Closed process for filling

Abstract

In some aspects, systems and methods for filling one or more fill units are disclosed herein. In some embodiments, systems and methods describe a filling system for filling a plurality of fill units in parallel. The fill units can be filled with a fill substance, such as a fluid, a solid substance, or any combination thereof. For example, the fill substance can include a pharmaceutical drug or material. The filling system can be a closed system in order to prevent and / or minimize the risk of contamination of the fill substance. The filling system can be configured to draw the fill substance from a source of the fill substance into the fill units. In some embodiments, the filling system is further configured to seal and / or separate the fill units after being filled with the fill substance, where the sealing and separating can occur substantially simultaneously.

Description

Cross-referencing

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 560,653, filed March 2, 2024, entitled “Closed Process for Filling,” the entire disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to a closed system for filling fluid into a filling unit in parallel. Specifically, this disclosure relates to a filling / trimming process that includes parallel filling and sealing and separating the filling unit while maintaining substantially sterility. Background Technology

[0003] Medical processing, biological sampling, hazardous materials, and high-value solutions often require the transfer from bulk solutions to multiple filling units with high dosing precision, while maintaining protection against environmental contaminants and / or protecting personnel from the solution. This is typically done in an environmentally controlled room, such as an isolator, chemical hood, or biosafety cabinet, where vials are filled to the required volume and then fitted with stoppers and caps.

[0004] Implementing fully automated filling processes is expensive, time-consuming, and requires significant expertise across multiple disciplines. Typical approaches are most economically efficient when a large number of filling units are available, resulting in a low cost-per-unit cost across all expenses. Current trends in medical treatment favor more precise therapies where the total number of filling units is intended for as few as one patient (personalized medicine, such as autologous CAR-T, personalized cancer immunotherapy, personalized siRNA, personalized gene therapy) or small patient groups <300 (e.g., early-stage clinical trials and orphan drugs). Summary of the Invention

[0005] In some aspects, this document discloses a system comprising: a fluid source containing fluid; a plurality of filling units fluidly connected to the fluid source; and means mechanically connected to one or more filling units; wherein the plurality of filling units are configured to use the means to draw fluid into the plurality of filling units in substantially parallel order.

[0006] In some embodiments, the system further includes a dispensing system that fluidly connects a fluid source to a plurality of filling units. In some embodiments, the fluid source, the dispensing system, and the plurality of filling units define a closed containment device for the fluid, the closed containment device being configured to maintain sterility therein, the fluid source being connected to the dispensing system via a first flow path. In some embodiments, the dispensing system includes: a manifold configured to receive fluid from the fluid source; and a plurality of second flow paths, each of the second flow paths fluidly connecting the manifold to a corresponding filling unit among the plurality of filling units. In some embodiments, the manifold includes a first channel having a first inlet opening fluidly connected to the first flow path and a plurality of openings fluidly connected to a corresponding second flow path among the plurality of second flow paths.

[0007] In some embodiments, the multiple filling units used in any system described herein include syringes, bags, vials, containers, bottles, or any combination thereof.

[0008] In some embodiments, the device is configured to interact with a plurality of filling units to i) draw at least a partial vacuum within the plurality of filling units to aspirate fluid into the plurality of filling units, ii) expel at least some of the fluid from the plurality of filling units, or iii) both. In some embodiments, the plurality of filling units include a plurality of syringes. In some embodiments, the device includes a lower support configured to engage with a distal portion of a plurality of syringes, wherein the lower support is configured to move longitudinally to correspondingly move corresponding plunger rods of the plurality of syringes, thereby being configured to draw at least a partial vacuum to aspirate fluid into the syringes, expel at least some of the fluid, or both. In some embodiments, the lower support is movable via a linear actuator. In some embodiments, the lower support is operatively connected to one or more processors such that the lower support is movable to aspirate fluid into the syringes, expel fluid from the syringes, or both, based on instructions received from one or more processors. In some embodiments, the lower support includes a plurality of lower support segments, each lower segment being configured to individually move the plunger rod of a respective syringe among a plurality of syringes, thereby enabling selective i) aspiration of fluid into a desired syringe, ii) discharge of fluid from the desired syringe, or iii) both.

[0009] In some embodiments, the device is configured to seal and isolate a plurality of filling units from a dispensing system. In some embodiments, the device is configured to separate a plurality of filling units from a dispensing system. In some embodiments, the device is configured to seal and separate a plurality of filling units substantially simultaneously.

[0010] In some embodiments, the device further includes a first beam having a first side and a second beam having a second side, wherein the first beam and the second beam are configured to be aligned with and spaced apart from each other such that the first side faces the second side. In some embodiments, each of the first side and the second side includes a groove configured to receive at least a portion of each of a plurality of filling units, such that the plurality of filling units are configured to slidably engage with the first beam and the second beam for arrangement between the first beam and the second beam.

[0011] In some embodiments, the first beam includes a first component that at least partially defines a first side; and the second beam includes a second component that at least partially defines a second side; wherein one or both of the first and second components are configured to be movable toward the other. In some embodiments, when a plurality of filling units are disposed between the first beam and the second beam, corresponding second flow paths are disposed between the first and second components, wherein each of the corresponding second flow paths includes a tube. In some embodiments, i) the first component defines a first profile having a raised first valley portion around the first side and a raised first platform portion around the first valley portion, and ii) wherein the second component defines a second profile having a raised second valley portion around the second side and a raised second platform portion around the second valley portion, such that a first portion of the tube of the plurality of filling units is configured to be clamped by the first platform portion and the second platform portion when one or both of the first and second components move toward each other.

[0012] In some embodiments, the system further includes a heating element configured to heat i) a first component, ii) a second component, or iii) at least a portion of both. In some embodiments, the device is configured to heat the first portion of the tubing when clamped between a first platform portion and a second platform portion, such that at least some of the tubing material from the first portion of the plurality of filling units is at least partially flowable and configured to at least partially push from the first portion of the tubing of the plurality of filling units to the second portion, thereby reducing the tubing material at the first portion of the plurality of filling units, the second portion of the tubing of the plurality of filling units being arranged between corresponding first and second valley portions remote from the first and second platform portions. In some embodiments, the device is configured to separate the tubing at the first portion of the plurality of filling units, wherein the second portion remains physically connected to the respective filling unit and is separated from the dispensing system. In some embodiments, the second portion is configured to seal via the combination of tubing material to close the passage within the tubing. In some embodiments, the separation of the tubing and the sealing of the second portion occur substantially simultaneously or at least partially sequentially.

[0013] In some embodiments, the heating element includes a recirculated heating fluid, a resistance heater, or both. In some embodiments, one or both of the first and second components are pneumatically, hydraulically, magnetically, electrically, or any combination thereof movable.

[0014] In some embodiments, the system further includes a sample unit fluidly coupled to a fluid source, the sample unit being configured to aspirate fluid into a plurality of filler units in parallel with a plurality of filler units therein. In some embodiments, the system further includes one or more additional filler unit subgroups, each filler unit subgroup comprising an equal number of filler units as the plurality of filler units, wherein the dispensing system includes one or more additional manifolds corresponding to each additional filler unit subgroup. In some embodiments, the filler units of the plurality of filler units and the one or more additional filler unit subgroups are configured to aspirate fluid from the fluid source in parallel. In some embodiments, the device is configured to seal the filler units of the plurality of filler units and the one or more additional filler unit subgroups from the dispensing system. In some embodiments, the device is configured to separate the filler units of the plurality of filler units and the one or more additional filler unit subgroups from the dispensing system. In some embodiments, the device further includes a first beam and a second beam of one or more pairs of additional beams of any of the beams described herein, the one or more pairs of additional first beams and second beams being configured to seal and separate the filler units of one or more additional filler unit subgroups.

[0015] In some embodiments, the system further includes an integrity testing component configured to perform integrity tests on the system or at least its components. In some embodiments, the integrity test includes pressurizing the system or at least its components and further detecting i) pressure decay, ii) detection of gas used to pressurize the system or at least its components outside the system, or iii) both.

[0016] In some respects, this document discloses a method comprising: fluidly connecting a plurality of filling units to a fluid source containing fluid; and simultaneously aspirating fluid into the plurality of filling units, wherein the plurality of filling units are fluidly connected to the fluid source in a closed configuration, thereby being configured to maintain the fluid isolated from the surrounding environment.

[0017] In some embodiments, fluid is drawn into a plurality of filling cells based at least in part on a plurality of filling cells that have at least a partial vacuum drawn within them. In some embodiments, fluidly coupling the plurality of filling cells to a fluid source includes fluidly coupling a dispensing system of any dispensing system described herein to the plurality of filling cells, and fluidly coupling the dispensing system to a fluid source.

[0018] In some embodiments, the plurality of filling units used in any of the methods described herein include syringes, bags, vials, containers, bottles, or any combination thereof.

[0019] In some embodiments, the method further includes degassing or at least partially degassing the fluid aspirated into the plurality of filling units. In some embodiments, degassing includes performing one or more sequential steps: i) discharging fluid from the plurality of filling units, and ii) aspirating fluid into the plurality of filling units. In some embodiments, performing the sequential steps includes means using any of the devices described herein, wherein discharging fluid from the plurality of filling units includes optionally moving a plunger rod to a maximum position within the syringe, and wherein aspirating fluid into the plurality of filling units includes optionally moving the plunger to extend: i) to a maximum position outside the syringe, or ii) to a target position corresponding to a desired filling volume of fluid aspirated into the syringe.

[0020] In some embodiments, the method further includes sealing the plurality of filling units. In some embodiments, sealing the plurality of filling units includes: moving one or both of the first and second components described herein toward each other, thereby clamping the tubing of the plurality of filling units at a first portion; applying heat to the tubing of the plurality of filling units to at least partially melt or soften the material of the respective tubing at least at the first portion, so that it is at least partially flowable; and optionally increasing the pressure between the first and second components; wherein the at least partially flowable tubing material is configured to push against the second portion of the respective tubing of the plurality of filling units. In some embodiments, the method further includes separating the respective tubing of the plurality of filling units at the first portion via pressure applied between the first and second platform portions, thereby separating the plurality of filling units from the fluid source. In some embodiments, sealing the plurality of filling units and separating the respective tubing of the plurality of filling units occur substantially simultaneously or substantially sequentially.

[0021] In some embodiments, the method further includes performing an integrity test on the dispensing system, the first flow path, or both. In some embodiments, the integrity test includes: i) pressurizing the dispensing system, the first flow path, or both, and ii) detecting any leaks. In some embodiments, detecting any leaks includes i) monitoring any pressure decay, ii) detecting the gas used for pressurization via a sniffing test, or iii) both. In some embodiments, performing an integrity test on the dispensing system includes: pressurizing the dispensing system, wherein the dispensing system includes a syringe of any syringe described herein and is fluidly coupled to the syringe, wherein the plunger rod of the syringe is in a first position; detecting any leaks; optionally sliding the plunger rod to multiple positions to perform integrity tests on multiple syringes at different fill volumes. Attached Figure Description

[0022] These and other features, aspects, and advantages are described below with reference to the accompanying drawings, which are intended to illustrate and not limit the invention. In the drawings, similar reference numerals are used consistently throughout similar embodiments to denote corresponding features.

[0023] Figure 1 The illustration shows a front perspective view of a filling system according to some embodiments.

[0024] Figure 2 The illustration shows, according to some embodiments, from Figure 1 Front view of the filling system's reservoir, pipes, connectors, filling components, and filling and sealing devices.

[0025] Figures 3A-3C Top view, front view and top view of the filling component according to some embodiments are illustrated.

[0026] Figure 4 The illustration shows a side view of a subgroup component according to some embodiments.

[0027] Figure 5 The illustrations depict some embodiments. Figure 4 The front stereo view of the subgroup components.

[0028] Figures 6A-6F The illustration shows a front view and a front sectional view of a syringe according to some embodiments, a sectional view of the plunger rod and plunger seal, a sectional view of the bellows seal portion, and a view from... Figure 6A A cross-sectional view of the locking portion of the syringe.

[0029] Figure 7 The illustrations depict some embodiments. Figure 2 The filling and sealing device.

[0030] Figures 8A-8B The illustration shows a front view of the sealing portion of a beam in a filling and sealing device according to some embodiments.

[0031] Figures 9A-9E The illustration shows a front view of the connector between the syringe and the lower support of the filling and sealing device according to some embodiments, as well as a front view of the lower support.

[0032] Figure 10 The illustration shows a front perspective view of the upper support of a filling and sealing device according to some embodiments.

[0033] Figure 11 The illustration shows a front perspective view of a beam of a filling and sealing device according to some embodiments, wherein a sub-assembly of syringes is connected to a sub-manifold inserted therein.

[0034] Figures 12A-12BThe illustration shows a front view of an integrity system and integrity system components connected to a filling system according to some embodiments.

[0035] Figures 13A to 13B The top and side views of the distributor panel system are shown respectively.

[0036] Figure 14 The illustration shows a top view of a manifold embodiment according to some embodiments.

[0037] Figure 15 The diagram shows Figure 14 A cross-sectional side view.

[0038] Figure 16 The illustration shows a front view of some components of a syringe according to some embodiments.

[0039] Figure 17 The illustration shows a front view of some components of a syringe according to some embodiments.

[0040] Figure 18 The illustration shows a cross-section of a filling assembly, according to some embodiments, designed for direct connection of bulk bags or storage containers without a main manifold.

[0041] Figure 19 The illustration shows a cross-section of a component having a sampling unit according to some embodiments.

[0042] Figure 20 The illustrations depict some embodiments. Figure 12A The system is shown in detail, and is further configured to perform sterile filtration of fluids.

[0043] Figures 21 to 28 The illustration shows a flowchart outlining a process using a filling system according to some embodiments.

[0044] Figure 29 The illustration shows a flowchart of a method for depicting and verifying the layout of a filling system according to some embodiments.

[0045] Figure 30 The illustration shows a flowchart depicting a method for receiving and preparing a filling system according to some embodiments.

[0046] Figure 31 The illustration shows a flowchart depicting a method for measuring the distance of a plunger in a filling system according to some embodiments.

[0047] Figures 32-34 The illustration shows a flowchart depicting a method for testing the integrity of a filling system according to some embodiments.

[0048] Figure 35The illustration shows a flowchart depicting a method for degassing and filling a container using a filling system, according to some embodiments.

[0049] Figure 36 The illustration shows a flowchart depicting a method for inspecting a filling system after filling has occurred, according to some embodiments.

[0050] Figure 37 The illustration shows a flowchart of a method for sealing and separating a container from a filling system according to some embodiments. Detailed Implementation

[0051] In some aspects, this document discloses systems and methods for filling one or more filler cells. In some embodiments, the systems and methods describe a filling system for filling multiple filler cells in parallel. The filler cells may be filled with a filler material, such as a fluid, a solid material, or any combination thereof. For example, the filler material may include a pharmaceutical drug or material. The filling system may be a closed system to prevent and / or minimize the risk of filler material contamination. The filling system may be configured to draw filler material from a filler material source into the filler cells.

[0052] In some embodiments, the filling system is also configured to seal the filling unit after filling with a filling material. The filling system can also be configured to provide the filling unit as a separate filling unit. The systems and methods described herein for filling, sealing, and / or separating filling units (as described herein) using filling materials (e.g., fluids as described herein) that can be filled in parallel can be performed manually and / or automatically using one or more processors operatively communicating with the systems described herein.

[0053] Figure 1 An example of the filling system 10 described herein is illustrated. The filling system 10 can be configured to draw filling material from a reservoir 102 (e.g., a filling material source) to be dispensed into one or more filling units 106 (e.g., one or more syringes 106). The filling material described herein can be a fluid, such as a liquid. Therefore, for any system and method embodiment described or envisioned herein, "filling material" may be referred to herein as a "fluid." The fluid can be a pharmaceutical product requiring a sterile or substantially sterile transfer process from reservoir 102 to filling unit 106. The fluid can include any range of properties, including any viscosity, temperature, pressure, vapor pressure, heating value, etc. For example, the viscosity of the fluid may be less than or equal to 100,000 centipoise (cP). The temperature of the fluid may be less than or equal to 100°C. In some cases where the fluid includes a high vapor pressure, additional components of the system may be provided to maintain the fluid in liquid or substantially liquid form.

[0054] Continue to refer to Figure 1The filling system 10 may include a reservoir 102, a filling assembly 302 (see FIG. 3), a filling and sealing device 108, an integrity testing assembly (e.g., integrity testing fitting 1202 and integrity testing facility 1204) (see FIG. 12), and one or more processors (e.g., in...). Figure 1 The fluid pathways between and / or through the reservoir and filling assembly, or any combination thereof, are provided within the housing 116, the housing (e.g., 112, 114), and the filling assembly. As described herein, the filling system 10 can provide a closed system to maintain or substantially maintain sterile conditions for the fluid as it is transferred from the reservoir 102 to the filling unit 106. In this way, all points of fluid containment and flow can be substantially sealed and substantially isolated from the external environment to prevent or minimize the risk of exposure to contaminants entering the closed system.

[0055] This document describes exemplary embodiments of the components of the filling system 10 in more detail. storage

[0056] In some embodiments, as described herein, the filling system 10 includes a compartment or attachment point for a reservoir 102 (e.g., the reservoir 102 may be the compartment itself), the reservoir 102 being configured to contain a filling material, such as a fluid, to be added to the filling unit. The reservoir 102 may be sealed or substantially sealed to i) maintain or substantially maintain the sterility and conditions of the fluid within it, ii) prevent or reduce the risk of the fluid being exposed to the surrounding environment (e.g., the fluid may be hazardous), or iii) both. The reservoir may be located at the site where the fluid is prepared, at a separate dispensing and packaging center, at any other location, or via, for example... Figure 20 The methods described are for filling and sealing.

[0057] The storage container 102 can be any type of container or containment for fluids. For example, the storage container 102 can be a bag, vial, can, bottle, barrel, storage tank, or other type of vessel. The storage container 102 can be flexible or at least partially flexible (e.g., a bag), and / or can be rigid or at least partially rigid. Figure 2 The storage device 102 in the illustration is, for example, a bag.

[0058] The reservoir 102 can be of any size and configured to hold any amount of fluid. For example, the reservoir can have a volumetric capacity of about 5 mL to about 500 L. The reservoir 102 can be portable and therefore easily transported by a person from one location to another. The reservoir 102 may include one or more fittings and / or connectors surrounding the fittings to enable positioning of the reservoir. For example, the reservoir 102 may include a hook or opening at the proximal portion to suspend the reservoir above, for example, a filling unit.

[0059] The reservoir 102 may also include one or more reservoir flow paths through which fluid is configured to flow out of the reservoir 102. For example, Figure 2 The reservoir 102 includes a reservoir flow path through a reservoir fitting 204 isolated by a reservoir connector 202. The connector 202 can be configured to fluidly connect the reservoir flow path to another flow path, such as an intermediate flow path through an intermediate fitting 205 separate from the reservoir 102. The reservoir connector 202 can be any sterile connector configured to help prevent or reduce the risk of fluid contamination and / or compromise of the fluid's sterility as it moves from the reservoir through the connector to another location and / or flow path. The sterile connector 202 can be any sterile operating connector or sterile connector.

[0060] As used herein, the term "flow path" can be a fitting, pipe, hose, conduit, closed channel, or any combination thereof. For the purposes of this disclosure, any reference herein to the term "fitting" may also include, among other forms of flow paths or alternatives to, pipes, etc. A flow path may also define a passage therein to allow fluid to flow through it.

