Closed process for filling

Abstract

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

Description

CLOSED PROCESS FOR FILLINGCROSS-REFERENCE

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

[0002] The present disclosure relates to a closed system for filling fluid into filling units in parallel. Specifically, the present disclosure relates to a fill / finish process that includes parallel filling, and sealing and separating of filling units while substantially maintaining sterility.BACKGROUND

[0003] Medical treatments, biological sampling, hazardous materials, and high-value solutions often require transfer from a bulk solution to many filled units with high dosing precision while maintaining protection from environmental contaminants and / or protection of personnel from the solution. This is typically accomplished in an environmentally controlled chamber (such as an Isolator, chemical hood, or biological safety cabinet), in which a vial is filled with the requisite fill quantity and then assembled with a stopper and crimp cap.

[0004] Implementation of the process equipment capable of a fully automated filling is expensive, takes a long time, and requires significant expertise within multiple disciplines. The economics of the typical approach work best when there is a large quantity of filled units, such that the per unit cost of all the expenses is low. Current trends in medical treatments are favoring more precision therapeutics wherein the total quantity of filled units is intended for as few as one patient (Personalized medicine, e.g., autologous CAR-T, personalized cancer immunotherapies, personalized siRNA, personalized gene therapies), or a small patient population <300 (e.g., early- stage clinical trials and orphan drugs).SUMMARY

[0005] Disclosed herein, in some aspects, is a system, including: a fluid source containing fluid; a plurality of filling units fluidly coupled with the fluid source; and an apparatus mechanically coupled to the one or more filling units; wherein the plurality of filling units is configured to draw the fluid therewithin substantially in parallel using the apparatus.

[0006] In some embodiments, the system further including a distribution system fluidly coupling the fluid source with the plurality of filling units. In some embodiments, the fluid source, the distribution system, and the plurality of filling units define a closed containment for the fluid configured to maintain a sterility therewithin, the fluid source coupled to the distribution system via a first flow pathway. In some embodiments, the distribution system includes a manifold configured to receive the fluid from the fluid source, and a plurality of second flow pathways each fluidly coupling the manifold with a corresponding filling unit of the plurality of filling units. In some embodiments, the manifold includes a first channel having a first inlet opening fluidly coupled to the first flow pathway, and a plurality of openings fluidly coupled with a corresponding second flow pathway of the plurality of second flow pathways.

[0007] In some embodiments, the plurality of filling units for any system described herein includes a syringe, a bag, a vial, a container, a bottle, or any combination thereof.

[0008] In some embodiments, the apparatus is configured to interact with the plurality of filling units so as to i) pull at least a partial vacuum within the plurality of filling units to draw the fluid therewithin, ii) expel at least some of the fluid from within 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 apparatus includes a lower rack configured to couple with a distal portion of the plurality of syringes, wherein the lower rack is configured to move longitudinally so as to correspondingly move a respective plunger rod of the plurality of syringes, thereby being configured to pull the at least partial vacuum to draw the fluid within the syringes, expel the at least some of the fluid, or both. In some embodiments, the lower rack is moveable via a linear actuator. In some embodiments, the lower rack is in operative communication with one or more processors, such that the lower rack is moveable to draw in fluid to within the syringes, expel fluid from the syringes, or both, based on instructions received from the one or more processors. In some embodiments, the lower rack includes a plurality of lower rack segments, each lower segment configured to individually move the plunger rod of a respective syringe of the pluralityof syringes, thereby enabling for selective i) drawing in of fluid within a desired syringe, ii) expelling of fluid from within the desired syringe, or iii) both.

[0009] In some embodiments, the apparatus is configured to seal the plurality of filling units from the distribution system. In some embodiments, the apparatus is configured to separate the plurality of filling units from the distribution system. In some embodiments, the apparatus is configured to seal and separate the plurality of filling units substantially simultaneously.

[0010] In some embodiments, the apparatus further including a first beam having a first side, and a second beam having a second side, wherein the first and second beams are configured to be aligned and spaced apart from each other, such that the first side faces towards the second side. In some embodiments, each of the first side and second side includes a groove configured to receive at least a portion of each filling unit of the plurality of filling units, such that the plurality of filling units is configured to slideably engage with the first and second beams so as to be disposed therebetween.

[0011] In some embodiments, the first beam includes a first component at least partially defining the first side; and the second beam includes a second component at least partially defining the second side; wherein one or both of the first component and second component are configured to be moveable towards the other. In some embodiments, when the plurality of filling units are disposed between the first and second beams, the corresponding second flow pathways are disposed between the first and second components, wherein the corresponding second flow pathways each include a tubing. In some embodiments, i) the first component defines a first profile having a raised first valley portion about the first side, and a raised first plateau about the first valley portion, and ii) wherein the second component defines a second profile having a raised second valley portion about the second side, and a raised second plateau about the second valley portion, such that a first portion of the tubing of the plurality of filling units is configured to be pinched by the first and second plateaus when one or both of the first component and the second component are moved towards each other.

[0012] The sys In some embodiments, the apparatus further includes a heating element configured to heat at least a portion of i) the first component, ii) the second component, or iii) both. In some embodiments, the apparatus is configured to heat the first portion of the tubing when pinched between the first and second plateaus, 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 be to at leastpartially pushed from the first portion to a second portion of the tubing of the plurality of filling units, 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 disposed between the respective first and second valley portions distal to the first and second plateaus. In some embodiments, the apparatus is configured to split the tubing at the first portion for the plurality of filling units, wherein the second portion remains physically coupled to the respective filling unit and separated from the distribution system. In some embodiments, the second portion is configured to be sealed via bonding of the tubing material to close a channel therewithin. In some embodiments, the splitting of the tubing and the sealing of the second portion occurs substantially simultaneously or at least partially sequentially.

[0013] In some embodiments, the heating element includes a recirculated heating fluid, an electric resistive heater, or both. In some embodiments, one or both of the first component and second component are moveable pneumatically, hydraulically, magnetically, electrically, or any combination thereof.

[0014] In some embodiments, the system further including a sample unit fluidly coupled with the fluid source, the sample unit configured to draw the fluid therewithin in parallel with the plurality of filling units drawing the fluid therewithin. In some embodiments, the system further including one or more additional subset of filling units, each subset of filling units including an equal number of filling units to the plurality of filling units, wherein the distribution system includes one or more additional manifolds corresponding to each additional subset of filling unit. In some embodiments, the plurality of filling units and the filling units of the one or more additional subset of filling units are configured to draw fluid from the fluid source in parallel. In some embodiments, the apparatus is configured to seal the plurality of filling units and the filling units of the one or more additional subset of filling units from the distribution system. In some embodiments, the apparatus is configured to separate the plurality of filling units and the filling units of the one or more additional subset of filling units from the distribution system. In some embodiments, the apparatus further includes one or more additional pairs of the first and second beams of any beam described herein configured to seal and split the filling units of the one or more additional subset of filling units.

[0015] In some embodiments, the system further including an integrity test assembly, the integrity test assembly configured to perform an integrity test on the system or at least a component thereof. In some embodiments, the integrity test includes pressurizing the system or at least the componentthereof, and further detecting for i) a decay in the pressure, ii) detection of a gas used to pressurize the system or at least the component thereof outside the system, or iii) both.

[0016] Disclosed herein, in some aspects, is a method including: fluidly coupling a plurality of filling units with a fluid source, the fluid source containing a fluid; and drawing the fluid into the plurality of filling units simultaneously, wherein the plurality of filling units are fluidly coupled with the fluid source in a closed configuration, thereby configured to maintaining a segregation of the fluid from a surrounding environment.

[0017] In some embodiments, drawing the fluid into the plurality of filling units is at least partially based on the plurality of filling units pulling at least a partial vacuum therewithin. In some embodiments, fluidly coupling the plurality of filling units to the fluid source including fluidly coupling a distribution system of any distribution system described herein to the plurality of filling units, and fluidly coupling the distribution system to the fluid source.

[0018] In some embodiments, the plurality of filling units for any method described herein includes a syringe, a bag, a vial, a container, a bottle, or any combination thereof.

[0019] In some embodiments, the method further including degassing or at least partially degassing the fluid drawn into the plurality of filling units. In some embodiments, degassing includes performing sequential steps of i) expelling the fluid from the within the plurality of filling units, and ii) drawing the fluid into the plurality of filling units, one or more times. In some embodiments, performing the sequential steps includes using the apparatus of any apparatus described herein, wherein expelling the fluid from within 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 to extend i) to a maximum position outside of the syringe, or ii) to a target position corresponding to a desired fill volume of the fluid drawn into the syringe.

[0020] In some embodiments, the method further including 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 of any first and second component described herein towards each other, thereby pinching the tubing of the plurality of filling units at the first portion; applying heat to the tubing of the plurality of filling units, so as to at least partially melt or soften the respective tubing material at least at the first portion, so as to be at least partially flowable; and optionally increasing a pressure between the first and second components; wherein the at least partially flowable tubingmaterial is configured to pushed to a second portion of the respective tubing of the plurality of filling units. In some embodiments, the method further including splitting the respective tubing at the first portion of the plurality of filling units, via pressure applied between the first and second plateaus, thereby separating the plurality of filling units from the fluid source. In some embodiments, sealing the plurality of filling units and splitting the respective tubing of the plurality of filling units occurs substantially simultaneously or substantially sequentially.

[0021] In some embodiments, the method further including performing an integrity test on the distribution system, the first flow pathway, or both. In some embodiments, the integrity test includes i) pressurizing the distribution system, the first flow pathway, or both, and ii) detecting for any leaks. In some embodiments, detecting for any leaks including i) monitoring for any pressure decay, ii) detecting a gas used for pressurization via a sniff test, or iii) both. In some embodiments, performing the integrity test for the distribution system includes: pressurizing the distribution system, wherein the distribution system includes the syringes of any syringe described herein and is fluidly coupled thereto, wherein the plunger rod of the syringes are located at a first position; detecting for any leaks; optionally stroking the plunger rod to multiple positions to perform an integrity test at different fill volumes for the plurality of syringes.BRIEF DESCRIPTION OF DRAWINGS

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

[0023] FIG. 1 illustrates a front perspective view of a filling system, according to some embodiments.

[0024] FIG. 2 illustrates a front view of reservoirs, tubing, connectors, a filling assembly, and a filling and sealing apparatus of the filling system from FIG. 1, according to some embodiments.

[0025] FIGS. 3A-3C illustrate a top-front perspective view, a front view, and a top view, respectively, of a filling assembly, according to some embodiments.

[0026] FIG. 4 illustrates a side view of a subset assembly, according to some embodiments.

[0027] FIG. 5 illustrates a front perspective view of the subset assembly of FIG. 4, according to some embodiments.

[0028] FIGs. 6A-6F illustrates a front view of a syringe, as well as a front cutaway view, a cutaway of the plunger rod and plunger seal, a cutaway view of the bellows sealing portion, and cutaway views of a locking portion of the syringe from FIG. 6A, according to some embodiments.

[0029] FIG. 7 illustrates the filling and sealing apparatus of FIG. 2, according to some embodiments.

[0030] FIGS. 8A-8B illustrate a front view of the sealing portion of the beams of a filling and sealing apparatus, according to some embodiments.

[0031] FIGS. 9A-9E illustrate front views of a coupling between the syringes and the lower rack, and front views of the lower rack, of a filling and sealing apparatus, according to some embodiments.

[0032] FIG. 10 illustrates a front perspective view of the upper rack of a filling and sealing apparatus, according to some embodiments.

[0033] FIG. 11 illustrates a front perspective view of the beams of a filling and sealing apparatus with subsets of syringes coupled to sub-manifolds inserted therein, according to some embodiments.

[0034] FIGS. 12A-12B illustrate a front view of the integrity system coupled to a filling system, and the integrity system components, according to some embodiments.

[0035] FIGS. 13A-13B illustrate a top view and a side view, respectively, of a distributor plate system.

[0036] FIG. 14 illustrates a top view of a manifold embodiment, according to some embodiments

[0037] FIG. 15 illustrates a cross-sectional side view of FIG. 14

[0038] FIGS. 16 illustrates a front view of some components of a syringe, according to some embodiments.

[0039] FIGS. 17 illustrates a front view of some components of a syringe, according to some embodiments.

[0040] FIG. 18 illustrates a cross-section of a filling assembly intended to directly couple a bulk bag or reservoir without a main manifold, according to some embodiments.

[0041] FIG. 19 illustrates a cross-section of an assembly with a sampling unit, according to some embodiments.

[0042] FIG. 20 illustrates an elaboration of the system of FIG. 12A, wherein the system is further configured to perform a sterile filtration of the fluid, according to some embodiments.

[0043] FIGS. 21-28 illustrate flowcharts depicting an overview of a process of using a filling system, according to some embodiments.

[0044] FIG. 29 illustrates a flowchart depicting a method of verifying a layout of the filling system, according to some embodiments.

[0045] FIG. 30 illustrates a flowchart depicting a method of receiving and preparing the filling system, according to some embodiments.

[0046] FIG. 31 illustrates a flowchart depicting a method of ranging plungers of the filling system, according to some embodiments.

[0047] FIGS. 32-34 illustrate flowcharts depicting methods of testing the integrity of the filling system, according to some embodiments.

[0048] FIG. 35 illustrates a flowchart depicting a method of degassing and filling containers using the filling the system, according to some embodiments.

[0049] FIG. 36 illustrates a flowchart depicting a method of inspecting the filling system after filling has occurred, according to some embodiments.

[0050] FIG. 37 illustrates a flowchart depicting a method of sealing and disconnecting containers from the filling system, according to some embodiments.DETAILED DESCRIPTION OF THE INVENTION

[0051] Disclosed herein, in some aspects, are systems and methods for filling one or more filling units. In some embodiments, the systems and methods describe a filling system for filling a plurality of filling units in parallel. The filling units may be filled with a filling substance such as a fluid, a solid substance(s), or any combination thereof. For example, the filling substance may include a pharmaceutical drug or material. The filling system may be a closed system so as to prevent and / or minimize the risk of contamination of the filling substance. The filling system may be configured to draw the filling substance into the filling units from a filling substance source.

[0052] In some embodiments, the filling system is further configured to seal the filling units after being filled with the filling substance. The filling system may also be configured to provide the filling units as separated filled units. The system and methods described herein for filling the filling units with the filling substance (e.g., fluid as described herein), which may be filled in parallel, sealing the filling units, and / or separating the filling units (as described herein), may be performedmanually, and / or automatically using one or more processors in operative communication with a system described herein.

[0053] FIG. 1 illustrates an example of a fdling system 10 described herein. The fdling system 10 may be configured to draw a filling substance from a reservoir 102 (e.g., a filling substance source) to be deposited into one or more filling units 106 (e.g., one or more syringes 106). The filling substance described herein may be a fluid, such as a liquid. Accordingly, the “filling substance” may be referred to herein as “the fluid” for any system and method embodiments described herein or contemplated. The fluid may be a pharmaceutical drug requiring a sterile or substantially sterile transfer process from the reservoir 102 to the filling units 106. The fluid may 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 to the system may be provided to maintain the fluid in liquid or substantially liquid form.

