Systems, methods, and apparatus for minimizing dead legs in bioreactor systems

Abstract

An apparatus for minimizing dead leg space in a vessel or tube includes a first member having a flange for mounting the first member against a wall of the vessel or tube and having at least one aperture, and a second member rotatably coupled to the first member, the second member having an upper end having at least one aperture and an open distal end, the second member being rotatable relative to the first member between a closed position in which the at least one aperture in the second member is misaligned with the at least one aperture in the flange to prevent the passage of fluid, and an open position in which the at least one aperture in the second member is aligned with the at least one aperture in the flange to allow the passage of fluid.

Description

Technical Field

[0001] Embodiments of the present invention generally relate to bioprocess systems and bioprocess methods, and more particularly to devices for minimizing or preventing the formation of dead leg spaces in bioprocess systems.

Background Art

[0002] In the biopharmaceutical industry, the use of single-use i.e., disposable containers or flexible bags is increasing. Such containers are flexible or collapsible plastic bags, which are supported by an outer rigid structure herein called a "vessel", such as a stainless steel shell. By using a sterilized disposable bag, the time-consuming step of cleaning this steel bioreactor vessel is eliminated and the potential for contamination is reduced. In use, the bag is filled with the fluid desired to be mixed, and agitator blades disposed within the bag are used to mix this fluid (driven by a magnetic drive system or motor positioned outside the vessel). Depending on the fluid to be processed, the system can include a plurality of fluid lines and various sensors, probes, and ports coupled to the bag for monitoring, analysis, sampling, and fluid transfer. For example, typically, a harvest port is located at the bottom of the disposable bag and the vessel, enabling a harvest line to be coupled to the bag for recovery and discharge from the bag after completion of the bioprocess.

[0003] Currently available single-use bioreactors use hose barbs or similar fittings welded to the bag film as inlet and outlet points for fluid transport. Drain line fittings typically have a tubular section that provides unidirectional fluid flow. The medium flows into this tubular section of the fitting, but the medium, cells, and other fluid components can remain stagnant and isolated from the larger bioreactor environment. When cells accumulate in this section of the fitting, they are generally deprived of nutrients, die, and release toxic compounds that can be detrimental to cell growth and production in bulk culture. When this occurs, the area where the medium and cells accumulate is called a dead leg or dead leg space. In mixed systems, minimizing the dead leg space promotes complete mixing and reduces the likelihood of solid sedimentation.

[0004] At present, there is no effective means to prevent or completely eliminate the formation of this fluid and cell isolation volume in the dead leg portion of the drain fitting. Existing systems typically use non-invasive pinch valves, and clamps or other means are used to close the channel in the drain line tube by clamping the drain line, but fluid can still collect and accumulate in the space above the clamp. [Overview of the project] [Problems that the invention aims to solve]

[0005] In light of the above, there is a need for devices and methods to prevent or substantially minimize the formation of dead leg space in drain lines or drain fittings of bioprocess systems using single-use flexible bioreactor vessels. [Means for solving the problem]

[0006] In one embodiment, a device is provided for minimizing dead leg space in a container or tube. The device comprises a first member having a flange, the flange for mounting the first member to the wall of a container or tube, and having at least one aperture; and a second member rotatably coupled to the first member, the second member having an upper end having at least one aperture and an open distal end. The second member is rotatable with respect to the first member between a closed position in which at least one aperture of the second member is misaligned with at least one aperture in the flange to prevent the passage of fluid, and an open position in which at least one aperture of the second member is aligned with at least one aperture in the flange to allow the passage of fluid.

[0007] In another embodiment, a device for minimizing dead leg space in a container or tube comprises a first member having a flange for mounting the first member to the wall of a container or tube and a substantially hollow sleeve extending from the flange, and a plunger slidably received within the hollow sleeve, having a tip configured to engage sealably with the first member. The plunger is slidable between a closed position in which the tip engages sealably with the sleeve adjacent to the flange to prevent the passage of fluid into the sleeve, and an open position in which the plunger is linearly displaced from the closed position to allow the passage of fluid into the sleeve.

[0008] In yet another embodiment, a device for minimizing dead leg space in a container or tube comprises a first member having a flange for mounting the first member to the wall of the container or tube, a substantially hollow sleeve extending from the flange, and a sealing element extending across the sleeve to close a passage through the sleeve, and a substantially hollow puncture member slidably received within the hollow sleeve, the puncture member having a puncture tip. The puncture member is movable between a first position in which the puncture tip is positioned below the sealing element, thereby preventing the passage of fluid beyond the sealing element by keeping the sealing element intact, and a second position in which the puncture member punctures the sealing element, the puncture tip extends into the container or tube, and the interior of the puncture member is in fluid communication with the interior of the container or tube, thereby allowing the passage of fluid into and beyond the hollow puncture member.

[0009] In yet another embodiment, a device for minimizing dead leg space in a container or tube comprises a flange for attaching a first member to the wall of the container or tube, the flange having an opening; a main body connected to the flange, the main body having a passage in fluid communication with the opening in the flange; a connecting member connected to the main body for connecting a drain tube to the device; and a valve positioned in the passage, the valve being operable between a closed position in which fluid flow through the passage is prevented and an open position in which fluid flow through the passage is allowed.

[0010] The present invention will be better understood by reading the following description of non-limiting embodiments with reference to the attached drawings. [Brief explanation of the drawing]

