Method and system for producing sterile solution filled containers - Patents.com

Abstract

A method for producing sterile solution filled containers includes positioning a cartridge on a filling machine. The cartridge includes a plurality of containers (26), a filter assembly (34), and a connecting line 46 in fluid communication with the filter assembly. Each of the plurality of containers includes a volume and a stem in fluid communication with the volume and in fluid communication with the connecting line. The method includes coupling the cartridge to a feed line in fluid communication with a mixing tank, activating a pump coupled to the feed line, and filling one or more of the volumes associated with the plurality of containers by at least partially pumping fluid through the feed line, the filter assembly, and the connecting line to generate one or more at least partially filled containers.

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 includes filling a bag with the solution in a clean environment, sealing the filled bag of solution, 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 required to suitably sterilize bags of solution for medical use. These autoclaves are generally not economical unless they can produce large volumes of terminally sterilized bags. Typically, centralized manufacturing facilities can result in capital investments 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] Aseptic manufacturing processes 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 it can be demonstrated that the solution entering the bag is sterile, there is a risk that contaminants may be inadvertently introduced into the solution during filling / sealing. Once introduced, the 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 a sterile solution filled container 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 and disposed upstream of the plurality of containers and disposed 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 filling one or more of the volumes associated with the plurality of containers, at least in part, by pumping fluid through the feed line, the filter assembly, the reservoir, and the connecting line, thereby generating 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 seal and cut assembly including a sealer, a cutter, and a carriage carrying the sealer and the cutter. The seal and cut 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 first, second, or third exemplary aspects described above, the methods, systems, and machines for producing a sterilization solution container 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 prior to filling the 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, a second pump may be positioned 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 isolating 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 a 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 a second bag in the first row after opening a third valve coupled to a 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 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 moving the sealing and cutting assembly longitudinally from the first row of the connection lines toward the second row of the connection lines prior to filling the second row of the connection 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 at least partially comprise a step of purging air from the connecting lines of the cartridge prior to 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, a 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, a filter assembly, and a connecting line in fluid communication with the filter assembly.

[0031] In a preferred form, which may be combined with any other form or portion thereof, each of the multiple containers of the different cartridges 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.

[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 of 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 a step of 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 a 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 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 a 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 the multiple 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 connecting line grid, 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 defining 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 portion thereof, a 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 filling 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 embodiment, which may be combined with any other embodiment or portion thereof, each row of the first and second rows of the connecting line grid 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 generated 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 the 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 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 multiple containers may include multiple containers and the volume is a bladder.

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

[0075] In a preferred form, which may be combined with any other form or portion thereof, the multiple containers may include multiple syringes. [Brief description of the drawings]

[0076] [Figure 1] FIG. 1 is a schematic diagram of an exemplary system for producing a sterile solution container in accordance with the teachings of the present disclosure.

[0077] [Diagram 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] [Diagram 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 a group of exemplary containers isolated from the cartridge of FIG.

[0080] [Diagram 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 can 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 can 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 a second bag in a first row of a 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 the cartridge.

[0093] [Figure 16] FIG. 16 is a schematic diagram of the system of FIG. 1 showing the filling phase of a second bag in a 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 and assembled in the system of FIG. 1 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.

[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] [Diagram 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 of 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 in accordance with 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 in accordance with the teachings of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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, for example, insulators and closed restrictive access barrier systems (RABS). The disclosed filling platform includes a filling system, a disposable cartridge of containers, and a filling machine, which increases filling capacity and efficiency, ensures sterility and safety of the final product, and automates production.

