Method and system for producing sterile solution filled containers

Abstract

A cartridge assembly for a filling machine includes a plurality of containers. Each container includes a volume and a stem connected to the volume. A connecting line grid is in fluid communication with each stem of the plurality of containers. The connecting line grid includes a first row connected to one or more of the plurality of containers and a second row connected to one or more of the plurality of containers. A filter assembly is coupled to the connecting line grid.

Description

[Technical Field]

[0001] The present disclosure relates to sterile solution filled containers, and more particularly to methods, systems, and machines for producing sterile solution filled containers. [Background technology]

[0002] A conventional method for manufacturing bags of sterile solution involves filling a bag with the solution in a clean environment, sealing the filled bag, and then sterilizing the fluid and bag in a sterilizing autoclave. This may be referred to as terminal sterilization. Another conventional method is to sterile filter the solution, fill and seal the sterile bag in a very high-quality environment designed and controlled to prevent contamination of the solution during the filling process, and seal the filled bag. This may be referred to as an aseptic filling process.

[0003] Terminal sterilization processes generally require one or more autoclaves to produce the sterilizing heat and steam needed to adequately sterilize bags of solution for medical use. These autoclaves are generally not economical unless they can produce large quantities of terminally sterilized bags. Typically, centralized manufacturing facilities can result in the capital investment and space requirements required to produce and ship sterile solution-filled bags. In addition to these costs, the application of terminal sterilization processes can degrade the solution formulation contained within the bag, thereby leading to incompatible or unstable formulations. Furthermore, terminal sterilization does not eliminate non-viable microbial contamination.

[0004] The aseptic manufacturing process must occur within a sterile work environment, requiring expensive equipment, rigorous procedures, and extensive monitoring to ensure that solution product bags meet certain environmental and manufacturing regulatory standards. Sterilizing the work environment itself can be costly and time-consuming. Additional precautions are applied to technicians involved in the filling process to ensure the production of a safe and sterile product. Even with these safety measures, unless the solution entering the bag can be verified as sterile, there is a risk that contaminants may be inadvertently introduced into the solution during filling / sealing. Once introduced, contaminants will remain in the solution unless the solution is subsequently passed through an effective sterilizing filter. Summary of the Invention [Means for solving the problem]

[0005] According to a first exemplary aspect, a method for producing sterilization solution-filled containers may include positioning a cartridge on a filling machine. The cartridge may include a plurality of containers, a filter assembly, a connecting line in fluid communication with the filter assembly, and a reservoir coupled to the connecting line, the reservoir being disposed upstream of the plurality of containers and downstream of the filter assembly. Each of the plurality of containers may include a volume, a stem having a first end in fluid communication with the volume and a second end in fluid communication with the connecting line. The method may include coupling the cartridge to a feed line in fluid communication with a fluid source and activating a pump coupled to the feed line. The method may include at least partially filling one or more volumes associated with the plurality of containers by pumping fluid through the feed line, the filter assembly, the reservoir, and the connecting line, thereby producing one or more at least partially filled containers. After filling, the method may include sealing the stem of each of the at least partially filled containers at a location between the connecting line and the volume of the at least partially filled container, thereby producing one or more at least partially filled and sealed containers. Finally, the method may include isolating each of the at least partially filled and sealed containers from the connecting line while maintaining at least a portion of the seal on the stem.

[0006] According to a second exemplary aspect, a cartridge assembly for a filling machine may include a plurality of containers. Each container may include a volume and a stem connected to the volume. A connecting line grid may be in fluid communication with each stem of the plurality of containers. The connecting line grid may include a first row connected to one or more of the plurality of containers and a second row connected to one or more of the plurality of containers. A filter assembly may be coupled to the connecting line grid.

[0007] According to a third exemplary aspect, a machine for producing a plurality of solution-filled containers may include a sealing and cutting assembly including a sealer, a cutter, and a carriage that carries the sealer and the cutter. The sealing and cutting assembly may be movable laterally and vertically. A bracket may receive a cartridge of containers. The machine may include a first group of pinch valves including a first column and a second column spaced apart from the first column. The second group of pinch valves may be disposed between the first column and the second column. The second group of pinch valves may be movable vertically.

[0008] According to any one or more of the aforementioned first, second, or third exemplary aspects, the methods, systems, and machines for producing sterilization solution containers may further include any one or more of the following preferred aspects:

[0009] In a preferred form, which may be combined with any other form or portion thereof, the method may include at least partially filling the reservoir with solution from the mixing tank before at least partially filling one or more volumes.

[0010] In a preferred form, which may be combined with any other form or portion thereof, the method may include activating a second pump, which is coupled to the connecting line.

[0011] In a preferred form, which may be combined with any other form or part thereof, the second pump may be located downstream of the reservoir and upstream of the plurality of containers.

[0012] In a preferred form, which may be combined with any other form or portion thereof, the method may include the step of reversing the second pump after separating each of the at least partially filled and sealed containers from the connecting line.

[0013] In a preferred form, which may be combined with any other form or portion thereof, the step of at least partially filling one or more of the volumes may include filling a first row of the connecting lines with the solution.

[0014] In a preferred form, which may be combined with any other form or portion thereof, the first row may include one or more containers.

[0015] In a preferred form, which may be combined with any other form or portion thereof, the step of filling a first bag of the first row may include the step of releasing a first valve coupled to a connecting line of the first row.

[0016] In a preferred form, which may be combined with any other form or portion thereof, the step of filling the first bag in the first row may include the step of releasing a second valve coupled to the stem of the first bag.

[0017] In a preferred form, which may be combined with any other form or portion thereof, the method may include filling the second bag in the first row after opening a third valve coupled to the stem of the second bag.

[0018] In a preferred form, which may be combined with any other form or portion thereof, the method may include closing a second valve coupled to the stem of the first bag.

[0019] In a preferred form, which may be combined with any other form or portion thereof, the method may include moving the sealing and cutting assembly laterally from a first bag in the first row to a second bag in the first row.

[0020] In a preferred form, which may be combined with any other form or portion thereof, the step of at least partially filling one or more of the volumes may include the step of filling a second row of the connecting lines with the solution after separating each of the at least partially filled and sealed containers from the first row of the connecting lines.

[0021] In a preferred form, which may be combined with any other form or portion thereof, the second row may be parallel to the first row and may include one or more containers.

[0022] In a preferred form, which may be combined with any other form or portion thereof, the method may include the step of moving the sealing and cutting assembly longitudinally from the first row of connecting lines toward the second row of connecting lines before filling the second row of connecting lines.

[0023] In a preferred form, which may be combined with any other form or portion thereof, the method may include, at least in part, purging air from the delivery line prior to filling one or more volumes.

[0024] In a preferred form, which may be combined with any other form or portion thereof, the method may include, at least in part, purging air from the connecting lines of the cartridge before filling one or more volumes.

[0025] In a preferred form, which may be combined with any other form or portion thereof, the step of purging air from the connecting line may include activating a second pump to deliver air from the connecting line to a reservoir located above the connecting line.

[0026] In a preferred form, which may be combined with any other form or portion thereof, purging air from the connecting lines may include purging a first row of the connecting lines by opening a first row supply valve and opening a first row return valve.

[0027] In a preferred form, which may be combined with any other form or portion thereof, the first row may include a first end, a second end, and one or more containers disposed between the first end and the second end.

[0028] In a preferred form, which may be combined with any other form or portion thereof, the first end may be coupled to a first row supply valve and the second end may be coupled to a first row return valve.

[0029] In a preferred form, which may be combined with any other form or portion thereof, the method may include the steps of decoupling the cartridge from the filling machine and coupling a different cartridge to the filling machine.

[0030] In a preferred form, which may be combined with any other form or portion thereof, the different cartridges may include a plurality of containers, filter assemblies, and connecting lines in fluid communication with the filter assemblies.

[0031] In a preferred form, which may be combined with any other form or portion thereof, the multiple containers of the different cartridges may each include a volume and a stem having a first end in fluid communication with the volume and a second end in fluid communication with the connecting line.

[0032] In a preferred form, which may be combined with any other form or portion thereof, sealing the stem may include capturing the stem with a sealing device and collecting seal sensor data associated with sealing the stem.

[0033] In a preferred form, which may be combined with any other form or portion thereof, at least one sensor is associated with a seal energy source, such as an RF generator.

[0034] In a preferred form, which may be combined with any other form or portion thereof, sealing the stem may include analyzing sensor data associated with the seal by one or more processors of the controller.

[0035] In a preferred form, which may be combined with any other form or portion thereof, sealing the stem may include identifying, by one or more processors, a status or condition associated with the seal based on analysis of the sensor data.

[0036] In a preferred form, which may be combined with any other form or portion thereof, the method may include accepting the seal if the average welding power is analyzed by the one or more processors to be within a stored acceptable welding power range.

[0037] In a preferred form, which may be combined with any other form or portion thereof, the method may include the step of rejecting the seal if the average welding power is analyzed by the one or more processors to be below a lower limit of a stored acceptable welding power range.

[0038] In a preferred form, which may be combined with any other form or portion thereof, the method may include a step of rejecting the seal if a direct short circuit is detected within the seal device by one or more processors.

[0039] In a preferred form, which may be combined with any other form or portion thereof, the method may include the step of rejecting the seal if the average welding power is analyzed by the one or more processors to be above an upper limit of a stored acceptable welding power range or below a lower limit of a stored acceptable power range.

[0040] In a preferred form, which may be combined with any other form or portion thereof, the method may include the step of resealing the stem.

[0041] In a preferred form, which may be combined with any other form or portion thereof, the filter assembly may include a first filter and a second filter arranged in series.

[0042] In a preferred form, which may be combined with any other form or part thereof, the reservoir may be coupled to a grid of connecting lines.

[0043] In a preferred form, which may be combined with any other form or part thereof, the reservoir may be located upstream of a plurality of containers.

[0044] In a preferred form, which may be combined with any other form or portion thereof, the reservoir may be located downstream of the filter assembly.

[0045] In a preferred form, which may be combined with any other form or portion thereof, the reservoir may include a volume, an inlet port, and an outlet port.

[0046] In a preferred form, which may be combined with any other form or part thereof, the reservoir may be positioned above the grid of connecting lines relative to gravity.

[0047] In a preferred form, which may be combined with any other form or portion thereof, the connecting line grid may include a network of interconnected tubing that defines a supply manifold, a return manifold, a first row, and a second row.

[0048] In a preferred form, which may be combined with any other form or portion thereof, the first and second rows may extend between a supply manifold and a return manifold.

[0049] In a preferred form, which may be combined with any other form or part thereof, the supply manifold of the connecting line grid may be coupled to the outlet port of the reservoir.

[0050] In a preferred form, which may be combined with any other form or portion thereof, the return manifold may be coupled to the inlet port of the reservoir.

[0051] In a preferred form, which may be combined with any other form or portion thereof, the network of interconnected tubing may include at least one rigid portion connected to at least one flexible portion.

[0052] In a preferred form, which may be combined with any other form or portion thereof, the first and second rows may each include a first end, a second end, and a fill manifold connecting the first and second ends.

[0053] In a preferred form, which may be combined with any other form or portion thereof, the first and second ends may be flexible and the filling manifold may be rigid.