[0011] [Figure 1] This is a front elevation view of a bioreactor system according to one embodiment of the present invention. [Figure 2]This is a perspective view of a device for minimizing dead leg space in a bioprocess system according to one embodiment of the present invention. [Figure 3] This is a cross-sectional perspective view of the upper member of the device shown in Figure 2. [Figure 4] Figure 2 is a cross-sectional perspective view of the lower member of the device. [Figure 5] This is a partially broken plan view of the apparatus in Figure 2, showing the closed position where fluid flow is prevented. [Figure 6] This is a partially fractured plan view of the apparatus in Figure 2, showing the open position where fluid flow is possible. [Figure 7] This is a perspective view of another apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention, showing an open position that allows fluid flow. [Figure 8] Figure 7 is a perspective view of the apparatus, showing the closed position where fluid flow is prevented. [Figure 9] This is a detailed enlarged view of area A in Figure 8. [Figure 10] This is a lateral cross-sectional view of the apparatus shown in Figure 7. [Figure 11] This is a perspective view of another apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 12] This is a lateral cross-sectional view of the device shown in Figure 11. [Figure 13] This is a perspective view of another apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 14] Figure 13 is a perspective view of the device, showing the closed position where fluid flow is prevented. [Figure 15] Figure 13 is a perspective view of the apparatus, showing the open position that allows fluid flow. [Figure 16] This is a lateral cross-sectional view of a device for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention, showing a closed position in which fluid flow is prevented. [Figure 17] This is a lateral cross-sectional view of the apparatus in Figure 16, showing the open position that allows fluid flow. [Figure 18] Side cross-sectional view of an apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention, showing a closed position where fluid flow is prevented. [Figure 19] Side cross-sectional view of the apparatus of FIG. 18, showing an open position where fluid flow is possible. [Figure 20] Enlarged cross-sectional view of the piercing tip of the apparatus of FIG. 18. [Figure 21] Perspective view of the spike member of the apparatus of FIG. 18. [Figure 22] Perspective view of a protective element for use with the apparatus of FIG. 18 according to one embodiment of the present invention. [Figure 23] Perspective view of a protective element for use with the apparatus of FIG. 18 according to another embodiment of the present invention. [Figure 24] Perspective view of an apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 25] Schematic view of a flexible bag of a bioprocess system using the apparatus of FIG. 24. [Figure 26] Schematic view of an apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 27] Enlarged detailed view of the sealing boundary of the apparatus of FIG. 26. [Figure 28] Schematic view of an apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 29] Perspective view of an apparatus for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 30] Cross-sectional view of the apparatus of FIG. 29. [Figure 31] Schematic view of an apparatus for minimizing dead leg space using a partition wall according to one embodiment of the present invention.. [Figure 32]This is a lateral cross-sectional view showing the closed position of a device for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 33] This is a lateral cross-sectional view of the device shown in Figure 32, indicating the open position. [Figure 34] This is a lateral cross-sectional view showing the closed position of a device for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Figure 35] This is a lateral cross-sectional view of the device shown in Figure 34, indicating the open position. [Figure 36] This is a cross-sectional perspective view of a device for minimizing dead leg space in a bioprocess system according to another embodiment of the present invention. [Modes for carrying out the invention]

[0012] The following describes exemplary embodiments of the present invention in detail. Examples of these embodiments are shown in the accompanying drawings. Wherever possible, the same reference numerals used across multiple drawings indicate the same or similar parts.

[0013] In this specification, the terms “flexible” or “collapsed” refer to structures or materials that are flexible, i.e., capable of bending without breaking, and further, materials that are compressible or expandable. An example of a flexible structure is a bag formed from polyethylene film. In this specification, the terms “rigid” and “semi-rigid” are used synonymously to describe structures that are “non-collapsed,” i.e., structures that do not bend, collapse, or otherwise deform to such an extent that their longitudinal dimensions are significantly reduced under normal forces. Depending on the context, “semi-rigid” may refer to structures that are more flexible than “rigid” elements, such as bendable tubes or conduits, but still do not collapse longitudinally under normal conditions and forces.

[0014] In this specification, “vessel” means, as it may be, a flexible bag, a flexible container, a semi-rigid container, a rigid container, or a flexible or semi-rigid tube. In this specification, the term “vessel” is intended to encompass bioreactor vessels having flexible or semi-rigid walls or part of walls, single-use flexible bags, and other containers or conduits commonly used in bioprocesses or biochemical processes, including, for example, cell culture / cell purification systems, mixing systems, medium / buffer preparation systems, and filtration / purification systems such as chromatography systems and tangential flow filter systems, as well as associated channels. In this specification, the term “bag” means a flexible or semi-rigid container or vessel used, for example, as a bioreactor or mixer for contents inside.

[0015] Embodiments of the present invention provide various devices for minimizing dead legs in the drain ports or drain line tubes of flexible single-use bioprocess bags, and / or achieving zero dead legs (prevention of dead leg formation) in the drain ports or drain line tubes of flexible single-use bioprocess bags. In this specification, the expression “minimizing dead legs” refers to the condition of reducing the dead leg volume of the drain port or drain line tube (i.e., the volume of the non-circulating portion of the tube or the volume of non-moving liquid in the container) compared to the dead leg volume without using the devices of the present invention (typically using clamps). While embodiments of the present invention are described in relation to flexible single-use bioprocess bags for use in the biopharmaceutical industry, the devices, systems, and methods for preventing or minimizing the formation of dead leg spaces described herein can be similarly and more generally used in containers, tubes, and vessels. In this specification, the terms “upper member” and “first member” are used synonymously to refer to the same component, and the same applies to the terms “lower member” and “second member.”

[0016] Referring to Figure 1, a bioreactor system 10 according to one embodiment of the present invention is illustrated. The bioreactor system 10 comprises a substantially rigid bioreactor vessel or support structure 12 mounted on top of a base 14 having a plurality of legs 16. The vessel 12 may be formed from, for example, stainless steel, polymer, composite material, glass, or other metal, and may have a cylindrical shape, but other shapes may also be used without departing from a broader embodiment of the present invention. The vessel 12 may include a lift assembly 18 that provides support to a single-use flexible bag 20 disposed within the vessel 12. The vessel 12 may include one or more viewing windows 22 that allow visual inspection of the fluid height in the flexible bag 20, and a window 24 positioned in the lower region of the vessel 12. The window 24 provides access to the interior of the vessel 12 for inserting and positioning various sensors and probes (not shown) into the flexible bag 20, and for connecting one or more fluid lines to the flexible bag 20 for adding fluids and gases, etc., to or withdrawing them from the flexible bag 20. The sensor / probe and control unit monitor and control important process parameters, including any one or more and combinations of temperature, pressure, pH, dissolved oxygen (DO), dissolved carbon dioxide (pCO2), mixing rate, and gas flow rate. The vessel 12 may also have an opening at its bottom, which allows a drain tube or discharge tube 26 to be connected to the flexible bag 20 by welding or other connectors for discharging and / or recovering the contents of the flexible bag 20.

[0017] In embodiments of the present invention, the drain outlet of the flexible bag 20 may be configured to have, or may include, a drain tube 26, associated connectors, and / or a device configured to minimize or prevent the formation of dead leg space in an adjacent area of ​​the flexible bag 20. Figures 2 to 6 show one possible configuration of a device 100 that can be integrated with the flexible bag 20 to prevent the formation of dead leg space in the flexible bag 20 and the discharge tube 26. As shown therein, the device 100 comprises a first upper member 110 and a second lower member 112 configured to be rotatably coupled to the upper member 110. Referring particularly to Figures 2 and 3, the upper member 110 comprises an annular flange 114 and a hollow stem 116 extending downward from the flange 114. The flange 114 has a plurality of apertures 118, each of which is spaced radially apart from the central axis 120 of the upper member 110, providing a passage for fluid to pass through the flange 114 and into the interior portion of the hollow stem 116, as will be discussed below. The distal end of the stem 116 also includes at least one projection or pin 121 extending outward from there, the purpose of which will be explained later.