[0061] The reservoir fitting 204 may have an inner diameter (“ID”) from about 0.1 mm to about 50 mm. As described herein, the intermediate fitting 205 may be used to fluidly connect the reservoir 102 to another location, such as the filling assembly 302 (see FIG. 3). The intermediate fitting 205 may include connectors, such as intermediate sterile connectors 203 at each end of the intermediate fitting 205 (e.g., as described for the reservoir connector 202). Thus, the intermediate fitting may be a separate fitting from the filling assembly 302 and the reservoir 102, and in some cases, the intermediate fitting may aseptically fluidly connect them together. The intermediate fitting 205 may have an ID of about 0.1 mm to about 50 mm.

[0062] As described herein, intermediate fitting 205 can be fluidly connected to reservoir fitting 204 via intermediate connector 203, which can be configured to mate with reservoir connector 202. Similarly, intermediate fitting 205 can be fluidly connected to filling assembly 302 via intermediate connector 203, which is configured to mate with filling assembly connector 206 (see [link to documentation]). Figure 2 (Figure 3), thereby fluidly connecting the reservoir 102 to the filling assembly 302. The filling assembly connector 206 may be similar to the reservoir connector 202. The filling assembly connector 206 may be a sterile connector as described herein.

[0063] As described herein, fluid can flow from reservoir 102 to filling assembly 302 at least partially by gravity. For example, reservoir 102 may be located at a height (e.g., proximal) higher than at least a portion of filling assembly 302, such that opening a fluid path (e.g., via connectors 202, 203 and / or 206) allows fluid to flow from reservoir 102 to filling assembly 302 by gravity.

[0064] Alternatively or concurrently, fluid may flow from the reservoir to the filling assembly at least partially via a power source. For example, fluid may flow from the reservoir 102 to a pump, which then outputs the fluid at a higher pressure to flow to the filling assembly 302. In other embodiments, fluid may flow from the reservoir 102 to the filling assembly 302 via a vacuum at least partially drawn into the filling assembly 302.

[0065] For any filling system 10 described herein, any number of storage units 102 may exist, such as from 1 to 100 or 1, 2, 3, 4, 5, 10, 15, 25 or more storage units, etc. Fill component

[0066] Figures 2 to 11 , Figure 17 and Figure 19 Exemplary embodiments of the filling component 302 and certain components thereof are illustrated as described herein.

[0067] For any embodiment of the filling assembly described or contemplated herein, filling unit 106 may include any type for receiving and / or storing fluid, which may include syringes, vials, bags, containers, bottles, etc. Referring to filling unit 106 as the syringe described herein is a non-limiting illustrative example for the filling unit.

[0068] In some embodiments, as described herein, the filling assembly 302 is configured to receive fluid from the reservoir 102 to be added to the filling unit 106. In contrast to a sequential approach, the filling assembly 302 may be configured to fill fluid into one or more filling units 106 in parallel (e.g., simultaneously). For example, as described herein, in some embodiments, the filling assembly is configured to add (e.g., fill) fluid into 1-5000, 2-2500, 3-1000, 4-500, 5-250, 10-100, 25-75, or 1, 2, 3, 4, 5, 10, 15, 25, 35, 50, 75, 100, 200, 500, 1000, or more filling units, which may be added in parallel or substantially in parallel.

[0069] As described herein, the filling system 10 may include a filling assembly connector 206 configured to provide access to the filling assembly 302 and / or isolate the filling assembly 302 from external components such as the reservoir 102 and / or reservoir fitting 204. The filling assembly 302 may also include a dispensing system to allow fluid from the reservoir 102 to be dispensed across the filling unit 106, thereby enabling the filling unit 106 to be filled in parallel or substantially in parallel.

[0070] A distribution system can provide a minimum flow path (in terms of distance) and / or maintain volume, enabling the simultaneous and parallel filling of filler cells. A distribution system can also help ensure that the fluid velocity at any given point does not generate shear, which would degrade the fluid and / or cause bubbles to burst, thereby increasing their surface area and being absorbed into the fluid.

[0071] In some embodiments, the dispensing system includes a manifold system, such as the one illustrated with filling component 302. Alternatively or additionally, the dispensing system may include a dispenser plate (see [link to dispensing system]). Figure 13A and Figure 13B (and further described herein). Alternatively or additionally, the distribution system may include a radial distributor (see...). Figure 14 (and further described herein). Alternatively or additionally, the distribution system may include a tapered distribution system (not shown).

[0072] Regarding the filling component 302 described herein (see example) Figures 2-3B The manifold system may include one or more main manifolds 104 and one or more sub-manifolds 216. In some embodiments, the manifold system may include only the main manifolds 104 for distributing fluid to the filling unit 106.

[0073] Regarding the filling assembly 302, the main manifold 104 is configured to receive fluid from the reservoir 102, for example via the filling assembly connector 206 and optionally via the filling assembly fitting 208. The main manifold 104 may define a receiving region therein for receiving fluid. The receiving region of the main manifold 104 may define a passage that can be isolated from the surrounding environment. The passage of the main manifold 104 may include an inlet opening configured to receive fluid from the reservoir 102 (e.g., via the filling assembly fitting 208). The passage of the main manifold 104 may also include one or more openings (not shown), for example, surrounding a distal surface within the main manifold 104. The one or more openings of the main manifold 104 may enable fluid communication with one or more sub-manifolds 216.

[0074] Each opening of the main manifold 104 can correspond to and be fluidly connected to a main manifold fitting 210, which extends from the opening to a connector 211. A sub-manifold fitting 214 having a connector 212 can then extend from the connector 211 to a corresponding sub-manifold 216 (e.g., the connector 212 can be connected to the connector 211 to fluidly connect the main manifold fitting 210 to the sub-manifold fitting 214). Each connector 211, 212 can be similar to a reservoir connector 202 and / or a filling component connector 206 (e.g., a sterile / aseptic operating connector). Thus, the main manifold 104 can be isolated from each sub-manifold 216 via the filling component connector 206 and the connector 211, wherein the filling component connector 206 and the connector 211 can be configured to isolate the main manifold 104 from the corresponding fitting.

[0075] Each submanifold 216 (see, for example, see...) Figure 4 The receiving area of ​​each sub-manifold 216 can be defined for receiving fluid therein. Similar to the main manifold 104, the receiving area of ​​each sub-manifold 216 can define a passage that can be isolated from the surrounding environment. The passage for each sub-manifold can include an inlet opening configured to receive fluid from the main manifold 104 (e.g., via the main manifold fitting 210 and / or the sub-manifold fitting 214). Each sub-manifold 216 may also include one or more openings (not shown), for example, surrounding a distal surface within the respective sub-manifold. The one or more openings of the sub-manifold 216 can provide fluid communication with one or more filling units 106 (as described herein).

[0076] In some embodiments, having multiple sub-manifolds 216 helps reduce the fluid velocity as it flows from the main manifold 104 to the filling unit 106. The manifold system may include tapered channels. For example, it may be advantageous to utilize tapered channels within the main manifold, sub-manifolds, or distributor plates (as described herein), such that the channel diameter at the fluid source (e.g., the main manifold, sub-manifold) is larger than the diameter at the manifold port connector (e.g., the corresponding opening of the main manifold, sub-manifold). For the same volumetric flow rate from the fluid source, a larger diameter can result in a lower velocity. The diameter of the openings further away from the corresponding inlet openings on the main manifold and sub-manifolds, and / or the channel dimensions (e.g., diameters) of the main manifold and sub-manifolds, can decrease as they move away from the corresponding inlet openings to help increase the fluid velocity, because less fluid is available as it first flows to other openings closer to the corresponding inlet opening.

[0077] like Figure 3A As depicted, the main manifold 104 is positioned at a higher height than the sub-manifold 216, such that fluid flows from the main manifold 104 to the sub-manifold at least partially by gravity. In some cases, as described herein, the filling unit 106 may be evacuated, including at least a partial vacuum, to draw fluid from the main manifold 104 to the sub-manifold 216.

[0078] Each opening of the corresponding sub-manifold 216 can be in fluid communication with the corresponding filling unit 106. For example, the filling unit fitting 304 (see, for example, see...) Figures 3A to 3B , Figure 4 The filling unit 106 can extend from the opening of the sub-manifold 216 to the corresponding filling unit 106. As described herein, the filling unit can be a syringe (among other possible types as described herein). The filling unit fitting 304 can be referred to as syringe fitting 304, which can still refer to any type of filling unit (e.g., syringe, vial, bag, etc.). Figure 4 The sample tube 306 is further illustrated, which may be similar to the filling unit tube 304, but is in fluid communication with a sample collection container, such as a syringe (as described herein). The filling unit tube 304 and / or the sample tube 306 may have an ID from about 0.1 mm to about 50 mm.

[0079] Each sub-manifold may be in fluid communication with a corresponding subgroup of filling unit 106 via, for example, an opening in the sub-manifold and a corresponding filling unit fitting 304 for each opening, and is configured to distribute fluid to the corresponding subgroup of the filling unit (e.g., see subgroup assembly 402). For example, Figure 4The subgroup of filling units 106 depicted includes twenty filling units 106 each fluidly connected to submanifold 216 via a corresponding filling unit fitting 304, and a sample filling unit (which may be substantially similar to filling unit 106) connected to submanifold 216 via sample fitting 306. The number of filling units in a subgroup fluidly connected to a given submanifold (e.g., in subgroup assembly 402) can be any number. For example, a subgroup of filling units 106 configured to receive fluid from submanifold 216 may include 1-10000, 10-5000, 25-2500, 50-1000, 100-500, 1, 2, 5, 10, 25, 50, 100, 500, 1000, 2500, 5000, 10000, or more filling units.

[0080] like Figures 3A to 3C As depicted, the plurality of sub-manifolds 216 can be aligned relative to each other, and in a first direction (e.g., see Figure 3C 308) extends along its length, wherein the filling unit 106 is similarly aligned along the first direction. Figure 5 As shown, the subgroup of filling units 106 can be aligned and at least partially held in place via alignment rod 404. Alignment rod 404 may include a plurality of protrusions 502, wherein each filling unit 106 is configured to be at least partially arranged and held between a pair of protrusions 502. In some embodiments, the plurality of protrusions 502 are arranged in pairs to align each filling unit 106 and its corresponding filling unit fitting 304 with the opening of the submanifold 216. Alignment rod 404 may also include a pull tab 406 at its end. Pull tab 406 may be configured to align and / or remove the submanifold 216 and / or the subgroup of filling units 106 (as described herein) relative to a portion of the filling and sealing device 108.

[0081] The main manifold 104 may extend in a second direction that is generally transverse to the first direction of the sub-manifold, such that the main manifold 104 extends across the arrangement of the sub-manifold 216.

[0082] The filling component 302 may include any number of sub-manifolds 216. For example, see reference... Figure 3CThe filling assembly 302 includes 20 sub-manifolds 216. The filling assembly may include 1, 2, 3, 4, 5, 10, 15, 25, 30, 50, 75, 100, 200, or more sub-manifolds 216. The filling assembly may include 1-200, 2-100, 5-50, 10-30, or 15-25 sub-manifolds. Therefore, when each sub-manifold 216 is fluidly connected to a subgroup of filling unit 106 (e.g., subgroup assembly 402), the filling assembly may include multiple filling units arranged in an array. For example, the filling assembly 302 may have an array of twenty (the number of subgroup assemblies 402) multiplied by twenty (the number of filling units 106 in each subgroup assembly 402) filling units plus twenty sample filling units.

[0083] As used herein, filling unit 106 can be of any type configured to receive and contain fluid within the filling unit. For example, filling unit 106 can be a syringe, vial, bag, bottle, or any combination thereof. As an exemplary embodiment, filling assembly 302 described herein includes a filling unit for syringe 106.

[0084] Figures 6A-6F , Figure 16 , Figure 17 An exemplary embodiment of the syringe 106 described herein is illustrated. Figure 6A The illustration shows a front view of the syringe 106, which serves as the filling unit. Figure 6B Depicting from Figure 6A A cross-sectional front view of syringe 106, as described herein.

[0085] Each syringe 106 may include a barrel 602 that defines an internal cavity configured to receive fluid. Figures 16-17 The illustration shows the source Figure 6A A front view of the syringe 106 further depicts the barrel 602, in which... Figures 6A-6B and Figures 16-17 An example of a plunger assembly at least partially disposed within the internal cavity of a cylinder 602 is illustrated. The plunger assembly may include a plunger seal 1502 movable within the internal cavity via a plunger rod 1504, wherein the plunger rod 1504 is movable in a longitudinal direction 1512 to proximal and distal (e.g., around) the distal end 1510 of the cylinder 602. Figure 6A The longitudinal axis 614 of the cylinder moves. The plunger seal 1502 can be configured to interact with the inner surface of the cylinder 602 to provide a leak-proof seal or a substantially leak-proof seal. The plunger rod 1504 can be configured to engage with the interior of the plunger seal 1502. For example, the plunger rod may include threads at a proximal portion configured to engage with the interior of the plunger seal, thereby securing the plunger rod to the plunger seal 1502.

[0086] Fluid can be configured to be received within the barrel 602 via the proximal end 1508. Therefore, the internal cavity portion between the plunger seal 1502 and the proximal end 1508, or at least the proximal portion, of the barrel 602 defines a filling volume 1506 for the syringe 106. The filling volume 1506 can be varied based on the longitudinal positioning of the plunger seal 1502 within the barrel 602, which can be controlled based on the movement of the plunger rod 1504. As described herein, fluid can be aspirated into and / or expelled from the filling volume 1506 within the barrel 602 via movement of the plunger rod 1504. For example, moving the plunger rod 1504 proximally to the proximal end 1508 of the barrel 602 can expel at least a majority of any fluid within the barrel 602. In contrast, moving the plunger rod 1504 distally can create a vacuum within the barrel 602 and / or aspirate fluid into the filling volume 1506.

[0087] Reference Figures 6A-6B The cylinder 602 may include a proximal portion 617 having a proximal flange 612 disposed at a proximal end of the cylinder. The proximal flange 612 and / or the proximal portion 617 may be configured to receive at least a portion of a filling unit tube 304 passing through it, and / or may be fluidly coupled to the filling unit tube 304 while providing a leak-proof seal or substantially leak-proof seal around the proximal end 1508 of the cylinder 602.

[0088] about Figure 6A , Figure 6B and Figure 6D The syringe 106 may include a bellows seal portion 616 coupled to the barrel 602 and configured to provide a leak-proof or substantially leak-proof seal around the distal end 1510 of the barrel 602. The bellows seal portion 616 may include a first distal flange 605, finger-shaped flanges 604 coupled to and / or arranged around the first distal flange 605, wherein the finger-shaped flanges 604 may include and / or be coupled to one or more extensions 607 arranged around the finger-shaped flanges 604. The bellows seal portion 616 may include an internal seal 619 configured to receive a plunger rod 1504 passing through it and to provide a seal between the bellows 606, for example via engagement with a proximal bellows hook 621.

[0089] like Figure 6A , Figure 6B , Figures 6E-6F , Figure 16 and Figure 17As illustrated, the plunger rod 1504 extends through the distal end of the barrel 602 and through the bellows seal portion 616 to reach the locking portion 609 of the syringe 106. The bellows 606 can extend between the bellows seal portion 616 and the locking portion 609. The plunger rod 1504 can extend from the bellows seal portion 616 to the locking portion 609 within the cavity defined by the bellows 606 (see example...). Figure 6B , Figure 16 , Figure 17 The bellows 606 can be compressed and expanded along the longitudinal axis 614. For example, the bellows 606 can expand and compress as the plunger rod 1504 moves proximally and distally along the longitudinal axes 614, 1512. The bellows 606 can provide a leak-proof or substantially leak-proof seal to the internal cavity within the bellows by means of its connection with the bellows sealing portion 616 and the locking portion 609 (e.g., via the interaction between the distal hook 623 and the second distal flange 608), and the plunger rod 1504 is arranged within the bellows through the internal cavity.

[0090] The syringe 106 may also include a second distal flange 608 and a locking nut 610 at the locking portion 609, the locking nut 610 being distal to and coupled to the second distal flange 608 (see example). Figure 6B , Figure 6E , Figure 6F The locking nut 610 and the second distal flange 608 may also be integrally coupled. The locking nut 610 may have a maximum dimension (such as, for example, diameter) smaller than the corresponding maximum dimension of the second distal flange 608. The locking nut 610 may include an end cap 611. The end cap 611 may have a maximum dimension larger than the maximum dimension of the locking nut 610. The plunger rod 1504 may be configured to extend through at least a portion of the locking portion 609 and be disposed within the internal cavity of the second distal flange 608 and / or the locking nut 610. The second distal flange 608, the locking nut 610, and / or the end cap 611 may also provide a leak-proof seal or substantially leak-proof seal around the locking portion 609, thereby isolating the plunger rod 1504 from the surrounding environment. The plunger rod 1504 at the distal portion may also have a reduction in size (e.g., diameter) such that the larger size provides a seal when the plunger rod rests within the interior of the locking portion 609 (see...). Figure 6F ).

[0091] Accordingly, the proximal flange 612, the first distal flange 605 and the second distal flange 608, the finger flange 604, the bellows 606, the locking nut 610, the end cap 611, or any combination thereof are configured to provide a leak-proof seal for the syringe 106, thereby helping to prevent or minimize the risk of contaminants entering the cartridge 602, which may contain fluid located within the filling volume 1506, and thereby helping to maintain sterility within the cartridge 602.

[0092] The filling unit can have any volumetric capacity for receiving and containing fluid therein. For example, for any syringe 106 described herein, syringe 106 can include a range of volumetric capacities between a minimum filling volume of about 0 mL–5 L (such as about 0 mL to about 1 mL), 2 mL, 5 mL, 10 mL, 25 mL, 50 mL, 75 mL, 100 mL, 250 mL, 500 mL, 1 L, 2 L, 5 L or greater, and a maximum filling volume (e.g., the extreme longitudinal position of the plunger seal within the barrel 602).

[0093] As described herein, filling assembly 302 can be configured to fill multiple filling units, such as syringe 106, in parallel (e.g., simultaneously). Fluid can be dispensed to syringe 106 using a manifold system as described herein, which may include a main manifold 104 and multiple sub-manifolds 216, wherein each sub-manifold is fluidly connected to a subgroup of syringe 106.

[0094] Any number and combination of reservoirs 102, main manifold 104, sub-manifold 216, and / or syringes 106 can be used with filling assembly 302. In some cases, a single reservoir 102 may be used to supply fluid to both main manifold 104 and sub-manifold 216. In other embodiments, two or more reservoirs 102 are configured to supply fluid to main manifold 104. For example, each reservoir 102 may be configured to supply fluid to main manifold 104 via a corresponding reservoir fitting 204, intermediate fitting 205, filling assembly fitting 208, and corresponding connectors (e.g., 202, 203, 206), such that main manifold 104 may have a separate inlet point for fluid. Additionally or alternatively, two different intermediate fittings 205 from two or more corresponding reservoirs 102 may be fluidly combined, for example, using connectors as described herein, such that the combined intermediate fitting is then coupled to a filling assembly connector 206 having a combined flow from at least some of the reservoirs 102. Therefore, the ratio between the reservoirs and filling components can be 1:1, or there can be multiple filling components for each reservoir, or multiple reservoirs for each component. Furthermore, the system 10 can be used to simultaneously fill any number of reservoirs 102 connected to any number of components 302 (e.g., filling 10 times the batch of material from 10 reservoirs 102 into separate main manifolds 104 connected to the required number of subgroup components 402 and syringes 106 for each batch).

