Dissolving system

Abstract

A dissolution system includes a dissolution line and a bypass line. A dissolution line fluidly couples the biological container, the pump, the cartridge, the upstream filter, and the downstream filter into a circulation loop. A bypass line is in fluid communication with the dissolution line at the upstream junction and the downstream junction such that the bypass line is in a parallel relationship with the cartridge. The flow control system is configured to control fluid flow through the cartridge such that fluid flow through at least one of the dissolution line and the bypass line is selectively controlled based on pressure in the dissolution line downstream of the cartridge between the cartridge and the biological container.

Description

Technical Field

[0001] This patent disclosure generally relates to a dissolution system, and more particularly to a dissolution system for preparing a buffer solution from buffer powder dissolved in a liquid medium. Background Art

[0002] Buffer solutions are typically made at full strength in a mixer and produced in large quantities for storage in shipments. A buffer dissolution system typically includes buffer powder loaded in bags. The buffer powder bags are usually prepared in one chamber and then transported to another chamber to prepare the buffer solution. The powder bags are typically lifted above the mixer using a lift, then opened and poured into the mixer, which mixes the contents emptied from the powder bag with the fluid all at once to provide a mixed solution. Next, the mixed solution is filtered using a sterile-grade or bioburden-reducing-grade filter, and then the filtered and mixed solution is transported to a storage or transfer tank.

[0003] For typical bioprocessing applications, multiple buffer solutions are used, and the requirements for each buffer solution are different. In some cases, the requirement for each buffer is approximately two thousand liters. Since the floor space of a bioprocessing facility is very valuable, shipments are transported from the buffer preparation area to the process suite. One chamber is dedicated to biopreparation, another chamber is for media and buffer preparation, and yet another chamber is for the process suite, so the bioprocessing operations take up a considerable amount of space. The sterility of the materials may be compromised at each transfer step. In addition, sometimes specialized mobile equipment is required for larger shipments, and there are risks associated with operating such machines and moving these loads.

[0004] There has been a need in the art to provide additional solutions to enhance the management of buffer solutions used in various bioprocessing applications. For example, there has been a need in the art to provide new and enhanced powder dissolution systems.

[0005] It will be understood that this background description is created to assist the reader and should not be regarded as indicating that any of the noted problems are themselves known in the art. While the described principles may alleviate problems inherent in other systems in some aspects and embodiments, it will be understood that the scope of the protected innovation is defined by the appended claims, rather than by the ability of any disclosed feature to solve any particular problem noted herein. Summary of the Invention

[0006] In one aspect, the present disclosure relates to embodiments of a dissolution system. In one embodiment, the dissolution system includes a biocontainer, a pump, a cartridge, an upstream filter, a downstream filter, and a dissolution pipeline. The dissolution pipeline fluidly couples the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter into a circulation loop.

[0007] A biocontainer defines a container inlet, a container outlet, and a storage volume. The container inlet and outlet are in fluid communication with the storage volume. The storage volume is configured to receive a fluid supply. A pump is in fluid communication with the storage volume of the biocontainer. The pump is adapted to receive the fluid supply from the container outlet of the biocontainer and to discharge a fluid flow therefrom in a circulation direction to the container inlet.

[0008] A cartridge defines a cartridge inlet, a cartridge outlet, and a storage chamber. The cartridge inlet and outlet are in fluid communication with the storage chamber. The storage chamber is configured to receive an amount of solute for dissolution into the fluid supply. The storage chamber is in fluid communication with the pump via the cartridge inlet to receive a fluid flow therefrom. The cartridge inlet, the storage chamber, and the cartridge outlet are configured such that the fluid flow is directed from the cartridge inlet through the storage chamber and out of the cartridge outlet to flow through the amount of solute in the storage chamber. The cartridge outlet is in fluid communication with the container inlet.

[0009] An upstream filter is in fluid communication with the biocontainer and the cartridge such that the upstream filter is upstream of the cartridge with respect to the circulation direction and is between the container outlet of the biocontainer and the cartridge inlet. A downstream filter is in fluid communication with the cartridge and the biocontainer such that the downstream filter is downstream of the cartridge with respect to the circulation direction and is between the cartridge outlet of the cartridge and the container inlet of the biocontainer.

[0010] In another embodiment, a dissolution system includes: a dissolution line that fluidly couples the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter into a circulation loop; a bypass line; and a device for controlling the fluid flow through the cartridge. The biocontainer is configured to receive a fluid supply. The pump is adapted to receive the fluid supply from the biocontainer and to discharge a fluid flow therefrom in a circulation direction. The cartridge is configured to receive an amount of solute for dissolution into the fluid supply. The cartridge is in fluid communication with the pump to receive a fluid flow therefrom and to pass the fluid flow therethrough. The upstream filter is in fluid communication with the biocontainer and the cartridge such that the upstream filter is upstream of the cartridge with respect to the circulation direction and is between the biocontainer and the cartridge, and the downstream filter is in fluid communication with the cartridge and the biocontainer such that the downstream filter is downstream of the cartridge with respect to the circulation direction and is between the cartridge and the biocontainer.

[0011] The dissolution line includes an upstream junction and a downstream junction. The upstream junction is disposed between the upstream filter and the cartridge upstream of the cartridge with respect to the circulation direction, and the downstream junction is disposed between the cartridge and the downstream filter downstream of the cartridge with respect to the circulation direction. The bypass line is in fluid communication with the dissolution line at the upstream junction and the downstream junction such that the bypass line is in parallel with the cartridge. The device for controlling the fluid flow through the cartridge is configured to selectively control the fluid flow through at least one of the dissolution line and the bypass line based on the pressure in the dissolution line between the cartridge and the biocontainer downstream of the cartridge.

[0012] In another aspect, the present disclosure relates to an embodiment of a method for preparing a buffer solution. In one embodiment, the method for preparing a buffer includes fluidly coupling a buffer cartridge in a circulation loop formed by a dissolution pipeline. The dissolution pipeline fluidly couples a bioreactor, a pump adapted to discharge a fluid flow therefrom in a circulation direction, the buffer cartridge, an upstream filter disposed between the bioreactor and the buffer cartridge upstream of the buffer cartridge with respect to the circulation direction, and a downstream filter disposed between the buffer cartridge and the bioreactor upstream of the buffer cartridge with respect to the circulation direction in the circulation loop. The buffer cartridge contains a certain amount of buffer solute. The fluid flow circulates through the circulation loop to entrain at least a portion of the buffer solute from the buffer cartridge into the fluid flow.

[0013] From the following detailed description and the drawings, further and alternative aspects and features of the disclosed principles will be understood. As will be appreciated, the dissolution system and the method for preparing a solution disclosed herein can be implemented in other and different embodiments and can be modified in various aspects. Accordingly, it will be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit the scope of the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is a schematic diagram of an embodiment of a dissolution system constructed in accordance with the principles of the present disclosure.

[0015] Figure 2 is a schematic diagram of an embodiment of a dissolution system and method constructed and executed in accordance with the principles of the present disclosure.

[0016] Figure 3 is a schematic diagram of an embodiment of a dissolution system constructed in accordance with the principles of the present disclosure.

[0017] Figure 4 illustrates an embodiment of a controller processing system that can be used with an embodiment of a dissolution system and method in accordance with the principles of the present disclosure.

[0018] It should be understood that the drawings are not necessarily drawn to scale and the disclosed embodiments are shown in diagrammatic and partial views. In some cases, details that are not necessary for understanding the present disclosure or details that make other details difficult to understand may be omitted. It should be understood that the present disclosure is not limited to the specific embodiments shown herein. DETAILED DESCRIPTION

[0019] An embodiment of a dissolution system constructed in accordance with the principles of the present disclosure can be applicable to an embodiment of a method for preparing a solution executed in accordance with the principles of the present disclosure. An embodiment of a dissolution system constructed in accordance with the principles of the present disclosure can be used in a biopharmaceutical environment, but can also be used in other applications such as those where different solutions, powders, biologic agents, fluids, reagents, and / or chemicals are used for preparation.

[0020] Embodiments of a dissolution system constructed in accordance with the principles of the present disclosure can be used to achieve direct dissolution and sterilization of powders through recirculation, and simplify the dilution of powders in biological processes, such as, for example, suitable buffer powders. For example, a buffer preparation process following the principles of the present disclosure can be used in the manufacture of biopharmaceuticals, such as, for example, the process of antibodies. Those skilled in the art will understand other uses of the systems and methods following the principles of the present disclosure, which are applicable to occasions where effective solute dissolution is desired, such as media preparation, where subsequent processes benefit from the aseptic addition of any final buffer or media. The present disclosure can also find uses outside the biopharmaceutical field, such as for the production of saline, which is a common requirement in hospitals.

[0021] Embodiments of a dissolution system constructed in accordance with the principles of the present disclosure can more easily maintain the sterility of a biological container during the dissolution process even when recirculating with a non-sterile powder container or buffer cartridge, while reducing the number of steps and the amount of time required to complete the dissolution of the solute into the solvent by utilizing effective solute distribution.

