Zero dead leg valve

Abstract

A valve is provided for use with a container for mixing biological fluids to facilitate homogeneous mixing and sampling. [Solution] The device comprises a body 14 having a first section 26 and a second section, an expansion flange disposed on the body 14, an elongated bore penetrating the body and having a proximal end and a distal end, a longitudinally displaceable plunger 62 disposed within the bore and extending along the bore, a diaphragm seal 60 that seals the bore, a gland seal 51 that seals the bore at a position midway between the diaphragm seal 60 and the distal end of the bore, the plunger 62 penetrating the gland seal 51 and being sealed and fixed to the gland seal 51, and a fluid transfer opening in the bore between the diaphragm seal 60 and the gland seal 51, wherein the longitudinal displacement of the plunger 62 moves the diaphragm seal 60 and opens the bore.

Description

Technical Field

[0001] This application claims the benefit of priority to U.S. Provisional Patent No. 62 / 864,648, filed Jun. 21, 2019, which is incorporated herein by reference in its entirety.

[0002] Embodiments of the present disclosure relate to containers useful as mixers or bioreactors. More particularly, embodiments disclosed herein include valves in fluid communication with the interior volume of the container.

Background Art

[0003] Conventionally, biological fluids have been processed in systems using stainless steel containers. These containers are sterilized after use so that they can be reused. The sterilization procedures are expensive, cumbersome, and often ineffective. More recently, the containers have included flexible containers, such as flexible containers made from flexible polymer films. To provide greater flexibility in manufacturing and reduce the time required for equipment sterilization and regeneration, manufacturers use disposable sterilized containers, such as bags, e.g., two-dimensional (pillow-type) or three-dimensional bags. Such bags are used once to process biological products and then discarded, regardless of whether they are in batch mode, semi-continuous mode, or continuous mode. These disposable bags consist of a system for mixing two or more components, at least one of which is a liquid and the remainder of which are liquids or solids, and the bag has mixing elements, etc., for mixing the contents as uniformly as possible.

[0004] It is often advantageous to supply materials and / or processing aids, such as defoamers and nutrients, to the system for cell growth in a bioreactor or for other purposes in a bag or mixer during processing. Typically, these materials are added through multiple ports at the top and bottom of the container or bag, and the mixing element distributes them. However, this is an inefficient method of distribution, as ports are typically located along the inner surface of the container, and the distribution of materials to where they are needed is often incomplete. For example, ports may be located at the bottom or side wall of the container and have tubes attached to them. The tubes may end up being filled with fluid at a different concentration than the fluid remaining in the container, i.e., with a lower or higher concentration of the component, thereby reducing the accuracy and potentially misleading the product sample taken. Similarly, if aids and drugs settle, whether introduced into the container from the top, bottom, or side wall, before dissolution, near the ports, or in the tubes (i.e., "dead legs"), those aids and drugs cannot be used for later mixing in the fluid, wasting valuable reagents. Traditionally, such waste has been avoided only by introducing reagents into the container very slowly, or by using a very fast but undesirable mixing rate that imparts shear stress. Furthermore, samples are often taken from ports or piping with dead legs that frequently have varying concentrations, and / or require the removal of a considerable amount of biological fluid, which is wasteful. While manufacturers can use immersion tubes to take samples from the container, these must be sterilized and could contaminate the fluid within the container. Therefore, the use of immersion tubes is undesirable.

[0005] Good mixing of drugs, adjuvants, and components helps optimize the bioreactor process. The manufacture of vaccines, liquids, and biological components often requires the addition of soluble solid processing agents. For example, aluminum salts are used as adjuvants to improve vaccine efficacy by enhancing the body's immune response. Unfortunately, adjuvants often consist of particles larger than 0.2 microns and tend to settle at the bottom of the container, after which they do not dissolve or mix with the solution.

[0006] A well-designed mixing system provides three basic functions: the creation of consistent conditions (nutrients, pH, temperature, etc.) in a homogeneous distribution; the distribution of gases, such as supplying oxygen and extracting carbon dioxide where and when needed within the bioreactor or container; and / or the optimization of heat transfer. Providing acceptable mixing without causing damaging shear effects becomes more difficult as the size and / or aspect ratio of the bioreactor container increases. Certain commercially available mixers and bioreactor platforms include a single bottom-mounted impeller. A single bottom impeller generates vortices with stagnant zones, reducing mixing. Multiple impellers and / or faster impeller speeds improve overall mixing and mixing rate. However, multiple impellers and / or faster impeller speeds, as well as faster shear rates associated with several baffles, can damage cells within the container. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Some bags, bioreactors, or containers include baffles formed vertically along at least a portion of the inner sidewall of the bag to improve mixing, whether rigid or flexible. These baffles are typically sleeves and often have rigid members such as wood, plastic, or metal shaped to fit inside the sleeve, which can damage the container. Large-capacity bags, e.g., 1000L to 3000L bags, containers, or bioreactors present the challenge of uniformly mixing components, particularly because mixing efficiency decreases as the height of these systems increases, despite the decreasing height-to-width aspect ratio. [Means for solving the problem]

[0008] Providing a valve for use with a container for mixing biological fluids to facilitate homogeneous mixing and sampling is an advance in the art. Furthermore, providing a disposable valve with a container for mixing biological fluids to facilitate homogeneous mixing and sampling is also an advance in the art. Providing a valve with zero dead leg in the process so that the concentration of components, drugs, or auxiliaries in the solution or fluid is consistent is a further advance.

[0009] A fluid transfer device such as a valve comprises a body having a first section and a second section; an expansion flange attached to the second section of the body or arranged as an integral part of the second section of the body; an elongated passage or bore penetrating the body and having a proximal end and a distal end; a longitudinally displaceable plunger disposed within the bore and extending along the bore, having a proximal end and a distal end, and having a first position displaced toward the distal end of the bore and a second position displaced toward the proximal end of the bore; and a diaphragm seal attached to the proximal end of the plunger and sealing the bore at its proximal end. The fluid transfer device or valve comprises a gland seal sealing the bore at a position midway between the diaphragm seal and the distal end of the bore, and a fluid transfer opening in the bore between the diaphragm seal and the gland seal, wherein the plunger penetrates the gland seal and is sealed and fixed to the gland seal, and longitudinal displacement of the plunger moves the diaphragm seal to open the bore, the gland seal extends in response to the displacement of the plunger and maintains a seal around the plunger, and a fluid passage is established between the proximal end of the bore opening and the fluid transfer opening, and when the plunger is longitudinally displaced toward its first position, the diaphragm moves and the bore opens. The fluid transfer device or valve optionally further comprises an expansion flange having a surface substantially coplanar with the surface of the second position when the plunger is displaced toward the passage or the proximal end of the bore, creating a zero dead leg condition as fully described by the claim, as substantially shown in and / or described in connection therewith in at least one of the drawings. Details of the various advantages, aspects, novel and inventive features of this disclosure, as well as its exemplary embodiments, will be better understood from the following description and drawings.

[0010] Embodiments of the present disclosure include a valve for fluid communication with a container such as a bag or bioreactor, comprising an internal volume formed of a flexible material, optionally one or more inlets in the container, optionally one or more outlets in the container, an impeller assembly at least partially mounted within the volume of the container, and a baffle within the internal volume of the container. In some embodiments, an expansion flange may be attached to the valve and the bag or bioreactor. In some embodiments, the expansion flange may be attached to the valve via a clamp. In some embodiments, the valve may have an expansion flange integrally formed for attachment to the bag or bioreactor. The flange is bonded to the bag, bioreactor, or container, for example, using an adhesive or by heat sealing. The bag or bioreactor may be a two-dimensional bag or a three-dimensional bag, as known to those skilled in the art.

