Patent Description:
Many commercial products are produced using chemical as well as biological processes. Pharmaceuticals, for example, are produced in commercial quantities using scaled-up reactors and other equipment. So-called biologics are drugs or other compounds that are produced or isolated from living entities such as cells or tissue. Biologics can be composed of proteins, nucleic acids, biomolecules, or complex combinations of these substances. They may even include living entities such as cells. For example, in order to produce biologics on a commercial scale, sophisticated and expensive equipment is needed. In both pharmaceutical and biologics, for example, various processes need to occur before the final product is obtained. In the case of biologics, mammalian cells may be grown in a container such as a growth chamber, reactor, bag or the like and nutrients may need to be carefully modulated into the unit holding the cells.

Importantly, biologic products produced by living cells or other organisms may need to be grown, filtered, extracted, concentrated, and ultimately collected from the growth container. Often reagents are loaded in growth containers and combined with other fluid stream(s) or inputs and require mixing. For example, buffer solutions are often added and mixed with other feed stream(s) during the manufacturing process. Waste products produced by cells typically have to be removed on a controlled basis from the growth container. Typically, desired biologic products produced by cells and/or waste products are pumped out of the container where growth occurs using a separate pumping device that is located downstream with respect container containing the cells. This pumped fluid that is removed from the growth chamber is typically subject to downstream processing such as separation or filtration.

As noted above, pumps are needed to move fluid and the contents thereof from one unit operation to another. In addition to actually moving fluid via pumps, mixing is often needed during one or more of these operations. For example, concentrated buffer solutions may be combined with a larger volume of water to make desired buffer concentrations that are used in one or more downstream processes. Typically, this happens in vessels or containers that contain a mixer therein.

<CIT> discloses a diaphragm pump for dispensing foam by mixing air with soap, for sanitary purposes.

<CIT> discloses a diaphragm gas-liquid mixing pump and a foam maker, for sanitary purposes.

<CIT> discloses a bioprocess vessel including a flexible bag or substantially rigid container that defines an interior volume and having a bottom surface, the bottom surface being open or containing an aperture therein for the passage of fluid. A diaphragm pump is secured to the bottom surface of the flexible bag or substantially rigid container. The diaphragm pump comprises an inlet located at a top of the pump, the inlet configured to be secured to a bottom of the vessel; a plurality of chambers disposed in the pump and fluidically connected to the inlet by respective check-valves; an outlet fluidically connected to the chambers, a diaphragm disposed in each of the plurality of chambers, the moveable diaphragms interfacing with a respective actuating element driven by a wobble plate operatively coupled to a motor or drive unit. Improvements are, however, desirable.

Existing pumps are known that are used in biopharmaceutical operations. For example, the Quattroflow™ four-piston diaphragm pump is known that does not use any wetted rotating parts but instead uses four separately actuated diaphragms that are used to pump fluid. A typical problem with pumps is that they are generally connected to a vessel through various conduits. When incorporating pumps into fluid pathways, there is a need to design such systems to avoid problems caused by cavitation, vacuum or pulsed flow condition. Cavitation and non-steady flow conditions tend to lyse the delicate mammalian cells that are used in these manufacturing processes. Unfortunately, when pumps are placed downstream from containers or vessels, this inevitably tends to produce cavitation, vacuum, and problematic flow conditions that tend to kill or disrupt cells or results in low flow conditions. This causes pulsation at low flow rates and does not solve the main problem of getting fluid into the pump efficiently. There thus is a need for improved pump and mixer devices.

The invention is directed to a pump/mixer device, according to claim <NUM>, including a main inlet located at the top or upper region of the pump/mixer, the main inlet configured to be secured to or integrated into a bottom of a vessel or container. An outer chamber is disposed in the pump/mixer and is fluidically connected to the main inlet. A plurality of lower chambers are disposed in the pump/mixer beneath the outer chamber and fluidically connected to the outer chamber by respective check valves interposed between the outer chamber and the plurality of lower chambers. A central chamber is disposed in the pump/mixer, wherein the central chamber is fluidically connected to the plurality of lower chambers with respective check valves interposed between the central chamber and the plurality of lower chambers. The pump/mixer has at least one outlet. The pump/mixer has one or more additional inlets fluidically coupled to the central chamber via respective inlet check valve(s). A moveable diaphragm is disposed in each of the plurality of lower chambers, the moveable diaphragms interfacing with a respective actuating element driven by a wobble plate or nutating disk operatively coupled to a motor or drive unit, wherein actuation causes each of the moveable diaphragms to move in opposing direction (e.g., up and down). This movement pumps fluid through the pump/mixer.

The invention is also directed to a method of operating the pump/mixer of the invention, according to claim <NUM>, including driving the motor or drive unit to actuate the wobble or nutating plate; inputting a first fluid from the vessel or container into the main inlet pump/mixer; inputting second or additional fluid(s) into the pump/mixer via the one or more additional inlets; mixing the first fluid and the second or additional fluid(s) in the central chamber of the pump/mixer; and outputting the mixed fluid via the at least one outlet.

<FIG> illustrates one embodiment of a pump <NUM> or a pump/mixer <NUM>. Whether the device is a pump <NUM> or a pump/mixer <NUM> depends on whether there are additional inlets <NUM>, as explained herein, integrated into the device beyond the main inlet <NUM>. The pump <NUM> or pump/mixer <NUM> includes a main inlet <NUM> that is located on the top or upper portion of the pump <NUM> as seen in <FIG>. In this way, the main inlet <NUM> is at least partially gravity fed from the top as explained herein. The main inlet <NUM> may include a flanged end <NUM> (best seen in <FIG>) that is coupled to the bottom of a vessel or container <NUM> as seen in <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG> via a port or coupler <NUM> using a sanitary clamp <NUM>. The port or coupler <NUM> may, in some embodiments, be integrated into the vessel or container <NUM>. In other embodiments, the pump <NUM> or pump/mixer <NUM> may be directly integrated in or bonded to the vessel or container <NUM>. For example, the pump <NUM> or pump/mixer <NUM> may be welded to or thermally/chemically bonded to or even integrated into the vessel or container <NUM>. Regardless on the manner in which the pump <NUM> or pump/mixer <NUM> is connected to the vessel or container <NUM> the main inlet <NUM> is in fluid communication with the interior of the vessel or container <NUM>.