[0022] In an embodiment, the dissolution line of a dissolution system constructed in accordance with the principles of the present disclosure can be operated to provide a closed-loop recirculation of a solvent through a quantity of solute stored in a cartridge. The closed-loop arrangement can improve operation by reducing exposure to external contaminants, such as the air interface of the mixing process, thereby further enhancing sterility confidence. Additionally, including a bypass line in an embodiment of a dissolution system constructed in accordance with the principles of the present disclosure can help prevent excessive solute accumulation in any one component of the system (e.g., filters, pre-filters, etc.).

[0023] Furthermore, embodiments of a dissolution system constructed in accordance with the principles of the present disclosure can contribute to improving industrial and manufacturing aspects. For example, in an embodiment, a buffer solution can be prepared on-site, such as in the same chamber as buffer storage or at the final use location. In an embodiment, preparing a buffer solution at or near the point of use can simplify the application and enable the combination of mixing, sterile filtration, and liquid storage in one process step, thereby reducing the footprint of the buffer preparation process. Material sub-inventory and material transportation logistics can be reduced and used to save space in a bioprocessing facility. The reduction in footprint not only saves costs, but also reduces the cost of the process itself with faster production times, the ability for immediate batch release, and a smaller set of components compared to current preparation processes.

[0024] In an embodiment of a dissolution system constructed in accordance with the principles of the present disclosure, the dissolution system includes a biological container, a pump, a cartridge, an upstream filter, a downstream filter, and a dissolution line. The dissolution line fluidly couples the biological container, the pump, the cartridge, the upstream filter, and the downstream filter into a circulation loop.

[0025] A biocontainer defines a container inlet, a container outlet, and a storage volume. The container inlet and outlet are in fluid communication with the storage volume. The storage volume is configured to receive a fluid supply. A pump is in fluid communication with the storage volume of the biocontainer. The pump is adapted to receive a fluid supply from the container outlet of the biocontainer and discharge a fluid flow therefrom in a circulation direction to the container inlet.

[0026] A cartridge defines a cartridge inlet, a cartridge outlet, and a storage chamber. The cartridge inlet and outlet are in fluid communication with the storage chamber. The storage chamber is configured to receive an amount of solute for dissolution into the fluid supply. In an embodiment, any suitable solute may be used, such as any suitable solid. In an embodiment, the solute may be in any suitable form, such as, for example, powder or granular form.

[0027] The storage chamber is in fluid communication with the pump via the cartridge inlet to receive a fluid flow therefrom. The cartridge inlet, the storage chamber, and the cartridge outlet are configured such that a fluid flow is directed from the cartridge inlet through the storage chamber and out of the cartridge outlet to flow through the amount of solute in the storage chamber. The cartridge outlet is in fluid communication with the container inlet.

[0028] An upstream filter is in fluid communication with the biocontainer and the cartridge such that the upstream filter is upstream of the cartridge relative to the circulation direction and between the container outlet of the biocontainer and the cartridge inlet. A downstream filter is in fluid communication with the cartridge and the biocontainer such that the downstream filter is downstream of the cartridge relative to the circulation direction and between the cartridge outlet of the cartridge and the container inlet of the biocontainer.

[0029] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure may include a valve adapted to selectively control the fluid flow through the cartridge. In an embodiment, a controller is provided that is configured to control the valve based on the pressure in a dissolution line between the cartridge and the biocontainer downstream of the cartridge. In an embodiment, a pressure sensor is disposed in the dissolution line and operatively arranged with the controller to transmit a pressure signal indicative of the pressure sensed by the sensor in the dissolution line.

[0030] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure may include a bypass line in fluid communication with the dissolution line at an upstream junction and a downstream junction such that the bypass line is in parallel relation with the cartridge. The dissolution system may include a flow control system configured to selectively control the fluid flow through at least one of the dissolution line and the bypass line.

[0031] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure may include a pre-filter in fluid communication with the cartridge and the downstream filter such that the pre-filter is between the cartridge and the downstream filter. The pre-filter may have an internal volume larger than the internal volume of the downstream filter.

[0032] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure may include a mixer in fluid communication with a cartridge and a downstream filter such that the mixer is interposed between the buffer cartridge and the downstream filter. In an embodiment, the mixer may be any suitable mixer, such as, for example, a static mixer.

[0033] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure may include a solution property sensor disposed in a dissolution pipeline. The solution property sensor is configured to generate a property signal corresponding to a value of a solution property sensed by the solution property sensor in the dissolution pipeline. At least one of a dissolution valve and a bypass valve may be adapted to operate based on a pressure signal.

[0034] In an embodiment, the solution property sensor may include any suitable sensor, such as, for example, a suitable pH sensor that generates a pH signal indicative of the pH sensed by the pH sensor. In an embodiment, the dissolution system may include a pH adjustment pipeline and a pH adjustment valve. A pH inlet pipeline is in fluid communication with the dissolution pipeline and is adapted to deliver a pH adjustment fluid supply to the dissolution pipeline. The pH adjustment valve is operable to selectively block the pH adjustment pipeline to interrupt the flow of the pH adjustment fluid supply to the dissolution pipeline. The pH adjustment valve is adapted to operate based on the pH signal under the control of a suitable controller.

[0035] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure may include means for controlling the fluid flow through the cartridge. The flow control means may be configured to selectively control the fluid flow through at least one of a dissolution pipeline and a bypass pipeline based on the pressure in the dissolution pipeline downstream of the cartridge and between the cartridge and the biocontainer. In an embodiment, the flow control means may include a dissolution pump disposed in the dissolution pipeline between an upstream junction and the cartridge inlet, a bypass pump disposed in the bypass pipeline, a pressure sensor disposed in the dissolution pipeline between the cartridge outlet and the container inlet, and a controller operably arranged with the pressure sensor, the dissolution pump, and the bypass pump. The pressure sensor is configured to generate a pressure signal corresponding to the pressure sensed by the pressure sensor in the bypass pipeline and transmit the pressure signal to the controller. The controller is configured to operate at least one of the bypass pump and the dissolution pump based on the pressure signal.

[0036] In an embodiment, a dissolution system constructed in accordance with the principles of the present disclosure can include means for controlling the fluid flow through the cartridge, which includes a pump, a dissolution valve, a bypass valve, a pressure sensor, and a controller disposed in a dissolution line between the cartridge outlet and the upstream junction. The dissolution valve is disposed in the dissolution line between the upstream junction and the cartridge inlet, the bypass valve is disposed in a bypass line, and the pressure sensor is disposed in the dissolution line between the cartridge outlet and the container inlet. The pressure sensor is configured to generate a pressure signal corresponding to the pressure sensed by the pressure sensor in the dissolution line and transmit the pressure signal to the controller. The controller is configured to operate at least one of the dissolution valve, the bypass valve, and the pump based on the pressure signal.

[0037] In an embodiment, a method of preparing a solution in accordance with the principles of the present disclosure includes using a recirculation system having a dissolution line, a bypass line, and a flow control system in accordance with the principles of the present disclosure. In an embodiment, a recirculation system constructed in accordance with the principles of the present disclosure includes: a storage biocontainer and a solid cartridge fluidly connected to each other via a dissolution line; a bypass line fluidly connected to the dissolution line such that the bypass line is in parallel relation with the cartridge; and a control system configured to selectively direct the flow through the cartridge or the bypass line.

[0038] Turning now to the drawings, Figure 1 an embodiment of a buffer dissolution system 1 constructed in accordance with the principles of the present disclosure is shown. In an embodiment, system 1 includes a disposable system.

[0039] In an embodiment, any suitable technique can be used to sterilize system 1. For example, in an embodiment, system 1 can be irradiated with gamma rays or X-rays to sterilize it. In other embodiments, other means can be used to sterilize system 1, such as ozonation or high-pressure air / water (steam) sterilization.

[0040] The illustrated dissolution system 1 includes a biocontainer 10, a pump 18, an upstream filter 20, a cartridge 26, a mixer 42, a pre-filter 6, a downstream filter 8, a dissolution line 24, a bypass line 28, and means 22, 23 for controlling the fluid flow through the cartridge 26 by selectively directing the fluid flow through the cartridge 26 and the bypass line 28. The dissolution line 24 fluidly couples the biocontainer 10, the pump 18, the upstream filter 20, the cartridge 26, and the downstream filter 8 into a circulation loop 69.

[0041] The biocontainer 10 is configured to hold a fluid supply. In an embodiment, the biocontainer 10 can be any suitable storage container configured to hold a desired volume of a liquid solution, such as a commercially available "2D" (or "two-dimensional") biocontainer bag or a "3D" (three-dimensional) biocontainer tank. The biocontainer 10 can be a rigid tank or bag, or a more flexible container. For example, the biocontainer 10 can be made of a mixture of low-density polypropylene and polyethylene.

[0042] Biological container 10 defines a container inlet 71, a container outlet 72, and a storage volume 73. The container inlet 71 and the container outlet 72 communicate with the storage volume 73. The storage volume 73 is configured to receive a fluid supply.

[0043] A pump 18 is in fluid communication with the storage volume 73 of the biological container 10. The pump 18 is adapted to receive a fluid supply from the container outlet 72 of the biological container 10 and discharge a fluid flow therefrom in a circulation direction 74 to the container inlet.