[0095] In some embodiments, the filling assembly 302 includes two or more separate manifold systems. For example, there may be two or more main manifolds 104, each fluidly connected to a corresponding number of sub-manifolds 216. In some embodiments, however, the two or more main manifolds 104 may be fluidly coupled to the same common sub-manifold 216. Figure 18 An example is illustrated in which subgroup component 402 can be directly fluidly coupled to a storage unit (not shown), eliminating the need for a main manifold.

[0096] As described herein, each submanifold 216 can be fluidly connected to a subgroup of filling units (e.g., syringe 106) via a corresponding number of filling unit fittings 304, thereby defining a subgroup assembly 402 (see, for example...). Figures 4-5 Any of the sub-manifolds 216 can also be fluidly connected via the sample fitting 306 to a sample syringe (which is the same as or substantially the same as syringe 106) (e.g., see...). Figures 4-5(402 in the document). Considering that multiple syringes 106 are filled in parallel, a sample syringe can be used to provide a representative sample of the fluid being dispensed into multiple syringes 106 (therefore the sample syringe will obtain the same batch and timing of the fluid to be dispensed into syringes 106). This can be advantageous compared to a sequential method of dispensing (e.g., filling) fluid into a filling unit (e.g., syringe 106), which may require a representative sample throughout the filling process to ensure that samples of fluid are obtained at different time points (because the fluid can change naturally or through external factors over time). Therefore, the systems and methods described herein can provide an efficient and effective means of obtaining a sample of fluid being filled into a filling unit, meeting industry requirements (e.g., pharmaceutical industry requirements), and / or minimizing the amount of fluid needed to meet sampling requirements. In some embodiments, a valve (see, for example, Figure 19 The 1902 in the sample line 306 may be arranged around the sample line 306 or elsewhere to control and / or regulate the fluid entering the sample filling unit (e.g., sample injector).

[0097] As described herein, filling component 302 may include other types of dispensing systems in addition to or in lieu of the manifold system described herein.

[0098] Figures 13A-13B Top and side views of the dispenser plate 1302 system are illustrated, respectively, in which openings 1304 are arranged in a grid, radial, star, or other pattern, with fluid originating from reservoir 102. In some embodiments, when not all openings 1304 are fluidly connected to their corresponding filling units (e.g., there are fewer filling units 106 requiring fluid filling than the openings in the dispenser plate), channel filler or void filler material 1306 may be provided.

[0099] Figure 14 The illustration shows a top view of an embodiment of a manifold, in which fittings and hose barbs are used to manufacture the molded manifold. Figure 15 The figure shows Figure 14 A side sectional view of an embodiment of the manifold. The figure illustrates the manifold as a matrix (all positions are connected to adjacent positions) rather than a row-based form (where each position is directly connected to only one other position within the same row). The figure also shows that the feed lines leading to the manifold are branched into multiple feed lines 1402 with different connection points within the manifold.

[0100] Another exemplary distribution system includes a manifold system, which may also be arranged in a grid, radial, star, or other pattern, wherein fluid originates from reservoir 102. The manifold system may have several connections and may be made from a number of internal components. To ensure the integrity of these components, the manifold may be cast into a resin or plastic overmolding.

[0101] Another exemplary distribution system may include a fitting manifold or distributor plate, wherein utilizing a tapered channel may be advantageous, such that the diameter of the channel at the source of reservoir 102 is larger than the diameter at the connection point to the filling unit. For the same volumetric flow rate from the source of reservoir 102, the larger diameter will result in a lower velocity.

[0102] In some embodiments, for any dispensing system used for the filling component 302 described herein, the dispensing system need not be symmetrical (e.g., if there are multiple sizes of syringes to be filled, the port allocation can be asymmetrical to match user needs).

[0103] For any dispensing system described herein, the manifold outlet may include a manifold port connector (e.g., a hose barb, Luer connection, threaded flange connection, needleless Luer port, or other type for connection to a fitting, tubing, or direct connection to a syringe barrel). These ports may be connected to the filling unit 106 using sterile disconnect fittings or devices (e.g., SmartSite™, NovaSeal™, Quickseal®, Clipster®, Biosealer®). Filling and sealing devices

[0104] As described herein, the filling system 10 may further include a filling and sealing device 108 configured to assist in the filling of fluid into and / or sealing of the filling unit 106 (e.g., syringe, bag, vial, bottle, container, etc.) to contain the fluid while preventing or reducing the risk of fluid contamination. The filling and sealing device 108 may be configured to support multiple sub-manifolds 216, as described herein, thereby enabling the parallel filling of multiple filling units 106. The filling and sealing device 108 may be further configured to decouple the filling unit 106 from the manifold system (or any other type of dispensing system described herein), such that the filling unit 106 can be configured for individual collection and dispensing.

[0105] For any embodiment of the filling and sealing device described or contemplated herein, the filling unit 106 may include any type for receiving and / or storing fluid, and may include a syringe, vial, bag, container, bottle, etc. Referring to the filling unit 106 as the syringe described herein is a non-limiting illustrative example for the filling unit.

[0106] Figure 7 An example of a filling and sealing device 108 is illustrated. Device 108 may include one or more beams 716 and an upper support 712, the beams 716 including a sealing portion 711. Device 108 may also include a lower support 714. The device may include a frame 718 that provides support and / or holds the sealing portion 711, upper support 712, lower support 714, or any combination thereof in place.

[0107] The device 108 may include any number of beams 716, such as about 1-100, 2-50, 5-25, 10-20, 1, 2, 3, 4, 5, 10, 15, 25, 35, 50, 100 or more beams. The beams 716 may be spaced apart so as to be configured to receive at least a portion of the syringe 106 and the filling unit tube 304 between the spacings of the beams 716. For example, the subgroup assembly 402 as described herein may be configured to be received at least partially within the spacing between adjacent beams 716.

[0108] Each beam 716 may include a first side 720 and a second side 722 opposite to the first side 720. Therefore, for an apparatus having multiple beams 716, the first side 720 of the beam 716 will face the second side 722 of the adjacent beam, and the syringe 106 and / or filling unit tubing 304 are arranged between these beams 716. The first sides 720 of any beam will be identical or substantially identical to each other, and the second sides 722 of any beam will be identical or substantially identical to each other.

[0109] Beam 716 and / or lower support 714 each extend laterally along a length substantially aligned with the length of sub-manifold 216 (when connected to device 108) (e.g., in Figure 3C (Extending in the first direction 308). See, for example. Figure 11 , Figure 11 The illustration shows a portion of a device 108 connected to a portion of the filling assembly 302, wherein a sub-manifold 216 extends along a length aligned or substantially aligned with the length of the beam 716. (See illustration for further details.) Figure 11 As depicted, subgroup components 402 (e.g., syringe 106 and filling unit fitting 304 connected to corresponding submanifolds 216) are configured to be arranged in the intervals between beams 716.

[0110] The frame 718 of device 108 may include a front wall extending longitudinally along the lateral ends of device 108 (see example...). Figure 10 (1002 in the original text) such that at least a portion of the upper support 712 and the sealing portion 711 extend along the length between the lateral ends of the frame 718. Therefore, the frame 718 can be configured to suspend at least a portion of the upper support 712 and the sealing portion 711 above the spacing 706 and / or at least a portion of the lower support 714.

[0111] Figure 10 The illustration shows a front perspective view of a portion of the device 108, indicating upper supports 712 for three adjacent beams 1004, 1006, and 1008. Thus, beams 716 (such as 1004, 1006, 1008, etc.) can define upper support assemblies via components of the respective upper supports 712 for each beam, wherein a frame 718 holds the beams together (e.g., via a front wall of a frame as described herein [see, for example, 1002]). A gap 708 between the upper supports 712 of any pair of beams can be configured to receive and / or support at least a portion of a corresponding sub-assembly 402. The front wall 1002 can define an opening to the gap 708 through which the sub-assembly 402 can be inserted between the pair of beams 716. For example, a syringe 106 is depicted arranged between beams 1006 and 1008. Furthermore, the upper support 712 may include a recess 704 extending along the length of the upper support (e.g., on either side of the beam). For example, the first syringe 106 is depicted as being removed around beam 1004 to illustrate a recess 704. The recess 704 may be configured to receive at least a portion of the finger flange 604 and / or at least a portion of the extension 607. For example, the extension 607 may be configured to slidably engage with the recess 704, such that a sub-group of syringes 106 (e.g., corresponding to sub-group assembly 402) may be configured to slidably engage with beams 716 by insertion into the gaps between beams 716 and to be supported via the interaction between the extension 607 of syringe 106 and the recess 704 of each of the pair of beams (e.g., 1004, 1006 and 1006, 1008).

[0112] Accordingly, the sub-assembly 402 may be aligned or substantially aligned with the beam 716. In some embodiments, one end of the recess 704 of each upper support 712 and / or one end of the alignment rod 404 (e.g., opposite the pull tab 406) may include a protrusion or stop to prevent the sub-assembly of the syringe 106 from sliding through the recess 704 of the pair of beams 716 and beyond the interval therebetween. In some embodiments, the protrusion or stop on the recess 704 and / or alignment rod 404 may be configured to align the locking portion 609 of the syringe 106 with the corresponding opening 906 and / or recess 908 on the lower support (as described herein), at least based on the positioning of the syringe sliding portion within the recess 704.

[0113] like Figure 11 As depicted herein, the five subgroups of syringe 106 are illustrated as being held by upper supports of opposing beams, wherein the barrels 602 of syringe 106 are arranged between gaps between upper supports 712 of adjacent beams 716. Furthermore, the bellows of each subgroup of syringe 106 is arranged within a gap 708 defined between upper and lower supports, wherein the gap may have a larger dimension (e.g., width) than the maximum dimension of the gap 708 between upper supports 712 of adjacent beams, and wherein the gap 708 may accommodate movement of the lower support 714 therein (as described herein). The gap may also be defined by the front wall of frame 718 (e.g., see 1002).

[0114] In some embodiments, the top of beam 716 may include a top surface that extends at least partially toward adjacent beams (e.g., see...). Figure 8A , Figure 11 (830 in the middle), so as to define the spacing between the top surfaces 830 (e.g., see 830). Figure 8A The interval (804 in the middle) is smaller than the interval between the upper supports 712 of the adjacent beams. This interval allows the sub-manifold to be supported by the top surface 830, and the sub-manifold can span a width greater than the interval (e.g., see...). Figure 11 (Sub-manifold 216 in the middle).

[0115] As described herein, device 108 may include a lower support 714 which may be arranged at least partially below or far from the upper support 712 and / or at least partially below or far from the interval defined between two adjacent beams (e.g., the interval between the upper supports 712 of two adjacent beams 716).

[0116] The lower support 714 can be configured to be movable relative to the upper support 712. For example, the lower support 714 can be configured to move longitudinally relative to the upper support (e.g., see...). Figure 9A(918 in the original text), for example, moving proximally and / or distally, wherein the upper support can be configured to remain stationary. The lower support 714 can be configured to move longitudinally via an actuator. For example, the lower support can be coupled to one or more linear actuators 710, which can be disposed below the lower support. The lower support 714 can be moved by any other device, including one or more actuators suspended from above, around the lateral side of, and / or below the lower support 714. The linear actuator can be hydraulically powered, pneumatically powered, electrically powered, manually powered (e.g., via an operator), or any combination thereof. The device 108 can also be coupled to the side panel 110 (e.g., see [link to device 108]). Figure 1 This can further facilitate longitudinal movement of the lower support 714. For example, the side panel 110 can be moved via a guide rail (e.g., see...). Figure 1 The lower support 714 (113) is coupled to the housing (e.g., the rear panel 111 of the housing), and the guide rail guides the longitudinal movement of the side panel 110. As described herein, one or more processors can be used to control the movement of the lower support 714.

[0117] In some embodiments, the lower support 714 may be configured to engage at least a portion of a sub-assembly of syringes 106, such that the lower support 714 is configured to move the plunger rod 1504 of each syringe 106 in the sub-assembly proximally and / or distally, thereby altering the filling volume of each syringe 106 (as described herein). Each lower support 714 may span a length generally parallel to the beam 716 (e.g., along...). Figure 3C The length of the first direction 308 shown. Figure 9A The diagram illustrates the connection between the filling assembly 302 and the lower support 714, with beam 716 and frame 718 removed from the illustration of device 108 for ease of reference. The lower support 714 can be supported on a lower support base 901 that spans beam 716 (e.g., in a direction transverse to 308). The lower support base 901 can be coupled to an actuator 710, as described herein, for moving the lower support 714.

[0118] Figures 9B-9D An example of the connection between syringe 106 and a given lower support 714 is illustrated. Syringe 106 may be connected to lower support 714 at a distal portion of syringe 106. For example, Figure 9C The illustration shows a lower support 714 without the depicted syringe 106, wherein the lower support 714 includes a lower support platform 904 having a locking tab 902 arranged around the platform 904. The locking tab 902 can be removably coupled to the platform 904. For example, regarding Figure 9DThe left-hand lower bracket illustration shows a lower bracket platform 904, where the locking tab 902 has been removed, and the right-hand lower bracket illustration shows the locking tab 902 in place. Platform 904 may include a groove 912 such that the locking tab 902 is configured to slidably engage with platform 904. (See reference...) Figure 9D The lower support on the left, where the locking tab has been removed, includes a platform 904 with a surface 910 configured to receive at least a portion of the locking tab 902 when it is received by the recess 912. The surface 910 may also include one or more recesses 908 arranged along the length of the lower support 714.

[0119] Regarding the connection of the lower support 714 to the subassembly of the syringe 106, the locking tab 902 arranged around the platform 904 includes one or more openings 906, wherein the openings 906 can be positioned or substantially aligned with the subassembly of the syringe 106 when the subassembly of the syringe 106 is connected to the upper support 712 as described herein. Figure 9E An example of a lower bracket 714 is illustrated, wherein the locking tab 902 includes a single opening 906. As illustrated, the opening 906 on the locking tab 902 includes a smaller portion 914 and a larger portion 916, wherein the larger portion 916 has a maximum dimension larger than the maximum dimension of the smaller portion 914. The maximum dimension can be a diameter, width, or any other dimensional measurement. The smaller portion 914 and the larger portion 916 can be open to each other. Figure 9E The diagram also illustrates that the platform surface 910 is located below the locking protrusion 902 and the corresponding opening 906, and the recess 908 is also shown. Figure 9E The example of the configuration of the opening 906 and the lower support shown in the figure can be applied to any lower support 714 with any number of openings 906 (e.g., with smaller portions and larger portions) having a similar configuration as described herein.

[0120] about Figures 9D-9E The locking tab 902 can be configured to move between a locked position and an unlocked position. In the unlocked position, the locking tab 902 can slidably engage with the platform 904 such that a larger portion 916 of one or more openings 906 is aligned or substantially aligned with one or more recesses 908 disposed around the surface 910. In the locked position, the locking tab 902 slides at least partially out of a recess 912 in the platform 904 such that a smaller portion 914 of one or more openings 906 is configured to align with one or more recesses 908. Figure 9E An example of the lower bracket 714 in the locked position is illustrated, wherein the first segment 914 is aligned or substantially aligned with the recess 908.

[0121] Regarding the connection of syringe 106 to the lower support 714, the distal portion of syringe 106 for the syringe subassembly (i.e., connected to a submanifold, for example, as described herein) is configured to align with corresponding openings 906 and recesses 908 (as described herein) when the syringe subassembly is slidably engaged with the upper support 712. The locking nut 610 and / or end cap 611 of each syringe may be configured to be inserted through the larger portion 916 of each corresponding opening 906 when the locking tab 902 is in the unlocked position, and further at least partially disposed within the corresponding recess 908 of the surface 910. For example, the larger portion 916 may have a maximum dimension (e.g., diameter, width, etc.) greater than the maximum dimension of the end cap 611 and / or locking nut 610.

[0122] Subsequently, moving the locking tab 902 to the locked position allows the smaller portion 914 of the opening 906 to slide around the locking nut 610 and / or the end cap 611, thereby securing the syringe 106 to the corresponding lower support. For example, the smaller portion 914 of the opening 906 can slide to at least partially surround the locking nut 610, while the end cap 611 can be at least partially disposed in the recess 908. The end cap 611 can have a maximum size that is larger than the maximum size of the smaller portion 914, thereby preventing the end cap 611 from passing through the smaller portion 914 and thus preventing or reducing the ability of the syringe to separate from the lower support 714.

[0123] Therefore, this connection between syringe 106 and lower support 714 allows the lower support to move the plunger rod 1504 proximally and distally along the longitudinal direction 1512 (e.g., via the connection between the lower support and the locking nut 610 and / or end cap 611 through the opening 906). For example, the lower support 714 can be configured to pull the plunger rod 1504 distally downward without separating the syringe 106 from the lower support 714. Furthermore, as described herein, the interaction between syringe 106 and upper support 712 and / or the interaction between sub-manifold 216 and the top of beam 716 (further described herein) provides sufficient fixation such that movement of the lower support 714 and plunger rod 1504 does not destabilize and / or disconnect the interaction between syringe 106 and beam 716, thereby preventing or reducing any interference with the fluid filling within syringe 106.

[0124] In some embodiments, additional or alternative configurations for attaching the syringe to the platform 904 of the lower support may be through other mechanical interactions (e.g., clamps, threads, positioning screws, clips), electromagnetic interactions, magnetic interactions, vacuum interactions, or any combination thereof.

[0125] The movement of the lower support can be controlled via one or more processors. One or more processors can be input with the size of the syringe 106, the desired filling volume, the maximum filling volume, the minimum filling volume, and the position of the plunger rod within the barrel 602 corresponding to each said filling volume. Thus, one or more processors can be configured to correlate the longitudinal position of the lower support with the filling volume of the syringe (e.g., based on the position of the plunger rod and plunger seal within each barrel 602). The processors can be configured to precisely control the movement of the lower support to maximize accuracy in obtaining the desired filling volume of fluid dispensed into the barrel of the syringe 106. For example, the longitudinal movement of the lower support can be controlled to 5 mm, 2 mm, 1 mm, 0.1 mm, 0.01 mm, or less. Therefore, assuming the plunger seal draws fluid into the syringe barrel, a precisely controlled amount of fluid can be dispensed into the syringe, and furthermore, the amount of fluid dispensed can be consistent across multiple syringes that are filling in substantially parallel.

[0126] As described herein, the filling and sealing device 108 can be further configured to seal the filling unit tubing 304 to contain fluid therein. This seal can maintain the separation of the fluid within the filling assembly 302 from the environment, and / or help i) prevent or reduce the risk of contamination of the fluid stored within the syringe (e.g., barrel 602), and / or ii) help prevent or reduce the risk of exposure of the fluid (which may be harmful) to the environment. The device 108 can also be configured to detach the syringe 106 from the manifold system (e.g., sub-manifold 216), thereby enabling the syringe 106 to be delivered detachably.

[0127] The sealing portion 711 of the device 108 can be configured to seal and / or separate the syringe 106. In some embodiments, the sealing portions 711 of adjacent beams 716 define regions 702 for enabling the syringe 106 to be sealed and / or separated. As described herein and in Figure 8B As depicted, for example, a filling unit tube 304 may be arranged between adjacent beams 716 in region 702. Thus, the syringe 106 can be sealed around its position on the filling unit tube 304. The filling unit tube 304 may also be cut to separate the syringe 106 from the manifold system (e.g., sub-manifold 216). In some embodiments, region 702 may be configured to simultaneously or substantially simultaneously seal and cut the filling unit tube 304 via corresponding sealing portions 711 of adjacent beams 716.

