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

Abstract

A device for minimizing dead space in a container or pipe includes a first component and a second component, the first component having a flange for attaching the first component to a wall of the container or pipe, the flange having at least one orifice, the second component rotatably coupled to the first component, the second component having an upper end and an open distal end, the upper end having at least one orifice. The second component is rotatable relative to the first component between a closed position and an open position, in which the at least one orifice of the second component is not aligned with at least one orifice in the flange to prevent fluid from passing through, and in which the at least one orifice of the second component is aligned with at least one orifice in the flange to allow fluid to pass through.

Description

Technical Field

[0001] Embodiments of the present invention relate generally to bioprocessing systems and methods, and more particularly, to apparatus for minimizing or preventing dead leg spaces in bioprocessing systems. Background Art

[0002] In the biopharmaceutical industry, single-use or disposable containers or flexible bags are increasingly used. Such containers can be flexible or collapsible plastic bags, which are supported by external rigid structures (such as stainless steel shells, referred to herein as "vessels"). The use of sterilized disposable bags eliminates the time-consuming steps of cleaning steel bioreactor vessels, and reduces the chance of contamination. In use, the bag is filled with the desired fluid for mixing, and the impeller (driven by a magnetic drive system or motor positioned outside the vessel) provided in the bag is used to mix the fluid. Depending on the fluid being processed, the system may include many fluid lines, and different sensors, probes and ports connected to the bag, for monitoring, analysis, sampling and fluid transmission. For example, a harvesting port is typically located at the bottom of the disposable bag and vessel, and allows the harvesting line to be connected to the bag, for harvesting and emptying of the bag after the completion of the bioprocess.

[0003] The currently available single-use bioreactor utilizes hose barbs or similar fittings, which are welded to bag films, as inlet and outlet points for conveying fluids. The discharge line fittings usually have a tubular portion that provides a one-way fluid flow. The culture medium flows into the tubular portion of the fitting, where culture medium, cells and other fluid components can precipitate and remain isolated from the overall bioreactor environment. When cells gather in this part of the fitting, cells are usually deprived of nutrients, die and release toxic compounds, which can be unfavorable to the growth and production of cells in a large number of cultures. When all this occurs, the region where culture medium and cells gather is referred to as dead space or dead space. For a hybrid system, minimizing the dead space promotes complete mixing and reduces the potential sedimentation of solids.

[0004] Currently, there is no effective means for preventing or completely eliminating this isolated volume of fluid and cells in the dead leg portion of the drain fitting. Existing systems typically employ non-invasive pinch valves whereby a clamp or other device is utilized to clamp the drain line to close the passage in the drain line tubing, however, fluid can still collect and settle in the space above the clamp.

[0005] In view of the foregoing, a need exists for apparatus and methods for preventing or substantially minimizing dead space in the discharge line or discharge fitting of a bioprocessing system employing a single-use flexible bioreactor container. Summary of the invention

[0006] In an embodiment, a device for minimizing dead space in a container or pipe is provided. The device includes a first component and a second component, the first component having a flange for attaching the first component to a wall of a container or pipe, the flange having at least one orifice, the second component rotatably coupled to the first component, the second component having an upper end and an open distal end, the upper end having at least one orifice. The second component is rotatable relative to the first component between a closed position and an open position, in which the at least one orifice of the second component is not aligned with at least one orifice in the flange to prevent fluid from passing through, and in the open position, the at least one orifice of the second component is aligned with at least one orifice in the flange to allow fluid to pass through.

[0007] In another embodiment, an apparatus for minimizing dead space in a container or pipe includes a first component having a flange for attaching the first component to a wall of the container or pipe and a generally hollow sleeve extending from the flange, the plunger being slidably received within the hollow sleeve, the plunger having a tip configured to sealingly engage the first component. The plunger is slidable between a closed position, in which the tip sealingly engages the sleeve adjacent to the flange to prevent fluid from entering the sleeve, and an open position, in which the plunger is linearly displaced from the closed position to allow fluid to enter the sleeve.

[0008] In yet another embodiment, an apparatus for minimizing dead space in a container or pipe includes a first component and a generally hollow piercing component, the first component having a flange for attaching the first component to a wall of the container or pipe, a generally hollow sleeve extending from the flange, and a sealing element extending across the sleeve for sealing a passage through the sleeve, the generally hollow piercing component being slidably received within the hollow sleeve, the piercing component having a piercing tip. The piercing component is movable between a first position, in which the piercing tip is positioned below the sealing element, whereby the sealing element remains intact to prevent fluid from overriding the sealing element, and a second position, in which the piercing component pierces the sealing element, and the piercing tip extends into the container or pipe, and the interior of the piercing component is in fluid communication with the interior of the container or pipe to allow fluid to enter the hollow piercing component and override the sealing element.

[0009] In yet another embodiment, an apparatus for minimizing dead space in a container or pipe includes a flange, a body, a connecting component, and a valve, wherein the flange is used to attach a first component to a wall of the container or pipe, the flange includes an opening, the body is connected to the flange, the body has a passage fluidly connected to the opening in the flange, the connecting component is connected to the body for connecting a discharge pipe to the apparatus, the valve is positioned in the passage, and the valve is actuable between a closed position and an open position, in which the closed position prevents fluid flow through the passage and the open position allows fluid flow through the passage. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The invention will be better understood by reading the following description of non-limiting embodiments with reference to the accompanying drawings, in which:

[0011] Figure 1 is a front elevation view of a bioreactor system according to an embodiment of the present invention.

[0012] Figure 2 is a perspective view of an apparatus for minimizing dead space in a biological processing system according to an embodiment of the present invention.

[0013] Figure 3 for Figure 2 A perspective cross-sectional view of the upper part of the device.

[0014] Figure 4 for Figure 2 A perspective cross-sectional view of the lower part of the device.

[0015] Figure 5 for Figure 2 A partially cut-away top plan view of a device illustrating a closed position, thereby preventing fluid flow.

[0016] Figure 6 for Figure 2 A partially cut-away top plan view of a device illustrating an open position thereby allowing fluid flow.

[0017] Figure 7 is a perspective view of another apparatus for minimizing dead space in a bioprocessing system according to another embodiment of the present invention, showing an open position thereby allowing fluid flow.

[0018] Figure 8 for Figure 7 A perspective view of the device showing a closed position, thereby preventing fluid flow.

[0019] Fig. 9 for Figure 8 Area A A zoomed-in, detailed view of the .

[0020] Fig.10 for Figure 7 A side cross-sectional view of a device.

[0021] Fig.11 is a perspective view of another apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention.

