Dissolution System

Abstract

The lysis system includes lysis piping and bypass piping. The lysis piping fluidly connects the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter in a circulation loop. The bypass piping is in fluid communication with the lysis piping at an upstream branch and a downstream branch in a parallel relationship with the cartridge. A flow control system is configured to control fluid flow through the cartridge such that fluid flow through at least one of the lysis piping and the bypass piping is selectively controlled based on pressure in the lysis piping downstream of the cartridge between the cartridge and the biocontainer.

Description

[Technical Field]

[0001] This patent disclosure relates generally to dissolution systems, and more particularly to dissolution systems for preparing buffer solutions from buffer powders dissolved in a liquid medium. [Background technology]

[0002] Buffer solutions are typically made at maximum concentration in a mixer and produced in bulk for storage in tote bags. Buffer dissolution systems typically include buffer powders that are loaded into bags. Bags of buffer powder are often compounded in one room and then transported to another room for compounding of the buffer solution. The powder bags are often elevated above a mixer using an elevator, then opened and emptied into the mixer, which simultaneously mixes the contents of the powder bag with a fluid to provide a mixed solution. The mixed solution is then filtered through a sterile-grade or bioburden-reducing filter, and the filtered mixed solution is then transported to a storage or transfer tank.

[0003] For a typical bioprocessing application, multiple buffer solutions are used, with the requirements for each buffer solution varying, in some situations as much as 2000 liters of each buffer. Due to the large footprint of a bioprocessing facility, totes are transported from the buffer formulation area to the process suite. If there is one room dedicated to biological formulation, another room for media and buffer formulation, and yet another room for the process suite, bioprocessing operations can consume a significant footprint. Sterility of materials can be compromised at each transfer step. Also, special transfer equipment may be required for larger totes, and there are hazards associated with operating such machinery and moving these loads. Summary of the Invention [Problem to be solved by the invention]

[0004] There continues to be a need in the art to provide additional solutions to enhance the management of buffer solutions used in various bioprocessing applications, for example, to provide new or improved powder dissolution systems.

[0005] It is understood that this background description is intended to assist the reader and that none of the problems indicated are to be construed as an indication of technical understanding per se. While the principles described may, in some aspects and embodiments, alleviate problems inherent in other systems, it is understood that the scope of the protected innovation is defined by the appended claims, and not by the ability of any disclosed feature to solve any particular problem described herein. [Means for solving the problem]

[0006] In one aspect, the present disclosure is directed to an embodiment of a lysis system. In one embodiment, the lysis system includes a biocontainer, a pump, a cartridge, an upstream filter, a downstream filter, and lysis piping. The lysis piping fluidly connects the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter in a circulation loop.

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

[0008] The cartridge defines a cartridge inlet, a cartridge outlet, and a storage chamber. The cartridge inlet and cartridge outlet are in communication with the storage chamber. The storage chamber is configured to hold a quantity of solute for dissolution into a supply of fluid. The storage chamber is in fluid communication with the pump via the cartridge inlet to receive a flow of fluid from the pump. The cartridge inlet, storage chamber, and cartridge outlet are configured such that a flow of fluid is directed from the cartridge inlet through the storage chamber and out of the cartridge outlet to flow past the quantity 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 so as to be interposed between a container outlet of the biocontainer and a cartridge inlet of a cartridge upstream of the cartridge in the direction of circulation, and a downstream filter is in fluid communication with the cartridge and the biocontainer so as to be interposed between a cartridge outlet of the cartridge and a container inlet of a biocontainer downstream of the cartridge in the direction of circulation.

[0010] In another embodiment, a dissolution system includes dissolution piping fluidly connecting a biocontainer, a pump, a cartridge, an upstream filter, and a downstream filter in a circulation loop, bypass piping, and a means for controlling fluid flow through the cartridge. The biocontainer is configured to hold a supply of fluid. The pump is adapted to receive a supply of fluid from the biocontainer and to discharge a flow of fluid from the biocontainer in a circulation direction. The cartridge is configured to hold a quantity of solute for dissolution into the supply of fluid. The cartridge is in fluid communication with the pump to receive the flow of fluid from the pump and to pass the flow of fluid through the pump. The upstream filter is in fluid communication with the biocontainer and cartridge such that it is interposed between the biocontainer and the cartridge upstream of the cartridge in the circulation direction, and the downstream filter is in fluid communication with the cartridge and biocontainer such that it is interposed between the cartridge and the biocontainer downstream of the cartridge in the circulation direction.

[0011] The dissolution piping includes an upstream branch and a downstream branch. The upstream branch is disposed between the upstream filter and the cartridge, upstream of the cartridge, in the direction of circulation, and the downstream branch is disposed between the cartridge and the downstream filter, downstream of the cartridge, in the direction of circulation. A bypass piping is in fluid communication with the dissolution piping at the upstream branch and the downstream branch so as to be in a parallel relationship with the cartridge. The means for controlling fluid flow through the cartridge is configured to selectively control fluid flow through at least one of the dissolution piping and the bypass piping based on pressure in the dissolution piping downstream of the cartridge, between the cartridge and the biocontainer.

[0012] In another aspect, the present disclosure is directed to a method embodiment for preparing a buffer solution. In one embodiment, the method for preparing a buffer solution includes fluidly connecting a buffer cartridge in a circulation loop formed by dissolution piping. The dissolution piping fluidly connects a biocontainer, a pump adapted to discharge a fluid flow from the biocontainer in a circulation direction, a buffer cartridge, an upstream filter disposed between the biocontainer and the buffer cartridge upstream of the buffer cartridge in the circulation direction, and a downstream filter disposed between the buffer cartridge and the biocontainer upstream of the buffer cartridge in the circulation direction. The buffer cartridge contains a quantity of buffer solute. A fluid flow is circulated through the circulation loop to entrain at least a portion of the buffer solute from the buffer cartridge into the fluid flow.

[0013] Further alternative aspects and features of the disclosed principles will become apparent from the following detailed description and accompanying drawings. As will be understood, the dissolution systems and methods of preparing solutions disclosed herein can be implemented in other and different embodiments and can be modified in various respects. It is therefore to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of the scope of the appended claims. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a schematic diagram of an embodiment of a lysis system constructed in accordance with the principles of the present disclosure. [Figure 2] 1 is a schematic diagram of an embodiment of a lysis system and process constructed and performed in accordance with the principles of the present disclosure. [Figure 3] 1 is a schematic diagram of an embodiment of a lysis system constructed in accordance with the principles of the present disclosure. [Figure 4] 1 is a diagram of an embodiment of a controller processing system usable with an embodiment of a lysis system and process according to the principles of the present disclosure; DETAILED DESCRIPTION OF THE INVENTION

[0015] It should be understood that the drawings are not necessarily to scale and that the disclosed embodiments are shown in schematic and partial views. In certain instances, details that are not necessary for an understanding of this disclosure or that provide other details that are difficult to understand may have been omitted. It should be understood that the present disclosure is not limited to the specific embodiments shown herein.

[0016] Embodiments of a dissolution system constructed in accordance with the principles of the present disclosure may be adapted for use with embodiments of a method for compounding a solution practiced in accordance with the principles of the present disclosure. Embodiments of a dissolution system constructed in accordance with the principles of the present disclosure may be used in a biologics environment, but may also be used in other applications, such as when different solutions, powders, biologics, fluids, reagents, and / or chemicals are used for compounding.

[0017] Embodiments of dissolution systems constructed according to the principles of the present disclosure can be used, for example, to enable direct dissolution and sterilization of powders by recirculation and to simplify the dilution of powders in bioprocesses, such as with appropriate buffer powders. For example, a buffer formulation process according to the principles of the present disclosure can be used in the process of manufacturing biological products such as antibodies. Those skilled in the art will recognize other uses for systems and methods according to the principles of the present disclosure that are suitable for situations where effective solute dissolution is desired, such as media formulation, where subsequent processes benefit from the sterile addition of either a final buffer or media. The present disclosure may also find use outside the field of biological products, such as for the production of saline, a common hospital commodity.

[0018] Embodiments of dissolution systems constructed according to the principles of the present disclosure can more easily maintain sterility of the biocontainer during the dissolution process, even when recirculating with a non-sterile powder container or buffer cartridge, while simultaneously utilizing effective solute partitioning to reduce the number of steps and length of time required to complete dissolution of the solute in the solvent.

[0019] In embodiments, the dissolution piping of a dissolution system constructed according to the principles of the present disclosure can be operated to provide closed-loop recirculation of solvent through a quantity of solute stored in a cartridge. A closed-loop arrangement can improve operation by reducing exposure to external contaminants, such as air interfaces, of the mixing process, further improving sterility reliability. Additionally, the inclusion of bypass piping in embodiments of a dissolution system constructed according to the principles of the present disclosure can help prevent excess solute from building up in any one component of the system, such as a filter, pre-filter, etc.