[0107] In FIG. 1, a schematic diagram of a system 10 for filling a plurality of 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 solution mixed in the mixing tank 14 is delivered to a plurality of containers, in this embodiment, 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 plurality of bags 26. In other embodiments, 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 the 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 plurality of 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 an isolation valve coupled to the feed line 18 and connecting line 46 of the cartridge 22, respectively, pump and control the flow of the 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 a plurality of containers 26, a filter assembly 34, a reservoir 38, and a connecting line 46. The plurality of containers 26 may be one of a variety of product bags 26, and 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 line 46 includes a solution distribution grid 56, which is a network of interconnected tubes and is in fluid communication with each stem 54 of the plurality of containers 26. The solution distribution grid 56 includes a supply manifold 58, a return manifold 62, and a plurality of rows 66 connecting the supply manifold 58 and the return manifold 62. The connecting line 46 includes a plurality of connected rigid sections to reduce lag and provide structure, and a plurality of flexible sections to allow for 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. Although 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 port being connected to the stem 54 of each 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 a group 67 of exemplary bags of a first exemplary cartridge 22. The group 67 includes multiple rows 66 that are connected together via connectors 82, 86 to form the 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, to another group 67, or to 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 the supply and return lines 110, 1106 and to the 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 groups 67 of bags 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 carriers that will be 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 with 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] As shown in FIGS. 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 that is disposed downstream of the filter assembly 34. In this embodiment, the reservoir 38 is a flexible bag 38, but may be a different type of container that can maintain 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 recovery port 168, and is coupled to the grid 56 of the cartridge 22 and supplies the 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 the 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 the 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 coupled to the return manifold 62, and connecting the return line 106, which is coupled 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 during operation of the system 10 during various cycles, delivering purged air and unused solution from the grid 56 to the reservoir 38.

[0115] The solution pumped from the mixing tank 14 must first pass through a 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, the sterilization technique, and the 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 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 bag 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 filter 118, 122, the operator may be able to detect such issues at the end of the cartridge fill by analyzing the filter via a filter integrity test and testing the contents of the sample bag 130 and the first and last filled bag 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 stop on the filled bag 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 being connected to the solution delivery system (i.e., mixing tank 14 and feed lines 18) to ensure that all surfaces in contact with the filtered solution are sterile. 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 bag 26 without any risk of contamination, (2) isolate unfilled product bags 26, (3) allow 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 to fill 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 may 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. Thus, for ease of reference, wherever possible, the same 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 a sterile solution. The two sterilizing grade filters 318, 322 sterilize enough solution to fill twice as many product bags as a single cartridge 22. As shown in Figure 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 of each individual grid 256A, 256B. In another embodiment, multiple individual cartridges may be assembled into a single filter row using additional connectors (Figure 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 improve 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 to connect to the 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 filters of the cartridges 422, 822 are not discarded after filling and may be used for the entire batch (e.g., more than 2,000 bags). After filling, a new cartridge 422, 822 is connected to the filter line. Other components of the cartridge 422, 822 of Figures 7 and 8 are otherwise identical to or substantially similar to the components of the cartridge 22 of Figure 2. The sterile cartridge connector may be an AseptikQuik® sterile connector.

[0120] Returning to Figure 1, the system 10 includes a number of isolation valves to control the flow of solution through the feed line 18, the connecting line 46, the supply line 110, the supply manifold 58, the return manifold 62, the return line 106, each of the fill manifolds 78, and each of the stems 54 of the plurality of bags 26. These valves are positioned adjacent to flexible portions of the tubing of the 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 the system 10. The first valve 165 is the main system isolation valve and is operated (e.g., open / close, release / pinch, or engage) to control the supply of solution from the mixing tank 14 to the cartridge 22. The main feed valve 134 is always closed after the first pump 42 is turned off to ensure that there is no back pressure or backflow through the filter. The third valve 138 is a supply valve and is 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 back into the reservoir 38.

[0121] In addition, 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 of 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 and 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] A second group of valves 160 are fill valves and are disposed 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 such that each valve 160 is adjacent to 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 to 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 the system 10 will be illustrated and described at different phases of the fill cycle. First, the feed line 18 is purged of any trapped air by running the first pump 42. As solution is drawn into the feed line 18 from the mixing tank 14, any air in the feed line 18 is pushed through a vent 164 located downstream of the first pump 42 and upstream of a main isolation valve 165. While the feed line 18 is being purged and vented through the vent 164, the main system isolation valve 165 closes, thereby isolating the entire cartridge 22 and filter assembly 34 from the feed line 18.

[0124] After air has been 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 to allow the filter assembly 34 to be adequately wetted and the reservoir 38 to be filled 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 assembly 34 ensures that the solution passing through to the reservoir 38 is sufficiently sterilized.