[0022] Fig.12 for Fig.11 A side cross-sectional view of a device.

[0023] Fig.13 is a perspective view of another apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention.

[0024] Fig.14 for Fig.13 A perspective view of the device showing a closed position, thereby preventing fluid flow.

[0025] Fig.15 for Fig.13 A perspective view of the device showing an open position, thereby allowing fluid flow.

[0026] Fig.16 is a side cross-sectional view of an apparatus for minimizing dead space in a bioprocessing system according to another embodiment of the present invention, showing a closed position, thereby preventing fluid flow.

[0027] Fig.17 for Fig.16 A side cross-sectional view of the device showing an open position, thereby allowing fluid flow.

[0028] Fig.18 is a side cross-sectional view of an apparatus for minimizing dead space in a bioprocessing system according to another embodiment of the present invention, showing a closed position, thereby preventing fluid flow.

[0029] Fig.19 for Fig.18 A side cross-sectional view of the device showing an open position, thereby allowing fluid flow.

[0030] Fig. 20 for Fig.18 An enlarged cross-sectional view of the piercing tip of the device.

[0031] Fig.21 for Fig.18 A perspective view of the spike component of the device.

[0032] Fig. 22 According to an embodiment of the present invention, Fig.18 A perspective view of a protective element used with the device.

[0033] Fig.23 According to another embodiment of the present invention, Fig.18 A perspective view of a protective element used with the device.

[0034] Fig.24 is a perspective illustration of an apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention.

[0035] Fig.25 To adopt Fig.24 Schematic representation of a flexible bag of a bioprocessing system of an apparatus.

[0036] Fig.26 is a schematic illustration of an apparatus for minimizing dead space in a biological treatment system according to another embodiment of the present invention.

[0037] Fig. 27 for Fig.26 An enlarged detailed view of the sealing interface of the device.

[0038] Fig.28 is a schematic illustration of an apparatus for minimizing dead space in a biological treatment system according to another embodiment of the present invention.

[0039] Fig.29 is a perspective view of an apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention.

[0040] Fig.30 for Fig.29 Cross-sectional view of the device.

[0041] Fig.31 is a schematic illustration of an apparatus for minimizing dead space using a diaphragm according to an embodiment of the present invention.

[0042] Fig.32 is a side cross-sectional view of an apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention, shown in a closed position.

[0043] Fig.33 for Fig.32 A side cross-sectional view of the device showing an open position.

[0044] Fig.34 is a side cross-sectional view of an apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention, shown in a closed position.

[0045] Fig.35 for Fig.34A side cross-sectional view of the device showing an open position.

[0046] Fig.36 is a cross-sectional perspective view of an apparatus for minimizing dead space in a biological processing system according to another embodiment of the present invention. DETAILED DESCRIPTION

[0047] Reference will now be made in detail to exemplary embodiments of the present invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference characters are used throughout the drawings to refer to the same or like parts.

[0048] As used herein, the terms "flexible" or "collapsible" refer to structures or materials that are soft or capable of bending without breaking, and may also refer to compressible or expandable materials. An example of a flexible structure is a bag formed from a polyethylene film. The terms "rigid" and "semi-rigid" are used interchangeably herein to describe "non-collapsible" structures, that is, structures that do not fold, collapse, or otherwise deform to significantly reduce their elongated dimensions under normal forces. Depending on the context, "semi-rigid" may also refer to structures that are more flexible than "rigid" elements (e.g., a bendable tube or catheter), but still refer to structures that do not collapse longitudinally under normal conditions and normal forces.

[0049] As used herein, the term "vessel" means a flexible bag, a flexible container, a semi-rigid container, a rigid container, or a flexible or semi-rigid conduit (as the case may be). As used herein, the term "vessel" is intended to include bioreactor vessels having flexible or semi-rigid walls or portions of walls, single-use flexible bags, and other containers or conduits commonly used in biological or biochemical processes, including, for example, cell culture / purification systems, mixing systems, media / buffer preparation systems, and filtration / purification systems (e.g., chromatography and tangential flow filter systems), and their associated flow paths. As used herein, the term "bag" means, for example, a flexible or semi-rigid container or vessel used as a bioreactor or mixer for the contents inside.

[0050] Embodiments of the present invention provide a variety of devices for minimizing dead space in a discharge port or discharge line conduit of a flexible single-use bioprocessing bag, and / or achieving zero dead space (preventing dead space) in a discharge port or discharge line conduit of a flexible single-use bioprocessing bag. As used herein, "minimizing dead space" refers to a condition in which the dead space volume of a discharge port or discharge line conduit (i.e., the volume of a non-circulating length of conduit, or the volume of a container in which there is no liquid movement) is reduced compared to the dead space volume in the absence of the apparatus of the present invention (where a clamp may typically be used). Although embodiments of the present invention are described in conjunction with flexible single-use bioprocessing bags for use in the biopharmaceutical industry, it is contemplated that the devices, systems, and methods described herein for preventing or minimizing dead space may be similarly used in containers (more generally, containers, conduits, and vessels). As used herein, the terms "upper component" and "first component" may be used interchangeably to refer to the same component, as may the terms "lower component" and "second component".

[0051] refer to Figure 1 , a bioreactor system 10 according to an embodiment of the present invention is illustrated. The bioreactor system 10 includes a generally rigid bioreactor vessel or support structure 12 mounted atop a base 14 having a plurality of legs 16. The vessel 12 may be formed, for example, of stainless steel, polymers, composites, glass, or other metals, and may be cylindrical in shape, although other shapes may also be utilized without departing from the broader aspects of the present invention. The vessel 12 may be equipped with a lifting 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 one to view the fluid level within the flexible bag 20; and a window 24 positioned at a lower region of the vessel 12. The window 24 allows access to the interior of the vessel 12 for insertion and positioning of a variety of sensors and probes (not shown) within the flexible bag 20, and for connecting one or more fluid lines to the flexible bag 20 for adding fluids, gases, etc. or extracting them from the flexible bag 20. Sensors / probes and controls for monitoring and controlling important process parameters include any one or more and combinations thereof: for example, temperature, pressure, pH, dissolved oxygen (DO), dissolved carbon dioxide (pCO2), mixing rate, and gas flow rate. The vessel 12 may also include an opening in its bottom to allow a drain or discharge conduit 26 to be connected to the flexible bag 20 via welding or other connectors for draining and / or harvesting the contents of the flexible bag 20.