[0054] In a preferred form, which may be combined with any other form or portion thereof, a supply manifold may be coupled to a first end of each of the first and second rows.

[0055] In a preferred form, which may be combined with any other form or portion thereof, a return manifold may be coupled to the second end of each of the first and second rows.

[0056] In a preferred form, which may be combined with any other form or portion thereof, the fill manifold of each of the first and second rows may include one or more ports corresponding to one or more containers in each of the first and second rows.

[0057] In a preferred form, which may be combined with any other form or portion thereof, each port, corresponding to one container, may be in fluid communication with one stem.

[0058] In a preferred form, which may be combined with any other form or portion thereof, each row of the first and second rows of the grid of connecting lines may be coupled to at least two of the plurality of containers.

[0059] In a preferred form, which may be combined with any other form or portion thereof, the sealing and cutting assembly may include at least one sensor and a controller.

[0060] In a preferred form, which may be combined with any other form or portion thereof, the controller may include one or more processors.

[0061] In a preferred form, which may be combined with any other form or portion thereof, the controller may include a memory communicatively coupled to one or more processors, the memory storing executable instructions that, when executed by the one or more processors, cause the one or more processors to receive data captured by at least one sensor, analyze the data, identify a status or condition associated with a seal produced by the sealer, and send a signal to a machine controller to accept or reject the seal.

[0062] In a preferred form, which may be combined with any other form or portion thereof, the conveyor may be positioned below the sealing and cutting assembly relative to gravity.

[0063] In a preferred form, which may be combined with any other form or portion thereof, the conveyor may be movable together with the sealing and cutting assembly.

[0064] In a preferred form, which may be combined with any other form or portion thereof, a bracket for the cartridge may be coupled to multiple rails.

[0065] In a preferred form, which may be combined with any other form or portion thereof, the bracket and the plurality of rails may be configured to remove or receive a cartridge of a container.

[0066] In a preferred form, which may be combined with any other form or portion thereof, the one or more containers may be one or more containers.

[0067] In a preferred form, which may be combined with any other form or portion thereof, the one or more containers may be one or more vials.

[0068] In a preferred form, which may be combined with any other form or portion thereof, the one or more containers may be one or more syringes.

[0069] In a preferred form, which may be combined with any other form or portion thereof, the step of positioning the cartridge on the filling machine may include a step of positioning a cartridge having a plurality of containers as a container, each product bag including a bladder as a volume.

[0070] In a preferred form, which may be combined with any other form or portion thereof, positioning the cartridge on the filling machine may include positioning a cartridge having a plurality of vials as a container.

[0071] In a preferred form, which may be combined with any other form or portion thereof, positioning the cartridge on the filling machine may include positioning a cartridge having a plurality of syringes as a container.

[0072] In a preferred form, which may be combined with any other form or portion thereof, the one or more containers may include one or more containers and the volume is a bladder.

[0073] In a preferred form, which may be combined with any other form or portion thereof, the plurality of containers may comprise a plurality of containers, and the volume is a bladder.

[0074] In a preferred form, which may be combined with any other form or portion thereof, the plurality of containers may comprise a plurality of vials.

[0075] In a preferred form, which may be combined with any other form or portion thereof, the multiple containers may include multiple syringes. The present invention provides, for example, the following. (Item 1) 1. A cartridge assembly for a filling machine, said assembly comprising: a plurality of containers, each container including a volume and a stem connected to the volume; a connecting line grid in fluid communication with each stem of the plurality of containers, the connecting line grid including a first row connected to one or more of the plurality of containers and a second row connected to one or more of the plurality of containers; a filter assembly coupled to the connecting line grid; An assembly comprising: (Item 2) Item 2. The assembly of item 1, wherein the filter assembly includes a first filter and a second filter arranged in series. (Item 3) 3. The assembly of claim 1, further comprising a reservoir coupled to the connecting line grid and positioned upstream of the plurality of containers and downstream of the filter assembly, the reservoir including a volume, a first port, and a second port. (Item 4) Item 4. The assembly of item 3, wherein the reservoir is positioned above the grid of connecting lines relative to gravity. (Item 5) 5. The assembly of claim 3 or 4, wherein the connecting line grid includes a network of interconnected tubing that defines a supply manifold, a return manifold, the first row, and the second row, the first row and the second row extending between the supply manifold and the return manifold. (Item 6) Item 6. The assembly of item 5, wherein the supply manifold of the connecting line grid is coupled to the outlet port of the reservoir and the return manifold is coupled to the inlet port of the reservoir. (Item 7) 7. The assembly of claim 5 or 6, wherein the network of interconnected tubing includes at least one rigid section connected to at least one flexible section. (Item 8) 31. The assembly of any one of items 27-30, wherein the first and second rows each include a first end, a second end, and a fill manifold connecting the first and second ends, the first and second ends being flexible, and the fill manifold being rigid. (Item 9) 9. The assembly of claim 8, wherein the supply manifold is coupled to a first end of each of the first and second rows, and the return manifold is coupled to a second end of each of the first and second rows. (Item 10) 10. The assembly of claim 8 or 9, wherein the filling manifold of each of the first and second rows includes one or more ports corresponding to the one or more containers in each of the first and second rows, each port of the one or more ports being in fluid communication with the stem of one of the one or more containers. (Item 11) 11. The assembly of any one of items 1-10, wherein each row of the first and second rows of the connecting line grid is coupled to at least two of the plurality of containers. (Item 12) 12. The assembly of any one of items 1-11, wherein the plurality of containers comprises a plurality of product bags and the volume is a bladder. (Item 13) 12. The assembly of any one of items 1-11, wherein the plurality of containers comprises a plurality of vials. (Item 14) 12. The assembly of any one of items 1-11, wherein the plurality of containers comprises a plurality of syringes. [Brief explanation of the drawings]

[0076] [Figure 1] FIG. 1 is a schematic diagram of an exemplary system for producing sterilizing solution containers according to the teachings of the present disclosure.

[0077] [Figure 2] 2 is a perspective view of a first exemplary cartridge of the system of FIG. 1 assembled in accordance with the teachings of the present disclosure.

[0078] [Figure 3] FIG. 3 is a perspective view of an exemplary row isolated from the cartridge of FIG.

[0079] [Figure 4] FIG. 4 is a perspective view of an exemplary group of containers isolated from the cartridge of FIG.

[0080] [Figure 5] FIG. 5 is a perspective view of a different exemplary cartridge with three groups of containers assembled in accordance with the teachings of the present disclosure.

[0081] [Figure 6A] 6A is a perspective view of a second exemplary cartridge, assembled, that can be used with the system of FIG. 1 in accordance with the teachings of the present disclosure.

[0082] [Figure 6B] FIG. 6B is a top view of the cartridge of FIG. 6A.

[0083] [Figure 6C] FIG. 6C is a side view of the cartridge of FIG. 6A.

[0084] [Figure 7] FIG. 7 is a perspective view of a third exemplary cartridge, assembled, that may be used with the system of FIG. 1 in accordance with the teachings of the present disclosure.

[0085] [Figure 8] FIG. 8 is a perspective view of a fourth exemplary cartridge, assembled, that may be used with the system of FIG. 1 in accordance with the teachings of the present disclosure.

[0086] [Figure 9] FIG. 9 is a schematic diagram of the system of FIG. 1 during a phase of the filling process showing the steps of wetting the filter assembly and filling the cartridge reservoir.

[0087] [Figure 10] FIG. 10 is a schematic diagram of the system of FIG. 1 showing the purge phase of the cartridge supply and return manifolds.

[0088] [Figure 11]FIG. 11 is a schematic diagram of the system of FIG. 1 showing the purge phase of the fill manifold of the first row of cartridges.

[0089] [Figure 12] FIG. 12 is a schematic diagram of the system of FIG. 1 showing the filling phase of the first bag of the first row of the cartridge.

[0090] [Figure 13] FIG. 13 is a schematic diagram of the system of FIG. 1 showing the filling phase of the second bag in the first row of the cartridge, where the first filled bag has been sealed and removed from the cartridge.

[0091] [Figure 14] FIG. 14 is a schematic diagram of the system of FIG. 1 showing the purge phase of the fill manifold of the second row of cartridges.

[0092] [Figure 15] FIG. 15 is a schematic diagram of the system of FIG. 1 showing the filling phase of the first bag of the second row of cartridges.

[0093] [Figure 16] FIG. 16 is a schematic diagram of the system of FIG. 1 showing the filling phase of the second bag of the second row of the cartridge, where the first filled bag has been sealed and removed from the cartridge.

[0094] [Figure 17] FIG. 17 is a schematic diagram of the system of FIG. 1 showing the solution recapture phase after all of the cartridge's containers have been filled, sealed, and removed from the cartridge.

[0095] [Figure 18A] 18A is a side view of a filling machine used in the system of FIG. 1 and assembled in accordance with the teachings of the present disclosure.

[0096] [Figure 18B] FIG. 18B is a front view of the filling machine of FIG. 18A.

[0097] [Figure 18C] FIG. 18C is a rear view of the filling machine of FIG. 18A.

[0098] [Figure 18D] FIG. 18D is a top view of the filling machine of FIG. 18A.

[0099] [Figure 19] FIG. 19 is a perspective view of a tray assembly for use with the filling machine of FIGS. 18A-18D.

[0100] [Figure 20] 20 is a perspective view of a gantry system of the filling machine of FIGS. 18A-18D holding the tray assembly of FIG. 19. FIG.

[0101] [Figure 21] FIG. 21 is a front perspective view of the sealing and cutting assembly of the filling machine of FIGS. 18A-18D.

[0102] [Figure 22] 22 is a rear perspective view of the seal and cut assembly of FIG. 21. FIG.

[0103] [Figure 23] FIG. 23 is a flow diagram of a first exemplary method for filling a plurality of containers with a sterilizing solution in accordance with the teachings of the present disclosure.

[0104] [Figure 24] FIG. 24 is a flow diagram of a second exemplary method for filling a plurality of containers with a sterilizing solution in accordance with the teachings of the present disclosure.

[0105] [Figure 25-1] FIG. 25 is an exemplary system of multiple cartridges connected to a single filter assembly assembled according to the teachings of the present disclosure. [Figure 25-2] FIG. 25 is an exemplary system of multiple cartridges connected to a single filter assembly assembled according to the teachings of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0106] Detailed Description The present disclosure relates to a flexible filling platform that can be used to sterile fill multiple containers with solutions without the need for specialized barrier systems, such as insulators and closed restrictive access barrier systems (RABS). The disclosed filling platform includes a filling system, disposable cartridges of containers, and filling machinery, increasing filling capacity and efficiency, ensuring sterility and safety of the final product, and automating production.