[0018] As shown in Figure 4, the lower member 112 comprises a substantially tubular body portion 122 having a substantially closed upper end 124 and an open bottom end 126. Multiple apertures 128 are formed at the upper end, and these apertures 128 are spaced apart from the central axis 131 of the lower member 112 at radial distances corresponding to the distance at which the apertures 118 of the upper member 110 are spaced apart from the central axis 120. Furthermore, the angular spacing between the apertures 128 of the lower member 112 corresponds to the angular spacing between the apertures 118 of the upper member 110. As also shown in Figure 4, the body portion 122 comprises an outwardly spaced annular sleeve or side wall portion 130 that defines an annular slot 132 for receiving the stem 116 of the upper member 110. In this regard, the inner diameter of the sleeve 130 is approximately equal to the outer diameter of the stem 116, and the inner diameter of the stem 116 is approximately equal to the outer diameter of the main body portion 122. As suggested above and as shown in Figures 5 and 6, the lower member 112 is provided with a keyway 136 configured to receive a projection 121 of the upper member 110 in order to selectively lock the aperture in the open and / or closed positions. In one embodiment, the distal end 126 of the lower member 112 may be provided with a hose barb connector 134 (or TC connector) for connection to the drain tube 26, as shown in Figure 2.

[0019] Referring further to Figure 2, the flange 114 is sealed to the inner surface of the flexible bag 20 by welding or the like, but other mounting means may be used without departing from a broader embodiment of the present invention. The stem 116 of the upper member 110 is slidably and rotatably received in an annular slot 132 in the lower member 112. When in use, the flexible bag 20 of the integrated device 100 is positioned within the bioreactor vessel 12 such that the device 100 extends through the drain opening / aperture at the bottom of the vessel 12 and is connected to the drain tube / drain line 26, as shown in Figures 1 and 2.

[0020] Referring to Figures 5 and 6, the lower member 112 is rotatable relative to the upper member 110 to selectively align (or misalign) apertures 118, 128. Specifically, before filling the flexible bag 20 with the process medium and before initiating bioprocessing, the lower member 112 is rotated to a closed position, as shown in area A of Figure 5, such that aperture 128 in the lower member 112 is not aligned with aperture 118 in the upper member 110. This orientation prevents fluid flow from passing through the apparatus 100 and out of the flexible bag 20. By positioning the flange 114 of the upper member 110 substantially coplanar with the bottom of the flexible bag 20, dead leg spaces located below the bottom of the flexible bag 20, such as in the discharge tube 26, are prevented from forming or substantially minimized. After the process or at any desired time, the lower member 112 may be rotated relative to the upper member 110 so as shown in area B of Figure 6, aligning the aperture 118 in the upper member 110 with the aperture 128 in the lower member. This alignment allows the fluid to flow from the flexible bag 20 through the device 100 into the connected discharge tube / drain tube 26. In one embodiment, the projection 121 and keyway 136 are operable to lock the device 100 in this open position.

[0021] Therefore, the device 100 is selectively operable to prevent or allow fluid flow from the flexible bag 20 and into the drain tube 26. In the closed position, when the apertures are misaligned, the flange 114 and apertures 118, 128 are substantially coplanar with the bottom of the flexible bag 20, so that the fluid is prevented from passing through the flange 114 and remains outside the main volume of the flexible bag 20 (i.e., outside the controlled bioreactor environment), such as in the drain tube 26. In one embodiment, it is expected that the lower member 112 may be connected to a motor or other rotary drive mechanism 180, thereby enabling automatic control of the position of the device 100.

[0022] Figures 7 to 10 show another configuration of apparatus 200 that can be integrated with the flexible bag 20 to prevent or minimize the formation of dead leg space in the flexible bag 20 and discharge tube 26. As shown, apparatus 200 is substantially similar in configuration and operation to apparatus 100 in Figures 2 to 6 and comprises an upper member 210 and a lower member 212 rotatably coupled to the upper member 210. The upper member 210 has an annular flange 214, a short hollow stem 216 extending downward from the flange 214, and a pair of elastic arms 218 extending downward from the stem 216. In one embodiment, the elastic arms 218 are spaced about 180 degrees apart and comprise a projection 220 and the distal end of each projection 220 extending toward the centerline or central axis 222 of apparatus 200. As shown in Figure 7, at least one aperture 224 is formed in the flange 214, which provides a passage for fluid to pass through the flange 214 and into the interior portion of the hollow stem 216, as will be discussed below. In one embodiment, the aperture 224 has a semicircular shape, but other shapes can also be used without departing from a broader aspect of the present invention.

[0023] Referring further to Figure 7, the lower member 212 comprises a substantially hollow tubular body portion 226 having an upper end 227 on which an aperture 228 is formed and a substantially open bottom end 230. In one embodiment, the aperture 228 has a semicircular shape, similar to the aperture 224, but other shapes are also possible. As shown in Figures 7 and 9, the body portion 226 of the lower member 212 further comprises a circumferential groove 232 defining a shoulder 234. The circumferential groove 232 is interrupted by at least one position stopper 236, the purpose of which will be explained later. Referring to Figure 10, the upper portion of the lower member 212 may further comprise a sealing element 238 disposed within the circumferential groove 240. In one embodiment, the distal end 230 of the lower member 212 may comprise a hose barb connector 242 for connection to a drain tube (not shown).

[0024] As best shown in Figure 10, the flange 214 of the upper member 210 is sealed to the inner surface of the flexible bag 20 by welding or the like, but other mounting means may also be used without departing from a broader embodiment of the present invention. The lower member 212 is received within the hollow stem 216 of the upper member 210 such that the O-ring 238 seals with the inner surface of the stem 216, preventing fluid from passing between the O-ring 238 and the stem 216. Once the lower member 212 is fully received within the stem 216, the elastic arm 218 of the upper member 210 is received within the circumferential groove 232 of the body portion 226 of the lower member 212. In this position, the projection 220 located at the end of the elastic arm 218 contacts the shoulder 234, preventing the upper member 210 and the lower member 212 from being disconnected from each other. In one embodiment, the device 200 may include a D-shaped O-ring (not shown) (or another shape configured to correspond to the shapes of apertures 224, 228), which, by being positioned between apertures 224, 228, provides a fluid seal between the rotating elements that prevents fluid leakage when in the closed position, as will be discussed below.