[0128] Reference Figure 8AEach sealing portion 711 of beam 716 may include two components, a first component 818 and a second component 820. The first component 818 may define a first profile (e.g., see 814), while the second component may define a second profile (e.g., see 816). In some embodiments, the first beam 716 (e.g., Figure 8A The first component 818 of (824) is configured to face the adjacent beam 716 (e.g., Figure 8A The second component 820 of the second component 822 moves such that at least a portion of the filling unit tubes 304 of the sub-assembly 402 arranged between and / or around the intervals of the two beams 822, 824 can be at least partially clamped together (e.g., the inner opposing walls of the filling unit tubes 304 are brought toward each other and can be in contact). In other embodiments, adjacent beams 716 (e.g., Figure 8A The first component 818 and the second component 820 of (822, 824) are both configured to move independently toward each other (e.g., Figure 8A (822), such that at least a portion of the filling unit tube 304 of the subgroup assembly 402 arranged between and / or around the interval of the two beams 822, 824 can be at least partially clamped together (e.g., the inner opposing walls of the filling unit tube 304 are brought toward each other and can contact each other).

[0129] Therefore, the first component 818 can be configured to move at least partially away from a portion of the second component 820 on the same beam (e.g., 824) and toward a second component 820 on an adjacent beam (e.g., 822) (and vice versa, wherein the second component can be configured to move at least partially away from a portion of the first component on the same beam toward a first component on an adjacent beam). Components 818 and 820 can be moved by an actuator, which can be a mechanical actuator and can be pneumatically, hydraulically, magnetically, and / or electrically actuated. For example, an electric actuator can be a piezoelectric actuator. A mechanical actuator can include hydraulic, magnetic, and / or pneumatic components.

[0130] The sealing portion 711 of each beam 716 may further be capable of sealing the filling unit tubing 304 for the syringe to provide a leak-proof or substantially leak-proof seal around a portion of the filling unit tubing 304. In some embodiments, the sealing portion 711 is configured to provide heat to the filling unit tubing 304 so that at least a portion of the filling unit tubing 304 can be sealed closed (or substantially sealed closed). The sealing portion 711 may also, or alternatively, be configured to seal the filling unit tubing 304 around the tubing using a metal crimp via ultrasonic tubing welding and / or via mechanical force tubing sealing.

[0131] Regarding the sealing (e.g., heat sealing) of the filler unit fitting 304 via heat, the first component 818 and / or the second component 820 of any given beam 716 can be configured to provide heat such that when at least a portion of the filler unit fitting 304 is clamped together (e.g., moving via the first component 818 of one beam toward the second component 820 of an adjacent beam, or vice versa), the heat allows the walls of the filler unit fitting 304 to at least partially mix and / or bond together. For example, the filler unit fitting 304 may comprise a plastic material (e.g., a thermoplastic elastomer material), such as, for example, PVC, C-Flex™, AdvantaFlex®, or rigid tubing [such as PVC (polyvinyl chloride), BS (acrylonitrile-butadiene-styrene), polypropylene (PP), acrylic (PMMA), etc.]. This material may begin to soften, melt at least in part due to exposure to heat and / or pressure (via the first component 818 and the second component 820), and / or acquire some viscosity when exposed to a certain temperature.

[0132] The sealing portion 711 can be heated by a recirculated temperature-regulating fluid arranged around the first component 818 and / or the second component 820, by electric heating (e.g., resistance heating or Peltier effect heating), any other type of heating, or any combination thereof. System 10 may include a source and / or prime mover that uses a recirculated fluid (e.g., heated oil, gas, other liquid). For example, the prime mover may include a pump and / or compressor to deliver the heated fluid (e.g., heated oil) to the sealing portion 711 of the plurality of beams 716.

[0133] The first component 818 and / or the second component 820 can be configured to reach temperatures from about 50°C to about 500°C. The sealing portion 711 for a given beam 716 may also include a temperature sensor to help reach the target temperature range, enabling, for example, controlled sealing and cutting of the filling unit fitting 304. If the temperature rises above a maximum limit, the temperature sensor may be further coupled to a switch to cut off heating. The switch may also cut off heating if a sensor malfunction is determined.

[0134] In some embodiments, the movement of the first component 818 and / or the second component 820 is configured to be controlled to sequentially move the first component toward an adjacent beam 716. For example, as described herein, the first component 818 may define a first profile 814, and the second component 820 may define a second profile 816. The first profile 814 may include a protrusion extending from the beam 716 (e.g., toward an adjacent beam). For example, the protrusion may extend relative to a baseline portion of the first profile (not shown on the first component, but equivalent to 810 on the second component 820). The protrusion of the first profile 814 may include a valley 812 extending a first distance relative to the baseline portion, and / or include a platform portion 808 extending a second distance relative to the valley 812 (e.g., the platform portion may be disposed along the valley 812).

[0135] Similarly, the second profile 816 may include a protrusion extending from the beam 716 (e.g., toward an adjacent beam). For example, the protrusion may extend relative to a baseline portion of the second profile (e.g., see 810). The protrusion of the second profile 816 may include a valley 804 extending a first distance relative to the baseline portion 810, and / or include a platform portion 806 extending a second distance relative to the valley 804 (e.g., the platform portion may be disposed along the valley 804).

[0136] Therefore, before the first component 818 and / or the second component 820 are moved toward each other, the interval between the platform portion 806 of the second profile 816 of the first beam 716 and the platform portion 808 of the first profile 814 of the adjacent beam can define a gap 803 therebetween, which can have a smaller size (e.g., width) than the gap 802 between the corresponding valley portions 804, 812 of the adjacent beams.

[0137] Accordingly, the first component 818 and / or the second component 820 can be configured to move to a first position to clamp (e.g., clamp) at least a portion of the filling unit tube 304 between the protrusions (e.g., 804, 806, 808, 812) of adjacent beams 716. The inner walls (e.g., the opposing wall portions of the tubes) of the filling unit tube 304 arranged between the platforms 806, 808 of the adjacent beams will be compressed more tightly together than between the corresponding valleys 804, 812 (due to the smaller spacing between the platforms 806, 808).

[0138] Subsequently, heat can be applied to one or both of the protrusions of the adjacent beams 716 to apply heat to the wall of the filling unit pipe 304, so as to allow the walls (e.g., the opposite walls of the pipe) to at least partially mix together (due to the reduced viscosity of the filling unit pipe material due to heating). In some embodiments, the protrusions of the adjacent beams comprise metallic material to increase the efficiency of heat transfer between the heating source (as described herein) and the filling unit pipe 304.

[0139] The pressure applied to the filling unit tube 304 between the first component 818 and the second component 820, combined with the applied heat, can allow for simultaneous or substantially simultaneous sealing and cutting of the filling unit tube. For example, when the filling unit tube 304 is heated (and thereby softens the walls of the tube 304, as described herein), the pressure applied to the filling unit tube 304 by the platform portions 806, 808 (see, for example...) Figure 8B The filling unit tube portion 826 in the middle can cause some of the filling unit tube wall material surrounding portion 826 to be pushed out toward the filling unit tube portions 828, 829 (towards and / or distally to the tube portion 826) at least between the valleys 804, 812. Therefore, tube portions 828, 829 may include additional tube material (e.g., thermoplastic material), while tube portion 826 may leave a thin layer or film of tube material 304.

[0140] The first component 818 and / or the second component 820 can then be configured to move further toward one or the other and / or increase the pressure between them, such that the filling unit fitting 304 is broken and / or cut at least at portion 826, thereby separating one portion (e.g., 828) of the filling unit fitting 304 from another portion (e.g., 829). Removing heat to the filling unit fitting 304, cutting the fitting 304, and / or removing the pressure applied to the fitting by the first component 818 and the second component 820 can enable the material of the fitting 304 to bond together around the fitting portions 828 and / or 829 (e.g., this can include hardening from a softened state), thereby providing a leak-proof or substantially leak-proof seal around it.

[0141] In some cases, bringing the two components 818, 820 close together through temperature, pressure and time may be sufficient to fuse the inner wall of the filling unit tube 304 in contact with the valley and to ensure that there is no material residue between the platforms, thereby cutting off the filling unit tube 304 while maintaining separation from the environment.

[0142] The fitting sections 828 and 829 may also include a more robust seal due to additional fitting material disposed therein (e.g., fitting material extending from fitting section 826). As described herein, the sealing and cutting of the filling unit fitting 304 may occur simultaneously or substantially simultaneously, and / or may occur at least partially sequentially, wherein there may be some partial overlap between the sealing and cutting.

[0143] The movement of the first component 818 and / or the second component 820 can be controlled via one or more processors. Similarly, the application of heat, ultrasound, electromagnetic waves (e.g., radio waves or microwaves), current, alternating magnetic fields, and / or pressure can also be started and / or stopped via one or more processors. In some embodiments, the movement and / or sealing / cutting application of components 818, 820 are automatically controlled, manually controlled (e.g., via an operator), or both. In some embodiments, the first component 818 and / or the second component 820 can be further divided into one or more segments, wherein actuation of any one or more of these segments of the sealing portion can be selectively engaged manually or selectively engaged automatically (e.g., via the processors described herein). Each segment can correspond to one or more syringes and filling unit fittings 304 of a given subgroup assembly 402. Each segment of the first component 818 and / or the second component 820 can be individually movable, and / or heat can be individually applied to one or more segments, thereby allowing the sealing portion 711 of beam 716 to selectively seal and / or cut the syringe. For example, any one or more syringes of subgroup component 402 can be selectively sealed and / or cut.

[0144] As described herein, both the first component 818 and the second component 820 can also be movable. For example, in the case of using a larger filling unit (e.g., a larger syringe 106), adjacent beams 716 can be further separated from each other to accommodate the larger syringe size. Therefore, enabling both the first component 818 and the second component 820 to be movable for ease of operation can facilitate the sealing and / or cutting of the filling unit tubing 304, since the first component 818 does not have to extend the entire distance to cover the increased spacing between the beams 716. The second component 820 can be moved using any of the methods described herein for the first component 818 (e.g., an airbag, etc.).

[0145] Once the filling unit tube 304 of the syringe sub-assembly has been sealed and cut, the syringe corresponding to the sub-assembly assembly 402 can be removed from the device 108 by moving the locking tab 902 (of the lower support) to the unlocked position and / or by sliding the syringe sub-assembly out of the groove 704 of the upper support. The syringe can still be engaged with the alignment rod 404, thereby facilitating the collection and delivery of the syringe via the sub-assembly. Integrity testing components

[0146] System 10 may also include an integrity testing component configured to test the integrity of one or more components of the filling system 10. For example, the integrity testing component may be configured to test the integrity of the entire filling assembly 302. The integrity testing component may be able to test specific portions of the filling assembly, such as only filling unit 106, filling unit 106 and sub-manifold 216, and / or only the manifold system. The integrity testing component may also be configured to test intermediate fitting 205 and / or any other flow path that the fluid can travel along.

[0147] In some embodiments, testing integrity may include testing for any leaks in the filling system 10. Such leaks may be potential contamination entry points into the system 10 and / or fluid leakage from the system 10. Integrity testing components may use pressure testing to detect any leaks in component 302 and its fluidly connected parts (including, but not limited to, connectors 202, 203; reservoir fittings 204; and the reservoir 102 itself). For example, integrity testing components may be configured to pressurize the system or a portion thereof and monitor any fluctuations in pressure within the system (e.g., pressure loss).

[0148] Figures 12A-12B The illustration shows an example of an integrity testing component configured to test a system (e.g., system 10). Figure 12A As illustrated, the integrity testing assembly may include a test facility 1204 and an integrity testing fitting 1202. The integrity testing fitting 1202 may be configured to be fluidly connected to system 10 to pressurize system 10, for example, using gas. System 10 may be configured to isolate different components of the system to allow integrity testing to be performed on specific sections. For example, a filler assembly 302 may be used via connector 206 and / or mechanical clamps (not shown) or other isolation devices to provide an isolated filler assembly 302 that can be coupled to integrity testing fitting 1202 to allow pressurization and testing. Similarly, an intermediate fitting 205 may be isolated via connector 203 and / or clamps (e.g., if it is connected to a filler assembly) to allow integrity testing of the intermediate fitting via its connection to integrity testing fitting 1202.

[0149] about Figure 12BThe integrity testing facility 1204 may include a compressed gas manifold 1206 configured to receive compressed gas from a gas supply 1210. The compressed gas may pass through a first regulator and filter 1208 before entering the gas manifold 1206. The gas may then flow to an integrity testing regulator and filter 1212, which is configured to reduce the pressure used for integrity testing as needed. A gas supply valve 1214 may be present to start and / or stop pressurization of the system 10 or its components. The integrity testing facility 1204 may also include a pressure sensor 1216, a flow meter 1218, a gas sniffer (e.g., if helium is used), other types of leak detection methods, or any combination thereof, to determine whether a leak exists in the system 10.

[0150] Integrity testing facility 1204 may further communicate with one or more processors 1220 configured to initiate / stop pressurization, monitor system 10 during integrity testing, and / or provide an alarm if a leak is detected. In some embodiments, where one or more filling assemblies having system 10 are present and / or multiple integrity testing fittings for different parts of system 10 are present, gas manifold 1206 may be configured to provide separate connections to said different integrity testing fittings (each including a regulator, supply valve, and / or detection device (as described herein)).

[0151] Integrity testing facility 1204 is illustrated together (e.g., Figure 12A (below the filling component 302 in the test facility), but the different components of the test facility 1204 can be arranged in any position and spaced apart from each other.

[0152] The integrity testing assembly can use any gas used to perform the test, such as air, nitrogen, helium, etc. The integrity testing assembly can pressurize the system from about 1 millibar (mbar) to about 5 bar. The integrity test may further utilize one or more filters to help ensure that the gas used to test system 10 is sterile or substantially sterile, and / or to help prevent or reduce the risk of contamination of assembly 302 and fluid connection by the gas. Additional optional components of the system

[0153] In some embodiments, it is required that the fluid be maintained at a certain temperature. Therefore, the system can be configured to include temperature control components to help maintain the fluid at a specific temperature. For example, a enclosure can be added to areas requiring temperature control, such as reservoir 102, manifold systems, and / or syringe 106, etc. In some embodiments, the entire enclosure (e.g., 112, 114, etc.) can be under temperature control. The temperature control components may include a temperature sensor configured to measure the temperature within a given area (as described herein) and provide feedback to a control system, which may include one or more processors. Heat pumps, temperature control units, Pelletier systems, and / or other devices for temperature control can be used to provide a regulated temperature, which can be combined with a fan for circulation within the temperature-controlled enclosure to help properly control the temperature. Temperature information is also available in automated history recorders and batch reports.

[0154] In some embodiments, the fluid may include an oxygen-sensitive liquid, and thus it is essential to adequately prevent the fluid from being exposed to oxygen (which may be present within the filling assembly, etc.). Therefore, the system can be configured to provide the ability to generate an inert gas cover for the desired effect of preventing oxygen exposure to the fluid. The system may have integrity testing capabilities (e.g., see...). Figures 12A-12B The filling component can be configured to connect to an integrity testing facility, and the system can also be configured to connect to a vacuum pump, a vacuum chamber, an inert gas source (e.g., a bottle or as a distributed utility system), and / or an additional gas control valve that allows for the timing control of integrity testing connections on syringes between vacuum cycles and the purging of the covering gas source.

[0155] For example, an example sequence includes: 1) applying an inert purge gas and having a plunger seal in the syringe aspirated to its maximum fill volume; 2) cutting off the purge gas and applying a vacuum to the syringe; 3) having a plunger rod pushed proximally in the syringe such that the plunger seal is positioned corresponding to the minimum fill volume in the cartridge (e.g., empty or substantially empty); 4) steps 1, 2, and 3 are performed multiple times in this sequence as needed to achieve the desired purity of the covering gas.

[0156] Furthermore, a vacuum may not be necessary to achieve the desired concentration. In this case, purging of the purge gas can be performed via a syringe cycle, where the exhaust is applied to the atmosphere rather than a vacuum. Once the syringe has been purged with the target covering gas and filled, it can be filled with fluid according to any of the methods described herein.

[0157] Regarding the overview of system 10, the fluid to be dispensed into the syringe may be located in reservoir 102, which may be suspended above all other components of the system. Reservoir fitting 204 may be suspended below reservoir 102, exiting from the lowest point of reservoir 102 (as necessary to enable extraction of all solutions). Reservoir fitting 204 may be aseptically connected to filling assembly fitting 208. Filling assembly 302 may include main manifold 104, one or more sub-manifolds 216, multiple syringes 106, and / or fittings connecting the components of the filling assembly together.

[0158] System 10 may also include a filling and sealing device 108, which may include a beam 716 having a fixed upper support 712 and a sealing portion 711, and the device also includes a movable lower support 714. The upper support 712 may be configured to remain stationary and hold the body of the syringe (e.g., the barrel), wherein the lower support is configured to be movable (e.g., longitudinally between a proximal and distal direction), wherein the lower support is configured to move all or part of the syringe that allows a change in the volume of the syringe (e.g., the barrel 602 or the tubular portion of the syringe will be held by the upper support 712, while the plunger is movably coupled to the movable lower support 714). The syringe being at a low point (e.g., relative to the manifold and / or reservoir) helps to facilitate the elimination of entrained gas by density (i.e., air bubbles in the assembly during infusion will float to the top and be trapped in the reservoir).

[0159] An example of the system housing (e.g., 111, 112, 114) may include casters for mobility on the floor. Alternatives could make it anchored to the floor, placed on top of a workbench, attached to a larger production slide, or suspended from the ceiling. The housing would have a filling assembly mounted thereon, thereby holding a stationary upper support, and a linear actuator connected to a movable lower support. By swishing the lower support (e.g., moving the movable support up and down), the device causes swishing of the syringe, and thus can cause a change in the internal volume of the syringe (e.g., the filling volume, as described herein). This change in the internal volume of the syringe can be used to generate the power to draw fluid from the reservoir through the manifold system and to each syringe. To draw fluid into the syringe, the filling volume within the syringe barrel can be increased (e.g., the lower support and / or a portion of the plunger rod moves away from the upper support). To expel fluid from the syringe barrel, the filling volume decreases (i.e., the lower support and / or a portion of the plunger rod moves closer to the upper support).

[0160] The system is designed and implemented in such a way that it can be achieved without a cleanroom, while ensuring that no contamination occurs. method

[0161] In some respects, this document describes example methods for injecting fluid into a filling unit using the system described herein. The order of the methods is described herein in a non-limiting order and may be performed in any order relative to each other.

[0162] In some embodiments, one or more filling units 106 are configured to draw fluid from one or more fluid sources (e.g., one or more reservoirs 102), wherein the fluid can be drawn into the one or more filling units in parallel. As described herein, the filling unit may include a syringe, vial, bottle, bag, container, etc. As an exemplary embodiment of the filling unit being a syringe, one or more filling units 106 may be configured to draw fluid (e.g., into the barrel 602) from one or more fluid sources (e.g., one or more reservoirs 102). One or more syringes 106 may include a plurality of syringes 106 configured to draw fluid in parallel (e.g., simultaneously). The plurality of syringes 106 may include one or more subgroups of syringes, as described herein (e.g., a plurality of syringes aligned with and fluidly coupled to corresponding submanifolds 216). Fluid may be drawn into the syringe (e.g., into the barrel) at least partially by gravity, by at least a partial vacuum pulled within the barrel 602 of these syringes, or both.

[0163] In some embodiments, the method further includes fluidly connecting one or more subgroup components 402 (e.g., see...). Figure 4 In some cases, the syringe subassemblies are provided already connected to the corresponding submanifold 216 (e.g., Figure 5 The method may also include connecting each sub-assembly of the syringe (e.g., connected to a corresponding sub-manifold 216) to the filling and sealing device 108 via the upper support 712, as described herein. For example, each sub-assembly of the syringe may slidably engage with the upper support recess 704. In some cases, the corresponding sub-manifold 216 of each sub-assembly may be arranged around the end cap 611 of the beam 716 and at least partially supported (e.g., see...). Figure 11 ).