[0107] 1, a schematic diagram of a system 10 for filling multiple containers with a sterile solution according to the teachings of the present disclosure is illustrated. The system 10 includes a fluid source, which may be a mixing tank 14, a feed line 18, and a cartridge 22. The mixed solution in the mixing tank 14 is delivered to multiple containers, in this example, the product bags 26 of the cartridge 22, by passing the solution through an endotoxin-removal batch filter 30, a filter assembly 34 of the cartridge 22, and a reservoir, which may be an intermediate container 38 of the cartridge 22, before the solution is pumped from a reservoir 38 into each of the multiple bags 26. In other examples, the fluid source 14 of the system 10 may have in-line mixing in combination with, or instead of, a mixing tank. The feed line 18 and connecting line 46 of the cartridge 22 are in fluid communication with each other, allowing the flow of solution from the mixing tank 14 into the connecting line 46 to fill the multiple bags 26 of the cartridge 22. The feed line 18 and connecting line 46 are connected at a sterile cartridge connector 50. First and second pumps 42, 44 and isolation valves, coupled to the feed line 18 and connecting line 46 of the cartridge 22, respectively, pump and control the flow of solution through the system 10. Specifically, a dual-pump configuration separates the pumping operations; i.e., the first pump 42 draws fluid from the mixing tank 14 for delivery to the cartridge 22, and the second pump 44 precisely pumps the fluid within the cartridge 22. In an alternative arrangement, the first pump 42 may also be replaced with a mixing tank pressurization system that uses pressurized filtered air or nitrogen to transport the solution to the reservoir 38.

[0108] 2 illustrates an exemplary cartridge 22 of the system 10 of FIG. 1. The cartridge 22 includes multiple containers 26, a filter assembly 34, a reservoir 38, and connecting lines 46. The multiple containers 26 may be one of a variety of product bags 26; in a preferred embodiment, each bag 26 is the same size and includes a volume 52 and a stem 54 connected to the volume 52. The connecting lines 46 include a solution distribution grid 56, which is a network of interconnected tubes that is in fluid communication with each stem 54 of the multiple containers 26. The solution distribution grid 56 includes a supply manifold 58, a return manifold 62, and multiple rows 66 connecting the supply manifold 58 and the return manifold 62. The connecting lines 46 include multiple connected rigid sections to reduce lag and provide structure, and multiple flexible sections to allow fluid isolation at various locations and stages or phases of the fill cycle.

[0109] Non-limiting examples of acceptable containers for the plurality of containers 26 of cartridge 22 are disclosed in U.S. Patent No. 10,617,603, U.S. Patent Publication No. 2020 / 0214938, U.S. Patent Publication No. 2020 / 0222281, U.S. Patent Publication No. 2020 / 0146932, U.S. Patent Publication No. 2020 / 0147251, U.S. Patent Publication No. 2020 / 0146931, and U.S. Patent Publication No. 2020 / 0147310, the entire contents of each of which are expressly incorporated herein by reference. While container 26 is illustrated in the figures as a product bag 26 with a bladder 52, the container may include a syringe, vial, bottle, or other vessel having a bladder, reservoir, or interior volume for holding a solution.

[0110] An exemplary row 66 of the solution distribution grid 56 of the first exemplary cartridge 22 is shown in more detail in FIG. 3 . The row 66 includes a first end 70, a second end 74, a fill manifold 78 connecting the first and second ends 70, 74, and ten product bags 26 in fluid communication with the fill manifold 78. The fill manifold 78 includes a plurality of ports, each connected to the stem 54 of a respective bag 26. The first and second ends 70, 74 of the row 66 are made from flexible tubing, such as, for example, flexible PVC tubing, while the fill manifold 78 is made from rigid tubing, such as, for example, PVC. The row 66 includes a supply connector 82 and a return connector 86 that connect the supply and return manifolds 58, 62 of the grid 56, respectively. In particular, the supply connectors 82 of row 66 connect together to form the sustained supply manifold 58, and the return connectors 86 of row 66 connect together to form the sustained return manifold 62. The supply and return connectors 82, 86 are T-shaped and made from a rigid plastic such as PVC.

[0111] 4 illustrates an exemplary group 67 of bags in a first exemplary cartridge 22. The group 67 includes multiple rows 66 connected together via connectors 82, 86 to form supply and return manifolds 58, 62. The group 67 is a modular unit having first and second open ends 71, 73 that can be connected to a final row 156, another group 67, or the supply and return lines 106, 110 of the cartridge 22. For example, in FIG. 5, the cartridge 22 includes three connected groups 67A, 67B, 67C. The first group 67A is connected to supply and return lines 110, 1106 and to a second group 67B of bags. The second group 67B is connected to the supply and return manifolds 58, 62 of the first and third groups 67A, 67C, and the third group 67C is connected to the second group 67B and the final row 156 to complete the closed cartridge. The modular arrangement of the bag groups 67 allows for more bags to be loaded per filtration assembly 34. As shown in FIG. 5, the supply and return manifolds 58, 62 of each group 67 are connected to provide a cartridge 22 with 270 bags.

[0112] Although the schematic cartridge 22 of FIG. 1 includes four rows 66 of eight product bags 26 and the exemplary cartridge 22 of FIG. 2 includes nine rows 66 of ten product bags 26, other exemplary cartridges 22 may include more or fewer rows 66 with more or fewer product bags 26. In fact, cartridge size may be determined based on the volume of gamma radiation carrier used to sterilize each cartridge prior to use. The cartridge of FIG. 5 includes three groups 67A, 67B, and 67C, but may be arranged to connect additional groups 67. The groups 67 of FIG. 4 are sized to maximize the number of bags per cartridge that can be gamma sterilized at one time. However, in other embodiments, the number of rows 66 and the number of bags 26 per row 66 may vary.

[0113] 1 and 2, the reservoir 38 is disposed upstream of the plurality of bags 26 and the second pump 44 and is coupled to a solution distribution grid 56, which is disposed downstream of the filter assembly 34. In this example, the reservoir 38 is a flexible bag 38, but may be a different type of container capable of maintaining the solution in a sterile environment. The reservoir 38, which may be an intermediate bag, includes a volume or bladder 90, an inlet port 94, an outlet port 98, and a solution return port 168 and is coupled to the grid 56 of the cartridge 22 to supply sterile solution to the plurality of bags 26. Because the reservoir 38 is disposed between the filter assembly 34 and the second pump 44, the second pump 44 draws filtered solution from the bladder 90 of the reservoir 38, fills the remainder of the connecting line 46 (downstream of the reservoir 38), and supplies sterile solution to the solution distribution grid 56.

[0114] Generally, the reservoir 38 is coupled to the grid 56 by connections at the inlet and outlet ports 94, 98, thereby forming a complete loop. The inlet port 94 of the reservoir 38 is connected to a T-connector 102 that receives both (1) the solution filtered through the filter assembly 34 and (2) the solution from a return line 106 of the grid 56. The outlet port 98 of the reservoir 38 is coupled to a supply line 110, which provides a solution path to the supply manifold 58. The supply line 110 includes a peristaltic tubing section 114 for operably coupling the connecting line 46 to the second pump 44, which may be a peristaltic pump. A closed loop is formed by connecting the outlet port 98 to the supply line 110, which is connected to the supply manifold 58, which is connected to the return manifold 62, and connecting the return line 106, which is connected to the return manifold 62, to the inlet port 94. So configured, the supply manifold 58 fluidly connects the first end 70 of each row 66 to the outlet port 98 of the reservoir 38, and the return manifold 62 fluidly connects the second end 74 of each row 66 to the inlet port 94 of the reservoir 38. In addition, as will be explained below, the return manifold 62 also provides a solution return path, delivering purged air and unused solution from the grid 56 to the reservoir 38 during operation of the system 10 during various cycles.

[0115] The solution pumped from the mixing tank 14 must first pass through the filter assembly 34 before reaching the reservoir 38. The filter assembly 34 of the cartridge 22 includes a first filter 118 and a second filter 122 arranged in series. Each filter 118, 122 is a sterilizing-grade filter and may be selected based on compatibility with the solution, sterilization technique, and required fill rate. As shown in FIG. 2 , each filter 118, 122 is coupled to a sample bag 126, 130, respectively. The sample bags 126, 130 are used to receive purged air and solution samples. The sample bag 126 receives a sample of the pre-filtered solution, and the sample bag 130 receives a solution sample after the first filter 118 and before the second filter 122. The sample bag 130 also receives purged air from the filter 118. The purged air from the second filter 122 is collected in the reservoir 38. The solution from the sample bag 130 is tested in the laboratory for any growths to determine its effectiveness. The first and last filled bags 26 from the cartridge 22 are tested to test the effectiveness of the filter assembly 34. The filter assembly 34 continues for the duration of the fill (i.e., the entire cartridge 22) with a stable flow rate and the ability to filter out any bioburden. However, if any shortcomings exist in the performance of either the first or second filters 118, 122, the operator may be able to detect such issues by analyzing the filters via a filter integrity test at the end of the cartridge fill and testing the contents of the sample bag 130 and the first and last filled bags 26 from the cartridge 22 for any particulate matter or biological contamination. At the end of the fill cycle, the filter assembly 34 is discarded along with the remainder of the single-use cartridge 22. The used filter cartridge 22 is tested for leaks using a vacuum leak detector. Any leaks detected in the cartridge 22 trigger an automatic shutoff on the filled bags 26.In another embodiment, the used filter cartridge 22 may be tested for defects using an integrity test method.

[0116] The cartridge 22 is pre-assembled in a clean room (ISO7 / ISO8) and gamma-sterilized prior to connection to the solution supply system (i.e., the mixing tank 14 and feed lines 18), ensuring that all surfaces that come into contact with the filtered solution are sterilized. The solution distribution grid 56 is primarily designed for "single use." However, the cartridge 22 may be adapted for multiple uses depending on the assembly components, component materials, safety, and sterilization methodology. The solution distribution grid 56 is designed to (1) ensure that solution is directed to the targeted product bags 26 without any risk of contamination, (2) isolate unfilled product bags 26, (3) allow for removal of any trapped air within the grid 56 prior to filling the product bags 26, and (4) provide a direct flow path to all product bags 26 within the grid 56, filling the bags 26 with a high level of accuracy and repeatability without the need for fill pump recalibration.

[0117] 6A, 6B, and 6C illustrate a second exemplary cartridge 222 that can be used with the system 10 of FIG. 1 to provide multiple sterile solution-filled product bags. The second exemplary cartridge 222 is similar to the first exemplary cartridge 22 of FIGS. 1-3. Therefore, for ease of reference, wherever possible, identical or similar components of the cartridge 222 will retain the same reference numbers as outlined above with respect to the first exemplary cartridge 22, but the reference numbers will be incremented by 200 and include an "A" or a "B," as appropriate. However, the second cartridge 222 differs from the first exemplary cartridge 22 by providing one filter assembly 234 coupled to two different solution distribution grids 256A, 256B.

[0118] As shown in FIG. 6A , the filter assembly 234 includes a first filter 318 and a second filter 322 arranged in series and coupled to a first reservoir 238A of the first solution distribution grid 256A and a second reservoir 238B of the second solution distribution grid 256B. So configured, the cartridge 222 is coupled to the feed line 18 of the system 10 of FIG. 1 at the cartridge connector 50. Just as the reservoir 38 of the first exemplary cartridge 22 is filled with solution, the first and second reservoirs 238A, 238B of the second exemplary cartridge 222 are also filled with sterile solution. The two sterilizing-grade filters 318, 322 sterilize enough solution to fill twice as many product bags as a single cartridge 22. 6A, the main connecting line 246 coupled to the filter assembly 234 is split into a first connecting line 246A and a second connecting line 246B, with each connecting line 246A, 246B connecting to a T-connector 302A, 302B on each individual grid 256A, 256B. In another embodiment, multiple individual cartridges may be assembled into a single filter train using additional connectors (FIG. 25).