[0054] With continued reference to FIG. 1, the filling system 10 may include the reservoir 102, a filling assembly 302 (see FIG. 3), a filling and sealing apparatus 108, an integrity test assembly (e.g., the integrity test tubing 1202 and the integrity test equipment 1204) (see FIG. 12), one or more processors (for example, within enclosure 116 of FIG. 1), a housing (e.g., 112, 114), the fluid pathway(s) between and / or through the reservoir and filling assembly, or any combination thereof. As described herein, the filling system 10 may 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 units 106. As such, all points of fluid containment and flow may be substantially sealed and substantially isolated from an external environment, so as to prevent or minimize a risk of exposure to contaminants entering within the closed system.

[0055] Example embodiments of the components of the filling system 10 are described herein in more detail.Reservoir

[0056] In some embodiments, as described herein, the filling system 10 includes a compartment or attachment points for a reservoir 102 (e.g., the reservoir 102 may be the compartment itself) configured to contain the filling substance, such as a fluid, to be deposited into the filling units. The reservoir 102 may be sealed or substantially sealed to i) preserve or substantially preserve thesterility and conditions of the fluid therewithin, ii) prevent or reduce the risk of exposure of the fluid to a surrounding environment (e.g., fluid may be hazardous), or iii) both. The reservoir may be filled and sealed at a location of preparation of the fluid, at a separate distribution and packing center, at any other location, or via means as depicted in FIG. 20.

[0057] The reservoir 102 may be any type of container or containment for the fluid. For example, the reservoir 102 may be a bag, a vial, a can, a bottle, a barrel, a tank, another type of vessel, etc. The reservoir 102 may be flexible or at least partially flexible (e.g., a bag), and / or may be rigid or at least partially rigid. The reservoir 102 in FIG. 2 illustrates a bag for example.

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

[0059] The reservoir 102 may further include one or more reservoir flow pathways through which the fluid is configured to flow out of the reservoir 102. For example, the reservoir 102 in FIG. 2 includes a reservoir flow pathway which flows through the reservoir tubing 204 that is isolated using a reservoir connector 202. The connector 202 may be configured to fluidly couple the reservoir flow pathway with another flow pathway, such as intermediary flow pathway flowing through the intermediary tubing 205 that is separate from the reservoir 102. The reservoir connector 202 may be any sterile connector, configured to help prevent or reduce the risk of contamination of the fluid, and / or compromising the sterility of the fluid, as it transfers from the reservoir, through the connector, and to another location and / or flow pathway. The sterile connector 202 may be any aseptic connector or sterile connector.

[0060] As used herein, the term “flow pathway” may be a tubing, piping, hosing, conduit, closed channel, or any combination thereof. For the purposes of this disclosure, any reference to the term “tubing” herein, may also include in addition or in the alternative to other form of flow pathways, such piping, etc. The flow pathway may also define a channel therewithin to allow for the flow of fluid therethrough.

[0061] The reservoir tubing 204 may have an internal diameter (“ID”) from about 0.1 mm to about 50 mm. As described herein, an intermediary tubing 205 may be used to fluidly couple to reservoir102 to another location, such as the filling assembly 302 (see FIG. 3). The intermediary tubing 205 may include a connector, such as an intermediary sterile connector 203 (e.g., as described for reservoir connector 202) at each end of the intermediary tubing 205. The intermediary tubing therefore may be a separate tubing from the filling assembly 302 and the reservoir 102 that can fluidly couple, in some cases aseptically, them together. The intermediary tubing 205 may have an ID from about 0.1 mm to about 50 mm.

[0062] As described herein, the intermediary tubing 205 may be able to fluidly couple with the reservoir tubing 204 with using the intermediary connector 203 that may be configured to mate with the reservoir connector 202. Similarly, the intermediary tubing 205 may be able to fluidly couple with the filling assembly 302 with the intermediary connector 203 configured to mate with a filling assembly connector 206 (see FIGS. 2-3), thereby fluidly coupling the reservoir 102 with 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, the fluid may flow from the reservoir 102 to the filling assembly 302 at least partially via gravity. For example, the reservoir 102 may be located at a higher elevation (e g., proximally) than at least a portion of the filling assembly 302, such that opening a fluid path (e.g., via the connectors 202, 203, and / or 206) may allow the fluid to flow from the reservoir 102 to the filling assembly 302 via gravity force.

[0064] Additionally or alternatively, the fluid may flow from the reservoir to the filling assembly at least partially via a motive force. For example, the fluid may flow from the reservoir 102 to a pump, which then will output the fluid at a higher pressure so as to flow to the filling assembly 302. In other embodiments, the fluid may flow from the reservoir 102 to the filling assembly 302 via a vacuum being pulled at least partially within the filling assembly 302.

[0065] For any filling system 10 described herein, there may be any number of reservoirs 102, such as from 1-100, or 1, 2, 3, 4, 5, 10, 15, 25 or more reservoirs.Filling Assembly

[0066] FIGs. 2-11, 17, and 19 illustrate an example embodiment of the filling assembly 302 and certain components of the filling assembly 302, as described herein.

[0067] For any embodiment of a filling assembly described herein or contemplated, the filling unit 106 may include any type for receiving and / or storing the fluid, which may include a syringe, avial, a bag, a container, a bottle, etc. The reference to a filling unit 106 as a syringe described herein is a non-limiting illustrative example for a filling unit.

[0068] In some embodiments, as described herein, the filling assembly 302 is configured to receive the fluid from the reservoir 102 to be deposited into the filling units 106. The filling assembly 302 may be configured to fill the fluid into one or more filling units 106 in parallel (e.g., simultaneously), as opposed to a sequential manner. For example, as described herein, in some embodiments, the filling assembly is configured to deposit (e.g., fill) the fluid into from 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 deposited into the filling units in parallel or substantially in parallel.

[0069] As described herein, the filling system 10 may include a filling assembly connector 206 configured to provide entry to and / or isolate the filling assembly 302 from external components, such as the reservoir 102 and / or reservoir tubing 204. The filling assembly 302 may further include a distribution system so as to enable the fluid from the reservoir 102 to be distributed across the filling units 106, thereby enabling parallel or substantially parallel filling of the filling units 106.

[0070] The distribution system may provide a minimum flow path, in distance, and / or hold-up volume, to enable simultaneous parallel filling of the filling units. The distribution system may also help ensure the velocity of the fluid at any given point does not create shear that would degrade the fluid and / or cause air bubbles to break apart, thereby increasing their surface area and absorption into the fluid.

[0071] In some embodiments, the distribution system includes a manifold system, such as illustrated with filling assembly 302. Alternatively or additionally, the distribution system may include a distributor plate (see FIGS. 13A and 13B, and described further herein). Alternatively or additionally, the distribution system may include a radial distributor (see FIG. 14, and described further herein). Alternatively or additionally, the distribution system may include a conical distribution system (not shown).

[0072] With respect to the filling assembly 302 described herein (see e.g., FIGs. 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 only include the main manifold 104 to distribute the fluid to the filling units 106.

[0073] With respect to the filling assembly 302, the main manifold 104 is configured to receive the fluid from the reservoir 102, for example via the filling assembly connector 206, and optionally via a filling assembly tubing 208. The main manifold 104 may define a receiving area for receiving the fluid therein. The receiving area of the main manifold 104 may define a channel that may be closed from a surrounding environment. The channel of the main manifold 104 may include an inlet opening, configured to receive the fluid from the reservoir 102 (e.g., via filling assembly tubing 208).. The main manifold 104 channel may further include one or more openings (not shown), for example about a distal surface within the main manifold 104. The one or more openings of the main manifold 104 may enable fluidic communication with the one or more submanifolds 216.

[0074] Each opening of the main manifold 104 channel may correspond to and be fluidly coupled with a main manifold tubing 210 that extends from the opening to a connector 211. A sub-manifold tubing 214 with a connector 212 may then extend from the connector 211 to the respective submanifold 216 (for example the connector 212 may connect with connector 211 to fluidly couple the main manifold tubing 210 with the sub-manifold tubing 214). Each connector 211, 212 may be similar to the reservoir connector 202 and / or filling assembly connector 206 (e.g., a sterile / aseptic connector). Accordingly, the main manifold 104, via the filling assembly connector 206 and connector 211, may be separable from each sub-manifold 216, wherein the filling assembly connector 206 and connector 211 may be configured to isolate the main manifold 104 and corresponding tubing.

[0075] Each sub-manifold 216 (see FIG. 4 for example), may define a receiving area for receiving the fluid therein. Similar to the main manifold 104, the receiving area for each sub-manifold 216 may define a channel that may be closed from a surrounding environment. The channel for each sub-manifold may include an inlet opening, configured to receive the fluid from the main manifold 104 (e.g., via main manifold tubing 210 and / or sub-manifold tubing 214). Each sub-manifold 216 may further include one or more openings (not shown), for example about a distal surface within the respective sub-manifold. The one or more openings of the sub-manifold 216 may enable fluidic communication with the one or more filling units 106 (as described herein).

[0076] In some embodiments, having a plurality of sub-manifolds 216 helps reduce the velocity of the fluid as it flows from the main manifold 104 to the filling units 106. The manifold system may include conical channels. For example, within the main manifold, sub-manifold, or distributorplate (as described herein), it may be beneficial to utilize conical channels such that the diameter of the channel at the source of the fluid (e.g., main manifold, sub-manifold) is larger than at the manifold port connector (e.g., respective openings of main manifold, sub-manifold). The larger diameter may result in lower velocity for the same volumetric flow from the source of fluid. The diameters for openings on the main manifold and sub-manifolds further away from the respective inlet opening, and / or the channel dimension (e.g., diameter) of the main manifold and submanifolds as it moves away from the respective inlet opening may decrease, so as to help increase the velocity of the fluid as there is less available fluid due to the fluid first flowing to the other openings that are closer to the respective inlet opening.

[0077] As depicted in FIG. 3 A, the main manifold 104 is disposed at a higher elevation than the sub-manifolds 216, such that the fluid flows from the main manifold 104 to the sub-manifold at least partially via gravity. In some cases, as described herein, the filling units 106 may pull a vacuum, including at least a partial vacuum, so as to draw the fluid from the main manifold 104 to the sub-manifolds 216.

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

[0079] Each sub-manifold may be in fluid communication with and configured to distribute the fluid to a corresponding subset of filling units 106, via, for example, the openings of the submanifold and corresponding filling unit tubing 304 for each opening (e.g., see subset assembly 402). For example, the subset of filling units 106 depicted in FIG. 4 includes twenty filling units 106 fluidly coupled to the sub-manifold 216, each via a corresponding filling unit tubing 304, plus one sample filling unit (which may be substantially similar to the filling unit 106) coupled to the sub-manifold 216 via a sample tubing 306. The number of filling units in a subset that is fluidly coupled with a given sub-manifold (e.g., in a subset assembly 402) may be any number. Forexample, the subset of filling units 106 configured to receive fluid therein from a sub-manifold 216 may include from 1-10,000, 10-5,000, 25-2,500, 50-1000, 100-500, 1, 2, 5, 10, 25, 50, 100, 500, 1,000, 2,500, 5,000, 10,000 or more filling units.

[0080] As depicted in FIGs. 3A-3C, the plurality of sub-manifolds 216 may be aligned with respect to each other, and extend along a length in a first direction (e.g., see 308 in FIG. 3C), wherein the filling units 106 are similarly aligned along the first direction. As illustrated in FIG. 5, the subset of filling units 106 may be aligned and held at least partially in place via an alignment stem 404. The alignment stem 404 may include a plurality of protrusions 502, wherein each filling unit 106 is configured to be at least partially disposed and held between a pair of protrusions 502. In some embodiments, the plurality of protrusions 502 are arranged in pairs, so as to align each filling unit 106 and corresponding filling unit tubing 304 with an opening of the sub-manifold 216. The alignment stem 404 may further include a pull tab 406 at an end of the alignment stem 404. The pull tab 406 may be configured to align and / or remove the sub-manifold 216 and / or subset of filling units 106 with respect to a portion of the filling and sealing apparatus 108 (as described herein).

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

[0082] The filling assembly 302 may include any number of sub-manifolds 216. For example, with respect to FIG. 3C, the 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. Accordingly, with each sub-manifold 216 being fluidly coupled with a subset of filling units 106 e.g., subset assembly 402), the filling assembly may include a plurality of filling units arranged in an array. For example, the filling assembly 302 may have an array of twenty (number of subset assemblies 402) by twenty (number of filling units 106 per subset assembly 402) filling units, plus twenty sample filling units.

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

[0084] FIGs. 6A-6F, 16, 17 illustrate example embodiments of a syringe 106 described herein. FIG. 6A illustrates a front view of a syringe 106 as a fdling unit, while FIG. 6B depicts a cutaway front view of the syringe 106 from FIG. 6A, as described herein.

[0085] Each syringe 106 may include a barrel 602 that defines an interior cavity configured to receive the fluid. FIGs. 16-17 illustrate a front view of a syringe 106 from FIG. 6A, further depicting the barrel 602, wherein FIGs. 6A-6B, and 16-17 illustrate an example of a plunger assembly at least partially disposed within the interior cavity of the barrel 602. The plunger assembly may include a plunger seal 1502, which may be moveable within the interior cavity via a plunger rod 1504, wherein the plunger rod 1504 may be moveable in a longitudinal direction 1512 to move proximally and distally (e.g., about a longitudinal axis 614 in FIG. 6A) through a distal end 1510 of the barrel 602. The plunger seal 1502 may be configured to interact with an interior surface of the barrel 602, so as to provide a leak-tight seal or a substantially leak-tight seal. The plunger rod 1504 may configured to be coupled to an interior of the plunger seal 1502. For example, the plunger rod may, at a proximal portion, may include threads configured to engage with the interior of the plunger seal, thereby securing the plunger rod with the plunger seal 1502.

[0086] The fluid may be configured to be received within the barrel 602 via the proximal end 1508 of the barrel 602. Accordingly, the interior cavity portion between the plunger seal 1502 and the proximal end 1508, or at least a proximal portion, of the barrel 602 defines a fill volume 1506 of the syringe 106. The fill volume 1506 may be varied based on a longitudinal positioning of the plunger seal 1502 within the barrel 602, which may be controlled based on movement of the plunger rod 1504. As described herein, the fluid may be drawn into and / or expelled from the fill 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 may expel at least a substantial portion of any fluid within the barrel 602. By contrast, moving the plunger rod 1504 distally may pull a vacuum within the barrel 602, and / or may draw in fluid into the fill volume 1506.

[0087] With reference to FIG. 6A-6B, the barrel 602 may include a proximal portion 617 having a proximal flange 612 disposed at the proximal end of the barrel. The proximal flange 612 and / or proximal portion 617 may be configured to receive at least a portion of the filling unit tubing 304 therethrough, and / or may be fluidly coupled with the filling unit tubing 304, while providing a leak-tight seal or substantially leak-tight seal about the proximal end 1508 of the barrel 602.

[0088] With respect to FIGS. 6A, 6B, and 6D, the syringe 106 may include a bellows sealing portion 616 coupled to the barrel 602 and may be configured to provide a leak-tight seal or substantially leak-tight seal about the distal end 1510 of the barrel 602. The bellows sealing portion 616 may include a first distal flange 605, a finger flange 604 coupled to and / or disposed about the first distal flange 605, wherein the finger flange 604 may include and / or be coupled to one or more extensions 607 disposed around the finger flange 604. The bellows sealing portion 616 may include an internal seal 619 configured to receive the plunger rod 1504 therethrough and provide a seal between the bellows 606, such as, for example, via a coupling with a proximal bellows clasp 621.

