Systems and methods for preparing fluids for bioprocess and pharmaceutical applications

Abstract

A system for preparing fluids for bioprocessing and pharmaceutical applications uses one or more flexible bags pre-filled with solid tablets of various buffer / media / physiological fluid components. These may include salts, acids, bases, preservatives, proteins, amino acids, growth factors, small molecules, and drugs. The flexible bag contains one or more sealed or sealable openings used to add water to the flexible bag's interior and remove fluids from the flexible bag. The one or more sealed openings can also be used as outlets for removing fluids (e.g., buffers) from the flexible bag. The flexible bag can be stored in a contracted state to facilitate storage and / or transportation of the flexible bag. Multiple flexible bags can be coupled to a manifold, which has valves for selectively filling and draining the flexible bags.

Description

Technical Field

[0001] The technical field generally relates to systems and methods for preparing fluids for bioprocesses and pharmaceutical applications. In particular, this technical field relates to the use of flexible containers (e.g., flexible bags) pre-loaded with solid tablets, etc. Water is put into this flexible container to dissolve the solid tablets and create a solution with a known concentration. A large amount of liquid with a desired concentration can be easily created.

[0002] Related applications This application claims the priority of U.S. Provisional Patent Application No. 63 / 081,737, filed on September 22, 2020, the content of which is incorporated herein by reference. The priority is claimed in accordance with 35 U.S.C. § 119 and other applicable laws.

Background Art

[0003] Buffers and solutions containing them are required in many applications. For example, buffer solutions are used in the manipulation of many pharmaceuticals and biopharmaceuticals. Buffer solutions are used in the preparation of drugs and other pharmaceuticals. For example, buffer solutions may be used in various washing, capture, and elution operations. Buffer solutions are also used to maintain cells and other organisms used in bioprocess operations as part of a growth or maintenance medium. Physiological solutions also often contain a buffered or buffer solution. Lactated Ringer's solution is well known as a physiological saline solution prepared by mixing sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. It is used for electrolyte hydration in people with low blood pressure or low blood volume.

[0004] Buffers and other solutions containing buffer species are often required in large quantities. For example, in biopharmaceutical applications, various buffers are often required in large quantities during the various processing operations performed. Traditionally, buffers are prepared manually as concentrates and diluted as needed. First, concentrated buffers must be prepared manually, which requires specialized equipment and knowledgeable individuals (e.g., the use of balances and laboratory equipment necessary for preparing concentrated buffers), but these are not always available. For example, in resource-constrained environments, laboratory equipment and trained personnel capable of preparing such stock solutions are often unavailable. Furthermore, because concentrated buffers are prepared manually, human error is possible in the process. Finally, the preparation of buffers and other physiological solutions requires the storage of large quantities of buffers and raw materials. In addition, in some cases, the final buffer or other physiological solution (e.g., a physiological solution required in a resource-constrained area) is needed in a remote location where there are not enough local resources to reliably produce its own concentrated solution that can later be diluted to the desired concentration.

[0005] Attempts have been made to automate the production of various buffers. For example, to prepare various different buffers, buffers are prepared using inline conditioning, where buffers are prepared from concentrated small amounts of single-component stock solutions. One example is GE Healthcare's inline buffer conditioning system. This system operates by diluting stock solutions of acids, bases, and salts with water for injection. An automated control system uses various feedback sensors to adjust the flow rate of the stock solutions to achieve the desired final buffer concentration. The automated control system used in GE's inline buffer conditioning system requires numerous sensors (e.g., pH, conductivity, flow sensors) used for feedback monitoring to ensure that the final desired buffer has the correct composition. Unfortunately, these sensors can malfunction or give incorrect readings, which means the buffer will not have the intended composition. Furthermore, inline buffer control is plagued by mixing problems, which can result in off-specification products. In addition, the control system is expensive, requiring complex and costly hardware and dedicated control software to control the entire system. Therefore, there is a need for alternative systems and methods for preparing fluids for bioprocess and pharmaceutical applications. [Overview of the project]

[0006] In one embodiment, a system for preparing fluids for bioprocess and pharmaceutical applications uses one or more flexible containers (e.g., bags) pre-loaded with solid tablets of various buffers / culture media / physiological fluid components. These may include salts, acids and bases, preservatives, proteins, amino acids, growth factors, small molecules, drugs, or other components that can be stored in solid form. The flexible containers are sterilized, for example, by gamma rays. The flexible containers include one or more sealed or sealable openings used to remove fluid from the flexible container, in addition to adding water to the inside of the flexible container. One or more sealed or sealable openings may also be used as outlets for removing fluid from the flexible container. The flexible containers can be stored in a deflated state to aid in the storage and / or transport of the flexible containers.