[0125] In the next phase of the fill cycle, shown in FIG. 10, the portion of the cartridge 22 downstream of the reservoir 38 opens in preparation for 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, respectively, coupled to the outlet and inlet ports 98, 94 of the reservoir 38, 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) close. The second pump 44 operates to purge the solution distribution grid 56 of any air trapped in the supply and return manifolds 58, 62. As shown by the arrows in FIG. 10, the solution from the reservoir 38 pushes air through the outlet port 98, the supply line 110, the supply manifold 58, the last row 156, the return manifold 62, the return line 106, and into the inlet port 94 of the reservoir 38. Located at least partially above the solution distribution grid 56 (vs. gravity), the reservoir 38 receives and captures the purged air in the head space of the reservoir 38. This configuration advantageously facilitates air management by using the buoyancy of the air to push the solution (coming from below the bag air, i.e., head space) and ensure a precise fill volume. As air is purged from the supply and return manifolds 58, 62, the sterilizing solution fills the perimeter of the 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 open and the supply and return manifold valves 152, 154 of the last row 156 close. The valves 146 and 150 from the other rows 66 remain closed. The second group of valves 160 remain 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.

[0128] This process is repeated for the remaining bags 26 in the first row 66A until each bag 26 has been 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 has been filled. The filling machine automates the filling cycle by communicating with the fill valve 160 and the sealing and cutting assembly such that the bag 26 is filled with a 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 in a lateral direction parallel to the row 66 and sequentially seal and cut 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, a sealing device of the sealing and cutting assembly may seal the stem 54 of the second filled bag 26 while a 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 located 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 of the first row 66A are separated from the grid 56 and the fill valves 160 engage the stems 54 of the bags 26 of 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 filling, sealing, and cutting phases are repeated for each of the remaining bags 26 in the second row 66B until each bag 26 has been filled, sealed, and removed from the grid 56. Again, the sealing and cutting assembly of the machine is dispatched to a position adjacent the first bag of the following row 66.

[0131] Finally, in the final phase of the fill cycle shown in FIG. 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, the supply manifold valves 146A-D, 152, and the 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 short, the reservoir 38 serves multiple roles in the fill cycle of the system 10. First, the reservoir 38 serves as an intermediate bag or volume of solution 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 wet the filters 118, 122 in this phase is not discarded, but is collected and used to fill the product bag 26. Second, the reservoir 38 serves as a volume for trapped air that is purged from the system 10 in the purge phase. As described above, the reservoir 38 is positioned above the grid 56, thereby receiving trapped air in its head space. Third, the reservoir 38 serves as an intermediate source of solution for filling the bag 26. Instead of drawing directly from the filter assembly 34, the second pump 44 draws sterilizing solution only 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 the metering pumps 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 the 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 safely returned to the mixing tank 14 without any risk of contamination.Finally, as will be explained in more detail below, the amount of solution in the reservoir 38 is carefully monitored for active fill management. This is accomplished by mounting the reservoir 38 on a load cell that monitors the exact amount of solution in the 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 the reservoir 38 to ensure that the 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 necessary to process the cartridges (e.g., seal and cut assemblies, pumps, gantry systems, isolation valves, etc.). However, for simplicity purposes, only one set of machine components will be labeled in the figures. Thus, it can be assumed that the components on the left side of machine 400 are the same and are 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 of 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 the proximity switches and other sensors, transmit commands or signals, operate the devices of the system 10 (e.g., pumps 42, 44, seal and cut assembly 404, first and second groups of valves 146, 150, 160), monitor sensors (e.g., load cell 412, sensors in the seal device), 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 isolated 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., 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 regarding 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, the corresponding bags 26 may each be quarantined for disposal.

[0137] The sealing and cutting assembly 404 shown in Figures 18D, 21, and 22 includes a seal controller 408, a sealing energy (e.g., RF generator) 490, a sealer 424, a cutter 428, a conveyor 432 (not shown in Figures 21 and 22) disposed below the sealer 424 and the cutter 428, one or more sensors, and a carriage 436 that carries the sealer 424 and the cutter 428. The sealing and cutting 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 sealing and cutting 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 sealer 424 and cutter 428 are spaced apart from each other by the same or similar distance between adjacent stems 54 in a given row 66. In this manner, the sealer 424 is in position to seal one stem 54 and the cutter 428 is in position to cut the adjacent sealed stem 54. After the sealing and cutting are performed, the carriage 436 moves the sealer 424 and cutter 428 to the next position to seal and cut the 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 has been severed from the cartridge 22, the seal and cut-off 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 bags 26 separated from cartridges 22 onto a 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 a bag 26, the chute is in the correct position to direct the separated bag 26 onto the conveyor 432. When the linear transport unit 433, carrying the sealing and cutting assembly 404 and valves 160, advances to a row, the conveyor 432 advances with it and is thus correctly positioned to receive a bag separated from a cartridge 22.