[0025] When in use, the flexible bag 20, having an integrated device 200, is positioned within the bioreactor vessel 12 such that the device 200 extends through a drain opening / drain aperture in the bottom of the vessel 12 and connects to a drain tube / drain line 26. Referring again to Figures 7 and 8, the lower member 212 is rotatable relative to the upper member 210 to selectively align (or misalign) the apertures 224, 228. Specifically, before filling the flexible bag 20 with the process medium and before starting bioprocessing, as shown in Figure 8, the lower member 212 is rotated to a closed position such that the aperture 228 of the lower member is not aligned with the aperture 224 of the flange 214. In this position, the closed upper surface 227 of the lower member 212 is located below the aperture 224. This orientation prevents fluid flow from passing through the device 200 and out of the flexible bag 20. The flange 214 of the upper member 210 is positioned substantially coplanar with the bottom of the flexible bag 20, thereby preventing the formation of dead leg space located below the bottom of the flexible bag 20, such as in the discharge tube 26, or substantially minimizing such dead leg space. After the process or at any desired time, the lower member 212 can be rotated relative to the upper member 210 in the direction of arrow B so that the apertures 224, 228 are aligned perpendicularly to each other. This vertical alignment allows the fluid to flow from the flexible bag 20 through the apparatus 200 into the connected discharge / drain tube 26. The position stopper 236 functions to prevent excessive rotation of the lower member 212, positioning the device 200 in the closed position when the lower member 212 is rotated in one direction until the projection 220 contacts the position stopper 236, and in the open position where the apertures 224 and 228 are aligned when the lower member 212 is rotated in the opposite direction until the projection 220 contacts the opposite position stopper 236. In this regard, the position stopper 236 provides tactile indication of the fully open and fully closed positions of the device 200.

[0026] Therefore, the device 200 is selectively operable to prevent or allow fluid flow from the flexible bag 20 and into the drain tube 26. In the closed position, where the apertures are misaligned, the flange 214 and apertures 224, 228 are substantially coplanar with the bottom of the flexible bag 20, so that the fluid is prevented from passing through the flange 214 and remains outside the main volume of the flexible bag 20, such as in the drain tube 26. As discussed above, in one embodiment, it is expected that the lower member 212 may be connected to a motor or other rotary drive mechanism, thereby enabling automatic control of the position of the device 200. Furthermore, in one embodiment, the device 200 may be provided with a locking mechanism for selectively locking the device 200 in the open or closed position as desired.

[0027] Figures 11 and 12 show another device 300 that can be integrated with the flexible bag 20 to prevent or minimize the formation of dead leg space in the flexible bag 20 and discharge tube 26. This device 300 is substantially similar in configuration and operation to the device 200 in Figures 7–10, and similar reference figures indicate similar parts. However, as shown in Figure 12, instead of using an elastic arm received in a circumferential slot to guide the rotation of the lower member relative to the upper member, the device 300 uses a tapered threaded portion 310 (having either a female or male thread) on the outer surface of the upper portion of the lower member 212. This tapered threaded portion 310 is configured to be screwed by a corresponding tapered threaded portion 312 (having the other either a male or female thread) on the inner surface of the stem 216 of the upper member 210. In this regard, the upper member 210 and the lower member 212 of the device 300 are screw-and-rotatably coupled to each other. During use, the user can rotate the lower member 212 to selectively align (or misalign) the aperture 228 of the lower member 212 with the aperture 224 of the upper member 210 to facilitate or prevent discharge from the bag 20 as desired. In one embodiment, the device 300 may include a D-shaped O-ring (not shown) (or other shapes configured to correspond to the shapes of the apertures 224, 228), which, by being positioned between the apertures 224, 228, provides a fluid seal between the rotating elements that prevents fluid leakage when in the closed position, as discussed below.

[0028] Similar to devices 100 and 200, it is also expected that automatic control of the position of device 300 will be possible by connecting the lower member 212 to a motor or other rotary drive mechanism.

[0029] Referring next to Figures 13-15, yet another apparatus 400 for preventing the formation of dead leg space in a bioprocess system is shown. The apparatus 400 comprises an upper member 410, which has a substantially annular flange 412 and a hollow tube or sleeve 414 extending downward and substantially vertically from the flange 412. The upper member 410 further comprises a Y-shaped leg or branching tube 416 extending downward at an angle from the sleeve 414. In one embodiment, the branching tube 416 may be a T-shaped leg. As shown in Figure 13, a drain line or drain tube 26 may be connected to the end of the branching tube 416 using a clamp 418, but other connecting means such as a hose barb on the distal end of the branching tube 416 may be used without departing from a broader aspect of the invention. In one embodiment, the sleeve 414 may be configured to have a radial projection or lug 428, the purpose of which will be discussed later.

[0030] Referring further to Figures 13 to 15, the apparatus 400 further comprises a plunger 422 that passes through the opening bottom end and is slidably received by a sleeve 414. The plunger 422 has a lower end that terminates with a T-shaped handle 424 for ergonomically efficient gripping, and an upper end that has a plunger tip 426 having an integral sealing element that seals tightly to the inner wall of the sleeve 414. The body of the plunger is configured to have a relief portion, a longitudinal groove portion, or a diameter smaller than the tip 426 to allow fluid flow to pass over the tip, as will be discussed later. As best shown in Figures 14 and 15, the plunger 422 further comprises a keyway 420 configured to receive a lug 428 on the sleeve 414. As shown in Figures 14 and 15, the keyway 420 may be substantially L-shaped.

[0031] During use, the flange 412 is attached to the inner surface of the flexible bag 20 by welding or the like, but other mounting means can also be used without departing from a broader embodiment of the present invention. Next, the drain tube 26 is fixed to the branch leg 416, and the plunger 422 is received in the sleeve 414 such that the lug 428 is positioned within the keyway 420. As shown in Figure 14, in the closed position, the tip of the plunger is seated within the sleeve 414 and substantially below the flange 412 to prevent fluid flow from flowing over the flange 412 to the outside of the flexible bag 20. In this position, the lug 428 is received within the uppermost part of the keyway 420. Referring to Figures 13 and 15, when discharge from the bag 20 is desired, the plunger 422 is biased upward in the direction of arrow A and protrudes above the flange 412, so that the fluid can flow over the tip 426 into the sleeve 414, through the branch leg 416, and into the drain tube 26. When the plunger is pushed upward to the open position, it rotates further in the direction of arrow B, positioning the lug 428 within the lower portion / leg of the keyway 420 as shown in Figure 15. Essentially, this locks the plunger 422 in the open position, thereby preventing it from moving upward or downward relative to the sleeve 414.

[0032] Figures 13 to 15 show one embodiment in which the plunger is biased upward, thereby breaking the seal between the plunger tip 426 and the inside of the sleeve 414, allowing the fluid to be discharged from the bag 20. In other embodiments, the apparatus 400 may be configured such that the plunger can be pulled back down the branch tube 416, allowing the contents of the bag 20 to be discharged into the branch leg 416 and the connected drain tube 26. Furthermore, as suggested above, in one embodiment, the plunger may be connected to an actuator 480 or a motor to enable automatic operation of the apparatus 400. As discussed above in relation to the embodiments described above, the apparatus 400 does not form any cavities below the bottom of the flexible bag 20 in which fluid could accumulate. In this respect, the apparatus 400 of the present invention prevents the formation of dead leg spaces that could adversely affect the batch being processed.