[0052] In embodiments of the present invention, the discharge outlet of the flexible bag 20 may be constructed or equipped with a device configured to minimize or prevent dead space in the discharge conduit 26 , associated connectors, and / or adjacent areas of the flexible bag 20 . Figure 2-6One possible configuration of the device 100 is shown, which can be integrated with the flexible bag 20 to prevent dead space in the flexible bag 20 and the discharge conduit 26. As shown therein, the device 100 includes a first upper component 110 and a second lower component 112, the second lower component 112 being configured to be rotatably coupled to the upper component 110. Figure 2 and Figure 3 , the upper component 110 includes an annular flange 114 and a hollow stem 116 extending downwardly from the flange 114. The flange 114 includes a plurality of apertures 118 formed therein, each of which is spaced a radial distance from a central axis 120 of the upper component 110 and provides a passage for fluid to pass through the flange 114 and into the interior portion of the hollow stem 116, as discussed below. The distal end of the stem 116 also includes at least one protrusion or pin 121 extending outwardly therefrom, the purpose of which will be described below.

[0053] like Figure 4 As shown in FIG. 1 , the lower member 112 includes a generally tubular body portion 122 having a generally closed upper end 124 and an open bottom end 126. The upper end includes a plurality of apertures 128 formed therein, each of the plurality of apertures 128 being spaced apart from the central axis 131 of the lower member 112 by a radial distance that corresponds to the distance that the apertures 118 of the upper member 110 are spaced apart from the central axis 120. Additionally, the angular spacing of the apertures 128 of the lower member 112 corresponds to the angular spacing of the apertures 118 of the upper member 110. As shown in FIG. Figure 4 As further shown in FIG. 1 , the body portion 122 includes an outwardly spaced annular sleeve or sidewall 130 that defines an annular groove 132 for receiving the rod 116 of the upper component 110. In this regard, the inner diameter of the sleeve 130 generally corresponds to the outer diameter of the rod 116, and the inner diameter of the rod 116 generally corresponds to the outer diameter of the body portion 122. As mentioned above and as Figure 5 and Figure 6 As shown in FIG. 1 , the lower component 112 also includes a keyway 136 configured to receive the protrusion 121 of the upper component 110 for selectively locking the device in an open and / or closed position. In an embodiment, the distal end 126 of the lower component 112 may include a hose barb connector 134 (or TC connector) for connecting to the exhaust conduit 26, such as Figure 2 As shown in .

[0054] Still further reference Figure 2, the flange 114 is sealingly attached to the inner surface of the flexible bag 20, such as by welding, although other attachment means may be utilized without departing from the broader aspects of the invention. The rod 116 of the upper member 110 is slidably and rotatably received in the annular groove 132 in the lower member 112. In use, the flexible bag 20 with the integrated device 100 is positioned within the bioreactor vessel 12 so that the device 100 extends through the discharge opening / orifice in the bottom of the vessel 12 and is connected to the discharge conduit / line 26, such as Figure 1 and Figure 2 As shown in the figure.

[0055] refer to Figure 5 and Figure 6 , the lower part 112 can be rotated relative to the upper part 110 to selectively align (or misalign) the orifices 118, 128. In particular, before filling the flexible bag 20 with process medium and before starting bioprocessing, the lower part 112 is rotated to a closed position so that the orifice 128 in the lower part 112 is not aligned with the orifice 118 in the upper part 100, as shown in FIG. Figure 5 Area A 2. This orientation prevents fluid flow through the apparatus 100 and out of the flexible bag 20. Because the flange 114 of the upper member 110 is substantially coplanar with the bottom of the flexible bag 20, dead space at a location below the bottom of the flexible bag 20 (such as in the discharge conduit 26) is prevented or substantially minimized. After treatment or at any desired time, the lower member 112 can be rotated relative to the upper member 110 to align the orifice 118 in the upper member 110 with the orifice 128 in the lower member (such as Figure 6 Area B ), which allows fluid to flow from the flexible bag 20 through the device 100 and into the connected discharge / exhaust conduit 26. In an embodiment, the protrusion 121 and the keyway 136 are operable to lock the device 100 in this open position.

[0056] The apparatus 100 is thus operable to selectively prevent or allow fluid flow from the flexible bag 20 and into the exhaust conduit 26. In the closed position, in which the apertures are misaligned, because the flange 114 and apertures 118, 128 are substantially flush with the bottom of the flexible bag 20, fluid is not permitted to pass over the flange 114 and collect outside the main volume of the flexible bag 20 (i.e., outside the conditioned bioreactor environment), such as in the exhaust conduit 26. In embodiments, it is contemplated that the lower member 112 may be connected to a motor or other rotational drive mechanism 180, thereby allowing for automated control of the position of the apparatus 100.

[0057] Figure 7-10Another configuration of the device 200 is shown, which can be integrated with the flexible bag 20 to prevent or minimize dead space in the flexible bag 20 and the discharge conduit 26. As shown therein, the device 200 is generally similar in construction and operation to the flexible bag 20 and the discharge conduit 26. Figure 2-6 The device 100 of the present invention includes 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 rod 216 extending downwardly from the flange 214, and a pair of resilient arms 218 extending downwardly from the rod 216. In an embodiment, the resilient arms 218 are spaced approximately 180 degrees apart and include protrusions 220 and their respective distal ends extending toward a centerline or central axis 222 of the device 200. Figure 7 , the flange 214 includes at least one aperture 224 formed therein that provides a passage for fluid to pass through the flange 214 and into the interior portion of the hollow stem 216, as discussed below. In an embodiment, the aperture 224 is semicircular in shape, however other shapes may be utilized without departing from the broader aspects of the invention.

[0058] Further references Figure 7 , the lower member 212 includes a generally hollow tubular body portion 226 having an upper end 227 with an aperture 228 formed therein and a generally open bottom end 230. In an embodiment, the aperture 228 (like the aperture 224) is semicircular in shape, however other shapes are possible. Figure 7 and Fig. 9 As shown in FIG. 2 , the body portion 226 of the lower component 212 also includes a circumferential groove 232 defining a shoulder 234. The circumferential groove 232 is interrupted by at least one position stop 236, the purpose of which will be described below. Fig.10 , the upper portion of the lower component 212 may further include a sealing element 238 disposed in a circumferential groove 240. In an embodiment, the distal end 230 of the lower component 212 may include a hose barb connector 242 for connection to a discharge conduit (not shown).