[0011] Embodiments of this disclosure also include methods for processing and / or sampling biological fluids. Biological fluids(s) may be delivered or otherwise provided into a bag or bioreactor having an internal volume. Fluid transfer devices, such as valves, are located downstream and are in fluid communication with the bag or bioreactor. Flanges may have a relatively large surface for mounting to the bag or bioreactor. The valve is mounted to the bag or bioreactor along an extended region of the flange that is attached to the valve or integral part of the valve. The biological fluids are mixed, for example, using an impeller and / or mixing blades. The impeller may be mounted on a physical shaft as a drive mechanism or may be powered by a magnetically driven pump using a balanced magnetic field to generate rotation of the impeller. Solid processing agents(s) may be delivered into the internal volume of the bag or bioreactor for mixing with the biological fluids. The valve may also include a plunger to provide a liquid-tight seal when in the closed position and to allow fluid delivery when in the open position. In some embodiments, the flange has an upper surface that is substantially coplanar with the surface of the plunger when in the closed position. In some embodiments, the plunger surface is higher than the top surface of the flange. Because the flange is bonded to the bag or bioreactor, mixing occurs without dead leg areas, significantly improving mixing efficiency. Furthermore, sampling during fluid processing also provides a better representation of the concentrations of cell cultures, viruses, various drugs, and / or auxiliaries.

[0012] Embodiments of valves having an expanded flange as described herein facilitate the mixing of various processing agents or auxiliary agents, such as adjuvants, cell culture media, nutritional additives, and defoaming agents. [Brief explanation of the drawing]

[0013] [Figure 1A] This is a cross-sectional view of one embodiment of the valve according to this disclosure in the closed position. [Figure 1B] This is a cross-sectional view of one embodiment of the valve according to this disclosure in the closed position. [Figure 1C] These are cross-sectional views of an embodiment of the valve shown in Figures 1A and 1B, which has a plunger in the open position. [Figure 2A] This is an exploded perspective view of an embodiment of the present disclosure, further including alternative embodiments of the upstream and downstream mounting components. [Figure 2B] This is an exploded perspective view of an embodiment of the present disclosure, further including alternative embodiments of the upstream and downstream mounting components. [Figure 3] This is a perspective view of a valve having an expansion flange according to an embodiment of the present disclosure. [Figure 4A] This is a perspective view of an embodiment according to the present disclosure, further comprising a removable expansion flange and clamp. [Figure 4B] This is a perspective view of an embodiment according to the present disclosure, further comprising a removable expansion flange and clamp. [Figure 4C] Figures 4A and 4B are front views of the assembled expanded flange, valve, and clamp. [Figure 5] Figure 4C is a cross-sectional front view of a valve having an expansion flange bonded to a bag or biocontainer, according to an embodiment of the present disclosure. [Figure 6] Figure 5 is a cross-sectional front view of a valve having an expanded flange attached to a bag or biocontainer, further illustrating an embodiment of a solid processing aid according to the present disclosure. [Figure 7] This is a perspective view of a second embodiment of a valve for use with a two-dimensional bag according to embodiments of the present disclosure. [Figure 8] This is a perspective view of a third embodiment of a valve for use with a two-dimensional bag according to embodiments of the present disclosure. [Figure 9] Figure 4C shows an assembled expansion flange, valve, and clamp according to an embodiment of the present disclosure, further comprising a drain plate in the exploded view. [Figure 10] This is a conventional system comprising a bag with ports, tube clamps, and a dead-leg tube region. [Figure 11] Perspective view of an additional embodiment of a locking tool for use with a valve and a bag, according to an embodiment of the present disclosure. [Figure 12] Front view of a valve for use with a bag, according to some embodiments of the present disclosure. [Figure 13] Perspective view of the valve of FIG. 12 disposed within the locking tool of FIG. 11 for a fluid transfer system, according to an embodiment of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

[0014] Thus, a more specific description of the embodiments of the present disclosure, briefly summarized above, can be obtained by referring to the accompanying drawings in a manner that enables a detailed understanding of the features disclosed herein. However, it should be noted that the accompanying drawings show only typical embodiments of the present disclosure and, therefore, should not be regarded as limiting the scope since the described and illustrated embodiments can recognize other equally valid embodiments. It should also be understood that elements and features of one embodiment can be found in other embodiments without further recitation and that the same reference numerals may be used to indicate equivalent elements common to the figures.

[0015] The term "dead leg" within the present disclosure is typically defined as an area within a conduit, tube, or channel leading to an outlet, where the outlet sees less fluid flow or turbidity than within the larger volume of the container with which it is in fluid communication, but the dead leg area is not necessarily insulated from the flow.

[0016] The term "valve" within the present disclosure is generally defined as a mechanical, electrical, or electromechanical device that can control the passage of fluid, i.e., the flow of fluid, through a channel or bore through the device.

[0017] The terms “bioreactor,” “bag,” and “container” are generally used interchangeably within this disclosure. A flexible bioreactor, bag, or container means a flexible container capable of containing, for example, a biological fluid, which can be folded, crushed, and expanded. A disposable bioreactor, bag, or container is typically a flexible container that is used once and then discarded.

[0018] The term "sterile" is defined as a state free from contaminants, and particularly within the bioprocess industry, free from viruses, bacteria, pathogens, and other microorganisms.

[0019] In this disclosure, the term “adjuvant” is defined as a substance that enhances, for example, the body’s immune response to an antigen.

[0020] The term "upstream" is defined as a state in which a fluid is positioned before another component in relation to the direction of fluid flow.

[0021] Generally, embodiments of the present disclosure describe sterile fluid transfer devices such as flow-through connectors or valves for transporting fluids, such as fluids, solutions, liquids and / or gases. In some embodiments, the fluid transfer device has a body, a bore located in an internal region of the body, and a movable plunger housed within the bore (linearly, e.g., by push / pull operation, and / or rotationally, e.g., by torque applied to the body to open and close the bore). The body is formed from first and second sections. The first section has a first end containing a first opening and an end mounting component, such as a flange surrounding the first opening, for attaching the body to an upstream component(s). The second section has a second end containing a second opening, and the bore connects the first and second openings. The first section can optionally rotate relative to a portion of the second section. In some embodiments, the first section and portions of the second section extend and retract in a push-pull manner.

[0022] The movable plunger includes a first end containing a first opening, a second end containing a second opening, and a fluid channel located inside the plunger connecting the first and second openings of the plunger. In some embodiments, the movable plunger rotates and moves linearly or axially. In some embodiments, the plunger includes components for facilitating and simultaneously preventing its linear or axial motion within the bore during rotation of the first section of the body when the device is operated (i.e., opened / closed). In some embodiments, the plunger includes components for facilitating and simultaneously preventing its linear motion within the bore during fitting of the first section of the body when the device is operated or manipulated (i.e., opened / closed).

[0023] The fluid transfer device, i.e., the valve, is in the closed position when the first end of the plunger is aligned with, for example, a mounting component surrounding the first opening of the body, where a fluid resistance seal is formed. In some embodiments, the surface of the plunger is higher than the top surface of the flange. A steam-resistant surface for sterilization purposes is also formed, and the flange is made of a steam-resistant plastic, such as polypropylene, acetal, or nylon. The device is in the open position when the first end of the plunger is not aligned with the mounting component surrounding the first opening of the body, and fluid can flow into the device from an upstream component, such as a bag, bioreactor, or biocontainer.