[0020] Still further, embodiments of dissolution systems constructed according to the principles of the present disclosure can help improve industrial and manufacturing aspects. For example, in embodiments, buffer solutions can be prepared on-site, such as in the same room as buffer storage or at the site of final use. In embodiments, preparing buffer solutions at or near the point of use can streamline application and allow for the combination of mixing, sterile filtration, and liquid storage in one process step, thereby reducing the footprint of the buffer preparation process. Material side inventories and material transport logistics can be reduced, which can be used to conserve space in bioprocessing facilities. Not only does the reduced footprint save costs, but faster production times, the ability for immediate batch release, and a smaller collection of components relative to current preparation processes also lower the cost of the process itself.

[0021] In an embodiment of a lysis system constructed according to the principles of the present disclosure, the lysis system includes a biocontainer, a pump, a cartridge, an upstream filter, a downstream filter, and lysis piping that fluidly connects the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter in a circulation loop.

[0022] The biocontainer defines a container inlet, a container outlet, and a storage volume. The container inlet and the container outlet are in communication with the storage volume. The storage volume is configured to hold a supply of fluid. The pump is in fluid communication with the storage volume of the biocontainer. The pump is adapted to receive the supply of fluid from the container outlet of the biocontainer and to discharge a flow of fluid from the biocontainer in a circular direction to the container inlet.

[0023] The cartridge defines a cartridge inlet, a cartridge outlet, and a storage chamber. The cartridge inlet and cartridge outlet are in communication with the storage chamber. The storage chamber is configured to hold a quantity of solute for dissolution into the fluid supply. In embodiments, any suitable solute may be used, such as any suitable solid. In embodiments, the solute may take any suitable form, such as in powder or pellet form.

[0024] The storage chamber is in fluid communication with the pump via the cartridge inlet for receiving a fluid flow from the pump. 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 the cartridge outlet to flow past a quantity of solute in the storage chamber. The cartridge outlet is in fluid communication with the container inlet.

[0025] An upstream filter is in fluid communication with the biocontainer and the cartridge so as to be interposed between a container outlet of the biocontainer and a cartridge inlet of a cartridge upstream of the cartridge in the direction of circulation, and a downstream filter is in fluid communication with the cartridge and the biocontainer so as to be interposed between a cartridge outlet of the cartridge and a container inlet of a biocontainer downstream of the cartridge in the direction of circulation.

[0026] In embodiments, a lysing system constructed according to principles of the present disclosure may include a valve adapted to selectively control fluid flow through the cartridge. In embodiments, a controller is provided that is configured to control the valve based on pressure in lysing piping downstream of the cartridge, between the cartridge and the biocontainer. In embodiments, a pressure sensor is disposed in the lysing piping and is configured to operate with the controller to transmit a pressure signal indicative of the pressure sensed by the sensor in the lysing piping.

[0027] In embodiments, a lysing system constructed according to principles of the present disclosure can include bypass piping in fluid communication with the lysing piping at the upstream branch and the downstream branch in a parallel relationship with the cartridge. The lysing system can include a flow control system configured to selectively control fluid flow through at least one of the lysing piping and the bypass piping.

[0028] In embodiments, a lysis system constructed according to the principles of the present disclosure can include a prefilter in fluid communication with the cartridge and the downstream filter so as to be interposed between the cartridge and the downstream filter, and the prefilter can have an internal volume greater than the internal volume of the downstream filter.

[0029] In embodiments, a lysis system constructed according to the principles of the present disclosure may include a mixer interposed between the buffer cartridge and the downstream filter and in fluid communication with the cartridge and the downstream filter. In embodiments, the mixer may be any suitable mixer, such as a static mixer.

[0030] In embodiments, a dissolution system constructed according to principles of the present disclosure may include a solution property sensor disposed in the dissolution piping, the solution property sensor configured to generate a property signal corresponding to a value of a solution property sensed in the dissolution piping by the solution property sensor, and at least one of the dissolution valve and the bypass valve may be adapted to operate based on a pressure signal.

[0031] In embodiments, the solution property sensor may comprise any suitable sensor, such as, for example, a suitable pH sensor that generates a pH signal indicative of the sensed pH. In embodiments, the dissolution system may comprise pH adjustment piping and a pH adjustment valve. pH inlet piping is in fluid communication with the dissolution piping and is adapted to deliver a supply of pH-adjusted fluid to the dissolution piping. The pH adjustment valve is operable to selectively block the pH adjustment piping to block the flow of the supply of pH-adjusted fluid to the dissolution piping. The pH adjustment valve is adapted to operate based on the pH signal via control by a suitable controller.

[0032] In embodiments, a lysing system constructed according to the principles of the present disclosure may include a means for controlling fluid flow through the cartridge. The flow control means may be configured to selectively control fluid flow through at least one of the lysing piping and the bypass piping based on pressure in the lysing piping downstream of the cartridge between the cartridge and the biocontainer. In embodiments, the flow control means may include a lysing pump disposed in the lysing piping between the upstream branch and the cartridge inlet, a bypass pump disposed in the bypass piping, a pressure sensor disposed in the lysing piping between the cartridge outlet and the container inlet, and a controller configured to operate the pressure sensor, the lysing pump, and the bypass pump. The pressure sensor is configured to generate a pressure signal corresponding to pressure sensed in the bypass piping by the pressure sensor and to transmit the pressure signal to the controller. The controller is configured to operate at least one of the bypass pump and the lysing pump based on the pressure signal.

[0033] In embodiments, a dissolution system constructed according to principles of the present disclosure may include means for controlling fluid flow through a cartridge, the means including a pump disposed in the dissolution piping between the cartridge outlet and an upstream branch, a dissolution valve, a bypass valve, a pressure sensor, and a controller. The dissolution valve is disposed in the dissolution piping between the upstream branch and the cartridge inlet, the bypass valve is disposed in the bypass piping, and the pressure sensor is disposed in the dissolution piping between the cartridge outlet and the container inlet. The pressure sensor is configured to generate a pressure signal corresponding to a pressure sensed in the dissolution piping by the pressure sensor and to 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.

[0034] In an embodiment, a method of preparing a solution according to the principles of the present disclosure includes using a recirculation system with lysis piping, bypass piping, and a flow control system according to the principles of the present disclosure. In an embodiment, a recirculation system constructed according to the principles of the present disclosure includes a storage bio-container and a solid cartridge in fluid communication with each other via lysis piping, bypass piping in fluid communication with the lysis in a parallel relationship with the cartridge, and a flow control system configured to selectively direct flow through either the cartridge or the bypass piping.

[0035] Turning now to the figures, there is shown in Figure 1 an embodiment of a buffered dissolution system 1 constructed in accordance with the principles of the present disclosure. In an embodiment, system 1 comprises a single use system.

[0036] In embodiments, system 1 can be sterilized using any suitable technique. For example, in embodiments, gamma or x-ray irradiation of system 1 can be used to sterilize system 1. In other embodiments, other methods of sterilizing system 1 can be used, such as ozonation or high-pressure air / water (steam) sterilization.

[0037] The illustrated lysing system 1 comprises a biocontainer 10, a pump 18, an upstream filter 20, a cartridge 26, a mixer 42, a prefilter 6, a downstream filter 8, lysing piping 24, a bypass piping 28, and means 22, 23 for controlling fluid flow through the cartridge 26 by selectively directing fluid flow to the cartridge 26 and the bypass piping 28. The lysing piping 24 fluidly connects the biocontainer 10, the pump 18, the upstream filter 20, the cartridge 26, and the downstream filter 8 in a circulation loop 69.

[0038] Biocontainer 10 is configured to hold a supply of fluid. In embodiments, biocontainer 10 may be any suitable storage vessel configured to hold a desired amount of liquid solution, such as a commercially available "2D" (or "two-dimensional") biocontainer bag or a "3D" (three-dimensional) biocontainer tank. Biocontainer 10 may be a rigid tank or bag, or a more flexible container. For example, biocontainer 10 may be made from a blend of low-density polypropylene and polyethylene.

[0039] Biocontainer 10 defines a container inlet 71, a container outlet 72, and a storage volume 73. Container inlet 71 and container outlet 72 are in communication with storage volume 73. Storage volume 73 is configured to hold a supply of fluid.

[0040] Pump 18 is in fluid communication with storage volume 73 of biocontainer 10. Pump 18 is adapted to receive a supply of fluid from container outlet 72 of biocontainer 10 and to discharge a flow of fluid from the biocontainer in a circulation direction 74 to the container inlet.