[0007] The flexible container may have a filling mark, mark, or other indication (or multiple lines, marks, or indications) that shows the level or amount of water to be added to the flexible container. The filling mark, mark, or other indication facilitates use, as it only requires filling the flexible container with water up to the filling mark. In other embodiments, the filling mark may be omitted, and the flexible container may be filled with fluid to substantially its entire volume. In any embodiment, the flexible container has a defined filling volume used to fill the flexible container with water. Since each flexible container contains a known amount of solid buffering component (or other fluid, e.g., component for growth media, physiological fluids, etc.), the concentration of the resulting solution can be easily determined. Powders or other additives do not need to be weighed or measured, as they are already present in the flexible container. Naturally, tablets contained in the flexible container need to be dissolved. The tablets may dissolve over time to form a solution. Agitation or other mixing means may also be used to aid in the dissolution of the tablets. For example, a flexible container may also contain internal components such as a magnetic stirrer (e.g., a magnetic stirring rod) that can be used to further aid in the dissolution of tablets.

[0008] The flexible container is pre-loaded with one or more tablets. Preferably, the tablets are loaded into the flexible container during or immediately after its formation. In one embodiment, all tablets are of the same type. In another embodiment, the tablets include several different types. In a preferred embodiment, a specific recipe or ingredients required to form the final buffer or other solution only require knowing the number and / or types of tablets to be placed in the flexible container. For example, a buffer might have a recipe requiring four tablets of type A, two tablets of type B, and five tablets of type C. This allows the necessary tablets to be easily pre-loaded into the flexible container, which, when dissolved, will yield the final buffer or other solution. In this case, only specific numbers of tablets of different types need to be added. This process can be done manually or automated. Tablet counters are well known and can be used to automatically distribute tablets into the flexible container during or after the manufacturing process.

[0009] After loading the required tablets into the flexible container, the flexible container and its contents can be sealed (if not already sealed). The flexible container and its contents can then be subjected to gamma irradiation (or other irradiation process to sterilize the flexible container). The flexible container can then be shipped or transported to the desired location for use. The user can fill the flexible container with the required amount of water. The tablets dissolve to produce the final buffer or other solution. In some embodiments, the flexible container can be held using hooks or the like through corresponding openings formed in the flexible container. The flexible container can be housed on or suspended from trolleys, carts, etc., or can be freestanding. The volume of the flexible container can vary, but is typically greater than 100 mL, up to approximately 2000 L, and more typically in the size range of approximately 2 L to 500 L.

[0010] In one embodiment, the multiple flexible containers described above are used in conjunction with a manifold that allows for the selective flow of water into the flexible containers. The fluid flow, including the dissolved species from the tablets, can also be discharged from the flexible containers. For example, in one embodiment, the multiple flexible containers are fluidly connected to the manifold via conduits or tubes, and each branch of the manifold has a valve (e.g., a pinch valve) that can control whether water flows into the flexible containers and whether the buffer containing the dissolved tablet contents is removed from the flexible bags (i.e., there are two pinch valves per flexible bag, one for the fluid entering the flexible container and the other for the fluid being removed from the flexible containers). In another embodiment, the manifold is used only to supply water to the various flexible containers, and another outlet of the flexible bag is used to extract the buffer (e.g., using gravity feed or a pump connected thereto). The multiple flexible containers connected to the manifold may have different tablet compositions tailored to a particular desired buffer. In this regard, multiple different types of buffers can be produced by selectively filling appropriate flexible containers using a single manifold coupled to a common water source. Naturally, the multiple flexible containers may use the same tablet recipe to prepare larger quantities of buffer.

[0011] Typically, the final buffer solution formed in the flexible container is further diluted with water before use. For example, the buffer solution produced in the flexible container may be concentrated to a dilution of approximately 5 to 10 times. This buffer solution can then be further diluted (e.g., 5 times) to produce a final buffer solution ranging from 1 to 2 times. In one embodiment, this further dilution is performed in a separate container or vessel. However, this further dilution can be achieved while the flexible container is coupled to the manifold. For example, additional water can be added to a flexible container containing a 5 to 10 times buffer solution to produce a final buffer solution that exits the manifold at a desired dilution of approximately 1 to 2 times or near that.