[0164] The method may also include connecting one or more main manifolds 104 to corresponding sub-manifolds 216 (e.g., sub-manifolds 216 that may or may not be connected to the filling and sealing device 108). For example, main manifold fitting 210 may be connected to sub-manifold fitting 204 using one or more connectors 211, 212 as described herein.

[0165] The method may also include, for example, engaging the lower support 714 with the syringe 106 (e.g., a corresponding lower support 714 for a subgroup of syringes) via a locking nut 610, an end cap 611, and / or a locking tab 902 as described herein. In some embodiments, the lower support 714 may be raised, and / or its longitudinal position may be adjusted to be configured to engage with the syringe. The method may also include, once the corresponding lower support is engaged with the syringe 106, moving the locking tab (e.g., 902) to a locking configuration, thereby securing the syringe (e.g., a subgroup of syringes) to the corresponding lower support.

[0166] The method may also include fluidly connecting one or more main manifolds 104 to one or more fluid sources (e.g., one or more reservoirs 102). This may include connecting the reservoir fitting 204 to the filling assembly fitting 208 via one or more connectors 202. In some cases, an intermediate fitting 205 may be used to fluidly connect the reservoir fitting 204 to the filling assembly fitting 208, wherein the intermediate fitting may include one or more connectors 203.

[0167] In some embodiments, the method may further include performing an integrity test on the system or at least a portion thereof. For example, the method may include performing an integrity test on the filling assembly 302 or at least a portion thereof. The method may include fluidly connecting the integrity test fitting 1202 to the main manifold 104 via a substantially leak-free and substantially sterile connection to enable testing of the filling assembly 302 (or at least a portion thereof). When performing the integrity test, the filling assembly may be isolated from the reservoir, reservoir fittings, and / or intermediate fittings.

[0168] Integrity testing can be performed by opening supply valve 1214 and monitoring pressure (e.g., via pressure sensor 1216). During initial pressurization, the reading of pressure sensor 1216 will be below the set point of regulator 1212. For example, a filling manifold, associated tubing, and syringe barrel are fluidly connected by pressurizing gas. Once the system (e.g., the filling assembly) has reached the regulator set point (e.g., pressure), the gas supply will be maintained (e.g., within the filling assembly) for a predetermined period of time to allow the material to reach equilibrium, which may exhibit minor variations due to its inherent elasticity and temperature changes in the gas due to expansion. After the predetermined period, supply valve 1214 is closed, and pressure decay is monitored. The integrity testing assembly can be pressurized using any gas (e.g., clean compressed air, nitrogen, helium, etc.).

[0169] In addition to or alternatively to having a gas supply, if the filling units 106 are syringes, they can be swung to their fully extended position to draw air in from the open vent, then the vent is closed and the syringe is compressed. This generates a higher pressure through which integrity can be monitored by pressure decay.

[0170] For the syringe filling unit, integrity testing may initially involve inserting the plunger rod 1504 (e.g., the plunger rod 1504 of each barrel of the syringe 106 included in the filling assembly 302) into the maximum position (such as a first position) within the barrel 602 of the syringe 106, such that the filling volume is a minimum or small amount (e.g., the plunger seal 1502 is positioned at its nearest side within the barrel 602). The plunger rod position may be moved to the first position via the lower support 714, as described herein. Prior to performing a leak test, the pressurized filling assembly 302 may be allowed to stabilize, which can be in any manner described herein. For example, leak testing may include monitoring pressure decay, monitoring supply flow rate, monitoring via a gas sniffer, monitoring for any bubbles, or any combination thereof.

[0171] If a pressure decay test is used, a pressure sensor 1216 downstream of the supply valve 1214 can measure the supplied pressure. For example, after a stabilization period, the supply valve 1214 can be closed, trapping pressure within the filling assembly, wherein the pressure sensor 1216 can be used to measure the pressure decay over a period of time, and wherein predetermined parameters for acceptable pressure decay can determine whether the integrity test passes or fails, and if it passes, the assembly is intact.

[0172] If a gas sniffer (e.g., a helium sniffer) is used for testing, pressurized gas can be introduced into the filling assembly 302, as described for a pressure decay test, and whereby, after stabilization, a gas (e.g., helium or other gas) sniffing instrument can be used to measure the area around the filling assembly, and if no detection occurs, the assembly is intact.

[0173] If a bubble test is used, pressurized gas can be introduced into the filling assembly, as described for a pressure decay test, where a soap solution can be applied or at least a portion of the filling assembly can be held underwater. The absence of bubble formation indicates that the assembly is intact.

[0174] If a flow rate test is used, pressurized gas can be introduced into the filling assembly, as described for a pressure decay test, wherein the gas supply is maintained while the gas flow rate into the system is monitored by flow meter 1218. Predetermined parameters of acceptable flow rate after a defined time and / or within a defined time period can be used to determine whether the integrity test has passed or failed, thus indicating whether the assembly is intact.

[0175] Regarding integrity testing, failures may require obtaining new populated components.

[0176] If the filling unit is a syringe, the method for performing an integrity test on the filling assembly may include testing the syringe 106 with the corresponding plunger rod 1504 in multiple positions to ensure the integrity of the syringe throughout its stroke. For example, if the integrity test is passed with the plunger rod in a fully compressed first position (as described herein), the lower support 714 may move the plunger rod distally to move the plunger seal to a second position, which may be associated with a target filling volume within the barrel 602. Another integrity test (pressurized filling assembly and leak detection) may be performed as described herein. If the integrity test passes at the second position, the lower support 714 may again lower the plunger rod 1504 to the maximum filling volume associated with a third position (e.g., the plunger rod maximally extended out of the barrel 602), and another integrity test may be performed.

[0177] The method for performing an integrity test may include stroking the syringe at one or two of the three locations. In other embodiments, the integrity test may include more than three locations, which may or may not include any of the first or second locations. In additional embodiments, the integrity test may include stroking the syringe to full extension and using slow compression of the syringe to build pressure in the component, such that the pressure trend can be compared with a known trend corresponding to positive integrity.

[0178] The method may also include performing an integrity test on reservoir fitting 204 or at least a portion thereof, intermediate fitting 205, filling component fitting 208, any connectors 202, 203, 206, 211, 212, or any combination thereof. The integrity test fitting 1202 may be fluidly connected to a connector (e.g., 202, 203, or 202, 206), or fluidly connected to either reservoir fitting 204 or intermediate fitting 205 (if present), or fluidly connected to filling component fitting 208. Fluid connection of the integrity test fitting 1202 may be achieved via hose barbs, threaded fittings, quick-connects, aseptic connections, aseptic tube welding, and / or using connectors as described herein. At the start of the integrity test, regulated compressed gas may have an open flow path to the reservoir, intermediate fitting, and filling component fitting. One or more clamping clamps or other valves may be applied to the reservoir fitting upstream of the integrity test fitting connection before fluidly connecting the integrity test fitting. Another clamping fixture can be applied downstream of the integrity test connection to the filling assembly fitting. With the aseptic operation connection area sealed by the clamp, the integrity test tubing can be connected to the system. For example, the connection from reservoir 102 to manifold assembly 302 can include welding using aseptic fittings: Terumo BCT's SCD 11B, GE Wave's aseptic fitting welder, Vante® 3960 aseptic fitting welder, Sartorius's Bioweller® TC; or aseptic operation connectors (Luer Lock, SmartSite™, AseptiQuik™). After connecting the integrity test fitting 1202, integrity testing can be prepared to be performed on the welded or aseptic operation connection (as described herein, similar to the filling assembly). After the integrity test, the clamping fixture and other fittings can be removed to allow an open flow path from reservoir 102 to syringe 106.

[0179] As described herein, the method may include filling syringe 106 with fluid, which may be parallel and filled to a desired filling volume (which may be related to a target filling volume in the syringe barrel). The fluid in the filling assembly may contain air or other gases (e.g., pressure test gas if an integrity test is performed on the filling assembly). Therefore, a degassing process may be performed before filling syringe 106 with fluid to help reduce or eliminate the amount of gas in the fluid to be injected into syringe 106. The degassing process may be performed by performing multiple cycles of filling and emptying (e.g., for a syringe with a plunger rod that is being swung, but this may include any other type of filling unit 106 described herein). Since syringe 106 (e.g., barrel 602) may be vertically oriented or substantially vertically oriented, with the proximal end of the syringe (e.g., the proximal end of barrel 602) pointing substantially upward, gas in the fluid (e.g., the fluid injected into the barrel) may naturally rise to the proximal end of the syringe barrel. Alternatively, in the case where filling unit 106 corresponds to a bag, the area surrounding the bag may have been evacuated, causing the bag to expand and draw in the fluid to be filled. Gas from the manifold is drawn into the bag before the fluid from the reservoir, and the gas rises to the top of the bag. By pressurizing the area surrounding the bag, the gas at the top is expelled from the bag, and then material is filled into it. At the reservoir, the material expelled from the bag (first gas, then fluid) is separated by buoyancy, such that when the bag is refilled (e.g., by creating a vacuum in the area surrounding the bag), it draws only fluid into the fluid filling assembly. Similarly, each time the syringe is filled (e.g., the cartridge is filled), any residual gas can float to the top of the syringe (e.g., the cartridge), and therefore the ejection of fluid can also expel residual gas from the syringe and / or from the filling assembly and / or into the reservoir. For example, once the reservoir is in fluid communication with the syringe 106 (via an open flow path), the lower support 714 can draw the maximum amount of fluid into the syringe by extending the plunger rod distally to its maximum position outside the barrel 602 (thereby creating at least a partial vacuum inside the barrel to at least partially aid in fluid aspiration) (such that the plunger seal 1502 corresponds to the position of maximum filling volume within the barrel). The fluid can preferentially flow below the gas in the syringe. The lower support 714 can then move the plunger rod proximally to its maximum position within the barrel 602 (such that the plunger seal 1502 corresponds to the position of minimum filling volume within the barrel), thereby expelling most of the fluid from the syringe 106.

[0180] This stroke, involving the movement of the plunger rod from the lower support to achieve maximum and minimum filling volumes, can be performed once or multiple times. This can cause air bubbles to float to the top and / or toward the reservoir, and thus away from the fluid near and / or adjacent to the syringe. Multiple cycles can be used to reduce the probability of stubborn air bubbles. Alternatively or additionally, other methods for degassing, such as vibration, shock, sound waves, and / or other physical mechanisms, can be used to release air bubbles that adhere to the surface via surface tension. For example, a vibration mechanism can be added to the device that allows the syringe to be shaken to remove air bubbles that may be stuck due to surface tension. Thus, the fluid can be completely degassed and mixed with little or no fluid loss.

[0181] The method may also include using a lower support to move (e.g., slide) the plunger rod to position the plunger seal at a desired or target filling volume, wherein the desired or target amount of fluid is aspirated into the syringe (e.g., barrel 602). As described herein, one or more processors may be used to control the movement of the lower support. The movement of the lower support may be controllable for precise movement, with an accuracy such as, for example, within 2 ml, 1 ml, 0.1 ml, 0.01 ml, 0.001 ml, or less. In some embodiments, the lower support 714 may be detachably movable such that only a specified syringe is filled with fluid at a given time.

[0182] In some embodiments, there may be situations where the amount of fluid in the reservoir is less than the sum of the target filling volume (e.g., target / desired filling volume) in the syringes. In such cases, no syringes may be filled. Disabling one or more syringes can be accomplished by i) syringe separation, ii) independent actuation of a specific syringe, iii) bypass valves, iv) specifying individual regions of the syringes for filling, v) plunger shaft penetration, or vi) any combination thereof. Disconnection methods include those described herein (e.g., see...). Figures 8A-8B Sealing and / or cutting methods (e.g., cutting syringe tubing for any number of syringes) can be used, whereby the syringes can be disconnected from the manifold system without compromising the sterility of the manifold. For example, the sealing portion of a selected beam can be activated (i.e., not all sealing portions of all beams need to be activated simultaneously). Since disconnected syringes can be avoided, the sealing tubing connected to the inlet / outlet ports of the syringes can then be removed to prevent pressure or vacuum from being created during syringe sequencing. Other means of preventing pressure or vacuum from being created for those unfilled syringes may include disconnecting the plunger rod or creating alternative venting in the syringe barrel or stopper, such as perforation.

[0183] Independent actuation may include providing an independent linear actuator for each lower support (and thus corresponding to a specific subgroup of syringes) and / or for each syringe (e.g., a single syringe within a subgroup), wherein any one or a specific number of syringes may have an independently controlled plunger rod. Further actuators may be disabled (e.g., mechanically and / or by software of a processor communicating with the actuators), such that a particular syringe is not filled.

[0184] The bypass may include a three-way valve that can be designed between the manifold system and a specific syringe, such that for syringes not intended for filling, the valve will be set to the closed position of the manifold system, but the syringe may be vented.

[0185] The syringe region may include cases where the syringe array can be configured with multiple regions, wherein the lower support can be divided into independently actuated sub-segments. These regions can be programmed to be non-actuated (and therefore not filled). Additionally, these regions can be used for alternative fill sizes (i.e., for each fill, multiple fill cell geometries may be desired, each requiring different stroke and fill targets [e.g., different fill volumes] to function correctly).

[0186] The plunger shaft through-hole may include a lower support for sequencing the plunger, which does not need to be a solid design. For example, the lower support may have a through-hole (e.g., through the platform 904 and / or concave surface 908) that can engage or disengage (e.g., by means of threaded engagement, quarter-turn release, or other means by which the distal portion of the syringe [as described herein] is attached to the lower support, such that when engaged, the plunger rod moves with the lower support, but when disengaged, the lower support moves, but the plunger rod may pass through the plane of the base of the lower support and remain stationary).

[0187] After filling the syringe, the method may optionally include prompting the operator to visually inspect the syringe to ensure there are no problems. This visual inspection can be facilitated by an add-on including a camera system capable of identifying the liquid level and fill volume. Furthermore, holding mechanisms for the lower and upper supports may optionally be mounted on the load unit, allowing for weight balancing or zeroing upon completion of air purging, and enabling the measurement of the total weight of the solution filled into the syringe upon completion of the stroke to the desired fill volume. This weight measurement can be checked to see if there is a match with the expected fill weight within acceptable measurement error and fill variability tolerances.

[0188] The method may further include: sealing and optionally cutting the syringe tubing once the syringe is filled to the target filling volume. The sealing portion 711 of beam 716 can compress the syringe tubing 304 (e.g., clamp the inner wall of tubing 304), as described herein. For example, a first component 818 for the first beam and / or a second component 820 for the adjacent beam (e.g., as described herein). Figures 8A-8B As described in [the text], it can begin to move toward another, thereby clamping a portion of the syringe tubing for the syringe sub-assembly (e.g., the inner walls of a given syringe tubing are clamped together). As in [the text] Figures 8A-8B As described herein, each of the first component 818 and the second component 820 may have corresponding profiles 814, 816 defining corresponding platform portions 806, 808 and corresponding valley portions 804, 812. An energy input (e.g., heating element, hot oil recirculation, ultrasonic or radio frequency energy, as described herein) can then be used to at least partially melt or soften the compressed (e.g., clamped) thermoplastic syringe tubing 304 to allow at least some of the tubing material (e.g., arranged between platform portions 806, 808) to flow out of the tubing portion 826, which may be done without cutting / shearing the tubing 304. After allowing flow to occur to a certain extent, material from the compression zones (e.g., the first portion of the fitting) is able to flow out between the compression zones, leaving only a thin film; the amount of energy and pressure used by the first component 818 and / or the second component 820 relative to each other is altered to allow sufficient flow and force to shear and cut the remaining film, thereby dividing the fitting 304 into two parts (e.g., 828, 829), and / or sealing the fitting portion around the cut location. This disconnects the syringes from the sub-manifold assembly (e.g., sub-assembly 402) into which they enter without compromising sterility. Sealing and cutting can be performed simultaneously or substantially simultaneously and / or at least partially sequentially.

[0189] In some cases, the syringe can be disconnected using thermoplastic elastomer tubing sealers (such as Biosaler® TC tubing sealers, Vante® 4600, Biosaler®, SEBRA® 2380, vascular sealers - MTBTS03) or by mechanical devices (such as NovaSeal™ cuffs and retractors), or alternatively by the sealing portion 711 of the device 108 as described in

[00109] .

[0190] The filling unit can then be removed from device 108. The embodiment described herein, referring to the syringe as filling unit 106, is a non-limiting example of the type of filling unit that can be used with the system 10, filling assembly 302, and / or sub-assembly assembly 402 described herein. As described herein, the filling unit used with the system 10, filling assembly 302, and / or sub-assembly assembly 402 described herein can be any one or more syringes, bags, vials, bottles, containers, etc.

[0191] The method may also include obtaining one or more samples of the fluid. For example, after the syringes have been filled (and / or separated from the submanifold), there may be residual fluid in the manifold system and / or reservoir (e.g., the amount of fluid in the reservoir may be greater than the sum of the filling volumes in the syringes to be filled). This residual fluid may represent the entire batch used to fill the syringes because the syringes are filled in parallel (e.g., unlike sequential filling over time, where fluid properties and / or conditions may vary between the first syringe being filled and the last syringe being filled). The remainder can be collected for QC sampling by attaching an additional sample container to the submanifold, or by using a tubing stripper to collect the material into a large bag (e.g., a reservoir) and providing it to QC with a large sample for aliquoting. The manifold may be designed to have side ports (see, for example...). Figure 19 This allows the remaining solution to be aspirated into a sample container (which could also be another type of collection container, such as a vial, bag, can, syringe, etc.) upon completion of filling, thus eliminating fluid waste or loss. Furthermore, the integrity testing component can be used to add gas to the filling component for the purpose of expelling any remaining solution. In some cases, collection for sampling is performed simultaneously with the filling of syringe 106 (e.g., via sample fitting 306).

[0192] In some embodiments, a post-use integrity test is performed on the component to detect any integrity test failures due to the sealing / cutting system. Since the seal on the filling unit 106 side (e.g., 829) of the manifold is symmetrical to the manifold side (e.g., 828), post-use integrity testing of a manifold with complementary sealing / cutting of the filling units can avoid the need to perform integrity testing on all filling units after manufacturing.

[0193] In some embodiments, the method may further include sterilizing the fluid before it is dispensed into the syringe. For example, in some cases, the fluid in the reservoir has been purified (e.g., sterilized). However, in some cases where the fluid has not been purified, the method may also include purifying the fluid. For example, the method may include sterilizing the fluid by means of filtration. Filtration may not be necessary for sterilization purposes, but may affect other qualities such as homogeneity, removal of contaminants, uniformity, catalytic conversion, etc. In such cases, the system may also include a pump, a filter or other flow unit, auxiliary lines for rinsing the solution, and an exhaust filter and / or integrity test connection.