[0041] In embodiments, pump 18 may be any suitable pump, as would be understood by one of ordinary skill in the art. For example, in embodiments, pump 18 may be, for example, a suitable peristaltic pump or a suitable variable displacement pump. In the embodiment of FIG. 1, pump 18 is shown as being located downstream of outlet tubing 16, although the location of pump 18 may vary relative to other components of system 1, as shown, for example, in the embodiments of FIGS. 2 and 3.

[0042] Cartridge 26 is configured to hold a quantity of solute for dissolution into a supply of fluid and is in fluid communication with pump 18 for receiving fluid flow from and passing fluid flow through pump 18.

[0043] Cartridge 26 defines a cartridge inlet 75, a cartridge outlet 76, and a storage chamber 77. Cartridge inlet 75 and cartridge outlet 76 are in communication with storage chamber 77. Storage chamber 77 is configured to hold a quantity of solute for dissolution into a supply of fluid. Storage chamber 77 is in fluid communication with pump 18 via cartridge inlet 75 to receive a flow of fluid from pump 18. Cartridge inlet 75, storage chamber 77, and cartridge outlet 76 are configured such that a flow of fluid is directed from cartridge inlet 75, through storage chamber 77, and out cartridge outlet 76 to flow past the quantity of solute in storage chamber 77. Cartridge outlet 76 is in fluid communication with container inlet 71.

[0044] An upstream filter 20 is in fluid communication with the biocontainer 10 and the cartridge 26 such that it is interposed between a container outlet 72 of the biocontainer 10 and a cartridge inlet 75 of the cartridge 26 upstream of the cartridge 26 relative to the circulation direction 74.

[0045] A downstream filter 8 is in fluid communication with the cartridge 26 and the biocontainer 10 such that it is interposed between a cartridge outlet 76 of the cartridge 26 and a container inlet 71 of the biocontainer 10 downstream of the cartridge 26 relative to the circulation direction 74.

[0046] Prefilter 6 is in fluid communication with cartridge 26 and downstream filter 8 such that it is interposed between cartridge 26 and downstream filter 8. In embodiments, prefilter 6 has an internal volume that is larger than the internal volume of downstream filter 8. Prefilter 6, upstream filter 20, and downstream filter 8 may comprise any suitable filters including any suitable filter membrane, such as, for example, a filter comprising a high-density polyethylene housing and a filter membrane made from polyethylene or polypropylene.

[0047] Mixer 42 is in fluid communication with cartridge 26 and downstream filter 8 such that it is interposed between cartridge 26 and downstream filter 8. In embodiments, mixer 42 may be any suitable mixer, such as a static mixer.

[0048] In an embodiment, buffer cartridge 26 is in fluid communication with prefilter 6, downstream filter 8, static mixer 42, and pressure sensor 34. Downstream filter 8 in the embodiment of FIG. 1 is preceded in circulation direction 74 by prefilter 6, which has a larger volume than downstream filter 8.

[0049] The dissolution line 24 includes an upstream branch 81 and a downstream branch 82. The upstream branch 81 is disposed between the upstream filter 20 and the cartridge 26, upstream of the cartridge 26 with respect to the circulation direction 74. The downstream branch 82 is disposed between the cartridge 26 and the downstream filter 8, downstream of the cartridge 26 with respect to the circulation direction 74. The bypass line 28 is in fluid communication with the dissolution line 24 at the upstream branch 81 and the downstream branch 82 so as to be in a parallel relationship with the cartridge 26.

[0050] The means 22, 23 for controlling fluid flow through the cartridge 26 are configured to selectively control fluid flow through at least one of the lysis piping 24 and the bypass piping 28 based on the pressure in the lysis piping 24 downstream of the cartridge 26 between the cartridge 26 and the biocontainer 10. In an embodiment, the flow control means comprises a suitable flow control system configured to selectively control fluid flow through the lysis piping 24 and the bypass piping 28 based on the pressure in the lysis piping 24 downstream of the cartridge 26 between the cartridge 26 and the biocontainer 10. A pressure sensor 34 may be used to detect the pressure in the lysis piping 24 downstream of the cartridge 26 between the cartridge 26 and the biocontainer 10.

[0051] Pump 18 is disposed in dissolution piping 24 between container outlet 72 and upstream branch 81 of biocontainer 10. In the embodiment shown in FIG. 1 , the flow control means comprises a flow control system including dissolution valve 22, bypass valve 23, and pressure sensor 34. Dissolution valve 22 is disposed in dissolution piping 24 between upstream branch 81 and cartridge inlet 75. Bypass valve 23 is disposed in bypass piping 28. Pressure sensor 34 is disposed in dissolution piping 24 between cartridge outlet 76 and container inlet 71 of biocontainer 10. Pressure sensor 34 is configured to generate a pressure signal corresponding to the pressure sensed in dissolution piping 24 by pressure sensor 34. In an embodiment, pressure sensor 34 is in operative communication with a suitable controller configured to operate at least one of dissolution valve 22 and bypass valve 23 based on the pressure signal. For example, when the pressure exceeds a predetermined value, the controller can be configured to open bypass valve 23 such that fluid is diverted from dissolution piping 24 to bypass piping 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 in the dissolution piping 24 as sensed by the pressure sensor 34 within a predetermined range.

[0052] In an embodiment, a solution property sensor 32 is disposed in the dissolution piping 24. The solution property sensor 32 may be configured to generate a property signal corresponding to a value of a solution property sensed in the dissolution piping 24 by the solution property sensor 32. In the illustrated embodiment, the solution property sensor includes a pH sensor and the property signal includes a pH signal.

[0053] System 1 includes pH adjustment piping 38 and pH adjustment valve 37. pH adjustment piping 38 is in fluid communication with dissolution piping 24 and is adapted to deliver a supply of pH adjustment fluid 39 to dissolution piping 24. pH adjustment valve 37 is operable to selectively block pH adjustment piping 38 to block the flow of the supply of pH adjustment fluid 39 to dissolution piping 24. pH adjustment valve 37 is adapted to operate based on a pH signal generated by pH sensor 32. In the illustrated embodiment, pH adjustment piping 38 is in fluid communication with dissolution piping 24 via bypass piping 28.

[0054] 2 , another embodiment of a lysing system 201 constructed in accordance with the principles of the disclosed system includes a flow control means comprising a flow control system configured to selectively control fluid flow through lysing piping 24 and bypass piping 28, the flow control system comprising: a bypass pump 18a disposed in bypass piping 28; a lysing pump 18b disposed in lysing piping 24 between upstream branch 81 and cartridge inlet 75; and a pressure sensor 34. Pressure sensor 34 is disposed in lysing piping 24 between cartridge outlet 76 and container inlet 71 of biocontainer 10. Pressure sensor 34 is configured to generate a pressure signal corresponding to the pressure sensed in lysing piping 24 by pressure sensor 34. In an embodiment, at least one of bypass pump 18a and lysing pump 18b is adapted to operate based on the pressure signal.

[0055] As shown in FIG. 2 , buffer cartridge 26 can be filled with a quantity of solid material 44, such as any suitable solute, for dissipation in a fluid. In embodiments, solute 44 can include any suitable solid for dissolution in a fluid, such as a suitable powder or pellet dissolved in a solvent. For example, in embodiments, solute 44 can include, for example, a buffer salt powder or other suitable powder. In embodiments, solute 44 can constitute a minor or major portion of the final solution concentration. Buffer cartridge 26 can hold solid 44 in a storage area or chamber, which can define a specific, fixed, or adjustable volume and can be in fluid communication with dissolution piping 24 of system 1. Buffer cartridge 26 can be filled with solid material 44 at one location and then transported to another location, such as a final use location or a buffer preparation location; location division line 50 in FIG. 2 schematically represents the division between the loading location and the other location. In embodiments, buffer cartridge 26 can be filled at the same location as system 1 without requiring additional space.

[0056] In embodiments, buffer cartridge 26 may comprise a single-use container for solid material to be dissipated in a fluid and introduced into system 1 as needed. Buffer cartridge 26 may be rigid, semi-rigid, or any degree of rigidity capable of withstanding a sufficient amount of pressure for its intended use. In embodiments, buffer cartridge 26 may be configured to accommodate solids of a predetermined size for dissolution in a fluid. In embodiments, system 1 may include multiple buffer cartridges 26 in series and fluid communication with each other 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 embodiments, buffer cartridge 26 may be sterilized using any suitable technique, as will be understood by those skilled in the art.

[0057] The fluid paths and piping of system 1 may be made from any suitable material, such as silicone tubing, thermoplastic polyethylene, or polypropylene. Any suitable valves may be used to selectively block the fluid paths and / or piping of the system. In embodiments, the piping may be made from a resilient, flexible material, and a suitable clamping (or pinching) valve may be used. While the fluid (solvent) is typically water, in embodiments, it may include or be other liquids and solvents, such as organic solvents or mixtures of organic solvents with water (e.g., ethanol and water).