[0024] Looking at the figures, Figures 1A and 1B are cross-sectional views of embodiments of the present disclosure in a closed position. Several embodiments of the present disclosure are shown in Figures 1A, 1B, and 1C, which include a fluid transfer device, for example, a valve 12 having a body 14 having an elongated bore 20 formed through at least a portion of the interior of the body 14, and a substantially hollow movable plunger 62, i.e., a longitudinally displaced plunger, housed within the bore 20. The bore 20 is a transverse central bore formed over the internal length of the body 14, as shown in Figure 1C. The body 14 is formed from two sections, as shown, a rotating first section 26 and a stationary second section 28. The first section 26 rotates partially around a portion of the stationary second section 28 and the plunger 62. The bore section 34 generally cooperates with the inner wall of the rotating first section 26, and the bore section 36 generally corresponds to the inner wall of the stationary second section 28. In the embodiment shown in Figure 1C, each of the bore sections (34, 36) has a different diameter. As will be described in more detail herein, the valve 12 is operated (i.e., opened and closed) when the first section 26 of the body 14 is rotated, engaging the stationary second section 28 of the body 14 with the plunger 62, driving the plunger 62 linearly (e.g., axially) within the bore 20, thereby operating (i.e., opening and closing) the valve 12.

[0025] Figure 1C is a cross-sectional view of an embodiment of the valve 12 of Figures 1A and 1B having a plunger in the open position. As shown in Figure 1C, the first section 26 of the body 14 is substantially hollow and has an opening 18 at one end to receive the plunger 62. The first section 26 includes a protruding lip or edge component 38 which is rotatably engaged by a stationary wall groove 44 of the outer stationary wall section 28. The stationary second section 28 of the body 14 is substantially hollow and has an opening 16 at one end which allows fluid supplied from an upstream source (not shown) to pass through while in the open position. The opening 16 also receives the bottom 63 of the plunger when the valve 12 is closed. The stationary section 28 includes an outer wall component 42 for rotatably engaging with the inner wall section 40 of the rotating section 26. As shown in Figure 1C, the inner wall of the second section 28 forms a stationary bore section 36 having four sections. Figure 1C shows a first stationary bore diameter 36a, a first transitional stationary bore section 36b, a second stationary bore diameter 36c, and a second transitional stationary bore section 36d. The first bore diameter 36a is smaller than the second bore diameter 36c. The second bore diameter 36c is a set diameter. The first transitional bore section 36b is located between the first and second bore diameters (36a, 36c) and has a tapered diameter that tapers outward along its length. In some embodiments, the diameter of the first transitional section 36b is a linear outward progression between the first and second bore diameters (36a, 36c). The diameter of the first transitional section 36b adjacent to the first diameter 36a is equal to diameter 36a, and the diameter of the first transitional section 36b adjacent to the second diameter 36b is equal to diameter 36b.

[0026] As shown in Figure 1C, the plunger 62 has three schematic regions comprising first, second, and third regions. The diameter of the first region 24 is less than or equal to the diameter of the first bore set 34a. The diameter of the second region 25 is less than or equal to the diameter of the second stationary bore 36c. The diameter of the third region 29 is less than or equal to the diameter of the first stationary bore diameter section 36a. As shown in Figure 1A, the plunger 62 has a bottom component 63 at the end of the third region 29 for sealing the opening 16 of the stationary section 28 when the device is in the closed position. Some embodiments of the present disclosure include a static diaphragm seal 60, as shown in Figure 1C, which is located at the bottom 63 of the plunger 62 and forms a liquid-tight fluid resistance seal between the outer wall 61 of the bottom end 63 of the plunger and the inner wall 82 of the stationary section 28 of the body that forms the opening 16.

[0027] The plunger 62 also has two openings, a first opening 64 and a second opening 66. A channel 68 is located inside the plunger and connects the first and second openings (64, 66), thereby forming a fluid path to a downstream component. As shown in Figure 1C, the first opening 64 is located in the first portion 24 of the plunger, and the second opening 66 is located in the second portion 25 of the plunger. In other embodiments, the plunger 62 may include additional openings and internal fluid paths. In some exemplary embodiments, the plunger 62 includes at least an opening in the second portion 25 (not shown).

[0028] As shown in Figures 1A to 1C, some embodiments of the present disclosure include a plunger 62 having components for preventing rotation of the plunger 62 in the bore 20 while facilitating the linear motion of the plunger 62 when the valve 12 is operated (i.e., opened and closed). As shown in Figure 1A, some embodiments for achieving the linear motion of the plunger 62 show a plunger having a pair of wings (74, 76), fins, etc., extending from the outer wall of the plunger 62 toward the inner wall of a second section 28 of the body 14. The second section 28 is a component having components for interacting with the pair of wings (74, 76), which have corresponding pairs of parallel slots (70, 72), grooves, etc., positioned in the inner wall of section 28 to receive the pair of wings (74, 76), in order to restrict the rotation of the plunger 62 and facilitate the linear motion of the plunger 62 in the bore 20. The pair of wings (74, 76) rest between each corresponding pair of slots (70, 72) to facilitate the linear motion of the plunger 62 within the bore 20 during the operation (opening and closing) of the valve 12.

[0029] In Figure 1C, when the valve 12 is in the closed position, the bottom end 63 of the plunger 62 aligns with the first flange 80 to form a surface 90. The valve 12 having surface 90 is a vapor-resistant surface and provides a sterile barrier to the environment for the interior of the apparatus 12, the plunger 62, and any downstream components therefrom. In the closed position, as shown in Figure 1A, the bottom end (not shown) of the plunger 62 prevents fluid from entering the valve opening 16 (shown in Figure 1C) from an upstream component (not shown), thereby preventing fluid from moving downstream.

[0030] In Figure 1C, the first section 26 also includes an inner wall having a stationary wall engagement section 40, forming a bore section 34 having four sections: a first bore setting diameter 34a, a transition bore section 34b, a second bore diameter 34c, and a third bore diameter 34d. The first setting diameter 34a engages with the plunger as it moves linearly within the bore 20. The transition section 34b is positioned between the first diameter and the second diameter (34a, 34c) and has a tapered diameter that tapers outward along its length. The diameter of the transition section 34b is preferably a linear outward progression from the first diameter section 34a, with the diameter of a transition section 34b adjacent to the first diameter 34a being equal to the first diameter 34a, and the diameter of a transition section 34b adjacent to the second diameter 34c being equal to the diameter 34c. In some embodiments, the third diameter 34d is preferably less than the diameter 34c, and in some embodiments, it is greater than the diameter 34a.

[0031] Figures 2A and 2B further illustrate alternative embodiments of the upstream and downstream mounting components. This is an exploded perspective view of an embodiment of the present disclosure. As shown in Figure 2A, the end of the first plunger region 24 includes a return end portion 92 for connecting the device to a downstream component, in this example, a pipe 72. As shown in Figure 2B, the end of the first plunger region 24 includes a terminal flange 78 for connecting the device 12 to a downstream component, such as a terminal flange 94. Not limited to, but as an example, the downstream component attached to the device by the terminal connection function of the plunger 62 may include a plastic pipe 72 attached to a plastic bag, container or bioreactor or other type of known receptacle (not shown), as shown in Figure 2A. As shown in Figures 2A and 2B, the valve 12 has a component at one end of the stationary section 28 of the body for attaching the device to an upstream component. In this embodiment, the first flange 80 is attached to a second flange 89 of the upstream component 88.

[0032] For example, the upstream components attached to the device may be pipes, stainless steel or disposable plastic tanks with outlets, or any other mounting modes for connecting components commonly known in the art to the transfer device, having mounting flanges (as shown in Figures 2A and 2B). For example, the flange 80 of valve 12 may be connected to a second flange 89 or pipe of the upstream component 88 by clamps such as Tri-Clover™ fittings / clamps (shown below), Ladish™ fittings, or ClickClamp™ clamps.