[0012] A key advantage of the current system is that it eliminates the possibility of human error in the preparation of concentration buffers. Since the process of weighing reagents to be dissolved later is already performed at the manufacturing site, local personnel do not need to do it. This is particularly advantageous in resource-constrained locations where laboratory equipment and / or trained staff are unavailable. Furthermore, because concentrated buffers can be produced only as needed, there is no need to store large quantities of pre-concentrated buffers. This reduces storage and transportation costs. It also eliminates the need for complex and expensive equipment used for inline calibrations that rely on various feedback sensors (which can fail or produce incorrect results, resulting in buffers not having the desired concentration or profile).

[0013] In one embodiment, a device for generating fluids for bioprocess and pharmaceutical applications includes a flexible bag, the flexible bag defining an internal volume and having at least one inlet and outlet, the flexible bag containing a plurality of tablets in its internal volume. To use the flexible bag, it is filled with a preset amount of water. The preset amount of water can be determined by a filling mark located on the flexible bag.

[0014] In another embodiment, a system for generating fluids for bioprocess and pharmaceutical applications includes a manifold having a first half and a second half surrounding a segment of flexible tubing, the segment of flexible tubing having a main line extending through the manifold and a plurality of branch lines connected to the main line. A plurality of flexible bags are fixed to the plurality of branch lines, each flexible bag containing an internal volume and having at least one inlet and outlet, and further containing a plurality of tablets in the internal volume of each of the plurality of flexible bags. A plurality of pinch valves are positioned on the manifold and configured to pinch the main line along one or more locations and the plurality of branch lines fixed to the plurality of flexible bags. To use the system, one or more of the plurality of valves are actuated to form an inlet channel from the main line into one or more flexible bags through at least one branch line. A preset amount of water is then allowed to flow into one or more flexible bags via the main line (for example, until the water level reaches a fill mark).

[0015] In another embodiment, a method for generating a fluid for bioprocess and pharmaceutical applications includes the operation of selecting a flexible bag, the flexible bag having a defined internal volume and at least one inlet and outlet, the flexible bag containing a plurality of tablets in its internal volume, and the selected flexible bag corresponding to a specific concentration of solute contained in the fluid. The flexible bag is filled with a known amount of water. [Brief explanation of the drawing]

[0016] [Figure 1] Figure 1 shows a flexible container in the form of a flexible bag according to one embodiment. Also shown is a recipe for buffer A containing three tablets of type #1, four tablets of type #2, and one tablet of type #3. The tablets are shown inside the flexible bag. The flexible bag includes a filling mark. [Figure 2]Figure 2 shows the flexible bag from Figure 1 in a folded state. The folded bag takes up minimal space and is useful for storage and transport. [Figure 3] Figure 3 shows a manifold according to one embodiment, used to control the inflow and outflow of a plurality of flexible bags. Valve closure points are indicated so that fluid can be loaded into individual flexible bags and / or fluid containing dissolved species from tablets present in the flexible bags can be removed. A main or central segment of tubing or conduit extends through the manifold and is used to transfer fluid into or from the flexible bags. [Figure 4] Figure 4 shows a side view of the type of manifold shown in Figure 3. However, in this embodiment, the manifold has four flexible bags coupled to one side of the branch line. [Figure 5] Figure 5A shows an example of a port that can be formed in a flexible bag. Figure 5B shows another example of a port that can be formed in a flexible bag. [Figure 6] Figure 6 shows a sequence of operations used to select the type of flexible bag disclosed herein for use in producing a desired buffer concentration. [Figure 7] Figure 7 shows a flexible bag attached to a pump and / or mixing device that can be used to drain and / or recirculate fluid within the flexible bag. It is a single-use flexible bag containing tablets (e.g., buffer tablets). Water is added to the flexible bag, where they dissolve to form a concentrated buffer solution. The fluid can be recirculated within the flexible bag to aid mixing, or pumped out for further dilution or processing. [Modes for carrying out the invention]

[0017] Figure 1 shows a flexible container in the form of a flexible bag 10 according to one embodiment of the present invention. The flexible bag 10 is typically made from a polymer or resin material and can have any number of shapes and sizes. The flexible bag 10 may be formed from multiple layers or a single layer. Depending on the size, the flexible bag 10 can be transported on a trolley, dolly, cradle, cart, holder, or other support container for holding the flexible bag 10 when filled with fluid. The flexible bag 10 defines its internal volume and typically has one or more distinct surfaces. For example, the flexible bag 10 typically has a bottom surface 12, a top surface 14, and one or more sides 16 (for example, various shapes are conceivable, but four sides are shown in Figure 1).