The vessel or container <NUM> may include both rigid vessels/containers and flexible vessels/containers (e.g., bags). For example, the vessel or container <NUM> may take the form of a tub, vat, barrel, bottle, tank (e.g., buffer tank), reactor (e.g., bioreactor), flask, or other container suitable for holding fluids, liquids, or materials with fluid-like properties. The vessel or container <NUM> may be made of any number of materials including metals, polymers, glass, and the like. In one preferred embodiment, the vessel or container <NUM> is formed from a polymer or resin material and is made as a single-use device. Likewise, one or more portions of the pump <NUM> or pump/mixer <NUM> that is directly or indirectly secured to the fluid vessel or container <NUM> may also be made from a polymer or resin material which facilitates integration or bonding of the pump <NUM> to the vessel or container <NUM>. In some embodiments, both the pump <NUM> (or pump/mixer <NUM>) and vessel or container <NUM> are made from same material. In other embodiments, the pump <NUM> (or pump/mixer <NUM>) and vessel or container <NUM> are made from different materials.

The vessel or container <NUM> may also be flexible such as a bag. The flexible vessel or container <NUM> (e.g., bag) is typically made from polymer or resin material(s) and may have any number of shapes and sizes. The flexible bag may be formed from multiple layers. The bag includes a pump <NUM> or pump/mixer <NUM> that is directly or indirectly secured to a bottom surface of the bag. The vessel or container <NUM> and attached or integrated pump <NUM> or pump/mixer <NUM> may be carried in a trolley, dolly, cradle, cart, holder, or other support container to hold the bag and pump <NUM> or pump/mixer <NUM> in the proper orientation. In some embodiments, both the pump <NUM> or pump/mixer <NUM> and bag are made from the same material. In other embodiments, the pump <NUM> or pump/mixer <NUM> and bag are made from different materials.

As noted above, the pump <NUM> or pump/mixer <NUM> may be secured to the bottom of the vessel or container <NUM> at port or coupler <NUM>. For example, a sanitary clamp <NUM> (e.g., Tri-clamp) and O-ring <NUM> such as that illustrated in <FIG> may be used to clamp the flanged end <NUM> of the pump <NUM> to another flanged end of the port or coupler <NUM> located on the bottom of the vessel or container <NUM>. In other embodiments, the main inlet <NUM> (or upper housing <NUM>) is directly integrated in or manufactured in the vessel or container <NUM>. For example, the main inlet <NUM> may be formed as an aperture or opening located in the bottom of the vessel or container <NUM>. The main inlet <NUM> is, in one embodiment, a circular shaped inlet that has a diameter of about one inch or more (although various dimensions may be used). For example, the main inlet <NUM> may have a diameter of <NUM> inches, <NUM> inches, <NUM> inches, or more. As seen in <FIG>, an optional vortex breaker <NUM> extends or projects from inlet <NUM> and includes a plurality of fins <NUM> formed about the periphery. The vortex breaker <NUM> extends into the bottom portion of the vessel or container <NUM>. The vortex breaker <NUM>, as its name implies, inhibits the formation or generation of a fluid vortex within the vessel or container <NUM> when the pump <NUM> or pump/mixer <NUM> is operating. In some embodiments of the pump <NUM> or pump/mixer <NUM> explained herein, the vortex breaker <NUM> may be omitted. This is seen, for example, in <FIG> and <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>.

As seen in <FIG>, the pump <NUM> or pump/mixer <NUM> includes one or more outlets <NUM>. Each outlet <NUM> may carry the same volume of fluid or the different outlets <NUM> may carry varying or different amounts of fluid. The outlets <NUM> may optionally include, incorporate, or be connected to valves that can be used (e.g., actuated) to selectively turn on/off (or modulate flow through) the various outlets <NUM>.

In the embodiment of <FIG>, a plurality of outlets <NUM> are illustrated (i.e., three (<NUM>) outlets <NUM>). In this particular embodiment, the outlets <NUM> are different sized (e.g., ¾ inch outlet, <NUM>-inch OD outlet, <NUM>-inch ID outlet). Of course, it should be appreciated that different sizes and types of outlets (e.g., outlet connector types) may be used with the pump <NUM> or pump/mixer <NUM>. In still another embodiment, all of the outlets <NUM> are of the same size and/or type. The outlets <NUM> may be removably secured to the body of the pump <NUM> via fasteners <NUM> (e.g., bolts) as illustrated. With reference to <FIG>, o-rings <NUM> may be used to seal the outlets <NUM> to the central housing <NUM> of the pump <NUM>. The bottom of the pump <NUM> or pump/mixer <NUM> may include a flange <NUM> (<FIG>) that is used to connect the pump <NUM> or pump/mixer <NUM> to a motor or drive unit <NUM> (as seen in <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG> and <FIG>) using a sanitary clamp <NUM>. The motor or drive unit <NUM> may include, for example, a brushless direct drive motor (e.g., AKM1™ Series motor available from Kollmorgen).