[0044] In an embodiment, the pump 18 can be any suitable pump, as will be understood by those skilled in the art. For example, in an embodiment, the pump 18 can be, for example, a suitable peristaltic pump or a suitable variable displacement pump. Although in Figure 1 the embodiment shown, the pump 18 is shown as being disposed downstream of the outlet line 16, the position of the pump 18 can be changed relative to other components of the system 1, such as, for example, as shown in Figure 2 and 3 the embodiment shown.

[0045] The cartridge 26 is configured to contain a quantity of solute for dissolution into the fluid supply. The cartridge 26 is in fluid communication with the pump 18 to receive a fluid flow therefrom and pass the fluid flow therethrough.

[0046] The cartridge 26 defines a cartridge inlet 75, a cartridge outlet 76, and a storage chamber 77. The cartridge inlet 75 and the cartridge outlet 76 communicate with the storage chamber 77. The storage chamber 77 is configured to contain a quantity of solute for dissolution into the fluid supply. The storage chamber 77 is in fluid communication with the pump 18 via the cartridge inlet 75 to receive a fluid flow therefrom. The cartridge inlet 75, the storage chamber 77, and the cartridge outlet 76 are configured such that a fluid flow is directed from the cartridge inlet 75 through the storage chamber 77 and exits the cartridge outlet 76 to flow through a quantity of solute in the storage chamber 77. The cartridge outlet 76 is in fluid communication with the container inlet 71.

[0047] An upstream filter 20 is in fluid communication with the biological container 10 and the cartridge 26 such that the upstream filter 20 is upstream of the cartridge 26 relative to the circulation direction 74 between the container outlet 72 of the biological container 10 and the cartridge inlet 75 of the cartridge 26.

[0048] A downstream filter 8 is in fluid communication with the cartridge 26 and the biological container 10 such that the downstream filter 8 is downstream of the cartridge 26 relative to the circulation direction 74 between the cartridge outlet 76 of the cartridge 26 and the container inlet 71 of the biological container 10.

[0049] The pre-filter 6 is in fluid communication with the cartridge 26 and the downstream filter 8 such that the pre-filter 6 is interposed between the cartridge 26 and the downstream filter 8. In an embodiment, the pre-filter 6 has an internal volume greater than the internal volume of the downstream filter 8. The pre-filter 6 and the upstream and downstream filters 20, 8 can include any suitable filter, which includes any suitable filter membrane, such as, for example, a filter including a high-density polyethylene housing and a filter membrane made of polyethylene or polypropylene.

[0050] The mixer 42 is in fluid communication with the cartridge 26 and the downstream filter 8 such that the mixer 42 is interposed between the cartridge 26 and the downstream filter 8. In an embodiment, the mixer 42 can be any suitable mixer, such as, for example, a static mixer.

[0051] In an embodiment, the buffer cartridge 26 is in fluid communication with the pre-filter 6, the downstream filter 8, the static mixer 42, and the pressure sensor 34. Figure 1 In an embodiment, the downstream filter 8 is located upstream of the pre-filter 6 in the circulation direction 74, wherein the pre-filter 6 has a greater volume than the downstream filter 8.

[0052] The dissolution line 24 includes an upstream junction 81 and a downstream junction 82. The upstream junction 81 is disposed upstream of the cartridge 26 with respect to the circulation direction 74 between the upstream filter 20 and the cartridge 26. The downstream junction 82 is disposed downstream of the cartridge 26 with respect to the circulation direction 74 between the cartridge 26 and the downstream filter 8. The bypass line 28 is in fluid communication with the dissolution line 24 at the upstream junction 81 and the downstream junction 82 such that the bypass line 28 is in a parallel relationship with the cartridge 26.

[0053] The devices 22, 23 for controlling the fluid flow through the cartridge 26 are configured to selectively control the fluid flow through at least one of the dissolution line 24 and the bypass line 28 based on the pressure in the dissolution line 24 downstream of the cartridge 26 between the cartridge 26 and the bioreactor 10. In an embodiment, the flow control device includes a suitable flow control system configured to selectively control the fluid flow through the dissolution line 24 and the bypass line 28 based on the pressure in the dissolution line 24 downstream of the cartridge 26 between the cartridge 26 and the bioreactor 10. The pressure sensor 34 can be used to detect the pressure in the dissolution line 24 downstream of the cartridge 26 between the cartridge 26 and the bioreactor 10.

[0054] The pump 18 is disposed in the dissolution line 24 between the container outlet 72 of the bioreactor 10 and the upstream junction 81. In Figure 1In the illustrated embodiment, the flow control device includes a flow control system that includes a dissolution valve 22, a bypass valve 23, and a pressure sensor 34. The dissolution valve 22 is disposed in a dissolution line 24 between an upstream junction 81 and a cartridge inlet 75. The bypass valve 23 is disposed in a bypass line 28. The pressure sensor 34 is disposed in the dissolution line 24 between a cartridge outlet 76 and a container inlet 71 of the bioreactor 10. The pressure sensor 34 is configured to generate a pressure signal corresponding to the pressure sensed by the pressure sensor 34 in the dissolution line 24. In an embodiment, the pressure sensor 34 is operably communicable with a suitable controller configured to operate at least one of the dissolution valve 22 and the bypass valve 23 based on the pressure signal. For example, when the pressure is above a predetermined value, the controller may be configured to open the bypass valve 23 such that fluid is diverted from the dissolution line 24 to the bypass line 28. In an embodiment, the controller may be configured to independently vary the position of each of the dissolution valve 22 and the bypass valve 23 between a fully open position and a fully closed position to maintain the pressure sensed by the pressure sensor 34 in the dissolution line 24 within a predetermined range.

[0055] In an embodiment, a solution property sensor 32 is disposed in the dissolution line 24. The solution property sensor 32 may be configured to generate a property signal corresponding to the value of the solution property sensed by the solution property sensor 32 in the dissolution line 24. In the illustrated embodiment, the solution property sensor includes a pH sensor and the property signal includes a pH signal.

[0056] System 1 includes a pH adjustment line 38 and a pH adjustment valve 37. The pH adjustment line 38 is in fluid communication with the dissolution line 24 and is adapted to convey a supply of pH adjustment fluid 39 to the dissolution line 24. The pH adjustment valve 37 is operable to selectively occlude the pH adjustment line 38 to interrupt the flow of the supply of pH adjustment fluid 39 to the dissolution line 24. The pH adjustment valve 37 is adapted to operate based on the pH signal generated by the pH sensor 32. In the illustrated embodiment, the pH adjustment line 38 is in fluid communication with the dissolution line 24 via the bypass line 28.

[0057] Reference Figure 2, Another embodiment of the dissolution system 201 constructed in accordance with the principles of the present disclosure includes a flow control device that includes a flow control system configured to selectively control the fluid flow through the dissolution line 24 and the bypass line 28, including a bypass pump 18a disposed in the bypass line 28, a dissolution pump 18b disposed in the dissolution line 24 between the upstream junction 81 and the cartridge inlet 75, and a pressure sensor 34. The pressure sensor 34 is disposed in the dissolution line 24 between the cartridge outlet 76 and the container inlet 71 of the bioreactor 10. The pressure sensor 34 is configured to generate a pressure signal corresponding to the pressure sensed by the pressure sensor 34 in the dissolution line 24. In an embodiment, at least one of the bypass pump 18a and the dissolution pump 18b is adapted to operate based on the pressure signal.

[0058] As Figure 2 shown, the buffer cartridge 26 can be filled with a quantity of solid material 44, such as any suitable solute, to be dispersed in the fluid. In an embodiment, the solute 44 can include any suitable solid for dissolution in the fluid, such as a suitable powder or granule to be dissolved in a solvent. For example, in an embodiment, the solute 44 can include a buffer salt powder, or other suitable powder. In an embodiment, the solute 44 can constitute a minority or majority of the final solution concentration. The buffer cartridge 26 can retain the solid 44 in a storage area or chamber, and the storage area or chamber that can define a specific, fixed, or adjustable volume can be in fluid communication with the dissolution line 24 of the system 1. The buffer cartridge 26 can be filled with the solid material 44 at one location and then transferred to another location, such as a final use location or a buffer preparation location, where Figure 2 the position dividing line 50 schematically represents the division between the filling location and the other location. In an embodiment, the buffer cartridge 26 can be filled at the same location as the system 1 without the need for an additional location.

[0059] In an embodiment, the buffer cartridge 26 can include a disposable container for dispersing the solid material in the fluid and introducing it into the system 1 as needed. The buffer cartridge 26 can be rigid, semi-rigid, or any rigidity capable of withstanding sufficient pressure to achieve its intended application. In an embodiment, the buffer cartridge 26 can be configured to hold a predetermined quantity of solid for dissolution in the fluid. In an embodiment, the system 1 can include a plurality of buffer cartridges 26 that are in fluid communication with each other in series for applications where the amount of solid material to be dissolved is greater than the amount that can be held by a single cartridge 26. In an embodiment, any suitable technique known to those skilled in the art can be used to sterilize the buffer cartridge 26.