[0033] Figures 16 and 17 show a device 500 according to another embodiment of the present invention, which can be integrated with the flexible bag 20, for preventing or minimizing the formation of dead leg space in the flexible bag 20 and discharge tube 26. Device 500 is substantially similar in configuration and operation to device 400 in Figures 13 to 15. Specifically, device 500 comprises an upper member 510 having a flange 512 configured to be mounted on the flexible bag 20 in the manner described above, and a substantially cylindrical, hollow slit 514 extending downward from the flange 512, the sleeve having an open top end 516 and an open bottom end 518. Device 500 also comprises a plunger 520 that is slidably received through the open bottom end 518 into the sleeve hollow tube or sleeve 514. The plunger 520 has a substantially hollow cylindrical first portion 522, a longitudinally grooved second portion 524 extending from the first portion 522, and a conical tip portion 526 connected to the second portion 524. The tip portion 526 is sized to form a liquid-tight seal with the inner sidewall of the sleeve 514 when the tip portion is received by the sleeve 514, as shown in Figure 16. In one embodiment, the tip portion 526 may be covered with or formed with silicone. Also as shown in Figure 16, the cylindrical portion 522 of the plunger 520 includes one or more sealing elements 528, such as an O-ring, which together with the sleeve 514 similarly form a liquid-tight seal. The distal end of the plunger 520 may be formed with a hose barb connector portion 530 for connecting a drain tube 26.

[0034] Referring further to Figure 16, in the closed position, the tip 526 is retracted into the sleeve 514, forming a seal with the sleeve 514 to prevent the passage of fluid from the bag 20. Referring to Figure 17, when discharge of the bag 20 is desired, the plunger is biased upward along the travel path B in the direction of arrow A, thereby disseating the tip 526 from the sleeve 514. In this position, the fluid can pass through the tip, through the longitudinally grooved portion 524 of the plunger, through the hollow cylindrical portion 522, and into the installed drain tube 26. In this way, the device 500 operates substantially the same as the device 400 in Figures 13 to 15.

[0035] Referring next to Figures 18 to 21, another device 600 for preventing the formation of dead leg space in a bioprocess system is shown. This device 600 has a substantially annular flange 610 configured to be connected to or integrated with a flexible bag 20, and a connector 612 mounted on or integrally formed with the annular flange 610. In one embodiment, the connector 612 is a sterile connector having a first connector member 614 and a second connector member 616, which are joined to each other in a paired manner, forming a puncturable or cleavable seal or partition 618 between them. In one embodiment, the connector 612 is a ReadyMate® disposable sterile connector manufactured by General Electric®. As shown in Figures 18 and 19, the second connector member 616 is connected to or integrally formed with a hollow cylindrical tube or sleeve 620 extending downward from there. The distal end of the sleeve 620 is provided with a flange that forms the handle grip 622. The connector 612 is illustrated as a two-piece component with a seal in between, but in one embodiment it may be a single component having a sealing element that allows fluid isolation between the inside of the flexible bag 20 and the sleeve 620.

[0036] Furthermore, as shown in Figures 18 and 19, the device 600 further comprises a hollow spike 624 slidably received within the sleeve 620. As shown in Figure 21, the terminal end of the spike 624 has a pointed canoe-shaped tip 626 for puncturing the seal 618, as will be discussed later. In one embodiment, the tip 626 may have any pointed shape suitable for puncturing thin films. The opposing distal end of the spike 624 has a hose barb connector 628 for connecting the drain tube 26. In one embodiment, the spike 624 may further comprise a complementary flange forming a second handle grip 630.

[0037] Referring particularly to Figure 18, when in use, the device 600 is connected to the flexible bioprocess bag 20 via the annular flange 610 in the manner described above. The hollow spike 624 is slidably received within the sleeve 620 such that its tip 626 is positioned below the sealing element 618 of the connector 612. As shown in Figure 18, in one embodiment, a removable clamp 632 can be positioned above the sleeve 620 and spike 624 midway between the flanges 622, 630 to prevent unintended operation (i.e., unintended puncture of the sealing element 618). In this state, the sealing element 618 is positioned substantially coplanar with the bottom of the flexible bag 20 so that the fluid in the bag 20 cannot enter any cavities or tubes outside the process volume of the bag 20. Thus, dead leg spaces where stagnation could occur are substantially eliminated. The drain tube 26 can be connected to the hose barb connector 628 on the distal end of the spike 624 at any point immediately before discharge, or at any point before discharge after the bag 20 has been positioned in the vessel 12. If it is desired to discharge the contents from the bag 20, the clamp 632 can be removed and the hollow spike 624 can be biased upward into the bag. This movement of the spike 624 functions to puncture the sealing element 618, thereby creating a path for the fluid to exit the flexible bag 20 by allowing the tip 626 of the spike 624 to enter the flexible bag 20 as shown in Figure 19. Specifically, the fluid can flow into the hollow spike 624 and out through its distal end into the connected drain tube 26.

[0038] In one embodiment, the apparatus 600 shown in Figures 18 to 21 may further utilize a device configured to protect the integrity of the flexible bag 20 during the discharge operation, including during puncture by the spike 624 and during the discharge process. For example, as shown in Figures 22 and 23, protective elements 640, 650 may be positioned inside 644 of the flexible bag 20. In some cases, the protective elements 640, 650 may comprise a flange 646 configured to operatively attach to or integrate with the inner wall of the flexible bag 20, and an upright cage element 648 with a plurality of apertures 652 or slots 654 formed therein. In one embodiment, the flange 646 may be the same flange as the flange 610 of the apparatus 600 or a different flange. The cage 648 functions to protect the flexible bag 20 from puncture when the spike is biased to penetrate the sealing element during discharge, and prevents contact between the sharp tip of the spike and the bag 20 by surrounding the spike as it protrudes into the bag 20. In one embodiment, a variety of hole or slot patterns may be used within the cage 648 to provide optimal fluid flow. In one embodiment, the protective elements 640, 650 may further include caps (not shown) to prevent any torn pieces of the bag 20 (which may result from a puncture) from becoming loose inside the bag 20.

[0039] Figures 24 and 25 show another apparatus 700 that is substantially similar in configuration and operation to the apparatus 600 described above and functions to minimize dead leg space in a bioreactor or bioprocess system. As shown herein, the apparatus 700 comprises a port element 710 having a flange 712 and a hollow cylindrical stem 714 hanging from the flange 712. Similar to the embodiments described above, the flange 712 is configured to connect to a flexible bag 20 so that the stem 714 forms a passage for fluid to exit the bag 20. As shown in Figure 24, the port element 710 comprises a punctureable or cleavable membrane 716 and a flexible partition wall 718. Figure 24 shows the membrane 716 located adjacent to the flange 712, but the membrane 716 may be located within the stem 714 to minimize the possibility of unintentional puncture. In one embodiment, and with reference to Figure 25, the port element 714 may be integrated with the flexible bag 20 at any position where discharge or sampling is desired, thereby forming a plurality of accessible ports 720.