[0018] In one embodiment, the flexible bag 10 is made from one or more polymer or resin materials. For example, medical-grade resins conforming to Class VI standards can be used. Additional examples include polyethylene (e.g., low-density polyethylene (LDPE)) or ultra-low-density polyethylene (ULDPE) or polypropylene (PP), ethylene vinyl acetate (EFA), polyethylene terephthalate (PET), polyvinyl acetate (PVA), and polyvinyl chloride (PVC). In some embodiments, the flexible bag 10 can be formed from multiple layers. For example, the inner layer that comes into contact with the fluid can be made from LDPE. A second layer of polyvinyl acetate (PVA) or flexible polyvinyl chloride (PVC) can be used as an intermediate layer. An outer layer of LDPE or PET can provide mechanical strength. It should be understood that the embodiments described herein can be used with any number of different structural types, materials, and layers used in the flexible bag 10.

[0019] The flexible bag 10 is typically larger than 100 mL and has an internal volume of up to approximately 2000 L. However, more typically, the volume size of the flexible bag 10 is approximately 2 L to 500 L. The flexible bag 10 includes one or more ports 18 or openings that provide access for fluid to flow into / out of the flexible bag 10. For example, Figure 1 shows two such ports 18a, 18b, where one port 18a is used for water supplied into the flexible bag 10 (i.e., as an inlet) and the second port 18b is used to remove the fluid solution from the flexible bag 10 (i.e., as an outlet) (in another embodiment, a single port 18 may be used as both an inlet and an outlet). The water that can be used typically includes water for injection (WFI), highly purified water (HPW), or purified water (PW). These types of water are typically used in pharmaceutical and bioprocess applications. Water can be pumped into the flexible bag 10 using a pump or the like, or supplied by gravity. The port 18 may be connected to a conduit or tube used to transfer fluid to and from the flexible bag 10. The port 18 may be integrated with the flexible bag 10 and may include connectors, flanges, or ends that allow easy connection of a tube or conduit (e.g., branch line 42) to the flexible bag 10, as shown in the ports of Figures 5A and 5B. For example, a nipple, a barb (Figure 5A), or a port 18 having a sterile connector known to those skilled in the art (e.g., a Tri-clamp (TC) shown in Figure 5B) may be used.

[0020] As shown in Figure 1, the interior of the flexible bag 10 contains one or more tablets 22. The term tablet 22 is not limited to salts, acids and bases, preservatives, proteins, amino acids, growth factors, small molecules, drugs, or other molecules and compounds that can be stored in solid or semi-solid form, but means to encompass a separate solid or semi-solid (e.g., gel) material containing such components. The tablets 22 may or may not be similar to conventional tablets. The solid component can be combined with an excipient such as a binder (e.g., natural polymers such as starch or gum, synthetic polymers, or sugars) and / or a preservative to form the tablet 22. Such excipients are well known in the formation of pharmaceutical tablets. The tablet 22 contains one or more solutes that dissolve in a solvent, typically water. Each tablet 22 contains a known amount (e.g., mass or volume) of substance. Different “types” of tablets 22 may have different sizes to achieve the desired correct final concentration. The tablets 22 are pre-loaded into the flexible bag 10 before use. That is, the tablets 22 are placed inside the flexible bag 10 during the manufacturing process or after the flexible bag 10 is formed. The number and properties of the tablets 22 contained in the flexible bag 10 vary depending on the composition of the final solution to be formed inside the flexible bag 10. For example, the tablets 22 may contain buffering components, i.e., weak conjugated acid-base pairs. The choice of desired buffering agent is associated with the recipe for the type and number of tablets 22 to be placed inside the flexible bag 10. Different tablets 22 made from different components may have different shapes and / or colors. This may be advantageous, for example, if the tablets 22 are added to the flexible bag 10 manually.

[0021] In the example of FIG. 1, the end user wants to make buffer "A". Buffer A is associated with a recipe (seen in the table of FIG. 1) that includes 3 tablets 22 of tablet type #1, 4 tablets 22 of tablet type #2, and 1 tablet 22 of tablet type #3. Each tablet 22 can contain different components. For example, tablet type #1 can contain a compound related to salt, and tablet type #2 is related to a compound used to form an acid or a base. The important thing is that since all the necessary tablets 22 are already pre-loaded inside the flexible bag 10 as part of the manufacturing process, the end user does not need to know, and doesn't even need to care about, the specific recipe used to make the flexible bag 10. The end user only needs to select the flexible bag 10 associated with buffer type "A". This is marked on the flexible bag 10 itself using labeling, marking, color coding, barcodes, QR codes, etc., so that the user can easily identify the flexible bag 10 required to make buffer A.