[0060] The flow paths and pipelines of System 1 can be made of any suitable material, such as silicone tubing, thermoplastic polyethylene, or polypropylene. Any suitable valve can be used to selectively occlude the flow paths and / or pipelines of the system. In embodiments where the pipelines are made of an elastic flexible material, suitable pinch (or clamping) valves can be used. Although the fluid (solvent) is typically water, in embodiments, the fluid can also include or be other liquids and solutions, such as organic solvents or mixtures of organic solvents and water (e.g., ethanol and water).

[0061] Reference Figure 1 , when the pinch valve 4 is open, the inlet pipeline 2 allows fluid to enter and be introduced into System 1. When the pinch valve 4 is closed, no more fluid is introduced into System 1 from the source of the inlet pipeline 2. Closing the pinch valve 4 can help ensure that once a specific volume of fluid is provided to System 1, the amount of fluid in System 1 will not change, thus helping to create a closed-loop circulation circuit.

[0062] The fluid can flow through the dissolution pipeline 24 in the circulation direction 74 from the inlet pipeline 2 via the operation of the pump 18. When the fluid initially flows through the dissolution pipeline 24, the circulating fluid can be bled from components of System 1, such as the pre-filter 6 and the sterile upstream and downstream filters 20, 8.

[0063] Before, during, or after bleeding from the pre-filter 6 and the upstream and downstream filters 20, 8, the fluid can fill the bioreactor 10 by flowing through the inlet 71 of the bioreactor 10. If the closable outlet 72 of the bioreactor 10 or the pinch valve 12 is closed, the bioreactor 10 can be filled to the desired volume before the fluid flows through the pinch valve 12 to other components of System 1. In embodiments, the bioreactor 10 can be filled with fluid, and the fill volume can be measured or determined by suitable means, such as weight measurement using a scale or flow measurement using a suitable flowmeter. The bioreactor 10 can be filled with or without the cartridge 26 in System 1, depending on the positioning and open or closed state of the valves 12, 22, 23 of System 1. Once a sufficient volume or amount of fluid is introduced into System 1, the connection to the fluid source can be removed from the open connection in the dissolution pipeline 24, and the buffer cartridge 26 can be introduced into the dissolution pipeline 24.

[0064] An outlet line 16 can be provided to facilitate the discharge of fluid from the system 1. The pinch valve 14 of the outlet line 16 can be kept closed such that the fluid can circulate through a closed loop formed by the dissolution line 24 and the bypass line 28. However, the initial flow into the system 1 can be assisted by keeping the pinch valve 14 open such that the fluid can flow through the outlet line 16 and flush various components of the system 1, carrying any particles picked up by the fluid during its passage through the system 1. In an embodiment, the outlet line 16 can include an additional sterile filter or a sterile breaker for further fluid processing. Additionally, the pinch valve 14 can be any suitable valve. In an embodiment, a selective filter can be provided additionally or in place of the valve 14, which directs a portion of the fluid to the outlet line 16 and retains a portion of the fluid in the system 1 based on any number of criteria such as the average particle size or the fluid pressure level applied to the pipeline at the location of the pinch valve 14.

[0065] In an embodiment, the biocontainer 10 is in fluid communication with the upstream filter 20, and the upstream filter 20 is in fluid communication with the bypass line 28 and the dissolution line 24. If the pinch valve 22 is at least partially open, the fluid can flow from the biocontainer 10 through the upstream filter 20 and into the dissolution line 24, and if the pinch valve 23 is at least partially open, the fluid can flow from the biocontainer 10 through the upstream filter 20 and into the bypass line 28.

[0066] In an embodiment, the bypass line 28 can have a cross-sectional area greater than that of the dissolution line 24 or be made of a different material than the buffer cartridge 26 such that it can carry more fluid or support a greater fluid pressure. For the initial fluid flow, the pinch valve 22 can be kept closed and the fluid can flow through the bypass line 28. The fluid can flow through the bypass line 28 and the pinch valve 30. The fluid flow can be recycled multiple times in this loop as desired. In an embodiment, the fluid flow does not circulate through the bypass line 28 at startup, and the circulation through the cartridge 26 to cause dissolution of the buffer powder can start at startup. Thus, the fluid can be selectively diverted into the bypass line 28 as desired. As mentioned above, the pinch valves 4, 12, 14, 23, 30 can be opened and closed at any time and to any extent during the initial flow cycle to increase, decrease, or exchange the fluid in the system 1 as desired, manage the circulation of the fluid, or manage the fluid pressure and volume in any particular component such as the biocontainer 10, as will be readily understood by those skilled in the art.

[0067] In an embodiment, the buffer cartridge 26 is in fluid communication with the dissolution line 24. Once the pinch valve 22 is at least partially open, the fluid can flow through the dissolution line 24 and into the buffer cartridge 26. The buffer cartridge 26 can accommodate any number of solid materials 44, such as substances that can dissolve into the fluid. In Figure 1In an embodiment, the solid material 44 is in powder form and the cartridge 26 contains a volume of buffering agent solute powder to dissolve into the fluid and produce a buffered preparation. The fluid can then flow into and out of the cartridge 26, picking up and carrying out the buffering agent solute powder.

[0068] As the fluid flows through the buffering agent cartridge 26, the fluid picks up a portion of the solute powder material 44 in the buffering agent cartridge 26 and carries the solute powder with it to the pre-filter 6 or the static mixer 42. After the fluid leaves Figure 2 the buffering agent cartridge 26 in the embodiment of Figure 1 and / or the static mixer 42 in the embodiment of

[0069] In Figure 1 an embodiment, the cartridge 26 has an inlet 75 and a separate outlet 76 such that the fluid can flow directly through the buffering agent cartridge 26 in the path of the dissolution line 24, which can help reduce turbulence in the buffering agent cartridge 26 and promote effective dispersion of the buffering agent solute powder from the buffering agent cartridge 26. The inlet 75 and the outlet 76 can include fluid connectors coupled to clamping valves or separate connectors such as snap or threaded connectors. The shape and size of the buffering agent cartridge 26 or components of the buffering agent cartridge 26 can vary as needed and can advantageously be adapted to reduce the risk of loss, damage, or contamination of the buffering agent solute during filling or connection. Additionally, if desired, a mesh can be installed at the inlet 75 or the outlet 76 of the buffering agent cartridge 26 to reduce the risk of large amounts of powder leaving the container and delivering too much solute to the circulation at once.

[0070] In other embodiments, the buffering agent cartridge 26 can have a large opening on the bottom, top, or side of the buffering agent cartridge 26 that serves as both an inlet and an outlet and has a grid at the interface of the buffering agent cartridge 26. The buffering agent cartridge 26 can also include an internal analytical sensor 36, such as a pH sensor or a conductivity sensor, as Figure 2 shown. A refractive index sensor can also be used as the analytical sensor 36 and is installed after the biocontainer 10 but before the upstream filter 8.

[0071] Embodiments of the present disclosure may utilize a pre-filter 6 and a downstream filter 8 in any desired relative size ratio to manage conditions of the system 1, such as pressure or fluid flow. Alternatively, the downstream filter 8 may have a larger volume or capacity, or may have both a pre-filter chamber and a sterile chamber, thereby increasing local dissolution and allowing the downstream filter 8 to operate with or without the pre-filter 6 upstream of the downstream filter 8. An additional pressure sensor, similar to the pressure sensor 34, may be placed after the downstream filter 8. Information from the additional pressure sensor may provide an indication of the pressure drop across the pre-filter 6 and the downstream filter 8, and may indicate the dissolution level of the fluid in the loop.

[0072] In an embodiment, the downstream filter 8 is in fluid communication with the storage chamber of the biocontainer 10. The downstream filter 8 may receive non-sterile fluid flowing out of the buffer cartridge 26 and ensure that the fluid containing entrained solute powder flowing into the biocontainer 10 is sterile before entering the biocontainer 10. The sterile upstream and downstream filters 20, 8 may be any suitable sterile barrier facilitating device, such as a filter disc, capsule, or cartridge, and may be of any suitable size. After the downstream filter 8 filters the fluid containing the solute to ensure sterility, the fluid and solute flow into the biocontainer 10.

[0073] If the biocontainer 10 serves as a reservoir, the fluid and solute will achieve a solute powder distribution proportional to the volume amount of solute in the fluid. Additionally, in an embodiment, the inlet and outlet of the biocontainer 10 may be configured and positioned to facilitate mixing. In an embodiment, the biocontainer 10 is in fluid communication with the upstream filter 8, and fluid flows from the biocontainer 10 into the upstream filter 8. The fluid may flow from the biocontainer 10 only by the pressure and flow generated by the pump 18, or other methods may be used in combination with the pump 18 to assist the flow, such as positioning the upstream filter 8 below or above the biocontainer 10 to increase or decrease the rate at which fluid enters the upstream filter 8, or to increase or decrease the amount or likelihood of fluid flowing back into the biocontainer 10 after leaving the biocontainer 10 but before entering the upstream filter 8.