[0033] When the valve 12 is used to fill a downstream component, such as a bag or any collection container attached to the piping 72, the device is opened by rotating the rotating section 26 of the body, which moves the plunger 62 (see Figure 1B) linearly away from the surface 90, allowing fluid to flow into the opening 16 (see Figure 1C) and eventually out through the piping 72 to the bag, any collection container, or other fluid transport device (not shown) from the opening outlet 64. When the bag or bioreactor is full, the rotating section 26 is rotated in the opposite direction to move the plunger linearly again, this time in the opposite direction, in order to seal the closed opening 16 from the fluid from the upstream component.

[0034] One or more seals are positioned along the length and ends of the plunger 62 to form a liquid-tight seal between the various parts of the plunger 62 and the bore 20 when the device is in the closed or open position. As shown in Figure 1A, the seals 60 and 54 are partially housed in grooves 46 and 48. As shown in Figures 1A to 1C, the seals may be mounted on the plunger 62. However, different configurations of the seals and their arrangement may also be used as needed. For example, Figure 1A shows the seals 46 and 60 formed in grooves of the plunger 62. A linear or gland seal 51 is held in groove 50 on the inner wall of the stationary bore section and in groove 46 of the plunger 62. Other embodiments of the present disclosure are also contemplated, such as molding the valve 12 into disposable plastic containers, such as disposable process bags for the manufacture and transfer of biotechnical products. Such bags are available, for example, from EMD Millipore Corporation (Burlington, Massachusetts, USA).

[0035] Figure 3 is a perspective view of a valve 12 having an expansion flange 110 according to an embodiment of the present disclosure. The expansion flange 110 has a process side 110a and a non-process side 110b opposite the process side 110a. The expansion flange 110 is bonded to a bag or biocontainer (not shown) by heat sealing, ultrasonic heating, chemical adhesive, etc. In some embodiments, the non-process side 110b of the expansion flange 110 is bonded to the bag or biocontainer. The valve 12 comprises a first section 26 and a second section 28. The first section 26 rotates partially around a portion of the second section 28 and a plunger 62. Optionally, the second section 28 further comprises one or more flat portions 114. A wrench can be engaged with the flat portion(s) 114 to prevent the second section 28 from moving during opening and closing of the valve. By restricting the movement of the second station 28, the bag bonded thereto is not subjected to stress, tearing, etc., when the first section 26 is rotated at the top that opens and closes the valve 12. The plunger 62 can accommodate one or more cams 56 (illustrated) that ride on one or more cam slots 58 (illustrated) located in the rotating section 26 of the body 14. The arrangement of the cams 56 and slots 58 acts to limit the length of linear movement of the plunger 62 within the bore (not shown) when the device is operated (opened or closed). When the valve 12 is in the closed position, the cam 56 is in the closed position of the cam slot 58, as shown in Figure 3. When the valve 12 is in the open position (not shown), the cam 56 is in the open position of the cam slot 58. The expansion flange 110 may be formed integrally with the second section 28, i.e., permanently bonded together, or formed together in an injection molding operation so that it cannot be separated, for example, without destruction.

[0036] Figures 4A and 4B are perspective views of an embodiment of the present disclosure comprising a valve 612, further comprising a removable expansion flange 210 and a clamp 150. The valve 612 comprises a second section 28a and a concave flange 80a on which an O-ring 91 can be seated. As shown in Figure 4B, the expansion flange 210 forms a central hole 132 and is positioned adjacent to a cylinder 130 and a shoulder 140 having a larger diameter than the cylinder 130. The outer diameter of the shoulder 140 is substantially the same as the outer diameter of the concave flange 80a. A triclam 150 with a fastener 170 is shown, but many clamps are suitable. When assembled, the expansion flange 210 fits with the valve 612, and the surface of the shoulder 140 distal to the cylinder 130 contacts the concave flange 80a. Typically, an O-ring 91 or other suitable sealing means is positioned between the shoulder 140 and the concave flange 80a. It should also be understood that the cylinder 130 may be long enough to incorporate one or more flat sections (as described above with respect to Figure 3).

[0037] Figure 4C is a front view of the embodiments of Figures 4A and 4B, showing the assembled expansion flange 210, valve, and clamp 150. As described above, when the shoulder portion 140 and the concave flange 80a are fitted together, the tri-clamp 150 is positioned around both. The fastener 170 can then be tightened to form a liquid-tight seal. In practice, the expansion flange 210 may first be bonded to the bag or container (shown below) and then assembled to the concave flange 80a using the clamp 150. The valve 612 then communicates with the bag or container. Once the valve 612 is connected, it can be operated. As shown, the valve 612 is in the closed position. To open the valve 612, the user can grasp the clamp 150 and the first section 26 of the body 14 with one hand. By rotating the body 14 while keeping the clamp 150 non-rotating, the user can open the valve 612 without damaging the seal between the bag and the expansion flange 210.

[0038] Figure 5 is a cross-sectional front view of the valve 612 of Figure 4C having an expansion flange 210 bonded to a bag or biocontainer 100, according to an embodiment of the present disclosure. The valve 612 operates similarly to the valve 12 described above (and valves 112, 212 described below). The valve 612 is bonded to the bag 100. The bag 100 has an inner surface 104 and an outer surface 102. The expansion flange 210 is bonded to the bag 100 on the inner surface 104. The plunger 62 also has at least two openings, namely a first opening 64 and a second opening 66. A channel 68 is located inside the plunger and connects the first opening 64 and the second opening 66, thereby forming a fluid path to a downstream component. The first opening 64 is located in a first portion 24 of the plunger, and the second opening 66 is located in a second portion 25 of the plunger. In some embodiments, the plunger 62 may include additional openings and internal fluid paths. As shown in the figure, when the valve 612 is in the closed position, the bottom end 63 of the plunger aligns with the flange 210, forming a surface 90, which provides the valve with a vapor-resistant surface and sterile barrier to the environment for the inside of the valve, plunger, and any downstream components. Note that the surface 90, the expanded flange 210, and the inner surface 104 of the bag 100 are substantially coplanar, and therefore no dead leg condition is created. In some embodiments, the surface of the plunger is higher than the top surface of the flange while in the closed position, and the seal condition is maintained by an O-ring. As shown in the figure, the plunger 62 is attached to the piping 202 downstream of the bag 100.

[0039] Figure 6 is a cross-sectional view of the valve 612 of Figure 5 having an expanded flange 210 bonded to a bag or biocontainer 100, according to an embodiment of the present disclosure, further showing the solid processing aid 99. As shown, the processing aid 99 is inside the bag 100. The valve 612 is closed, and all of the processing aid 99 is clearly available for dissolution. Thus, there is no dead leg region. In other words, all of the processing aid 99 is similarly located within the bag 100. Also, there is no region within the bag 100 that is expected to have any different physical properties (such as concentration differences within the liquid solution in the bag 100). The systems (bag 100) and valves (12, 112, 212, 612) described herein may further be referred to as having a “negative” dead leg. When the plunger 62 is in the closed position, the surface 90 of the plunger 62 actually protrudes or juts out over the inner surface 104 of the bag 100 and / or the expansion flanges 80a, 80b, 80c, 110, 210, etc., so that no dead legs can be formed for processing aids or stagnant areas within the bag 100.

[0040] Figure 7 is a perspective view of a second embodiment of a valve 112 for use with a two-dimensional bag (not shown) according to the present disclosure. The valve 112 comprises a first opening 64 adjacent to a plunger 62. The plunger 62 comprises a return end 92 for connecting the valve to a downstream component at the first end. The valve 112 further comprises a first flange 80b having a mounting area 122. The mounting area 122 can be attached to a 2D bag, bioreactor, or container (not shown). The mounting area 122 may be bonded to the bag, for example, via adhesive and / or heat seal. The face 90 of the plunger 62 (while in the closed position) also extends within the closed volume of the 2D bag (not shown). When filling a downstream component such as a collection container using the valve 112, the valve 112 is opened by rotating the first section 26, which moves the plunger 62 linearly away from the face 90, allowing fluid to enter the opening and eventually exit through the opening 64. When the bag or bioreactor is full, the first section 26 rotates in the opposite direction to move the plunger linearly again, this time in the opposite direction, in order to seal the closed opening to the fluid from the upstream components. In practice, when the mounting area 122 is bonded to the bag, the second section 28 is held stationary and the first section 26 is rotated so as not to compress the bond between the mounting area 122 and the bag or bioreactor 100. As described above, a flat portion may be positioned or molded into the second section 28 to facilitate gripping.