<FIG> illustrates an exploded view of the pump <NUM> or pump/mixer <NUM>. Reference will be made to pump <NUM> for ease of reference and because there are no additional inlets making this embodiment a pump <NUM>. As seen in <FIG>, the pump <NUM> is formed from a number of assemblies or components that together create the pump <NUM>. The pump <NUM> may be made from metal (e.g., stainless steel) or a polymer (e.g., polypropylene or polycarbonate, etc.) or combinations thereof. In some instances, the pump <NUM> or components thereof may be reusable (after appropriate sterilization or other hygienic cleaning). In other embodiments, the pump <NUM> or components thereof may be single-use or disposable. This may include, as explained below, the upper housing <NUM>, central housing <NUM>, or bottom housing or plate <NUM>.

The pump <NUM> (or pump/mixer <NUM> when including one or more additional inlets <NUM> as explained herein) includes an upper housing <NUM> that includes the main inlet <NUM> as well as an optional mount <NUM> (e.g., threaded opening that receives a threaded post) for the optional vortex breaker <NUM>. Of course, when the vortex breaker <NUM> is omitted there is no need for a mount <NUM>. The main inlet <NUM> includes a central opening that leads to a plurality of passageways <NUM> that extend through the upper housing <NUM>. The upper housing <NUM> further includes a series of fasteners <NUM> (e.g., bolts) that secure the upper housing <NUM> to the central housing <NUM>. The central housing <NUM> includes a central chamber <NUM> that holds pressurized fluid generated by the pumping action of the pump <NUM> (or pump/mixer <NUM>) just prior to exiting the pump <NUM> via the one or more outlets <NUM>. The central housing <NUM> includes a separate outer chamber <NUM> that circumscribes the central chamber <NUM> as an annulus. A wall thus separates outer chamber <NUM> from the central chamber <NUM>. Two separate O-rings <NUM>, <NUM> are interposed between the upper housing <NUM> and the central housing <NUM> with the O-rings <NUM>, <NUM> located on the wall and outer perimeter of the outer chamber <NUM>. The inner O-ring <NUM> is more robust or thicker than the outer O-ring <NUM> (due to the exposure to the higher pressure from the central chamber <NUM>).

The central chamber <NUM> includes outlet passageways <NUM> (<FIG>, <FIG>, <FIG>, <FIG>) for each of the outlets <NUM>. The outlet passageways <NUM> allow pressurized fluid from the central chamber <NUM> to exit the pump <NUM> (or pump/mixer <NUM>) via the outlets <NUM>. As best seen in <FIG>, fluid enters the central chamber <NUM> in the following manner with reference to arrow A. Fluid first enters the pump <NUM> via the main inlet <NUM> where the fluid then flows into the plurality of passageways <NUM>. The fluid then enters the outer chamber <NUM>. During operation of the pump <NUM>, in response to actuation of the diaphragms <NUM> as explained herein, the fluid within this outer chamber <NUM> then passes through a corresponding check valve <NUM> that permits the one-way flow of fluid into a corresponding lower chamber <NUM> located in the central housing <NUM>. The lower chambers <NUM> are separate from one another and are associated with a particular check valve <NUM>. The fluid passes through a second one-way check valve <NUM> that permits the one-way flow of fluid into the central chamber <NUM>. The check valves <NUM>, <NUM> are polymeric check valves that open in one direction in response to a fluid pressure differential in one direction but remain closed when the fluid pressure differential is not present or reverses. For example, there may be three sets of check valves <NUM>, <NUM> (a total of six for the three flow passages) although more or less may be used. The check valves <NUM> located in the outer chamber <NUM> are positioned symmetrically about the outer chamber <NUM> (e.g., about <NUM>° apart from one another). A series of holes or apertures <NUM> (<FIG>) permit the passage of fluid from the outer chamber <NUM> to a lower chamber <NUM> associated with each of the check valve <NUM> (fluid flows down; in one direction). The check valve <NUM> allows fluid flow through the holes or apertures <NUM> in the flow direction but blocks flow in the reverse (up) direction by covering the holes or apertures <NUM>. The check valves <NUM> located in the central chamber <NUM> are also positioned symmetrically about the central chamber <NUM> (e.g., about <NUM>° apart from one another in this embodiment) (<FIG>). A series of holes or apertures <NUM> also permits the passage of fluid from the lower chambers <NUM> to the central chamber <NUM> associated with each of the check valve pair <NUM>, <NUM> (fluid flows inward to the central chamber <NUM> in one direction as seen by arrow A). The check valve <NUM> allows fluid flow through the holes or apertures <NUM> in the flow direction but blocks flow in the reverse direction by covering the holes or apertures <NUM>. While three (<NUM>) pairs of check valves <NUM>, <NUM> and three diaphragms <NUM> are illustrated, in other embodiments, there may be different numbers. For example, a single pair of check valves <NUM>, <NUM> and a single diaphragm <NUM> could be used. Preferably, there are a plurality of pairs of check valves <NUM>, <NUM> and a plurality of diaphragms <NUM>. While both even and odd numbers of check valve pairs and diaphragms <NUM> are contemplated, an odd number may be preferred in some embodiments so as to reduce unwanted pulsatile flow effects. This includes <NUM>, <NUM>, <NUM>, <NUM>, etc. diaphragms <NUM> and check valve pairs <NUM>, <NUM>. In other embodiments, an even number of diaphragms may be used (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>).