[0058] 1, when clamping valve 4 is opened, inlet piping 2 allows fluid to enter and be introduced into system 1. When clamping valve 4 is closed, no additional fluid is introduced into system 1 from the source in inlet piping 2. Closing clamping valve 4 can help ensure that once a particular volume of fluid has been provided to system 1, the amount of fluid in system 1 does not change, thereby helping to create a closed-loop circulation circuit.

[0059] Fluid can flow in a circulation direction 74 from inlet piping 2 through dissolution piping 24 via operation of pump 18. As fluid initially flows through dissolution piping 24, the circulating fluid can vent components of system 1, such as pre-filter 6, sterile upstream filter 20, and downstream filter 8.

[0060] Fluid can fill biocontainer 10 by flowing through inlet 71 of biocontainer 10 before, during, or after venting prefilter 6, upstream filter 20, and downstream filter 8. When either biocontainer 10's closable outlet 72 or constriction valve 12 is closed, biocontainer 10 can be filled to a desired volume before fluid flows through constriction valve 12 to other components of system 1. In embodiments, biocontainer 10 is filled with fluid, and the filled volume can be measured or determined via suitable means, such as gravitational measurement with a scale or flow measurement with an appropriate flow meter. Filling biocontainer 10 can be done with or without cartridge 26 in system 1, depending on the positioning and open or closed status of valves 12, 22, and 23 of system 1. Once a sufficient volume or amount of fluid has been introduced into system 1, the connection to the fluid source can be removed from the open connection in dissolution piping 24, and buffer cartridge 26 can be introduced into dissolution piping 24.

[0061] Outlet piping 16 may be provided to facilitate flushing of fluid in system 1. The pinch valve 14 of outlet piping 16 may be kept closed so that fluid can circulate through the closed loop formed by dissolution piping 24 and bypass piping 28. However, initial flow into system 1 may be assisted by leaving pinch valve 14 open so that fluid can flow through outlet piping 16, flushing various components of system 1 and carrying any particles the fluid has acquired along the way through system 1. In embodiments, outlet piping 16 may include an additional sterile filter or a sterile disconnector for further fluid processing. Also, pinch valve 14 may be any suitable valve. In embodiments, selective filters may be provided in addition to or instead of valve 14 that direct a portion of the fluid to outlet piping 16 and maintain a portion of the fluid in system 1 based on several criteria, such as average particle size or the level of fluid pressure exerted on the piping at the location of pinch valve 14.

[0062] In an embodiment, biocontainer 10 is in fluid communication with upstream filter 20, which is in fluid communication with bypass piping 28 and dissolution piping 24. From biocontainer 10, fluid can flow through upstream filter 20 and into dissolution piping 24 if clamping valve 22 is at least partially open, or into bypass piping 28 if clamping valve 23 is at least partially open.

[0063] In embodiments, bypass piping 28 can have a larger cross-sectional area than dissolution piping 24 or can be made of a different material than buffer cartridge 26 so that it can carry more fluid or support greater fluid pressure. For the initial fluid flow, clamping valve 22 can remain closed and fluid can flow through bypass piping 28. Fluid can flow through bypass piping 28 and clamping valve 30. Fluid flow can be recirculated in this circulation loop as many times as desired. In embodiments, fluid flow is not circulated through bypass piping 28 at startup, and circulation through cartridge 26 to cause buffer powder dissolution can begin upon startup. As a result, fluid can be selectively diverted to bypass piping 28 as desired. As previously described, the constriction valves 4, 12, 14, 23, 30 can be opened and closed to any degree at any time in the initial flow cycle as desired to add, remove, or exchange fluid in the system 1, to manage the circulation of fluid, or to manage the pressure and volume of fluid in any particular component, such as the biocontainer 10, as will be readily understood by those skilled in the art.

[0064] In an embodiment, the buffer cartridge 26 is in fluid communication with the dissolution piping 24. When the clamp valve 22 is at least partially open, fluid can flow through the dissolution piping 24 and into the buffer cartridge 26. The buffer cartridge 26 can include any number of solid materials 44, such as substances that can dissolve in the fluid. In the embodiment of FIG. 1, the solid materials 44 are in the form of powders, and the cartridge 26 includes a specific volume of buffer solute powder for dissolution in the fluid to create a buffer formulation. As such, fluid can flow into and out of the cartridge 26, capturing and carrying away the buffer solute powder.

[0065] As the fluid flows through the buffer cartridge 26, it picks up a portion of the solute powder material 44 in the buffer cartridge 26 and carries the solute powder to the prefilter 6 or to the static mixer 42. After the fluid exits the buffer cartridge 26 in the embodiment of FIG. 2 and / or the static mixer 42 in the embodiment of FIG. 1, the fluid can flow through the prefilter 6 and then through the downstream filter 8. The larger volume of the prefilter 6 can help facilitate better localized dissolution of the solute powder before entering the downstream filter 8.

[0066] In the embodiment of FIG. 1 , cartridge 26 has an inlet 75 and a separate outlet 76 to allow fluid to flow directly through buffer cartridge 26 in the path of dissolution piping 24, which can help reduce turbulence in buffer cartridge 26 and facilitate effective dissipation of buffer solute powder from buffer cartridge 26. Inlet 75 and outlet 76 can include fluid couplings in conjunction with clamping valves or separate couplings, such as snap or threaded couplings. The shape and size of buffer cartridge 26 or components of buffer cartridge 26 can be varied as needed and advantageously adapted to reduce the risk of buffer solute loss, damage, or contamination when filled or connected. Furthermore, a mesh can be installed at inlet 75 or outlet 76 of buffer cartridge 26, if desired, to reduce the risk of a large amount of powder exiting the container and sending excessive solute into circulation at one time.

[0067] In other embodiments, the buffer cartridge 26 may have one large opening at the bottom, top, or side of the buffer cartridge 26 that acts as both an inlet and an outlet with a mesh at the interface of the buffer cartridge 26. The buffer cartridge 26 may also include an internal analytical sensor 36, such as a pH sensor or a conductivity sensor, as shown in Figure 2. A refractive index sensor may also be utilized as the analytical sensor 36, placed after the biocontainer 10 but before the upstream filter 20.

[0068] Embodiments of the present disclosure can utilize any desired relative size ratio of the pre-filter 6 and downstream filter 8 to manage conditions of the system 1, such as pressure or fluid flow. Alternatively, the downstream filter 8 can have a larger volume or capacity, or can have both a pre-filter chamber and a sterile chamber to increase localized lysis, and the downstream filter 8 can be operated with or without the pre-filter 6 before the downstream filter 8. An additional pressure sensor similar to pressure sensor 34 can be positioned after the downstream filter 8. Information from the additional pressure sensor can provide an indication of the pressure drop through the pre-filter 6 and downstream filter 8, which can indicate the level of lysis of the fluid in the circulation.

[0069] In an embodiment, downstream filter 8 is in fluid communication with the storage chamber of biocontainer 10. Downstream filter 8 can receive non-sterile fluid flowing from buffer cartridge 26 and ensure that fluid containing entrained solute powder flowing into biocontainer 10 is sterile before entering biocontainer 10. Sterile upstream filter 20 and downstream filter 8 can be any suitable sterility barrier enhancing device, such as a filter disc, capsule, or cartridge, and can be of any suitable size. After downstream filter 8 filters the solute-containing fluid to ensure sterility, the fluid and solute flow into biocontainer 10.

[0070] When biocontainer 10 acts as a reservoir, the fluid and solute achieve a distribution of solute powder proportional to the amount of solute by volume in the fluid. Furthermore, in embodiments, the inlet and outlet of biocontainer 10 may be configured and arranged to promote mixing. In embodiments, biocontainer 10 is in fluid communication with upstream filter 20, and fluid flows from biocontainer 10 to upstream filter 20. Fluid can flow from biocontainer 10 solely by pressure and flow generated by pump 18, or other methods can be utilized in combination with pump 18 to assist flow, such as positioning upstream filter 20 below or above biocontainer 10 to increase or decrease the velocity of fluid into upstream filter 20, or to increase or decrease the amount or likelihood of fluid flowing back into biocontainer 10 after exiting biocontainer 10 and before entering upstream filter 20.