[0040] Referring again to Figure 24, the apparatus 700 may further include a spike 730 for puncturing the membrane 716 when access to the contents of the bag 20 is desired, such as for discharge or sampling. In one embodiment, the spike 730 may be substantially similar to the spike 624 in Figures 18-21 and comprises a sharp tip 732, a flange 734 for gripping, and a hose barb connector 736 for selectively connecting a tube for discharge or other processes.

[0041] During operation, the flexible bag 20 may be manufactured having multiple ports composed of port elements 710. Access to the contents of the bag 20 is achieved by inserting a hollow spike 730 into the stem 714 to puncture the membrane 716. When the spike is forced into the bag 20, the partition wall 718 forms a seal along the outer circumference of the spike 730 to prevent leakage. At this position, the fluid can flow into the spike 730 and out of the connected tube. In yet another embodiment, the partition wall functions as an auto-sealing element, in which case the spike 730 is pushed into the bag 20 for discharge or sampling, and when the spike 730 is pulled back or removed, the partition wall functions to close the opening and prevent fluid leakage.

[0042] Referring next to Figure 26, in one embodiment, the port element 710 may be used in combination with a protective element 760 positioned inside 762 of the flexible bag 20. In one embodiment, the protective element 760 may take the form of the protective element 640 or 650 shown in Figures 22 and 23 and described above. As previously stated herein, the protective element 760 functions to prevent accidental puncture or tearing of the flexible bag when the spike 730 is biased into the bag 20 during discharge. In embodiments in which the device includes the protective element 760, as shown in Figure 26, the membrane 716 may be sandwiched between the flange of the port element and the flange of the protective element. This configuration is shown more clearly in Figure 27. As shown in Figures 26 and 27, in one embodiment, the spike 730 itself may include a plurality of apertures 764 for allowing fluid to pass through. Specifically, the spike 730 may have multiple apertures 764 that are in close relation to the aperture 766 in the protective element 760 when it is pressed into the flexible bag 20. This configuration facilitates fluid flow when the volume inside the bag is low.

[0043] Referring to Figure 28, in one embodiment, the spike 730 may be incorporated into the port element 710 as a sterile connector. As shown, the spike 730 and port connector are substantially the same as those in the apparatus 700 described above, except that the apparatus 700 further includes a sterile coupling mechanism 770. In any of the embodiments described above in relation to Figures 24 to 28, it is expected that the spike 730 may be coupled to an actuator to facilitate the automated puncture and entry of the membrane into the bag.

[0044] Finally, referring to Figures 29 to 31, yet another device 800 for minimizing or preventing the formation of dead leg space in a bioprocess system is shown. The device 800 comprises a flange 810 and a substantially spherical body 812 operably coupled to the flange. The flange 810 has an opening 814 in fluid communication with a fluid passage 816 extending through the main body portion 812. The main body further comprises a valve 818 positioned within the fluid passage 816 and an actuator handle or lever 820 rotatable to selectively open and close the valve 818. In one embodiment, the valve 818 and lever 820 form a stopcock. As shown in Figures 29 and 30, the lower end of the main body 812 may have a hose barb connector 822 for connecting a drain tube 26 in the manner described above.

[0045] During use, the device 800 may be operationally coupled to the flexible bag 20 via the flange 810 in the manner described above. The user can then rotate the lever 820 to selectively open and close the valve 818, thereby allowing or preventing fluid flow from the bag 20. The device 800 is expected to be used throughout a bioprocess system in which the drain valve may be opened and closed multiple times. Furthermore, the reversible nature of the device 800 facilitates its use for both discharge and supply operations. In one embodiment, the lever 820 is expected to be coupled to an actuator to facilitate the automatic operation of the valve 818.

[0046] It is expected that any possible dead leg volume can be further minimized by incorporating the partition into the design of any of the devices described herein, such as device 800. Figure 31 shows the location of partition 830, which may be integrated with one or more of the embodiments described herein.

[0047] Referring next to Figures 32 and 33, another device 900 for preventing the formation of dead leg space in the bioprocess system is shown. The device 900 has a substantially annular flange 910 configured to be connected to or integrated with the flexible bag 20 by welding or the like, as discussed above. The annular flange 910 has a hanging leg portion that defines a substantially cylindrical hollow outer sleeve 912. A hollow inner sleeve 914 is slidably received within the outer sleeve 912. The inner sleeve 914 may include a gasket 916, which is configured to prevent fluid flow through the outer sleeve 912 by sealingly engaging with the inner wall of the outer sleeve 912. As shown in Figure 32, the inner sleeve 914 further includes a thin film 918, which extends across the top opening of the inner sleeve 914 to prevent fluid flow from the bag 20 into the inner sleeve 914. The device 900 further comprises a hollow spike 920 or puncture member that is stationary below the membrane 918 within the inner sleeve 914.

[0048] During operation, the lower portion of the inner sleeve 914 is gripped and pulled downward in the direction of arrow A to discharge from the bag 20. This action causes the gasket 916 to slide along the inner surface of the outer sleeve 912. As the inner sleeve 914 is further biased downward, the membrane 918 comes into contact with the sharp tip of the spike 920, thereby causing the spike to penetrate the membrane 918 as shown in Figure 33. At this position, the fluid in the bag can flow through the rupture in the membrane 918 and through the spike 920 to discharge the contents of the bag 20.

[0049] Referring to Figures 34 and 35, another device 1000 for preventing the formation of dead leg space in a bioprocess system is shown. This device 1000 is configured to be positioned within a drain port 1010 of a flexible process bag 20. In one embodiment, the drain port may be configured to have an annular flange, which is welded to the bag 20 and has a cylindrical outlet opening for draining the contents of the bag, as described above. The device 1000 comprises a compressible gasket 1012 (half of which is shown in Figures 34 and 35) positioned within the drain port 1010, and a clave device / clave needle 1014 received within a central passage 1016 of the gasket 1012. As shown herein, the clave needle 1014 comprises a fluid opening 1018 located at its top and a central fluid passage 1020 extending from the opening 1018 through the needle 1014.

[0050] As shown in Figure 34, in the closed position, the opening 1018 is positioned below the bottom surface of the bag 20 (and / or the top surface of the gasket 1012), so that fluid cannot flow into the opening 1018. Referring to Figure 35, in order to discharge from the bag 20, the clave needle 1014 is biased upward in the direction of arrow A until the contents can be discharged through the opening 1018 and the fluid passage 1020, by making the opening 1018 fluidly connected to the inside of the bag 20. As shown herein, when the gasket 1012 is compressed by the upward movement of the clave needle 1014, the outer portion of the gasket is reduced by a distance d due to the tapered configuration of the outer surface of the clave needle 1014.