[0074] After the fluid has flowed from the upstream filter 8, the fluid continues to recirculate throughout the system 1 and deposits increasing amounts of buffer solute in the bioreactor 10. At some point, the desired buffer preparation is achieved in the bioreactor 10. In some embodiments, the fluid gradually withdraws more solute powder from the buffer cartridge 26 in each cycle until the ratio of solute to solvent inside the buffer cartridge 26 is the same as the ratio of solute to solvent in the bioreactor 10. In another embodiment, the fluid is circulated until the solute powder in the buffer cartridge 26 is emptied and the fluid circulating through the bioreactor 10 has all the desired solute powder. In some embodiments, the fluid pressure and flow rate are gradually increased over a number of cycle periods to facilitate the effective release of the solute powder and to manage the fluid pressure in the system 1. Once the desired preparation is achieved, the buffer preparation can be removed and used as the buffer solution 46 in a desired application, such as tangential flow filtration (TFF) or chromatography 48, as Figure 2 shown in the embodiments of

[0075] Reference Figure 2 , to assist in adjusting or determining the condition of the fluid in the bioreactor 10 or the fluid flowing through the dissolution line 24 and / or the bypass line 28, at least one analytical sensor 36 can be used, such as for example a pH sensor, a conductivity sensor or a refractive index sensor, and some components capable of responding to the use of the analytical sensor 36, such as a feedback system 32 or a pH adjustment supply. The analytical sensor 36 can be used to provide information about the characteristics and content of the fluid in the system 1, or about the characteristics and contents of the fluid in a more specific component (e.g., the bioreactor 10), and information about whether the contents of the bioreactor 10 are acceptable. If acceptable, the contents of the bioreactor 10 can be automatically released to the buffer solution application 46 via the outlet line 16, a separately designated bioreactor outlet line, or an automated exchange bioreactor 10. Additionally, a pH sensor can be used to automatically introduce fluid from the pH adjustment supply into the system 1 via a secondary pH inlet line 38 as a way to balance the pH of the fluid in the system 1 before or during the cycle period. The analytical sensor 36 can be used to assist in confirming the homogeneity of the solution, completing the buffer solution or media preparation via pH adjustment, and other functions that will be understood by those skilled in the art.

[0076] During the cycle, it can be advantageous to monitor the magnitude of the pressure applied to the various lines and components of the system 1. For example, if it is necessary to reduce the pressure to prevent damage to the buffer cartridge 26, or to better dissolve the solute powder in the buffer cartridge 26 when the fluid is circulated through the dissolution line 24, the flow rate in the dissolution line 24 can be reduced. To prevent excessive pressure in the buffer cartridge 26 and the dissolution line 24, for example, the bypass line 28 can be used to divert at least some of the fluid flow from the dissolution line 24 and bypass the cartridge 26. In Figure 1In the embodiments shown, a bypass valve 23 can be provided and controlled by a controller to selectively open the bypass valve 23 to relieve pressure on the dissolution line 24. The degree of opening of the bypass valve 23, or Figure 2 and 3 the degree of opening of pumps 18a and 18b in the embodiments of Figure 1 can be adjusted by the controller to assist in transferring at least a certain amount of fluid from the dissolution line 24 to the bypass line 28, where the fluid then combines with the fluid leaving the buffer cartridge 26 and is recycled together. Thus, the fluid separated and entering the dissolution line 24 and the bypass line 28 then recombines and is recycled together, allowing pressure to be managed within the buffer cartridge 26 without severely affecting the fluid flow rate or fluid pressure in the overall system 1.

[0077] To assist in managing the fluid pressure in the lines and components of the system and to assist in achieving effective movement of the solute from the buffer cartridge 26, a feedback system 32 can be implemented in the system 1. The feedback system 32 can assist in controlling the fluid flow through the system 1 and specific components (such as the buffer cartridge 26). The feedback system 32 can selectively control the fluid flow through the dissolution line 24, the bypass line 28, and other components of the system 1. In an embodiment, the feedback system 32 can control the fluid flow based on the pressure in the dissolution line 24 downstream of the buffer cartridge 26 between the cartridge 26 and the bioreactor 10. In other embodiments, the feedback system 32 can control the fluid flow based on local pressures at different locations in the system 1.

[0078] In Figure 1In an embodiment, the fluid can interact with the pressure sensor 34 on its way to the pre-filter 6 so that the pressure sensor detects the pressure exerted by the fluid flow circulating through the dissolution line 24. In the illustrated embodiment, the pressure sensor 34 is located downstream of the cartridge 26, between the cartridge 26 and the bioreactor 10, and more specifically, between the cartridge 26 and the pre-filter 6. The pressure sensor 34 can be used in combination with information available from other sensors or systems in the feedback system 32, which is configured to adjust the pressure in the system 1, such as by controlling the open state or degree of the pinch valve 22. In an embodiment, the feedback system 32 interacts with the pressure sensor 34 and at least one other pressure or flow sensor located on the system 1, such as a sensor located at another position in the dissolution line 24, including, for example, upstream of the buffer cartridge 26, upstream or downstream of the upstream filter 20, downstream of the downstream filter 6, and / or a sensor located in the bypass line 28. In an embodiment, the feedback system 32 and the pressure sensor 34 can be part of a device for controlling the fluid flow through the cartridge, wherein the flow control device is configured to selectively control the fluid flow through at least one of the dissolution line 24 and the bypass line 28 based on the pressure in the dissolution line 24 between the cartridge 26 and the bioreactor 10 downstream of the cartridge 26.

[0079] The feedback system 32 can be configured to receive information from the pressure sensor 34 and any other sensors included in the system 1 and transmit control signals to one or more other components, such as the pump 18, the dissolution valve 22, and / or the bypass valve 23. The feedback system 32 can be configured to automatically adjust the pump 18, the dissolution valve 22, and / or the bypass valve 23 to maintain the fluid flow through the dissolution line 24 within a specified fluid pressure range. For example, the feedback system 32 can use an actuator or other automatic control to adjust the open degree of the pinch valves 22, 23 or the operating degree of the pumps 18 and Figure 2 and Figure 3 the pumps 18a, 18b. The feedback system 32 can also be configured to provide an indication of the operating position and status of the pinch valves or pumps of the system 1 to the operator of the system 1, as well as an operator interface adapted to allow the operator to adjust one or more selected pinch valves or pumps. The feedback system 32 can also communicate electronically with the various components of the system 1 (such as the pinch valves 22, 23 and the pump 18 or the pumps 18a, 18b) so that the feedback system 32 automatically controls the operation of the pump or the pinch valve.

[0080] In an embodiment, the pressure sensor 34 can be enhanced, replaced, or consist of various devices for evaluating pressure. For example, a mechanical or electronic (e.g., electromagnetic) flow sensor can be used to replace or combine with the pressure sensor 34. Additionally, a timing system, timing component, and / or multiple timing components can be utilized to measure the flow rate of the fluid moving through the system 1, whether at one location in the system 1 or at multiple locations along the system 1. Further, based on approximations of water volume, pipe cross-sectional area, and fluid flow rate, or by measuring and determining the tension in the pipe of a non-rigid plastic tube, these can be used alone or together, to replace or combine with the pressure sensor 34. Additionally, the feedback system 32 can operate without using electrical sensors or circuits, such as by having a pressure sensor 34 with spring-based valve management that responds proportionally to the pressure applied to the spring-based valve.

[0081] Monitoring and controlling the pressure in the system 1 (such as the pressure in the dissolution line 24 or the bypass line 28) can be beneficial. For example, if the dissolution valve 22 is in the open position and is overly open and / or the pump 18 generates an excessive fluid flow, pressure buildup may occur in the buffer cartridge 26 due to powder blockage, or pressure buildup may occur in the filters 8, 20 due to excessive fluid pressure and / or solute blockage. Any of these blockages can impede or stop the fluid flow through the circulation loop, reduce the efficiency of the system 1, cause the entire buffer or media preparation process to stop, and / or damage the lines 24, 28, connectors, or other components of the system 1. Further, since the actual settings of the pressure and pump flow will vary depending on the type of buffer added, such as its solubility characteristics and the relative proportion of the buffer to the total liquid, the settings of various components (such as pinch valves and pumps) may change when preparing different buffer solutions. Therefore, the combination of the pressure sensor 34 and the feedback system 32 can be used to follow a protocol to enable an appropriate progressive fluid flow profile through the buffer cartridge 26 and the system 1.

[0082] In Figure 2 an embodiment, the system 1 includes two pumps 18a, 18b for adjusting the fluid flow through the system 1. The bypass pump 18a can operate on the bypass line 28, while the dissolution pump 18b can operate on the dissolution line 24. In Figure 2 an embodiment, the dissolution pump 18a is in fluid communication with the upstream filter 8 and the pre-filter 6, while the pump 18b is in fluid communication with the buffer cartridge 26 and the downstream filter 8. The bypass pump 18a and the dissolution pump 18b can be located in the bypass line 28 and the dissolution line 24 respectively, such that the pumps 18a, 18b respectively affect the fluid flow through the bypass line 28 and the dissolution line 24, thereby effectively acting as part of a flow control system and part of a device for controlling the fluid flow through the cartridge.