[0071] After the fluid flows from the upstream filter 20, it continues to recirculate through the system 1, accumulating increasing amounts of buffer solute in the biocontainer 10. At some point, the desired buffer formulation is achieved in the biocontainer 10. In some embodiments, the fluid gradually draws more solute powder from the buffer cartridge 26 with each circulation until the ratio of solute to solvent inside the buffer cartridge 26 is the same as in the biocontainer 10. In other embodiments, the fluid circulates until the buffer cartridge 26 is emptied of solute powder and the fluid circulating through the biocontainer 10 has all the desired solute powder. In some embodiments, the fluid pressure and flow rate are gradually increased over many circulation cycles to facilitate effective release of the solute powder and to manage the fluid pressure in the system 1. Once the desired formulation is achieved, the buffer formulation can be removed for use as a buffer solution 46 in a desired application, such as a tangential flow filtration (TFF) or chromatography process 48, as shown in the embodiment of FIG. 2.

[0072] 2 , to help regulate or determine the condition of the fluid in biocontainer 10 or the condition of the fluid flowing through dissolution piping 24 and / or bypass piping 28, at least one analytical sensor 36, such as a pH sensor, conductivity sensor, or refractive index sensor indicator, can be used, along with several components that can be used in response to analytical sensor 36, such as feedback system 32 or a pH adjustment supply. Analytical sensor 36 can be used to provide information about the properties and contents of the fluid in system 1, or in more specific components, such as biocontainer 10, and whether the contents of biocontainer 10 are acceptable. If acceptable, automatic release of the contents of biocontainer 10 to buffer solution application 46 can occur through outlet piping 16, separate dedicated biocontainer outlet piping, or automatic replacement of biocontainer 10. A pH sensor can also be used to automatically introduce fluid from the pH adjustment supply into system 1 through secondary pH inlet piping 38 as a way to equilibrate the pH of the fluid in system 1 before or during a circulation cycle. Analytical sensors 36 may be used to help verify solution homogeneity, to finalize buffer solutions or media formulations through pH adjustment, and other functions as will be understood by those skilled in the art.

[0073] During circulation, it may be advantageous to monitor the amount of pressure exerted on the various piping and components of system 1. For example, flow may be reduced in dissolution piping 24 if pressure reduction is necessary to prevent damage to buffer cartridge 26 or to facilitate better dissolution of the solute powder in buffer cartridge 26 while fluid is circulating through dissolution piping 24. To prevent excessive pressure in buffer cartridge 26 and dissolution piping 24, for example, bypass piping 28 may be used to divert at least a portion of the fluid flow from dissolution piping 24 and to bypass cartridge 26. In the embodiment shown in FIG. 1, a bypass valve 23 may be provided and may be controlled by the controller to selectively open bypass valve 23 to relieve pressure in dissolution piping 24. The degree to which bypass valve 23 is opened, or pumps 18a and 18b in the embodiments of Figures 2 and 3, are operated, can be adjusted by a controller to help divert at least some fluid from dissolution piping 24 to bypass piping 28, where the diverted fluid is later combined and recirculated with the fluid exiting buffer cartridge 26. Thus, fluids that split into dissolution piping 24 and bypass piping 28 are later recombined and recirculated together, allowing pressure to be managed within buffer cartridge 26 without significantly affecting fluid flow or fluid pressure throughout system 1. Pump 18 of Figure 1 may be utilized in embodiments to adjust pressure or fluid flow.

[0074] A feedback system 32 may be implemented in system 1 to assist in managing fluid pressures in the system piping and components and to help enable effective transfer of solutes from buffer cartridge 26. Feedback system 32 can help control fluid flow through system 1 and certain components, such as buffer cartridge 26. Feedback system 32 can selectively control fluid flow through lysis piping 24, bypass piping 28, and other components of system 1. In embodiments, feedback system 32 can control fluid flow based on pressure in lysis piping 24 downstream of buffer cartridge 26 between cartridge 26 and biocontainer 10. In other embodiments, feedback system 32 can control fluid flow based on local pressures at different locations in system 1.

[0075] 1 , the fluid can interact with pressure sensor 34 on its way to prefilter 6, such that the pressure sensor detects the pressure exerted by the flow of fluid circulating through dissolution piping 24. In the illustrated embodiment, pressure sensor 34 is positioned downstream of cartridge 26, between cartridge 26 and biocontainer 10, and more specifically, between cartridge 26 and prefilter 6. Pressure sensor 34 can be used in conjunction with other sensors or information available to the system in a feedback system 32 configured to regulate the pressure in system 1, such as by controlling the state or degree to which clamping valve 22 is opened. In an embodiment, feedback system 32 interacts with pressure sensor 34 and at least one other pressure or flow sensor positioned in system 1, such as one positioned elsewhere in dissolution piping 24, including, for example, upstream of buffer cartridge 26, upstream or downstream of upstream filter 20, downstream of downstream filter 8, and / or one positioned in bypass piping 28. In an embodiment, the feedback system 32 and the pressure sensor 34 can be part of a means for controlling the flow of fluid through the cartridge, and the flow control means is configured to selectively control the flow of fluid through at least one of the dissolution piping 24 and the bypass piping 28 based on the pressure in the dissolution piping 24 downstream of the cartridge 26 between the cartridge 26 and the biocontainer 10.

[0076] Feedback system 32 may be configured to receive information from pressure sensor 34 and any other sensors included in system 1 and to send control signals to one or more other components, such as pump 18, dissolution valve 22, and / or bypass valve 23. Feedback system 32 may be configured to automatically adjust pump 18, dissolution valve 22, and / or bypass valve 23 to maintain fluid flow through dissolution piping 24 within a particular fluid pressure range. For example, feedback system 32 may utilize actuators or other automatic controls to adjust the degree to which clamping valves 22, 23 are opened or the degree to which pump 18 and pumps 18a, 18b of FIGS. 2 and 3 are operated. Feedback system 32 may be configured to provide an indication to an operator of system 1 of the operating position and status of the clamping valves or pumps of system 1 and an operator interface adapted to allow the operator to adjust one or more selected clamping valves or pumps. The feedback system 32 may be in electronic communication with various components of the system 1, such as the clamping valves 22, 23 and the pump 18 or pumps 18a, 18b, such that the feedback system 32 automatically controls the operation of the pumps or clamping valves.

[0077] In embodiments, pressure sensor 34 may be augmented, replaced, or comprised of various means for assessing pressure. For example, mechanical or electronic flow sensors, such as electromagnetic, may be used in place of or in conjunction with pressure sensor 34. Additionally, a timing system, component, and / or components may be utilized to measure the flow rate of fluid moving through system 1 at one location in system 1 or at multiple locations along system 1. Also, estimates based on water volume, pipe cross-section, and fluid flow rate, or by measuring and determining tube tension in non-rigid plastic tubing, may be used in place of or in conjunction with pressure sensor 34, all separately or together. Additionally, feedback system 32 may be operable without the use of electrical sensors or circuitry, such as through pressure sensor 34 with spring-based valve operation responding proportionally to pressure exerted on the spring-based valve.

[0078] It can be advantageous to monitor and control pressure in system 1, such as in dissolution piping 24 or bypass piping 28. For example, if dissolution valve 22 is in too open a position and / or pump 18 is creating excessive fluid flow, a pressure buildup can occur in buffer cartridge 26 caused by powder blockage, or in filters 8, 20 as a result of excessive fluid pressure and / or solute blockage. Any of these blockages can impede or interrupt fluid flow through the circulation loop, reduce the efficiency of system 1, stop the entire buffer or medium preparation process, and / or damage piping 24, 28, connections, or other components of system 1. Furthermore, the actual settings for pressure and pump flow will vary depending on the type of buffer added, including the solubility characteristics and the relative proportion of buffer to the total liquid, so settings for various components, such as clamping valves and pumps, can change when preparing different buffer solutions. As such, pressure sensor 34 in combination with feedback system 32 can be used to follow protocols with appropriate gradual fluid flow profiles through buffer cartridge 26 and system 1 .

[0079] In the embodiment of Figure 2, system 1 includes two pumps 18a, 18b for regulating fluid flow through system 1. Bypass pump 18a can operate in bypass piping 28, and dissolution pump 18b can operate in dissolution piping 24. In the embodiment of Figure 2, bypass pump 18a is in fluid communication with upstream filter 20 and pre-filter 6, and pump 18b is in fluid communication with buffer cartridge 26 and downstream filter 8. Bypass pump 18a and dissolution pump 18b can be positioned in bypass piping 28 and dissolution piping 24, respectively, to affect fluid flow therethrough, effectively acting as part of a flow control system and as part of a means for controlling fluid flow through the cartridges.