[0059] like Fig.102, the flange 214 of the upper component 210 is sealingly attached to the inner surface of the flexible bag 20, such as by welding, although other attachment means may be utilized without departing from the broader aspects of the present invention. The lower component 212 is received within the hollow stem 216 of the upper component 210 such that the O-ring 238 sealingly engages the inner surface of the stem 216 to prevent fluid from passing therebetween. When the lower component 212 is fully received within the stem 216, the resilient arm 218 of the upper component 210 is received within the circumferential groove 232 of the body portion 226 of the lower component 212. In this position, the protrusion 220 on the end of the resilient arm 218 contacts the shoulder 234, thereby preventing the upper component 210 and the lower component 212 from being disengaged from each other. In an embodiment, the device 200 may also include a D-shaped O-ring (not shown) (or other shape configured to correspond to the shape of the orifices 224, 228) positioned between the orifices 224, 228 to allow a fluid seal between the rotating elements, which prevents fluid leakage when in the closed position, as discussed below.

[0060] In use, the flexible bag 20 with the integrated device 200 is positioned within the bioreactor vessel 12 such that the device 200 extends through a discharge opening / aperture in the bottom of the vessel 12 and is connected to the discharge conduit / line 26. Again referring to Figure 7 and Figure 8 , the lower part 212 can be rotated relative to the upper part 210 to selectively align (or misalign) the orifices 224, 228. In particular, before filling the flexible bag 20 with process medium and before starting bioprocessing, the lower part 212 is rotated to a closed position so that the orifice 228 of the lower part is not aligned with the orifice 224 in the flange 214, as shown in FIG. Figure 8224. This orientation prevents fluid flow through the apparatus 200 and out of the flexible bag 20. Because the flange 214 of the upper member 210 is substantially flush with the bottom of the flexible bag 20, dead space at a location below the bottom of the flexible bag 20 (such as in the drain conduit 26) is prevented or substantially minimized. After treatment or at any desired time, the lower member 212 can be rotated relative to the upper member 210 in the direction of arrow B to align the orifices 224, 228 vertically with each other, which allows fluid to flow from the flexible bag 20 through the apparatus 200 and into the connected drain / exhaust conduit 26. The position stop 236 acts to prevent over-rotation of the lower component 212 and is positioned such that when the lower component 212 is rotated in one direction until the protrusion 220 contacts the position stop 236, the device 200 is in the closed position, and when the lower component 212 is rotated in the opposite direction until the protrusion 220 contacts the opposing position stop 236, the device 200 is in the open position with the apertures 224, 228 aligned. In this regard, the position stop 236 provides a tactile indication of the fully open position and the fully closed position of the device 200.

[0061] The device 200 is thus operable to selectively prevent or allow fluid flow from the flexible bag 20 and into the drain conduit 26. In the closed position, in which the apertures are misaligned, because the flange 214 and apertures 224, 228 are substantially flush with the bottom of the flexible bag 20, fluid is not permitted to pass over the flange 214 and collect outside the main volume of the flexible bag 20, such as in the drain conduit 26. As discussed above, in embodiments, it is contemplated that the lower member 212 may be connected to a motor or other rotational drive mechanism, thereby allowing for automatic control of the position of the device 200. Additionally, in embodiments, the device 200 may include a locking mechanism for selectively locking the device 200 in an open or closed position, as desired.

[0062] Fig.11 and Fig.12 Another device 300 is depicted that can be integrated with the flexible bag 20 to prevent or minimize dead space in the flexible bag 20 and the discharge conduit 26. The device 300 is substantially similar in construction and operation to the flexible bag 20 and the discharge conduit 26. Figure 7-10 The apparatus 200, wherein like reference numerals indicate like parts. Fig.12As shown in FIG. 1 , the device 300 employs a tapered threaded portion 310 (having one of male or female threads) on the outer surface of the upper portion of the lower component 212, rather than utilizing a resilient arm received in a circumferential groove to guide the rotation of the lower component relative to the upper component, the tapered threaded portion 310 being configured to be threadably received by a corresponding tapered threaded portion 312 (having the other of male or female threads) on the inner surface of the stem 216 of the upper component 210. In this regard, the upper component 210 and the lower component 212 of the device 300 are threadably and rotatably coupled to one another. In use, the user can rotate the lower component 212 as desired to selectively align (or misalign) the orifice 228 of the lower component 212 with the orifice 224 of the upper component 210 to facilitate or prevent emptying of the bag 20. In an embodiment, the device 300 may also include a D-shaped O-ring (not shown) (or other shape configured to correspond to the shape of the orifices 224, 228) positioned between the orifices 224, 228 to allow a fluid seal between the rotating elements, which prevents fluid leakage when in the closed position, as discussed below.

[0063] Like devices 100 and 200 , it is similarly contemplated that lower member 212 may be connected to a motor or other rotational drive mechanism, thereby allowing for automatic control of the position of device 300 .

[0064] Now turn to Figure 13-15 , another device 400 for preventing dead space in a biological treatment system is shown. The device 400 includes an upper member 410 having a generally annular flange 412 and a hollow tube or sleeve 414 extending downwardly and substantially vertically from the flange 412. The upper member 410 further includes a Y-shaped leg or branch pipe 416 extending downwardly at a certain angle from the sleeve 414. In an embodiment, the branch pipe 416 can be a T-shaped leg. Fig.13 , the discharge line or conduit 26 can be connected to the end of the branch tube 416 using a clamp 418, however other connection means (such as a hose barb on the distal end of the branch tube 416) can be utilized without departing from the broader aspects of the invention. In an embodiment, the sleeve 414 can be configured with radial protrusions or lugs 428, the purpose of which will be discussed below.

[0065] Further references Figure 13-15, the device 400 further includes a plunger 422 that is slidably received by the sleeve 414 through its open bottom end. The plunger 422 has a lower end that terminates in a T-shaped handle 424 that provides an ergonomic grip and an upper end that has a plunger tip 426 with an integrated sealing element that sealingly engages the inner wall of the sleeve 414. The body of the plunger is configured with a release portion, a grooved portion, or a smaller diameter than the tip 426 to allow fluid flow through the tip, as discussed below. As described in Fig.14 and Fig.15 As best shown in FIG. 4 , the plunger 422 also includes a keyway 420 configured to receive a lug 428 on the sleeve 414. Fig.14 and Fig.15 As shown in FIG. 4 , the keyway 420 may be generally L-shaped.

