The field of the invention generally relates to fluid-based systems and processes used in the manufacture, production, or capture of products. More specifically, the invention pertains to vessels such as bioprocess or pharmaceutical fluid containers, media and buffer bags, reactors, and fermentation units used in connection with pharmaceutical, biological, gene therapy applications or other hygienic process industries.
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 filtered, extracted, concentrated, and ultimately collected from the growth container. 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. Filtration is performed to separate or concentrate a fluid solution and in biotechnology and pharmaceutical manufacturing processes is critical for the successful and efficient production of drugs and other desirable products.
Various separation and filtration devices can be used to process the fluid pumped of the container unit where cell growth takes place. One common technique that is used to filter or separate components from the fluid is tangential flow filtration (TFF) where a filter or membrane is used to filter species contained in the fluid based on, for example, physical size. The flow is tangential to the membrane to reduce the accumulation of waste products, dead cells, and biofilm that tends to clog the filter membrane. Another separation technique utilizes acoustic wave separation (AWS) technology for cell harvesting and clarification. In contrast to methods like TFF. AWS does not achieve separation of cells using a physical barrier or filter, but with high-frequency resonant ultrasonic waves.
More recently, perfusion methods for growing cells have been developed. In the perfusion method, culture medium which is depleted of nutrients and contains waste products generated by the cells, is continuously removed from the cell culture and replaced with fresh culture media. The perfusion method enables one to achieve high concentrations of cells and permits the production process to run continuously unlike batch process. In perfusion methods, there still is a need to separate and/or filter the generated drugs and waste products from the continuously circulate cells. Perfusion methods, however, are known to have lower reliability because the cells are frequently damaged during the separation and/or filtration process which separates the medium from the cells. Various solutions have been proposed to address the known disadvantages of perfusion growth methods. U.S. Pat. No. 6,544,424 discloses a fluid filtration system that attempts to address the low reliability of perfusion methods. The system described in the '424 patent utilizes a hollow fiber module that is coupled at one end to a separate diaphragm pump. The pump is used to generate alternating flow across follow fibers or a filter screen.
A problem with solutions such as that disclosed in the '424 patent is that the separate pump located downstream of the vessel containing cells is connected to the vessel through various conduits and the hollow fiber module. 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. Pumping and vessel systems must therefore be designed to avoid these problems. Technically, this means that the pump and system must be designed such that the Net Positive Suction Head Available (NPSHA) exceeds the Net Positive Suction Head Available Required (NPSHR) to ensure the pump will operate without cavitation or other adverse flow conditions. Unfortunately, when pumps are placed downstream from the container like that disclosed in the '424 patent, this inevitably tends to produce cavitation, vacuum, and problematic flow conditions that tend to kill or disrupt cells.
In addition, in many cell growth systems like those discussed above, a flexible segment of tubing connects the cell-containing vessel to the pump and any associated filtration/separation devices. Unfortunately, this configuration suffers from a problem in that due to upstream “negative” pumping pressure, the flexible tubing may collapse in on itself. This collapse of the tubing causes the inner surfaces of the tubing to contact one another and thereby prevents the further flow of fluid in the tubing. Even if the tubing does not fully close off, the presence of the tubing may lead to cavitation and other deleterious pulsatile flow conditions. For example, the irregular and often tortious paths of the tubing or conduit disrupts the fragile state of cells. These flow conditions may cause damage to the pump as well as disrupting and interfering with the cells contained in the fluid. Attempts have been made to address this in pump design. For example, the Quantum peristaltic pump made by Watson Marlow attempts to reduce shear using a single-use cartridge but this pump still is connected via a feed line that is located some distance from the reservoir. This causes pulsation at low flow rates and does not solve the main problem of getting fluid into the pump efficiently.
International Patent Application No. PCT/US2018/015777, which is incorporated herein by reference, describes a fluid vessel for containing biological/pharmaceutical fluids that overcomes the above limitations by incorporating a pump that is either directly or indirectly incorporated into the fluid vessel. Additional improvements in the designs of such fluid vessels having an integrated pump are desired.