[0080] 2, bypass pump 18a and dissolution pump 18b may be used in place of or in addition to restrictive valves located in bypass piping 28 and dissolution piping 24, respectively, as part of a flow control means configured to selectively control fluid flow through at least one of the dissolution piping and the bypass piping. In an embodiment, bypass pump 18a and dissolution pump 18b replace or function as valves controlling fluid flow through bypass piping 28 and dissolution piping 24, respectively. Bypass pump 18a and dissolution pump 18b act as valves by either operating to effectively open the piping to the other piping when the other pump is not operating (or operating at a slower speed), or by not operating to effectively close the piping to the other piping when the other pump is operating (or operating at a higher speed). For example, pumps 18a, 18b can be operated or not operated to exert pressures or fluid flow rates equivalent to the pressures or fluid flow rates in dissolution piping 24 and bypass piping 28 that result from corresponding operation of clamp valves 22, 23 in the embodiment of Figure 1. Also, bypass pump 18a and dissolution pump 18b can be configured to allow fluid to flow through pumps 18a, 18b in a pass-through mode, e.g., when pumps 18a, 18b are not operating, and / or to prevent fluid from passing through pumps 18a, 18b when pumps 18a, 18b are not operating. Furthermore, bypass pump 18a can be configured to operate differently than dissolution pump 18b; e.g., bypass pump 18a can be configured to duplicate or replace bypass valve 23, while dissolution pump 18b is not, or vice versa.

[0081] In the embodiment of FIG. 3 , bypass clamp valve 23 and dissolution clamp valve 22 are used in conjunction with bypass pump 18a and dissolution pump 18b as part of the means for controlling fluid flow through cartridge 26. In embodiments, different combinations of clamp valves may be operable with different combinations of pumps to achieve effective flow control within dissolution piping 24 and bypass piping 28. For example, while FIG. 3 shows bypass clamp valve 23 following bypass pump 18a and dissolution clamp valve 22 following dissolution pump 18b, clamp valves 22, 23 may precede pumps 18a, 18b. Furthermore, clamp valves may be operable and positioned as desired to fluidly isolate pumps 18a, 18b from other components of system 1. System 1 may include bypass piping 28 without clamp valve 23 while dissolution piping 24 includes clamp valve 22, or vice versa.

[0082] Bypass pump 18a and dissolution pump 18b can be operated independently or based on the operation of an additional pump, such as pump 18 in the embodiment of FIG. 1 , located upstream of the upstream branch 81 from which bypass piping 28 branches. For example, bypass pump 18a and dissolution pump 18b, or the additional pump, can be operated such that an increase or decrease in fluid pressure or velocity exerted by one pump, such as pump 18, directly affects the fluid pressure or velocity exerted by one or both of the other pumps, such as pumps 18a and 18b. Furthermore, either pump 18a or pump 18b, or the additional pump, can be configured to operate in any combination independent or dependent on one another. For example, pump 18b can be configured to adjust the fluid pressure or velocity based on the fluid pressure or velocity exerted by pump 18a, while pump 18a can be configured not to adjust the fluid pressure or velocity based on the fluid pressure or velocity exerted by pump 18b, or vice versa.

[0083] The placement of the upstream filter 20 and the downstream filter 8 can help achieve a number of advantages. For example, as shown diagrammatically in FIG. 2, the system 1 can be divided along a sterile line 40 that defines a sterile portion (to the right of the sterile line 40) and a non-sterile portion (to the left 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 the diagrammatic embodiment of FIG. 2 includes all components to the right of the sterile line 40. The ability to create a sterile environment in the portion of the circulation loop between the sterile filters 8, 20 allows the buffer cartridge 26 to be either sterile or non-sterile without affecting the sterility of the biocontainer 10. Additionally, extending the bypass piping 28 in parallel with the buffer cartridge 26 in the dissolution piping 24 reduces the risk of blockages occurring anywhere in the circulation loop due to excessive presence or accumulation of buffer solutes, such as in the pre-filter 6 or downstream filter 8.

[0084] Referring to FIG. 4 , the system may include a suitable controller 900 for use with the feedback system 32, pressure sensor 34, analytical sensor 36, and any other suitable sensors desired to be used. 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 sensors disposed in communication therewith. In embodiments, any suitable commercially available controller may be used. In embodiments, the controller 900 may include one or more processing units 902, 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 of the controller systems disclosed herein.

[0085] The processing unit 902 may include one or more separate processing units, each having one or more cores. Each of the separate processing units may have the same or different architectures. The processing unit 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 processing units 902 may be mounted on a common substrate or on multiple different substrates.

[0086] Processing unit 902 is configured to perform (e.g., configure to provide execution of) a particular function, method, or operation when at least one of one or more separate processing units is capable of performing the operations embodying the function, method, or operation. Processing unit 902 can perform the operations embodying the function, method, or operation, for example, by executing code stored in memory 904 (e.g., interpreting a script) and / or by communicating data through one or more ASICs. Processing unit 902, and therefore control unit 900, can be configured to automatically perform any and all functions, methods, and operations disclosed herein. As such, control unit 900 can be configured to implement any (e.g., all) of the protocols, devices, mechanisms, systems, and methods described herein.

[0087] For example, when this disclosure states that a method or device performs mission "X" (or that mission "X" is performed), such statement should be understood to disclose that controller 900 can be configured to perform mission "X." Controller 900 is configured to perform a function, method, or operation, at least when processor 902 is configured to do the same.

[0088] 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 located in multiple separate locations and each having a different structure. Memory 904 may include remotely hosted (e.g., cloud) storage.

[0089] Examples of memory 904 include non-transitory computer-readable media such as RAM, ROM, flash memory, EEPROM, any type of optical storage disk such as a DVD, Blu-Ray® disk, magnetic storage device, holographic storage device, HDD, SSD, any medium that can be used to store program code in the form of instructions or data structures, etc. Any and all methods, functions, and operations described herein may be embodied entirely in the form of tangible and / or non-transitory machine-readable code (e.g., interpretable script) stored in memory 904.

[0090] The input-output devices 906 may include any components for communicating data, such as ports, antennas (i.e., transceivers), printed conductive tracks, etc. The input-output devices 906 may enable wired communication via USB, DisplayPort, HDMI, Ethernet, etc. The input-output devices 906 may enable electronic, optical, magnetic, and holographic communication with suitable memory 904. The input-output devices 906 may enable wireless communication via Wi-Fi, Bluetooth, cellular systems (e.g., LTE, CDMA, GSM, WiMax, NFC), GPS, etc. The input-output devices 906 may include wired and / or wireless communication paths.

[0091] Sensors 908, such as pressure sensors 34, can capture physical measurements of the environment and report them to the processing unit 902. The user interface 910 can include a display, physical buttons, a speaker, a microphone, a keyboard, etc. The actuators 912 can enable the processing unit 902 to control mechanical forces.

[0092] The controller 900 may comprise a distributed processing system. For example, some components of the processing system 900 may reside on a remote host network service (e.g., a cloud computing environment), while other components of the processing system 900 may reside on a local computing system. The controller 900 may have a modular design, with specific modules including multiple features / functions illustrated in FIG. 4. For example, an I / O module may comprise volatile memory and one or more processing units. As another example, individual processing unit modules may include read-only memory and / or a local cache.

[0093] Embodiments of a system constructed according to the principles of the present disclosure can function with many relative positionings of the various components changed relative to one another, such as, for example, the positioning of pump 18, bypass piping 28, and dissolution piping 24, as well as repositioning of sterile filters 8, 20 relative to other components or each other. Embodiments of a system constructed according to the principles of the present disclosure can function with the addition or omission of various components of system 1, such as, for example, by adding additional clamping valves or pumps to system 1 to differentially regulate flow in the various fluid piping, or by removing pre-filter 6 or incorporating downstream filter 8 into the pre-filter. System 1 can also be compatible with various other systems and processes and may have additional piping and / or fluid connections to operate with those other systems. Additional flow sensors can be incorporated into system 1 at multiple locations for better process control, even into other existing components such as pump 18. Additional vents may also be incorporated into system 1 to selectively open or close in the event that air or other substances accumulate or become trapped in a particular location in system 1, further assisting in managing the sterility and / or pressure levels of system 1. Braided tubing may be utilized in areas of system 1 that experience sufficient pressure, such as dissolution piping 24.

[0094] The construction and materials of the components of system 1 can be selected according to various advantages and requirements. For example, all components can be reusable, disposable, or supported by hardware, such as steel or other rigid elements, depending on cost, hygiene, and portability considerations of the buffer or media formulation process. If the fluid stored in biocontainer 10 does not need to be sterile, the sterile filters 8, 20 can be eliminated to reduce unnecessary costs. Additionally, certain components or piping of system 1 can be transparent to provide better visual feedback of dissolution circulation, such as tracking the rate of solute dissolution or air / particle flow in the fluid.