[0119] Other cartridge configurations are also possible and may be specifically designed to address the needs or budget constraints of the system 10 or various environments. For example, the placement of the cartridge connector 50 may be varied to enhance the versatility of the cartridge configuration. For example, the different exemplary cartridge 422 in FIG. 7 includes a sterile cartridge connector 450 adjacent to the single filter 522 of the filter assembly for connection to a mating connector 50 in the feed line 18. In yet another embodiment in FIG. 8, the exemplary cartridge 822 has a sterile cartridge connector 850 located downstream of the filter assembly. This configuration reduces production costs for larger batches. Compared to the filters 118, 122 of the cartridge 22 in FIGS. 2 and 5, the upstream filter of the cartridge 422, 822 is not discarded after filling and may be used for the entire batch (e.g., greater than 2,000 bags). After filling, a new cartridge 422, 822 is connected to the filter line. The other components of cartridge 422, 822 of Figures 7 and 8 are otherwise identical to or substantially similar to the components of cartridge 22 of Figure 2. The sterile cartridge connector may be an AseptikQuik® sterile connector.

[0120] 1 , system 10 includes a plurality of isolation valves to control the flow of solution through feed line 18, connecting line 46, supply line 110, supply manifold 58, return manifold 62, return line 106, each fill manifold 78, and each stem 54 of the plurality of bags 26. These valves are positioned adjacent to flexible portions of the tubing of system 10 to isolate, pinch, engage, or otherwise close the flexible tubing to prevent solution from flowing through the flexible tubing, or to open, release, or otherwise disengage the flexible tubing to allow solution to flow through the valves and continue through system 10. First valve 165 is the primary system isolation valve and is operated (e.g., open / close, release / pinch, or engage) to control the supply of solution from mixing tank 14 to cartridge 22. The main feed valve 134 is always closed after the first pump 42 is turned off, ensuring that there is no back pressure or backflow through the filter. The third valve 138 is a supply valve located downstream of the reservoir 38 and upstream of the second pump 44. The supply valve 138 is operated to distribute solution from the reservoir 38 into the solution distribution grid 56. The fourth valve 142 is a return valve located on the return line 106 and controls the return of either purged air or unused solution from the grid 56 into the reservoir 38.

[0121] Additionally, the system 10 includes two groups of isolation valves that are operated to control the flow of solution through each row 66 of the bags 26. The first group of isolation valves includes a first column 146 of supply manifold valves (which may include one or more valves, depending on the number of rows 66 in the cartridge 22) and a second column 150 of return manifold valves. The first and second columns 146, 150 are pinch valves and are arranged according to the number of rows and the layout of the grid 56. Specifically, the first and second columns 146, 150 are arranged near the first and second ends 70, 74 of the rows 66, respectively. However, in other embodiments, these isolation valves may be different types of valves and may be arranged in different configurations according to the layout of the solution distribution grid 56. The supply manifold valves 152 and the return manifold valves 154 are coupled to the last row 156 of the grid 56. The final row 156 does not include any fill ports connected to the product bags 26; instead, the final row 156 connects the supply and return manifolds 58, 62, completing the loop of the grid 56 and purging either air or solution from the grid 56, depending on the phase of the fill cycle.

[0122] The second group of valves 160 are fill valves and are positioned between the first and second columns 146, 150 of valves. The fill valves 160, which may also be pinch valves, may be operated to control the flow of solution from the fill manifold 78 into each bladder 52 of the plurality of bags 26. The fill valves 160 are positioned so that each valve 160 is adjacent the flexible tubing of the stem 54 of one of the plurality of bags 26. As shown in FIG. 1 , the fill valves 160 are adjacent the stems 54 of the plurality of bags 26 in the first row 66. As discussed below, the fill valves 160 are movable relative to the cartridge 22 to engage the stems 54 of the plurality of bags 26 in each additional row 66. However, in another exemplary arrangement, the system 10 may include additional sets of valves 160 corresponding to the number of rows 66 in the cartridge 22, such that there is a pinch valve for each stem 54 of the cartridge 22.

[0123] 9-17, the fill cycle of system 10 will be illustrated and described at different phases of the fill cycle. First, feed line 18 is purged of any trapped air by operating first pump 42. As solution is drawn into feed line 18 from mixing tank 14, any air in feed line 18 is pushed through vent port 164, which is located downstream of first pump 42 and upstream of main isolation valve 165. While feed line 18 is being purged and vented through vent port 164, main system isolation valve 165 closes, thereby isolating cartridge 22 and the entire filter assembly 34 from feed line 18.

[0124] After air is purged from the feed line 18, the main system isolation valve 165 opens, the supply valve 138 and the return valve 142 close, and the first pump 42 pumps solution from the mixing tank 14 to wet the filter assembly 34 of the cartridge 22 and fill the reservoir 38 with the desired amount of solution. As shown in FIG. 9 , the portion of the cartridge 22 downstream of the reservoir 38 is isolated, allowing the filter assembly 34 to be properly wetted and the reservoir 38 to fill with enough solution to purge the supply and return manifolds 58, 62 and the first fill manifold 78 of the cartridge 22 before filling the bag 26. The first pump 42 runs at a pace that adequately wets the filters without collapsing the system 10. The sample bag 126 of the filter assembly 34 may later be analyzed to confirm suitable performance of the first filter 118 in the filter assembly 34. If the first filter 118 is compromised, the additional filter 122 of the two-filter filter assembly 34 ensures that the solution passing into the reservoir 38 is sufficiently sterilized.

[0125] 10 , the portion of the cartridge 22 downstream of the reservoir 38 opens, preparing the system 10 to purge trapped air from the cartridge 22 and then fill the bag 26 with solution. In this phase, the supply valve 138 and return valve 142 coupled to the outlet and inlet ports 98, 94 of the reservoir 38, respectively, open. In addition, the supply manifold valve 152 and return manifold valve 154 coupled to the last row 156 of the solution distribution grid 56 open as well. The fill manifolds 78 of each row 66 (not including the last row 156) are isolated as each supply manifold valve 146 and return manifold valve 150 (not including the supply and return manifold valves 152, 154 of the last row 156) closes. The second pump 44 operates to purge trapped air in the supply and return manifolds 58, 62 from the solution distribution grid 56. As shown by the arrows in Figure 10, solution from reservoir 38 pushes air through outlet port 98, supply line 110, supply manifold 58, last row 156, return manifold 62, return line 106, and into inlet port 94 of reservoir 38. Positioned at least partially above solution distribution grid 56 (against gravity), reservoir 38 receives and captures purged air within the headspace of reservoir 38. This configuration advantageously facilitates air management by using the buoyancy of air to push solution (coming from below the bag air, i.e., headspace) and ensure a precise fill volume. As air is purged from supply and return manifolds 58, 62, sterilizing solution fills the perimeter of grid 56.

[0126] 11, the first row 66A of the grid 56 is purged of air trapped within the fill manifold 78A. To purge the air, the first supply manifold valve 146A and the first return manifold valve 150A on opposite ends of the row 66A are opened, and the supply and return manifold valves 152, 154 of the last row 156 are closed. The valves 146 and 150 from the other rows 66 remain closed. A second group of valves 160 remains closed, isolating the plurality of bags 26. As indicated by the arrows, air trapped within the grid 56 is purged from only the first row 66A.

[0127] 12 illustrates the first bag 26A of the first row 66A being filled. To fill the bags 26 of the first row 66A, the supply manifold valve 146A of the first row 66A remains open and the return manifold valve 150A of the first row 66A closes, allowing solution to fill the fill manifold 78A of the first row 66A. The first fill valve 160A opens, allowing solution to flow through the stem 54 and into the bladder 52 of the first bag 26A. The second pump 44 meters the required solution into the first bag 26A to avoid under- or over-filling each bag 26 during the fill cycle. Once the first bag 26A is filled, the first fill valve 160A closes around the stem 54 of the first bag 26A, and the second fill valve 160B of the adjacent second product bag 26B opens. While the second bag 26B is being filled, the stem 54 of the first bag 26A is sealed in place between the bladder 52 and the fill manifold 78, specifically below the first fill valve 160A. After the proper seal is made, the first bag 26A is separated from the fill manifold 78A of the cartridge 22, as shown in FIG. 13.

[0128] This process is repeated for the remaining bags 26 in the first row 66A until each bag 26 is filled, sealed, and separated from the grid 56. As will be explained below, the sealing and cutting assembly of the filling machine may automatically seal and cut each stem 54 once each bag 26 is filled. The filling machine automates the fill cycle by communicating with the fill valve 160 and the sealing and cutting assembly so that the bag 26 is filled with the required volume of solution, the fill valve 160 closes around the stem 54, and a suitable seal is formed on the stem 54 before each bag 26 is cut from the grid 56.

[0129] The sealing and cutting assembly is configured to move laterally parallel to the row 66, sequentially sealing and cutting each stem 54 of the plurality of bags 26 in the row 66. Filling, sealing, and cutting may occur simultaneously on different bags 26 in the same row. For example, when a third bag 26 is being filled, the sealing device of the sealing and cutting assembly may seal the stem 54 of the second filled bag 26, while the cutting device of the sealing and cutting assembly cuts the stem 54 at the seal of the first filled bag 26. Each filled, sealed, and cut bag 26 is separated from the cartridge 22 and received by a chute and / or conveyor belt positioned below the grid 56. After the last bag 26 is sealed and removed from the row 66, the sealing and cutting assembly returns to its initial position (i.e., adjacent to where the first bag 26A was suspended before being separated from the grid 56) and moves toward the second row 66B of the cartridge 22.

[0130] 14, the bags 26 in the first row 66A are separated from the grid 56, and the fill valves 160 engage the stems 54 of the bags 26 in the second row 66B. The first supply and return manifold valves 146A, 150A close, and the second supply and return manifold valves 146B, 150B associated with the second row 66B open. The second pump 44 pumps solution from the reservoir 38 through the supply line 110 and a portion of the supply manifold 62 and into the second fill manifold 78B. As a result, any trapped air in the second fill manifold 78B of the second row 66B is purged through the return line 106 and into the inlet port 94 of the reservoir 38. In Figure 15, the return manifold valve 150B of the second row 66B closes, the supply manifold valve 146B remains open, and the first fill valve 160A opens, allowing solution to fill the first bag 26C of the second row 66B. In Figure 16, the first bag 26C of the second row 66B is sealed and removed from the grid 56, while the second bag 26D of the second row 66B is filled. The fill, seal, and cut phases are repeated for each remaining bag 26 in the second row 66B until each bag 26 has been filled, sealed, and removed from the grid 56. Again, the sealing and cut assembly of the machine is dispatched to a position adjacent the first bag in the following row 66.