In one embodiment, a fluid vessel for containing biological or pharmaceutical fluids includes a pump that is either directly or indirectly incorporated into the fluid vessel. In one embodiment, a hole or aperture is located in a bottom surface of the vessel that allows passage of fluid out of the vessel. The hole or aperture, in some embodiments, may actually encompass some, most, or all of the bottom surface of the vessel, leaving a perimeter or circumferential surface to which the pump is adhered to. The pump is incorporated into or attached to the vessel at the location of the aperture or opening at the bottom of the vessel. In some embodiments, the pump is secured to the vessel through an intermediate component such as a port or flange that passes through the aperture and is secured to the vessel in a fluid tight arrangement (or manufactured in conjunction with the vessel). The pump is then secured to the flange. In another embodiment, the pump is directly secured to the vessel. For example, the pump head of the pump may be integrally formed with the vessel during the manufacturing process. Alternatively, in still another embodiment, the pump head may be secured to the vessel using one or more fasteners. The pump head may also be directly bonded to the vessel using thermal bonding, an adhesive, glue, weld, or the like.
As explained herein, the pump or pump head may incorporate a plurality of outlets. For example, the pump or pump head which forms part of the pump may have 2, 3, 4, 5, 6, 7, 8, 9, 10, or more separate outlets. The outlets may be designed to accommodate the same or different flows from each outlet. The outlets may be positioned about the periphery or sides of the pump or pump head in symmetrical or asymmetrical manner. The outlets of the pump 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 outlets may optionally include or incorporate a valve directly or indirectly in one or more of the outlets. Tubing or other conduit may also interface directly with the outlets of the pump (e.g., by welding to the outlets or the like). In still another embodiment, the outlets of the pump may simply be an aperture or opening through which fluid passes. This aperture or opening may be threaded internally so that the outlets can accommodate a threaded connecting component or insert that interfaces with the threaded outlets of the pump.
The outlets may lead to separate fluid lines (e.g., tubing or conduit) that are returned to the vessel. In other embodiments, these fluid lines are directed to different processes and unit operations prior to returning to the fluid vessel. As one example, the fluid line connected to the outlet may also operate as a return line that returns fluid directly the fluid vessel. The fluid line from other outlets may perform one or more active operations. For example, the fluid line may lead to a filter, gas sparger, waste remover, sensing unit (e.g., pH and conductivity), media addition unit, or separation unit prior to being returned to the fluid vessel. The fluid lines may include rigid pipe or conduit in one embodiment. In another embodiment, the fluid lines may also include a flexible tubing or conduit (e.g., silicone tubing). In some embodiments, for example, where fluid pressures are high, the flexible conduit or tubing is encapsulated using one or more external two-piece jackets that surround the flexible tubing and resist the high fluid pressures that exist within the flexible tubing. These jackets may be connected to other components (e.g., valves, process units, and the like) or to each other in an end-to-end arrangement until the fluid line returns to the fluid vessel.
The fluid lines that are connected to the plurality of outlets, in some embodiments, eventually return to the fluid vessel or are connected to other fluid lines that return to the fluid vessel. These “return lines” enter the fluid vessel from the top or side and have a length that extends some distance into the interior of the fluid vessel. In one embodiment, the different return lines may extend different distances into the interior of the fluid vessel. For example, one return line may have a length that places an end close to the bottom of the fluid vessel. Conversely, another return line may have a length that places an end close to the top of the fluid vessel. Other return lines may have lengths that are the same or different lengths (e.g., in between). In still other embodiments, the fluid lines that are connected to the plurality of outlets do not return to the vessel. That is to say, the outlet lines may be connected to other downstream systems or processes. For example, for a buffer preparation or inline dilution application, one or more of the outlets may lead to a downstream vessel or the like where fluid and/or reagents may be added and then pumped out in a similar manner.
In one preferred embodiment, the return lines inside the vessel are formed from flexible tubing so that when fluid is actually pumped through the return lines and into the interior of the fluid vessel the return lines move, snake, or oscillate back and forth to provide agitation or mixing of the liquid contained in the fluid vessel. The flexible tubing may be the same or different tubing used outside the vessel environment. The movement of the return lines resembles the snaking movement that a water hose makes when left on an unattended. This random movement of the return line aids in agitating and mixing the fluid contained in the fluid vessel. In some embodiments, the return lines may include one or more end features that aid in agitating and/or mixing the fluid contained. For example, the return lines may include fins, protuberances, branches, or other surface features. The return lines may also include holes or apertures formed in the ends which may further enable snaking back-and-forth motion within the liquid contained in the fluid vessel.