[0089] As illustrated in FIGS. 6A, 6B, 6E-6F, 16, and 17, the plunger rod 1504 extends through the distal end of the barrel 602, and through the bellows sealing portion 616, to a locking portion 609 of the syringe 106. A bellows 606 may extend between the bellows sealing portion 616 and the locking portion 609. The plunger rod 1504 may extend within a cavity defined by the bellows 606 from the bellows sealing portion 616 to the locking portion 609 (see, for example, FIG. 6B, 16, 17). The bellows 606 may be compressible and expandable along a longitudinal axis 614. For example, the bellows 606 may expand and compress as the plunger rod 1504 moves proximally and distally longitudinally 614, 1512. The bellows 606, with the coupling with the bellows sealing portion 616 and locking portion 609 (e.g., via interaction between distal clasp 623 and the second distal flange 608), may provide a leak-tight seal or substantially leak-tight seal to an interior cavity within the bellows, and through which the plunger rod 1504 is disposed within.

[0090] The syringe 106, at the locking portion 609 may further include a second distal flange 608 and a locking nut 610 distal and coupled to the second distal flange 608 (see FIGS. 6B, 6E, 6F for example). The locking nut 610 and second distal flange 608 may also be integrally coupled. The locking nut 610 may have a maximum dimension, such as, for example, a diameter, that is less than a 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, disposed within an interior cavity of the second distal flange 608 and / or the locking nut 610. The second distal flange, 608, locking nut 610 and / or the end cap 611 may further provide a leak-tight seal or substantially leak-tight seal about the locking portion 609, thereby segregating the plunger rod 1504 from a surroundingenvironment. The plunger rod 1504 at a distal portion may also have a reduction in a dimension (e.g., diameter) such that a larger dimension provides a seal as it rests within the interior of the locking portion 609 (see FIG. 6F).

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

[0092] The filling unit may have any volumetric capacity for receiving and containing the fluid within. For example, for any syringe 106 described herein, syringe 106 may include a volumetric capacity range between a minimum fill volume and a maximum fill volume (e.g., extreme longitudinal positions of the plunger seal within the barrel 602) from about 0 mL - 5 L, such as from 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 more.

[0093] As described herein, the filling assembly 302 may be configured to fill a plurality of filling units, such as syringes 106, in parallel (e.g., simultaneously). The fluid may be distributed to the syringes 106 using the manifold system, as described herein, which may include a main manifold 104 and a plurality of sub-manifolds 216, wherein each sub-manifold is fluidly coupled with a subset of syringes 106.

[0094] Any number and combination of reservoirs 102, main manifolds 104, sub-manifolds 216, and / or syringes 106 may be utilized with a filling assembly 302. In some cases, a single reservoir 102 may be used to provide the fluid to the main manifold 104 and sub-manifolds 216. In other embodiments, two or more reservoirs 102 are configured to supply the fluid to the main manifold 104. For example, each reservoir 102 may be configured to supply the fluid to the main manifold 104 via a respective reservoir tubing 204, intermediary tubing 205, fill assembly tubing 208, and respective connectors (e.g., 202, 203, 206), such that the main manifold 104 may have separate points of inlet for the fluid. Additionally or alternatively, two different intermediary tubing 205 from two or more corresponding reservoirs 102 may be fluidly combined, for example, using a connector as described herein, such that a combined intermediary tubing then couples with a filling assembly connector 206 that has a combined flow from at least some of the reservoirs 102. Accordingly, there may be a 1 : 1 reservoir to filling assembly, or multiple filling assemblies perreservoir, or multiple reservoirs per assembly. Furthermore, a system 10 may be used to simultaneously fill any number of reservoirs 102 coupled to any number of assemblies 302 (e.g., filling lOx bulk lots of material from lOx reservoirs 102 each into a separate main manifold 104, coupled to the requisite number of subset assemblies 402 and syringes 106 for each lot).

[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 coupled with a respective number of sub-manifolds 216. In some embodiments, the two or more main manifolds 104 may nonetheless be fluidly coupled to the same common sub-manifolds 216. FIG. 18 illustrates an example where a subset assembly 402 may be directly fluidly coupled with a reservoir (not shown), such that a main manifold is not needed.

[0096] As described herein, each sub-manifold 216 may be fluidly coupled with a subset of filling units (e g., syringes 106) via a corresponding number of filling unit tubing 304, thereby defining a subset assembly 402 (see FIGS. 4-5 for example). Any one sub-manifold 216 may also be fluidly coupled with a sample syringe (which is the same or substantially the same as syringe 106) via a sample tubing 306 (see 402 in FIGS. 4-5, for example). The sample syringe may be used to provide a representative sample of the fluid that was deposited into the plurality of syringes 106, considering that the plurality of syringes 106 were filled in parallel (thus the sample syringe would obtain the fluid from the same batch and timing of the fluid deposited in the syringes 106 to be distributed). This may be advantageous compared to sequential methods of depositing (e.g., filling) fluid into filling units (e.g., syringes 106), which may require representative samples throughout the filling process to ensure samples of the fluid are obtained at different time periods (since the fluid may be altered, naturally or through external factors, over time). Accordingly, the systems and methods described herein may provide an efficient and effective means for obtaining a sample of the fluid being filled in the filling units, satisfying industry requirements (e.g., pharmaceutical industry requirements), and / or minimizing the amount of fluid needed to be obtained to satisfy the sampling requirements. In some embodiments, a valve (see e.g., 1902 in FIG. 19) may be disposed about the sample tubing 306 or elsewhere to control and / or regulate the fluid entering the sample filling unit (e.g., sample syringe).

[0097] As described herein, in addition to or alternatively to the manifold system described herein, the filling assembly 302 may include other types of distribution systems.

[0098] FIGS. 13 A-13B illustrate a top view and a side view, respectively, of a distributor plate 1302 system, wherein openings 1304 are laid out in a grid, radial, star, or other pattern with the fluid coming from the reservoir 102. In some embodiments, a channel filler or void filler material 1306 may be provided when not all the openings 1304 are fluidly coupled with a corresponding filling unit (e.g., there are less filling units 106 needing fluid deposited therein than openings in the distributor plate).

[0099] FIG. 14 illustrates a top view of a manifold embodiment in which tubing and hose barbs are used to make the molded manifold. FIG. 15 illustrates a side cutaway view of the manifold embodiment from FIG. 14. The diagram shows the manifold as being matrixed (all positions connected to adjacent positions) rather than row-based (wherein each position is only directly connected to another position within the same row). This diagram also shows the feed line to the manifold being branched into multiple feed lines 1402 with different connections points within the manifold.

[0100] Another example distribution system includes a tubing manifold system, which may also be laid out in a grid, radial, star, or other pattern with fluid coming from a reservoir 102. The tubing manifold system may have several connections and may be made of many of internal components. To ensure the integrity of these components, the tube manifolds may be cast into a resin or plastic over-mold.

[0101] Another example distribution system may include the tubing manifold or distributor plate, and where it may be beneficial to utilize conical channels such that the diameter of the channel at the source of reservoir 102 will be larger than at the connection point to the filling units. The larger diameter will result in lower velocity for the same volumetric flow from the source of reservoir 102.

[0102] In some embodiments, for any distribution system used for a filling assembly 302 described herein, the distribution system need not be symmetrical (e.g., if there are multiple sizes of syringes to be filled, the distribution of ports may be asymmetrical to match the user needs).

[0103] For any distribution system described herein, an outlet of a manifold may include manifold port connectors (e.g., hose barb, Luer connection, threaded flanged connection, Needle free Luer port, or other types used to connect either to tubing, piping, or directly to the syringe barrel). These ports may be connected to the filling units 106 using a tube or means of sterile disconnection (e.g., SmartSite™, NovaSeal™, Quickseal®, Clipster®, Biosealer®).Filling and Sealing Apparatus

[0104] As described herein, the filling system 10 may further include a filling and sealing apparatus 108 configured to help with depositing fluid into the filling units 106 (e.g., syringes,bags, vials, bottles, containers, etc.) and / or sealing the filling units 106, so as to contain the fluid therein, while preventing or reducing the risk of contamination of the fluid. The filling and sealing apparatus 108 may be configured to support a plurality of sub-manifolds 216, as described herein, thereby enabling filling a plurality of filling units 106 in parallel. The filling and sealing apparatus 108 may further be configured to separate the filling units 106 from the manifold system (or any other type of distribution system described herein), so that the filling units 106 may be configured to be individually collected and distributed.

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

[0106] FIG. 7 illustrates an example of a filling and sealing apparatus 108. The apparatus 108 may include one or more beams 716 that may include a sealing portion 711, and an upper rack 712. The apparatus 108 may further include a lower rack 714. The apparatus may include a frame 718 that provides supports and / or holds in position the sealing portion 711, the upper rack 712, the lower rack 714, or any combination thereof.

[0107] The apparatus 108 may include any number of beams 716, such as from 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 filling unit tubing 304 between the spacing of the beams 716. For example, a subset assembly 402, as described herein may be configured to be at least partially received within the spacing between adjacent beams 716.

[0108] Each beam 716 may include a first side 720 and a second side 722 opposite the first side 720. Accordingly, for an apparatus having a plurality of beams 716, the first side 720 of the beams 716 will face the second side 722 of the adjacent beams, with the syringes 106 and / or filling unit tubing 304 disposed between the pair of beams 716. The first side 720 of any of the beams will be the same or substantially the same as each other, while the second side 722 of any of the beams will be the same or substantially the same as each other.

[0109] The beams 716 and / or the lower racks 714 each extend laterally, along a length that is substantially aligned with a length of the sub-manifolds 216 when coupled with the apparatus 108 (e g., extend in the first direction 308 from FIG. 3C). See for example FIG. 11, which illustrates aportion of the apparatus 108 coupled with a portion of the filling assembly 302, wherein the submanifolds 216 extend along a length that is aligned or substantially aligned with the length of the beams 716. As depicted in FIG. 11, the subset assembly 402 (e.g., the syringes 106 and filling unit tubing 304 coupled with a respective sub-manifold 216) are configured to be disposed within a spacing between the beams 716.

[0110] The frame 718 of the apparatus 108 may include front walls (see, for example, 1002 in FIG. 10) that extend longitudinally along the lateral ends of the apparatus 108, such that at least a portion of the upper rack 712 and sealing portion 711 extend along a length between the lateral ends of the frame 718. Accordingly, the frame 718 may be configured to suspend at least a portion of the upper rack 712 and the sealing portion 711 above a spacing 706 and / or above at least a portion of the lower rack 714.[OUl] FIG. 10 illustrates a front perspective view of a portion of the apparatus 108, wherein the upper rack 712 for three adjacent beams 1004, 1006, 1008 are indicated. Accordingly, an assembly of beams 716 (such as 1004, 1006, 1008) via the respective upper rack 712 for each beam, may define an upper rack assembly, wherein the frame 718 secures the beams together (e.g., via front walls [see e.g., 1002] of the frame as described herein). The spacing 708 between the upper racks 712 between any pair of beams may be configured to receive and / or support at least a portion of a respective subset assembly 402. t, wherein front walls 1002 may define an opening to the spacing 708 through which the subset assembly 402 may be inserted between the pair of beams 716. For example, syringes 106 are depicted as being disposed between beams 1006, 1008. Moreover, the upper racks 712 may include a groove 704 that extends along a length of the upper rack (e.g., on either side of the beams). For example, the first syringe 106 is depicted as being removed about the beam 1004 to illustrate the groove 704. The groove 704 may be configured to receive at least a portion of the finger flange 604, and / or at least a portion of the extensions 607. For example, the extensions 607 may be configured to slideably engage with the groove 704, such that a subset of syringes 106 (for example corresponding to subset assembly 402) may be configured to slideably engage with the beams 716 by being inserted in a spacing between the beams 716, and supported via the interaction between the extensions 607 of the syringes 106 and the groove 704 for each beam of the pair of beams (e.g., 1004, 1006, and 1006, 1008).

[0112] Accordingly, the subset assembly 402 may be aligned or substantially aligned with the beams 716. In some embodiments, one end of the groove 704 for each upper rack 712, and / or anend of the alignment stem 404 (e.g., opposite to pull tab 406), may include a protrusion or stopper, so as to prevent a subset of syringes 106 sliding all the way through the groove 704 of the pair of beams 716 and beyond the spacing therebetween. In some embodiments, said protrusion or stopper on the groove 704 and / or the alignment stem 404 may be configured to align the locking portion 609 of the syringe 106 with the corresponding opening 906 and / or recessed portion 908 on the lower rack (as described herein), based at least on a positioning of the syringe sliding portion within grooves 704.

[0113] As depicted in FIG. 11, five subsets of syringes 106 are illustrated as being held by the upper racks of corresponding pairs of beams, wherein the barrel 602 of the syringes 106 is disposed between a spacing between the upper racks 712 of adjacent beams 716. Moreover, the bellows of each subset of syringes 106 are disposed within a spacing 708 defined between the upper racks and lower racks, wherein said spacing may have a maximum dimension (e g., width) that is larger than the spacing 708 between upper racks 712 of adjacent beams, and wherein said spacing 708 may accommodate the movement of the lower rack 714 therewithin (as described herein). Said spacing may also be defined by the front walls (e.g., see 1002) of the frame 718.

[0114] In some embodiments, a top portion of the beams 716 may include a top surface (e.g., see 830 in FIG. 8A, 11) that at least partially extends towards an adjacent beam, so as to define a spacing (e.g., see valley 804 in FIG. 8A) between the top surfaces 830 that is smaller than a spacing between the upper racks 712 of the adjacent beams. Such spacing may allow for the sub-manifolds to be supported by the top surface 830, which may span a width greater than spacing (e.g., see submanifold 216 in FIG. 11).

[0115] As described herein, the apparatus 108 may include a lower rack 714 that may be at least partially disposed below or distal to the upper rack 712, and / or at least partially disposed below or distal to the spacing defined between two adjacent beams (e.g., spacing between upper racks 712 of two adjacent beams 716).

[0116] The lower rack 714 may be configured to be moveable, relative to the upper rack 712. For example, the lower rack 714 may be configured to moved longitudinally (e.g., see 918 in FIG. 9A), e.g., proximally and / or distally, relative to the upper rack, wherein the upper rack may be configured to remain stationary. The lower rack 714 may be configured to move longitudinally via an actuator. For example, the lower rack may be coupled with one or more linear actuators 710, that may be disposed beneath the lower rack. The lower rack 714 may be moved through any othermeans, including one or more actuators suspended from above, about lateral sides of the lower rack 714, and / or below the lower rack 714. The linear actuators may be hydraulically powered, pneumatically powered, electrically powered, manually powered (e.g., via an operator), or any combination thereof. The apparatus 108 may also be coupled with side panels 110 (e.g., see FIG. 1), which may further facilitate longitudinal movement of the lower rack 714. For example, the side panels 110 may be coupled with the housing (e.g., back panel 111 of housing) via a rail (e.g., see 113 in FIG. 1) that guides longitudinal movement of the side panels 110. As described herein, the lower rack 714 movement may be controlled using one or more processors.

