixed to the handling system by means of brackets 270 belonging to the handling system, such that a handling robot can move easily and in an exact manner to the accesses 110, 120 of the multi-connector port 200. It is shown here by way of example how the tip 285 of a handling robot 280 penetrates the self-closing diaphragm 115 of the access 110. As can be seen, the tip 285, configured here as a hollow needle, penetrates through the diaphragm into the connecting piece 110, such that liquid can be released into the connecting piece 110 and its adjoining line 112 and thereby reaches the bioreactor 250. The multi-connector port 200 has an air connection 230 which is configured by way of a screw thread for the connection of a line for sterile air. By means of this connection, it is possible for a reservoir or a line for sterile air, which reservoir is already present at the respective workstation, to be used to purge the multi-connector port 200 and to force any residues out of accesses, connecting pieces, or lines into the connected bioreactor 250. The multi-connector port 200 otherwise shares the advantages that have been described with regard to the multi-connector port 100 in FIG. 1.
[0051] FIG. 3a shows a further embodiment of a multi-connector port 300 according to the first aspect of the invention. The embodiment shown here differs from that in FIGS. 1 and 2 in that, in the embodiment shown, only one connecting piece 311 is provided on which there are arranged two accesses 310, 320, each with a self-closing diaphragm 315, 325, and in that the air connection 330 with the further self-closing diaphragm 335 and the sterile filter 340 is in this case not fluidically connected to the connecting piece 311. In the embodiment shown, the sterile filter 340 is in contact with the outside air on its side 341 facing away from the further self-closing diaphragm. If a tip is now introduced from above through the self-closing diaphragm 330, then air can be drawn in through the sterile filter 340 via said tip and transferred into a reservoir connected to the tip. Following this, the tip can be introduced into one of the accesses 310, 320 and air can thus be applied into connecting piece 311 and line 312, such that medium situated in the access, connecting piece, or line from a previous filling or withdrawal process is forced into the reaction vessel 350 that is connected here. The multi-connector port 300 also has an air connection for sterile air 330, which air connection has a further self-closing diaphragm 335 and a sterile filter 340. Furthermore, the multi-connector port 300 has a fixing device 360 for integration into a handling system. The embodiment shown can be used, in particular, for vessels or intended purposes in the case of which there is little space available for the multi-connector port 300 and the use cannot result in problematic contamination in a common line or, for example, the intended purpose involves only additions or only withdrawals. To further reduce the space requirement, it is also possible for only one access, for example the access 310, to be provided, such that the multi-connector port 300 can be implemented in an extremely small space.
[0052] The embodiment shown in FIG. 3b differs from that in FIG. 3a merely in that the air connection 330 is not connected by means of the fixing device 360 to accesses 310, 320. The air connection 330 is configured separately here; this is particularly advantageous in embodiments (not shown here) of the multi-connector port which have a multiplicity of accesses, all of which can be purged by means of the one air connection 330. These embodiments of the multi-connector port allow a large number of bioreactors to be connected at the same time.
[0053] FIG. 4 shows a further embodiment of a multi-connector port 400 according to the first aspect of the invention. In the embodiment shown, the accesses 410, 420 are routed entirely separately from one another. A connecting piece 411, 421, on which in each case one line 412, 422 is also arranged, is arranged at each access 410, 420. Each of the accesses 410, 420 has a self-closing diaphragm 415, 425, in this case in the form of a pierceable silicone septum. The access 410 is preferably provided for addition and the access 420 for withdrawal, such that no adulteration occurs. The multi-connector port 400 furthermore has a fixing device 460 by means of which the multi-connector port 400 can easily be connected to a handling system. The fixing device 460 mechanically connects the accesses 410, 420 and the air connection 430 at the same time. As already described in detail with regard to the multi-connector port 300 and its air connection 330, said fixing device is equipped with a sterile filter 440 and a further self-closing diaphragm such that ambient air can be drawn in via the air connection 430 and sterilized in the filter 440 and can then, via a tip with a connected reservoir, be passed for purging into one of the previously used accesses. In the embodiment shown, the lines 412, 422 are plugged into a connection 456 in the head plate 455 of a bioreactor 450, which can be filled, and from which samples can be taken, via the multi-connector port 400.