[0066] In use, the flange 412 is attached to the inner surface of the flexible bag 20, such as by welding, although other attachment means may be utilized without departing from the broader aspects of the invention. The discharge conduit 26 is then secured to the branch leg 416, and the plunger 422 is received in the sleeve 414 so that the lug 428 is positioned in the keyway 420. Fig.14 , in the closed position, the plunger tip is seated within the sleeve 414 and generally below the flange 412, thereby preventing any fluid from flowing past the flange 412 and out of the flexible bag 20. In this position, the lug 428 is received in the uppermost portion of the keyway 420. Fig.13 and Fig.15 When emptying of the bag 20 is desired, the plunger 422 moves along the arrow A 412, thereby allowing fluid to flow through the tip 426, into the sleeve 414, through the branch leg 416 and into the discharge conduit 26. Once the plunger is pushed upward to the open position, the plunger can also be rotated in the direction of arrow B to position the lug 428 in the lower portion / leg of the keyway 420, as shown in FIG. Fig.15 This essentially locks the plunger 422 in the open position, thereby preventing the plunger 422 from moving upward or downward relative to the sleeve 414.

[0067] Although Figure 13-15The illustrated embodiment, whereby the plunger is pushed upward to break the seal between the plunger tip 426 and the interior of the sleeve 414 to allow the fluid to drain from the bag 20, but in other embodiments, the device 400 may be configured so that the plunger can be retracted below the branch legs 416 to allow the contents of the bag 20 to drain into the branch legs 416 and the connected drain conduit 26. In addition, as mentioned above, in embodiments, the plunger can be connected to an actuator 480 or motor, thereby allowing automatic operation of the device 400. As discussed above in conjunction with the previous embodiments, the device 400 eliminates any cavity below the bottom of the flexible bag 20, in which fluid can accumulate. In this regard, the device 400 of the present invention prevents dead space, which can adversely affect the batch being processed.

[0068] Fig.16 and Fig.17 The apparatus 500 according to another embodiment of the present invention is shown and can be integrated with the flexible bag 20 to prevent or minimize dead space in the flexible bag 20 and the discharge conduit 26. The apparatus 500 is substantially similar in construction and operation to the flexible bag 20 and the discharge conduit 26. Figure 13-15 400. In particular, the device 500 includes an upper member 510 having a flange 512 configured for attachment to the flexible bag 20 in the manner described above, and a generally cylindrical and hollow sleeve 514 extending downwardly from the flange 512, the sleeve having an open top end 516 and an open bottom end 518. The device 500 also includes a plunger 520 slidably received within the sleeve hollow tube or sleeve 514 through the open bottom end 518. The plunger 520 has a generally hollow cylindrical first portion 522, a grooved second portion 524 extending from the first portion 522, and a conical tip 526 connected to the second portion 524. The tip 526 is sized to form a fluid-tight seal with the interior sidewall of the sleeve 514 when the tip is received by the sleeve 514, as shown in FIG. Fig.16 In an embodiment, the tip 526 may be covered with or formed with silicone. Fig.16 As also shown in FIG. 5 , the cylindrical portion 522 of the plunger 520 includes one or more sealing elements 528 (such as O-rings) that also form a fluid-tight seal with the sleeve 514. The distal end of the plunger 520 may be formed with a hose-barb connector 530 for connecting to the discharge conduit 26.

[0069] Further references Fig.16 In the closed position, the tip 526 is retracted within the sleeve 514 and forms a seal with the sleeve 514 to prevent fluid from leaving the bag 20. Fig.17 When emptying of the bag 20 is desired, the plunger may be moved along the travel path B along the arrow AThe tip 526 is pushed upward in the direction of the piston, thereby disengaging the tip 526 from the sleeve 514. In this position, fluid is allowed to flow through the tip, through the grooved portion 524 of the plunger, through the hollow cylindrical portion 522, and into the attached discharge conduit 26. In this manner, the device 500 is substantially similar to Figure 13-15 The device 400 is operated.

[0070] Reference now Figure 18-21 , another device 600 for preventing dead space in a bioprocessing system is shown. The device 600 has a generally annular flange 610 configured to be connected or integrated with the flexible bag 20, and a connector 612 attached to or integrally formed with the annular flange 610. In an embodiment, the connector 612 is a sterile connector having a first connector part 614 and a second connector part 616, which are matingly connected to each other and form a pierceable or breakable seal or diaphragm 618 between them. In an embodiment, the connector 612 is a General Electric ® Made by ReadyMate TM Disposable sterile connector. Fig.18 and Fig.19 , the second connector component 616 is connected or integrally formed with a hollow cylindrical tube or sleeve 620 extending downwardly therefrom. The distal end of the sleeve 620 includes a flange forming a handle grip 622. Although the connector 612 is illustrated as a two-piece component with a seal therebetween, in embodiments, the connector may be a single component with a sealing element that provides fluid isolation between the sleeve 620 and the interior of the flexible bag 20.

[0071] If further Fig.18 and Fig.19 As shown in FIG. 6 , the device 600 also includes a hollow spike 624 that is slidably received within the sleeve 620. Fig.21 6, the terminal end of the spike 624 has a pointed canoe-shaped tip 626 for piercing the seal 618, as discussed below. In embodiments, the tip 626 may have any pointed shape suitable for piercing a thin membrane. The opposite distal end of the spike 624 has a hose barb connector 628 for connecting to the exhaust conduit 26. In embodiments, the spike 624 may also include a complementary flange forming a second handle grip 630.

[0072] Specific reference Fig.18 In use, the device 600 is connected to the flexible bioprocessing bag 20 via the annular flange 610 in the manner described above. The hollow spike 624 is slidably received within the sleeve 620 so that the tip 626 is positioned below the sealing element 618 of the connector 612. Fig.18 624 to prevent accidental activation (i.e., accidental puncture of the sealing element 618). In this state, the sealing element 618 is positioned substantially flush with the bottom of the flexible bag 20 so that fluid within the bag 20 is not allowed to enter any cavity or conduit outside the processing volume of the bag 20. Thus, dead space in which precipitation may occur is substantially eliminated. Just prior to discharge or at any time prior to discharge after the bag 20 is positioned within the vessel 10, the discharge conduit 26 can be connected to the hose barb connector 628 on the distal end of the spike 624. When it is desired to discharge the contents of the bag 20 from the bag 20, the clamp 632 can be removed and the hollow spike 624 can be pushed upward into the bag. This movement of the spike 624 acts to puncture the sealing element 618, thereby causing the tip 626 of the spike 624 to enter the flexible bag 20 (e.g., Fig.19 ), thereby providing a path for the fluid to leave the flexible bag 20. In particular, the fluid can flow into the hollow spike 624 and out of its distal end and into the connected discharge conduit 26.