[0117] In some embodiments, the lower rack 714 may be configured to couple with at least a portion of the subset of syringes 106, such that the lower rack 714 is configured to move the plunger rod 1504 for each syringe 106 of the subset proximally and / or distally, thereby varying the fill volume of each syringe 106 (as described herein). Each lower rack 714 may span a length substantially parallel with the length of the beams 716 (e.g., along a first direction 308 illustrated in FIG. 3C). FIG. 9A illustrates a coupling of the fill assembly 302 with the lower rack 714, wherein the beams 716 and frame 718 have been removed from depiction of the apparatus 108 for ease of reference. The lower racks 714 may be supported on a lower rack base 901, that may span across the beams 716 (e.g., in a direction traverse to 308). The lower rack base 901 may be coupled with the actuator 710, as described herein, for movement of the lower racks 714.

[0118] FIGS. 9B-9D illustrate an example of the coupling between the syringes 106 and a given lower rack 714. The syringes 106 may be coupled to the lower racks 714 at a distal portion of the syringes 106. For example, FIG. 9C illustrates a lower rack 714, without the syringes 106 depicted, wherein the lower rack 714 includes a lower rack platform 904 having a locking tab 902 disposed about the platform 904. The locking tab 902 may be removably coupled to the platform 904. For example, with respect to FIG. 9D, the lower rack on the left illustrates the lower rack platform 904 wherein the locking tab 902 has been removed, and wherein the lower rack on the right illustrates the locking tab 902 in place. The platform 904 may include grooves 912, such that the locking tab 902 is configured to be slideably engaged with the platform 904. With reference to the lower rack on the left of FIG. 9D, wherein the locking tab has been removed, the platform 904 includes a surface 910 that is configured to receive at least a portion of the locking tab 902 when received through the grooves 912. The surface 910 may further include one or more recessed portions 908 disposed along a length of the lower rack 714.

[0119] With respect to coupling a lower rack 714 with a subset of syringes 106, the locking tab 902, as disposed about the platform 904, includes one or more openings 906, wherein the openings 906 may align or substantially align with a positioning of the subset of syringes 106 when coupled with the upper rack 712 as described herein. FIG. 9E illustrates an example of a lower rack 714 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 that is larger than a maximum dimension of the smaller portion 914. The maximum dimension may be a diameter, width, or any other size measurement. The smaller portion 914, and the larger portion 916 may be open to each other. Also illustrated in FIG. 9E, the platform surface 910 is disposed underneath the locking tab 902 and underneath corresponding opening 906, wherein a recessed portion 908 is also illustrated. The example of the configuration of the opening 906 and lower rack as illustrated in FIG. 9E may be applicable to any lower rack 714 described herein, having any number of openings 906 similarly configured (e.g., with a smaller portion and larger portion).

[0120] With respect to FIGS. 9D-9E, the locking tab 902 may be configured to move between a locked position and an unlocked position. In the unlocked position, the locking tab 902 may be slideably engaged with the platform 904 such that the larger portion 916 of the one or more openings 906 is aligned or substantially aligned with the one or more recessed portions 908 disposed about the surface 910. In the locked position, the locking tab 902 slides at least partially out of the grooves 912 of the platform 904, such that the smaller section 914 of the one or more openings 906 is configured to be aligned with the one or more recessed portions 908. FIG. 9E illustrates an example of a lower rack 714 in the locked position, wherein the first section 914 is aligned or substantially aligned with the recessed portion 908.

[0121] With respect to coupling the syringes 106 to the lower racks 714, the distal portions of the syringes 106 for a subset of syringes (that is, for example, coupled with a sub-manifold, as described herein) are configured to be aligned with corresponding openings 906 and recessed portions 908 when the subset of syringes is slideably engaged with the upper rack 712 (as described herein). 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, and further at least partially disposed within the corresponding recess 908 of the surface 910, when the locking tab 902 is in the unlocked position. For example, the larger portion 916 may have a maximum dimension (e.g.,diameter, width, etc.) larger than a maximum dimension of the end cap 61 1 and / or locking nut 610.

[0122] Thereafter, moving the locking tab 902 to the locked position may then slide the smaller section 914 of the opening 906 about the locking nut 610 and / or end cap 611, thereby securing the syringes 106 to the respective lower rack. For example, the smaller section 914 of the opening 906 may slide to at least partially surround the locking nut 610, whereas the end cap 611 may be disposed at least partially in the recessed portion 908. The end cap 611 may have a maximum dimension that may be larger than a maximum dimension of the smaller portion 914, such that the end cap 611 is prevented from passing through the smaller portion 914 and thereby preventing or reducing the ability of the syringe from being separated from the lower rack 714.

[0123] Accordingly, such coupling between the syringes 106 and the lower rack 714 may allow for the lower rack to move the plunger rod 1504 both proximally and distally along a longitudinal direction 1512 (for example, via the coupling between the opening 906 and the locking nut 610 and / or the end cap 611). For example, the lower rack 714 may be configured to pull the plunger rod 1504 down distally, without having the syringe 106 separate from the lower rack 714. Moreover, as described herein, the interaction between the syringes 106 and the upper rack 712, and / or the interaction between the sub-manifold 216 with a top portion of the beams 716 (further described herein), may provide sufficient securement such that movement by the lower rack 714 and the plunger rod 1504 may not destabilize and / or decouple the interaction between the syringes 106 and the beams 716, so as to prevent or reduce any interference with the filling of fluid within the syringes 106.

[0124] In some embodiments, additional or alternative configurations for coupling the syringes to the platform 904 of the lower rack may be through other mechanical interactions (e.g., clamp, thread, set screw, clip), electromagnetic interactions, magnetic interactions, vacuum interactions, or any combination thereof.

[0125] The movement of the lower rack may be controlled via one or more processors. The one or more processors may be inputted with a size of the syringes 106, desired fill volumes, maximum fill volumes, minimum fill volumes, and a plunger rod position within the barrel 602 that corresponds to each one of said fill volumes. Accordingly, the processor(s) may be configured to associate a longitudinal position of the lower rack with a fill volume of the syringes (e.g., based on a position of the plunger rod and plunger seal within each barrel 602). The processor may beconfigured to move the lower rack with a precise control, to maximize accuracy in obtaining a desired fill volume of fluid deposited in the barrel of the syringes 106. For example, the longitudinal movement of the lower rack may be controlled to 5mm, 2 mm, 1 mm, 0.1 mm, 0.01 mm or less. Accordingly, given that the plunger seal will be drawing in the fluid to within the syringe barrel, a precisely controlled amount of fluid may be deposited within the syringe, and moreover, the amount of fluid deposited may be consistent across a plurality of syringes, filled substantially in parallel.

[0126] As described herein, the filling and sealing apparatus 108 may be further configured to seal the filling unit tubing 304 so as to contain the fluid therein. Such sealing may maintain the segregation of the fluid within the filling assembly 302 and 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 hazardous) to the environment. The apparatus 108 may also be configured to separate the syringes 106 from the manifold system, e.g., the sub-manifold 216, thereby enabling the syringes 106 to be separably deliverable.

[0127] The sealing portion 711 of the apparatus 108 may be configured to seal and / or separate the syringes 106. In some embodiments, the sealing portion 711 of adjacent beams 716 define a zone 702 for enabling the sealing and / or separating of the syringes 106. As described herein, and depicted in FIG. 8B, for example, the filling unit tubing 304 may be disposed between adjacent beams 716 in the zone 702. Accordingly, the syringes 106 may be sealed about a location on the filling unit tubing 304. The filling unit tubing 304 may also be cut so as to separate the syringe 106 from the manifold system (e.g., sub-manifold 216). In some embodiments, the zone 702, via the respective sealing portions 711 of adjacent beams 716 may be configured to seal and cut the filling unit tubing 304 simultaneously or substantially simultaneously.

[0128] With reference to FIG. 8 A, each sealing portion 711 of a beam 716 may include two components, a first component 818 and a second component 820. The first component 818 may define a first profile (see e.g., 814), while the second component may define a second profile (see e.g., 816). In some embodiments, the first component 818 of a first beam 716 (e.g., 824 of FIG. 8A) is configured to move towards the second component 820 of an adjacent beam 716 (e.g., 822 of FIG. 8A) such that at least a portion of the filling unit tubing 304 of the subset assembly 402 disposed between and / or about a spacing of the two beams 822, 824 may be at least partiallyclamped together (e.g., internal opposite walls of the filling unit tubing 304 are brought towards each other and may be touching). In other embodiments, the first component 818 and second component 820 of adjacent beams 716 (e.g., 822, 824 of FIG. 8A) are both configured to independently move towards each other (e.g., 822 of FIG. 8A), such that at least a portion of the filling unit tubing 304 of the subset assembly 402 disposed between and / or about a spacing of the two beams 822, 824 may be at least partially clamped together (e.g., internal opposite walls of the filling unit tubing 304 are brought towards each other and may be touching).

[0129] The first component 818 therefore may be configured to at least partially move away from a portion of the second component 820 of the same beam (e.g., 824), and move towards the second component 820 of the adjacent plate (e.g., 822) (and vice versa where the second component may be configured to at least partially move away from a portion of the first component of the same beam towards the first component of the adjacent beam). The components 818, 820 may be moveable by an actuator, which may be a mechanical actuator, and which may be actuated pneumatically, hydraulically, magnetically, and / or electrically. For example, the electric actuation may be a piezo-electric driven actuator. The mechanical actuator may include a hydraulic component, a magnetic component, and / or a pneumatic component.

[0130] The sealing portion 711 of each beam 716 may further be able to seal the filling unit tubing 304 for the syringes, so as to provide a leak-tight seal, or substantially leak-tight seal about 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 as to enable at least a portion of said filling unit tubing 304 to be sealed shut (or substantially sealed shut). The sealing portion 711 may also or alternatively be configured to seal the filling unit tubing 304 via ultrasonic tube welding, and / or mechanical force tube sealing with metal crimp around tubing.

[0131] With respect to sealing the filling unit tubing 304 via heat (e.g., heat sealing), the first component 818 and / or the second component 820 of any given beam 716 may be configured to provide heat, such that when at least a portion of the filling unit tubing 304 is clamped together (e.g., via the first component 818 of one beam moved towards the second component 820 of an adjacent beam, or vice-versa), the heat allows the walls of the filling unit tubing 304 to at least partially mix and / or bond together. For example, the filling unit tubing 304 may include a plastic material (e.g., a thermoplastic elastomeric material), such as, for example, PVC, C-Flex™, AdvantaFlex® Or a rigid tubing [such as PVC (Polyvinyl Chloride), BS (Acrylonitrile ButadieneStyrene), Polypropylene (PP), Acrylic (PMMA)]. Such material may begin to soften, at least partially melt due to the exposure to the heat and / or pressure (via the first and second components 818, 820), and / or obtain somewhat adhesive properties when exposed to a certain temperature.

[0132] The sealing portion 711 may be heated through a recirculating tempered fluid disposed about the first component 818 and / or second component 820, through electric heating (e.g., electrical resistive heating, or Peltier effect heating), any other type of heating, or any combination thereof. The system 10 may include a source and / or motive force where recirculating fluids are used (e.g., heating oil, gas, other liquid). For example, the motive force may include a pump and / or a compressor to deliver the heating fluid (e.g., heating oil) to the sealing portion 711 of the plurality of beams 716.

[0133] The first component 818 and / or second component 820 may be configured to reach a temperature from about 50C to about 500C. The sealing portion 711 for a given beam 716 may also include a temperature sensor to help attain the target temperature range, so as to enable controlled sealing and cutting of the filling unit tubing 304 (for example). The temperature sensor may further be coupled with a switch to shut off the heating if the temperature rises above a maximum limit. The switch may also shut off the heating if the sensor is determined to be faulty.

[0134] In some embodiments, the movement of the first component 818 and / or second component 820 is configured to be controlled so as to sequentially move the first components towards 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 raised portion that extends from the beam 716 (e.g., towards an adjacent beam). For example, the raised portion may extend relative to a baseline portion of the first profile (not shown for the first component, but equivalent to 810 on the second component 820). The raised portion of the first profile 814 may include a valley 812 that extends a first distance relative to the baseline portion, and / or include a plateau 808 that extends a second distance relative to the valley 812 (e.g., the plateau may be disposed along the valley 812).

[0135] Similarly, the second profile 816 may include a raised portion that extends from the beam 716 (e.g., towards an adjacent beam). For example, the raised portion may extend relative to a baseline portion of the second profile (e.g., see 810). The raised portion of the second profile 816 may include a valley 804 that extends a first distance relative to the baseline portion 810, and / orinclude a plateau 806 that extends a second distance relative to the valley 804 (e.g., the plateau may be disposed along the valley 804).

[0136] Thus, prior to having the first and / or second components 818, 820 moved towards each other, the spacing between plateau 806 of the second profile 816 of a first beam 716 and the plateau 808 of the first profile 814 of an adjacent beam may define a spacing 803 therebetween, which may have a dimension (e.g., width) that is less than a spacing 802 between the corresponding valleys 804, 812 of the adjacent beams.

[0137] Accordingly, the first component 818 and / or second component 820 may be configured to move to a first position so as to clamp (e.g., pinch) at least a portion of the filling unit tubing 304 between the raised portions (e.g., 804, 806, 808, 812) of adjacent beams 716. The inner walls of the filling unit tubing 304 (e.g., opposite wall portion of the tubing) disposed between the plateau 806, 808 of adjacent beams will be compressed more tightly together than between the corresponding valleys 804, 812 (due to the less spacing between the plateaus 806, 808).

[0138] Thereafter, heat may be applied to one or both of the raised portions of the adjacent beams 716 to apply heat to the filling unit tubing walls 304, to allow the walls (e.g., opposite walls of tubing) to at least partially blend together (due to the decreased viscosity of the filling unit tubing material due to the heating). In some embodiments, the raised portions of the adjacent beams include a metal material, so as to increase the efficiency of heat transfer between the heating source (as described herein) and the filling unit tubing 304.

[0139] The combination of the pressure applied on the filling unit tubing 304 by and between the first and second components 818, 820, along with the heat applied, may allow for the simultaneous or substantially simultaneous sealing and cutting of the filling unit tube. For example, as the filling unit tube 304 is heated (and thereby softening the walls of the tubing 304, as described herein), the pressure applied on the filling unit tubing 304 by the plateaus 806, 808 (see e.g., filling unit tubing portion 826 in FIG. 8B) may cause some of the filling unit tube wall material about the portion 826 to be pushed out towards the filling unit tubing portion 828, 829 between at least the valleys 804, 812 (proximally and / or distally to the tubing portion 826). Accordingly, tubing portion 828, 829 may include additional tubing material (e.g., thermoplastic material), while the tubing portion 826 may be left with a thin layer or film of tubing 304 material.

[0140] The first component 818 and / or second component 820 may then be configured to move further towards one or the other, and / or increase a pressure therebetween such that the filling unittubing 304 at least at the portion 826 becomes fractured and / or cut, thereby separating one portion (e.g., 828) of the fdling unit tubing 304 from another portion (e.g., 829). The removal of heat to the fdling unit tubing 304, the cutting of the tubing 304, and / or the removal of pressure applied by the first and second components 818, 820 on the tubing may enable the tubing 304 material to bond together (e.g., which may include harden from a soften state) about tubing portions 828 and / or 829, thereby providing a leak-tight or substantially leak-tight seal thereabout.