Flexible diaphragm(s) <NUM> (<FIG>, <FIG>, <FIG>, <FIG>) is/are located at the bottom of each lower chamber <NUM> and is used to "pull" and "push" fluid through the pump <NUM> (or pump/mixer <NUM>). The flexible diaphragms <NUM> are held about their periphery in a bottom housing or plate <NUM> that is secured to the central housing <NUM> via one or more fasteners <NUM> (e.g., bolts). Each flexible diaphragm <NUM> is also secured at its central region to an actuating element <NUM> (e.g., <FIG>, <FIG>, <FIG>, <FIG>). Movement of the actuating element <NUM> in the up or down direction causes the flexible diaphragm <NUM> to move similarly in the up or down direction (e.g., opposing directions). When the flexible diaphragm <NUM> moves in a first or down direction, this pulls fluid into the lower chamber <NUM>. Conversely, when the flexible diaphragm <NUM> moves in the second or up direction (e.g., opposing direction), this pushes fluid into the central chamber <NUM>. This is what causes the "pull" and "push" of fluid through the pump <NUM> or pump/mixer <NUM>.

In particular, sequential activation of diaphragms <NUM> is caused by actuating element(s) <NUM> secured to an actuating ring <NUM> (<FIG>, <FIG>, <FIG>, <FIG>) via fasteners <NUM> as seen in <FIG> (e.g., bolts) which are also attached to the actuating element(s) <NUM> or respective flexible diaphragm(s) <NUM> and move the diaphragm(s) <NUM> in the up/down direction. This causes the volume of each lower chamber <NUM> to either increase or decrease. Sequential activation of the diaphragms <NUM> is accomplished using a wobble plate or nutating disk <NUM> that is secured to the actuating ring <NUM> (<FIG>, <FIG> and <FIG>). The wobble plate or nutating disk <NUM> includes first and second bearings <NUM>, <NUM> mounted in the center thereof. The inner bearing surfaces of bearings <NUM>, <NUM> are secured to the shaft <NUM> of an eccentric drive shaft <NUM>. The eccentric drive shaft <NUM> includes a shaft <NUM> that is slightly angled (e.g., several degrees from vertical (~<NUM>°)) and the eccentric drive shaft <NUM>, when rotated, causes the wobble plate or nutating disk <NUM> to wobble. The eccentric drive shaft <NUM> includes a shaft hole <NUM> that receives a motor shaft <NUM> of the motor or other drive unit <NUM>. The motor shaft <NUM> is secured to the eccentric drive shaft <NUM> via a set screw <NUM> as illustrated in <FIG> and <FIG>. Rotation of the motor shaft <NUM> (which is secured to the eccentric drive shaft <NUM>) causes the wobble plate or nutating disk <NUM> to sequentially actuate the actuating elements <NUM> with an up/down motion (via the wobble motion of the wobble plate or nutating disk <NUM>). This up/down motion of the actuating elements <NUM> and secured diaphragms <NUM> creates the pumping action. For example, in a three diaphragm <NUM> configuration (first, second and third diaphragms <NUM>), a first diaphragm <NUM> may move downward to pull fluid into the lower chamber <NUM> while the second and/or third diaphragms <NUM> may move upward to push fluid into the central chamber <NUM>. The wobble plate or nutating disk <NUM> then "wobbles" to a next position/orientation to push the first diaphragm <NUM> upward while the second and/or third diaphragms <NUM> may move downward to pull fluid into the lower chamber <NUM> via the actuators/actuating element <NUM>. This continues in sequential fashion to create the pumping action of the pump <NUM> (or pump/mixer <NUM>).

<FIG> illustrates the direction of flow of fluid into the pump <NUM> or pump/mixer as shown by arrow A. Fluid flows downward from the main inlet <NUM> where the fluid then flows into the plurality of passageways <NUM>. The fluid then enters the outer chamber <NUM>. During operation of the pump <NUM>, in response to actuation of the diaphragms <NUM> (in the down direction), the fluid within this outer chamber <NUM> then passes through a first check valve <NUM> that permits the one-way flow of fluid into a lower chamber <NUM> located in the central housing <NUM>. Actuation of the diaphragm <NUM> in the opposite direction (in the up direction) in response to the actuating elements <NUM> pushes fluid into the central chamber <NUM>. In particular, the fluid passes through a second check valve <NUM> into the central chamber <NUM>. From the central chamber <NUM> the fluid which is under pressure can then leave the pump via the one or more outlets <NUM>. Other pairs of first and second check valves <NUM>, <NUM> operate in a similar manner.

As explained herein, in other embodiments, a combination pump/mixer device <NUM> (providing both pumping and mixing functionality) is provided (described herein as pump/mixer <NUM>). This is illustrated in <FIG>, <FIG> and <FIG>, <FIG>, <FIG>, <FIG>, <FIG>, <FIG>. The pump/mixer device <NUM> is similar to the pump <NUM> described herein with the exception of a few modifications to the design. The pump/mixer device <NUM> includes the same components of the pump <NUM> as described above but adds several additional elements. Those common elements use the same reference numbers as the pump <NUM> embodiment herein and will not be described again so as to avoid repetitive disclosure. The pump/mixer device <NUM> includes not only the top or upper "main" inlet <NUM> but also includes one or more additional inlets <NUM> that are located on the central housing <NUM> (or elsewhere on the pump/mixer device <NUM> such as upper housing <NUM> as seen in <FIG>) and fluidically communicate with the central chamber <NUM> via inlet check valves <NUM> associated with each inlet <NUM> (best seen in <FIG>, <FIG>). The flow passage(s) that lead(s) from the inlet(s) <NUM> to the central chamber <NUM> may include jet structures (e.g., narrowed or tapered passageways as seen in <FIG>) to further aid in mixing of the fluids in the central chamber <NUM>. These jet structures may increase turbulent mixing that occurs within the central chamber <NUM>. The central chamber <NUM> in the pump/mixer <NUM> embodiments effectively becomes a mixing chamber whereby the fluid from main inlet <NUM> and the additional inlet(s) <NUM> are able to mix with one another prior to being pumped out.