[0073] In an embodiment, Figure 18-21 The apparatus 600 may also employ a device configured to protect the integrity of the flexible bag 20 during the expulsion operation, including during puncture by the spike 624 and during the expulsion process. Fig. 22 and Fig.23 , the protective elements 640, 650 may be positioned within the interior 644 of the flexible bag 20. The protective elements 640, 650 may include a flange 646 configured for operative attachment or integration with the inner wall of the flexible bag 20, and an upstanding cage element 648 having a plurality of apertures 652 or slots 654 formed therein, as the case may be. In embodiments, the flange 646 may be the same flange as the flange 610 of the device 600 or a different flange. The cage 648 functions to protect the flexible bag 20 from puncture when the spike is pushed through the sealing element during discharge, and to enclose the spike when it protrudes into the bag 20, thereby preventing contact between the sharp tip of the spike and the bag 20. In embodiments, different hole or slot patterns within the cage 648 may be employed to provide optimal fluid flow. In an embodiment, the protective elements 640 , 650 may further include a cover (not shown) to prevent any cut portions of the bag 20 (which may be caused by the puncturing operation) from becoming loose inside the bag 20 .

[0074] Fig.24 and Fig.25Another device 700 is illustrated, which is generally similar in construction and operation to the device 600 described above, and functions to minimize dead space in a bioreactor or bioprocessing system. As illustrated therein, the device 700 includes a port element 710 having a flange 712 and a hollow cylindrical stem 714 depending therefrom. Like the embodiments described above, the flange 712 is configured for connection with the flexible bag 20, so that the stem 714 forms a passage for fluid to flow out of the bag 20. As shown in FIG. Fig.24 As shown in FIG. 7 , the port element 710 includes a pierceable or rupturable membrane 716 and a flexible diaphragm 718. Although Fig.24 The membrane 716 is depicted as being positioned adjacent to the flange 712, but the membrane 716 may also be located within the stem 714 to minimize the possibility of accidental puncture. Fig.25 , the port element 714 can be integrated with the flexible bag 20 at any location where drainage or sampling may be desired, thereby forming a plurality of accessible ports 720.

[0075] Again, reference Fig.24 , the device 700 may also include a spike 730 for piercing the membrane 716 when access to the contents of the bag 20 is desired (such as for discharge or sampling). In an embodiment, the spike 730 may be substantially similar to Figure 18-21 The spike 624 has a pointed tip 732, a flange 734 for gripping, and a hose barb connector 736 for selectively connecting a tube (for drainage or other processes).

[0076] In operation, the flexible bag 20 can be manufactured with multiple ports formed by the port element 710. Access to the contents of the bag 20 is achieved by inserting the hollow spike 730 into the rod 714 to pierce the membrane 716. When the spike is pushed into the bag 20, the diaphragm 718 forms a seal around the outer periphery of the spike 730, thereby preventing leakage. In this position, fluid is allowed to flow into the spike 730 and out of the connected pipeline. In some other embodiments, the diaphragm acts as a self-sealing element, whereby the spike 730 can be pushed into the bag 20 for drainage or sampling, and when the spike 730 is retracted or removed, the diaphragm acts to close the opening and prevent fluid leakage.

[0077] Now turn to Fig.26 In an embodiment, the port element 710 can be used in conjunction with a protective element 760, which is positioned within the interior 762 of the flexible bag 20. In an embodiment, the protective element 760 can take the form of Fig. 22 and Fig.23760 is in the form of protective element 640 or 650 shown in and described above. As described above, when spike 730 is pushed into bag 20 during discharge, protective element 760 acts to prevent unintentional puncture or tearing of the flexible bag. Fig.26 In an embodiment where the device includes a protective element 760, the membrane 716 may be sandwiched between a flange of the port element and a flange of the protective element. Fig. 27 As shown more clearly in Fig.26 and Fig. 27 , in an embodiment, the spike 730 itself may include a plurality of apertures 764 for fluid to pass through. In particular, the spike 730 may have a plurality of apertures 764 that are placed in close association with apertures 766 in the protective element 760 when the spike 730 is advanced into the flexible bag 20. This configuration facilitates fluid flow in a small volume in the bag.

[0078] refer to Fig.28 In an embodiment, spike 730 can be integrated into port element 710 as a sterilization connector. As shown, spike 730 and port connector are substantially similar to the spike and port connector in device 700 described above, however, the device further includes a sterilization connection mechanism 770. Figure 24-28 In any of the described embodiments, it is contemplated that spike 730 may be coupled to an actuator to facilitate automatic piercing of the film and entry into the bag.

[0079] Final Turn Figure 29-31 , yet another device 800 for minimizing or preventing dead space in a bioprocessing system is illustrated. The device 800 includes a flange 810 and a generally spherical body 812 operatively connected to the flange 810. The flange 810 includes an opening 814 in fluid communication with a fluid flow passage 816 that extends through the body portion 812. The body portion also includes a valve 818 positioned within the fluid flow passage 816, and an actuator handle or rod 820 that can be rotated to selectively open or close the valve 818. In an embodiment, the valve 818 and the rod 820 form a stopcock. As shown in FIG. Fig.29 and Fig.30 As shown in FIG. 8 , the lower end of the body 812 may include a hose barb connector 822 for connecting to the exhaust conduit 26 in the manner described above.

[0080] In use, the device 800 can be operatively connected 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 or close the valve 818 to allow or prevent fluid flow from the bag 20. It is contemplated that the device 800 can be used throughout a bioprocess in which the discharge valve can be opened and closed multiple times. In addition, the openable and closable nature of the device 800 facilitates the use of the device 800 for both discharge operations and supply operations. In an embodiment, it is contemplated that the lever 820 can be coupled to an actuator to facilitate automatic operation of the valve 818.

[0081] It is contemplated that a diaphragm may be incorporated into the design of any of the devices described herein, such as device 800, to further minimize any potential dead volume. Fig.31 Illustrated is the location of a diaphragm 830 that may be integrated with one or more of the embodiments described herein.

[0082] Reference now Fig.32 and Fig.33 , another apparatus 900 for preventing dead spaces in a bioprocessing system is shown. The apparatus 900 has a generally annular flange 910 configured for connection or integration with a flexible bag 20, such as by welding, as discussed above. The annular flange 910 includes a depending leg portion that defines a generally 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 configured to sealingly engage an inner wall of the outer sleeve 912 to prevent fluid from flowing through the outer sleeve 912. As shown in FIG. Fig.32 As shown in FIG. 1 , the inner sleeve 914 also includes a thin membrane 918 extending across the top opening of the inner sleeve 914 to prevent fluid from flowing from the bag 20 into the inner sleeve 914. The device 900 further includes a hollow spike 920 or piercing member in a static position within the inner sleeve 914 below the membrane 918.