[0141] In some cases, the two components 818, 820 being brought closer together via temperature, pressure, and time may be sufficient to fuse the inner walls of the filling unit tubing 304 in contact with the valleys, and such that no material remains between the plateaus, thusly severing the filling unit tubing 304, while preserving the segregation from the environment.

[0142] The tubing portions 828, 829 may further include a more robust sealing due to the added tubing material disposed therein (e.g., that was pushed out from tubing portion 826). As described herein, the sealing and cutting of the filling unit tubing 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 may be controlled via one or more processors. Similarly, the application of heat, ultrasound, electromagnetic wave (e.g., radio wave or microwave), electrical current, alternating magnetic field, and / or pressure may also be started and / or stopped via one or more processors. In some embodiments, the movement of the components 818, 820 and / or the sealing / cutting application are automatically controlled, manually controlled (e.g., via an operator), or both. In some embodiments, the first and / or second components 818, 820 may further be divided into one or more segments, wherein The actuation of any one or more of the segments of the sealing portion may be selectively manually engaged or selectively engaged through automation (e.g., via through a processor described herein). Each segment may correspond to one or more syringes and filling unit tubings 304 of a given subset assembly 402. Each of the segments of the first and / or second components 818, 820 may be individually moveable, and / or heat may be individually applied to the one or more segments, thereby allowing the sealing portion 711 of the beams 716 to selectively seal and / or cut syringes. For example, any one or more syringes of a subset assembly 402 may be selectively sealed and / or cut.

[0144] As described herein, both the first and second components 818, 820 may also be moveable. For example, where larger filling units, e.g., larger syringes 106, are used, adjacent beams 716 may be separated from each other further to accommodate the larger syringe sizes. Accordingly, for ease of operation, having both the first component 818 and second component 820 capable of moving, this may facilitate sealing and / or cutting of the filling unit tubing 304 since the first component 818 would not have to extend the full distance to cover the increased spacing between the beams 716. The second component 820 may be moveable using any method described herein for the first component 818 (e.g., gas bladder, etc ).

[0145] Once the filling unit tubing 304 of the subset of syringes has been sealed and cut, the syringes corresponding to a subset assembly 402 may be then removed from the apparatus 108 by moving the locking tab 902 (of the lower rack) to the unlocked position, and / or sliding the subset of syringes out from the grooves 704 of the upper rack. The syringes may still be coupled with the alignment stem 404, thereby facilitating the collection and delivery of the syringes by subset.Integrity Test Assembly

[0146] The system 10 may further include an integrity test assembly configured to test the integrity of one or more components of the filling system 10. For example, the integrity test assembly may be configured to test the integrity of the entire filling assembly 302. The integrity test assembly may be able to test specific sections of the filling assembly, such as just the filling units 106, the filling units 106 and the sub-manifolds 216, and / or just the manifold system. The integrity test assembly may also be configured to test the intermediary tubing 205 and / or any other flow pathways that may be traveled by the fluid.

[0147] In some embodiments, testing the integrity may include testing for any leaks in the filling system 10. Such leaks may be a point of potential contamination entry for the system 10, and / or leakage of fluid from the system 10. The integrity test assembly may use a pressure test to detect for any leaks in the assembly 302 and fluidly coupled components thereof, including but not limited to: connectors 202, 203; reservoir tubing 204, and the reservoir itself 102. For example, the integrity test assembly may be configured to pressurize the system or a portion thereof, and monitor any fluctuations in the pressure (e.g., loss of pressure) in the system.

[0148] FIGS. 12A-12B illustrate an example of an integrity test assembly configured to test a system (e.g., system 10). As illustrated in FIG. 12A, the integrity test assembly may include testing equipment 1204 and the integrity test tubing 1202. The integrity test tubing 1202 may beconfigured to fluidly couple with the system 10, to pressurize the system 10, for example using a gas. The system 10 may be configured to isolate various components of the system, so as to allow the integrity test to be performed for a specific section. For example, the filling assembly 302, via connector 206, and / or a mechanical clamp (not shown), or other isolation means, may be used to provide an isolated filling assembly 302 that can be coupled with the integrity test tubing 1202 to allow for pressurization and testing. Similarly, the intermediary tubing 205 may be isolated via connectors 203, and / or clamps (e.g., if it is connected to the filling assembly) to allow for integrity testing of said intermediary tubing via coupling with the integrity test tubing 1202.

[0149] With respect to FIG. 12B, the integrity test equipment 1204 may include a compressed gas manifold 1206, configured to receive compressed gas from a gas supply 1210. The compressed gas may be passed through a first regulator and filter(s) 1208 prior to entering the gas manifold 1206. The gas may then flow to an integrity test regulator(s) and filter(s) 1212 configured to reduce the pressure for the integrity test if need be. There may be a gas supply valve 1214 so as to start and / or stop pressurization of the system 10 or a component thereof. The integrity test equipment 1204 may further include a pressure sensor 1216, a flow meter 1218, a gas sniffer (e.g., if helium is used), other types of detection methods for a leak, or any combination thereof to determine if there is a leak in the system 10.

[0150] The integrity test equipment 1204 may further be in communication with one or more processors 1220 configured to start / stop the pressurization, monitor the system 10 during the integrity test, and / or provide an alert if a leak is detected. In some embodiments, where there are one or more filling assemblies with a system 10, and / or there are multiple integrity test tubing for different parts of the system 10, the gas manifold 1206 may be configured to provide separate connections to said different integrity test tubing, each including a regulator, supply valve, and / or a detection equipment (as described herein).

[0151] The integrity test equipment 1204 is illustrated as being together (e.g., underneath the filling assembly 302 in FIG. 12A), but different components of the test equipment 1204 may be disposed in any location, and spaced apart from each other.

[0152] The integrity test assembly may use any gas for performing the test, such as air, nitrogen, helium etc. The integrity test assembly may pressurize the system from about 1 millibar (mbar) to about 5 bar. The integrity test may further use one or more filters to help ensure the gas being usedfor testing the system 10 is sterile or substantially sterile, and / or to help prevent or reduce the risk of contamination of the assembly 302 and fluidly coupled by the gas.Additional Optional Components of the System

[0153] In some embodiments, the fluid is required to be maintained at a certain temperature. Accordingly, the system may be configured to include a temperature control assembly to help maintain the fluid at the certain temperature. For example, an enclosure may be added the areas needed for temperature control, such as the reservoir 102, the manifold system, and / or the syringes 106. In some embodiments, the entire housing (e.g., 112, 114, etc.) may be under temperature control. The temperature control assembly 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). A heat pump, temperature control unit, Pelletier system, and / or other means of controlling temperature may be used to provide a modulated temperature, which may be combined with a fan for circulation within a temperature control enclosure, to help control the temperature appropriately. The temperature information may also be available in an automated historian and batch report.

[0154] In some embodiments, the fluid may include an oxygen sensitive liquid, and thereby, the fluid must be sufficiently prevented from oxygen exposure (which may be present within the filling assembly, etc.). Accordingly, the system may be configured to provide for the ability to generate an overlay of inert gas for the desired effect of preventing oxygen exposure to the fluid. Wherein the system may be provided with the integrity testing capability (e.g., see FIG. 12A-12B), and the filling assembly may be configured to couple with the integrity test equipment, the system may also be configured to couple with a vacuum pump, vacuum chamber, inert gas source (e.g., bottle or as a distributed utility system) and / or additional gas control valves which allow for sequencing the integrity testing connection on the syringes between vacuum cycles, and purge of overlay gas source.

[0155] For example, an example sequence would include: 1) the inert purge gas would be applied and the syringes have the plunger seal drawn to their maximum fill volume; 2) the purge gas would be shut off and vacuum applied to the syringes; 3) the syringes would have the plunger rods pushed proximally so that the plunger seal positioning corresponds to the minimum fill volume in the barrel (e.g., empty or substantially empty); 4) steps 1, 2, and 3 would be performed in such sequence multiple times as necessary to attain the desired overlay gas purity.

[0156] Furthermore, the vacuum may not be necessary to attain the desired concentration. In such cases, the venting of the purge gas could be performed by the syringe cycling with discharge applied to atmosphere instead of vacuum. Once the syringes have been purged and fdled with the target overlay gas, the syringes may be fdled with fluid according to any method described herein.

[0157] With respect to a system 10 overview, the fluid to be deposited in the syringes may be located in a reservoir 102, which may be suspended above all other components of the system. The reservoir tubing 204 may hang below the reservoir 102, emanating from the lowest point of the reservoir 102 (as may be necessary to enable the extraction of all solution). The reservoir tubing 204 may be aseptically coupled to the fdling assembly tubing 208. The fdling assembly 302 may include a main manifold 104, one or more sub-manifolds 216, a plurality of syringes 106, and / or tubing coupling the components of the fdling assembly together.

[0158] The system 10 may further include a fdling and sealing apparatus 108, which may include a beam 716 having a stationary upper rack 712 and a sealing portion 711, the apparatus further including a moveable lower rack 714. The upper rack 712 may be configured to remain stationary and holds the body (e.g., barrel) of the syringes, wherein the lower rack is configured to be moveable (e.g., longitudinally between a proximal and distal direction), wherein the lower rack is configured to move all of or a portion of the syringes that allows for varying the volume of the syringes (e.g., the barrel 602 or tubular portion of the syringe would be held by the upper rack 712, while the plunger is moveably coupled to the mobile lower tack 714). The syringes being at a low point (e.g., with respect to the manifold and / or reservoir) helps facilitate elimination of entrained gasses by density (i.e., bubbles in the assembly during priming would float to the top and be captured in the reservoir).

[0159] One example of the housing (e.g., I l l, 112, 114) of the system may include it on the floor with caster wheels for mobility. Alternates may have it anchored to the floor, placed on a bench top, appended to a larger production skid, or suspended from the ceiling. The housing would have a fdling assembly installed atop it whereby the housing holds the stationary upper rack, and linear actuators are connected to the mobile lower rack. By stroking the lower rack (e.g., moving the mobile rack up and down), the apparatus causes stroking of the syringes and thus can cause changes in the internal volume of the syringes (e.g., fdl volume, as described herein). The changing internal volume of the syringes may be utilized to generate a motive force for pulling the fluid from the reservoir, through the manifold system, and to each of the syringes. To draw the fluidinto the syringes, the fill volume within the barrel of the syringes may be increased (e.g., the lower rack, and / or a portion of the plunger rod are moved away from the upper rack). To expel fluid from within the barrel of the syringes, the fill volume is decreased (i.e., the lower rack, and / or a portion of the plunger rod, are moved closer to the upper rack).

[0160] The design and implementation of the system is such that it may be implemented without the need for a cleanroom while ensuring that no contamination occurs.Methods

[0161] Described herein, in some aspects, are example methods for depositing fluid into filling units using a system described herein. The order of the methods are described herein in a nonlimiting sequence, and may be performed in any order with respect to each other.

[0162] In some embodiments, one or more filling units 106 are configured to draw in fluid from one or more fluid sources (e.g., reservoir(s) 102), wherein the fluid may be drawn in the one or more filing units in parallel. As described herein, filling units may include syringes, vials, bottles, bags, containers, etc. As an example embodiment with filling units as syringes, the one or more filling units 106 may be configured to draw in fluid (e.g., to within the barrel 602) from one or more fluid sources (e.g., reservoir(s) 102). The one or more syringes 106 may include a plurality of syringes 106, that are configured to draw in fluid in parallel (e.g., simultaneously). The plurality of syringes 106 may include one or more subsets of syringes, as described herein (e.g., a number of syringes aligned and fluidly coupled to a respective sub-manifold 216). The fluid may be drawn into the syringes (e.g., to within the barrel) via at least partially by gravity, via at least a partial vacuum being pulled within the barrel 602 of the syringes, or both.

[0163] In some embodiments, the method further includes fluidly coupling the one or more subset assemblies 402 (e.g., see FIG. 4). In some cases, the subsets of syringes are provided as already coupled with a corresponding sub-manifold 216 (e.g., FIG. 5). The method may further include coupling each subset of syringes (e.g., coupled with a corresponding sub-manifold 216) with the filling and sealing apparatus 108 via the upper rack 712, as described herein. For example, each subset of syringes may be slideably engaged with the upper rack grooves 704. In some cases, the corresponding sub-manifold 216 for each subset may be disposed and at least partially supported about an end cap 611 of the beams 716 (see FIG. 11 for example).

[0164] The method may further include coupling one or more main manifolds 104 with the corresponding sub-manifolds 216 (e.g., sub-manifolds 216 that may or may not be coupled withthe filling and sealing apparatus 108). For example, main manifold tubing 210 may be coupled with sub-manifold tubing 204 using one or more connectors 211, 212 as described herein.

[0165] The method may further include coupling the lower racks 714 with the syringes 106 (e.g., a respective lower rack 714 for a respective subset of syringes), for example via the locking nut 610, end cap 611, and / or locking tab 902 as described herein. In some embodiments, the lower racks 714 may be raised, and / or its longitudinal position may be adjusted so as to be configured to engage with the syringes. The method may further include moving a locking tab (e.g., 902) to a locked configuration once a respective lower rack is coupled with the syringes 106, thereby securing the syringes (e.g., from a subset of syringes) with the respective lower rack.

[0166] The method may further include fluidly coupling the main manifold(s) 104 to the fluid source(s) (e.g., reservoir(s) 102). This may include coupling the reservoir tubing 204 with the filling assembly tubing 208, which may be via one or more connectors 202, 206. In some cases, an intermediary tubing 205 may be used to fluidly couple the reservoir tubing 204 with the filling assembly tubing 208, wherein the intermediary tubing 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 coupling the integrity testing tubing 1202 with the main manifold 104 via a substantially leak free and substantially sterile connection, so as to enable the filling assembly 302 (or at least a portion thereof) to be tested. The filling assembly may be isolated from the reservoir, reservoir tubing, and / or intermediary tubing, when having an integrity test performed.

[0168] Integrity testing may be performed by opening the supply valve 1214 and monitoring the pressure (e.g., via pressure sensor 1216). During initial pressurization, the pressure sensor 1216 will read lower than the regulator 1212 setpoint. The pressurization, e.g., via a gas, will fill the manifold, associated tubing, and be in fluid communication with the syringe barrels. Once the system (e.g., filling assembly) has achieved the regulator setpoint (e.g., pressure), the gas supply will be maintained (e.g., within the filling assembly) for a predetermined period of time to enable the materials, which may have minor changes due to their inherent elasticity and temperature change in the gas due to expansion, to equilibrate. After the predefined period of time, the supply valve 1214 is closed, and pressure is monitored for decay. The integrity test assembly may pressurize the filling assembly using any gas (e.g., clean compressed air, nitrogen, helium, etc ).

[0169] In addition to or alternate to having a gas supply, if the filled units 106 are syringes they may be stroked to their fully extended position, so as to draw in air from an open vent, followed by closing the vent and compressing the syringes. Thus generating a higher pressure that can be monitored for integrity via pressure decay.

[0170] For a syringe filled unit, the integrity test may initially include the plunger rod 1504 (e.g., which may be for each barrel of the syringes 106 included with the filling assembly 302) to be inserted at a maximum position within the barrel 602 of the syringe 106 (e.g., such as a first position), such that the fill volume may be at a minimum or small amount (e.g., the plunger seal 1502 is located at its most proximal location within the barrel 602). The plunger rod position may be moved to the first position via the lower rack 714, as described herein. The pressurized filling assembly 302 may be allowed to stabilize before performing a leak test, which may be any manner described herein. For example, the leak test may include monitoring for pressure decay, monitoring supply flow rate, monitoring via a gas sniffer, monitoring for any bubbles, or any combination thereof.