[0140] Separately, the sealer 424 and cutter 428 are also pneumatically controlled to 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, which will be described in more detail below, the sealer 424 retracts back to the carriage 436. The carriage is then sent out 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, the sealer 424 and cutter 428 both 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 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 a seal, the sealer 424 of the seal and cut assembly 404 extends towards the stem 54 of the bag 26 in the open position and crimps onto the stem 54 once in place. The seal tool 424 is connected to a radio frequency ("RF") generator with 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 seal tool 424 creates a seal wide enough to provide the correct welded length on each end after the bag 26 is cut apart. The sealed portion of the tube is cut into two sections, the upper section stays with the cartridge 22 and the 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 that 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 may 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 direct shorts 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 set to establish an acceptable average weld power range for the fill tube weld (i.e., the average power over the duration of the weld). During the sealing operation, the PLC 402 compares the real-time weld data captured by the RF generator to 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 a 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 ensure that the fill cycle does not continue until the stem 54 is resealed. If the captured average welding power is above the upper limit of the acceptable welding power range, it indicates an overseal. In this embodiment, 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 the load cell 412 to monitor the amount of solution flowing through the system 10 to fill the multiple bags 26 to avoid unnecessary waste. As described above, the reservoir 38 is mounted on the load cell 412, which monitors the exact amount of solution in the reservoir 38 at any 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. Towards the end of the fill cycle, the PLC 402 actively manages the amount of solution in the reservoir 38 to ensure that the reservoir 38 is nearly empty when the cartridge 22 is fully filled. After all the bags 26 of the cartridge 22 are 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 end of the collection cycle, 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 and includes a frame 419 that supports the grid 56 of cartridges 22 and a rotatable swing arm 421. In the illustrated embodiment, the frame 419 includes slots or grooves that are 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 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, it is not necessarily in the proper position to interact with the isolation valves 146, 150, 160. Thus, to set 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 to abut 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 the cartridges 22. However, other mechanisms and arrangements of the machine 400 may also be used to perform each phase of the machine cycle. For example, movement of the gantry system 416 may be facilitated by an operator by sliding the gantry system 416 into position along rails 458 of the machine 400. In yet another embodiment, the sealing and cutting operations of each bag 26 may be semi-automated or fully manual. Based on the material of the tubes 54, other sealing techniques may also be used, such as, for example, heat transfer, ultrasonic welding, or other suitable methods.

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

[0150] The system 610 of FIG. 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 that is 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 that is 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, the 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 the 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 a manifold 613 containing two filters 619, 622 (e.g., both sterilizing grade filters) and 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, for example, and the second connector 650B is arranged to connect the second connecting line 646B to the second cartridge 622B. However, the solution distribution grid 611 may include sterile connectors for all cartridges that require filling in a batch.

[0152] In the illustrated embodiment, one or more pinch valves may be arranged to crimp onto the manifold line 613 and control the fluid flow rate into the cartridges 622A, 622B. For example, the pinch valve adjacent line 615A may be opened to allow fluid to flow from the manifold 613 into the first line 615A to begin filling the first cartridge 622A, while the pinch valve adjacent line 615B may be closed to prevent fluid from flowing into the second cartridge 622B. At the end of the manifold 613 opposite the filter assembly 634, a reservoir 619 is in fluid communication with the manifold 613 to receive purged air from the 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 such that only a percentage of the 20 connectors 650 are coupled to the 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) that is 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 implementing 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 first end of which is connected to manifold 613 and the other end of which is connected to cartridge 622. Once connected, the filling operation proceeds as previously described. At the end of filling, after solution recovery, connection line 646 is sealed and then cut 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 with one of the unused sterile connectors from the filter set connector manifold. This ensures a sterile fill for all cartridges 622.