[0083] In operation, to empty the bag 20, the lower portion of the inner sleeve 914 is moved along the arrow A The inner sleeve 914 is grasped and pulled downwardly in the direction of the outer sleeve 914. This movement causes the washer 916 to slide along the inner surface of the outer sleeve 912. The continued downward push of the inner sleeve 914 causes the film 918 to contact the sharp tip of the spike 920, thereby causing the spike to pierce through the film 918, as shown in FIG. Fig.33 In this position, the fluid within the bag is allowed to flow through the tear in the film 918 and through the spike 920 to discharge the contents of the bag 20.

[0084] refer to Fig.34 and Fig.35, another apparatus 1000 for preventing dead spaces in a bioprocessing system is shown. The apparatus 1000 is configured to be positioned within a discharge port 1010 of a flexible processing bag 20. In an embodiment, the discharge port may be configured with an annular flange that is welded to the bag 20 and has a cylindrical outlet opening (similar to those described above) for discharging the contents of the bag. The apparatus 1000 includes a compressible gasket 1012 (one half of which is located at the bottom of the discharge port 1010) positioned within the discharge port 1010. Fig.34 and Fig.35 ), and a clave device / needle 1014 received within a central passage 1016 of a gasket 1012. As shown therein, the clave needle 1014 includes a fluid opening 1018 at its top, and a central fluid passage 1020 extending from the opening 1018 through the needle 1014.

[0085] like Fig.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) such that fluid cannot flow into the opening 1018. Fig.35 To empty the bag 20, the split needle 1014 is moved along the arrow A 1014 is pushed upward in the direction of the opening 1018 until the opening 1018 is in fluid communication with the interior of the bag 20, thereby allowing the contents to be discharged through the opening 1018 and the fluid passage 1020. As shown therein, due to the tapered configuration of the outer surface of the split needle 1014, the upward movement of the split needle 1014 compresses the gasket 1012, thereby reducing the distance between the lateral portions of the gasket d .

[0086] Final Reference Fig.36 , another apparatus 1100 for preventing dead spaces in a biological treatment system is shown. The apparatus 1100 is configured to be positioned within a discharge port 1110 of a flexible processing bag 20. In an embodiment, the discharge port 1110 may be configured with an annular flange that is welded to the bag 20 and has a cylindrical outlet opening (similar to those described above) for discharging the contents of the bag. The apparatus 1100 is generally similar to Fig.18 and Fig.19 , and includes a syringe assembly 1112 connected to the bag port 1110 via a first mating connector 1114 and a second mating connector 1116. The syringe assembly 1112 includes a hollow plunger 1118, the lower end of which is configured for connection to a discharge conduit 1120. Similar to the embodiments described above, the plunger 1118 can be slid upward into the bag 20 to allow fluid communication with the opening in the plunger 1118 and the interior of the bag 20. Fig.36, the sealing element 1122 can form a fluid seal with the interior of the port 1110. The device 1100 can also include a locking mechanism 1124 (e.g., a latch or L-lock mechanism) and a safety device 1126 that prevents upward travel of the plunger 1118 until the safety device 1126 is removed. The device 1100 can further include a cage element 1128 to protect the bag 20 from puncture when the plunger 1118 is pushed upward into the interior of the bag.

[0087] As described herein, the embodiments of the invention described can be used to prevent or substantially minimize dead spaces in a bioprocessing system, and in particular dead spaces in discharge piping, associated connectors or components of the discharge system of a bioreactor. By minimizing dead spaces, culture medium, cells, and other fluid components are prevented from settling in areas where they can be isolated from the main bioreactor environment, which minimizes the likelihood that cells will be deprived of nutrients and die. Therefore, by minimizing these dead spaces, maximum yields can be achieved and sedimentation can be reduced.

[0088] In an embodiment, a device for minimizing dead space in a container or pipe includes a first component and a second component, the first component having a flange for attaching the first component to the wall of the container or pipe, the flange having at least one orifice, the second component rotatably coupled to the first component, the second component having an upper end and an open distal end, the upper end having at least one orifice. The second component is rotatable relative to the first component between a closed position and an open position, in which the at least one orifice of the second component is not aligned with at least one orifice in the flange to prevent fluid from passing through, and in the open position, the at least one orifice of the second component is aligned with at least one orifice in the flange to allow fluid to pass through. In an embodiment, the at least one orifice in the flange is a plurality of orifices radially offset from the centerline of the flange, and the at least one orifice in the upper end of the second component is a plurality of orifices corresponding to the plurality of orifices of the flange. The plurality of orifices in the upper end of the second component are located at radial positions and angular positions corresponding to the radial positions and angular positions of the plurality of orifices of the flange. In an embodiment, the first component may include one of a keyway and a protrusion, and the second component may include the other of the keyway and the protrusion, wherein the keyway and the protrusion are operable to selectively lock the second component in an open position. In an embodiment, the first component includes a pair of resilient arms, and the second component includes a circumferential groove, wherein the resilient arms engage the circumferential groove and facilitate the second component to rotate between an open position and a closed position. In an embodiment, the circumferential groove includes at least one position stop, and at least one position stop limits the rotation of the second component relative to the first component. In an embodiment, at least one position stop is positioned so that the second component rotates to a position in which one of the resilient arms contacts the position stop corresponding to an open position of the device. In an embodiment, the first component includes a first threaded portion, and the second component includes a second threaded portion, the second threaded portion being configured to threadably engage the first threaded portion to allow the second threaded portion to rotate relative to the first threaded portion. In an embodiment, the distal end of the second component includes a hose barb connector for connecting a discharge conduit to the device. In an embodiment, the container or conduit is a flexible single-use bioprocessing bag.

[0089] In another embodiment, a device for minimizing dead space in a container or pipe includes a first component and a plunger, the first component having a flange for attaching the first component to the wall of the container or pipe and a generally hollow sleeve extending from the flange, the plunger being slidably received in the hollow sleeve, the plunger having a tip configured to sealingly engage the first component. The plunger is capable of sliding between a closed position and an open position, in which the tip is adjacent to the flange and sealingly engages the sleeve to prevent fluid from entering the sleeve, and in which the plunger is linearly displaced from the closed position to allow fluid to enter the sleeve. In an embodiment, the plunger includes at least one release area or passage below the tip to allow fluid to pass through. In an embodiment, the first component further includes a branch leg extending from the sleeve, the branch leg terminating in a hose barb connector for connection of a discharge pipe. In an embodiment, the plunger includes one of an L-shaped keyway and a lug, and the sleeve includes the other of the keyway and the lug, and the plunger is rotatably and linearly movable relative to the sleeve such that when the lug is received in an upper portion of the keyway, the plunger is in a closed position, and when the lug is received in a lower portion of the keyway, the plunger is locked in an open position. In an embodiment, the plunger includes a handle on a distal end of the plunger. In an embodiment, the container or tubing is a flexible single-use bioprocessing bag.