<FIG>, <FIG>, <FIG>, <FIG>, <FIG>, and <FIG> illustrate the central housing <NUM> showing five (<NUM>) additional inlets <NUM> and a single outlet <NUM> that communicate with the central chamber <NUM> and each additional inlet <NUM> has a corresponding check valve <NUM>. The check valves <NUM> are one-way valves that let fluid enter the central chamber <NUM> from the inlets <NUM> but not in the opposite direction (i.e., fluid cannot flow out of the inlets <NUM> from the central chamber <NUM>). The additional inlet(s) <NUM> may also be located on the upper housing <NUM> as illustrated in <FIG>. For example, the additional inlets <NUM> may be located in both the upper housing <NUM> and the central housing <NUM>. This provides the ability to locate a large number of inlets <NUM> about the periphery of the pump/mixer <NUM>. This may also require increasing the size of the central chamber <NUM> to accommodate the check valves <NUM> in the wall of the central chamber <NUM>.

The inlets <NUM> may be the same size and type. Of course, it should be appreciated that different sizes and types of inlets <NUM> (e.g., inlet connector types) may be used with the pump/mixer <NUM>. These may be barbed inlets <NUM>, inlets <NUM> with sanitary connections, and the like. The inlets <NUM> may optionally be removably secured to the body of the pump/mixer <NUM> via fasteners <NUM> (e.g., bolts) as illustrated. The inlets <NUM> may also be integrated into the body of the pump/mixer <NUM>. In addition, in this embodiment, a single outlet <NUM> is illustrated. Other embodiments may include a plurality of outlets <NUM>. For example, the pump/mixer <NUM> may include a plurality of inlets <NUM> and a plurality of outlets <NUM>. The inlets <NUM> and outlet(s) <NUM> include O-rings <NUM> (<FIG>) for a fluid-tight connection to the pump/mixer <NUM>.

The outlet(s) <NUM> and inlet(s) <NUM> of the pump <NUM> or pump/mixer <NUM> may terminate in a variety of ends or connectors used in biopharmaceutical processes. These include hygienic connectors, barb locks, hose barbs, flanges, TC connectors, disposable aseptic connectors (DAC), and the like. The outlet(s) <NUM> and inlet(s) <NUM> may optionally include or incorporate a valve directly or indirectly therein. Tubing or other conduit <NUM> (<FIG>) may also interface with the outlet(s) <NUM> and inlet(s) <NUM> of the pump <NUM> or pump/mixer <NUM>. The conduit <NUM> may be removably attached to the outlet(s) <NUM> and inlet(s) <NUM> of the pump <NUM> or pump/mixer <NUM>. In still another embodiment, the outlet(s) <NUM> and inlet(s) <NUM> of the pump <NUM> or pump/mixer <NUM> may simply be an aperture or opening through which fluid passes. This aperture or opening may be threaded internally so that the outlet(s) <NUM> and/or inlet(s) <NUM> can accommodate a threaded connecting component or insert that interfaces with the threaded outlet(s) <NUM> and inlet(s) <NUM> of the pump <NUM> or pump/mixer <NUM>.

<FIG> illustrates an embodiment of a pump/mixer <NUM> with a large number of additional inlets <NUM> (eleven (<NUM>) are illustrated in this embodiment). The number of outlets <NUM> and number of additional inlets <NUM> varies and is application specific. For some applications the pump/mixer <NUM> may only have a single outlet <NUM>, however, other applications may include two (<NUM>), three (<NUM>), four (<NUM>), or five (<NUM>) outlets <NUM>. Likewise, the number of inlets <NUM> is application dependent. This may include between one (<NUM>) and twenty (<NUM>) additional inlets <NUM>. Larger sized pump/mixers <NUM> may include, for example, fifteen (<NUM>) to twenty (<NUM>) additional inlets <NUM>. More typically, in smaller sized pump/mixers <NUM> there are typically less than ten (<NUM>) additional inlets. Each inlet <NUM> in this particular embodiment includes barbed ends that interface with conduits or tubing <NUM> (see e.g., <FIG>). <FIG> further illustrate a sanitary clamp <NUM> that can be used to secure the pump-mixer <NUM> to the bottom of the container or vessel <NUM> such as illustrated in <FIG>, <FIG>, and <FIG>. Additional sanitary clamps <NUM> may be used to secure devices, devices, tubing (e.g., tubing <NUM>) to the outlets <NUM>.

<FIG> illustrates the operation of the pump <NUM> according to one embodiment. In this embodiment, a container or vessel <NUM> is provided with the pump <NUM> secured to the bottom or lower side via a port or coupler <NUM> (or other attachment scheme). A plurality of outlets <NUM> are located on the pump <NUM>. The container or vessel <NUM> is filled with a fluid. The pump <NUM> is turned on by providing power the motor or other drive unit <NUM> secured to the pump <NUM>. Fluid contained in the container or vessel <NUM> then enters the main inlet <NUM> as described herein and is pumped out the plurality of outlets <NUM>. Arrows indicate the direction of flow. The speed of the motor or other drive unit <NUM> may be controlled to adjust the flow rate through the pump <NUM>. This may occur through an automated controller or other control circuitry that is operably connected to the motor or drive unit <NUM>.