In one embodiment, the fluid vessel is a substantially rigid container. For example, the vessel may take the form of a tub, vat, barrel, bottle, tank (e.g., buffer tank), reactor, flask, or other container suitable for holding liquids. The fluid vessel may be incorporated into processes, in some embodiments, where the vessel is used as a bioreactor or fermenter. The fluid vessel may be made of any number of materials including metals, polymers, glass, and the like. In one preferred embodiment, the vessel is formed from a polymer or resin material and is made as a single-use device. Likewise, one or more portions of the pump (e.g., pump head) that is directly or indirectly secured to the vessel may also be made from a polymer or resin material which facilitates integration or bonding of the pump to the vessel. In some embodiments, both the pump and vessel are made from same material. In other embodiments, the pump and vessel are made from different materials.
In another embodiment, the fluid vessel is flexible container such as a bag. The 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 one or multiple layers. The bag includes a pump that is directly or indirectly secured to a bottom surface of the bag. The bag and attached or integrated pump may be carried in a trolley, dolly, cradle, cart, holder, or other support container to hold the bag and pump in the proper orientation. In some embodiments, both the pump and bag are made from the same material. In other embodiments, the pump and bag are made from different materials.
In one embodiment, regardless of whether the vessel is flexible or substantially rigid, the pump includes a separate motor that is used to power and operate the pump. For example, one preferred embodiment of the pump is a diaphragm pump because of the gentle nature of the flows produced during operation. A diaphragm pump or membrane pump operates as positive displacement pump that uses moving membrane in combination with valves to pump fluid. In one embodiment, the drive shaft of the motor may be used to drive a nutating disk or wobble plate to actuate the diaphragm membrane to drive fluid through the pump. Alternatively, servo motors or electronic/magnetic actuators may be used to sequentially actuate the diaphragm membrane to achieve a similar pumping action. The pump includes an inlet port that receives the incoming fluid that passes through the aperture in the vessel or the open vessel bottom and outlet ports through which the pumped fluid passes.
In one embodiment of the invention the vessel itself is made to be single use or disposable. In addition, one or more components of the pump may be made disposable. For example, the pump head which in some embodiments is integrally formed with the vessel may be disposable or contain disposable components. In other embodiments where the pump head is secured to the vessel, the pump head may also be formed from one or more components that are single use components. Alternatively, the vessel, pump, and any interface components between the two like a port or flange may be sterilizable for reuse. The motor or other drive mechanism that is used to power and operate the pump is typically reusable.
In one embodiment, a vessel that is used, for example, bioprocess or pharmaceutical operations includes an integrated or connected pump. The vessel includes a flexible bag or a substantially rigid container defining an interior volume and having a bottom surface, the bottom surface containing an aperture therein for the passage of fluid. A pump is secured to the bottom surface of the vessel, the pump having an inlet in fluid communication with the interior volume via the aperture and a plurality of outlets, wherein the pump pumps fluid from the interior volume of the vessel into the inlet of the pump and out the plurality of outlets: and one or more conduits or tubing comprising return lines that are connected at one end to the plurality of outlets and having flexible free ends extending into the interior volume of the vessel.
In another embodiment, a method of pumping fluid from a vessel that is formed from a flexible bag or a substantially rigid container is disclosed. The vessel defines an interior volume and has a bottom surface, the bottom surface containing an aperture therein for the passage of fluid and wherein a pump is secured to the bottom surface of the vessel having an inlet in fluid communication with the interior volume via the aperture and a plurality of outlets coupled to respective conduits or tubing comprising return lines that are connected at one end to the plurality of outlets and having flexible free ends extending into the interior volume of the vessel. The method includes pumping a fluid contained in the vessel out the plurality of outlets of the pump and back into the vessel via the return lines.
The vessels described herein may include an optional that is secured either to the vessel itself or to the pump. The powder barrier at least partially covers a portion of the inlet to the pump. The powder barrier may be used to prevent solids and other materials that are fed into the vessel from directly entering the inlet of the port prior to properly mixing with the fluid. The powder barrier may also be omitted entirely.