[0090] In yet another embodiment, a device for minimizing dead space in a container or pipeline includes a first component and a generally hollow piercing component, the first component having a flange for attaching the first component to the wall of the container or pipeline, a generally hollow sleeve extending from the flange, and a sealing element extending across the sleeve for sealing a passage through the sleeve, the generally hollow piercing component being slidably received in the hollow sleeve, the piercing component having a piercing tip. The piercing component is movable between a first position and a second position, in which the piercing tip is positioned below the sealing element, whereby the sealing element remains intact to prevent fluid from exceeding the sealing element, in which the piercing component pierces the sealing element, and the piercing tip extends into the container or pipeline, and the interior of the piercing component is in fluid communication with the interior of the container or pipeline to allow fluid to enter the hollow piercing component and exceed the sealing element. In an embodiment, the sealing element forms part of a sterile connector integrated with the first component. In an embodiment, the device further comprises a protective element positioned inside the container or pipe, the protective element having a side wall surrounding the opening in the flange to prevent the piercing tip from contacting the container or pipe, and the side wall comprising a plurality of slots or apertures for passing fluid. In an embodiment, the piercing member comprises a hose barb connector on a distal end of the piercing member for connecting a discharge pipe to the device.

[0091] In yet another embodiment, an apparatus for minimizing dead space in a container or pipe includes a flange, a body, a connecting component, and a valve, wherein the flange is used to attach a first component to a wall of the container or pipe, the flange includes an opening, the body is connected to the flange, the body has a passage fluidly connected to the opening in the flange, the connecting component is connected to the body for connecting a discharge pipe to the apparatus, the valve is positioned in the passage, and the valve is actuable between a closed position and an open position, in which the closed position prevents fluid flow through the passage and the open position allows fluid flow through the passage.

[0092] In yet other embodiments, a bioprocessing system is provided. The system includes a single-use flexible bioreactor bag having a discharge opening or outlet port and an apparatus or device positioned within the discharge opening and attached to the flexible bag for minimizing dead space in the flexible bioreactor bag and / or associated discharge piping and / or components. The apparatus may be a combination of the above Figure 2-31 Any of the devices described. The bioreactor bag with the device may be suitably pre-sterilized, for example by radiation sterilization (typically involving exposure to gamma radiation under conditions well known in the art).

[0093] In yet other embodiments, a method for minimizing dead space in a bioprocessing vessel or conduit is provided. The method comprises: positioning a flexible single-use bioreactor bag in a support vessel, the flexible bioprocessing bag comprising a device configured to minimize dead space in an outlet port or discharge opening positioned in the flexible bag; and connecting a discharge tube to the device. The device may be a combination of the above Figure 2-31 Any of the apparatus described herein. The method further comprises actuating the device to place the interior of the flexible bag in fluid communication with the drain so that fluid from the flexible bag can flow through the device and into the drain.

[0094] As used herein, an element or step described in the singular and preceded by the word "one" or "a kind of" should be understood as not excluding a plurality of said elements or steps, unless such exclusion is explicitly stated. In addition, reference to "one embodiment" of the present disclosure is not intended to be interpreted as excluding the existence of additional embodiments of the features also incorporated into the narration. In addition, unless explicitly stated to the contrary, embodiments that "comprise," "include," or "have" one or more elements having a particular property may include additional such elements that do not have that property.

[0095] This written description uses examples to disclose several embodiments of the invention (including the best mode), and also to enable one of ordinary skill in the art to practice the embodiments of the invention (including making and using any devices or systems and performing any incorporated methods). The patentable scope of the invention is defined by the claims, and may include other examples that occur to one of ordinary skill in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that are not different from the literal language of the claims, or if such other examples include equivalent structural elements that are not substantially different from the literal language of the claims.

Claims

1. An apparatus for minimizing dead space in a container or pipe, comprising: a first component having a flange for attaching the first component to a wall of the container or pipe, the flange having at least one aperture and being flush with a bottom of the container or pipe; as well as a second member rotatably coupled to the first member, the second member having an upper end and an open distal end, the upper end having at least one aperture; wherein the second component is rotatable relative to the first component between a closed position in which the at least one aperture of the second component is misaligned with the at least one aperture in the flange to prevent passage of fluid, and an open position in which the at least one aperture of the second component is aligned with the at least one aperture in the flange to allow passage of fluid; The second component is axially fixed relative to the first component, so that the axial position of the second component relative to the first component is maintained during the rotation of the second component relative to the first component.

2. The device according to claim 1, characterized in that: The at least one aperture in the flange is a plurality of apertures radially offset from a centerline of the flange; and said at least one aperture in said upper end of said second member being a plurality of apertures corresponding to said plurality of apertures of said flange; wherein the plurality of apertures in the upper end of the second component are located at radial and angular positions corresponding to radial and angular positions of the plurality of apertures of the flange.

3. The device according to claim 1 or claim 2, characterized in that: The first member includes one of a keyway and a protrusion; and the second member including the other of the keyway and the projection; Wherein the keyway and the projection are operable to selectively lock the second component in the open position.

4. The device according to claim 1 or claim 2, characterized in that: The first member includes a pair of resilient arms; and The second component includes a circumferential groove; Wherein the resilient arm engages the circumferential groove and facilitates rotation of the second component between the open position and the closed position.

5. The device according to claim 4, characterized in that: The circumferential groove includes at least one position stop that limits rotation of the second component relative to the first component.

6. The device according to claim 5, characterized in that: The at least one position stop is positioned such that rotation of the second component to a position in which one of the resilient arms contacts the position stop corresponds to the open position of the device.

7. The device according to claim 1 or claim 2, characterized in that: The first component includes a first threaded portion; and The second component includes a second threaded portion configured to threadably engage the first threaded portion to allow the second threaded portion to rotate relative to the first threaded portion.

8. The device according to claim 1 or claim 2, characterized in that: The distal end of the second component includes a hose barb connector for connecting a discharge conduit to the device.

9. The device according to claim 1 or claim 2, characterized in that: The container is a flexible, single-use bioprocessing bag.

10. A flexible single-use bioreactor bag comprising a device according to any preceding claim.

11. The flexible single-use bioreactor bag according to claim 10, characterized in that The flexible single-use bioreactor bags are pre-sterilized.

12. The flexible single-use bioreactor bag according to claim 11, characterized in that The flexible single-use bioreactor bag is pre-sterilized by radiation sterilization.

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