<FIG> illustrates the operation of the pump/mixer <NUM> according to one embodiment. In this embodiment, a container or vessel <NUM> is provided with the pump/mixer <NUM> secured to the bottom or lower side via a port or coupler <NUM>. In this embodiment, there is a single outlet <NUM> and a plurality of inlets <NUM> located on the pump/mixer <NUM>. The container or vessel <NUM> is filled with a fluid. The plurality of inlets <NUM> are fluidically connected via conduits, tubing, or the like (e.g., tubing <NUM> of <FIG>) to one or more sources of fluid that have their own separate pumps <NUM> that pump fluid into the central chamber <NUM> such as that illustrated in <FIG>. Note that the separate pumps <NUM> may in some embodiments include conventional pumps. In other embodiments, the separate pump(s) <NUM> may include the pumps <NUM> or pump/mixers <NUM> described herein (<FIG>). The flow rate of the fluids through the plurality of inlets <NUM> may be individually controlled to adjust the mixing of fluids in the pump/mixer <NUM>. For example, the flow rate of the fluids into the different additional inlets <NUM> may be controlled through the operation of the respective pump(s) <NUM> that is used to pump the applicable fluid into the pump/mixer <NUM>. In addition, in some embodiments, valves may be incorporated into the plurality of inlets <NUM> (or fluidically coupled thereto) to selectively turn on/off various inlets <NUM> (or adjust flow into the inlets <NUM> or out of outlet <NUM>). The pump/mixer <NUM> is turned on by providing power the motor or other drive unit <NUM> secured to the pump/mixer <NUM>. Fluid contained in the container or vessel <NUM> then enters the main inlet <NUM> as described herein (illustrated by down arrow) and is mixed with the fluid(s) from the one or more inlets <NUM> inside the central chamber <NUM> and is pumped out the one or more outlets <NUM>.

It should be appreciated that for an embodiment of a pump/mixer <NUM> that includes a plurality of additional inlets <NUM>, respective fluids that are pumped into the additional inlets <NUM> into the pump/mixer <NUM> may be done simultaneously or sequentially. For example, consider a pump/mixer <NUM> that includes a main inlet <NUM> that receives fluid A, a single outlet <NUM>, and three (<NUM>) additional inlets <NUM> each coupled to respective fluids B, C, and D. In one embodiment, the pump/mixer <NUM> operates to sequentially mix fluid A with fluid B, then mix fluid A with fluid C, then mix fluid A with fluid D. This may be done by sequentially pumping fluids B, C, and D into the pump/mixer <NUM> while it draws fluid A from the main inlet <NUM>. Alternatively, fluids B, C, and D may be simultaneously mixed with fluid A by pumping the respective fluids into the three different additional outlets <NUM>. Of course, different combinations thereof may also be used.

It should be appreciated that a plurality of pump <NUM> and/or pump/mixer <NUM> may be combined together in various systems depending on the application. For example, multiple pumps <NUM> and/or pump/mixers <NUM> may be combined to operate a dilution system whereby concentrated feedstock fluid media is subject to a dilution with a diluent such as water. Concentrated media may be pumped out of the container or vessel <NUM> using a pump <NUM> and/or pump/mixer <NUM>. This output may then serve as the input to one or more additional downstream such as illustrated in <FIG>. Likewise, the pump <NUM> and/or pump/mixer <NUM> may be used in connection with a container or vessel <NUM> (or multiple such containers or vessels <NUM>) that is/are used as a bioreactor container or vessel <NUM> as illustrated in <FIG>, <FIG>, <FIG>. Fluid contained in the bioreactor may be, for example, pumped using a pump and/or pump mixer <NUM> and subject to processing (e.g., filtration, aeration, gas exchange, and the like) and returned to the container or vessel <NUM>. The additional inlets <NUM> may be used to mix the bioreactor contents with reagents, buffers, chemicals, and the like.

<FIG> illustrates one exemplary system <NUM> that is used to generate different buffer solutions as needed. The system <NUM> enables the generation of buffer solutions of different compositions and/or concentrations. The system <NUM> includes multiple pump/mixers 70a, 70b, 70c that are fluidically connected to respective containers or vessels 100a, 100b, 100c. Each container or vessel 100a, 100b, 100c contains a different buffer concentrate. While three (<NUM>) such different buffer concentrates are illustrated more or less may be used. Each pump/mixer 70a, 70b, 70c has two outlets 18a, 18b that lead to respective fluid paths (e.g., using conduits or tubing coupled to the outlets 18a, 18b). Valves <NUM> are located in the fluid paths that can be used to open/close the respective fluid flows from outlets 18a, 18b. Fluid paths 204a, 204b, 204c recirculate fluid back into the respective container or vessel 100a, 100b, 100c. Fluid paths 206a, 206b, 206c leads to additional inlets <NUM> of another pump/mixer 70d (e.g., in this example there are three (<NUM>) such inlets <NUM>). This pump/mixer 70d is fluidically coupled to a container or vessel 100d that contains a diluent such as water. The water is used to dilute the concentrated buffer that arrives from fluid paths 206a, 206b, 206c. The pump/mixer 70d in combination with the container or vessel 100d operates as a dilution functional unit <NUM> as is illustrated.

The pump/mixer 70d includes three outlets 18c, 18d, 18e that lead to respective fluid paths <NUM>, <NUM>, <NUM>. Valves <NUM> are located in the fluid paths <NUM>, <NUM>, <NUM> can be used to open/close the respective fluid flows from outlets 18c, 18d, 18e. A first outlet 18c leads to fluid path <NUM> enters another pump mixer 70e via an inlet <NUM>. This pump/mixer 70e is fluidically coupled to a container or vessel 100e. The pump/mixer 70e includes two outlets 18f, <NUM> that lead to respective fluid paths <NUM>, <NUM>. Fluid path <NUM> recirculates fluid back into the container or vessel 100e. Fluid path <NUM> leads to the process <NUM> as illustrated in <FIG>. The process <NUM> generically refers to any downstream process that requires the appropriate buffer. The second outlet 18d is located in fluid path <NUM> which leads to waste <NUM>. The third outlet 18e is located in fluid path <NUM> and leads to another pump/mixer 70f via an inlet <NUM>. This pump/mixer 70f is fluidically coupled to a container or vessel 100f. The pump/mixer 70f includes three outlets <NUM>, 18i, 18j that lead to respective fluid paths <NUM>, <NUM>, <NUM>. Fluid path <NUM> leads to the process <NUM> as illustrated in <FIG>. Fluid path <NUM> recirculates fluid back into the container or vessel 100f. Fluid path <NUM> is directed to another dilution functional unit <NUM>. This additional dilution functional unit <NUM> operates similar to the pump/mixer 70d and associated container or vessel 100d which is used to dilute the concentration of the buffer from container or vessel 100f. This is illustrated in <FIG>, whereby a diluted buffer <NUM> (e.g., Buffer Y, concentration <NUM>) is generated. This diluted buffer is then directed to process <NUM>.