[0051] Finally, referring to Figure 36, another device 1100 for preventing the formation of dead leg space in the bioprocess system is shown. The device 1100 is configured to be positioned within the drain port 1110 of the flexible process bag 20. In one embodiment, the drain port 1110 may be configured to have an annular flange, which is welded to the bag 20 and has a cylindrical outlet opening for discharging the contents of the bag, as described above. The device 1100 is substantially the same as the embodiments shown in Figures 18 and 19 and comprises a syringe assembly 1112 connected to the bag port 1110 via a first pair connector 1114 and a second pair connector 1116. The syringe assembly 1112 comprises a hollow plunger 1118, the lower end of which is configured to be connected to a drain tube 1120. Similar to the embodiments described above, the plunger 1118 is slidable upward into the bag 20 to allow fluid communication between the opening in the plunger 1118 and the interior of the bag 20. As shown in Figure 36, the sealing element 1122 may form a fluid seal together with the interior of the port 1110. The device 1100 may also include a locking mechanism 1124 (e.g., a latch or L-lock mechanism) and a safety device 1126 that prevents the plunger 1118 from moving upward until it is removed. The device 1100 may further include a cage element 1128 to protect the bag 20 from puncture when the plunger 1118 is biased upward into the bag.

[0052] As described herein, the embodiments of the invention described herein can be used to prevent or substantially minimize the formation of dead leg spaces in bioprocess systems, and specifically in drain tubes, associated connectors, or components of a bioreactor drain system. By minimizing dead leg spaces, media, cells, and other fluid components are prevented from remaining in areas where they can be isolated from the main bioreactor environment, thereby minimizing the possibility of cells being deprived of nutrients and dying. Thus, by minimizing these dead leg spaces, maximum production can be achieved and precipitation is reduced.

[0053] In one embodiment, a device for minimizing dead leg space in a container or tube comprises a first member having a flange for mounting the first member to the wall of a container or tube, the flange having at least one aperture. The device further comprises a second member rotatably coupled to the first member, the second member having an upper end having at least one aperture and an open distal end. The second member is rotatable with respect to the first member between a closed position in which the passage of fluid is prevented by at least one aperture of the second member being misaligned with at least one aperture in the flange, and an open position in which the passage of fluid is enabled by at least one aperture of the second member being aligned with at least one aperture in the flange. In one embodiment, the at least one aperture in the flange is a plurality of apertures radially offset from the centerline of the flange, and the at least one aperture in the upper end of the second member is a plurality of apertures corresponding to the plurality of apertures of the flange. Multiple apertures in the upper end of the second member are located in radial and angular positions corresponding to the radial and angular positions of multiple apertures of the flange. In one embodiment, the first member may include either a keyway or a projection, and the second member may include the other, the keyway and projection being operable to selectively lock the second member in the open position. In one embodiment, the first member includes a pair of elastic arms, and the second member includes a circumferential groove, the elastic arms engaging with the circumferential groove to facilitate rotation of the second member between an open position and a closed position. In one embodiment, the circumferential groove includes at least one position stopper, which restricts the rotation of the second member relative to the first member. In one embodiment, the at least one position stopper is positioned such that rotation of the second member to a position where one of the elastic arms contacts the position stopper corresponds to the open position of the device.In one embodiment, the first member has a first threaded portion, and the second member has a second threaded portion, which is configured to screw onto the first threaded portion so that the second threaded portion can rotate relative to the first threaded portion. In one embodiment, the distal end of the second member is provided with a hose barb connector for connecting a drain tube to the device. In one embodiment, the container or tube is a flexible single-use bioprocess bag.

[0054] In another embodiment, a device for minimizing dead leg space in a container or tube comprises a first member having a flange for mounting the first member to the wall of the container or tube and a substantially hollow sleeve extending from the flange, and a plunger slidably received within the hollow sleeve, the plunger having a tip configured to engage sealably with the first member. The plunger is slidable between a closed position in which the tip engages sealably with the sleeve adjacent to the flange to prevent the passage of fluid into the sleeve, and an open position in which the plunger is linearly displaced from the closed position to allow the passage of fluid into the sleeve. In one embodiment, the plunger is provided with at least one relief area or passage below the tip to allow the passage of fluid. In one embodiment, the first member further comprises a branching leg extending from the sleeve, the branching leg terminated with a hose barb connector for connecting a drain tube. In one embodiment, the plunger comprises one of an L-shaped keyway and lug, and the sleeve comprises the other of the keyway and lug, and the plunger is rotatable and linearly movable relative to the sleeve such that the plunger is in a closed position when the lug is received in the upper portion of the keyway, and the plunger is locked in an open position when the lug is received in the lower portion of the keyway. In one embodiment, the plunger comprises a handle at the distal end of the plunger. In one embodiment, the container or tube is a flexible single-use bioprocess bag.

[0055] In yet another embodiment, a device for minimizing dead leg space in a container or tube comprises a first member having a flange for mounting the first member to the wall of the container or tube, a substantially hollow sleeve extending from the flange, and a sealing element extending across the sleeve to seal a passage through the sleeve. Furthermore, the device comprises a substantially hollow puncture member slidably received within the hollow sleeve, the puncture member having a puncture tip. The puncture member is movable between a first position in which the puncture tip is positioned below the sealing element, thereby preventing the passage of fluid beyond the sealing element by keeping the sealing element intact, and a second position in which the puncture member punctures the sealing element, the puncture tip extends into the container or tube, and the interior of the puncture member becomes fluidly connected to the interior of the container or tube, thereby allowing the passage of fluid into and beyond the hollow puncture member. In one embodiment, the sealing element forms part of a sterile connector integrated with the first member. In one embodiment, the device further comprises a protective element positioned inside a container or tube, the protective element having a side wall surrounding an opening in a flange to prevent contact of the puncture tip with the container or tube, the side wall comprising a plurality of slots or apertures for fluid passage. In one embodiment, the puncture member comprises a hose barb connector at the distal end of the puncture member for connecting a drain tube to the device.

[0056] In yet another embodiment, a device for minimizing dead leg space in a container or tube comprises a flange for mounting a first member to the wall of the container or tube, the flange having an opening. Furthermore, the device comprises a main body connected to the flange, the main body having a passage in fluid communication with the opening in the flange. Furthermore, the device comprises a connecting member connected to the main body for connecting a drain tube to the device, and a valve positioned within the passage. The valve is operable between a closed position, which prevents fluid flow through the passage, and an open position, which allows fluid flow through the passage.

[0057] In yet another embodiment, a bioprocess system is provided. This system comprises a single-use flexible bioreactor bag having a drain opening or outlet port, and a device or apparatus positioned within the drain opening and mounted on the flexible bag for minimizing dead leg space in the flexible bioreactor bag and / or associated drain tube and / or components. This apparatus may be any of the apparatuses described above in relation to Figures 2 to 31. The bioreactor bag having this apparatus can be appropriately supplied after being pre-sterilized, for example, by radiation sterilization, which typically involves exposure to gamma radiation under conditions well known in the art.