[0054] FIG. 5 shows an embodiment of a method according to the second aspect of the invention for filling or withdrawal via a multi-connector port. For preparatory purposes, in step S1, the at least one line of the multi-connector port is connected to a vessel, in particular, to a bioreactor. In the simplest case, the connection may be made by introducing the line, which is, for example, configured as a hose, into a diaphragm or a septum, for example, in a head plate of a bioreactor. If the multi-connector port is used in conjunction with a handling system, this step also includes exact positioning and optionally fixing in relation to the handling system, such that tips and other parts of the handling system can move easily and in an exact manner to the multi-connector port.
[0055] In the optional step S2a, a cap arranged over the at least one access or the air connection is removed; the cap is optionally cleaned beforehand, for example, with a cleaning agent and/or disinfectant. In step S2b, an outer surface of the at least one access and/or an outer surface of the air connection is then cleaned. This is preferably performed by rinsing, spraying, or wiping with a cleaning agent and/or disinfectant such as isopropanol. If the multi-connector port is integrated into a handling system, this step can be performed, in particular, in automated fashion by the handling system.
[0056] In step S3, the self-closing diaphragm of the at least one access is penetrated with a tip, in particular, in the form of a hollow needle, a pipette tip or a male connecting piece, and either a medium is introduced to the vessel, or a sample or a medium is withdrawn, via the tip.
[0057] In step S4, sterile air is applied into the previously used access of the multi-connector port. This may be performed via a fluidic connection between the air connection and the access or, in one embodiment, include the following sub-steps: penetrating the further self-closing diaphragm of the air connection with a tip; drawing ambient air through the sterile filter via the tip into a reservoir connected to the tip; removing the tip from the further self-closing diaphragm, penetrating the self-closing diaphragm of the at least one access of the multi-connector port with the tip, and finally applying air from the reservoir into the access.
[0058] In an optional step S5a, cleaning is then performed again, for example, by rinsing, spraying, or wiping with a cleaning liquid and, finally, if caps are used, these are mounted again in step S5b, and the caps are optionally sprayed with disinfectant.
[0059] If the multi-connector port is used further at the same location and with the same reaction vessel, this is then followed again by the optional step S2a. Otherwise, positioning of the multi-connector port, or connection to a further reaction vessel, is performed again in step S1.
[0060] FIG. 6 shows an embodiment of a system 1000 according to the third aspect of the invention. In the embodiment shown, the system 1000 comprises a multi-connector 500 comprising an air connection for sterile air and also at least one access arranged on a connecting piece and at least one line arranged on the connecting piece, wherein the access comprises a self-closing diaphragm as described in detail, for example, in FIGS. 1 to 4. The system 1000 furthermore comprises a handling system 606 with at least one tip 680, in this case in the form of a hollow needle. In the illustration shown, only part of the handling system is shown. With the system 1000, if the multi-connector port 500 is connected to, for example, a bioreactor, withdrawals or additions from or to this can now be performed in automated fashion in a non-sterile environment.
[0061] FIG. 7 shows a detail view of parts of an embodiment of a system according to the third aspect of the invention. Here, in detail, a tip 780 of a handling system 700 (not illustrated any further) is illustrated as part of the system, wherein the system comprises a nozzle device 790 with a nozzle for causing sterile air to flow around the tip 780. The nozzle is connected to a connection for sterile air 791 and is directed toward the tip such that sterile air is caused to flow around said tip, and said tip has no contact with the ambient air, over a length L. A sterile air curtain 792 around the tip is thus established by means of the nozzle device 790. The sterile air may be caused to flow around permanently, or at least during a penetration of the tip until it has penetrated fully, and for as long as the tip is not penetrating.
[0062] FIG. 8 shows a detail view of parts of an embodiment of a system according to the third aspect of the invention in two states. The system, parts of which are illustrated here, comprises an encapsulating device in the form of a self-closing casing 890, which is designed here as a silicone cap with a cross-shaped slot; here, at an end facing away from an open end of the tip 880, the silicone cap has an opening for receiving the tip, and at its opposite end facing toward the open end of the tip, said silicone cap has the cross-shaped slot. In the upper Figure, the tip 880 of the handling system of the system is free and encapsulated with respect to the ambient air by the self-closing casing. If, as illustrated in the lower Figure, the tip 880 is now pushed, for example, into a self-closing diaphragm 815, then the self-closing casing is pushed open when the self-closing casing 890 and the self-closing diaphragm 815 come into contact, such that a part of the tip 880 can penetrate into the self-closing diaphragm whilst the further parts of the tip 880 surrounded by the casing 890 remain protected by the latter. The casing 890 together with the self-closing diaphragm 815 then closes off the tip with respect to the ambient air. As soon as the tip 880 is withdrawn, the casing 890 wraps itself back around the tip 880.