In one preferred embodiment, one or more of the ports 20 may also provide access for return lines 24 that return fluid to the vessel 10. The return lines 24 in one embodiment are at least partially formed from a flexible material such that the return lines 24 when inside the vessel 10 are able to bend and twist in response to fluid flow as explained herein in more detail. The flexible tubing or conduit that makes up the return lines 24 may be formed using an unreinforced polymer conduit or tube in some embodiments. For example, the flexible tubing or conduit 24 may be formed from platinum cured silicone however other materials may be used. These include, for example, a polymer such as thermoplastic elastomers (TPE), thermoplastic rubber (TPR), silicone, or other materials commonly used in pharmaceutical/biopharmaceutical application. The flexible tubing/conduit of the return lines 24 may have may have a variety of diameters and lengths. There may be any number of return lines 24 present in the vessel 10. This may include, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more return lines 24. In some embodiments, the number of return lines 24 equals the number of outlets 52 from the pump 12 (described below) although there may be more or fewer return lines than the number of outlets 52 in other embodiments. The return lines 24 may return directly to the vessel 10 in some embodiments. In other embodiments, the return lines 24 may contain sensors or processing units 100 (like illustrated in
With reference to
In one preferred embodiment, when multiple return lines 24 are used, different return lines 24 have free ends 42 of the flexible tubing or conduit that terminate at different depths within the vessel 10 as seen in
The flexible tubing or conduit of the return lines 24 have “free” ends 42 that extend into the interior of the vessel 10 and have an open end through which fluid exits the return lines 24 into the vessel 10. The free ends 42 are preferably submerged in the fluid when present. The return lines 24 are configured to be freely hanging such that when liquid fluid flows through the return lines 24 and into the vessel 10 the return lines 24 undergo back-and-forth, undulating motion, or snake-like movement within liquid contained in the vessel 10 (illustrated in
In one optional embodiment, as illustrated in
In some embodiments, like that illustrated in
In one embodiment, the vessel 10 is flexible bag. The flexible bag, in one embodiment, is made from one or more polymers or resin materials. For example, medical-grade resins compliant with class VI standards may be used. Additional examples include polyethylene (PE), e.g., low density polyethylene (LDPE) or ultra-low-density polyethylene (ULDPE) or polypropylene (PP), ethylene vinyl acetate (EFA), polyethylene terephthalate (PET), polyvinyl acetate (PVA), polyvinyl chloride (PVC), ethylene-vinyl alcohol copolymer (EVOH), and the like are also contemplated. In some embodiments, the flexible bag may be formed from multiple layers. For example, the inner layer that contacts the fluid may be made from LDPE or PE and an outer layer made from EVOH. In some embodiments, a second layer of polyvinyl acetate (PVA) or flexible polyvinyl chloride (PVC) may be used as an intermediate layer. An outer layer of LDPE or PET may provide mechanical strength. Of course, the flexible bag may include fewer or more layers or even a single layer. It should be appreciated that the integrated pump 12 embodiments described herein may be used with any number of different construction types, materials, and layer(s) used for the flexible bag.
In another embodiment, such as that illustrated in
The tank vessel 10 and lid or top surface 16 may be made from a polymer, plastic material, or resin that mimics the performance of glass or stainless steel. The polymer material preferably complies with Class VI or ISO-10993 standards or higher levels (or whatever regulatory requirements may be required for the particular application) of biocompatibility and chemical resistance as needed, and is free of or contains low amounts of leachable and extractable material. Examples of polymers that can be used to form the substantially rigid container include polyethylene, polycarbonate, and as well as the materials noted above with respect to the flexible bag embodiment. Medical-grade resins compliant with class VI standards may also be used. Alternatively, the tank vessel 10 and/or lid or top surface 16 may be made from a metal such as stainless steel. The tank vessel 10 and/or lid or top surface 16 may also be made of glass. In some embodiments, the vessel 10 is designed as a single-use vessel 10 that is discarded after a batch or continuous run of products has completed. In other embodiments, the vessel 10 may be designed to be sterilized and reused.
The pump 12 may be connected to the vessel 10 directly or indirectly as explained herein. A direct connection connects one or more surfaces of an inlet 54 of the pump 12 to the vessel 10. In contrast, an indirect connection connects the pump 12 (or inlet 54 of pump 12) to the vessel 10 using a connecting port 22 (as seen in
The connecting port 22 may be welded to the bottom surface 18 of the vessel 10 in some embodiments. Any known method of welding such components together including heat welding, resistive welding, spin welding, friction welding, laser welding, and the like. An adhesive may also be used to secure the connecting port 22 the bottom surface 18. Alternatively, the connecting port 22 may be integrally formed with the vessel 10 during the manufacturing process (e.g., in the molding or formation of the vessel 10 (e.g., flexible bag or rigid container or tank)). The connecting port 22 may also be made from a polymer or resin material than can bond the vessel 10 in response to, for example, applied heat.