[0194] Example methods for sterilizing fluids may include: 1) installing a sterilization and filling assembly 2016 into a device including a connector 2006; 2) passing a tubing through a pump 2008; 3) connecting a flushing solution 2004; 4) flushing a filter 2011 and wetting a membrane using the pump 2008 while transferring the solution to a flushing container 2012; 5) stopping the pump 2008 when a sufficient amount has passed through the filter 2011; 6) disconnecting the flushing solution 2004 from the assembly via the connector 2006 (e.g., including isolating it from the pump 2008); 7) using the pump 2008 to deliver any remaining flushing solution. 8) Ensure no flushing solution remains in the pipeline; 9) Connect the integrity test fitting 1202 to the exhaust filter 2010 or integrity test connection; 10) Perform the integrity test; 11) Disconnect the integrity test fitting 1202; 12) Close / clamp the exhaust filter 2010 or integrity test connection and flush the container; 13) Connect the unfiltered reservoir 2002 to the assembly 2016 (e.g., connected to the pump 2008); 14) Use the pump 2008 to pass the unfiltered fluid through the filter 2011 and into the reservoir 102; 15) Perform syringe filling as described herein.

[0195] Aseptic filtration is typically a critical operation. It is common to have two filters in series, and to test the integrity of one or both (individually or in series). Examples of system operations

[0196] Figure 21The diagram illustrates a flowchart outlining a process for using a filling system (e.g., 10 as described herein) according to some embodiments. The process begins (at step 2100). At this stage, the filling system is idle and no assembly or product is installed. In some embodiments, the user logs in to the system (at step 2102). This can be used for verification purposes. According to some embodiments, the user selects a formulation (at step 2104), for example, for the fluid to be dispensed within the filling unit described herein. The filling unit may be interchangeably referred to as a unit. The filling unit can be of any type described herein, including syringes, vials, bottles, containers, bags, etc. Various chemical combinations can be possible with the filling system, and the user can be able to select pre-formulated formulations for specific chemical components or customize the components if desired. Different formulations may need to be created for each container type (e.g., syringes, bags, vials, etc.) and each product type.

[0197] Next, the user can select how many filler units to fill (at step 2106). The filling system may include an array of filler units (e.g., syringe 106) connected to a dispensing system (e.g., a manifold system as described herein), each filler unit being configured to receive fluid (e.g., a formulation selected above). In some embodiments, the user can select the number of filler units to be filled, and only that number of filler points fluidly connected to the corresponding filler units will receive fluid (or will be shut off so that fluid does not leave from those filler points). By way of example, assuming the filling system supports a depth of ten filler units, the user can select the number of rows to obtain that number multiplied by the fluid in ten filler units.

[0198] In some embodiments, the system sends all movable items to their initial positions (at step 2108). This prepares the system for filling the container. According to some embodiments, the system displays confirmation of the layout (at step 2110). In the following... Figure 29 The confirmation of the layout step is described in further detail below. Following this step, the method continues as follows: Figure 22 The process is roughly outlined in the description.

[0199] Figure 22 The illustration is a continuation of a flowchart depicting an overview of a process for using a filling system according to some embodiments. In some embodiments, the method includes confirming when a component is installed (at step 2200). This confirmation can serve as a safety measure to ensure the filling system is ready to properly fill the container. According to some embodiments, the method includes installing a disposable manifold (at step 2202). This installation can follow the steps below. Figure 30 The additional steps are detailed in the method for receiving and preparing the filling system. The user can then confirm the installation (at step 2204).

[0200] In some embodiments, the method includes performing a distance measurement on the bottoming out of any existing plunger (at step 2206). The filling system can be operated by a vacuum. In a fully sealed system, a vacuum can be created between an existing reservoir (which contains the formulation) and the container to be filled (e.g., a filling unit as described herein). The formulation is aspirated into the container by moving the plunger, while preventing contaminants from entering the system. However, the filling system may need to know how far the plunger can move, and therefore this distance measurement step for the bottoming out of the plunger can be performed. (See below...) Figure 31 The section further details the range of contact for the plungers (multiple plungers). Following this step, the method continues as follows: Figure 23 The general overview process described in the document.

[0201] Figure 23 The illustration is a continuation of a flowchart depicting an overview of a process using a filling system according to some embodiments. In some embodiments, the method includes the filling system displaying "Ready to start integrity test?" (at step 2302). This step may be to inform the user that an integrity test is about to be performed, or to give the user the option to bypass the test. According to some embodiments, the user confirms that they and the system are ready to start the integrity test.

[0202] The filling system can then perform an integrity test (at step 2304). This initial integrity test can be applied to the flow path from the storage. Further integrity testing is described below. Figures 32-34 The details are as follows. After this step, the method continues as follows: Figure 24 The process is roughly outlined in the description.

[0203] Figure 24 The illustration continues with a flowchart outlining an overview of a process using a filling system according to some embodiments. In some embodiments, the method includes the filling system displaying "Integrity test passed. Clamp the inlet port and connect the product." (at step 2400). This conveys to the user that the filling system has passed the integrity test for the inlet port and indicates that it is ready for flow to a container (e.g., a filling unit as described herein). According to some embodiments, the user confirms the message (at step 2402).

[0204] The filling system can then perform an additional integrity test (at step 2404). This integrity test can be applied to the flow path to the container to be filled. This integrity test can be the same as the integrity test mentioned in step 2304 above, and therefore, this integrity test is further performed in the following... Figures 32 to 34 The details are as follows. After this step, the method continues as follows: Figure 25The process is roughly outlined in the description.

[0205] Figure 25 The illustration continues with a flowchart depicting an overview of a process using a filling system according to some embodiments. In some embodiments, the system performs degassing and filling (at step 2500). The degassing and filling process is described below. Figure 35 This will be further detailed below. Following this step, the method continues as follows: Figure 26 The process is roughly outlined in the description.

[0206] Figure 26 The diagram continues with a flowchart illustrating an overview of the process of using a filling system according to some embodiments. According to some embodiments, the system displays "Fill complete. Perform visual inspection." (at step 2600). The visual inspection process is described below. Figure 36 This will be further detailed below. Following this step, the method continues as follows: Figure 27 The general overview process described in the document.

[0207] Figure 27 The illustration continues with a flowchart outlining an overview of a process using a filling system according to some embodiments. The method may include sealing and disconnecting all units / containers (at step 2700). As detailed above, the filling system may heat-seal the container or a portion of the passageway to the container to prevent any chance of contamination of the container's contents. This sealing step may include cutting or otherwise disconnecting the container from the flow path to create individual disconnected containers filled with the selected formulation. This sealing and disconnecting step is described below. Figure 37 This will be further detailed below. Following this step, the method continues as follows: Figure 28 The process is roughly outlined in the description.

[0208] Figure 28 The illustration continues with a flowchart depicting an overview of the process of using the filling system according to some embodiments. In some embodiments, the system displays "Sequence complete. [XX] units filled, processing time [YY] minutes, alarm [alarm message array]" (at step 2800). [XX] may indicate the number of containers specified by the user in step 2106 above. [YY] may indicate the processing time from the start of using the filling system, the total time from the start of the integrity test to the completion of disconnecting the filled containers, or the total time for filling the containers themselves. The [alarm message array] may convey any relevant information to the user about the filling system or containers, or about the filling process. After this step, the process of using the filling system ends (at step 2802).

[0209] Figure 29The illustration shows a flowchart depicting a method for verifying the layout of a filling system according to some embodiments. After the system displays confirmation of the layout (at step 2110), the system may prompt the user to verify the layout (at step 2900). Verifying the layout may include the user interacting with a matrix (or array) of symbols indicating flow paths from the reservoir to the location used to fill the container. The user can select each flow path to be utilized (turning the symbol corresponding to that flow path green). Unused flow paths may remain red, or turn red when the user selects a corresponding symbol to deactivate a flow path. In additional or alternative embodiments, other colors may be used for activating or deactivating flow paths, and symbols indicating the corresponding state of the flow paths.

[0210] Figure 30 A flowchart illustrating a method for receiving and preparing a filling system according to some embodiments is shown. In some embodiments, the component arrives in the box (at step 3000). The component as described herein can be any part of the filling system (such as a separate manifold, etc.) or the complete filling system. The transport and receiving facility or personnel responsible for transport and receiving can then confirm that no damage has occurred in the component during transport, receive the component in the warehouse / storage facility, and update their inventory to indicate that delivery has arrived and it is available for use (at step 3002).

[0211] When assembly is required, the production department or the personnel responsible for production can notify the transport and receiving party (or other responsible party) of their need for units in the warehouse. The party can then remove the components from the box and update the inventory (at step 3004). The transport and receiving party (or other responsible party) can then transfer the components to the production party and perform sterilization of the outer packaging on the components (at step 3006).

[0212] The manufacturer can then record the component's serial number in the master boot record, remove the outer packaging and any shipping pads or supports, and then install the component into the filling system (when the component is part of the filling system, rather than as part of the complete filling system) (at step 3008). At this point, a disposable manifold is installed (at step 2202).

[0213] Figure 31 The illustration shows a flowchart depicting a method for ranging the plunger of a filling system according to some embodiments (as described in step 2206). In some embodiments, the user of the filling system sets the integrity test valve to vent (at step 3100). According to some embodiments, the system then compresses the syringes until a specific amount of force is encountered (at step 3102). The operator can then be prompted to verify that all syringes are fully compressed (at step 3104).

[0214] If all syringes are fully compressed, the operator can then be prompted to verify the stroke length (possibly in millimeters) for the type of syringe provided (at step 3106). If the operator verifies the stroke length for the syringe type, the method returns to the above... Figure 23 At step 2300, the system displays "Ready to start integrity test?".

[0215] If the operator does not verify that the correct stroke length is being displayed (at step 3106), the operator can be prompted to select a syringe type from the list of pre-programmed options (at step 3108). This causes the filling system to automatically update the stroke length based on the selected syringe type. The operator can then be prompted again to verify the stroke length for the selected syringe type (at step 3106), adding double verification to ensure the settings / parameters are correct.

[0216] If the operator does not verify that all syringes are fully compressed (at step 3104), the operator may be prompted to check the syringes and / or other components of the filling system for obstructions and proper installation (at step 3110). Once this check has been performed, the operator and / or the filling system can return the plunger to its loading position (at step 3112). The filling system will then then compress the syringes again until a specific amount of force is encountered (at step 3102).

[0217] The above steps can be used alternatively or additionally for other types of containers, such as bags or vials, where a plunger is used to fill the container. Additionally, steps in this flowchart can be included to ensure that all syringe (container) barrels are aligned and that the filling system accurately knows where the full compression limit of each syringe (container) is located. Based on the full compression limit (along the Z-axis), the system can invoke a variable of the syringe (container) body length to determine the Z-axis coordinates for the full extension stroke and the target filling stroke (i.e., the target displacement of the plunger to fill the syringe or container to the desired filling level).

[0218] Figure 32 The diagram illustrates a flowchart depicting a method for testing the integrity of a filling system according to some embodiments. When the filling system performs an integrity test (at step 2304), the system or operator can set the integrity test valve to supply gas (at step 3200). At this time, the operator can choose to perform a helium test (at step 3202) and / or a pressure decay test (at step 3204). The filling system can also automatically perform either a helium test (at step 3202) or a pressure decay test (at step 3204). The helium test is described below. Figure 33 Further details will be provided below. Figure 34The pressure decay test is described in further detail.

[0219] If the operator or filling system does not require either the helium test or the pressure decay test to be performed, the method may move to ensure that all locations have been tested and passed (at step 3206). Similarly, once the helium test and / or pressure test has been successfully passed, the method may move to ensure that all locations have been tested and passed (at step 3206).

[0220] If all positions are not tested or fail the test, the method may include moving the plunger to the next position (i.e., full compression, midpoint, target fill volume, full extension, etc.). The system may then perform the helium test (at step 3202) and / or the pressure decay test (at step 3204) again.

[0221] If all positions have been tested and passed, the operator or filling system can set the integrity valve to vent (at step 3210). In some embodiments, the plunger moves back to its fully compressed state (at step 3212). After this occurs, the method can proceed to degassing and filling the container (at step 2500), as described above. Figure 25 As described in detail in [the text].

[0222] During the first pass of these steps, the syringe (plunger) can be in its fully compressed position because the filling system's range is to find the plunger's bottoming position (as described above). Figure 31 (Detailed in the above). Assembly integrity testing (from the above) Figure 23 Step 2304 in the above) and the aseptic connection integrity test (from the above) Figure 24 Step 2404 in the text can be the same sequence of steps, but with different parameters for timeout and maximum pressure decay.

[0223] Figure 33 The diagram illustrates a flowchart depicting a method for performing a helium test according to some embodiments. In some embodiments, the method includes pressurizing the filling system to a set point (at step 3300). According to some embodiments, the set point is reached (at step 3302) and the pressure is maintained for a predetermined specified holding time (at step 3304). The filling system can then begin a helium sniffing test to confirm when the test has been completed (at step 3306). If the helium sniffing test does not return a value higher than or equal to the nominal value (at step 3308), the method returns to confirm that all positions of the plunger have been tested and passed (as described above). Figure 32 (Step 3206).

[0224] If the helium sniffing test does indeed return a high value or outside the nominal value (at step 3308), the user is prompted to either stop the container filling because damage has been detected and contamination of the formulation may have occurred, or to retry the helium sniffing test (at step 3314). If the user chooses to stop the container filling, the program stops completely (at step 3316). If the user chooses to retry the helium sniffing test, the method returns to attempting to pressurize the filling system to the set point.

[0225] If the filling system attempts to pressurize to the set point (at step 3300) but does not complete the process before the timeout timer is reached (at step 3310), the filling system indicates to the user that such a timeout has been reached and instructs the user to check the connections between the components of the filling system (at step 3312).

[0226] Once the user receives the notification, they can be prompted to either stop filling the container due to the discovery of damage and potential contamination of the formulation, or retry pressurizing the filling system to the set point (at step 3314). If the user chooses to stop filling the container, the program stops completely (at step 3316). If the user chooses to retry pressurizing the filling system to the set point, the method returns to the starting point at step 3300.

[0227] Figure 34 The diagram illustrates a flowchart depicting a method for performing a pressure decay test according to some embodiments. In some embodiments, the method includes pressurizing the filling system to a set point (at step 3400). According to some embodiments, the set point is reached (at step 3402) and the pressure is maintained for a predetermined specified holding time (at step 3404). The filling system can then begin the pressure decay test (at step 3406). If no pressure decay value is exceeded (at step 3408), the method returns to confirming that all positions of the plunger have been tested and passed (as described above). Figure 32 (Step 3206).

[0228] If the pressure decay value is exceeded (at step 3408), the user is prompted to either stop the container filling due to detected damage and possible contamination of the formulation, or retry the pressure decay test (at step 3414). If the user chooses to stop the container filling, the program stops completely (at step 3416). If the user chooses to retry the helium sniffing test, the method returns to attempting to pressurize the filling system to the set point.

[0229] If the filling system attempts to pressurize to the set point (at step 3400) but does not complete the process before the timeout timer is reached (at step 3410), the filling system indicates to the user that such a timeout has been reached and instructs the user to check the connections between the components of the filling system (at step 3412).

[0230] Once the user receives the notification, they can be prompted to either stop filling the container due to the discovery of damage and possible contamination of the formulation, or retry pressurizing the filling system to the set point (at step 3414). If the user chooses to stop filling the container, the program stops completely (at step 3416). If the user chooses to retry pressurizing the filling system to the set point, the method returns to the starting point at step 3400.

[0231] Figure 35 The illustration shows a flowchart of a method for degassing and filling a container using a filling system according to some embodiments. In some embodiments, the method includes setting an integrity test valve to closed (at step 3500). According to some embodiments, the method includes moving a plunger to a fully extended position (at step 3502).

[0232] The method may include impacting or vibrating a plunger, container, manifold, or integral filling system for a number of repetitions or a predetermined duration (at step 3504). In some embodiments, the method includes prompting the user or filling system to verify that all air bubbles are in the top space of the syringe (or container) (at step 3506). According to some embodiments, the method includes moving the plunger to a fully compressed position (at step 3508).

[0233] The method may include confirming that steps 3502 through 3508 have been repeated a specified number of times based on the selected formulation (at step 3510). If the specified number of repetitions has been performed, the plunger is moved to the target filling volume (at step 3512), thereby filling the associated container with the desired amount of formulation. Thereafter, the method may include a system display of the above... Figure 26 The step 2600 reads "Fill complete. Perform visual inspection".

[0234] If steps 3502 through 3508 are not repeated the specified number of times, the filling system will move the plunger back to the fully extended position (at step 3502) and repeat the above steps.

[0235] Figure 36The illustration shows a flowchart depicting a method for inspecting a filling system after filling has occurred, according to some embodiments. In some embodiments, the method includes a visual inspection unit (at step 3600). This step can be performed automatically by an operator of the system or by a vision system included within the filling system.

[0236] If air bubbles are present in the container, the steps for degassing and filling these containers are repeated (either by an operator or automatically by the filling system) (at step 3602). If a component problem is detected, the filling system returns BDP (e.g., this may include fluid) to the container (at step 3606). In addition to or replacing sealing and disconnecting all units (as described above) Figure 27 (Step 2700 in the above) These steps can be performed before the system performs degassing and container filling (in the above) Figure 25 (Step 2500 in the text).

[0237] Figure 37 The illustration shows a flowchart of a method for sealing and disconnecting a container from a filling system according to some embodiments. In some embodiments, the method includes checking for the presence of a desired headspace (at step 3700). If the desired headspace is present, the method may include prompting the user or the filling system to open an auxiliary collection port on the manifold and confirming when drainage is complete (at step 3702). According to some embodiments, the method includes moving a plunger to a calculated position (at step 3704). This calculated position can be determined by adding the target filling volume of the container to the headspace volume of the container.

[0238] After moving the plunger to its calculated position, all sealing strips are raised to a predetermined temperature (at step 3706). Similarly, if the desired top space does not exist (from step 3700), the method can also proceed directly to raising all sealing strips to a predetermined temperature (at step 3706). In some embodiments, the method includes achieving the desired predetermined temperature for all sealing strips (at step 3708).

[0239] According to some embodiments, the method includes closing the sealing strips and holding them in place for a predetermined amount of time (such as seconds) or until a signal occurs (which may include a limiting switch indicating that the heated surfaces of the sealing strips have met) (at step 3710). This step can seal the container without exposing the contents to the surrounding environment (e.g., the ambient environment), thereby preventing contaminants from entering the container. After the container has been sealed and separated from the filling system, the system can then display "Sequence complete. [XX] units filled, processing time [YY] minutes, alarm [alarm message array]." (as in the above) Figure 28(as detailed in step 2800).

[0240] The following is a restatement of the foregoing systems, flowcharts, and methods presented in an alternative manner. This disclosure provides a method for implementing a system for filling containers (i.e., syringes, vials, bags, etc.) while eliminating the risk of contamination of the container or the material filling it without the need for a cleanroom. The provided systems and methods combine multiple means to allow for the safe filling of these containers while also reducing cost and complexity.

[0241] These methods include verifying the integrity of the filling assembly before use, verifying the integrity of aseptic connection before use, directing flow to multiple containers without significant product loss due to “stagnation” in the system, locating and sequencing the syringe unit receiving the product, assembling the necessary components into the functional cartridge and filling assembly, performing the necessary operations with the machine to achieve the desired filling, and many additional configurations that may be required for different use cases. Each of these methods will be explored in more detail below.

[0242] Regarding the verification of the integrity of the filling component before use, the filling component can be provided as a consumable for processing. This means that once the filling component has served its purpose, the entire component can be discarded. In some embodiments, the filling component includes all necessary flow paths and components for the filling operation. According to some embodiments, the filling component is installed in a machine. According to some embodiments, an integrity test is performed on the filling component using an integrity test connector and a machine before performing aseptic connection with a mass storage device.

[0243] In some embodiments, the machine requires a compressed gas source (which may be in the form of a bottle or a utility). According to some embodiments, the machine contains a compressed gas regulator and filter, a compressed gas manifold, an integrity test regulator and filter, an integrity test gas supply valve, a pressure sensor, a flow meter, and connections to the integrity test fittings. Integrity testing can be performed by opening the supply valve and monitoring the pressure.