[0155] After the sterile connector ends 650A and 650A-A and connector ends 650B and 650B-B for the first two cartridges in batches 622A and 622B are connected, the fill cycle begins as described above by activating the first pump 642 and purging the feed line 618. The primary isolation valve 765 closes and air is vented through the vent 764. The primary isolation valve 765 then opens, wetting the filters 630, 722 of the filter assembly 634 and filling the reservoirs 638A and 638B. Air trapped within each grid 656A, 656B is then purged by closing the main feed valves 734A, 734B and opening the supply valves 738A, 738B (FIG. 25), the supply manifold valve 152, the return manifold valve 154, and the return valve 142, as shown in FIG. 10. In step 612, multiple steps are performed by the 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, the captured air from the first row 66A is purged through the connecting lines 46 of the cartridge 22 prior to filling the first bladders 52 of the bags 26, as shown in FIG. 11. When purging the first row 66 of the connecting lines 46, the machine 400 opens the first row supply manifold valve 146A and the first row return manifold valve 150A. 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 so that 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 and into reservoir 38. Pump 44 communicates with PLC 402 to close return manifold valve 150A of the first row 66A, step 620, as shown in FIG. 12. 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 the return manifold valve 150A, the first fill valve 160A, which is coupled to the stem 54 of the first bag 26A, opens, bringing solution into the bladder 52 of the first bag 26A. The load cell 412 monitors the reservoir 638 to ensure that there is sufficient volume in the reservoir 38 to begin the purge / fill process. The second pump 44 meters the desired volume of solution into each of the product bags 26. As the fill proceeds, the load cell 412 will control the first pump 42 to transport fluid from the mixing tank 14 through the filter assembly 634 and into the reservoir 638 such that there will be enough solution for the fill process to proceed. As the fill process nears completion, the load cell 412 targets a minimum remaining volume in the 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. Thereafter, step 628 is repeated for the second bag 26B of the first row 66A. Specifically, the second bag 26B of 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 of sealing and cutting the first bag 26A is performed, as shown in FIG. 13, and the first bag 26 is removed from the cartridge 22.

[0159] In step 636, sealing and cutting the bag 26 includes initiating a program of one or more processors of the PLC 402. The stored program is executed by the PLC 402 by commanding the sealing and cutting 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 just 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 for 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 weld power analyzed by the one or more processors of the PLC 402 is within the stored acceptable weld power range, (2) reject the seal if the average weld power analyzed by the one or more processors of the PLC 402 is below the lower limit of the stored acceptable weld 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 weld power analyzed by the one or more processors of the PLC 402 is above the upper limit of the stored acceptable weld 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 is moved away from the stem 54, as shown in FIG. 13, and the cutting tool 428 is moved 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 66 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 of the 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. Solution is pushed into the reservoir 38.

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

[0162] In the 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 the case 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. 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 sterile. It is also possible to test only one of the filters and only test the other if the first one fails the filter integrity test.

[0163] The filter testing device may be pre-programmed 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. The 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 having 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 and compromise or contaminate the sterile environment of the bladder.

[0164] To perform a filter integrity test using the pressure drop 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 vacuum to the chamber. The time required to generate a certain level of vacuum is measured. If the time required exceeds a pre-verified time or if it is not possible to reach the required verified vacuum pressure, the cartridge is considered to have failed the vacuum test. The used cartridge 22 is placed into the chamber, which is sealed. The chamber is connected to a vacuum level sensor and a 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 the 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 has the potential to be 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 a plurality of product bags with a sterilization solution will generally be described. The method 500 may be performed with or without a machine 400 and the same, similar, or different cartridges 22, 222 described herein.

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

[0170] Step 512 of activating the first pump 42 of the system 10 of FIG. 1 starts a filling cycle to fill the plurality of bags 26 of the cartridge 22 with the filtered solution. By activating the first pump 42, the feed line 18 is purged of air and vented through the vent 164 while the isolation valve 165 is in the closed position. The 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 the sterilizing solution before filling the remainder of the cartridge 22 with the solution. The reservoir 38 is coupled to the connecting line 46, which is disposed upstream of the plurality of bags 26 and downstream of the filter assembly 34. In step 516, the 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 disposed 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 provide numerous advantages for producing sterile solution filled containers. The machine 400 is modular, portable, and self-contained, allowing 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. In addition, 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 that other systems require, 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 procedures that need to be performed in the terminal sterilization and aseptic filling process, thereby resulting in less operator intervention. In one embodiment, where the cartridge 22 contains 360 bags, the operator may only be required to load the cartridge every 15-30 minutes, or for every 360 bags that are filled.