[0095] A process for preparing a buffer solute according to the principles of the present disclosure may be used in any one of the systems of Figures 1-3. In an embodiment, buffer cartridge 26 may be filled with solid material 44, such as a suitable buffer solute in the form of a powder or pellet to be dissolved. Crimp valves 4, 12, 23, and 30 are opened to selectively perform a pre-circulation in which fluid is circulated from biocontainer 10 through the piping of system 1, excluding lysis piping 24, and back to biocontainer 10. Crimp valve 4 is opened and clamp valves 14 and 30 are closed. Upstream filter 20 is vented, and biocontainer 10 is partially filled. Crimp valve 30 is then opened. Biocontainer 10 is filled, and both prefilter 6 and downstream filter 8 are vented. After biocontainer 10 is filled, clamp valve 4 is closed.

[0096] Fluid flow is initiated in the bypass line 28 either by opening the clamping valve 23 to a desired amount or by operating, for example, the pump 18a associated with the bypass line 28. The buffer cartridge 26 is introduced into the system 1 as in FIG. 2, and fluid flow is initiated in the dissolution line 24 either by opening the clamping valve 22 to a desired amount as in the embodiment of FIG. 1 or by operating the pump 18 associated with the dissolution line 24 as in FIG. 2, or a combination of either or both as in the embodiment of FIG. 3. The flow in the dissolution line 24 can be parallel to the flow in the bypass line 28, and fluid can be diverted as desired between the dissolution line 24 and the bypass line 28. Through this process, the fluid traveling through the buffer cartridge 26 picks up a substance 44, such as a buffer solute or powder, and flows to the inlet of the prefilter 6. The fluid flow through the bypass line 28 comes into contact with the buffer solute being pushed out of the buffer cartridge 26 immediately after the clamping valve 30, accumulating in front of the prefilter 6. Fluid flow through bypass tubing 28 can facilitate dissolution of buffer solutes into the solvent or fluid phase, which allows for flow of solution through both prefilter 6 and downstream filter 8. In an embodiment, pressure sensor 34 is located upstream of prefilter 6 and configured to cooperate with feedback system 32 to enable control of fluid flow through dissolution tubing 24 to prevent excess solute from being flushed from buffer cartridge 26, which could result in potential blockages and abrupt termination of the process.

[0097] In embodiments, the fluid pressure in the dissolution piping 24 is also monitored. If the pressure in the dissolution piping 24 is below a predetermined threshold or decreases more than a predetermined rate, the flow of fluid in the dissolution piping 24 can be increased. If the pressure in the dissolution piping 24 is above a predetermined threshold or increases more than a predetermined rate, the flow of fluid in the dissolution piping 24 can be decreased. In embodiments, the controller 900 cooperates with the pressure sensor 34 to monitor and adjust the fluid flow, either autonomously or in conjunction with other systems or operators. Additionally, monitoring the pressure in the dissolution piping 24 can be achieved indirectly, such as by monitoring other parts of the system 1 and adjusting the fluid flow and pressure in the system 1 to achieve the same effect as monitoring the dissolution piping 24. Once the clamping valve 22 is fully open and maximum flow through the dissolution piping 24 and the buffer cartridge 26 is achieved, the process can continue until the buffer solute is sufficiently and completely dissolved. In an embodiment, the bypass valve 23 may be closed progressively either when the dissolution valve 22 is fully opened or as the dissolution valve 22 moves through a range of progression from a fully closed position to a fully open position.

[0098] Once the sensor signal values ​​collected from analytical sensors 36 become constant (or fall within a predetermined range), pH adjustment can begin for the final preparation of the buffer solution. Once all sensor signal values ​​become constant (or fall within a predetermined range) after pH adjustment, the buffer preparation in biocontainer 10 can be moved to the next processing step 48 for batch 46 either by modular removal or by flushing biocontainer 10 through outlet piping 16 by opening clamp valve 14. Prefilter 6 may be vented to allow air to enter prefilter 6. Pump 18 or pumps 18a, 18b may be operated in the opposite direction until the piping of system 1 and biocontainer 10 are empty.

[0099] In an embodiment, in an initial step, buffer cartridge 26 can be filled with the buffer solute to be dissolved, inlet valve 4 and bypass valve 23 are opened, and outlet valve 14, dissolution valve 22, and inlet valve 30 are closed. After a predetermined period of time has elapsed since the initial step, inlet valve 30 is opened, upstream filter 20 is vented, biocontainer 10 is partially filled to an initial volume, and bypass valve 23 is closed. After a predetermined period of time has elapsed since the initial step, biocontainer 10 is filled from the initial volume to a larger target volume, and both prefilter 6 and downstream filter 8 are vented. After a predetermined period of time has elapsed since the initial step, clamp valve 23 is opened and pump 18 is started.

[0100] The fluid pressure in the dissolution line 24 is then monitored. When the pressure in the dissolution line 24 drops below a threshold, the flow of fluid in the dissolution line 24 can be increased. The pressure in the system 1 can be monitored, and the dissolution valve 22 and bypass valve 23 can be adjusted as needed over a predetermined period of time. The system 1 can be flushed by opening the bleed valve 14.

[0101] In other embodiments, pump 18 may be positioned at a different location in the hydraulic circuit, as desired. In embodiments, additional pumps, stronger or more reinforced tubing, and / or better or larger filters may be used to increase the efficiency of embodiments of the present disclosure and shorten the time required to complete a formulation, or to increase the quality or quantity of the formulation within the same time period. In embodiments, impact forces may be exerted on various components of system 1 to help prevent passageway clogging caused by solute buildup.

[0102] In embodiments of methods of preparing solutions according to the principles of the present disclosure, any suitable embodiment of a dissolution system constructed according to the principles discussed herein may be used. In embodiments, a method of preparing solutions according to the principles of the present disclosure includes using a recirculation system with dissolution piping, bypass piping, and a flow control system according to the principles of the present disclosure.

[0103] In one embodiment, a method for preparing a buffer solution includes fluidly connecting a buffer cartridge in a circulation loop formed by dissolution piping that fluidly connects a biocontainer, a pump adapted to discharge a fluid flow from the biocontainer in a circulation direction, the buffer cartridge, an upstream filter disposed between the biocontainer and the buffer cartridge upstream of the buffer cartridge in the circulation direction, and a downstream filter disposed between the buffer cartridge and the biocontainer downstream of the buffer cartridge in the circulation direction. The buffer cartridge contains a quantity of buffer solute.

[0104] The fluid stream is circulated through the circulation loop to entrain at least a portion of the buffer solute from the buffer cartridge into the fluid stream. In an embodiment of the method for preparing a buffer solution, circulating the fluid stream through the circulation loop includes controlling the fluid flow through the buffer cartridge based on pressure in dissolution piping downstream of the buffer cartridge between the buffer cartridge and the biocontainer.

[0105] In an embodiment of the method of preparing a buffer solution, the buffer solute comprises a powder. The method may further comprise filling the buffer cartridge with a quantity of the buffer solute in the buffer transport chamber prior to fluidly connecting the buffer cartridge in the circulation loop.

[0106] In an embodiment of the method for preparing a buffer solution, the dissolution piping includes an upstream branch and a downstream branch. The upstream branch is disposed between the upstream filter and the buffer cartridge, upstream of the buffer cartridge, relative to the direction of circulation, and the downstream branch is disposed between the buffer cartridge and the downstream filter, downstream of the buffer cartridge, relative to the direction of circulation. The method may further include diverting at least a portion of the fluid flow from the dissolution piping to a bypass piping. The bypass piping is in fluid communication with the dissolution piping at the upstream branch and the downstream branch so as to be in parallel with the cartridge.

[0107] In at least some of such embodiments, diverting at least a portion of the fluid flow from the dissolution piping to the bypass piping includes adjusting the amount of fluid flow diverted to the bypass piping based on a pressure in the dissolution piping between the cartridge and the biocontainer downstream of the cartridge. In at least some of such embodiments, adjusting the amount of fluid flow diverted to the bypass piping based on a pressure in the dissolution piping between the cartridge and the biocontainer downstream of the cartridge includes adjusting a speed of a pump in the dissolution piping inversely related to the pressure.

[0108] In an embodiment of a method for preparing a buffer solution, the method may include entraining substantially all of the buffer solutes in a buffer cartridge into a fluid stream. The fluid stream is circulated through a circulation loop to substantially dissolve the buffer solutes and form a buffer solution. The pH value of the buffer solution is sensed using a sensor. The pH of the buffer solution is adjusted to a target pH range by introducing a pH adjustment feed into the buffer solution based on the sensed pH value.

[0109] All references, including publications, patent applications, and patents, mentioned in this specification are hereby incorporated by reference to the same extent as if each reference was individually indicated to be incorporated by reference and as if set forth in its entirety herein.