[0131] 17 , each bag 26 from the cartridge 22 is removed, and the stem 54 is sealed, isolating the fill port of the fill manifold 78. The supply valve 138, supply manifold valves 146A-D, 152, and return manifold valves 150A-D, 154 open, the return valve 142 closes, and the second pump 44 reverses, drawing any solution disposed within the grid 56 and delivering the remaining solution through the supply line 110 and into the reservoir 38 through the outlet port 98. The inlet and outlet ports 94, 98 of the reservoir 38 are sealed, and the reservoir 38 is removed from the cartridge 22. The third port 168 of the reservoir 38 may then be connected to the mixing tank 14 to transport the recovered solution back into the mixing tank 14.

[0132] In summary, the reservoir 38 serves multiple roles in the fill cycle of the system 10. First, the reservoir 38 serves as an intermediate solution bag or volume downstream of the filters 118, 122 to collect solution used during the wetting phase of the filters 118, 122 of the filter assembly 34. The solution used to wetting the filters 118, 122 during this phase is collected and used to fill the product bag 26, rather than being discarded. Second, the reservoir 38 serves as a volume for trapped air that is purged from the system 10 during the purge phase. As described above, the reservoir 38 is positioned above the grid 56, thereby receiving trapped air within its headspace. Third, the reservoir 38 serves as an intermediate solution source for filling the bag 26. Instead of drawing directly from the filter assembly 34, the second pump 44 draws sterilizing solution exclusively from the reservoir 38. This ensures that filling can be performed at the desired flow rate without increasing the pressure drop across the filter assembly 34, thereby protecting the integrity of the filters 118, 122. This configuration also helps improve filling accuracy by isolating the second pump 44 from the inherent variability introduced by the filters 118, 122 during its use cycle (as the filter pores gradually become clogged, the pressure drop for a given flow rate through the filter begins to change, which would otherwise adversely affect the filling accuracy of a metering pump positioned upstream relative to the filters 118, 122). Fourth, the reservoir 38 serves to minimize waste in the system 10 by receiving any unused solution (i.e., not delivered to the product bag 26) from the distribution grid 56. After all solution has been drawn back into the reservoir 38, the supply and return ports 94, 98 of the bag 38 are sealed, and the bag 38 is disconnected from the distribution grid 56. Using the third port 168 of the reservoir 38, the contents of the reservoir 38 can be returned safely to the mixing tank 14 without any risk of contamination.Finally, as will be explained in more detail below, the amount of solution in reservoir 38 is carefully monitored for active fill management. This is accomplished by mounting reservoir 38 on a load cell that monitors the exact amount of solution in reservoir 38 at any time during the fill cycle. Towards the end of the bag fill phase, the machine's control system actively manages the amount of solution in reservoir 38, ensuring that reservoir 38 is nearly empty when the cycle ends.

[0133] The exemplary system 10 and method for producing sterile solution-filled product bags 26 may be used in conjunction with a machine such as machine 400 in Figures 18A-18D. Machine 400 automates many of the phases of the fill cycle described above by including a programmable logic controller ("PLC") 402, a seal and cut assembly 404, a seal controller 408, a seal energy (e.g., RF generator) 490, a load cell 412 communicatively coupled to first and second pumps 42, 44, a gantry system 416, supply and return manifold valves 146, 150, and a fill valve 160. Machine 400 also includes a user interface 420 to display various commands, messages, and status updates and to operate the PLC 402 of machine 400. Machine 400 of Figures 18A-18D is capable of processing two separate cartridges 22 simultaneously and therefore includes respective sets of components (e.g., seal and cutting assemblies, pumps, gantry systems, isolation valves, etc.) necessary to process the cartridges. However, for simplicity purposes, only one set of machine components will be labeled in the figures. Thus, the components on the left side of machine 400 can be assumed to be the same and mirror images of the labeled components on the right side of the machine (as depicted in Figure 18A).

[0134] The on-board PLC 402 of the machine 400 is configured to operate and control the various components of the system 10 during the filling process and to interact with the operator via a user interface 420 by displaying commands, communicating results, providing status updates, and alerting the operator to system or performance errors. Generally, the PLC 402 includes one or more processors and a memory coupled to the one or more processors that stores executable instructions for running a fill cycle. The PLC 402 is configured to receive signals from proximity switches and other sensors, transmit commands or signals, operate devices of the system 10 (e.g., pumps 42, 44, seal and cut-off assembly 404, first and second valve groups 146, 150, 160), monitor sensors (e.g., load cell 412, sensors in seal devices), and process information collected and received from the sensors.

[0135] For example, the PLC 402 communicates with the first pump 42 to begin pumping solution from the mixing tank 14 to wet the filter assembly 34, as shown and described above with respect to FIG. 9. The PLC 402 also communicates with the load cell 412 to determine the amount of solution being pumped into the reservoir 38, and subsequently each individual bag 26 of the cartridge 22, as a secondary check. The PLC 402 communicates with the second pump 44 to stop pumping solution once each product bag 26 is filled to its desired capacity. In addition, the PLC 402 signals the second pump 44 to reverse after all bags 26 are filled, sealed, and separated from the grid 56, as shown in FIG. 17. Furthermore, the PLC 402 is configured to communicate with (i.e., to open or close) each isolation valve 165, 134, 138, 142, 146, 150, 152, 154, 160 during each phase of the fill cycle 500. In the illustrated example, the PLC 402 controls the operation of the machine 400 locally (e.g., via a wired connection) and may be accessed by a user interface 420 of the machine 400. In other embodiments, the PLC 402 may control the operation of the machine 400 remotely via a wireless communication system. The RF generator 490, the load cell 412, and the peristaltic pumps 42, 44 each include a controller. The PLC communicates with each of the controllers to set process parameters, send instructions, and receive process data.

[0136] The PLC 402 may be programmed to store data for each batch of valid product bags 26 that have been filled and tested for sterility. Prior to filling, an operator may key a serial number associated with the cartridge 22 into the PLC 402 via the user interface 420 and store the solution type, solution expiration date, fill date and location, fluid conductivity and integrity results, and other information about the product bags 26. In other embodiments, each batch of filled product bags 26 may be assigned a serial number by other means, with or without the use of the PLC 402. For example, the bags 26 may be labeled before or after the bags 26 are filled. If both filters 118, 122 of a cartridge 22 fail, each corresponding bag 26 may be quarantined for disposal.

[0137] 18D, 21, and 22 includes a seal controller 408, a seal energy (e.g., RF generator) 490, a sealer 424, a cutter 428, a conveyor 432 (not shown in FIGS. 21 and 22) disposed below the sealer 424 and cutter 428, one or more sensors, and a carriage 436 that transports the sealer 424 and cutter 428. The seal and cut assembly 404 is servo-controlled using linear transport units 433, 434 to move in directions parallel to the respective X and Y axes of the machine 400. For example, the X-direction linear transport unit 433 moves the two carriages 436 of the two seal and cut assemblies 404 in the X-direction. The linear transport unit 433 includes two independently driven linear drive units. Each carriage 436 is coupled to only one linear drive unit but uses the guide rails of the other linear drive unit for support via floating linear bearings mounted on the guide rails of the other linear drive unit. Thus, the two seal and cut heads may each be driven independently and can fully support the two seal control units 408 attached to the two seal and cut assemblies 404. The linear transport unit 434 moves the two seal and cut assemblies 404 and the two valve assemblies 160 in the Y-direction. In one embodiment, the transport unit 434 includes two linear drive units coupled via a coupling shaft connected to a single servo motor.

[0138] To seal and cut each stem 54 of the bags 26 in a row 66, the carriage 436 moves the sealer 424 and cutter 428 along the X-axis. The carriage 436 moves to a programmed position to align the sealer 424 and cutter 428 with the stems 54 of the bags 26. The sealers 424 and cutters 428 are spaced the same or similar distances from each other between adjacent stems 54 in a given row 66. In this manner, the sealer 424 is in a fixed position to seal one stem 54, and the cutter 428 is in a fixed position to cut the adjacent sealed stem 54. After sealing and cutting, the carriage 436 moves the sealer 424 and cutter 428 to the next position to seal and cut stems 54 until all of the bags 26 in a row 66 have been removed from the cartridge 22. After the last bag 26 in the row 66 is cut from the cartridge 22, the seal and cut assembly 404 and valve 160, which are mounted on the transport unit 434, move along or parallel to the Y axis.

[0139] In some embodiments, a chute may be positioned below the sealer 424 and cutter 428 to direct the bags 26 separated from the cartridges 22 onto the conveyor 432. The chute may be coupled to the sealing and cutting unit, while the conveyor 432 is mounted directly to the linear transport unit 433. When the sealing and cutting assembly 404 positions itself for the bags 26, the chute is in the correct position to direct the separated bags 26 onto the conveyor 432. When the linear transport unit 433, carrying the sealing and cutting assembly 404 and valve 160, advances to a row, the conveyor 432 advances with it and is therefore correctly positioned to receive the bags separated from the cartridges 22.

[0140] Separately, the sealer 424 and cutter 428 are also pneumatically controlled and move relative to the carriage 436 as they perform their respective sealing and cutting functions. For example, after the bag 26 is filled and the fill valve 160 engages the stem 54, the sealer 424 extends in the Y direction away from the carriage 436 to engage the stem 54 and create a seal. After the seal is determined to be satisfactory, as described in more detail below, the sealer 424 retracts back to the carriage 436. The carriage is then advanced in the X direction, with the sealer 424 again extending in the Y direction to seal the second stem 54 and the cutter 428 extending in the Y direction away from the carriage 436 to cut the first sealed stem 54. After the cutter 428 cuts the first stem 54 and the sealer 424 seals the second stem 54, both the sealer 424 and the cutter 428 return to the carriage 436 before the carriage 436 again moves in the X direction to process the next bag 26. However, in another embodiment, the sealer 424 and the cutter 428 do not simultaneously engage different stems 54 of adjacent bags 26. Rather, the sealer 424 extends and seals one stem 54, retracts after the stem 54 is properly sealed, and then the carriage 436 moves forward to position the cutter 428 in front of the stem 54 before the cutter 428 extends and cuts the stem 54.

[0141] To create the seal, the sealer 424 of the sealing and cutting assembly 404 extends toward the stem 54 of the bag 26 in the open position and, once in place, crimps onto the stem 54. The sealing tool 424 is connected to a radio frequency (“RF”) generator using the controller 408. The sealer emits RF energy between the opposing crimped surfaces, heating the polymer of the stem 54 sufficiently to melt, bond, and form a seal. The sealing tool 424 creates a seal wide enough to provide the proper welded length on each end after the bag 26 is cut apart. The sealed portion of the tubing is cut into two sections: an upper section stays with the cartridge 22 and a lower section becomes part of the bag 26. The width of the seal depends on the nature of the tubing of the stem 54 and can ensure the seal will withstand a squeeze test on the bag at 20 psi for at least 10 seconds. The cutter 428 is arranged to cut at or near the midpoint of the width of the seal to create two sealed ends (i.e., a sealed end of the stem 54 that connects to the bag 26 and a sealed end of the upper section of the stem 54 that remains with the cartridge 22) so that the cartridge 22 remains closed.