[0173] The exemplary cartridges 22, 222 of the disclosed system 10 may also be customized according to specific needs, allowing for better production. Each fill cycle includes processing multiple bags 26 in a single step. In one embodiment, the cartridge 22 includes 90 bags 26, and the second exemplary cartridge 222 includes 180 bags 226. In fact, 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 the cartridge connector 50, to increase the number of units that may be 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 since the only connection between the solution source (i.e., the mixing tank 14 and the 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. Additionally, the stem 54 is sealed and cut after filling so that environmental exposure of the fluid cannot occur. 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., dual cartridges of 180 bags per grid 56), reduces the overall cost of the system 10 because more bags 26 are filled per filter 118, 122. In addition, fewer bags 26 are discarded over time because there is a significantly reduced chance that both filters 118, 122 will fail. 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 an entire batch of bags, which may be 360 ​​bags.

[0176] In another aspect of the cartridge 22, the reservoir 38 plays a variety of important roles that increase the efficiency and accuracy of the filling system 10. Compared to the filling 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, and not from the filter assembly 34. By drawing from the bag 38, the filling cycle increases efficiency and reduces the strain that typically is placed on the filter assembly. This ensures that filling can be performed 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 filling 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 filling 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 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, not the additional estimated head space created from air trapped in the stem and / or connecting lines.

[0178] In addition, the reservoir 38 improves the durability of the filling system 10 by recovering any unused sterilized solution of each filling 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 of 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 has been drawn back into the reservoir 38, the contents of the reservoir 38 are returned safely and without any contamination risk to the mixing tank 14. This reduces solution waste and controls environmental contamination in a simple and safe manner. Finally, the amount of solution used to fill the 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. Although numerous examples are shown and described herein, those skilled in the art will readily appreciate that the details of the various embodiments are not necessarily mutually exclusive. Instead, those skilled in the art should be able to combine one or more features of one embodiment with one or more features of the remaining embodiments upon perusal of the teachings herein. Furthermore, it should also be understood that the illustrated embodiments are merely exemplary and should not be taken 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 terminology (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 limitations on the scope of the invention. No term in this specification should be construed to indicate any non-claimed element as essential to the practice of the invention.

Claims

1. 1. A method for producing a sterile solution filled container, the method comprising: Positioning a cartridge on a filling machine, the cartridge including a plurality of containers, each of the plurality of containers including a volume and a stem having a first end in fluid communication with the volume; coupling the cartridge to a feed line in fluid communication with a mixing tank; pumping fluid through the feed line, the filter assembly, a connecting line in fluid communication with the filter assembly, and a reservoir coupled to the connecting line, thereby generating one or more at least partially filled product containers; sealing a stem of each of the at least partially filled containers at a location between the connecting line and a volume of the at least partially filled container, thereby producing one or more at least partially filled and sealed containers; isolating each of said at least partially filled and sealed containers from said connecting lines; A method comprising:

2. The method of claim 1, further comprising at least partially filling the reservoir with solution from the mixing tank prior to generating the one or more at least partially filled product containers.

3. The method of claim 2, further comprising activating a pump and at least partially filling the plurality of containers, the reservoir being disposed between the pump and the filter assembly.

4. 4. The method of claim 2 or 3, further comprising reversing the pump after isolating each of the at least partially filled and sealed containers from the connecting line.

5. A method according to any one of claims 1 to 4, wherein generating one or more at least partially filled product containers comprises filling a first row of the connection lines with solution, the first row comprising one or more containers.

6. 6. The method of claim 5, wherein filling a first container in the first row includes releasing a first valve coupled to a connecting line in the first row.

7. 7. The method of claim 6, wherein filling a first container in the first row includes releasing a second valve coupled to a stem of the first container.

8. The method of claim 7, further comprising filling the second container in the first row after opening a third valve coupled to a stem of a second container and closing a second valve coupled to the stem of the first container.

9. 9. The method of claim 8, further comprising moving a sealing and cutting assembly laterally from a first container in the first row to a second container in the first row.

10. A method according to any one of claims 5 to 9, wherein producing one or more at least partially filled product containers comprises separating each of the at least partially filled and sealed containers from a first row of the connection lines and then filling a second row of the connection lines with solution, the second row being parallel to the first row and including one or more containers.

11. 11. The method of claim 10, further comprising moving a sealing and cutting assembly longitudinally from the first row of the connection lines toward a second row of the connection lines prior to filling the second row of the connection lines.