[0083] InFigure 2 In an embodiment, the bypass pump and the dissolution pumps 18a, 18b can replace or supplement the clamping valves correspondingly provided in the bypass line and the dissolution line 28, 24, and as part of the flow control device, are configured to selectively control the fluid flow through at least one of the dissolution line and the bypass line. In an embodiment, the bypass pump and the dissolution pumps 18a, 18b replace or serve as valves for correspondingly controlling the fluid flow through the bypass line 28 and the dissolution line 24. By operating to effectively open a line with respect to another line in which the other pump is not operating (or operating at a lower rate), or not operating to effectively close a line with respect to another line in which the other pump is operating (or operating at a higher rate), the bypass pump and the dissolution pumps 18a, 18b act as valves. For example, the pumps 18a, 18b can be operated or not operated to apply a pressure or fluid flow rate equal to the pressure or fluid flow rate in the dissolution line 24 and the bypass line 28, which is generated by Figure 1 the corresponding operation of the clamping valves 22, 23 of the embodiment. Additionally, the bypass and dissolution pumps 18a, 18b can be configured such that fluid flows through the pumps 18a, 18b in a through mode while the pumps 18a, 18b are not operating, and / or such that no fluid can pass through the pumps 18a, 18b when the pumps 18a, 18b are not operating. Furthermore, the bypass pump 18a can be configured to operate in a different state from the dissolution pump 18b. For example, the bypass pump 18a can be configured to replicate or replace the bypass valve 23, while the dissolution pump 18b is not configured, and vice versa.

[0084] In Figure 3 an embodiment, the bypass and dissolution clamping valves 23, 22 are used in combination with the bypass and dissolution pumps 18a, 18b as part of a device for controlling the fluid flow through the cylinder 26. In an embodiment, different combinations of clamping valves can be operated together with different combinations of pumps to achieve effective flow control within the dissolution and bypass lines 24, 28. For example, although Figure 3 shows the bypass clamping valve 23 located after the bypass pump 18a and the dissolution clamping valve 22 located after the dissolution pump 18b, the clamping valves 22, 23 can be located before the pumps 18a, 18b. Additionally, the clamping valves can be positioned according to the desired operation to fluidly isolate the pumps 18a, 18b from other components of the system 1. The system 1 can also include a bypass line 28 without the clamping valve 23, while the dissolution line 24 includes the clamping valve 22, and vice versa.

[0085] The bypass pump and the dissolution pumps 18a, 18b can be operated independently or based on an additional pump (such as Figure 1operated by the operation of the pump 18) in the embodiment, which is disposed upstream of the upstream junction 81 where the bypass line 28 branches. For example, the bypass pump and the dissolution pumps 18a, 18b or additional pumps may be operated such that an increase or decrease in the fluid pressure or velocity applied by one pump (e.g., pump 18) directly affects the fluid pressure or velocity applied by one or both of the other pumps (e.g., pumps 18a, 18b). Additionally, the pump 18a or pump 18b or additional pumps may be configured to operate in any combination of independent or dependent manners. For example, the pump 18b may be configured to adjust the fluid pressure or velocity based on the fluid pressure or velocity applied by the pump 18a, while the pump 18a may not be configured to adjust the fluid pressure or velocity based on the fluid pressure or velocity applied by the pump 18b, and vice versa.

[0086] The placement of the upstream filter 20 and the downstream filter 8 can contribute to achieving many advantages. For example, as Figure 2 schematically shown, the system 1 may be divided along the sterile line 40, which defines a sterile portion (on the right hand side of the sterile line 40) and a non-sterile portion (on the left hand side of the sterile line 40) of the system 1. The biocontainer 10 is located in the sterile portion of the system 1. The sterile portion of the circulation cycle can be created and maintained in the system 1 and the biocontainer 10 between the sterile filters 8, 20, which in Figure 2 the schematic embodiment includes all components on the right side of the sterile line 40. The ability to create a sterile environment in the circulation loop portion between the sterile filters 8, 20 allows the buffer cartridge 26 to be sterile or non-sterile without affecting the sterility of the biocontainer 10. Additionally, operating the bypass line 28 in parallel with the buffer cartridge 26 in the dissolution line 24 reduces the risk of blockage at certain points in the circulation loop due to excessive or accumulated buffer solutes, such as in the pre-filter 6 or the downstream filter 8.

[0087] Referring to Figure 4 , the system may include a suitable controller 900 for use with the feedback system 32, the pressure sensor 34, the analysis sensor 36, and any other suitable sensors desired for use. The controller may be configured to control the operation of one or more valves and / or one or more pumps based on sensor signals received from the sensors communicatively arranged therewith. In an embodiment, any suitable commercially available controller may be used. In an embodiment, the controller 900 may include one or more processors 902, a memory 904, one or more input / output devices 906, one or more sensors 908, one or more user interfaces 910, and one or more actuators 912. The controller 900 may represent each controller system disclosed herein.

[0088] The processor 902 may include one or more different processors, each processor having one or more cores. Each different processor may have the same or different architectures. The processor 902 may include one or more central processing units (CPUs), one or more graphics processing units (GPUs), circuitry (e.g., application specific integrated circuits (ASICs)), digital signal processors (DSPs), etc. The processor 902 may be mounted on a common substrate or multiple different substrates.

[0089] The processor 902 is configured to perform a specific function, method, or operation (e.g., configured to provide the execution of a function, method, or operation) at least when one of the one or more different processors is capable of performing the operations that embody the function, method, or operation. The processor 902 may perform the operations that embody the function, method, or operation by, for example, executing code (e.g., interpreted scripts) stored on the memory 904 and / or by transmitting data through one or more ASICs. The processor 902 and the controller 900 may be configured to automatically perform any and all of the functions, methods, and operations disclosed herein. Thus, the controller 900 may be configured to implement any (e.g., all) of the protocols, apparatuses, mechanisms, systems, and methods described herein.

[0090] For example, when the present disclosure states that a method or apparatus performs task “X” (or task “X” is performed), such a statement should be understood to disclose that the controller 900 may be configured to perform task “X”. The controller 900 is configured to perform the same function, method, or operation at least when the processor 902 is configured to perform the function, method, or operation.

[0091] The memory 904 may include volatile memory, non-volatile memory, and any other medium capable of storing data. Each of the volatile memory, non-volatile memory, and any other type of memory may include multiple different memory devices, which are located at multiple different positions and each memory device has a different architecture. The memory 904 may include remotely hosted (e.g., cloud) storage.

[0092] Examples of the memory 904 include non-transitory computer-readable media such as RAM, ROM, flash memory, EEPROM, any type of optical storage disk such as DVD, disk, magnetic storage, holographic storage, HDD, SSD, any medium that can be used to store program code in the form of instructions or data structures, etc. Any and all of the methods, functions, and operations described herein may be fully embodied in the form of tangible and / or non-transitory machine-readable code (e.g., interpreted scripts) stored in the memory 904.

[0093] The input / output device 906 may include any component for transmitting data, such as ports, antennas (i.e., transceivers), printed conductive paths, etc. The input / output device 906 may implement wired communication via Ethernet, etc. The input / output device 906 may implement electronic, optical, magnetic, and holographic communication with a suitable memory 906. The input / output device 906 may implement wireless communication via cellular (e.g., ), GPS, etc. The input / output device 906 may include wired and / or wireless communication paths.

[0094] The sensor 908 (e.g., pressure sensor 34) may capture physical measurements of the environment and report them to the processor 902. The user interface 910 may include a display, physical buttons, speakers, microphones, keyboards, etc. The actuator 912 may enable the processor 902 to control mechanical forces.

[0095] The controller 900 may include a distributed processing system. For example, some components of the processing system 900 may reside in a remotely hosted network service (e.g., a cloud computing environment), while other components of the processing system 900 may reside in a local computing system. The controller 900 may have a modular design, where certain modules include Figure 4 the multiple features / functions shown in. For example, the I / O module may include volatile memory and one or more processors. As another example, a single processor module may include read-only memory and / or a local cache.

[0096] Embodiments of a system constructed in accordance with the principles of the present disclosure can operate with changes in the relative positioning of various components with respect to each other. For example, changing the positioning of the pump 18, the bypass line 28, and the dissolution line 24, or even changing the positioning of the sterile filters 8, 20 with respect to other components or each other. Embodiments of a system constructed in accordance with the principles of the present disclosure can operate with the addition or omission of various components of the system 1, such as by adding additional pinch valves or pumps to the system 1 to adjust the flow rates on various fluid lines differently, or for example by removing the pre-filter 6 or integrating the pre-filter with the downstream filter 8. The system 1 can also be compatible with various other systems and processes and can have additional lines and / or fluid connections to work with those other systems. Additional flow sensors can be integrated at multiple locations in the system 1 to better control the process and can even be integrated into other existing components, such as the pump 18. Additional bleed sections can also be integrated into the system 1 to selectively open or close when air or other substances accumulate or become trapped at certain locations in the system 1, thereby further helping to manage the sterility and / or pressure levels of the system 1. Braided tubing can also be used in areas of the system 1 that are subject to sufficient pressure, such as the dissolution line 24.

[0097] The structure and materials of the components of the system 1 can be selected based on various advantages and desires. For example, all components can be reusable, such as steel or other rigid elements, or disposable, or supported by hardware, depending on cost, hygiene, and mobility considerations for the buffer or media preparation process. If the fluid stored in the biocontainer 10 does not require sterility, the sterile filters 8, 20 can be removed to reduce unnecessary costs. Additionally, certain components or lines of the system 1 can be transparent to provide better visual feedback of the dissolution cycle, such as tracking the rate of solute dissolution or the air / particle flow in the fluid.