[0142] The sealing tool 424 is electrically coupled to a seal controller 408, which in turn is coupled to an RF generator 490 associated with the sealer 424. The RF generator communicates with the PLC 402 of the machine 400 so that the PLC 402 can control and / or monitor the adequacy of the seal. Sensors in the sealing and cutting assembly 404 are arranged to measure incident and reflected power. The seal controller 408 controls the delivery of power to the sealing jaws during a welding cycle to prevent over-sealing or under-sealing. A memory coupled to the PLC 402 stores executable instructions that, when executed by the PLC 402, cause one or more processors to receive data captured by the RF generator, analyze the data, identify a status or condition associated with the seal generated by the sealer 424, and signal the machine 400 to accept or reject the seal. The seal controller 408 can sense the direct short and the RF generator 490 can sense the amount of incident (forward) energy and reflected energy during sealing.

[0143] Prior to running the machine 400, the PLC 402 may be configured to establish an acceptable average weld power range (i.e., average power over the duration of the weld) for the fill tube weld. During the sealing operation, the PLC 402 compares real-time weld data captured by the RF generator with the acceptable average weld power range stored in memory. Based on this comparison, the PLC 402 makes one of the following decisions: (1) accept the seal; (2) reject the seal; or (3) signal the sealing tool 424 to reseal the stem 54. For example, a seal is accepted when the average weld power is within the stored acceptable weld range, or the seal is rejected when the average weld power is below the lower limit of the acceptable average weld range or if a short is detected in the clamp of the sealer 424.

[0144] If the captured average welding power is below the lower limit of the acceptable average welding range, the machine 400 will automatically attempt to reseal, assuming the maximum number of sealing attempts has not been reached. Specifically, the PLC 402 makes such a determination and communicates with the seal tool 424 to prevent the fill cycle from continuing until the stem 54 is resealed. If the captured average welding power exceeds the upper limit of the acceptable welding power range, this indicates an over-seal. In this example, the clamp of the sealer 424 is held closed around the stem 54, and the operator is instructed to manually seal the stem 54 and remove the bag 26 from the cartridge 22. In addition to the primary automated sealer 424, the machine 400 is equipped with a second manual handheld sealer and cutter. If a short circuit is detected in the seal clamp, the seal controller 408 immediately cuts off power to the seal clamp, and the seal clamp remains in the closed position. The machine 400 then prompts the operator to manually seal and remove the bag 26. If the seal is rejected, the machine 400 advances to the next bag 26 in the cartridge 22 only after successful completion of corrective steps. Seal data for all bags 26 is recorded and stored in a secure database and reported for batch release purposes.

[0145] The PLC 402 also communicates with a load cell 412 to monitor the amount of solution flowing through the system 10 to fill multiple bags 26 to avoid unnecessary waste. As described above, the reservoir 38 is mounted on a load cell 412, which monitors the exact amount of solution in the reservoir 38 at any given time during the fill cycle. At different phases of the fill cycle, the load cell 412 will communicate with the PLC 402 and the first pump 42 to add more solution to the reservoir 38. Toward the end of the fill cycle, the PLC 402 actively manages the amount of solution in the reservoir 38, ensuring that the reservoir 38 is nearly empty when the cartridge 22 is fully filled. After all bags 26 of the cartridge 22 have been filled, the PLC 402 registers a weight input from the load cell 412 before reversing the direction of the second pump 44 and withdrawing solution from the filled cartridge, as described in connection with FIG. 17 . After the collection cycle is complete, the PLC 402 again registers the weight of the reservoir 38. The weight of the collected solution is calculated from the initial and final weights of the reservoir 38 measured by the PLC 402, which is then compared to a historical average using the data. A collected weight below the average may indicate a leak in the cartridge 22.

[0146] The gantry system 416 is a movable gripper configured to receive and position the cartridges 22 relative to the machine 400 for a fill cycle. In FIG. 19 , a tray 417 is shown carrying the cartridges 22. The tray 417 is a support structure that secures the cartridges 22 to the gantry system 416. The tray 417 includes a frame 419, which supports the grid 56 of cartridges 22, and a rotatable swing arm 421. In the illustrated embodiment, the frame 419 includes slots or grooves shaped to hold each row 66 of cartridges. In FIG. 19 , the swing arm 421 is positioned over the tubing of each row 66 in the closed position, thereby crimping the cartridges 22 to the tray 417. In FIG. 20 , the tray capture mechanism of the gantry system 416 is shown holding the tray 417 and cartridges 22 of FIG. 19 . The gantry system 416 securely receives and couples to the tray 417 and positions the supply end 58 and return end 62 of each row 66 with the corresponding supply and return manifold valves 146, 150. In FIG. 18D, the gantry system 416 is configured to receive the tray 417 from the end of the machine 400 and position the tray 417 adjacent to the sealing and cutting assembly 404.

[0147] As described above, the supply and manifold valves 146, 150 form two columns, each column adjacent opposite ends of each row 66 of cartridges 22. The supply and manifold valves 146, 150 are suspended from an upper rack 460 of the machine 400 by suspension rods 464. When a cartridge 22 is loaded into the machine 400, the cartridge 22 is not necessarily in the proper position to interact with the isolation valves 146, 150, 160. Therefore, to position the cartridge 22 in the proper location for a fill cycle, the gantry system 416 moves the cartridge 22 in a direction parallel to the Z axis until it abuts the stationary isolation valves 146, 150, 160 of the machine 402.

[0148] The illustrated exemplary machine 400 is a fully automated machine, with automated loading and unloading, filling, sealing, and cutting of cartridges 22. However, other mechanisms and arrangements for machine 400 may be used to perform each phase of the machine cycle. For example, movement of gantry system 416 may be facilitated by an operator sliding gantry system 416 into position along rails 458 of machine 400. In yet another embodiment, the sealing and cutting operations of each bag 26 may be semi-automated or fully manual. Depending on the material of tube 54, other sealing techniques may also be used, such as heat transfer, ultrasonic welding, or other suitable methods.

[0149] Turning now to Figure 24, a method 600 of filling multiple product bags 26 using machine 400 will be described with reference to the filling operation steps described in Figures 9-17 for a multi-cartridge batch in Figure 25. Figure 25 is a schematic diagram of an exemplary system 610 for filling multiple containers of a multi-cartridge batch with sterilant solution. System 610 is similar to system 10 of Figure 1, described above, and uses like reference numbers (except increased by 600) for like components, but includes a different filter assembly 634 and cartridge arrangement. It should be understood that system 610 of Figure 25 operates slightly differently than system 10 of Figure 1.

[0150] 25 is arranged to deliver solution to multiple containers from a solution source, e.g., a mixing tank 614, through a filter assembly 634, and into a multi-cartridge connection and solution distribution grid 611. A sterile connector 651 of a feed line 618 is arranged to connect to a corresponding sterile connector 653 coupled to the filter assembly 634. An endotoxin filter 630 is connected in the feed line 618 upstream of a first fill pump 642. The filter assembly 634 includes a first sterilizing-grade filter 619 and a final sterilizing-grade filter 622. Each filter 619, 622 is coupled to a sample bag 726, 730, respectively. The sample bags 726, 730 are used to receive purged air disposed in the feed line 618 and the filter 619. Additionally, sample bag 726 may receive solution from feed line 618, and sample bag 730 may receive solution passing through first filter 619, which can be monitored to ensure suitable performance and / or tested to determine the effectiveness of filter 619. The first and last filled bags from the cartridge are tested to verify the effectiveness of second filter 622.

[0151] Unlike the first system 10, system 610 includes a multi-cartridge connection and solution distribution grid 611 and provides several sterile connectors arranged to sterilely connect one or more cartridges 622A, 622B to a manifold 613 downstream of a filter assembly 634. The solution distribution grid 611 and filter set 634 are part of the same assembly and are sterilized together. In the illustrated embodiment, the manifold 613 includes 20 separate lines 615, which may be flexible silicone tubing, arranged to connect the manifold 613 to 20 different sterile connectors 650, which may be, for example, AseptikQuik® sterile connectors. The filter set 634 includes two filters 619, 622 (e.g., both sterilizing-grade filters) and the manifold 613, which contains several male / female / genderless ends of sterile connectors 650A, 650B. The other male / female / genderless sterile connector ends 650A-A-650B-B are attached to each of the cartridges 622A, 622B that need to be filled. Schematically, only two cartridges 622A, 622B are shown. The first connector 650A is arranged to connect the first connecting line 646A to the first cartridge 622A, and the second connector 650B is arranged to connect the second connecting line 646B to the second cartridge 622B, for example. However, the solution distribution grid 611 may include sterile connectors for all cartridges requiring filling in a batch.

[0152] In the illustrated embodiment, one or more pinch valves may be arranged to crimp onto manifold line 613 and control the fluid flow rate into cartridges 622A, 622B. For example, the pinch valve adjacent line 615A may be opened to allow fluid to flow from manifold 613 into first line 615A and begin filling first cartridge 622A, while the pinch valve adjacent line 615B may be closed to prevent fluid from flowing into second cartridge 622B. At the end of manifold 613 opposite filter assembly 634, reservoir 619 is in fluid communication with manifold 613 and receives purged air from manifold 613. In other embodiments, the manifold 613 may be arranged to have more or fewer connectors 650 than those shown, and / or may be arranged so that only a percentage of the 20 connectors 650 are coupled to cartridges 622A, 622B as shown in FIG. 25.

[0153] Similar to the first system 10, a first pump 642 is coupled to the feed line 618 and pumps solution from the fluid source 614 through the feed line 618 and into the filter assembly 634. Each cartridge 622A, 622B, which is coupled to the manifold 613, is separately coupled to a second pump (e.g., a peristaltic pump) arranged to interact with the tubing sections 714A, 714B of each individual supply line 710A, 710B. The multi-pump configuration separates the pumping operations of the system 710; i.e., the first pump 642 draws fluid from the mixing tank 614 for delivery to the manifold 613, and the second pump precisely pumps fluid from the reservoirs 638A, 638B into the containers 626A, 626B of each cartridge 622A, 622B.

[0154] Machine 400 ensures the production of sterile solution-filled product bag 626 by performing the multiple steps of method 600. In method 600, filter set 634 is loaded into machine 400 separately from cartridges 622A, 622B. After both cartridges 622A, 622B and filter set 634 are loaded, the operator connects the two ends of sterile connector 650, one end connected to manifold 613 and the other end connected to cartridge 622. Once connected, the filling operation proceeds as described above. At the end of filling, after solution recovery, connecting line 646 is sealed and then severed into two sections: one section remains with the used sterile connector on filter set 634 and the other section remains with the used cartridge 622. The used cartridge is removed and replaced with a new cartridge, but filter set 634 remains on the machine. When a new cartridge 622 is loaded, the sterile connector end of the cartridge 622 is connected to one of the unused sterile connectors from the filter set connector manifold. This ensures a sterile fill for all cartridges 622.