The system <NUM> of <FIG> is used to generate buffer fluids of different compositions and/or concentrations. In this example, buffer X is generated using the first dilution functional unit <NUM> that includes pump/mixer 70d and associated container or vessel 100d. The generated buffer X may be stored temporarily in container or vessel 100e until needed. The pump/mixer 70e can be used to recirculate buffer X to maintain the buffer and prevent, for example, precipitation of buffer species or constituents. Buffer Y is also generated using the first dilution functional unit <NUM> which is stored in container or vessel 100f. Note that water may be used to flush the pump/mixer 70d between creation of buffer X and buffer Y. This wash may be sent to waste <NUM>. Buffer Y may be stored temporarily in container or vessel 100f until needed. The pump/mixer 70f can be used to recirculate buffer Y to maintain the buffer as explained herein. Buffer Y may be used in the process <NUM> using fluid path <NUM>. Alternatively, buffer Y may need further dilution in which case fluid path <NUM> is used to direct buffer Y to another dilution functional unit <NUM> to create diluted buffer Y (e.g., buffer Y at concentration <NUM>). This diluted buffer can then be sent to the process <NUM>.

It should be appreciated that <FIG> illustrates one illustrative embodiment of a system <NUM> that uses a constellation of pump/mixers <NUM>. Different configurations and modifications may be made depending on the need. Different numbers of pump/mixers <NUM> (or pumps <NUM>) may be used. The pump/mixers <NUM> that are used may include different numbers of additional inlets <NUM> and outlets <NUM> may be used. Additional levels or cascades of pumps/mixers <NUM> may be used as well.

<FIG>, <FIG>, <FIG> illustrate embodiments in which the pump/mixer <NUM> is used in connection with a container or vessel <NUM> used as a bioreactor (these may include flexible bags as illustrated or other rigid containers as explained herein). The pump/mixer <NUM> is coupled to each container or vessel <NUM> via a port or coupler <NUM> as seen in <FIG>. Of course, it should be appreciated that the pump/mixer <NUM> may by secured to the container or vessel <NUM> via different couplings or even integrated directly into the container or vessel <NUM>. For example, the pump/mixer <NUM> may be welded to or thermally/chemically bonded to the container or vessel <NUM>. Regardless of the mode of connection, the main inlet <NUM> of the pump/mixer <NUM> is in fluid communication with the interior of the container or vessel <NUM>.

The bioreactor may be used to grow, culture, or maintain live cells or other organisms. <FIG> and <FIG> illustrates two containers or vessels <NUM> (i.e., two bioreactors) each coupled to their own respective pump/mixer <NUM>. Fluid from the container or vessel <NUM> enters the main inlet <NUM> of the pump/mixer <NUM> as explained herein previously. Each pump/mixer <NUM> includes multiple outlets <NUM>, some of which, lead to fluid-carrying conduits or lines <NUM>, <NUM> that ultimately return to the container or vessel <NUM>. As seen in <FIG> and <FIG>, fluid conduit or line <NUM> includes a gas transfer unit <NUM> interposed in the flow path and is used to gas transfer and/or exchange. Fluid conduit or line <NUM> includes a filter unit <NUM> interposed in the flow path and is used for filtration. After passing through gas transfer unit <NUM> and filter unit <NUM>, the respective fluid conduits or lines <NUM>, <NUM> return flow to the container or vessel <NUM> via ports <NUM>. In one preferred embodiment, the ports <NUM> are located in the top of the container or vessel <NUM>. In this regard, the ports <NUM> are located above the fluid level contained in the container or vessel <NUM> which is advantageous as it avoids possible leaks. Each port <NUM> is connected to respective outlet lines <NUM> that terminate at various depths or locations within the container or vessel <NUM>. Additional ports <NUM> may be provided on the container or vessel <NUM> that are used to input fluids, gases, or even solids into the interior of the container or vessel <NUM>.

Each pump/mixer <NUM> includes one or more additional inlets <NUM> that are used to introduce fluids for mixing into the pump/mixer <NUM> via conduit or line <NUM>. The inlet(s) <NUM> may be used to adding buffers, wash fluid, other fluids, chemicals, reagents, special cell nutrients, drugs or therapeutics, and the like as needed by the particular process taking place in the bioreactor. The pump/mixer <NUM> may include additional outlets <NUM> that are used to evacuate the contents of the container or vessel <NUM> or for transport to another downstream processing operation. While <FIG> and <FIG> illustrate a gas transfer unit <NUM> and a filter unit <NUM>, it should be understood that other operations may be optionally integrated into fluid conduits/lines <NUM>, <NUM> (in some embodiment these may be omitted and lines <NUM>, <NUM> just serve as return lines). As seen in <FIG> and <FIG>, the pump/mixers <NUM> are supported by a housing or base <NUM>. The housing or base <NUM> contains the motors or drive units <NUM> and electronics used to power and drive the pump/mixers <NUM>.