[0022] The flexible bag 10 can be used to create not only physiological solutions but also any number of different types of solutions used in biopharmaceutical processes. Examples include phosphates, acetates, citrates, tris(hydroxymethyl)-aminomethane (Tris), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), pH adjusters (e.g., HCl and NaOH), etc. Exemplary phosphate buffers include potassium dihydrogen phosphate (KH2PO4), dipotassium hydrogen phosphate (K2HPO4), disodium hydrogen phosphate (Na2HPO4), and sodium dihydrogen phosphate (NaH2PO4). Examples of acetates include ethanoic acid, acetic acid, and sodium acetate. An example of a citrate is citric acid. Also, the tablets 22 can be used in growth or maintenance media used to support live cells (e.g., eukaryotic cells, bacteria, or yeast). <000.org / 10.1007 / s00216-018-1247-6" target="_blank">

[0023] Referring further to FIG. 1, the flexible bag 10 can have a fill mark 20 that can include markings, lines or other indicators showing the level or water to be added to the flexible bag 10. The fill mark 20 can be disposed on one or all of the sides 16 of the flexible bag 10. The fill mark 20 facilitates use because the flexible bag 10 only needs to be filled with water up to the fill mark 20. In other embodiments, the fill mark 20 can be omitted and the flexible bag 10 can be filled with fluid to substantially its entire volume. In any embodiment, the flexible bag 10 has a preset fill volume that is used to fill the flexible bag 10 with water. In some embodiments, the flexible bag 10 can include a sealable port 18 so that the flexible bag 10 can be stored for later use after adding water. The sealable port 18 can include a cap, pinch line, self-sealing valve, manual valve, membrane, plug, etc. One or more seal ports 18 disposed on the flexible bag 10 can also be used as an outlet for removing fluid from the flexible bag 10. The ports 18 can be disposed on different faces of the flexible bag 10. FIG. 1 shows openings or ports 18a, 18b located on the top surface 14, but it will be understood that the ports 18 can be provided on other faces as well. For example, for gravity drainage, the outlet port 18 can be disposed on the bottom surface 12 of the flexible bag 10.

[0024] Figure 2 shows the flexible bag 10 in a folded state. In the folded state, the volume occupied by the flexible bag 10 is reduced, making the folded state useful for storage and transport. In some embodiments, a vacuum can be applied inside the flexible bag 10 to substantially remove air or other gases contained within the internal volume or space of the flexible bag 10. The tablets 22 are pre-loaded inside the flexible bag 10, as shown in Figures 1 and 2. This process can be performed manually or automated. Tablet counters are well known and can be used to automatically distribute the tablets 22 into the flexible bag 10 during or after the manufacturing process. The tablet counter may be computer-controlled and include a recipe for a specific fluid type (e.g., buffer) associated with the manufactured flexible bag 10.

[0025] For example, in the examples shown in Figures 1 and 2, three tablets 22 of tablet type #1, four tablets 22 of tablet type #2, and one tablet 22 of tablet type #3 are automatically supplied to the flexible bag 10. Optionally, a magnetic stirrer (e.g., a magnetic stirring rod) can be added inside the flexible bag 10 during the manufacturing process. For example, the flexible bag 10 can be placed on top of a magnetic stirrer that rotates a stirring rod located inside the flexible bag 10 to help dissolve the tablets 22.

[0026] After loading the necessary tablets 22 into the flexible bag 10, the flexible bag 10 and its contents can be sealed (if not already sealed). Then, in one embodiment, the flexible bag 10 and its contents can be subjected to gamma irradiation (or another irradiation process to sterilize the flexible bag 10). The flexible bag 10 can then be shipped or transported to the desired location for use. The user can then fill the flexible bag 10 with the required amount of water (e.g., up to the filling mark 20). The tablets 22 can dissolve to produce the final desired solution (e.g., buffer solution, physiological solution, cell culture solution, etc.). In some embodiments, the flexible bag 10 can be held using a hook or the like that passes through a corresponding opening formed in the flexible bag 10. The flexible bag 10 can also be housed in or suspended from a trolley, cart, etc., or it can stand on its own. The volume of the flexible bag 10 varies, but is typically larger than 100 mL, up to approximately 2000 L, and more typically in the size range of approximately 2 L to 500 L.