12. A method according to any one of claims 1 to 11, further comprising purging air from the feed line prior to producing the one or more at least partially filled product containers.

13. A method according to any one of claims 1 to 12, further comprising purging air from the connecting lines of the cartridge prior to producing the one or more at least partially filled product containers.

14. 14. The method of claim 13, wherein purging air from the connecting line includes activating a pump to deliver air from the connecting line to a reservoir disposed above the connecting line.

15. 15. The method of claim 13 or claim 14, wherein purging air from the connecting lines comprises purging a first row of the connecting lines by opening a first row supply valve and opening a first row return valve, the first row comprising a first end, a second end and one or more containers disposed between the first and second ends, the first end coupled to the first row supply valve and the second end coupled to the first row return valve.

16. The method of any one of claims 1 to 15, further comprising decoupling the cartridge from the filling machine, coupling a different cartridge to the filling machine, and repeating the filling cycle.

17. Sealing the stem comprises: capturing the stem with a seal device and collecting seal sensor data with a sensor associated with a seal on the stem; one or more processors of a controller analyzing the sensor data associated with the seal; one or more processors identifying a status or condition associated with the seal based on an analysis of the sensor data. The method according to any one of claims 1 to 16, comprising:

18. The method of claim 17, further comprising accepting the seal if the average welding power analyzed by the one or more processors is within a stored acceptable welding power range.

19. A method as described in claim 17 or 18, further comprising rejecting the seal if the average welding power analyzed by the one or more processors is below a lower limit of a stored acceptable welding power range.

20. The method of any one of claims 17 to 19, further comprising rejecting the seal if a direct short is detected in the seal device by the one or more processors.

21. A method according to any one of claims 17 to 20, further comprising rejecting the seal if the average welding power analyzed by the one or more processors exceeds an upper limit of a stored acceptable welding power range.

22. 22. The method of claim 20 or 21, further comprising resealing the stem.

23. A method according to any preceding claim, wherein positioning the cartridge on the filling machine comprises positioning a cartridge having a plurality of product bags as a container, each product bag comprising a bladder as a volume.

24. A method according to any preceding claim, wherein positioning a cartridge on a filling machine comprises positioning a cartridge having a plurality of vials as a container.

25. A method according to any preceding claim, wherein positioning the cartridge on the filling machine comprises positioning a cartridge having a plurality of syringes as a container.

26. The method of any one of claims 1 to 22, wherein the one or more containers comprise one or more product bags and the volume is a bladder.

27. 1. A machine for producing a plurality of solution filled containers, the machine comprising: a sealing and cutting assembly including a sealer, a cutter, and a carriage carrying said sealer and said cutter, said sealing and cutting assembly being movable laterally and vertically; a bracket for receiving a cartridge of the container; a first group of pinch valves, the first group of pinch valves including a first column and a second column spaced from the first column; a second group of pinch valves disposed between the first column and the second column, the second group of pinch valves being movable in the vertical direction; A machine equipped with:

28. The sealing and cutting assembly includes at least one sensor and a controller, the controller comprising: one or more processors; a memory communicatively coupled to the 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: receiving data captured by the at least one sensor; analyzing the data to identify a status or condition associated with a seal generated by the sealer; sending a signal to a controller of the machine to accept or reject the seal; memory and 28. The machine of claim 27, comprising:

29. 29. The machine of claim 27 or 28, further comprising a pump and a load cell communicatively coupled to the pump.

30. The controller further comprises: one or more processors; a memory communicatively coupled to the 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: receiving data captured by the load cell; analyzing the data to identify a status or condition associated with the load cell; sending a signal to the pump to activate or deactivate the pump based on the identified status or condition; memory and A machine according to any one of claims 27 to 29, comprising:

31. A machine according to any one of claims 27 to 30, further comprising a conveyor positioned below the sealing and cutting assembly relative to gravity, the conveyor being movable together with the sealing and cutting assembly.

32. A machine according to any one of claims 27 to 31, wherein the bracket is coupled to a plurality of rails, the bracket and the plurality of rails being configured to removably receive a cartridge of a container.

33. The method of any one of claims 1 to 26, wherein pumping the fluid through the filter assembly comprises pumping the fluid through two filters in series.

34. The method of claim 33, further comprising placing purged air and solution samples in sample bags coupled to each of the filters.

Images