[0098] A method of preparing a buffer solution in accordance with the principles of the present disclosure can be used with Figures 1 - 3 any of the systems. In an embodiment, the buffer cartridge 26 can be filled with a solid material 44, for example, a suitable buffer solute in the form of a powder or granules to be dissolved. A pre-circulation can be selectively performed, where the pinch valves 4, 12, 23, and 30 are opened and the fluid is circulated from the biocontainer 10 through the lines of the system 1 (except the dissolution line 24) and back to the biocontainer 10. The pinch valve 4 is opened and the pinch valves 14, 30 are closed. The upstream filter 8 is bled and the biocontainer 10 is slightly filled. Then the pinch valve 30 is opened. The biocontainer 10 is filled and both the pre-filter 6 and the downstream filter 8 are bled. After the biocontainer 10 is filled, the pinch valve 4 is closed.

[0099] A fluid flow is initiated in the bypass line 28 by opening the clamping valve 23 to a desired amount or, for example, by operating the pump 18a associated with the bypass line 28. As Figure 2 described in Figure 1 , the buffer cartridge 26 is introduced into the system 1 and a fluid flow is initiated in the dissolution line 24 by opening the clamping valve 22 to a desired amount (as in the embodiment of Figure 2 ), or, for example, by operating the pump 18 associated with the dissolution line 24 (as in Figure 3 ), or by combining either or both (as in the embodiment of

[0100] ). The flow in the dissolution line 24 can be in parallel with the flow in the bypass line 28 and the fluid can be transferred between the dissolution line 24 and the bypass line 28 as desired. Throughout this process, the fluid passing through the buffer cartridge 26 picks up the fluid-absorbing material 44, such as a buffer solute or powder, and is flushed at the inlet of the pre-filter 6. The fluid flow through the bypass line 28 contacts the buffer solute pushed in from the buffer cartridge 26 directly after the clamping valve 30 and accumulates in front of the pre-filter 6. The fluid flow through the bypass line 28 promotes the dissolution of the buffer solute into the solvent or fluid phase, which allows the solution to flow through both the pre-filter 6 and the downstream filter 8. In an embodiment, a pressure sensor 34 is provided upstream of the pre-filter 6 and is configured to cooperate with the feedback system 32 to allow control of the fluid flow through the dissolution line 24 such that not too much solute is flushed out of the buffer cartridge 26, as too much solute flushing out could result in potential blockages and a sudden end to the process.

[0101] Once the sensor signal values collected from the analysis sensor 36 are constant (or within a predetermined range), pH adjustment can be started to ultimately prepare a buffer solution. Once all the sensor signal values are constant (or within a predetermined range) after pH adjustment, the buffer preparation in the biocontainer 10 can be transferred to the next processing step 48 of batch 46, and the biocontainer 10 can be drained either by modular removal or by opening the clamping valve 14 via the outlet line 16. The pre-filter 6 can be vented to allow air to enter the pre-filter 6. The pump 18 or pumps 18a, 18b can also be actuated in the opposite direction until the lines of the system 1 and the biocontainer 10 are emptied.

[0102] In an embodiment, in an initial step, the buffer cartridge 26 can be filled with the buffer solute to be dissolved, the inlet valve 4 and the bypass valve 23 are opened, and the outlet valve, the dissolution valve, and the inlet valves 14, 22, 30 are closed. After a predetermined period of time has elapsed after the initial step, the inlet valve 30 is opened, the upstream filter 20 is vented, and the biocontainer 10 is slightly filled to the initial volume, and the bypass valve 23 is closed. After a predetermined period of time has elapsed after the initial step, the biocontainer 10 is filled from the initial volume to a larger target volume, and both the pre-filter 6 and the downstream filter 8 are vented. After a predetermined period of time has elapsed after the initial step, the clamping valve 23 is opened and the pump 18 is started.

[0103] Then the fluid pressure in the dissolution line 24 is monitored. When the pressure in the dissolution line 24 drops below a threshold value, the fluid flow in the dissolution line 24 can be increased. The pressure in the system 1 can be monitored, and the dissolution and bypass valves 22, 23 can be adjusted within a predetermined period of time as needed. The system 1 can be drained by opening the drain valve 14.

[0104] In other embodiments, the pump 18 can be positioned at different locations in the hydraulic circuit according to the desire. In an embodiment, additional pumps, stronger or more robust pipes, and / or better or larger filters can be used to improve the efficiency of the embodiments of the present disclosure and reduce the time required to complete the preparation or improve the quality or quantity prepared within the same period of time. In an embodiment, an impact force can be applied to each component of the system 1 to help prevent channel blockage due to solute accumulation.

[0105] In an embodiment of a method of preparing a solution in accordance with the principles of the present disclosure, any suitable embodiment of a dissolution system constructed in accordance with the principles discussed herein can be used. In an embodiment, a method of preparing a solution in accordance with the principles of the present disclosure includes using a recirculation system having a dissolution line, a bypass line, and a flow control system in accordance with the principles of the present disclosure.

[0106] In one embodiment, a method of preparing a buffer solution includes fluidly coupling a buffer cartridge into a circulation loop formed by a dissolution pipeline. The dissolution pipeline fluidly couples a bioreactor, a pump adapted to discharge a fluid flow therefrom in a circulation direction, the buffer cartridge, an upstream filter disposed between the bioreactor and the buffer cartridge upstream of the buffer cartridge with respect to the circulation direction, and a downstream filter disposed between the buffer cartridge and the bioreactor upstream of the buffer cartridge with respect to the circulation direction in the circulation loop. The buffer cartridge contains a certain amount of buffer solute.

[0107] The fluid flow circulates through the circulation loop to entrain at least a portion of the buffer solute from the buffer cartridge into the fluid flow. In an embodiment of the method of preparing a buffer solution, circulating the fluid flow through the circulation loop includes controlling the fluid flow through the buffer cartridge based on the pressure in the dissolution pipeline between the buffer cartridge and the bioreactor downstream of the buffer cartridge.

[0108] In an embodiment of the method of preparing a buffer solution, the buffer solute includes powder. The method may further include filling the buffer cartridge with a certain amount of buffer solute in a buffer transfer chamber before fluidly coupling the buffer cartridge into the circulation loop.

[0109] In an embodiment of the method of preparing a buffer solution, the dissolution pipeline includes an upstream junction and a downstream junction. The upstream junction is disposed between the upstream filter and the buffer cartridge upstream of the buffer cartridge with respect to the circulation direction, and the downstream junction is disposed between the buffer cartridge and the downstream filter downstream of the buffer cartridge with respect to the circulation direction. The method may further include transferring at least a portion of the fluid flow from the dissolution pipeline into a bypass pipeline. The bypass pipeline is in fluid communication with the dissolution pipeline at the upstream junction and the downstream junction such that the bypass pipeline is in a parallel relationship with the cartridge.

[0110] In at least some such embodiments, transferring at least a portion of the fluid from the dissolution pipeline into the bypass pipeline includes regulating the amount of fluid flow transferred into the bypass pipeline based on the pressure in the dissolution pipeline between the cartridge and the bioreactor downstream of the cartridge. In at least some such embodiments, regulating the amount of fluid flow transferred into the bypass pipeline based on the pressure in the dissolution pipeline between the cartridge and the bioreactor downstream of the cartridge includes regulating the speed of the pump in the dissolution pipeline in an inverse relationship to the pressure.

[0111] In an embodiment of the method of preparing a buffer solution, the method may include entraining substantially all of the buffer solute in the buffer cartridge into the fluid flow. The fluid flow circulates through the circulation loop to substantially dissolve the buffer solute to form a buffer solution. A sensor is used to sense the pH value of the buffer solution. The pH of the buffer solution is adjusted to a target pH range by introducing a pH adjustment supply into the buffer solution based on the sensed pH value.

[0112] All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference to the extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0113] In the context of describing the present invention (especially in the context of the appended claims), the use of the terms "a," "an," and "the," and similar referents shall be construed to cover both the singular and the plural, unless otherwise specified herein or the context clearly dictates otherwise. The terms "comprising," "having," "including," and "containing" shall be construed as open-ended terms (i.e., meaning "including but not limited to"), unless otherwise specified. The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise specified herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise specified herein or the context clearly dictates otherwise. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is merely intended to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise stated. Any language in the specification should not be construed as indicating any non-claimed element as essential to the practice of the invention.

[0114] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for practicing the invention. Variations of these preferred embodiments will be apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors expect the invention to be practiced otherwise than as specifically described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. In addition, unless otherwise specified herein or the context clearly dictates otherwise, the invention covers any combination of the above elements in all possible variations thereof.