[0041] Figure 8 is a perspective view of a third embodiment of a valve 212 for use with a two-dimensional bag according to embodiments of the present disclosure. The valve 212 comprises a first opening 64 adjacent to a plunger 62. The plunger 62 comprises a return end portion 92 for connecting the valve 212 to a downstream component of the first end. The valve 212 further comprises a first flange 80c which can be attached to a bag, bioreactor, or container (not shown). The flat portion may be located or molded in the second section 28 as described above.

[0042] Figure 9 is an exploded view of an assembled expansion flange 210, valve 612, and clamp 150 according to an embodiment of the present disclosure, as shown in Figure 4C, further comprising a drain plate 190. The drain plate 190 has a first plane 199, which contacts the expansion flange 210 when assembled, as will be described later. Opposite the first plane 199 are a first surface 198 and a second surface 196, the second surface being distal to the first plane 199, and the first surface 198 being positioned between the first plane 199 and the second surface 196. The second surface 196 has a diameter smaller than the diameter of the first surface 198. A through slot 192 having a width w traverses at least half the diameter of the drain plate 190. A second slot 194 at the distal end of the through slot 192 traverses about half the thickness t of the drain plate 190. The width w of the through-slot 192 is smaller than the width of the clamp 150.

[0043] The drain plate 190 may be positioned below the expansion flange 210. The clamp 150 has a hinge 180 on the opposite side of the fastener 170. As described above, once the clamp, i.e., the tri-clamp 150, is assembled with the valve, the fastener 170 can be tightened to form a liquid-tight seal, as shown in the valve 612. In practice, the expansion flange 210 may first be bonded to a bag or container (shown below) and then assembled to the concave flange as described above. Once the valve 612 is assembled, it can be operated. As shown, the valve 612 is in the closed position. The hinge 180 slides into the second slot 194. At least a portion of the second surface 196 is positioned between the expansion flange 210 and the clamp 150. The drain plate 190 may be manufactured from any suitable material, e.g., metal, ceramic, plastic, etc. At least one exemplary material is steel, particularly stainless steel. A stainless steel drain plate 190 can be easily cleaned and reused.

[0044] To open the valve 612, the user does not need to grip the clamp 150. In contrast, the user can rotate the first section 26 of the body 14 with one hand. By rotating the body 14 of the valve 612 while keeping the clamp 150 from rotating, the user can open the valve 612 without damaging the seal between the bag and the expansion flange 210 and without gripping the clamp 150. Furthermore, due to interference between the clamp 150, the drain plate 190, and the expansion flange 210, rotational force is not transmitted to the expansion flange 210, and therefore there is no risk of damaging the seal between the bag (not shown) and the expansion flange 210.

[0045] Since the fluid transfer devices or valves 12, 112, 212, 612, and 1112 are preferably installed in a sterile condition (i.e., the inside of the system and any components connected downstream of the valves are pre-sterilized with gamma rays, ethylene gas, etc., and shipped in a sterile condition), some type of usage indicator (not shown) may be useful to notify the user when the system has been used. Alternatively, or in addition to any of the indicator mechanisms described above, a shrink wrap indicator (not shown) may be placed on the valve or at least on the first rotating section of the device to indicate whether the valve has been used.

[0046] Valves 12, 112, 212, 612, and 1112 may be made of plastic material and may be formed by machining the body and plunger assembly and then adding the necessary seals, etc., or, in some embodiments, by molding the body and plunger separately and assembling them with the seals and other components. Alternatively, the body may be molded into two separate halves, for example, longitudinal halves, and assembled by attaching the plunger assembly with the seals and other components to one half of the body, and then attaching the plunger, seals, other components, and the remaining half of the body to the first half of the body.

[0047] Valves 12, 112, 212, 612, and 1112 can be made of metal and / or any plastic material that can withstand steam sterilization. The temperature and pressure of such sterilization are typically about 121°C and 1 bar above atmospheric pressure. In some cases, more severe conditions such as 142°C and up to 3 bar above atmospheric pressure may be used. The body and at least the surface of the plunger can withstand these conditions. In some embodiments, valves 12, 112, 212, 612, and 1112 are made of the same material and can withstand these conditions. Suitable materials for this valve include, but are not limited to, PEI (polyetherimide), polyetheretherketone (PEEK), polyetherketone (PEK), polysulfone, polyarylsulfone, polyalkoxysulfone, polyethersulfone, polyphenylene oxide, polyphenylene sulfide, polytetrafluoroethylene (PTFE), and / or mixtures thereof. Alternatively, surface portions can be fabricated from ceramic or metal inserts alone, or overmolded with a plastic cover. A plasma coating process can also be used to form a polymer surface with a metal outer layer.

[0048] The aforementioned embodiments of this disclosure solve the problem of the dead leg in the prior art (see, for example, Figure 10). Figure 10 shows a prior art system 900 comprising a bag 100 having a port 908, a tube clamp 906, and a tube 902 (cross section), thereby forming a dead leg region. The prior art system 900 has been used to mix, sample, and / or deliver a biological fluid 120 containing a processing aid 99 such as an adjuvant from the bag 100. The fluid 120 from the bag 100 (having a closed volume, not shown) flows from the closed volume into the tube 902 in direction A. The tube 902 is connected to the bag 100 via a port 908 having a return connector 904. The tube 902 is pinched off by the tube clamp 906. In some systems, a disposable valve (not shown) may be placed between the port 908 and the tube 902. The fluid 120 can be dispensed from the system 900 by opening the tube clamp 906. A drawback of this system is that the fluid 120 can flow freely through port 908 into tube 902, and region 910 represents a dead leg region. As shown in the figure, the dead leg region 910 contains processing aid 99 that has settled into the dead leg region 910 from bag 100 or bioreactor. Any portion of tube 902 from upper point B to lower point C represents the dead leg region 910. Any processing aid 99 in the dead leg region 910 can no longer be dissolved in bag 100, i.e., becomes waste. Furthermore, a sample taken from bag 100 through the dead leg region 910 is unlikely to have a concentration representing the fluid in bag 100. Attempts to construct a system without a dead leg region have also failed. For example, the clamp 906 cannot be brought close to bag 100. Because port 908 and tube 902 overlap, a proper seal cannot be obtained. Furthermore, damage occurs to port 908 and / or bag 100. Lowering the clamp position so that port 908 and tube 902 do not overlap inevitably creates a dead leg region.Furthermore, when clamp 906 is very close to port 908, return connector 904 moves away from tube 902, forming a leak area.

[0049] Figure 11 is a perspective view of an additional embodiment of a valve for use with a bag, according to embodiments of the present disclosure. Some smaller valves, for example, valves attached to piping with a diameter of less than approximately 15–30 mm, may be difficult to operate manually. Some embodiments operate via rotation of valve components, i.e., may be difficult to open and close. Therefore, some embodiments of the present disclosure include valves in which the valve is opened and closed using a push-pull operation.