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

[0172] If testing using a gas sniffer (e.g., helium sniffer), the pressurized gas may enter the filling assembly 302, as described for the pressure decay test, and wherein after stabilization, the gas (e.g., helium or other gas) sniffing instrument may be used to measure the area surrounding the filling assembly, and if no detection occurs, the assembly is integral.

[0173] If testing using bubble, the pressurized gas may enter the filling assembly as described for the pressure decay test, wherein a soapy solution may be applied or at least a portion of the filling assembly may be held under water. A lack of bubble formation indicates the assembly is integral.

[0174] If testing using flow rate, the pressurized gas may enter the filling assembly as described for the pressure decay test, wherein the gas supply is maintained while the flow rate of gas into the system is monitored via Flow Meter 1218. Predetermined parameters for acceptable flow after adefined time and / or for a defined time may be used to determine if the integrity test passes or fails, indicating if the assembly is integral.

[0175] With respect to the integrity tests, a failing result may require getting a new filling assembly.

[0176] If the filled units are syringes, the method of performing an integrity test of the filling assembly may include testing the syringes 106 with the respective plunger rods 1504 in multiple positions to ensure integrity of the full stroke of the syringes. For example, if the integrity test passes with the plunger rod at a fully compressed first position (as described herein), the lower rack(s) 714 may move the plunger rod distally, to move the plunger seal to a second position, which may correlate with a target fill volume within the barrel 602. Another integrity test may be performed (pressurized filling assembly, and detection for leak), as described herein. If the integrity test passes at the second position, the lower rack(s) 714 may again lower the plunger rod 1504 position to a maximum fill volume (e.g., plunger rod extended maximum out of barrel 602), correlating with a third position, and another integrity test may be performed.

[0177] The method for performing the integrity test may only include stroking the syringe at one or two of the three positions. In other embodiments, the integrity test may include more than three positions, which may or may not include any of the first, second, or positions. In yet other embodiments, the integrity test may include stroking the syringes to fully extended and using a slow compression of the syringes to build pressure in the assembly such that the trend of pressure can be compared to a known trend corresponding to positive integrity.

[0178] The method may further include performing an integrity test on the reservoir tubing 204 or at least a portion thereof, the intermediary tubing 205, the filling assembly tubing 208, any connectors 202, 203, 206, 211, 212 or any combination thereof. The integrity test tubing 1202 may be fluidly coupled at the connectors (e.g., 202, 203, or 202,206), or any one of the reservoir tubing 204 or intermediary tubing 205 (if present), or filling assembly tubing 208. The fluidic coupling by the integrity test tubing 1202 may be via a hose barb, threaded fitting, quick connect, aseptic connection, sterile tubing weld, and / or using a connector as described herein. Upon starting an integrity test, the regulated compressed gas may have an open flowpath to the said reservoir, intermediary, and filling assembly tubing. Prior to fluidly coupling the integrity test tubing, one or more pinch clamps or other valves may be applied to the reservoir tubing upstream of the integrity test tubing connection. Another pinch clamp may be applied to the filling assembly tubingdownstream of the integrity test connection. With the area of aseptic connection sealed off by the clamps, the integrity test tubing may be connected to the system. For example, said connection of the reservoir 102 to the manifold assembly 302 may include, using a sterile tubing weld: Terumo BCT Inc SCD IIB, GE Wave Sterile Tubing Welder, Vante® 3960 Sterile Tube Welder, Biowelder® TC By Sartorius; or aseptic connector Luer lock, SmartSite™, AseptiQuik™). After the integrity test tubing 1202 is connected, it may be ready for the integrity test to be performed on the weld or aseptic connection (as described herein, similar for the filling assembly). The pinch clamps and other fittings may be removed after the integrity test, to allow for an open flow path from the reservoir(s) 102 to the syringes 106.

[0179] As described herein, the method may include filling the syringes 106 with the fluid, which may be in parallel, and filled to a desired fill volume (which may correlate with the target fill volume in the syringe barrels). The fluid in the filling assembly may have air or other gases (e.g., if integrity testing is performed on the filling assembly, the pressure test gas). Thus, prior to filling the syringes 106 with the fluid, a degassing process may be performed to help reduce or eliminate the amount of gas in the fluid to be deposited into the syringes 106. The degassing process may be performed by performing multiple cycles of filling and emptying (e.g., for syringes stroking the syringes’ plunger rod, but this may include any other type of filling unit 106 described herein). Since the syringes 106 (e.g., barrel 602) may be vertically oriented or substantially vertically oriented with the proximal ends of the syringes (e.g., proximal end of barrel 602) substantially pointing upward, the gas within the fluid (e.g., of fluid that was deposited within the barrel) may naturally rise to the proximal ends of the syringe barrels. Alternatively, where a filled unit 106 corresponds to bags, an area around the bag may have vacuum pulled causing the bag to expand, drawing in fluid to be filled. Gas from within the manifold will be drawn into the bag before the fluid from the reservoir, and the gas will rise to the top of the bag. By pressurizing the area around the bag, the gas at the top will be pushed out of the bag followed by the material filled into it. At the reservoir the material expelled from the bag (first the gas, and then the fluid) is segregated by buoyancy such that when the bag is filled again (e.g., by vacuum in the area around the bag) it draws in only fluid to the fluid filled assembly. Similarly, each time a syringe is filled (e.g., barrel is filled), any residual gas may float to the top of the syringes (e.g., barrel), and thus an ejection of the fluid may also push residual gas out of the syringe, and / or out of the filling assembly, and / or into the reservoir. For example, once the reservoir is in fluid communication with the syringes 106(via open flow pathways), the lower rack 714 may draw in a maximum amount of fluid into the syringes (such that the plunger seal 1502 corresponds to a maximum fill volume position within the barrel), by distally extending the plunger rod to a maximum position outside of the barrel 602 (thereby pulling at least a partial vacuum within the barrel to at least partially help draw the fluid in). The fluid may preferentially flow to be below the gas in the syringes. The lower rack 714 may then move the plunger rod proximally to extend to a maximum position within the barrel 602 (such that the plunger seal 1502 corresponds to a minimum fill volume position within the barrel), thereby pushing a substantial portion of the fluid out of the syringes 106.

[0180] This stroking of maximum and minimum fill volume via movement of the plunger rod by the lower rack may be performed once or multiple times, which may result in bubbles to float to the top and / or towards the reservoir, and thereby out of the fluid near and / or about the syringes. The multiple cycles may be used to reduce the probability of a recalcitrant gas bubble. Additionally or alternatively, other methods for degassing may occur, such as vibratory, impact, sonic, and / or other physical mechanisms may be used to liberate gas bubbles adhered to surfaces via surface tension. For example, a vibrational mechanism may be added to the apparatus that allows for shaking of the syringes to dislodge bubbles which may be stuck due to surface tension. Accordingly, the fluid may be degassed, mixed, all without or with a minimum amount of loss of fluid.

[0181] The method may further include using the lower rack to move (e.g., stroke) the plunger rod to place the plunger seal at the desired or target fill volume, where the desired or target amount of fluid is drawn into the syringes (e.g., barrel 602). As described herein, movement of the lower rack may be controlled using one or more processors. The movement of the lower rack may be controllable to 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 racks 714 may be separably moveable, such that only specified syringes are filled with the fluid at a given time.

[0182] In some embodiments, situations may present whereby the amount of fluid in the reservoir is less than the sum of the target fill quantities (e.g., target / desired fill volume) in the syringes. In such cases, any number of syringes may not be filled. Disabling one or more syringes may be done by i) disconnection of the syringes, ii) independent actuation of specific syringes, iii) a bypass valve, iv) designating various zones of syringes for filling, v) a plunger shaft passthrough, or vi) any combination thereof. Disconnection methods include sealing and / or cutting methods (e.g.,cutting syringe tubing for any number of syringes) as described herein (e.g., see FIGS. 8A-8B), wherein syringes may be disconnected from the manifold system without compromising the sterility of the manifold. For example, the sealing portion of select beams may be activated (i.e., not all the sealing portion of all beams need to be activated simultaneously). Since the syringes that are disconnected may not be used, the sealed tubing connected to the inlet / outlet port of the syringes can then be removed so as not to generate pressure or vacuum during the sequencing of the syringes. Other means of preventing the build of pressure or vacuum for those syringes not to be filled, may include disconnection of a plunger rod or creating an alternate ventilation such as a puncture in the syringe barrel or stopper.

[0183] Independent actuation may include providing an independent linear actuator for each lower rack (thus corresponding to a specific subset of syringes) and / or for each syringe (e.g., a single syringe within a subset), wherein any one or specific number of syringes may have the plunger rods independently controlled. More actuator(s) may be disabled (e.g., mechanically, and / or from the software of a processor in communication with the actuators), such that the specific syringes are not filled.

[0184] A bypass may include a 3 -way valve, that may be designed between the manifold system and the specific syringe(s), such that, for syringes not intended to be filled, the valve would be set to a position where the manifold system is closed off, but the syringes may be venting.

[0185] Syringe zones may include where the syringe array may be configurable with multiple zones, where the lower rack may be broken into subsections that are independently actuated. These zones can be programmed to not actuate (therefore not fill). Additionally, these zones may be used for alternate fill sizes (i.e., a variety of filling unit geometries may be desired for each fill, each of which requiring a different stroke and fill target [e.g., different fill volume] for proper functioning).

[0186] Plunger shaft passthrough may include wherein the lower rack used for sequencing the plunger does not need to be of solid design. For example, the lower rack may have through holes (e.g., through the platform 904 and / or recessed surface 908) which may be engaged or disengaged (e.g., by threaded fitting, quarter turn release, or other means by which to attach the syringe distal portions [as described herein] to the lower rack, whereby when engaged, the plunger rod moves with the lower rack, but when disengaged, the lower rack moves but the plunger rod may pass through the plane of the base of the lower rack and remain stationary).

[0187] After filling of the syringes, the method may optionally include an operator being prompted to visually inspect the syringes to ensure there are no issues. This visual inspection may be facilitated by add-on equipment including a camera system which may be capable of identifying liquid levels and fill volumes. Additionally, the holding mechanisms for the lower rack and upper rack may optionally be mounted onto load cells such that at the completion of air purge the weight may be tared / zeroed, and at the completion of stroking to the desired fill quantity, the total weight of the solution filled into the syringes can be measured. This weight measurement may be checked against to see if there is a match with an expected fill weight within acceptable measurement error and fill variability tolerance.

[0188] The method may further include, once the syringes are filled to the target fill volume, sealing and, optionally, cutting the syringe tubing. The sealing portion 711 of the beams 716 may compress the syringe tubing 304 (e.g., pinch the internal walls of the tubing 304), as described herein. For example, a first component 818 for a first beam and / or a second component 820 of an adjacent beam (e.g., as described in FIGS. 8A-8B) may be initiated to be moved towards the other, thereby pinching a portion of the syringe tubing for a subset of syringes (e.g., the internal walls of a given syringe tubing are pinched together). As described in FIGS. 8A-8B, each of the first and second components 818, 820 may have corresponding profiles 814, 816 that define respective plateau 806, 808 and respective valley 804, 812 portions. Energy input (e.g., heating elements, hot oil recirculation, ultrasonic, or radio frequency energy, as described herein) may then be used to at least partially melt or soften the compressed (e.g., pinched) thermoplastic syringe tubing 304, to allow for flowing of at least some of the tubing material out of tubing portion 826 (e.g., disposed between plateaus 806, 808), which may be without cutting / shearing the tubing 304. After allowing for the flow to occur to a degree, where material from the compressed area (e.g., first portion of tubing) is able to flow out from between the compressed area leaving only a thin film remaining; the amount of energy and pressure used by the first and / or second components 818, 820 against each other are changed to enable sufficient flow and force to shear and cut the remaining thin film, thereby splitting the tubing 304 to two portions (e.g., 828, 829), and / or sealing the tubing portions about the cut locations. This disconnects the syringes from the sub-manifold assembly (e.g., subset assembly 402) they came in without compromising sterility. The sealing and cutting may be performed simultaneously or substantially simultaneously, and / or at least partially sequentially.

[0189] In some cases, the syringes may be disconnected using a thermoplastic elastomer tubing sealer (Such as Biosealer® TC Tube Sealer, Vante® 4600, Biosealer®, SEBRA® 2380, Blood Tube Sealer - MTBTS03) or by mechanical means (Such as NovaSeal™ cuff and crimp), or alternatively using the sealing portion 711 of the apparatus 108 as described in

[0109] ,

[0190] The filling units may then be removed from the apparatus 108. The embodiments described herein referring to syringes as the filling units 106 are a non-limiting example of the types of filling units that may be used for a system 10, filling assembly 302, and / or subset assembly 402 described herein. As described herein, the filling units used with a system 10, filling assembly 302, and / or subset assembly 402 described herein may be any one or more of syringes, bags, vials, bottles, containers, etc.

[0191] The method may further include obtaining one or more samples of the fluid. For example, after the syringes have been filled (and / or separated from the sub-manifold), there may be remaining fluid in the manifold system and / or reservoir (for example, the amount of fluid in the reservoir may be greater than the sum of fill volumes in the syringes to be filled). Such remaining fluid may be representative of the whole batch that was used to fill the syringes, since the syringes were filled in parallel (e.g., as opposed to sequentially over time, where the fluid properties and / or conditions may change between the first syringe being filled and the last syringe being filled). The remaining portion may be collected for QC sampling through additional sample containers attached to the sub-manifolds, or through use of tube strippers to pool the material into the bulk bag (e.g., reservoir) and provide QC with one large sample for aliquoting. The manifold may be designed with a side port (see e.g., see FIG. 19) whereby at the completion of the filling, the remaining solution may be drawn into the sample container (which may also be another type of collection container, such as a vial, bag, tank, syringe, etc.), such that there is no waste or loss of fluid. Furthermore, the integrity test assembly may be used to add gas to the filling assembly for the purpose of pushing out remaining solution. In some cases, the collection for sampling is done simultaneously with the filling of the syringes 106 (e.g., via sample tubing 306).

[0192] In some embodiments, a post use integrity test is performed on the assembly to detect if there are any integrity test failures from the Seal / Cut system Since the seals on the filled unit 106 side (e.g., 829) of the manifold are symmetrical with the manifold side (e.g., 828), the post use integrity test of the manifold with complimentary seal / cut to the filled units may avoid necessity to integrity test all the filled units after manufacturing.

[0193] In some embodiments, the method may further include sterilizing the fluid prior to depositing into the syringes. For example, in some cases, the fluid within the reservoir is already purified (e.g., sterile). In some cases, however, where the fluid is not purified, the method may further include purifying the fluid. For example, this method may include sterilization of the fluid by means of filtration. The filtration may not need be for the purpose of sterilization but may imbue another quality such as uniformity, removal of contaminants, homogeneity, catalytic conversion, etc. In said circumstances, the system may further include a pump, a filter or other flow through unit, an auxiliary line for flush solution, and a vent filter and / or integrity test connection.