[0027] Figures 3 and 4 show a manifold 30 used to regulate the inflow and outflow to a plurality of flexible bags 10. The manifold 30 includes a rigid two-part housing 32 (best seen in Figure 4) surrounding a flexible tube or conduit 36 ​​interposed between two halves 32a, 32b of the housing 32. The housing 32 can be made of metal or a rigid polymer. The flexible tube or conduit 36 ​​can be made of unreinforced silicone or other polymer material, such as thermoplastic elastomer (TPE), thermoplastic rubber (TPR), etc. The manifold halves 32a, 32b include opposing surfaces, which have semi-annular recesses that accommodate and enclose the flexible tube or conduit 36 ​​when the manifold halves 32a, 32b are fastened to each other via one or more fasteners 38. The fasteners 38 can be latches, clips, bolts, screws, etc. In this regard, the two-part manifold 30 fits snugly around the flexible tube or conduit 36. The tube or conduit 36 ​​includes a main line 40 or segment, one end of which passes through the manifold 30 and exits from the opposite end, and includes a number of branch lines 42 (e.g., branch lines 42a, 42b as described herein) extending from the main line 40. Water flows through the main line 40 in the direction of arrow A in Figure 3 (and arrow B for Figure 4).

[0028] As is most commonly seen in Figure 3, two branch lines 42a and 42b are fluidically coupled to each separate flexible bag 10. The first branch line 42a is used to fill the flexible bag 10 with water from the main line 40. The second branch line 42b is used to draw fluid (e.g., buffer) from the flexible bag 10, and in this embodiment, the drawn fluid enters the main line 40. In this embodiment, the second branch line 42b is used to remove fluid from the flexible bag 10. In other embodiments, the second branch line 42b can be omitted entirely. For example, fluid can also be removed from the flexible bag 10 using another port 18 connected to the flexible bag 10. For example, fluid can also be removed from the flexible bag 10 (via gravity supply or using an attached pump) using an opening in the bottom surface 12 of the flexible bag 10. In the embodiments of Figures 3 and 4, a valve 50 is used to selectively control the flow of fluid into and out of the flexible bag 10. Valves 50 are located in branch lines 42a and 42b and along the main line 40. Valves 50 along the main line 40 are located between branch lines 42a and 42b for different flexible bags 10 so that flows into and out of specific flexible bags 10 can be isolated. Figure 3 shows various valve closure points 52 for valves 50 that can be used to isolate each individual flexible bag 10 (or flows into and out of multiple flexible bags 10). That is, valves 50 are actuated to create different flow paths between the various flexible bags 10 connected to the tubing or conduits 36 of the manifold 30.

[0029] In a preferred embodiment, a pinch valve 50 located on the manifold 30 is used to selectively pinch a flexible tube or conduit 36 ​​at a valve closure point 52. The pinch valve 50 may include an automatically controlled valve 50 (e.g., a fluid pressure valve) or a manually operated pinch valve 50 controlled by rotation, such as a bonnet. The pinch valve 50 includes a stem that extends axially to pinch the flexible tube or conduit 36 ​​when operated and to stop the flow of fluid at one or more valve closure points 52. By moving the stem of the pinch valve 50 in the opposite direction, the flexible tube or conduit 36 ​​is opened, allowing fluid to flow. The pinch valve 50 may be located on the main line 40 or the branch line 42.

[0030] In the embodiment shown in Figure 3, ten flexible bags 10 are fluid-coupled to the branching line 42 of the manifold 30, but it should be understood that fewer or more flexible bags 10 may exist. In one embodiment, the flexible bags 10 coupled to the manifold 30 may be designed for different buffers. For example, in this particular embodiment, a single manifold 30 (each flexible bag 10 containing a different combination of tablets 22) can be used to produce ten different buffers. Alternatively, some or all of the flexible bags 10 may be used to create the same buffer. For example, the manifold 30 may be used to make multiple flexible bags 10 containing the same buffer. Naturally, it should be understood that various combinations are possible depending on the type of flexible bags 10 coupled to the manifold 30. The various flexible bags 10 fluid-coupled to the manifold 30 may be connected via sterile connectors so that, in some embodiments, the flexible bags 10 can be removed from the manifold 30 once they are filled. It should be understood that while they may include Tri-clamp (TC) connectors, other sanitary connectors (including dedicated connectors) such as male / female connectors and flange connectors can be used. Figure 4 shows a side view of the manifold 30, showing the two-part housings 32a and 32b of the manifold housing 32 and the branch lines contained therein that lead to different flexible bags 10. Pinch valves used to control the flow in the various branch lines are shown on the manifold.