[0050] Figure 11 is a perspective view of one embodiment of a locking tool 1000 for use with a valve and bag according to an embodiment of the present disclosure. The locking tool 1000 comprises an upper plane 1002 and a lower plane 1004, with a vertical wall 1014 positioned between them. The vertical wall 1014 faces a lower slot 1008 and an upper slot 1006. The vertical wall 1014 forms a small arc connecting the upper plane 1002 and the lower plane 1004. The upper slot 1006 has a slot width W that is less than or equal to the width of the lower slot 1008. The locking tool 1000 optionally comprises a distal circular region 1012. Two ribs 1010 are formed adjacent to the distal circular region 1012. The ribs 1010 can position a valve (shown below) in the upper slot 1006 and lock it in a releaseable manner. The radius of the distal circular region 1012 may be substantially equal to the radius of curvature of the valve positioned therein. The locking tool 1000 allows an operator to operate a valve, as will be described more fully below, when the valve connected to the bag is located inside as described above. The locking tool 1000 may be manufactured from any suitable material, such as metal, ceramic, or plastic. At least one exemplary material is steel, particularly stainless steel. A stainless steel locking tool 1000 can be easily cleaned and reused. Alternatively, a plastic locking tool 1000 may be easier to sterilize and less expensive, and may be chosen for disposable applications.

[0051] Figure 12 is a front view of a valve 1112 for use with a bag, according to some embodiments of the present disclosure. The valve 1112 can be actuated by a push-pull operation. For example, an operator can hold the conical body section 1028 of the valve 1112 and pull the valve 1112 to open it, or push the valve 1112 to close it by gripping the lower section 1060. However, the operator does not need to hold the body section 1028 while pulling and / or pushing the valve 1112. The operator can simply pull or push the lower section 1060. The locking tool 1000 supports the valve 1112 when pulled or pushed. The lower section 1060 has a bore connected to it and extends and retracts within the body section 1028. The body section 1028 may have an operating slot 1058 located therein. The upper part 1030 of the body section 1028 can be fitted with the locking tool 1000, as fully shown below. The expansion flange 210 further comprises a shoulder portion 140 for mating with the valve 1112. The operating slot 1058 has a closed end 1058b and an open end 1058a. A pin 1054 is connected to a plunger (not shown) of the valve 1112. The operating slot 1058 restricts the linear and axial motion of the plunger from the open end 1058a to the closed end 1058b via the pin 1054. The plunger is connected to a surface 90 at its distal end, and the plunger is positioned within the bore as described above. The plunger may have two or more circumferential seals (not shown) whose openings (not shown) lead to a central plunger bore for fluid transfer. The seals, such as an O-ring 91, surround the surface 90 and provide a liquid-tight seal with a hole in the expansion flange 210 when in the closed position, as shown. When valve 1112 is opened, face 90 and O-ring 91 retract through the expansion flange 210, providing fluid communication between the plunger and the bag (not shown, but as described above) through the lower section 1060 and opening 64 and the channel or bore. A return fitting 92 for accommodating piping is also shown, for example.To prevent accidental movement of pin 1054 from the valve closed position 1058b and valve open position 1058a, a lock 1056 may be positioned in the operating slot 1058, and vice versa.

[0052] Figure 13 is a perspective view of the valve of Figure 12 positioned within the locking tool of Figure 11 for a fluid transfer system according to an embodiment of the present disclosure. The zero deadleg fluid transfer system comprises a valve, the valve having a conical body section having a lower body section and an upper body section, the conical body section having an expansion flange joined to the upper body section; a plunger having a central bore positioned within the conical upper body section, the plunger having at least one seal adjacent to a surface, the valve being opened and closed via a pull / push operation that allows the plunger to be displaced longitudinally within the conical body section; and a locking tool having an upper plane and a lower plane, with a vertical wall positioned between them, and further having a lower slot and a vertical wall opposite the upper slot, the conical body section of the valve being positioned within at least one of the lower slot or the upper slot, and at least one seal on the plunger forming a liquid-tight seal between the plunger and the expansion flange.

[0053] A fluid transfer device, for example, a valve 1112 having a body section 1028 with an elongated bore (not shown), is formed, as described above, through at least a portion of the lower section 1060, such as a substantially hollow movable plunger, i.e., a longitudinally displaceable plunger housed within the elongated bore. The plunger moves axially and linearly relative to the body section 1028. The plunger in the valve 1112 is driven linearly (e.g., axially), thereby operating the valve 1112 (i.e., opening and closing). The surface 90 is retracted into the valve 1112 when it is in the open position (as shown, the valve is in the closed position). The expansion flange 210 is attached to the surface of the bag (not shown in Figure 13, and substantially as described above), for example, either the outer surface of the bag or the inner surface of the bag. The operator can position the locking tool 1000 around the upper part 1030 of the body section 1028 and firmly pull the lower section 1060 of the valve 1112 to open the valve 1112 without tearing the bag. The operator can place their hand under the locking tool 1000 while pulling the lower part 1060 with the other hand. However, as described above, only one hand is required, whether pulling or pushing the lower part 1060. Similarly, the operator can grip the locking tool 1000 and push the lower part 1060 to close the valve 1112 without jeopardizing the integrity of the bag. The expansion flange 210 is attached to the body section 1028 adjacent to the upper part 1030. The expansion flange 210 is attached to the bag and has a face 90 of the plunger and a hole 1034 through which the O-ring 91 on the face 90 is recessed to allow fluid communication with the hollow plunger and to form a liquid-tight seal with the hollow plunger. In some embodiments, a tube, such as a tube with an inner diameter of 10 to 25 mm or less, is attached to the return fitting 92.

[0054] Embodiments of this disclosure also include methods for processing biological fluids. For example, biological fluids may be delivered or otherwise provided into a bag or bioreactor having an internal volume. Fluid transfer devices, such as valves, are in fluid communication downstream with the bag or bioreactor. Generally, downstream components such as valves are located at or near the bottom of the bag or bioreactor. The fluid transfer device is attached to the bag or bioreactor along a flange attached to the fluid transfer device or along an extended area of ​​an integral part of the fluid transfer device. The biological fluids are mixed. Typical means for mixing biological fluids include an impeller and / or mixing blades. The impeller may be mounted on a physical shaft as a drive mechanism. Alternatively, the impeller may be powered by a magnetically driven pump, using a balanced magnetic field to generate rotation of the impeller. During rotation, the rotating magnetic field affects the internal impeller magnets. When the two magnets begin to rotate together, the impeller begins to rotate and thus displace the fluid. Furthermore, a solid treatment agent may be delivered into the internal volume. The solid treatment agent is mixed with the biological fluid. In some embodiments, the fluid transfer device includes a flange. The flange may have a relatively large surface for attachment to a bag or bioreactor. The fluid transfer device may also include a plunger that provides a liquid-tight seal when in the closed position and allows fluid delivery when in the open position. In some embodiments, the flange has an upper surface that is substantially coplanar with the surface of the plunger when in the closed position. In some embodiments, the surface of the plunger is higher than the upper surface of the flange. Because the flange is bonded to the bag or bioreactor, mixing occurs without dead leg areas, and mixing efficiency is greatly improved. Furthermore, if a sample is required during the processing of the fluid, for example, the sample will also better represent the concentrations of various drugs and adjuvants. For example, one drug that is difficult to mix is ​​aluminum salt, which is typically used as an adjuvant. In some embodiments, the method includes a biological fluid for culturing, such as a monoclonal antibody.