[0194] An example method for sterilizing the fluid may include 1) install sterilization and filling assembly 2016 into the apparatus, which includes connections 2006; 2) pass tubing through the pump 2008; 3) connect flush solution 2004; 4) use pump 2008 to flush filter 2011 and wet the membrane while diverting solution to the flush container 2012; 5) stop the pump 2008 when sufficient quantity has passed the filter 2011; 6) disconnect the flush solution 2004 from the assembly via connections 2006 (e.g., includes isolating from the pump 2008); 7) use the pump 2008 to transfer any remaining flush solution such that none remains in the lines; 8) connect the integrity test tubing 1202 to vent filter 2010 or integrity test connection; 9) perform integrity test; 10) disconnect integrity test tubing 1202; 11) close off / clamp shut the vent filter 2010 or integrity test connection and flush container; 12) connect the unfiltered reservoir 2002 to the assembly 2016 (e.g., coupling with pump 2008); 13) use the pump 2008 to transfer the unfiltered fluid through the filter 2011 and into the reservoir 102; 14) perform filling of syringes as described herein.

[0195] A sterile filtration is typically a critical operation. It may be common to have two filters in series with filter integrity testing of one or both (individually or in series).Examples of System Operation

[0196] FIG. 21 illustrates a flowchart depicting an overview of a process of using a filling system (e.g., 10 as described herein), according to some embodiments. The process starts (at step 2100). At this stage the filling system is idle, and there is no assembly or product installed. In some embodiments, a user of the system logs in (at step 2102). This may be for verification purposes. According to some embodiments, the user selects a recipe (at step 2104), for example for a fluid to be deposited within a filling unit described herein. The filling unit may be interchangeably referred to unit. The filling unit may be any type described herein, including a syringe, a vial, a bottle, a container, a bag, etc. Various chemical combinations may be possible through the fillingsystem, and the user may be able to select a prefabricated recipe for a specific chemical composition, or customize the composition if desired. A different recipe may need to be created for each container type (e.g., syringe, bag, vial, etc.), as well as each product type.

[0197] Next, the user may select how many filling units are to be filled (at step 2106). The filling system may include an array of filling units (e g., syringes 106) connected to a distribution system (e.g., manifold system as described herein), each filling unit configured for receiving the fluid (e.g., selected recipe from above). In some embodiments, the user can select the number of filling units to be filled, and only that number of fill-points that are fluidly coupled to a respective filling unit will receive the fluid (or will be closed off so the fluid does not exit from those fill-points). By way of example, assuming the filling system supports a depth of ten filling units, the user can select a number of rows to get that quantity multiplied by ten filling units worth of the fluid.

[0198] In some embodiments, the system sends all moveable items to their home position (at step 2108). This may be to prepare the system for filling of the containers. According to some embodiments, the system displays confirmation of the layout (at step 2110). This confirmation of the layout step is detailed further in FIG. 29 below. After this step, the method continues with the basic overview process as described in FIG. 22 below.

[0199] FIG. 22 illustrates a continuation of the flowchart depicting the overview of the process of using the filling system, according to some embodiments. In some embodiments, the method includes confirming when an assembly is installed (at step 2200). This confirmation may act as a safety to make sure the filling system is ready to properly fill containers. According to some embodiments, the method includes installing a single-use manifold (at step 2202). This installation may follow additional steps as detailed in the method of receiving and preparing the filling system in FIG. 30 below. The user may then confirm this installation (at step 2204).

[0200] In some embodiments, the method includes performing ranging for the bottoming out of any present plungers (at step 2206). The filling system may operate by way of drawing a vacuum. In a fully sealed system, it is possible to form a vacuum between a present reservoir (which holds the recipe) and the containers to be filled (e.g., filling unit, as described herein). By moving a plunger, the recipe is drawn into the container while preventing contaminants from entering the system. However, the filling system may need to know how far the plunger can be moved, and thus may perform this step of ranging for the bottoming out of the plunger(s). This ranging for thebottoming out of the plunger(s) is detailed further in FIG. 31 below. After this step, the method continues with the basic overview process as described in FIG. 23 below.

[0201] FIG. 23 illustrates a continuation of the flowchart depicting the overview of the process of using the fdling system, according to some embodiments. In some embodiments, the method includes the fdling system displaying “Ready to begin integrity test?” (at step 2300). This step may be to convey to a user that integrity testing is going to be performed, or to give the user an option to bypass this testing. According to some embodiments, the user confirms that they and the system are ready to begin the integrity test (at step 2302).

[0202] The filling system may then perform the integrity test (at step 2304). This initial integrity test may be for the flowpath coming from the reservoir. The integrity test is detailed further in FIGS. 32-34 below. After this step, the method continues with the basic overview process as described in FIG. 24 below.

[0203] FIG. 24 illustrates a continuation of the flowchart depicting the overview of the process of using the filling system, according to some embodiments. In some embodiments, the method includes the filling system displaying “Integrity test passed. Clamp inlet port and connect product.” (at step 2400). This may convey to the user that the filling system has passed the integrity test for the inlet port, and instruct them prepare the flowpath to the containers (e.g., filling units as described herein). According to some embodiments, the user confirms this message (at step 2402).

[0204] The filling system may then perform an additional integrity test (at step 2404). This integrity test may be for the flowpath going toward the containers to be filled. This integrity test may be same integrity test as that mentioned in step 2304 above, and as such, this integrity test is detailed further in FIGS. 32-34 below. After this step the method continues with the basic overview process as described in FIG. 25 below.

[0205] FIG. 25 illustrates a continuation of the flowchart depicting the overview of the process of using the filling system, according to some embodiments. In some embodiments, the system performs degassing and filling (at step 2500). The degassing and filling process is detailed further in FIG. 35 below. After this step the method continues with the basic overview process as described in FIG. 26 below.

[0206] FIG. 26 illustrates a continuation of the flowchart depicting the overview of the process of using the filling system, according to some embodiments. According to some embodiments, the system displays “Filling complete. Perform visual inspection.” (at step 2600). The visualinspection process is detailed further in FIG. 36 below. After this step, the method continues with the basic overview process as described in FIG. 27 below.

[0207] FIG. 27 illustrates a continuation of the flowchart depicting the overview of the process of using the 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 pathway leading to the container, in order to prevent any chance of contamination of the contents of the container. This sealing step may include cutting, or otherwise disconnecting, the containers from the flowpath, so as to create individual, disconnected containers full of the chosen recipe. This sealing and disconnecting step is detailed further in FIG. 37 below. After this step the method continues with the basic overview process as described in FIG. 28 below.

[0208] FIG. 28 illustrates a continuation of the flowchart depicting the overview of the process of using the filling system, according to some embodiments. In some embodiments, the system displays “Sequence finished. [XX] units filled [YY] minutes process time alarms [array of alarm messages].” (at step 2800). The [XX] may indicate the number of containers the user specified in step 2106 above. The [YY] may indicate the processing time, either from beginning of the use of the filling system, total time from beginning of integrity testing to finishing disconnecting the filled containers, or total time to fill the containers itself. The [array of alarm messages] may convey any pertinent information, either about the filling system or containers, or about the filling procedure, to the user. After this step, the process of using the fillings system ends (at step 2802).

[0209] FIG. 29 illustrates a flowchart depicting a method of verifying a layout of the filling system, according to some embodiments. After the system displays confirmation of a layout (at step 2110), the system may ask the user to verify the layout (at step 2900). Verifying the layout may include the user interacting with a matrix (or array) of symbols indicative of flowpaths from the reservoir to locations for filling containers. The user may select each flowpath that will be utilized (turning a symbol corresponding with this flowpath) green. Unused flowpaths may remain red, or turn red upon the user selecting the corresponding symbol for deactivation of that flowpath. In additional or alternate embodiments, other colors may be used for activated or deactivated flowpaths, as well as symbols indicating the corresponding status of the flowpath.

[0210] FIG. 30 illustrates a flowchart depicting a method of receiving and preparing the filling system, according to some embodiments. In some embodiments, the assembly arrives in a box (atstep 3000). The assembly as described herein may be any component of the fdling system, such as an independent manifold, or the fdling system as a whole. The shipping and receiving facility, or person responsible for shipping and receiving, may then confirm that no damage has been incurred in the assembly during transit, receive the assembly into the warehouse / storage facility, and update their inventory to indicate the delivery has arrived and is available for use (at step 3002).

[0211] When the assembly is needed, the production department, or person responsible for production, may inform shipping and receiving (or other responsible party) of their needs from the unit from storage. This party may then remove the assembly from the box and make an update to the inventory (at step 3004). Shipping and receiving (or other responsible party) may then transfer the assembly to production and perform sanitization of the overwrap on the assembly (at step 3006).

[0212] Production may then document the serail number of the assembly in the master boot record, remove the overwrap and any shipping shims or scaffolds, and then install the assembly into the filling system (when the assembly is a portion of the filling system, and not the filling system as a whole) (at step 3008). At this point, the single use manifold is installed (at step 2202).

[0213] FIG. 31 illustrates a flowchart depicting a method of ranging plungers of the filling system (as described in step 2206), according to some embodiments. In some embodiments, the user of the filling system sets the integrity test valve to venting (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 may then be prompted to verify that all syringes are fully compressed (at step 3104).

[0214] If all of the syringes are fully compressed, the operator may then be prompted to verify the stroke length of an amount of distance, perhaps in millimeters, for the type of syringe being provided (at step 3106). If the operator verifies the stroke length for the syringe type, the method returns to the system displaying “Ready to begin integrity test?” at step 2300 of FIG. 23 above.

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

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

[0217] The steps above may additionally or alternatively be used for other types of containers, such as bags or vials, wherein a plunger is used to fill the container. Additionally, the steps in this flowchart may be included in order to ensure that all of the syringe (container) barrels are aligned, and that the filling systems knows accurately where the fully compressed limit is for each syringe (container). Based on the fully compressed limit (along the Z-axis), the system may call the variable for the syringe (container) body length to determine the Z-axis coordinate for a fully extended stroke as well as a targeted fill stroke (i.e., the target displacement of the plunger to fill the syringe or container to a desired fill level).

[0218] FIG. 32 illustrates a flowchart depicting a method of testing the integrity of the filling system, according to some embodiments. When the filling system performs the integrity test (at step 2304), the system or operator may set the integrity test valve to supply (at step 3200). At this point, the operator may choose to perform helium testing (at step 3202) and / or pressure decay testing (at step 3204). The filling system may also automatically perform either of the helium testing (at step 3202) or the pressure decay testing (at step 3204). The helium testing is detailed further below in FIG. 33. The pressure decay testing is detailed further below in FIG. 34.

[0219] If the operator or filling system do not need to perform either of the helium testing or the pressure decay testing, the method may move to ensuring that all positions have been tested and passed (at step 3206). Similarly, once the helium testing and / or pressure testing has been successfully passed, the method may move to ensuring that all positions have been tested and passed (at step 3206).

[0220] If all positions have not been tested or not passed the test, the method may include moving the plungers to the next position (i.e., fully compressed, midpoint, target fill volume, fullyextended, etc.) (at step 3208). After this, the system may once again perform helium testing (at step 3202) and / or pressure decay testing (at step 3204).

[0221] If all positions have been tested and passed the test, then the operator or fdling system may set the integrity valve to venting (at step 3210). In some embodiments, the plungers are moved once again to their fully compressed state (at step 3212). After this occurs, the method may continue to performing degassing and filling the container (at step 2500) as detailed in FIG. 25 above.

[0222] On a first pass of these steps, the syringes (plungers) may be in their fully compressed position because of the ranging of the filling system of finding the bottom out position of the plunger (as detailed in FIG. 31 above). The assembly integrity test (coming from step 2304 in FIG. 23 above) and the sterile connection integrity test (coming from step 2404 in FIG. 24 above) may be the same sequence of steps, but with different parameters for timeout and maximum pressure decay.

[0223] FIG. 33 illustrates a flowchart depicting a method of performing helium testing, according to some embodiments. In some embodiments, the method includes pressurizing the filling system to a setpoint (at step 3300). According to some embodiments, the setpoint is reached (at step 3302) and the pressure is held for a predetermined specified hold time (at step 3304). The filling system may then begin a helium sniffing test, confirming when the test has been completed (at step 3306). If the helium sniffing test does not return with a high or outside of nominal value (at step 3308), the method returns to confirming that all positions of the plunger have been tested and passed (at step 3206 of FIG. 32 above).

[0224] If the helium sniffing test does return with a high or outside of nominal value (at step 3308), the user is prompted to either abort the filling of the containers, as a breach has been found and contamination of the recipe may have occurred, or retry the helium sniffing test (at step 3314). If the user chooses to abort the filling of the containers, the procedure stops entirely (at step 3316). If the user chooses to retry the helium sniffing test, the method returns to attempting to pressurize the filling system to a setpoint.

[0225] If, while the filling system is attempting to pressurize to a setpoint (at step 3300), and it fails to do so before a timeout timer is reached (at step 3310), the filling system indicates to the user that such a timeout time has been reached and indicates to the user to check the connections between components of the filling system (at step 3312).

[0226] Once the user receives this notification, they may be prompted to either abort the filling of the containers, as a breach has been found and contamination of the recipe may have occurred, or retry pressurizing the filling system to a setpoint (at step 3314). If the user chooses to abort the filling of the containers, the procedure stops entirely (at step 3316). If the user chooses to retry pressurizing the filling system to a setpoint, the method returns to the start point at step 3300.

[0227] FIG. 34 illustrates a flowchart depicting a method of performing pressure decay testing, according to some embodiments. In some embodiments, the method includes pressurizing the filling system to a setpoint (at step 3400). According to some embodiments, the setpoint is reached (at step 3402) and the pressure is held for a predetermined specified hold time (at step 3404). The filling system may then begin a pressure decay test (at step 3406). If the pressure decay value is not exceeded (at step 3408), the method returns to confirming that all positions of the plunger have been tested and passed (at step 3206 of FIG. 32 above).

[0228] If the pressure decay value is exceeded (at step 3408), the user is prompted to either abort the filling of the containers, as a breach has been found and contamination of the recipe may have occurred, or retry the pressure decay test (at step 3414). If the user chooses to abort the filling of the containers, the procedure stops entirely (at step 3416). If the user chooses to retry the helium sniffing test, the method returns to attempting to pressurize the filling system to a setpoint.

[0229] If, while the filling system is attempting to pressurize to a setpoint (at step 3400), and it fails to do so before a timeout timer is reached (at step 3410), the filling system indicates to the user that such a timeout time has been reached and indicates to the user to check the connections between components of the filling system (at step 3412).

[0230] Once the user receives this notification, they may be prompted to either abort the filling of the containers, as a breach has been found and contamination of the recipe may have occurred, or retry pressurizing the filling system to a setpoint (at step 3414). If the user chooses to abort the filling of the containers, the procedure stops entirely (at step 3416). If the user chooses to retry pressurizing the filling system to a setpoint, the method returns to the start point at step 3400.

[0231] FIG. 35 illustrates a flowchart depicting a method of degassing and filling containers using the filling the system, according to some embodiments. In some embodiments, the method includes setting the integrity test valve to closed (at step 3500). According to some embodiments, the method includes moving the plungers to a fully extended position (at step 3502).

[0232] The method may include striking or vibrating the plungers, containers, manifold, or filling system as whole, for either a certain number of repetitions or a predetermined duration of time (at step 3504). In some embodiments, the method includes prompting the user or the filling system for verification that bubbles are all in the headspace of the syringe (or container) (at step 3506). According to some embodiments, the method includes moving the plungers to a fully compressed position (at step 3508).