[0155] For the first two cartridges in batches 622A and 622B, after sterile connector ends 650A and 650A-A and connector ends 650B and 650B-B are connected, the fill cycle begins as described above by activating first pump 642 and purging feed line 618. Primary isolation valve 765 closes and air is vented through vent port 764. Primary isolation valve 765 then opens, wetting filters 630, 722 of filter assembly 634 and filling reservoirs 638A and 638B. Air trapped within each grid 656A, 656B is then purged by closing main feed valves 734A, 734B and opening supply valves 738A, 738B (FIG. 25), supply manifold valve 152, return manifold valve 154, and return valve 142, as shown in FIG. 10. In step 612, multiple steps are performed by machine 400 to fill multiple bags 626A, 626B, with step 612 being repeated for all rows 666 for each solution distribution grid 656A, 656B of cartridges 622A and 622B. In other words, method steps 620-636 are performed for each row 666A, 666B before advancing to the next row 666 and repeating the fill cycle of step 612. For ease of reference, the steps performed on each grid 656A, 656B will be described with reference to the first exemplary cartridge 22 and system 10 of FIGS.

[0156] In step 620, trapped air from the first row 66A is purged through the connecting lines 46 of the cartridge 22 before filling the first bladders 52 of the bags 26, as shown in FIG. 11 . When purging the first row 66A of the connecting lines 46, the machine 400 opens the first row supply manifold valve 146A and the first row return manifold valve 150A. Because the first end 70 of the supply manifold 78A of the first row 66A is coupled to the first row supply manifold valve 146A and the second end 74 is coupled to the first row return manifold valve 150A, air and solution can flow throughout the fill manifold 78A of the first row 66A. However, solution does not enter the bladders 52 of each bag 26 because the isolation valve 160 coupled to the stem 54 is closed. To purge air from the fill manifold of row 66, a pre-verified volume of solution is pumped by pump 44 through the fill manifold and back to reservoir 38, which is located at least partially above connecting line 46. This pushes air from the fill manifold of row 66 into reservoir 38. Pump 44 communicates with PLC 402 to close return manifold valve 150A of the first row 66A, as shown in FIG. 12 , in step 620. This is repeated for each subsequent row 66 after all bags in the previous row have been filled, sealed, and removed by cutting. This is done by operating the supply and return manifold valves 146, 150 corresponding to each row 66.

[0157] Immediately after closing return manifold valve 150A, first fill valve 160A, coupled to stem 54 of first bag 26A, opens, allowing solution into bladder 52 of first bag 26A. Load cell 412 monitors reservoir 638 to ensure there is sufficient volume in reservoir 38 to begin the purge / fill process. Second pump 44 meters the desired volume of solution into each of product bags 26. As filling proceeds, load cell 412 will control first pump 42 to transport fluid from mixing tank 14, through filter assembly 634, and into reservoir 638 so that there will be enough solution for the filling process to proceed. As the filling process nears completion, load cell 412 targets a minimum remaining volume in reservoir 638.

[0158] Once the first bag 26A is filled, the first fill valve 160A closes, isolating the filled bladder 52 of the first bag 26A. Immediately thereafter, step 628 is repeated for the second bag 26B in the first row 66A. Specifically, the second bag 26B in the first row 66A is filled after opening the fill valve 160B coupled to the stem 54 of the second bag 26B and closing the fill valve 160A coupled to the stem 54 of the first bag 26A. While the second bag 26B is being filled, step 636 is performed, sealing and cutting the first bag 26A, as shown in FIG. 13 , and the first bag 26A is removed from the cartridge 22.

[0159] In step 636, sealing and severing the bag 26 includes activating a program in one or more processors of the PLC 402. The stored program is executed by the PLC 402 by instructing the sealing and severing assembly 404 to seal the stem 54 of the first bag 26A with the sealing device 424. This includes moving the sealing device 424 toward the stem 54, crimping the stem 54 at a location directly below the fill valve 160A and above the bladder 52, and RF sealing the stem 54. The RF generator captures seal power data associated with the sealing of the stem 54, and the one or more processors of the PLC 402 analyze the power data (incident or forward power and reflected power) associated with the seal. For example, the one or more processors of the PLC 402 compare the captured data with stored data regarding a good seal and then identify a status or condition associated with the seal based on the analysis of the data. The machine 404 will then either (1) accept the seal if the average welding power analyzed by the one or more processors of the PLC 402 is within the stored acceptable welding power range, (2) reject the seal if the average welding power analyzed by the one or more processors of the PLC 402 is below the lower limit of the stored acceptable welding power range, (3) reject the seal if a short circuit is detected in the sealer 424 by the RF control 408, or (4) reject the seal if the average welding power analyzed by the one or more processors of the PLC 402 is above the upper limit of the stored acceptable welding power range. If the seal is rejected, the PLC 402 signals the sealing device 424 to reseal the stem 54, provided the maximum number of verified reseals allowed has not been exceeded. If the seal is acceptable, the seal device 424 moves away from the stem 54, as shown in FIG. 13, and the cutting tool 428 moves toward the seal, cutting the stem 54 at the seal into two sections and separating the bag 26A from the filling manifold 78A.This may include moving the seal and cut assembly 404 laterally from the first bag 26A in the first row 66A to the second bag 26B in the first row 66A, as described above. However, if the seal is rejected (either after a reseal or due to a short circuit), the PLC 402 will generate an alert, display an error on the user interface 420, and instruct the operator to manually seal the stem 54 and cut the bag 26 from the cartridge 22.

[0160] Steps 628 and 632 of method 600 are repeated to fill, seal, and cut each bag 26 from the first row 66A. Step 640 of moving to the next row 66A is performed by feeding the sealing and cutting assembly 404 laterally (along the X-axis of the machine 400) back to its initial position adjacent the stem 54 of the first bag 26A and then longitudinally (along the Y-axis of the machine 400) from the first row 66A toward the second row 66B. After step 640 is completed, steps 620 and 624 are performed for the second row 66B before steps 628, 632, and 636 are performed to fill, seal, and cut each bag 26 in the second row 66B, as shown in FIGS. 14-16 . This cycle is repeated for each row 66 of the solution distribution grid 56 until all bags 26 have been removed from the grid 56, as shown in Figure 17. At this point, the PLC 402 commands the second pump 44 to reverse, the return valve 142 to close, and the return and supply manifold valves 156, 154, 152, 146 to open in order to purge the grid 56 of any remaining solution in the supply and return manifolds 58, 62 and fill manifold 78 of each row 66. The solution is pushed into the reservoir 38.

[0161] Finally, step 644 involves uncoupling cartridge 622 from filling machine 400, coupling a different cartridge 622 to filling machine 400, and repeating the fill cycle. The different cartridge may be the same or similar to the previously filled cartridge, and PLC 402 may run on a different program depending on the size and number of bags 26 in cartridge 622. Filter set assembly 634 remains on machine 400.

[0162] In method 600, after the last cartridge 622 in a given batch is filled, the filter assembly 34 is sealed and separated from the connection line 646 of the last cartridge 622 for testing in a filter integrity testing machine or device to ensure the sterility of the contents of the product bag 26. In cases where the filter assembly 34 is integrated with the cartridge 22, the filter assembly 34 is sealed and separated from the used cartridge to check the filter integrity. Both filters 118, 122 from the filter assembly 34 are tested to determine with a high degree of certainty that the solution in the filled product bag 26 is sufficiently sterile. Even if one of the filters 118, 122 of the filter assembly 634 fails and the other does not, the solution in the bag 26 will still be sterilized. It is also possible to test only one of the filters, testing the other only if the first fails the filter integrity test.

[0163] The filter testing device may be preprogrammed or controlled to perform a filter integrity test, such as a foam test, a pressure drop test, a water intrusion test, a water flow test, or any suitable test known in the art. A pressure drop test is a method for testing the quality of a filter either before or after the filter is used. To perform the integrity test, the test head of the filter testing device engages the inlet of the filter assembly 34. The filter integrity test determines the presence of any structural defects in the filter membrane that may prevent the filter 118, 122 from properly sterilizing a solution. For example, pores in the filter membrane with a diameter greater than 0.2 microns (μm) may allow particulates in the fluid, whether viable or non-viable, to pass through the filter 118, 122, compromising or contaminating the sterile environment of the bladder.

[0164] To perform a filter integrity test using the pressure decay test procedure, a test head engages the inlet of the filter 118, 122 and applies a predetermined value of air pressure to the inlet 65 and filter membrane. In one embodiment, the predetermined value is the pressure at which gas cannot permeate the membrane of an acceptable filter. A pressure sensor or other method of measuring the integrity of the filter is located within the test head and measures the pressure decay or diffusion rate through the filter membrane. The results from the integrity test are evaluated to determine the quality of the filter 118, 122 and, therefore, the quality of the solution in the filled product bag 26. If the pressure sensor measures decay or an unexpected decay rate, the filter 118, 122 fails the test.

[0165] Alternatively, in a bubble point test, the test head gradually increases the pressure applied to the filter 118, 122, and the increase in pressure is measured in parallel with the diffusion rate of the gas through the filter media. Any non-proportional increase in diffusion rate relative to the applied pressure may indicate a hole or other structural defect in the filter membrane, and the filter 118, 122 will fail the integrity test.

[0166] In addition to a filter integrity test for the filter, a vacuum leak test is performed on all used cartridges. The used cartridge is placed inside a chamber, which is sealed before applying a vacuum to the chamber. The time required to generate a certain level of vacuum is measured. If the required time exceeds a pre-verified time or if it is impossible to reach the required verified vacuum pressure, the cartridge is considered to have failed the vacuum test. The used cartridge 22 is placed inside the chamber, which is sealed. The chamber is connected to a vacuum level sensor and vacuum pump, and a vacuum is applied (i.e., a vacuum is drawn at a verified rate). If the desired level of vacuum is not reached within the pre-verified time, the cartridge 22 is considered to have failed the leak test.

[0167] Based on the results of the filter integrity test and cartridge vacuum test, a determination can be made with a high degree of certainty that the solution in the filled product bag 26 is either sterile or potentially compromised. Even if one filter 118, 122 of the filter assembly 34 fails the filter integrity test, there is a high chance that the solution in the bag 26 is still sterile, since both filters 118, 122 of the filter assembly 34 would need to fail to compromise the solution. The filter integrity tests performed in the filter integrity test machine and vacuum test described above are not limited to those methods described herein and may include different acceptability tests designed to assess the quality and performance of the filters 118, 122 and cartridges.

[0168] 23, a first exemplary method 500 of filling multiple product bags with a sterilization solution will generally be described. The method 500 may be performed with or without the machine 400 and the same, similar, or different cartridges 22, 222 described herein.

[0169] Method 500 begins at step 504 with positioning cartridge 22 on a filling machine, such as filling machine 400 of FIGS. 18A-18D. The following method is described with reference to the first exemplary cartridge of FIGS. 2-3, although the second exemplary cartridge 222 of FIGS. 6A-6C may similarly be used in method 500. First, a fresh and gamma-sterilized cartridge 22 is loaded onto gantry system 416 or other holding mechanism of machine 400. During step 504, peristaltic tubing 114 of connecting line 46 of cartridge 22 is coupled to second pump 44, and reservoir 38 and filter assembly 34 are loaded into machine 400 such that reservoir 38 is at least partially positioned above grid 56 and engaged with load cell 412. Next, cartridge 22 is coupled to feed line 18 in step 508.