On one embodiment, the connecting port 22 may include a flanged surface located outside of the vessel 10 that is a hygienic clamp that is commonly used in bioprocess and pharmaceutical systems. For example, tri-clamp (TC) type flanged surface is one type of hygienic clamp that is commonly used in bioprocess and pharmaceutical systems. In hygienic clamp connections two mating flanged surfaces are connected to one another at an interface that typically contains a ferrule gasket 56 (
As best seen in
The outlets 52 of the pump 12 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 outlets 52 may include or incorporate a valve directly or indirectly in the outlet 52. Tubing or other conduit may also interface directly with the outlets 52 of the pump 12 (e.g., by welding to the outlet 52 or the like). In still another embodiment, the outlets 52 of the pump 12 may simply be an aperture or opening through which fluid passes. This aperture or opening may be threaded internally so that the outlets 52 can accommodate a threaded connecting component or insert that is screwed into the threaded outlet 52 of the pump 12. This may include a connector (not shown) that is screwed into the internally threaded outlet 52. The threaded connecting component or insert may include any number of ends or connectors used in biopharmaceutical/pharmaceutical processes such as those described herein.
The outlets 52 are generally illustrated in the FIGS. as being oriented generally orthogonal to vertical axis of the vessel 10. It should be appreciated that the outlets 52 may exit the pump 12 at an angle. For example, the outlets 52 may be angled downward to facilitate easier usage. An angle (relative to horizontal) of about 15° to 45° would be common, although other angles are contemplated.
The pump 12, in one embodiment, operates as a diaphragm pump. A diaphragm pump operates by the actuation of multiple diaphragms 66 (
While there are four (4) diaphragms 66 illustrated in
With reference back to
While
The use of the two-piece jackets 26 is optional as described herein. In other configurations, the flexible conduit or tubing that forms the return lines 24 have no encapsulating structures. This may be the case, for example, when operating pressures are low and the risk of the flexible conduit or tubing bursting or otherwise failing is low. The return lines 24 may return directly to the vessel 10 or the return lines may have one or more processing units 100 disposed inline as disclosed in the embodiments of
The addition of multiple, pump outlets 52 from a common vessel 10 provides added functionality that does not exist currently. While it is known that a single vessel can have multiple gravity discharging outlets, these outlets can be subjected to ballooning due to over pressurization, collapse due to vacuum, kinking due to poor organization of the conduits or even people stepping on them. By employing multiple pump outlets 52, this solves some of these issues. Moreover, combining the multiple outlet design with the encapsulating jackets 26 for the flexible tubing and processing units 100 with multiple streams to manage more efficiently the biological or chemical makeup of the volume in the vessel 10 solves even more problems with current setups. The use of a single or common vessel 10 with multiple, pumped outlets 52 can be a basic building block that makes any pump 12 in a bioprocess/pharmaceutical system work better and enables next generation processing to move forward.
While some of the pump embodiments described herein utilize conduit or tubing as return lines 24 that return to the vessel 10 it should be appreciated that in some embodiments there may be no return lines. For example, the conduit or tubing that are coupled to the pump outlets 52 of pump 12 may lead to separate processing units 100 as described herein. For example,
While embodiments of the present invention have been shown and described, various modifications may be made without departing from the scope of the present invention. Moreover, it should be appreciated that aspects of one embodiment may be utilized in other embodiments described herein. Thus, feature(s) of one embodiment may be substituted or used in other embodiments. This includes, by way example, the powder barrier, ports, pumps, pump connection types, jackets (or lack thereof), motors, and the like. In addition, while the embodiments described herein have largely been described being used in the context of a bioprocess or pharmaceutical operation, the embodiments are not limited to those applications. For example, the concepts and embodiments described herein may be applied to high-purity chemical systems or in other industries. The invention, therefore, should not be limited except to the following claims and their equivalents.
This application claims priority to U.S. Provisional Patent Application No. 63/197,250 filed on Jun. 4, 2021, which is hereby incorporated by reference in its entirety. Priority is claimed pursuant to 35 U.S.C. § 119 and any other applicable statute.
Filing Document | Filing Date | Country | Kind |
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PCT/US2022/031966 | 6/2/2022 | WO |
Number | Date | Country | |
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63197250 | Jun 2021 | US |