<FIG> illustrate another embodiment of a container or vessel <NUM> that is used as a bioreactor. This embodiment illustrates a pump/mixer <NUM> with one or more inlets <NUM> and multiple outlets <NUM> secured to the bottom of the container or vessel <NUM> via a port or coupler <NUM> using a sanitary clamp <NUM> (other attachment scheme). The main inlet <NUM> to the pump/mixer <NUM> is located at the bottom of the container or vessel <NUM>. In this embodiment, there are five (<NUM>) outlets with four (<NUM>) of the outlets leading to respective fluid-carrying conduits or lines <NUM>, <NUM>, <NUM>, <NUM> that eventually return fluid to the container or vessel <NUM>. The additional inlets <NUM> are coupled to fluid-carrying tubing or conduits <NUM> that carry fluid that enters the inlets <NUM> of the pump/mixer <NUM> for mixing with the fluid that enters the main inlet <NUM>. As with the embodiment of <FIG>, <FIG>, one or more processing units may be interposed in the conduits or lines <NUM>, <NUM>, <NUM>, <NUM>. These may include, for example, a gas transfer unit <NUM>, a filter unit <NUM>, or the like. Ports <NUM> are provided at the top of the container or vessel <NUM> that are connected to respective outlets lines <NUM> that terminate at various locations with the container or vessel <NUM>. In this particular embodiment, the container or vessel <NUM>, which is a flexible bag, is held within a frame <NUM> that includes a bottom surface and side walls to hold the flexible bag (one wall is omitted for clarity purposes). Of course, other ways of holding the container or vessel <NUM> are contemplated. For example, the flexible bag may be secured within a dolly or carrier or held in place with hooks, retainers, or the like. As with the prior embodiment, a housing or base <NUM> supports the pump/mixer <NUM> and contains the motor or drive unit <NUM> and electronics used to power and drive the pump/mixer <NUM>.

One advantage of the bioreactor embodiments of <FIG>, <FIG> is that mixing takes place inside the pump/mixer <NUM> and is then transferred into the container or vessel <NUM> via ports <NUM> located at the top of the container. These ports <NUM> are located above the fluid line to thereby reduce risk of leaks and/or contamination. In addition, this reduces the total number of ports as the return lines <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> are used to carry mixed fluid in addition can be used to recirculate fluid within the bioreactor. Mixing feeds can be directly input to the pump/mixer <NUM> and there is no need for a separate inlet port to the container or vessel <NUM> and no need for agitators and/or mixers within the container or vessel <NUM>. Conditions inside the container or vessel <NUM> can be tuned as needed by controlling the input feeds to the additional inlets <NUM> and also running the bioreactor contents through one or more external processing units. For example, these processing units (e.g., a gas transfer unit <NUM>) can perform gas exchange similar to the way a person's lungs operate to exchange oxygen and carbon dioxide during respiration. Likewise, a filter unit <NUM> may eliminate waste products and operate similar to a person's liver or kidneys. At the same time, the input conditions to the container or vessel <NUM> can be adjusted or tuned by adjusting the compositions and/or flow rates of input fluids to the interior of the container or vessel <NUM> (e.g., to adjust or tune the growth media present therein). It should be appreciated that the specific bioreactor setups illustrated in <FIG> and <FIG> are exemplary. Different bioreactor setups appropriate for a particular application(s) can be used that incorporate the pump/mixer(s) <NUM>.

The pumps <NUM> and/or pump/mixers <NUM> may also be used in industrial applications. For example, the <NUM> and/or pump/mixers <NUM> may be used with Intermediate Bulk Containers (IBC). IBCs are used to storing and transporting bulk quantities of materials including fluids or liquids. The contents of IBCs serving as the container or vessel <NUM> may be pumped and/or mixed using the pumps <NUM> and/or pump/mixers <NUM>. The pumps <NUM> and/or pump/mixers <NUM> may also be used in food manufacturing applications to mix and/or pump food ingredients, additives, or the like. While the pumps <NUM> and/or pump/mixers <NUM> are principally designed to operate on fluids or liquids that are contained in the container or vessel <NUM> it should be appreciated that some applications (such as food) may involve some solid materials or contents that may be viscous or have fluid-like properties. The pumps <NUM> and/or pump/mixers <NUM> may also be used in semiconductor or other industrial applications.

Claim 1:
A pump/mixer device (<NUM>) comprising:
a main inlet (<NUM>) located at a top or upper region of the pump/mixer device (<NUM>), the main inlet (<NUM>) configured to be secured to or integrated into a bottom of a vessel or container (<NUM>);
an outer chamber (<NUM>) disposed in the pump/mixer device (<NUM>) and fluidically connected to the main inlet (<NUM>);
a plurality of lower chambers (<NUM>) disposed in the pump/mixer device (<NUM>) beneath the outer chamber (<NUM>) and fluidically connected to the outer chamber (<NUM>) by respective check valves (<NUM>) interposed between the outer chamber (<NUM>) and the plurality of lower chambers (<NUM>);
a central chamber (<NUM>) disposed in the pump/mixer device (<NUM>), the central chamber (<NUM>) fluidically connected to the plurality of lower chambers (<NUM>) with respective check valves (<NUM>) interposed between the central chamber (<NUM>) and the plurality of lower chambers (<NUM>);
at least one outlet (<NUM>) fluidically connected to the central chamber (<NUM>);
one or more additional inlets (<NUM>) fluidically coupled to the central chamber (<NUM>) via respective inlet check valve(s) (<NUM>); and
a moveable diaphragm (<NUM>) disposed in each of the plurality of lower chambers (<NUM>), the moveable diaphragms (<NUM>) interfacing with a respective actuating element (<NUM>) driven by a wobble plate or nutating disk (<NUM>) operatively coupled to a motor or drive unit (<NUM>), wherein actuation causes each of the moveable diaphragms (<NUM>) to move in opposing directions.