[0031] Referring to Figure 3, the manifold 30 can be used to selectively fill (and remove fluid from) various flexible bags 10 attached thereto. For example, the flexible bag 10 labeled Bag #1 in Figure 3 can be filled with water by opening a valve 50 located in the inflow branch line 42a. The water is filled into the flexible bag 10 until it reaches the filling mark 20 (or until the flexible bag 10 is completely filled). In this embodiment, the tablet 22 is a buffer tablet. The buffer tablet 22 contained in the flexible bag 10 dissolves over time or by mixing or agitation assistance (e.g., a magnetic stirring rod). Once the tablet 22 has dissolved, the resulting buffer can be removed from the flexible bag 10. This can be done in several different ways. In one embodiment, after removing the flexible bag 10 from the manifold 30, the fluid contained therein can be further diluted. In another embodiment, the flexible bag 10 may include an outlet port 18 (for example, on the bottom 12), and the buffer is discharged from the flexible bag 10 using gravity flow or with pump assistance. In another embodiment, water is introduced into the flexible bag 10 using flow from the main line 40 and then sent into an open branch line 42a coupled to the flexible bag 10. The outlet branch line 42b is open and can take the buffer out of the flexible bag 10 and send it into the main line 40, and discharge it from the manifold 30 in the direction of arrow B (or downstream toward another coupling process or operation). Note that as water is added to the flexible bag 10, the buffer contained therein is removed and diluted at the same time.

[0032] Typically, the final buffer solution formed in the flexible bag 10 is further diluted with water before use. For example, the buffer solution created in the flexible bag 10 can be concentrated by a dilution of approximately 5 to 10 times. This buffer solution can then be further diluted (e.g., 5 times) to produce final buffer solution dilutions ranging from 1 to 2 times. In one embodiment, this further dilution is performed in a separate container or vessel. However, this further dilution can be achieved when water is added to the flexible bag 10 while the flexible bag 10 is coupled to the manifold 30 as described above. For example, additional water can be added to the flexible bag 10 containing the buffer solution at a dilution of 5 to 10 times to produce a final buffer solution that exits the manifold 30 at a desired dilution of approximately 1 to 2 times or near that dilution.

[0033] Figure 6 shows an exemplary flowchart or sequence of operations performed by an end user using the flexible bag 10 described herein. In this example, the end user identifies the type of solution (e.g., buffer type B) that they wish to create, as seen in operation 200. For example, the end user might wish to create a 100 mM phosphate buffer. In this example, the user selects a flexible bag 10 specifically designed with a tablet recipe for producing a 100 mM phosphate buffer. This is seen in operation 210 of Figure 6. The user can identify the flexible bag 10 to use based on labeling, markings, color codes, barcodes, QR codes, etc., found on the flexible bag 10 (for example, the user might select a green flexible bag 10). The user then fills the flexible bag 10 with water until the filling mark 20 is reached (or until the flexible bag 10 is completely filled), as seen in operation 220. The tablet 22 contained in the flexible bag 10 is then dissolved to produce a 100 mM phosphate buffer. Subsequently, this flexible bag 10 containing 100 mM buffer type B can be used directly (operation 230), or alternatively, the buffer contained therein can be further diluted, for example, by transferring the solution to another container or vessel and adding more water. This further dilution can also be performed using the manifold 30 as described above, where water is used to simultaneously drain and dilute the contents of the flexible bag 10. This further dilution operation is shown in operation 240 of Figure 6. For example, a 5-fold dilution can be performed to create a 20 mM phosphate buffer. This further diluted buffer can then be used as seen in operation 250.

[0034] As mentioned above, it should be noted that the end user does not need to weigh any buffering material to prepare the initial concentrated buffer. Also, since the tablets are already pre-loaded in the flexible bag 10, the end user does not need to add the tablets 22 to the flexible bag 10. The end user only needs to find the appropriate flexible bag 10 to use to obtain the desired 100 mM phosphate buffer concentration. In this step, the user only needs to identify the flexible bag 10 associated with the 100 mM phosphate buffer concentration, and this operation can be performed by a person with minimal or no training. Further dilution can also be performed as easily as described above. As can be seen from the above, no expensive laboratory equipment is required, and since the tablets 22 are already pre-loaded in the flexible bag 10, there is no possibility of errors in weighing solid materials.