[0244] In some embodiments, during initial pressurization, the pressure sensor reading will be below the regulator setpoint. Once the system has reached the regulator setpoint, the gas supply can be maintained for a predetermined period of time to allow the material to equilibrate, although the material may exhibit slight changes due to its inherent elasticity and temperature variations caused by expansion within the gas. After the predetermined time, the integrity test gas supply valve can be closed, and the pressure decay can be monitored.

[0245] Pressure decay can indicate a leak and may necessitate the acquisition of a new component. Alternatively, the compressed gas may be helium or some other gas that can be detected using external instruments. During integrity testing, it may be desirable to test the integrity of a filling assembly with filling cells in multiple positions (i.e., fully closed, partially filled, fully open, etc.). In some embodiments, the filling assembly can be aseptically connected to a mass storage device upon successful integrity testing.

[0246] Regarding the verification of aseptic connection integrity before use, large-capacity reservoirs can be connected to filling components without compromising the sterility of the product. This can be done without a sterile environment. Typical solutions include aseptic connections using fitting welds or aseptic connectors with a non-zero failure rate. Alternatively, specialized fitting connectors can be used to perform weld integrity testing before releasing the clamping fixture. The steps for performing integrity testing to verify the integrity of aseptic connections can be the same as those for performing integrity testing to verify the integrity of filling components, as detailed in the preceding paragraphs.

[0247] To direct flow to multiple containers without significant product loss due to system "stagnation," a manifold can be provided to distribute the solution to be filled into the filling units within the cartridge. The manifold provides a minimum flow path (both distance and volume retention) so that all filling units can be filled simultaneously, while also ensuring that the velocity at any given point does not generate shear that would degrade the solution to be filled or cause bubbles to burst, thereby increasing their surface area and being absorbed into the solution. In some embodiments, to ensure this, the system can be designed as described in the following paragraphs.

[0248] In some embodiments, the system includes distributor beam manifolds arranged in a grid, radial, star, or other pattern, with feed coming from the solution to be filled. The solution may be without internal connections and can be made with a minimal number of components.

[0249] According to some embodiments, the system includes a manifold arranged in a grid, radial, star, or other pattern, with feed coming from a solution to be filled. The solution can have numerous internal connections and can be made from many internal components. To ensure the integrity of these components, the manifold can be cast into a resin or plastic overmolding.

[0250] In some embodiments, the system includes a main manifold and sub-manifolds. To reduce velocity, it may be advantageous to employ a larger diameter sub-manifold with channels connected via the larger manifold. This can reduce the required flow velocity at the midpoint of the manifold by distributing the inflow more evenly over the larger manifold. In some embodiments, this is depicted as a fitting manifold, but it can also be applied to other manifold concepts, such as the distributor beam manifold detailed above.

[0251] In any of the above disclosures, the design does not need to be symmetrical (for example, if there are multiple sizes of containers (or syringes) to be filled, the port distribution can be asymmetrical to match the user's needs).

[0252] At the manifold outlet, a manifold port connector (e.g., a hose barb, Luer connection, threaded flange connection, needleless Luer port, or any other connector that a person skilled in the art would use to connect to a fitting, pipe, or directly to a syringe barrel) may be present. These ports can be connected to the filled unit using tubing or a sterile disconnect device.

[0253] Regarding the positioning and sequencing of the filling units for receiving products, the filling units can be any container with variable volume, such as syringes, vials, bags, etc. The container can be arranged in the upper support, thereby ensuring the orientation and layout of the syringes. In some embodiments, the upper support is connected to a barrel flange hook as a device for securing the barrel, while the lower support is attached to the plunger flange using a barrel flange hook or other connecting device.

[0254] Following the plunger seal, a bellows may be present, which can be modified to provide a device for attaching the lower support to the plunger flange. This can occur via mechanical attachment (such as plunger flange latches, magnetic couplings, vacuum-sealed attachments, automatic latches, or any other means available to those skilled in the art). According to some embodiments, the lower support is actuated for individual containers (i.e., each container has a linear actuator and can be filled and emptied independently) or up to all such containers can be actuated together using a single linear actuator.

[0255] Regarding the cartridge, it may include an integrity test connector, a manifold, filling units, and a support. The filling assembly may be fully closed and integrated using end caps, seals, aseptic operation connectors, or any other closure device that may be employed by a person skilled in the art. In some examples, the filling assembly may be an integral system that, when connected to an integral mass reservoir containing the solution to be filled, enables the transfer of fluid to each of the filling units without exposure to the environment.

[0256] Regarding the machine, it can provide a user interface, allowing the operator to log in and command various system functions, such as loading cartridges, performing calibration, maintenance modes, integrity testing, and various operator formulations for different filler unit sizes / quantities, fill levels, and parameters for steps performed in the formulation. In some embodiments, the machine is designed such that, after the filler assembly is installed, the upper support is securely held by the machine, the lower support is held by linear actuators on a machine operating platform connected to multiple filler units on the machine, and an integrity test connector is connected to the machine's integrity test fitting.

[0257] In some embodiments, the operation of the machine is achieved via a linear actuator that powers the movement of the syringe plunger. According to some embodiments, the operation of the machine includes units for integrity testing, filling, and disconnecting the filling process.

[0258] Regarding integrity testing, a compressed gas utility supply can be provided to the machine. In some embodiments, the machine contains a compressed gas regulator and filter, a compressed gas manifold, an integrity test regulator and filter, an integrity test gas supply valve, a pressure sensor, a flow meter, and connections to the integrity test fitting. At the start of integrity testing, the regulated compressed gas can have an open flow path to the integrity test fitting and the integrity test connection. Before aseptic operation connection, a clamping fixture or other valve can be applied from the mass storage tank upstream of the aseptic operation connection to the mass storage tank fitting.

[0259] In some embodiments, another clamping fixture is applied to the filling assembly tubing, extending to the cartridge downstream of the integrity test coupling. An aseptic operation connection can be formed where the area of ​​the aseptic operation connection is sealed by the clamp. After the aseptic connection is made, preparation for pressure testing can be made.

[0260] For pressure tests using pressure decay, a pressure sensor downstream of the gas supply valve can measure the supplied pressure. In some embodiments, after a stabilization period, the gas supply valve is closed, thereby trapping the pressure within a fitting containing aseptically operated connections. The pressure sensor can measure the pressure decay over a period of time, and a predetermined parameter for acceptable pressure decay can be used to determine whether the integrity test has passed or failed.

[0261] For pressure testing using a helium sniffer, pressurized gas can be introduced into the fitting as described above for pressure decay testing. In some embodiments, a helium (or other gas) sniffing instrument is used to measure the area around the aseptically operated connection, and if no detection occurs, the seal is intact.

[0262] For pressure testing using bubbles, pressurized gas can be introduced into the fitting as described above for the pressure decay test. In some embodiments, a soap solution is applied, or the fitting is submerged underwater. The absence of bubble formation indicates that the seal is intact.

[0263] Regarding filling, upon successful completion of the pressure test, the flow path from the solution to be filled may have a clamping fixture that can be removed and / or opened, or other types of valves / reversible closures to create an open flow path. In some embodiments, the filling assembly will initially have internal air or (if an integrity test is performed on the filling assembly) a pressure test gas. This gas can be purged during filling by circulating the filling unit multiple times.

[0264] According to some embodiments, as the filling unit is vertically oriented with its tip pointing upwards, the gas naturally rises to the tip of the filling unit. Each time the container is filled, any residual gas can float to the top of the filling unit, thus the injection of the solution to be filled can have the ability to expel residual gas from the filling assembly and into a large-capacity storage container.

[0265] In some embodiments, multiple cycles are used to reduce the probability of stubborn bubbles. Alternatively, a vibration mechanism can be added to the machine that allows the cartridge to shake to expel bubbles that may be stuck due to surface tension.

[0266] According to some embodiments, upon completion of air purging, the machine moves the filling unit to the desired filling volume. The operator may be prompted to visually inspect the filling unit to ensure there are no problems. In some embodiments, this inspection may be facilitated by additional equipment, such as a camera system capable of identifying liquid level and filling volume.

[0267] The retaining mechanisms for the movable and stationary portions of the support can be optionally mounted to the load unit, allowing for weight balancing or zeroing upon completion of air purging, and enabling the measurement of the total weight of the solution filled into the filling unit upon completion of the paddle to the desired filling volume. In some embodiments, the weight measurement should match the expected filling weight within acceptable measurement errors and filling variability tolerances.

[0268] For units with disconnected filling, thermoplastic elastomer tubular sealant can be used, or the units with disconnected filling can be disconnected by mechanical means.

[0269] Regarding fine-tuning of multiple filling units, there may be embodiments where the amount of solution to be filled is less than the sum of the target filling amounts in the filling units. In such embodiments, the user can disable the number of filling units that will not be filled. Disabling the syringe can be achieved by disconnecting the connection, independent actuation, bypassing, zoning, and / or penetrating the plunger shaft.

[0270] Regarding disconnection, the filling unit can be disconnected from the manifold without compromising its sterility. In some embodiments, because the filling unit is not used, the sealing fittings connected to the inlet / outlet ports can be removed so that no pressure or vacuum is generated during cartridge sequencing. Additional or alternative means exist to prevent pressure or vacuum buildup, including disconnection of the plunger shaft or the generation of alternative venting in the syringe body or stop, such as perforation.

[0271] Regarding independent actuation, if each filling unit has an independent linear actuator, then the actuator can be disabled in the software so that the filling unit is not filled.

[0272] Regarding the bypass, a three-way valve can be designed between the manifold and the filling unit so that for filling units that are not intended for filling, the valve will be set to a position where the manifold is closed but the filling unit is still venting.

[0273] Regarding the regions, the cartridge can be configured with multiple regions, wherein the lower support is divided into multiple independently actuated sub-segments. These regions can be programmed to be non-actuated and thus record filling. In some embodiments, these regions are used to replace fill size (i.e., for each fill, multiple fill cell geometries may be desired, each requiring different strokes and fill targets for proper operation).

[0274] The lower support for sequencing the plungers may not be solid, as opposed to the plunger shaft through-hole. In some embodiments, the lower support includes a through-hole that can engage and disengage (e.g., by threaded engagement, quarter-turn release, or by attaching the plunger to another device on the lower support, whereby when engaged, the plunger moves with the lower support, but when disengaged, the lower support moves through the plane of the plunger through the base and remains stationary).

[0275] For auxiliary samples, there may be a situation where the amount of solution to be filled is greater than the total amount in the filling units. In some embodiments, the manifold is designed with a side port, whereby, upon completion of filling, any remaining solution can be aspirated into the auxiliary container, thus preventing material waste or loss. According to some embodiments, an integrity test coupling is used to add gas to the filling assembly for the purpose of expelling any remaining solution.

[0276] Regarding temperature control, if there are temperature requirements for the material to be filled, a built-in temperature control can be implemented. In some embodiments, a casing is added to the necessary areas (e.g., large-capacity storage containers and cartridges or the entire filling system). According to some embodiments, a temperature sensor within the casing measures the temperature and provides feedback to the control system. A heat pump, temperature control unit, pelletizing system, or other device for controlling the temperature can be used to provide a modulated temperature, which, in combination with a fan for circulation within the casing, can appropriately control the temperature. In some embodiments, the temperature information is then made available in an automated history recorder and batch report.

[0277] Regarding oxygen-sensitive liquids, the disclosures provided herein can provide the ability to generate an inert gas cover for the desired effect of preventing oxygen exposure of the liquid. In some embodiments, the machine is equipped with an integrity test coupling, and the filling assembly is equipped with an integrity test coupling. The apparatus may also be equipped with a vacuum pump, a vacuum chamber, an inert gas source (e.g., bottled or as a distributed utility system), and an additional gas control valve that allows for the sequencing of integrity test ports on the cartridge between vacuum cycles and purge or cover gas sources.

[0278] According to some embodiments, this configuration allows the application of an inert purge gas and the evacuation of the filling units to their maximum fill level. This configuration may also allow the purge gas to be cut off and a vacuum to be applied to the filling assembly. In some embodiments, this configuration allows the filling units to be pushed to their minimum, nearly empty volume. According to some embodiments, this configuration allows these three steps to be performed sequentially multiple times as needed to achieve the desired covering gas purity.

[0279] In some embodiments, a vacuum is not necessary to obtain the desired concentration. In such cases, the venting of the purge gas can be performed by a syringe cycle that applies discharge to the atmosphere rather than a vacuum.

[0280] Regarding starting materials requiring additional filtration or treatment, the aforementioned systems and apparatus may have already assumed that the solution is filled and purified (e.g., sterile). In some embodiments, the filling assembly and machine may be extended to include additional steps. According to some embodiments, this is sterilization of the solution to be filled by means of filtration. However, filtration may not be necessary for sterilization purposes, but may provide other qualities such as homogeneity, removal of contaminants, uniformity, catalytic conversion, etc. In such embodiments, the machine and filling assembly are provided with pumps, filters or other flow units, auxiliary lines for rinsing the solution, and exhaust filters or integrity test connections.

[0281] In some embodiments, the operation sequence includes installing the filling assembly into the machine. According to some embodiments, the operation sequence includes passing a tubing through a pump. The operation sequence may include connecting a flushing solution. In some embodiments, the operation sequence includes using the pump to flush the filter and wet the membrane while transferring the solution to a flushing container.

[0282] According to some embodiments, the operating sequence includes stopping the pump when a sufficient amount has passed through the filter. The operating sequence may include disconnecting the flushing solution from the filling assembly. In some embodiments, the operating sequence includes using the pump to remove any remaining flushing solution, such that no flushing solution remains in the line. According to some embodiments, the operating sequence includes connecting the integrity test tube to the exhaust filter or integrity test coupling.

[0283] The operational sequence may include performing an integrity test. In some embodiments, the operational sequence includes disconnecting the integrity test fitting. According to some embodiments, the operational sequence includes closing / clamping the exhaust filter or integrity test coupling and the flushing container. The operational sequence may include connecting an unfiltered mass reservoir to the filling assembly.

[0284] In some embodiments, the operation sequence includes using a pump to transfer an unfiltered bulk volume through a filter and into a bulk reservoir. According to some embodiments, the operation sequence includes performing a filling operation as described above. Aseptic filtration can often be a critical operation. In some embodiments, it is common to have two filters in series, wherein filter integrity testing is performed individually or in series (or both). Exemplary embodiments

[0285] Example 1: A system comprising: a fluid source containing fluid; A plurality of filling units fluidly connected to a fluid source; and a device mechanically connected to one or more filling units; wherein the plurality of filling units are configured to draw fluid into them substantially in parallel using the device.

[0286] Example 2: The system according to Example 1, wherein the system further includes a distribution system that fluidly connects a fluid source to a plurality of filling units.

[0287] Example 3: The system according to Example 1 or 2, wherein a fluid source, a dispensing system and a plurality of filling units define a closed containment device for the fluid, the closed containment device being configured to maintain sterility therein, and the fluid source being connected to the dispensing system via a first flow path.

[0288] Example 4: The system according to any one of Examples 1 to 3, wherein the distribution system includes a manifold configured to receive fluid from a fluid source; and a plurality of second flow paths, each of the plurality of second flow paths fluidly connecting the manifold to a corresponding filling unit among a plurality of filling units.

[0289] Example 5: According to the system of Example 4, the manifold includes a first channel having a first inlet opening fluidly connected to a first flow path and a plurality of openings fluidly connected to corresponding second flow paths in a plurality of second flow paths.

[0290] Example 6: The system according to any one of Examples 1-5, wherein the device is configured to interact with a plurality of filling units to i) draw at least a partial vacuum within the plurality of filling units to draw fluid therein, ii) discharge at least some fluid from the plurality of filling units, or iii) both.

[0291] Example 7: The system according to Example 6, wherein the plurality of filling units include a plurality of syringes.

[0292] Example 8: The system according to Example 7, wherein the device includes a lower support configured to be connected to the distal portion of a plurality of syringes, wherein the lower support is configured to move longitudinally to correspondingly move the respective plunger rods of the plurality of syringes, thereby being configured to draw at least a partial vacuum to aspirate fluid into the syringes, expel at least some or both of the fluid.

[0293] Example 9: The system according to Example 8, wherein the lower support is movable via a linear actuator.

[0294] Example 10: The system according to Example 8 or 9, wherein the lower support is operatively connected to one or more processors such that the lower support is movable to aspirate fluid into the syringe, expel fluid from the syringe, or both, based on instructions received from one or more processors.

[0295] Example 11: The system according to any one of Examples 8-10, wherein the lower support includes a plurality of lower support sections, each lower section being configured to individually move the plunger rod of a corresponding syringe among a plurality of syringes, thereby enabling selective i) aspiration of fluid into a desired syringe, ii) discharge of fluid from the desired syringe, or iii) both.

[0296] Example 12: The system according to any one of Examples 1-11, wherein the device is configured to seal a plurality of filling units from the dispensing system.

[0297] Example 13: The system according to any one of Examples 1-12, wherein the device is configured to separate a plurality of filling units from the dispensing system.

[0298] Example 14: The system according to Example 13, wherein the device is configured to seal and separate multiple filling units substantially simultaneously.

[0299] Example 15: The system according to any one of Examples 1-15 further includes a first beam having a first side and a second beam having a second side, wherein the first beam and the second beam are configured to be aligned with each other and spaced apart such that the first side faces the second side.

[0300] Example 16: The system according to Example 15, wherein the first side and the second side each include a groove, the groove being configured to receive at least a portion of each of a plurality of filling units, such that the plurality of filling units are configured to slidably engage with the first beam and the second beam for arrangement therebetween.

[0301] Example 17: The system according to Example 15 or 16, wherein: the first beam includes a first component that at least partially defines a first side; and the second beam includes a second component that at least partially defines a second side; wherein one or both of the first and second components are configured to be movable toward the other.

[0302] Example 18: According to the system described in Example 17, when multiple filling units are disposed between the first beam and the second beam, the corresponding second flow path is disposed between the first component and the second component, wherein each of the corresponding second flow paths includes a pipe.

[0303] Example 19: The system of Example 18, wherein i) a first component defines a first profile having a raised first valley portion around a first side and a raised first platform portion around the first valley portion, and ii) wherein a second component defines a second profile having a raised second valley portion around a second side and a raised second platform portion around the second valley portion, such that a first portion of the tube of a plurality of filling units is configured to be clamped by the first platform portion and the second platform portion when one or both of the first component and the second component move toward each other.

[0304] Example 20: The system according to Example 19, wherein the device further includes a heating element configured to heat i) a first component, ii) a second component or iii) at least a portion of both.

[0305] Example 21: According to the system of Example 20, the device is configured to heat the first portion of the pipe when it is sandwiched between the first platform portion and the second platform portion, such that at least some of the pipe material from the first portion of the plurality of filling units is at least partially flowable and is configured to be at least partially pushed from the first portion of the pipe of the plurality of filling units to the second portion, thereby reducing the pipe material at the first portion of the plurality of filling units, the second portion of the pipe of the plurality of filling units being arranged between the corresponding first valley portion and the second valley portion away from the first platform portion and the second platform portion.

[0306] Example 22: The system according to Example 21, wherein the device is configured to separate the tubing at a first portion of a plurality of filling units, wherein a second portion remains physically connected to the respective filling unit and is separated from the dispensing system.

[0307] Example 23: The system according to Example 22, wherein the second part is configured to be sealed to close the channel therein via a combination of tubular materials.