Claims

1. A dissolution system, the dissolution system comprising: a bioreactor that defines a reactor inlet, a reactor outlet, and a storage volume, the reactor inlet and the reactor outlet being in communication with the storage volume, and the storage volume being configured to receive a fluid supply; a pump that is in fluid communication with the storage volume of the bioreactor, the pump being adapted to receive the fluid supply from the reactor outlet of the bioreactor and discharge a fluid flow therefrom in a circulation direction to the reactor inlet; a cartridge that defines a cartridge inlet, a cartridge outlet, and a storage chamber, the cartridge inlet and the cartridge outlet being in communication with the storage chamber, the storage chamber being configured to receive an amount of solute for dissolution into the fluid supply, the storage chamber being in fluid communication with the pump via the cartridge inlet to receive the fluid flow therefrom, the cartridge inlet, the storage chamber, and the cartridge outlet being configured such that the fluid flow is directed from the cartridge inlet through the storage chamber and exits the cartridge outlet to flow through the amount of solute in the storage chamber, the cartridge outlet being in fluid communication with the reactor inlet; an upstream filter that is in fluid communication with the bioreactor and the cartridge such that the upstream filter is upstream of the cartridge with respect to the circulation direction and is between the reactor outlet of the bioreactor and the cartridge inlet; a downstream filter that is in fluid communication with the cartridge and the bioreactor such that the downstream filter is downstream of the cartridge with respect to the circulation direction and is between the cartridge outlet of the cartridge and the reactor inlet of the bioreactor; a dissolution pipeline that fluidly couples the bioreactor, the pump, the cartridge, the upstream filter, and the downstream filter into a circulation loop.

2. The dissolution system according to claim 1, further comprising: a pre-filter that is in fluid communication with the cartridge and the downstream filter such that the pre-filter is between the cartridge and the downstream filter, the downstream filter having a first internal volume, and the pre-filter having a second internal volume that is greater than the first internal volume.

3. The dissolution system according to claim 1 or claim 2, further comprising: a mixer that is in fluid communication with the cartridge and the downstream filter such that the mixer is between the cartridge and the downstream filter.

4. The dissolution system according to claim 3, wherein the mixer comprises a static mixer.

5. The dissolution system according to any one of claims 1 to 5, further comprising: a valve that is adapted to selectively control the fluid flow through the cartridge based on the pressure in the dissolution pipeline between the cartridge and the bioreactor downstream of the cartridge.

6. The dissolution system according to any one of claims 1 to 5, wherein The dissolution pipeline includes an upstream joint and a downstream joint. The upstream joint is arranged upstream of the cartridge between the upstream filter and the cartridge inlet with respect to the circulation direction, and the downstream joint is arranged downstream of the cartridge between the cartridge outlet of the cartridge and the downstream filter with respect to the circulation direction. The dissolution system further includes: A bypass pipeline, which is in fluid communication with the dissolution pipeline at the upstream joint and the downstream joint, such that the bypass pipeline is in a parallel relationship with the cartridge.

7. The dissolution system according to claim 6, further includes: A flow control system configured to selectively control the fluid flow through at least one of the dissolution pipeline and the bypass pipeline.

8. The dissolution system according to claim 7, wherein, The pump includes a dissolution pump, which is arranged in the dissolution pipeline between the upstream joint and the cartridge inlet, and wherein the flow control system includes a bypass pump and a pressure sensor. The bypass pump is arranged in the bypass pipeline, and the pressure sensor is arranged in the dissolution pipeline between the cartridge outlet and the container inlet. The pressure sensor is configured to generate a pressure signal corresponding to the pressure sensed by the pressure sensor in the dissolution pipeline, and at least one of the bypass pump and the dissolution pump is adapted to operate based on the pressure signal.

9. The dissolution system according to claim 7, wherein, The pump is arranged in the dissolution pipeline between the container outlet and the upstream joint, and wherein the flow control system includes a dissolution valve, a bypass valve and a pressure sensor. The dissolution valve is arranged in the dissolution pipeline between the upstream joint and the cartridge inlet, the bypass valve is arranged in the bypass pipeline, and the pressure sensor is arranged in the dissolution pipeline between the cartridge outlet and the container inlet. The pressure sensor is configured to generate a pressure signal corresponding to the pressure sensed by the pressure sensor in the dissolution pipeline, and at least one of the dissolution valve and the bypass valve is adapted to operate based on the pressure signal.

10. The dissolution system according to claim 9, further includes: A solution property sensor arranged in the dissolution pipeline, configured to generate a property signal corresponding to the value of the solution property sensed by the solution property sensor in the dissolution pipeline.

11. The dissolution system according to claim 10, wherein, The solution property sensor includes a pH sensor, and the property signal includes a pH signal. The system further includes: A pH adjustment pipeline and a pH adjustment valve. The pH adjustment pipeline is in fluid communication with the dissolution pipeline and is adapted to supply and transport pH adjustment fluid to the dissolution pipeline. The pH adjustment valve is operable to selectively block the pH adjustment pipeline to interrupt the flow of the pH adjustment fluid supply to the dissolution pipeline, and the pH adjustment valve is adapted to operate based on the pH signal.

12. The dissolution system according to claim 11, Wherein, the pH adjustment pipeline is in fluid communication with the dissolution pipeline via the bypass pipeline.

13. A dissolution system, the dissolution system comprising: a dissolution pipeline that fluidly couples a bioreactor, a pump, a cartridge, an upstream filter, and a downstream filter into a circulation loop, the bioreactor configured to accommodate a fluid supply, the pump adapted to receive the fluid supply from the bioreactor and discharge a fluid flow therefrom in a circulation direction; the cartridge configured to accommodate a quantity of solute for dissolution into the fluid supply, the cartridge being in fluid communication with the pump to receive the fluid flow therefrom and pass the fluid flow therethrough, the upstream filter being in fluid communication with the bioreactor and the cartridge such that the upstream filter is upstream of the cartridge with respect to the circulation direction and between the bioreactor and the cartridge, and the downstream filter being in fluid communication with the cartridge and the bioreactor such that the downstream filter is downstream of the cartridge with respect to the circulation direction and between the cartridge and the bioreactor, wherein the dissolution pipeline includes an upstream joint and a downstream joint, the upstream joint being disposed between the upstream filter and the cartridge upstream of the cartridge with respect to the circulation direction, and the downstream joint being disposed between the cartridge and the downstream filter downstream of the cartridge with respect to the circulation direction; a bypass pipeline that is in fluid communication with the dissolution pipeline at the upstream joint and the downstream joint such that the bypass pipeline is in parallel with the cartridge; a device for controlling the fluid flow through the cartridge, the flow control device being configured to selectively control the fluid flow through at least one of the dissolution pipeline and the bypass pipeline based on the pressure in the dissolution pipeline between the cartridge and the bioreactor downstream of the cartridge.

14. A method for preparing a buffer solution, the method comprising: fluidly coupling a buffer cartridge in a circulation loop formed by a dissolution pipeline, the dissolution pipeline fluidly coupling a bioreactor, a pump adapted to discharge a fluid flow therefrom in a circulation direction, the buffer cartridge, an upstream filter disposed between the bioreactor and the buffer cartridge upstream of the buffer cartridge with respect to the circulation direction, and a downstream filter disposed between the buffer cartridge and the bioreactor upstream of the buffer cartridge with respect to the circulation direction, the buffer cartridge containing a quantity of buffer solute; circulating a fluid flow through the circulation loop to entrain at least a portion of the buffer solute from the buffer cartridge into the fluid flow.

15. The method according to claim 14, further comprising: before fluidly coupling the buffer cartridge in the circulation loop, filling the buffer cartridge with the quantity of buffer solute in a buffer transfer chamber, the buffer solute including powder.

16. The method according to claim 14 or claim 15, wherein, Circulating the fluid stream through the circulation loop includes controlling the fluid stream through the buffer cartridge based on the pressure in the dissolution line between the buffer cartridge and the bioreactor downstream of the buffer cartridge.

17. The method according to any one of claims 14 to 16, wherein, the dissolution line includes an upstream junction and a downstream junction, the upstream junction is disposed between the upstream filter and the buffer cartridge upstream of the buffer cartridge with respect to the circulation direction, and the downstream junction is disposed between the buffer cartridge and the downstream filter downstream of the buffer cartridge with respect to the circulation direction, the method further includes: transferring at least a portion of the fluid stream from the dissolution line into a bypass line, the bypass line being in fluid communication with the dissolution line at the upstream junction and the downstream junction such that the bypass line is in parallel relation with the buffer cartridge.

18. The method according to claim 17, wherein, transferring at least a portion of the fluid stream from the dissolution line into a bypass line includes regulating the amount of the fluid stream transferred into the bypass line based on the pressure in the dissolution line between the buffer cartridge and the bioreactor downstream of the buffer cartridge.

19. The method according to claim 18, wherein, regulating the amount of the fluid stream transferred into the bypass line based on the pressure in the dissolution line between the buffer cartridge and the bioreactor downstream of the buffer cartridge includes regulating the speed of the pump in the dissolution line in an inverse relationship to the pressure.

20. The method according to any one of claims 14 to 19, further includes: entraining substantially all of the buffer solute in the buffer cartridge into the fluid stream; circulating the fluid stream through the circulation loop to substantially dissolve the buffer solute to form a buffer solution; using a sensor to sense the pH value of the buffer solution; based on the sensed pH value, adjusting the pH of the buffer solution to a target pH range by introducing a pH adjustment supply into the buffer solution.

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