[0170] Step 512 of activating the first pump 42 of the system 10 of FIG. 1 initiates a fill cycle, filling the plurality of bags 26 of the cartridge 22 with filtered solution. By activating the first pump 42, the feed line 18 is purged of air and vented through the vent port 164 while the isolation valve 165 is in a closed position. Solution is then pumped from the mixing tank 14 through the feed line 18, the filter assembly 34, and the connecting line 46 of the cartridge 22. This step also includes filling the reservoir 38 with a desired amount of sterilizing solution before filling the remainder of the cartridge 22 with solution. The reservoir 38 is disposed upstream of the plurality of bags 26 and coupled to the connecting line 46, which is disposed downstream of the filter assembly 34. In step 516, solution from the reservoir 38 is used to at least partially fill one or more bladders 52 of the plurality of bags 26 of the cartridge 22 by activating the second pump 44. A second pump 44 is positioned downstream of the reservoir 38 and upstream of the plurality of bags 26, which are coupled to a connecting line 46. The second pump 44 operates to first purge any air trapped within the connecting line 46 and then fill each of the plurality of bags 26, one at a time, with the sterilizing solution.

[0171] In step 520, the method 500 includes sealing the stem 54 of each of the at least partially filled product bags 26 at a location between the connecting line 46 and the bladder 52, thereby producing one or more at least partially filled and sealed product bags 26. Finally, each bag 26 is separated from the connecting line 46 in step 524. As described above, the sealing and cutting assembly 404 of the machine 400 may automatically seal and cut each stem 54 of the product bag 26 after each bag 26 is filled with solution. However, in another embodiment, the stem 54 of each bag 26 may be manually sealed and cut. Finally, after separating each of the at least partially filled and sealed product bags 26 from the connecting line 46 in step 524, the second pump 44 is reversed to recapture any unused solution from the cartridge 22.

[0172] The system 10, machine 400, and methods 500, 600, and cartridges 22, 222, 422, 822 disclosed herein offer numerous advantages for producing sterile solution filled containers. The machine 400 is modular, portable, and self-contained, allowing for customization of the filling system to meet specific facility specifications or market demands. One exemplary machine 400 has a footprint of approximately 6 feet by 7 feet. Additionally, the methods 500 and 600 described herein provide sterile solution bags 26 without the use of sterile autoclaves and / or expensive sterilization equipment required to sterilize the work environment, eliminating the risk of formulation degradation due to heat exposure. Because the system 10 and machine 400 do not need to be decontaminated or cleaned (i.e., downtime) to the extent required by other systems, the system 10 and machine 400 are available 24 hours a day, 7 days a week. Additionally, the self-contained and fully automated machine 400 reduces the number of sterilization steps that need to be performed in the terminal sterilization and aseptic filling process, thereby resulting in less operator intervention. In one embodiment, where cartridge 22 contains 360 bags, the operator may only be required to load the cartridge every 15 to 30 minutes, or for every 360 bags filled.

[0173] The exemplary cartridges 22, 222 of the disclosed system 10 also allow for greater manufacturability and may be customized according to specific needs. Each fill cycle includes processing multiple bags 26 in a single step. In one example, the cartridge 22 includes 90 bags 26, and a second exemplary cartridge 222 includes 180 bags 226. In practice, the number of bags 26, 226 / cartridges 22, 222 may vary depending on the requirements of the system 10. Additionally, multiple cartridges 22, 222 may be connected together using a sterile connector, such as cartridge connector 50, to increase the number of units processed before a filter change is required.

[0174] The pre-gamma-sterilized cartridge 22, 222 configuration disclosed herein also reduces the risk of contamination. The system 10 is completely closed because the only connection between the solution source (i.e., the mixing tank 14 and feed line 18) and the cartridge 22, 222 is at the cartridge connector 50. Once the solution passes through the filter assembly 34, the sterile solution is never exposed to the environment before flowing into the product bag 26, 226, thereby producing a product bag 26, 226 filled with fluid undergoing terminal sterile filtration. Furthermore, the stem 54 is sealed and severed after filling to prevent environmental exposure of the fluid. If the sterile filter 118, 122 is determined to be compromised, the bag 26, 226 containing the fluid from that filter will be contained and discarded without contaminating the machine's processing equipment or other product bags being processed.

[0175] In addition to the disclosed cartridge 22, the filter assembly 34 also reduces the risk of contamination and improves product safety. The filter assembly 34 has a high filtration capacity by including two filters 118, 122 arranged in series. This dual filter configuration provides a built-in filter contingency plan in the unlikely event that one of the filters 118, 122 fails during a fill cycle. The filter assembly 34, which can be used to filter 360 individual bags 26 of solution (i.e., a dual cartridge of 180 bags per grid 56), reduces the overall cost of the system 10 because more bags 26 are filled per filter 118, 122. Additionally, because there is a significantly reduced chance that both filters 118, 122 will fail, fewer bags 26 are discarded over time. Furthermore, there are significantly fewer filter changes per batch, resulting in fewer filter integrity tests. For example, instead of testing a filter for every bag (eg, when there is a 1:1 filter to bag ratio), one filter is tested for the entire batch of bags, which may be 360 ​​bags.

[0176] In another aspect of the cartridge 22, the reservoir 38 serves a variety of important roles that increase the efficiency and accuracy of the fill system 10. Compared to the fill times required in other terminal sterilization methods, the time to fill the bag 26 of the system 10 disclosed herein is significantly reduced because the solution is drawn directly from the reservoir 38 rather than from the filter assembly 34. By drawing from the bag 38, the fill cycle increases efficiency and reduces the strain typically placed on the filter assembly. This ensures that the fill can be carried out at the maximum possible speed without increasing the pressure drop across the filter assembly 34, thereby protecting the integrity of the filters 118, 122. The reservoir 38 also helps improve fill accuracy by eliminating the inherent variability introduced by the filter during its use cycle (i.e., as the filter pores gradually become clogged, the flow rate through the filter begins to change, thereby adversely affecting fill accuracy).

[0177] Accuracy is also increased because the reservoir 38 is placed on a load cell 412, which monitors the exact amount of solution placed in the reservoir 38 at any time during the fill cycle. The system 10 does not need to consider the amount of head space required in each given product bag 26 when filling each product bag 26 with solution because any air trapped in the connecting lines 46 that are typically forced into the product bag 26 is first purged and forced into the reservoir 38 before the bag 26 is filled. This increases fill accuracy because only the amount of solution needs to be measured and monitored, rather than additional estimated head space created from air trapped in the stem and / or connecting lines.

[0178] Additionally, the reservoir 38 improves the durability of the filling system 10 by recovering any unused sterilized solution from each fill cycle. First, the reservoir 38 serves as a volume that receives the solution required to wet the filter assembly 34 that would otherwise be discarded and / or wasted. Primarily, the reservoir 38 serves to minimize waste in the system 10 by receiving any unused solution (i.e., not delivered to the product bag 26) from the distribution grid 56. After all the solution is drawn back into the reservoir 38, the contents of the reservoir 38 are safely returned to the mixing tank 14 without any risk of contamination. This reduces solution waste and controls environmental contamination in a simple and safe manner. Finally, the amount of solution used to fill multiple bags 26 is carefully monitored for more precise delivery by mounting the reservoir 38 on a load cell 412. Towards the end of the bag filling phase, the control system 402 of the machine 400 actively manages the amount of solution in the reservoir 38 to ensure that the reservoir 38 is nearly empty when the cycle ends.

[0179] Preferred embodiments of the present invention are described herein, including the best mode or modes for carrying out the invention known to the inventors. While numerous examples are shown and described herein, those skilled in the art will readily understand that the details of various embodiments are not necessarily mutually exclusive. Instead, those skilled in the art will be able to combine one or more features of one embodiment with one or more features of remaining embodiments upon perusal of the teachings herein. Furthermore, it should be understood that the illustrated embodiments are exemplary only and should not be construed as limiting the scope of the invention. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any example or exemplary language (e.g., "etc.") provided herein is intended merely to better illustrate aspects of the exemplary embodiment or embodiments of the invention and does not impose a limitation on the scope of the invention. No language herein should be construed as indicating any non-claimed element as essential to the practice of the invention.

Claims

1. 1. A cartridge assembly for a filling machine, said cartridge assembly comprising: a plurality of containers, each container including a volume and a stem connected to the volume; a connecting line grid in fluid communication with each stem of the plurality of containers, the connecting line grid including a first row connected to one or more containers of the plurality of containers and a second row connected to one or more containers of the plurality of containers; a filter assembly coupled to the connecting line grid; Equipped with a cartridge assembly, wherein the connecting line grid includes a network of interconnected tubing defining a supply manifold, a return manifold, the first row, and the second row, the first row and the second row extending between the supply manifold and the return manifold.

2. The cartridge assembly of claim 1 , wherein the filter assembly includes a first filter and a second filter arranged in series.

3. 3. The cartridge assembly of claim 1, further comprising a reservoir coupled to the connecting line grid and positioned upstream of the plurality of containers and downstream of the filter assembly, the reservoir including a volume, a first port, and a second port.

4. The cartridge assembly of claim 3 , wherein the reservoir is positioned above the grid of connecting lines relative to gravity.

5. 5. A cartridge assembly according to claim 3 or 4, wherein the supply manifold of the grid of connecting lines is coupled to an outlet port of the reservoir and the return manifold is coupled to an inlet port of the reservoir.

6. A cartridge assembly according to any one of claims 3 to 5, wherein the network of interconnected tubing comprises at least one rigid section connected to at least one flexible section.

7. The cartridge assembly of any one of claims 3 to 6, wherein the first and second rows each include a first end, a second end, and a filling manifold connecting the first and second ends, the first and second ends being flexible, and the filling manifold being rigid.

8. 8. The cartridge assembly of claim 7, wherein the supply manifold is coupled to a first end of each of the first and second rows, and the return manifold is coupled to a second end of each of the first and second rows.

9. 9. The cartridge assembly of claim 7 or 8, wherein the filling manifold of each of the first and second rows includes one or more ports corresponding to the one or more containers of each of the first and second rows, and each of the one or more ports is in fluid communication with the stem of one of the one or more containers.

10. The cartridge assembly of any preceding claim, wherein each row of the first and second rows of the grid of connecting lines is coupled to at least two of the plurality of containers.

11. The cartridge assembly of any preceding claim, wherein the plurality of containers comprises a plurality of product bags and the volume is a bladder.

12. The cartridge assembly of any preceding claim, wherein the plurality of containers comprises a plurality of vials.

13. The cartridge assembly of any preceding claim, wherein the plurality of containers comprises a plurality of syringes.

14. The cartridge assembly of claim 1 or 2, further comprising a reservoir coupled to the connecting line grid and a pump, the reservoir being positioned between the pump and the filter assembly.

15. 15. The cartridge assembly of claim 14, wherein the connecting line grid includes a network of interconnected tubing defining a supply manifold, a return manifold, the first row, and the second row, the first row and the second row extending between the supply manifold and the return manifold.

16. The cartridge assembly of claim 15 , wherein the return manifold of the grid of connecting lines is coupled to an inlet port of the reservoir.

17. 17. A cartridge assembly according to claim 15 or 16, wherein the network of interconnected tubing comprises at least one rigid section connected to at least one flexible section.

18. 18. The cartridge assembly of any one of claims 1 to 17, further comprising a sample bag coupled to each filter in the filter assembly, the sample bag configured to receive purged air and solution samples.

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