[0308] Example 24: The system according to Example 23, wherein the separation of the pipe fittings and the sealing of the second part occur substantially simultaneously or at least partially sequentially.

[0309] Example 25: The system according to any one of Examples 20 to 24, wherein the heating element comprises a recirculated heating fluid, a resistance heater, or both.

[0310] Example 26: The system according to any one of Examples 17 to 25, wherein one or both of the first component and the second component are pneumatically, hydraulically, magnetically, electrically, or any combination thereof movable.

[0311] Example 27: The system according to any one of Examples 1-26 further includes a sample unit fluidly connected to a fluid source, the sample unit being configured to draw fluid into it in parallel with a plurality of filling units into which fluid is drawn.

[0312] Example 28: The system according to any one of Examples 4 to 27 further includes one or more additional filling unit subgroups, each filling unit subgroup including a number of filling units equal to the number of filling units, wherein the dispensing system includes one or more additional manifolds corresponding to each additional filling unit subgroup.

[0313] Example 29: The system according to Example 28, wherein the filling units in a plurality of filling units and one or more additional filling unit subgroups are configured to draw fluid from a fluid source in parallel.

[0314] Example 30: The system according to Example 29, wherein the device is configured to seal the filling units of a plurality of filling units and one or more additional filling unit subgroups with the dispensing system.

[0315] Example 31: The system according to any one of Examples 29 to 30, wherein the device is configured to separate the filling units of a plurality of filling units and one or more additional filling unit subgroups from the dispensing system.

[0316] Example 32: The system according to Example 31, wherein the device further includes one or more pairs of additional first beams and second beams according to any one of Examples 17-24, the one or more pairs of additional first beams and second beams being configured to seal and separate the filling units of one or more additional filling unit subgroups.

[0317] Example 33: The system according to any one of Examples 1 to 31 further includes an integrity testing component configured to perform integrity testing on the system or at least its components.

[0318] Example 34: The system according to Example 33, wherein the integrity test includes pressurizing the system or at least the components of the system, and further detecting i) pressure decay, ii) detection of gas used to pressurize the system or at least the components of the system outside the system, or iii) both.

[0319] Example 35: A method comprising: fluidly connecting a plurality of filling units to a fluid source, the fluid source containing fluid; and simultaneously drawing fluid into the plurality of filling units, wherein the plurality of filling units are fluidly connected to the fluid source in a closed configuration, thereby being configured to maintain the fluid isolated from the surrounding environment.

[0320] Example 36: The method according to Example 35, wherein the fluid is drawn into a plurality of filling cells based at least in part on a plurality of filling cells in which at least a partial vacuum is drawn.

[0321] Example 37: The method according to Examples 35-36, wherein fluidly connecting the plurality of filling units to a fluid source includes fluidly connecting the dispensing system according to any one of Examples 1-28 to the plurality of filling units, and fluidly connecting the dispensing system to a fluid source.

[0322] Example 38: The method according to any one of Examples 35-37 further includes degassing or at least partially degassing the fluid drawn into the plurality of filling units.

[0323] Example 39: The method according to Example 38, wherein degassing includes performing one or more of the following sequential steps: i) discharging fluid from multiple packing cells, and ii) drawing fluid into multiple packing cells.

[0324] Example 40: The method according to Example 39, wherein the sequential steps include using the apparatus according to any one of Examples 6 to 11, wherein discharging fluid from the plurality of filling units includes: optionally moving the plunger rod to extend to a maximum position within the syringe, and wherein drawing fluid into the plurality of filling units includes optionally moving the plunger to extend: i) to a maximum position outside the syringe, or ii) to a target position corresponding to the desired filling volume of fluid drawn into the syringe.

[0325] Example 41: The method according to any one of Examples 35-40 further includes sealing a plurality of filling units.

[0326] Example 42: The method according to Example 36, wherein sealing the plurality of filling units comprises: moving one or both of the first and second components according to any one of Examples 17-26 toward each other, thereby clamping the tubing of the plurality of filling units at a first portion; applying heat to the tubing of the plurality of filling units to at least partially melt or soften the corresponding tubing material at least at the first portion so that it is at least partially flowable; and optionally increasing the pressure between the first and second components; In this configuration, at least a portion of the flowable pipe material is arranged to be pushed into the second part of the corresponding pipe in a plurality of filling units.

[0327] Example 43: The method according to Example 41 or 42 further includes separating the respective pipes at the first portion of the plurality of filling units by applying pressure between the first platform portion and the second platform portion, thereby separating the plurality of filling units from the fluid source.

[0328] Example 44: According to the method of Example 43, the sealing of multiple filling units and the separation of the corresponding fittings of the multiple filling units occur approximately simultaneously or approximately sequentially.

[0329] Example 45: The method according to any one of Examples 35-44 further includes performing an integrity test on the distribution system, the first flow path, or both.

[0330] Example 46: The method according to Example 45, wherein the integrity test includes i) pressurizing the distribution system, the first flow path or both, and ii) detecting any leaks.

[0331] Example 47: The method according to Example 46, wherein detecting any leak includes i) monitoring any pressure decay, ii) detecting the gas used for pressurization via a sniffing test, or iii) both.

[0332] Example 48: The method according to any one of Examples 45-47, wherein performing an integrity test for the dispensing system includes pressurizing the dispensing system, wherein the dispensing system includes and is fluidly connected to the syringe according to any one of Examples 7-11, wherein the plunger rod of the syringe is in a first position; Detect any leaks; optionally, slide the plunger rod to multiple positions to perform integrity tests on multiple syringes at different fill volumes.

[0333] Example 49: For any of Examples 1-48, the plurality of filling units include syringes, bags, vials, containers, bottles, or any combination thereof.

[0334] Some components listed herein use the same numbering as those in the figures. It should be understood that these components use the same numbers only for ease of reference and reader comprehension. While the same number of these components may be used, differences may exist among them, as shown in the various figures in which they appear and as described in the specification herein.

[0335] None of the steps described herein are necessary or indispensable. Any step may be adjusted or modified. Other or additional steps may be used. Any step, process, structure, and / or part of any device disclosed or shown in one embodiment, flowchart, or example of this specification may be combined or used in conjunction with or in place of any other step, process, structure, and / or part of any device disclosed or shown in different embodiments, flowcharts, or examples. The embodiments and examples provided herein are not intended to be discrete and separate from each other.

[0336] The chapter titles and subtitles provided herein are non-limiting. Chapter titles and subtitles do not indicate or limit the full scope of the embodiments described in the chapter to which the title and subtitle belong. For example, a chapter entitled “Topic 1” may include embodiments that do not relate to Topic 1, and embodiments described in other chapters may be applied to and in combination with the embodiments described in the “Topic 1” chapter.

[0337] The various features and methods described above can be used independently of each other or can be combined in different ways. All possible combinations and sub-combinations are intended to fall within the scope of this disclosure. Furthermore, in some embodiments, certain methods, events, states, or process blocks may be omitted. The methods, steps, and processes described herein are not limited to any particular order, and the blocks, steps, or states associated with them may be performed in other suitable orders. For example, the described tasks or events may be performed in an order different from that specifically disclosed. Multiple steps may be combined in a single block or state. Example tasks or events may be performed serially, in parallel, or in some other manner. Tasks or events may be added to or removed from the disclosed example embodiments. The example systems and components described herein may be configured differently from those described. For example, elements may be added, removed, or rearranged compared to the disclosed example embodiments.

[0338] The conditional language used herein, among other things, such as “can,” “could,” “might,” “may,” “e.g.,” etc., unless otherwise explicitly stated or understood in the context of its use, is generally intended to convey that certain embodiments include (while other embodiments do not) certain features, elements, and / or steps. Therefore, this conditional language is not generally intended to imply that features, elements, and / or steps are necessary in any one or more embodiments in any way, or that one or more embodiments necessarily include logic for determining whether such features, elements, and / or steps are included or will be performed in any particular embodiment, with or without author input or prompting. The terms “comprising,” “including,” “having,” etc., are synonymous and used inclusively in an open-ended manner, and do not exclude additional elements, features, actions, operations, etc. Furthermore, the term “or” is used in its inclusive sense (rather than its exclusive sense) such that, for example, when used to connect a list of elements, the term “or” refers to some or all of the elements in that list. Unless otherwise specifically stated, associative language (such as the phrase "at least one of X, Y, and Z") is understood in context to generally convey that an item, term, etc., may be X, Y, or Z. Therefore, such associative language is generally not intended to imply that some embodiments require at least one of X, at least one of Y, and at least one of Z to be present respectively.

[0339] The term "and / or" means that "and" applies to some embodiments and "or" applies to some embodiments. Therefore, A, B, and / or C can be replaced by A, B, and C written in one sentence and A, B, or C written in another sentence. A, B, and / or C means that some embodiments may include A and B, some embodiments may include A and C, some embodiments may include B and C, some embodiments may include only A, some embodiments may include only B, some embodiments may include only C, and some embodiments may include A, B, and C. The term "and / or" is used to avoid unnecessary redundancy.

[0340] The term "approximately" refers to a variation less than or equal to + / -1%, + / -2%, + / -3%, + / -4%, + / -5%, + / -6%, + / -7%, + / -8%, + / -9%, + / -10%, + / -11%, + / -12%, + / -14%, or + / -15%. As a non-limiting example, depending on the embodiment, "approximately parallel" means a range from -1 degree to 1 degree difference, -5 degrees to 5 degrees difference, or -15 degrees to 15 degrees parallel difference.

[0341] The term “maximum size” or “size” can refer to any form of measurement of size, such as diameter, width, length, thickness, height, spacing, etc.

[0342] While certain exemplary embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the invention disclosed herein. Therefore, nothing in the foregoing description is intended to imply that any particular feature, characteristic, step, module, or block is necessary or indispensable. In fact, the novel methods and systems described herein can be embodied in many other forms; furthermore, various omissions, substitutions, and changes can be made to the form of the methods and systems described herein without departing from the spirit of the invention disclosed herein.

Claims

1. A system comprising: A fluid source that contains fluid; Multiple filling units, wherein the multiple filling units are fluidly connected to the fluid source; as well as An apparatus, mechanically connected to the plurality of filling units; The plurality of filling units are configured to draw the fluid into the plurality of filling units in substantially parallel using the device.

2. The system according to claim 1, wherein, The system also includes a distribution system that fluidly connects the fluid source to the plurality of filling units.

3. The system according to claim 2, wherein, The fluid source, the dispensing system, and the plurality of filling units define a closed containment device for the fluid, the closed containment device being configured to maintain sterility within the closed containment device, and the fluid source being connected to the dispensing system via a first flow path.

4. The system according to claim 3, wherein, The distribution system includes: a manifold configured to receive the fluid from the fluid source; and a plurality of second flow paths, each of the plurality of second flow paths fluidly connecting the manifold to a corresponding filling unit among the plurality of filling units.

5. The system according to claim 4, wherein, The manifold includes a first channel having a first inlet opening fluidly connected to the first flow path and a plurality of openings fluidly connected to corresponding second flow paths in the plurality of second flow paths.

6. The system according to claim 4, wherein, The device is configured to interact with the plurality of filling units to i) draw at least a partial vacuum within the plurality of filling units to draw the fluid into the plurality of filling units, ii) discharge at least some of the fluid from the plurality of filling units, or iii) both.

7. The system according to claim 6, wherein, The plurality of filling units include a plurality of syringes.

8. The system according to claim 7, wherein, The device includes a lower support configured to engage with the distal portion of the plurality of syringes, wherein the lower support is configured to move longitudinally to correspondingly move the respective plunger rods of the plurality of syringes, thereby being configured to draw at least the partial vacuum to aspirate the fluid into the syringes and expel at least some or both of the fluid.

9. The system according to claim 8, wherein, The lower support is movable via a linear actuator.

10. The system according to claim 8, wherein, The lower support is operatively connected to one or more processors, such that the lower support is movable to aspirate fluid into the syringe, expel fluid from the syringe, or both, based on instructions received from the one or more processors.

11. The system according to claim 8, wherein, The lower support includes multiple lower support sections, each of which is configured to individually move the plunger rod of a corresponding syringe among the plurality of syringes, thereby enabling selective i) aspiration of fluid into a desired syringe, ii) discharge of fluid from the desired syringe, or iii) both.

12. The system according to claim 2, wherein, The device is configured to seal the plurality of filling units with the dispensing system.

13. The system according to claim 12, wherein, The device is configured to separate the plurality of filling units from the dispensing system.

14. The system according to claim 13, wherein, The device is configured to seal and separate the plurality of filling units approximately simultaneously.

15. The system of claim 1, further comprising a first beam having a first side and a second beam having a second side, wherein, The first beam and the second beam are configured to be aligned with each other and spaced apart, such that the first side faces the second side.

16. The system according to claim 15, wherein, Each of the first side and the second side includes a groove configured to receive at least a portion of each of the plurality of filling units, such that the plurality of filling units are configured to slidably engage with the first beam and the second beam for arrangement between the first beam and the second beam.

17. The system according to claim 15, wherein: The first beam includes a first component that at least partially defines the first side; and the second beam includes a second component that at least partially defines the second side; wherein one or both of the first component and the second component are configured to be movable toward the other.

18. The system according to claim 17, wherein, When the plurality of filling units are disposed between the first beam and the second beam, the corresponding second flow path is disposed between the first component and the second component, wherein each of the corresponding second flow paths includes a pipe fitting.

19. The system according to claim 18, wherein, i) The first component defines a first profile, the first profile having a raised first valley portion surrounding the first side and a raised first platform portion surrounding the first valley portion, and ii) wherein, The second component defines a second profile having a raised second valley portion around the second side and a raised second platform portion around the second valley portion, such that a first portion of the tube of the plurality of filling units is configured to be clamped by the first platform portion and the second platform portion when one or both of the first component and the second component move toward each other.

20. The system according to claim 19, wherein, The device further includes a heating element configured to heat i) the first component, ii) the second component, or iii) at least a portion of both.

21. The system according to claim 20, wherein, The device is configured to heat the first portion of the tube when it is clamped between the first platform portion and the second platform portion, such that at least some of the tube material from the first portion of the plurality of filling units is at least partially flowable and is configured to be at least partially pushed from the first portion of the tube of the plurality of filling units to the second portion, thereby reducing the tube material at the first portion of the plurality of filling units, the second portion of the tube of the plurality of filling units being arranged between corresponding first valley portions and second valley portions away from the first platform portion and the second platform portion.

22. The system according to claim 21, wherein, The device is configured to separate the tubing at a first portion of the plurality of filling units, wherein a second portion remains physically connected to the respective filling unit and is separated from the dispensing system.

23. The system according to claim 22, wherein, The second portion is configured to be sealed by the combination of the materials of the pipe to close the channel within the second portion.

24. The system according to claim 23, wherein, The separation of the pipe fitting and the sealing of the second part occur substantially simultaneously or at least partially sequentially.

25. The system according to claim 20, wherein, The heating element includes a recirculated heating fluid, a resistance heater, or both.

26. The system according to claim 17, wherein, One or both of the first and second components are pneumatically, hydraulically, magnetically, electrically, or any combination thereof movable.

27. The system of claim 1, further comprising a sample unit fluidly connected to the fluid source, the sample unit being configured to aspirate the fluid within the sample unit in parallel with the plurality of filling units therein.

28. The system of claim 4, further comprising one or more additional filler unit subgroups, each filler unit subgroup comprising the same number of filler units as the plurality of filler units, wherein, The distribution system includes one or more additional manifolds corresponding to each additional filler unit subgroup.

29. The system according to claim 28, wherein, The filling units of the plurality of filling units and the filling units of the one or more additional filling unit subgroups are configured to draw fluid from the fluid source in parallel.

30. The system according to claim 29, wherein, The device is configured to seal the filling units of the plurality of filling units and the one or more additional filling unit subgroups with the dispensing system.

31. The system according to claim 30, wherein, The device is configured to separate the filling units of the plurality of filling units and the one or more additional filling unit subgroups from the dispensing system.

32. The system according to claim 31, wherein, The device further includes one or more pairs of additional first beams and second beams according to any one of claims 17 to 24, the one or more pairs of additional first beams and second beams being configured to seal and separate the filling units of the one or more additional filling unit subgroups.

33. The system of claim 1 further includes an integrity testing component configured to perform integrity testing on the system or at least a component of the system.

34. The system according to claim 33, wherein, The integrity test includes pressurizing the system or at least a component of the system, and further detecting i) pressure decay, ii) detection of gas used to pressurize the system or at least a component of the system outside the system, or iii) both.

35. A method comprising: Multiple filling units are fluidly connected to a fluid source that contains fluid; as well as The fluid is simultaneously drawn into the plurality of filling units, wherein the plurality of filling units are fluidly connected to the fluid source in a sealed configuration, thereby being configured to maintain the isolation of the fluid from the surrounding environment.

36. The method according to claim 35, wherein, The fluid is drawn into the plurality of filling cells at least in part based on the plurality of filling cells pulling at least a partial vacuum within the plurality of filling cells.

37. The method of claim 36, wherein, Fluidly connecting the plurality of filling units to the fluid source includes: fluidly connecting the dispensing system according to claim 3 to the plurality of filling units, and fluidly connecting the dispensing system to the fluid source.

38. The method of claim 35, further comprising degassing or at least partially degassing the fluid aspirated into the plurality of filling units.

39. The method according to claim 38, wherein, Degassing includes performing one or more of the following sequential steps: i) discharging the fluid from the plurality of filling units, and ii) drawing the fluid into the plurality of filling units.

40. The method according to claim 39, wherein, Performing the sequential steps includes using the apparatus of claim 6, wherein discharging the fluid from the plurality of filling units includes: optionally moving the plunger rod to extend to a maximum position within the syringe, and wherein drawing the fluid into the plurality of filling units includes optionally moving the plunger rod to extend: i) to a maximum position outside the syringe, or ii) to a target position corresponding to a desired filling volume of the fluid drawn into the syringe.

41. The method of claim 35, further comprising sealing the plurality of filling units.

42. The method according to claim 36, wherein, Sealing the plurality of filling units includes: Move one or both of the first and second components according to claim 19 toward each other, thereby clamping the tubes of the plurality of filling units at the first portion; Heat is applied to the tubing of the plurality of filling units to at least partially melt or soften the material of the respective tubing at least at the first portion, so that it is at least partially flowable; and Optionally, the pressure between the first component and the second component can be increased; In this configuration, the material of the pipe, which is at least partially flowable, is arranged to be pushed onto the second portion of the respective pipe of the plurality of filling units.

43. The method of claim 42, further comprising separating the plurality of filling units from the fluid source by applying pressure between the first platform portion and the second platform portion to separate the respective tubing at the first portion of the plurality of filling units.

44. The method according to claim 43, wherein, The sealing of the plurality of filling units and the separation of the corresponding tubing of the plurality of filling units are performed substantially simultaneously or substantially sequentially.

45. The method of claim 35, further comprising performing an integrity test on the distribution system, the first flow path, or both.

46. ​​The method according to claim 45, wherein, The integrity test includes: i) pressurizing the distribution system, the first flow path, or both, and ii) detecting any leaks.

47. The method according to claim 46, wherein, Detecting any leaks includes: i) monitoring any pressure drop, ii) detecting the gas used for pressurization through a sniffing test, or iii) both.

48. The method according to claim 45, wherein, Performing the integrity test on the allocation system includes: The dispensing system is pressurized, wherein the dispensing system includes the syringe according to claim 7 and is fluidly coupled to the syringe, wherein the plunger rod of the syringe is located in a first position; Detect any leaks; and Optionally, the plunger rod can be moved to multiple positions to perform integrity tests on multiple syringes at different filling volumes.

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