[0058] In yet another embodiment, a method is provided for minimizing dead leg space in a container or tube of a bioprocess system. This method includes the steps of positioning a flexible single-use bioreactor bag within a support vessel, wherein the flexible bioprocess bag comprises a device configured to minimize dead leg space, positioned within an outlet port or drain opening in the flexible bag, and connecting a drain tube to this device. This device may be any of the devices described above in relation to Figures 2 to 31. The method also further includes the step of operating the device to place the inside of the flexible bag in fluid communication with the drain tube so that fluid from the flexible bag can flow through the device into the drain tube.

[0059] In this specification, any element or step mentioned singularly and preceded by the word “a, an” should be understood not to exclude multiple such elements or steps unless such exclusion is explicitly stated. Furthermore, any reference to “one embodiment” of the present invention should not be construed as excluding the existence of further embodiments incorporating the listed features in a similar manner. Moreover, unless explicitly stated otherwise, an embodiment “equipped,” “included,” or “having” one or more elements having a particular characteristic may encompass further such elements that do not possess that characteristic.

[0060] The detailed description of this invention discloses several embodiments of the invention, including the best embodiment, and further uses examples that enable a person skilled in the art to carry out embodiments of the invention, including the fabrication and use of any device or system and the implementation of any incorporated method. The patentability of the invention is defined by the claims and may include other examples that a person skilled in the art can conceive. Such other examples are intended to be included within the claims if they have structural elements that do not depart from the language of the claims, or if they have equivalent structural elements that do not substantially differ from the language of the claims. [Explanation of symbols]

[0061] 10 Bioreactor Systems 12. Approximately rigid bioreactor vessel, support structure 14 Base 16 Legs 18 Lift Assembly 20 Single-use flexible bags, flexible process bags, flexible bioprocess bags 22 peepholes 24 windows 26 Drain tubes, discharge tubes, drain lines 28 Hose barb connection 100 devices 110 First upper member 112 Second lower member 114 Annular flange 116 Hollow Stem 118 Aperture 120 center axis 121 Protrusion, pin 122. A roughly tubular main body 124 The upper end is partially closed. 126 Open bottom end, distal end 128 Aperture 130 Annular sleeve, side wall 131 Central axis 132 ring slots 134 Hose barb connection 136 keyways 180 Motor or other rotary drive mechanism 200 equipment 210 Upper member 212 Lower member 214 Annular flange 216 Hollow Stem 218 Elastic Arm 220 Protrusion 222 Center line, center axis 224 Aperture 226. A roughly hollow tubular body portion. 227 Upper end, upper surface 228 Aperture 230 Circumferentially open bottom end, distal end 232 Circumferential groove 234 Shoulder 236 Position Stopper 238 Sealing elements, O-rings 240 Circumferential groove 242 Hose barb connection 300 equipment 310 Tapered thread portion 312 Tapered thread portion 400 equipment 410 Upper member 412 Flange 414 sleeves 416 Y-shaped leg, branched tube, branched leg 418 Clamp 420 keyways 422 Plunger 424 T-shaped handle 426 Plunger tip 428 rugs 480 Actuators 500 devices 510 Upper member 512 Flange 514 A roughly cylindrical and hollow slit, sleeve hollow tube, sleeve 516 Opening top end 518 Open bottom end 520 plunger 522 Part 1 522 Cylindrical section 522 Hollow cylindrical portion 524 Second section, section with vertical grooves 526 Conical tip 528 sealing element 530 Hose barb connection 600 equipment 610 Annular flange 612 connector 614 First connector member 616 Second connector member 618 Punctureable or cleavable seal or partition, sealing element 620 Hollow cylindrical tube, sleeve 622 Handle grips, flange 624 Hollow Spikes 626 Sharp canoe-shaped tip 628 Hose barb connection 630 Second handle grip, flange 632 Removable Clamp 640 protective elements 644 Internal 646 Flange 648 Erect cage elements 650 protective elements 652 Aperture 654 slots 700 equipment 710 Port Element 712 Flange 714 Hollow cylindrical stem, port element 716 Membrane 718 Flexible Bulkhead 720 Accessible Ports 730 Spikes 732 Sharp tip 734 Flange 736 Hose barb connection 760 protective elements 762 Internal 764 Aperture 766 Aperture 770 Sterile Connection Mechanism 800 equipment 810 flange 812 Main body part 814 Aperture 816 Fluid flow path 818 valve 820 Actuator handle, lever 822 Hose barb connection 830 Bulkhead 900 equipment 910 Approximately annular flange 912 A roughly cylindrical hollow outer sleeve 914 Hollow Inner Sleeve 916 Gasket 918 Thin film 920 Hollow Spikes 1000 devices 1010 Drain Port 1012 Compressible Gasket 1014. Clever device, clever needle 1016 Central aisle 1018 Aperture 1018 Fluid opening 1020 Central fluid passage 1100 equipment 1110 Drain port, bag port 1112 Syringe Assembly 1114 First paired connector 1116 Second paired connector 1118 Hollow plunger 1120 Drain tube 1122 Seal elements 1124 Locking mechanism 1126 Safety Devices 1128 Cage elements

Claims

1. A device for minimizing dead leg space in a container or tube, A first member comprising a flange for attaching the first member to the wall of the container or tube and a substantially hollow sleeve extending from the flange, A plunger slidably received within the substantially hollow sleeve, having a tip portion configured to engage sealably with the first member. Equipped with, The plunger is slidable between a closed position in which its tip engages in a sealed manner with the sleeve adjacent to the flange, preventing fluid from passing into the sleeve, and an open position in which the plunger is linearly displaced from the closed position, allowing fluid to pass into the sleeve. The plunger comprises either an L-shaped keyway or a lug, The sleeve comprises the other of the L-shaped keyway and the lug, The plunger is rotatable and linearly movable relative to the sleeve such that the plunger is in the closed position when the lug is received in the upper portion of the L-shaped keyway, and the plunger is locked in the open position when the lug is received in the lower portion of the L-shaped keyway. The first member further comprises a branching leg extending from the substantially hollow sleeve, the branching leg being terminated with a hose barb connector for connecting a drain tube. The device wherein the branched leg opens into the space within the substantially hollow sleeve.

2. The apparatus according to claim 1, wherein the plunger is provided with at least one relief-processed area or passage below the tip portion that allows fluid to pass through.

3. The apparatus according to claim 1 or 2, wherein the plunger is provided with a handle at its distal end.

4. The apparatus according to any one of claims 1 to 3, wherein the container or tube is a flexible single-use bioprocess bag.

5. A flexible single-use bioreactor bag comprising the apparatus according to any one of claims 1 to 4.

6. A flexible single-use bioreactor bag according to claim 5, which is pre-sterilized by radiation sterilization or the like.

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