[0110] The use of the terms "a," "an," and "the" and similar referents in the context of describing the present invention (particularly in the context of the claims below) shall be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "comprising" shall be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted. The recitation of ranges of values ​​herein, unless otherwise indicated herein, is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or illustrative language (e.g., "such as") provided herein is intended only to further clarify the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0111] Preferred embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that such variations will be employed by those skilled in the art as appropriate, and the inventors intend that the invention be practiced otherwise than as expressly described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is covered by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. [Explanation of symbols]

[0112] 1. Buffered dissolution system 2 Inlet piping 4. Tightening valve, inlet valve 6 Pre-filter 8 Downstream Filter 10 Bio Container 12 tightening valve 14. Constriction valves, outlet valves, and outflow valves 16 Outlet piping 18 Pump 18a Bypass pump 18b Dissolution Pump 20 Upstream filter 22 Control means, dissolution valve, dissolution clamping valve 23 Control means, bypass valve, bypass tightening valve 24 Melting piping 26 Buffer cartridge 28 Bypass piping 30. Tightening valve, inlet valve 32 Solution property sensors, pH sensors, feedback systems 34 Pressure Sensor 36 Internal analytical sensors 37 pH adjustment valve 38 pH adjustment piping, pH inlet piping 39 pH adjustment fluid 40 Sterile wire 42 Mixer 44 Solid materials, solutes, substances 46 Buffer solutions, batches 48 Chromatography Process, Processing Steps 50 Location dividing line 69 Circulation Loop 71 Container Entrance 72 Container Exit 73 Storage volume 74 Circulation direction 75 Cartridge inlet 76 Cartridge outlet 77 Storage room 81 Upstream branch 82 Downstream Branch 201 Dissolution System 900 Control device, processing system 902 Processing equipment 904 memory 906 Input / Output Devices 908 Sensor 910 User Interface 912 Actuator

Claims

1. a biocontainer defining a container inlet, a container outlet, and a storage volume, the container inlet and the container outlet communicating with the storage volume, the storage volume configured to hold a supply of fluid; a pump in fluid communication with the storage volume of the biocontainer, the pump adapted to receive a supply of the fluid from the container outlet of the biocontainer and to discharge a flow of fluid from the biocontainer to the container inlet in a circular direction; a cartridge defining 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 hold a quantity 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 from the pump, 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 out of the cartridge outlet to flow past the quantity of solute in the storage chamber, the cartridge outlet being in fluid communication with the container inlet; an upstream filter in fluid communication with the biocontainer and the cartridge, the upstream filter being interposed between the container outlet of the biocontainer and the cartridge inlet of the cartridge upstream of the cartridge in the circulation direction; a downstream filter in fluid communication with the cartridge and the biocontainer, the downstream filter being interposed between the cartridge outlet of the cartridge and the container inlet of the biocontainer downstream of the cartridge in the circulation direction; dissolution piping fluidly connecting the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter in a circulation loop; A dissolution system comprising:

2. 10. The dissolution system of claim 1, further comprising a prefilter in fluid communication with the cartridge and the downstream filter so as to be interposed between the cartridge and the downstream filter, the downstream filter having a first internal volume and the prefilter having a second internal volume, the second internal volume being larger than the first internal volume.

3. 3. The dissolution system of claim 1 or 2, further comprising a mixer in fluid communication with the cartridge and the downstream filter so as to be interposed between the cartridge and the downstream filter.

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

5. 5. The lysis system of claim 1, further comprising a valve adapted to selectively control the flow of the fluid through the cartridge based on pressure in the lysis piping downstream of the cartridge between the cartridge and the biocontainer.

6. the dissolution pipe includes an upstream branch portion and a downstream branch portion, the upstream branch portion being disposed upstream of the cartridge in the circulation direction between the upstream filter and the cartridge inlet of the cartridge, and the downstream branch portion being disposed downstream of the cartridge in the circulation direction between the cartridge outlet of the cartridge and the downstream filter; 6. The dissolution system of claim 1, further comprising a bypass pipe in fluid communication with the dissolution pipe at the upstream branch and the downstream branch so as to be in a parallel relationship with the cartridge.

7. 7. The lysis system of claim 6, further comprising a flow control system configured to selectively control the flow of the fluid through at least one of the lysis piping and the bypass piping.

8. 8. The dissolution system of claim 7, wherein the pump includes a dissolution pump, the dissolution pump being disposed in the dissolution piping between the upstream branch and the cartridge inlet; the flow control system comprising a bypass pump and a pressure sensor, the bypass pump being disposed in the bypass piping, the pressure sensor being disposed in the dissolution piping between the cartridge outlet and the container inlet, the pressure sensor being configured to generate a pressure signal corresponding to a pressure sensed in the dissolution piping by the pressure sensor, and at least one of the bypass pump and the dissolution pump being adapted to operate based on the pressure signal.

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

10. 10. The dissolution system of claim 9, further comprising a solution property sensor disposed in the dissolution piping, the solution property sensor configured to generate a property signal corresponding to a value of a solution property sensed in the dissolution piping by the solution property sensor.

11. the solution property sensor comprises a pH sensor, and the property signal comprises a pH signal; 11. The dissolution system of claim 10, further comprising pH adjustment piping and a pH adjustment valve, the pH adjustment piping in fluid communication with the dissolution piping and adapted to deliver a supply of pH adjustment fluid to the dissolution piping, the pH adjustment valve operable to selectively block the pH adjustment piping to block flow of the supply of pH adjustment fluid to the dissolution piping, and the pH adjustment valve adapted to operate based on the pH signal.

12. 12. The dissolution system of claim 11, wherein the pH adjustment piping is in fluid communication with the dissolution piping via the bypass piping.

13. 1. A dissolution system comprising: dissolution piping fluidly connecting the biocontainer, the pump, the cartridge, the upstream filter, and the downstream filter in a circulation loop, the biocontainer is configured to hold a supply of fluid; the pump is adapted to receive a supply of fluid from the biocontainer and to expel a flow of fluid from the biocontainer in a circular direction; the cartridge is configured to hold a quantity of solute for dissolution into the fluid supply, the cartridge being in fluid communication with the pump for receiving the fluid flow from the pump and for passing the fluid flow through the pump; the upstream filter is in fluid communication with the biocontainer and the cartridge such that the upstream filter is interposed between the biocontainer and the cartridge upstream of the cartridge in the circulation direction; the downstream filter is in fluid communication with the cartridge and the biocontainer such that the downstream filter is interposed between the cartridge and the biocontainer downstream of the cartridge in the circulation direction; a dissolution pipe including an upstream branching portion and a downstream branching portion, the upstream branching portion being disposed between the upstream filter and the cartridge and upstream of the cartridge in the circulation direction, and the downstream branching portion being disposed between the cartridge and the downstream filter and downstream of the cartridge in the circulation direction; a bypass line in fluid communication with the dissolution line at the upstream branch and the downstream branch in a parallel relationship with the cartridge; a means for controlling fluid flow through the cartridge, the flow control means being configured to selectively control the flow of fluid through at least one of the lysis piping and the bypass piping based on a pressure in the lysis piping downstream of the cartridge between the cartridge and the biocontainer; A dissolution system comprising:

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

15. 15. The method of claim 14, further comprising filling the buffer cartridge with the amount of buffer solute in a buffer transport chamber prior to fluidly coupling the buffer cartridge in the circulation loop, the buffer solute comprising a powder.

16. 16. The method of claim 14 or 15, wherein circulating the fluid flow through the circulation loop comprises controlling the fluid flow through the buffer cartridge based on pressure in the dissolution piping downstream of the buffer cartridge between the buffer cartridge and the biocontainer.

17. the dissolution pipe includes an upstream branch portion and a downstream branch portion, the upstream branch portion being disposed between the upstream filter and the buffer cartridge and upstream of the buffer cartridge in the circulation direction, and the downstream branch portion being disposed between the buffer cartridge and the downstream filter and downstream of the buffer cartridge in the circulation direction; 17. The method of any one of claims 14 to 16, further comprising diverting at least a portion of the fluid flow from the dissolution piping to a bypass piping, the bypass piping being in fluid communication with the dissolution piping at the upstream branch and the downstream branch in a parallel relationship with the buffer cartridge.

18. 18. The method of claim 17, wherein diverting at least a portion of the fluid flow from the lysis piping to a bypass piping comprises adjusting the amount of the fluid flow diverted to the bypass piping based on a pressure in the lysis piping downstream of the buffer cartridge between the buffer cartridge and the biocontainer.

19. 20. The method of claim 18, wherein adjusting the amount of fluid flow diverted to the bypass piping based on pressure in the dissolution piping downstream of the buffer cartridge between the buffer cartridge and the biocontainer comprises adjusting a speed of the pump in the dissolution piping inversely related to the pressure.

20. 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; sensing the pH value of the buffer solution using a sensor; adjusting the pH of the buffer solution to a target pH range by introducing a pH adjustment feed into the buffer solution based on the sensed pH value; 20. The method of any one of claims 14 to 19, further comprising:

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