[0055] According to certain embodiments, bags, bioreactors, or disposable containers are designed to receive and retain fluids. In some embodiments, bags, bioreactors, or disposable containers have single-wall or multi-wall flexible walls formed from polymer compositions such as polyethylene, including ultra-high molecular weight polyethylene (UHMWPE), ultra-low density polyethylene (ULDPE), linear low density polyethylene (LLDPE), low density polyethylene (LDPE), medium density polyethylene (MDPE), polypropylene (PP), ethylene vinyl alcohol (EVOH), polyvinyl chloride (PVC), polyvinyl acetate (PVA), ethylene vinyl acetate copolymer (EVA copolymer), thermoplastic elastomer (TPE), and / or blends or alloys of any of the aforementioned materials, as well as various other thermoplastic materials and additives known to those skilled in the art. Disposable containers may be formed by a variety of processes including, but not limited to, co-extrusion of similar or different thermoplastic resins, multi-layer lamination of different thermoplastic materials, welding and / or heat treatment, heat scribing, calendering, and the like. Any of the processes described above may further comprise layers such as adhesives, binding layers, primers, and surface treatments to facilitate adhesion between adjacent layers. “Different” means different polymer types, such as polyethylene layers having one or more layers of EVOH, as well as different properties of the same polymer type, such as molecular weight, linear or branched polymer, and fillers, as contemplated herein. Typically, medical plastics, and in some embodiments, plastics free of animal-derived materials, are used to manufacture the containers. Medical plastics can be sterilized, for example, by steam, ethylene oxide, or radiation including beta and / or gamma rays. Also, most medical plastics are specified for low-gas transport with good tensile strength. In some embodiments, medical plastics include polymer materials that are transparent or translucent, allowing visual monitoring of the contents, and are typically weldable and unsupported. In some embodiments, the container may be a bioreactor capable of supporting a biologically active environment, such as a bioreactor capable of growing cells in a cell culture environment.In some embodiments, the bag, bioreactor, or container may be a two-dimensional (2D) or "pillow" bag, or alternatively, the container may be a three-dimensional (3D) bag. The specific geometric shape of the container or bioreactor is not limited to any embodiment disclosed herein. In some embodiments, the container may include a rigid base providing access points such as ports or vents. Any container described herein may have one or more inlets, one or more outlets, and optionally other features such as sterile gas vents, spurgers, and ports for sensing the liquid inside the container for parameters known to those skilled in the art, such as conductivity, pH, temperature, and dissolved gases, such as oxygen and carbon dioxide. The containers are sized to accommodate fluids such as cells and culture media mixed in a bioreactor of, for example, 3000 L or more, ranging from benchtop scale to large enough to hold.

[0056] The inner wall of the plastic film may be specified to heat-seal with a fluid transfer device, such as a valve flange. Similarly, where a specific plastic film is indicated, a flange generally containing a polymer material may be specified to heat-seal with the specific plastic film. In some embodiments, a bond can be created between the flange and the plastic film using ultrasonic welding, RF welding, contact heating, induction heating, and other heating methods known to those skilled in the art. In some embodiments, a primer can be used between the plastic film and the flange. In some embodiments, an adhesive bonding layer is used to bond the plastic film and the flange. The flange may be of any suitable thickness. In some embodiments, the thickness of the flange is a function of the desired stiffness. For example, a flange containing a polypropylene polymer material may be about, for example, 1.0 to 3.0 millimeters thick. In some embodiments of this disclosure, the flange may include surface treatments, such as ozone treatment, to enhance the bond with the plastic film. In some embodiments, the flange is stable to steam and / or gamma rays for sterilization purposes. In some embodiments, the diameter of the flange may be specified for a particular application. For example, in applications requiring large quantities of difficult-to-dissolve processing aids, users may need to use larger flanges so that the undissolved material remains in the area of ​​the bioreactor where mixing is most efficient. In some embodiments, flanges can be used as a means for positioning / orienting the apparatus. For example, see U.S. Patent No. 9,187,240, U.S. Patent No. 9,272,840, and U.S. Patent No. 9,090,398 filed by EMD Millipore Corporation, in which the technique is incorporated in whole by reference.

[0057] Some embodiments of the valves described herein are found, for example, in U.S. Patent No. 8,690,120 and U.S. Patent No. 10,247,312 filed by EMD Millipore Corporation, each of which is incorporated in whole by reference.

[0058] In some embodiments, the bag, bioreactor, or container may be a disposable, deformable, collapsible bag that defines a closed volume, is sterilizable for single use, can contain contents such as biopharmaceutical fluids in a fluid state, and can partially or completely house a mixing device within the closed volume of the container, for example, within the working volume. In some embodiments, the closed volume can be opened by a suitable valve or the like to introduce fluid into the volume and discharge fluid therefrom, for example, after mixing is complete.

[0059] In some embodiments, each container houses, partially or completely, an impeller assembly for mixing, dispersing, homogenizing, and / or circulating one or more liquids, gases, and / or solids contained within the container. The impeller assembly may include one or more blades that are movable by rotation or vibration around an axis. The impeller assembly converts rotational motion into a force that mixes the fluids it comes into contact with. The impeller assembly may be formed at the top of the container and extend downward into the container volume via a shaft. The shaft is connected to a motor outside the container, and the shaft has one or more impeller blades on it. Such assemblies are often referred to as “lightning-style” assemblies. In some embodiments, the impeller assembly may also be formed at the bottom of the container and connected to a motor by a direct shaft to a motor outside the container, or alternatively, magnetically coupled to the motor so that the shaft does not need to penetrate the container wall.

[0060] All ranges of the formulas enumerated herein may include ranges between them, and may include or exclude endpoints. Optionally included ranges are those starting from integer values ​​between them (or including one original endpoint), in the order of the enumerated magnitudes or the next smallest magnitude. For example, if the lower range value is 0.2, optionally included endpoints may be 0.3, 0.4, ... 1.1, 1.2, etc., and 1, 2, 3, etc. If the larger range is 8, optionally included endpoints may be 7, 6, etc., and 7.9, 7.8, etc. Unilateral ranges such as 3 or more also include consistent ranges (or ranges) starting from the enumerated magnitudes or the next smaller integer value. For example, 3 or more includes 4 or 3.1 or more.

[0061] Throughout this specification, any reference to “one embodiment,” “a particular embodiment,” “one or more embodiments,” “several embodiments,” or “embodiments” indicates that the features, structures, materials, or properties described in relation to an embodiment are included in at least one embodiment of this disclosure. Therefore, throughout this specification, any occurrence of phrases such as “in one or more embodiments,” “in a particular embodiment,” “in one embodiment,” “several embodiments,” or “in an embodiment” does not necessarily refer to the same embodiment.

[0062] While several embodiments have been described above, other implementations and applications are also within the scope of the following claims. Although this specification describes specific embodiments with reference, it should be understood that these embodiments are merely illustrative of the principles and applications of the disclosure. Therefore, it should be further understood that numerous modifications can be made to the exemplary embodiments, and other arrangements and patterns can be devised without departing from the spirit and scope of the embodiments provided hereto. Furthermore, specific features, structures, materials, or properties can be combined in any suitable manner in any one or more embodiments.

[0063] Publications of patent applications, patents, and other non-patent literature cited herein are incorporated herein by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated herein by reference as if it were fully described. Any patent application for which this application claims priority is also incorporated herein by reference in the same manner as described above with respect to publications and references.

Claims

1. It is a valve, A body having a first section and a second section, A long, narrow bore that penetrates the main body and has a proximal end and a distal end, A plunger disposed within a bore and extending along the bore, which is displaceable in the longitudinal direction, having a proximal end and a distal end, having a first position displaced toward the distal end of the bore and a second position displaced toward the proximal end of the bore, and further having an upper surface, A diaphragm seal is attached to the proximal end of the plunger and seals the bore at that proximal end, A gland seal that seals the bore at a position midway between the diaphragm seal and the distal end of the bore, A flange attached to a second section of the main body, or positioned as an integral part of the second section of the main body, wherein the upper surface of the flange is substantially coplanar with the upper surface of the plunger, or the upper surface of the plunger is higher than the upper surface of the flange, The fluid transfer opening in the bore between the diaphragm seal and the gland seal, Equipped with, The plunger penetrates the gland seal and is sealed and secured to the gland seal. The longitudinal displacement of the plunger moves the diaphragm seal to open the bore, and the gland seal extends in response to the plunger's displacement to maintain the seal around the plunger, and a fluid passage is established between the proximal end of the bore opening and the fluid transfer opening, and when the plunger is displaced longitudinally toward its first position, the diaphragm moves and the bore opens. valve.