[0035] Figure 7 shows a single-use flexible bag 10 fixed to a pump and / or mixing device 60 that can be used to drain and / or recirculate fluid within the flexible bag 10. The pump and / or mixing device 60 can be fixed to the bottom surface 12 of the flexible bag 10. The pump and / or mixing device 60 can be fixed to the flexible bag 10 using a port 18, for example, disclosed in Figure 5B. An example of the pump and / or mixing device 60 can be found in International Patent Application Publication WO2021 / 158448A1 (PCT / US2021 / 015917), which is incorporated by reference. The pump and / or mixing device 60 may have a fitting flange that can be fixed to the port 18 via a clamp, for example. In this embodiment, the port 18 functions as an outlet for the fluid contained in the flexible bag 10, which then enters the inlet of the pump and / or mixing device 60. The pump and / or mixing device 60 has one or more outlets 62 from which the fluid exits. The outlets 62 can be connected to a fluid line or conduit 64. As seen in Figure 7, one such outlet 62 is used to recirculate the fluid into the flexible bag 10 via port 18. Another such outlet 62 is used to send the fluid to a further process (e.g., further dilution). Figure 7 shows a removable clip 66 that is secured around the flexible bag 10. The removable clip 66 is secured around the flexible bag 10 while water is added to dissolve the tablet 22. After the tablet 22 has dissolved sufficiently, the removable clip 66 can be removed, thereby allowing the fluid to access the pump and / or mixing device 60. In this example, water is then added to the flexible bag 10 to dissolve the buffer tablet 22 in order to form a concentrated buffer, thereby dissolving the buffer tablet and forming a concentrated buffer. The fluid can be recirculated back into the flexible bag 10 or pumped out for further dilution or processing.

[0036] While embodiments of the present invention have been disclosed and described, various modifications can be made without departing from the scope of the invention. For example, although the present application has focused on buffers, it should be understood that any number of types of fluids can be created in the flexible bag 10. These include growth fluids or maintenance fluids for supporting cells. They may also include physiological solutions such as IV solutions (e.g., Ringer's solution) administered to a subject. For this reason, the present invention should not be limited except to the following claims and their equivalents.

Claims

1. A system for generating a fluid for pharmaceutical use, A manifold having first and second halves surrounding a segment of a flexible tube, wherein the segment of the flexible tube has a main line extending through the manifold and forming an inlet and an outlet, and a plurality of branch lines connected to this main line, A plurality of flexible bags fixed to the plurality of branch lines, each flexible bag having an internal volume and at least one inlet and at least one outlet, and further comprising a plurality of tablets in the internal volume of each of the plurality of flexible bags, A plurality of pinch valves arranged on the manifold, wherein each pinch valve is configured to sandwich the main line along one or more positions and to sandwich a plurality of branch lines fixed to the plurality of flexible bags, Equipped with, The plurality of branch lines comprises an inlet branch line and an outlet branch line for each of the plurality of flexible bags, each inlet branch line is connected to the at least one inlet of each of the plurality of flexible bags, and each outlet branch line is connected to the at least one outlet of each of the plurality of flexible bags, and each inlet branch line and each outlet branch line has their respective associated pinch valves. A system characterized by the following features.

2. In the system described in claim 1, A system characterized in that at least a portion of the flexible bag contains multiple tablets of different compositions.

3. In the system described in claim 1, A system characterized in that at least a portion of the flexible bag contains one or more tablets selected from salts, acids, and bases.

4. In the system described in claim 1, A system characterized in that at least a portion of the flexible bag contains a plurality of tablets that include a cell growth medium or maintenance medium.

5. In the system described in claim 1, The system is characterized in that the flexible bags each include a filling mark located on the surface of each flexible bag.

6. In the system described in claim 1, The system is characterized in that the flexible bag is exposed to a sterilizing agent that sterilizes or makes the internal volume of the flexible bag sterile.

7. In the system described in claim 1, The system is characterized in that each of the aforementioned flexible bags has one or more sealed ports or ports that can be sealed.

8. In the system described in claim 1, A system characterized in that the flexible bag is vacuum-sealed.

9. In a method of using the system described in claim 1, The steps include: activating one or more of a plurality of valves to form an inlet passage that enters one or more flexible bags through at least one inlet branch line from the main line; A method characterized by comprising the step of flowing a predetermined amount of water into the one or more flexible bags via the main line and the at least one inlet branch line.

10. In a method of using the system described in claim 9, A method further comprising the step of removing the one or more flexible bags from the manifold.

11. In a method of using the system described in claim 9, A method further comprising the step of flowing additional water along the inlet channel into the inlet of the main line and into the one or more flexible bags to drain and dilute the contents of the one or more flexible bags, and removing the contents of the one or more flexible bags via the outlet branch line which is reconnected to the main line.

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