2. The valve according to claim 1, wherein the flange surface is substantially coplanar with the surface at the second position when the plunger is displaced toward the proximal end of the bore, forming a zero dead leg position.

3. The valve according to claim 1 or 2, wherein a portion of the bore between the diaphragm seal and the gland seal is substantially sterile.

4. The valve according to claim 3, further comprising a substantially sterile connecting component for attaching the valve to an upstream component.

5. The valve according to any one of claims 1 to 4, wherein the diaphragm seal is at least partially positioned inside the proximal end of the bore before the plunger is displaced.

6. The valve according to any one of claims 1 to 5, wherein the gland seal and / or diaphragm seal are constructed of a silicone elastomer or a solvent-resistant fluoroelastomer.

7. The valve according to any one of claims 1 to 6, wherein the body comprises a substantially cylindrical outer portion, at least one alignment slot for a plunger, and a groove for a gland seal.

8. The valve according to any one of claims 1 to 7, wherein the flange further comprises a boss extending into an elongated bore.

9. The valve according to any one of claims 1 to 8, wherein the flange can form a joint with a flexible bioreactor bag.

10. The valve according to claim 9, wherein the flange forms a heat-seal or adhesive bond with the flexible bioreactor bag.

11. A fluid transfer kit, the fluid transfer kit includes a valve, The valve is A body having a first section and a second section, A long, narrow bore that penetrates the main body and has a proximal end and a distal end, A plunger disposed within a bore and extending along the bore, displaced longitudinally, having a proximal end and a distal end, and having a first position displaced toward the distal end of the bore and a second position displaced toward the proximal end of the bore, A diaphragm seal is attached to the proximal end of the plunger and seals the bore at that proximal end, A gland seal that seals the bore at a position midway between the diaphragm seal and the distal end of the bore, A flange attached to the second section of the main body, or positioned as an integral part of the second section of the main body, A flexible bag attached to a flange, wherein the flange is substantially flat and includes an expandable region that can be attached to the flexible bag, Equipped with, The longitudinal displacement of the plunger moves the diaphragm seal to open the bore, the gland seal extends in response to the plunger's displacement to maintain the seal around the plunger, a fluid passage is established between the proximal end of the bore opening and the fluid transfer opening, and when the plunger is displaced toward the proximal end of the bore, the flange surface is substantially coplanar with the plunger surface, creating a zero dead leg position. kit.

12. The kit according to claim 11, wherein a valve, a connecting component for attaching the valve to an upstream component, a flexible pipe of at least one length, and at least one sample container are connected and substantially sterile.

13. It is a valve, and the valve is The main unit and A long, narrow bore that penetrates the main body and has a proximal end and a distal end, A plunger disposed within a bore and extending along the bore, which is displaceable in the longitudinal direction, having a proximal end and a distal end, and having a first position displaced toward the distal end of the bore and a second position displaced toward the proximal end of the bore, At least one seal attached to the plunger so as to form a liquid-tight seal between the plunger and the bore, A fluid transfer opening within the plunger between the proximal end and the distal end of the plunger, Equipped with, The longitudinal displacement of the plunger opens the bore, forming a fluid path from the upstream component to the downstream component through the fluid transfer opening and the channel within the plunger. valve.

14. The valve according to claim 13, wherein at least one seal is a diaphragm seal.

15. The valve according to claim 13 or 14, wherein a diaphragm seal is attached to the proximal end of the plunger and seals the bore at the proximal end.

16. The valve according to any one of claims 13 to 15, wherein at least one seal is a gland seal.

17. The valve according to claim 15, wherein the valve further comprises at least one gland seal.

18. The valve according to claim 17, wherein the gland seal seals the bore at a position midway between the diaphragm seal and the distal end of the bore.

19. The valve according to claim 17, wherein the plunger penetrates at least one gland seal and is sealed and fixed to at least one gland seal.

20. The valve according to claim 17, wherein at least one gland seal extends to maintain a seal around the plunger in response to the displacement of the plunger.

21. The valve according to claim 15, wherein a longitudinal displacement of the plunger toward a first position moves the diaphragm to open the bore.

22. The valve according to claim 19, wherein a portion of the bore between the diaphragm seal and at least one gland seal is substantially sterile.

23. The valve according to claim 22, further comprising a substantially sterile tank mount.

24. The valve according to claim 15, wherein the diaphragm seal is at least partially positioned inside the proximal end of the bore before the displacement of the plunger.

25. The valve according to any one of claims 13 to 24, wherein at least one seal is constructed of a silicone elastomer.

26. The valve according to any one of claims 13 to 25, wherein at least one seal is constructed of a solvent-resistant fluoroelastomer.

27. The valve according to claim 17, wherein the body comprises a substantially cylindrical outer portion, at least one alignment slot for a plunger, and a groove for a gland seal.

28. A method for processing biological fluids, The steps include providing a biological fluid into a bag or bioreactor having an internal volume, A step of providing a valve that communicates fluid downstream with a bag or bioreactor, wherein the valve is attached to the bag or bioreactor along an extended flange region, The steps include providing a means for mixing biological fluids, A step of delivering a solid treatment agent to the internal volume, A step of mixing a solid treatment agent with a biological fluid, wherein the mixing is carried out without dead leg regions, A method for providing this.

29. The method according to claim 28, wherein the upper surface of the valve plunger is coplanar with the surface of the flange.

30. The method according to claim 28, wherein the valve is the valve described in claim 1.

31. The method according to claim 28, wherein the means for mixing comprises an impeller.

32. The method according to claim 31, wherein the impeller is a magnetically driven impeller.

33. The method according to claim 28, wherein the solid treatment agent is an aluminum salt.

34. The method according to claim 28, further comprising the step of obtaining a sample of a biological fluid from within the internal volume of a bag or bioreactor via a valve.

35. The method according to claim 28, wherein the biological fluid comprises a monoclonal antibody.

36. The method according to claim 28, further comprising the step of sterilizing the valve.

37. A zero-dead-leg fluid transfer system, the zero-dead-leg fluid transfer system is It is a valve, A conical body section having a lower body section and an upper body section, wherein an expansion flange is joined to the upper body section, A plunger having a central bore located within a conical upper body section, wherein the plunger comprises at least one seal adjacent to a surface, and the valve is opened and closed via a pull / push operation that allows the plunger to be displaced longitudinally within the conical body section, A valve equipped with, A locking tool comprising an upper plane and a lower plane having a vertical wall positioned between them, further comprising a lower slot and a vertical wall opposite the upper slot, the conical body section of the valve being located within at least one of the lower slot or the upper slot, the locking tool, A zero-dead-leg fluid transfer system in which at least one seal on the plunger forms a liquid-tight seal between the plunger and the expansion flange.

38. The fluid transfer system according to claim 37, wherein at least one seal is a diaphragm seal.

39. The fluid transfer system according to claim 37 or 38, wherein the diaphragm seal is attached to the proximal end of the plunger and seals the bore at the proximal end.

40. The fluid transfer system according to any one of claims 37 to 39, wherein at least one seal is constructed of a silicone elastomer or a solvent-resistant fluoroelastomer.

41. A fluid transfer system according to any one of claims 37 to 40, wherein an expansion flange is attached to a bag.

42. A fluid transfer system according to any one of claims 37 to 41, wherein the plunger comprises a pin.

43. The fluid transfer system according to claim 42, wherein the main body section comprises an operating slot for housing a pin, the pin restricting the movement of the plunger.

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