[0233] The method may include confirming that a number of repetitions of steps 3502 through 3508 has been performed a specified number of times based on the chosen recipe (at step 3510). If the number of repetitions has been performed the specified number of times, then the plungers are moved to a targeted fill volume (at step 3512), thereby filling the associated container with the desired amount of the recipe. After this, the method may include system displaying “Filling complete. Perform visual inspection” at step 2600 in FIG. 26 above.

[0234] If the number of repetitions of steps 3502 through 3508 have not been performed the specified number of times, the filling system moves the plungers back to the fully extended position (at step 3502) and repeats the aforementioned steps.

[0235] FIG. 36 illustrates a flowchart depicting a method of inspecting the filling system after filling has occurred, according to some embodiments. In some embodiments, the method includes visually inspecting the filled units (at step 3600). This step may be performed by the operator of the system, or a vision system included within the filling system to automatically perform these actions.

[0236] If there are bubbles included in the container, the steps for degassing and filling the containers are reperformed (either by the operator or automatically by the filling system) (at step 3602). If there is a detected issue with the assembly, the filling system returns the BDP (e.g., this may include the fluid) to the container (at step 3606). These steps may be performed prior to the system performing degassing and filling the containers (at step 2500 in FIG. 25 above), in addition to, or instead of, sealing and disconnecting all units (at step 2700 in FIG. 27 above).

[0237] FIG. 37 illustrates a flowchart depicting a method of sealing and disconnecting containers from the filling system, according to some embodiments. In some embodiments, the method includes checking if there is headspace desired (at step 3700). If there is headspace desired, the method may include prompting the user or the filling system to open the satellite collection port on the manifold, and confirming when draining is completed (at step 3702). According to someembodiments, the method includes moving the plungers to a calculated position (at step 3704). This calculated position may be calculated through adding the targeted fdl volume of the containers to the headspace volumes of the containers.

[0238] After moving the plungers to their calculated position, all sealing bars are raised to a predetermined temperature (at step 3706). Similarly, if there is no headspace desired (from step 3700), the method may also move directly to raising all sealing bars to the predetermined temperature (at step 3706). In some embodiments, the method includes achieving the desired predetermined temperature for all sealing bars (at step 3708).

[0239] According to some embodiments, the method includes closing the sealing bars and holding them in place for either a predetermined amount of time (such as in seconds), or until a signal occurs (which may include a limit switch indicating the heated faces of the sealing bars have met) (at step 3710). This step may seal the container without exposing the contents to the ambient environment (e.g., surrounding environment), thereby preventing contaminant from entering the containers. After the containers have been sealed and decoupled from the fdling system, the system may then display “Sequence finished. [XX] units filled [YY] minutes process time alarms [array of alarm messages].” (as detailed in step 2800 in FIG. 28 above).

[0240] The below is a restatement of the preceding systems, flowcharts, and methods, stated in an alternate way. Provided in the present disclosure is a method for implementing a system for filling contains (i.e., syringes, vials, bags, etc.) while eliminating the risk of contamination of the containers or substance filling the containers, without necessitating a cleanroom. The provided system and methods incorporate multiple means to enable the safe filling of these containers while also reducing cost and complexity.

[0241] These means include confirmation of filling assembly integrity prior to use, confirmation of aseptic connection integrity prior to use, directing flow to a plurality of containers without significant loss of product in the system’s “holdup,” positioning and sequencing the syringe units receiving the product, combining the requisite parts into a cassette and filling assembly that is functional, performing the requisite operations with a machine to achieve the desired fill, and a number of additional configurations which may be required by various use cases. Each of these means will be explored in greater depth below.

[0242] With respect to confirmation of filling assembly integrity prior to use, the filling assembly may be provided as a consumable for the processing. This means that once the filling assemblyhas served its purpose, the entire assembly may be discarded. In some embodiments, the fdling assembly includes all necessary flowpaths and parts for the filling operations. According to some embodiments, the filling assembly is installed in the machine. According to some embodiments, before performing an aseptic connection to a bulk reservoir, an integrity test is performed on the filling assembly using an integrity test coupling and the machine.

[0243] In some embodiments, the machine requires a compressed gas source (which may either be in the form of bottled or utility). According to some embodiments, within the machine there is a compressed gas regulator and filter, compressed gas manifold, integrity test regulator and filters, integrity test gas supply valve, pressure sensor, flow meter, and connection to the integrity test tubing. Integrity testing may be performed by opening the supply valve and monitoring the pressure.

[0244] In some embodiments, during initial pressurization, the pressure sensor will read lower than the regulator setpoint. Once the system has achieved the regulator setpoint, the gas supply may be maintained for a predetermined period of time to enable the materials, which may have minor changes due to their inherent elasticity and temperature change in the gas due to expansion, to equilibrate. After the predetermined amount of time, the integrity test gas supply valve may be closed, and the pressure monitored for decay.

[0245] A decay in pressure may be indicative of a leak and may require acquiring a new assembly. Additionally or alternatively, the compressed gas may be helium or some other gas capable of being detected using an external instrument. In the course of integrity testing, it may be desirable to test the integrity of the filling assembly with the filled units in multiple positions (i.e., fully closed, partially filled, fully open, etc.). In some embodiments, upon successful integrity testing of the fill assembly, the fill assembly may be aseptically connected to the bulk reservoir.

[0246] With respect to confirmation of aseptic connection integrity prior to use, the bulk reservoir may be connected to the fill assembly without compromising the sterility of the product. This may be accomplished without the need for a sterile environment. Typical solutions include the aseptic connection being made using a tubing weld or aseptic connector, which have non-zero failure rates. Instead, a specialized tubing connector may be used to perform an integrity test of the weld before releasing the pinch clamps. The steps for performing the integrity test for confirmation of aseptic connection integrity may be the same as those for performing the integrity test for filling assembly integrity as detailed in the preceding paragraphs.

[0247] With respect to directing flow to a plurality of containers without significant loss of product in the system “holdup,” a manifold may be provided to distribute a solution to be filled into the fill units within the cassette. The manifold may provide a minimum flowpath (both in distance and hold up volume) in order to enable all filled units to fill simultaneously, while also ensuring velocity at any given point does not create shear that would degrade the solution to be filled or cause air bubbles to break apart increasing their surface area and absorption into the solution. In some embodiments, to ensure that this is the case, the system may be designed as described in the forthcoming paragraphs.

[0248] In some embodiments, the system includes a distributor beam manifold laid out in a grid, radial, star, or other pattern with feed coming from the solution to be filled. This solution may have no internal connections, and may be made of a minimal number of pieces.

[0249] According to some embodiments, the system includes a tubing manifold laid out in a grid, radial, star, or other pattern with feed coming from the solution to be filled. This solution may have many internal connections and may be made of many internal components. To ensure the integrity of these components, the tube manifolds may be cast into a resin or plastic over-mold.

[0250] In some embodiments, the system includes a primary manifold and a sub-manifold. In order to reduce velocity, it may be beneficial to employ a larger diameter sub-manifold which has channels that connect through the larger manifold. This may reduce the velocity of flow required at the midpoint of the manifold by distributing the influx more equally across the larger manifold. In some embodiments, this is depicted as a tubing manifold, but is also applicable in other manifold concepts such as the distributor beam manifold detailed above.

[0251] In any of the above disclosure, the designs may not need to be symmetrical (e.g., if there are multiple sizes of containers (or syringes) to be filled, the distribution of ports may be asymmetrical to match the needs of the user.

[0252] At the outlet of the manifold, there may be manifold port connectors (e.g., hose barb, Luer connection, threaded flanged connection, needle-free Luer port, or any other connector a person having ordinary skill in the art would use to connect either to tubing, piping, or directly to a syringe barrel. These ports may be connected to the filled units using a tube or means of sterile disconnection.

[0253] With respect to positioning and sequencing the filled units receiving the product, the filled units may be any container with variable volume, such as syringes, vials, bags, etc. The containersmay be arranged in an upper rack, whereby the orientation and layout of the syringes may be assured. In some embodiments, the upper rack is connected to the barrel flange clasp as a means of securing the barrel, while a lower rack attached to a plunger flange using a barrel flange clasp or other connection means.

[0254] Behind the plunger seal there may be a bellows, which may be modified to provide means for the lower rack to attach to the plunger flange. This may occur via mechanical attachment such as a plunger flange clasp, a magnetic coupling, an attachment using vacuum, an automated clasp, or any other means that may be employed by a person having ordinary skill in the art. According to some embodiments, the lower rack is actuated either for individual containers (i.e., each container has a linear actuator and can be filled and emptied independently) or as many as all of them that can be actuated together using a single linear actuator.

[0255] With respect to the cassette, the cassette may include an integrity test coupling, a manifold, filled units, and racks. The fill assembly may be fully closed and integral by means of an end cap, a seal, an aseptic connector, or any other means of closure which may be employed by a person having ordinary skill in the art. In some examples, the fill assembly may be an integral system, which, when connected to an integral bulk reservoir containing solution to be filled, is capable of transferring that fluid to each of the fill units without exposure to the environment.

[0256] With respect to the machine, the machine may provide a user interface whereby an operator can login and command various system functions such as loading the cassette, performing calibration, maintenance mode, integrity testing, and various operator recipes for different fill unit sizes / quantities, fill levels, and parameters for steps performed in the recipe. In some embodiments, the machine is designed such that, after installation of the fill assembly, the upper rack is held securely by the machine, the lower rack is held by a linear actuator on the machine opr platform connected to a multitude of filled units on the machine, and the integrity test coupling is connected to an integrity test tube of the machine.

[0257] In some embodiments, the operation of the machine is achieved via linear actuator(s) which provide the motive force for movement of the syringe plungers. According to some embodiments, operations of the machine include integrity testing, filling, and disconnecting filled units.

[0258] With respect to integrity testing, a compressed gas utility supply may be provided to the machine. In some embodiments, within the machine there is a compressed gas regulator and filter, compressed gas manifold, integrity test regulator and filters, integrity test gas supply valve,pressure sensor, flow meter, and connection to the integrity test tubing. Upon starting an integrity test, the regulated compressed gas may have an open flowpath to the integrity test tube and integrity test coupling. Prior to making an aseptic connection, punch clamps or other valves may be applied to the bulk reservoir tubing from the bulk reservoir upstream of the aseptic connection.

[0259] In some embodiments, another pinch clamp is applied to the fdling assembly tubing to the cassette downstream of the integrity test coupling. With the area of aseptic connection sealed off by the clamps, the aseptic connections mya be formed. After the aseptic connection is made, it may be ready for a pressure test.

[0260] For pressure tests using pressure decay, the pressure sensor downstream of the gas supply valve may measure the pressure supplied. In some embodiments, after a stabilizing period, the gas supply valve closes, trapping pressure within the tubing containing the aseptic connection. The pressure sensor may measure the pressure decay for a period of time and using predetermined parameters for acceptable pressure decay may determine if the integrity test passes or fails.

[0261] For pressure tests using a helium sniffer, the pressurized gas may enter the tubing as described above for the pressure decay test. In some embodiments, a helium (or other gas) sniffing instrument is used to measure the area surrounding the aseptic connection, and if no detection occurs, the seal is integral.

[0262] For pressure tests using a bubble, the pressurized gas may enter the tubing as described above for the pressure decay test. In some embodiments, a soapy solution is applied, or the tubing is held under water. Lack of formation of a bubble may indicate that the seal is integral.

[0263] With respect to filling, upon successful completion of the pressure test, the flowpath from the solution to be filled may have pinch clamps or other types of valves / reversible closures removed and / or opened to enable an open flowpath. In some embodiments, initially, the filling assembly will have air or (if integrity testing is performed on the filling assembly) the pressure test gas inside. This gas may be purged at the time of filling by multiple cycles of stroking the filled units.

[0264] According to some embodiments, as the filled units are vertically oriented with the filled unit tip pointing upward, the gas naturally rises to the filled unit tip. Each time the container is filled, any residual gas may float to the top of the filled unit, thus an ejection of the solution to be filled may have the capacity to push residual gas out of the filling assembly and into the bulk reservoir.

[0265] In some embodiments, multiple cycles are used to reduce the probability of a recalcitrant gas bubble. Additionally or alternatively, a vibrational mechanism may be added to the machine that allows for shaking of the cassette to dislodge bubbles which may be stuck due to surface tension.

[0266] According to some embodiments, at the completion of the air purge, the machine strokes the fill units to a desired fill quantity. An operator may be prompted to visually inspect the fill units to ensure there are no issues. In some embodiments, this inspection may be facilitated by add-on equipment such as a camera system which is capable of identifying liquid levels and fill volumes.

[0267] The holding mechanisms for the mobile and stationary portions of the rack may optionally be mounted onto load cells such that at the completion of the air purge the weight may be tared / zeroed, and at the completion of stroking to the desired fill quantity, the total weight of the solution filled into the fill units can be measured. In some embodiments, the weight measurement should match an expected fill weight within acceptable measurement error and fill variability tolerance.

[0268] With respect to disconnecting filled units, filled units may be disconnected using a thermoplastic elastomer tubing sealer, or by mechanical means.

[0269] With respect to fine tuning a number of filled units, there may be embodiments whereby the amount of solution to be filled is less than the sum of the target fill quantities in the fill units. In such embodiments, the user may disable the number of fill units that will not be filled. Disabling the syringe may be accomplished through disconnection, independent actuation, bypass, zones, and / or plunger shaft passthrough.

[0270] With respect to disconnection, the fill units may be disconnected from the manifold without compromising the sterility of the manifold. In some embodiments, as the fill units will not be used, the sealed tubing connected to the inlet / outlet port are capable of being removed so as not to generate pressure or vacuum during the sequencing of the cassette. There are additional or alternative means of preventing the build of pressure or vacuum, including disconnection of the plunger shaft or creating an alternate ventilation such as a puncture in the syringe body or stopper.

[0271] With respect to independent actuation, if each fill unit has an independent linear actuator, the actuator(s) may be disabled from software such that the fill units are not filled.

[0272] With respect to bypass, a three-way valve may be designed between the manifold and the fill unit such that, for fill units not intended to be filled, the valve would be set to a position where the manifold is closed off but the fill unit is still venting.

[0273] With respect to zones, a cassette may be configurable with multiple zones where the lower rack is broken into subsections that are independently actuated. These zones may be programmed to not actuate, and therefore note fill. In some embodiments, these zone are used for alternate fill sizes (i.e., a variety of fill unit geometries may be desired for each fill, each of which require a different stroke and fill target for proper functioning).

[0274] With respect to plunger shaft passthrough, the lower rack used for sequencing the plunger may not be of solid design. In some embodiments, the lower rack includes through holes which can be engaged and disengaged (e.g., by threaded fitting, quarter turn release, or other means by which to attach the plunger to the lower rack, whereby when engaged, the plunger moves with the lower rack, but when disengaged, the lower rack moves by the plunger passes through the plane of the base and remains stationary).

[0275] With respect to satellite samples, situations may occur in which the amount of solution to be filled is greater than the sum total of the fill units. In some embodiments, the manifold is designed with a side port, whereby at the completion of the filling, the remaining solution may be drawn into the satellite container such that there is no waste or loss of material. According to some embodiments, the integrity test coupling is used to add gas to the filling assembly for the purpose of pushing out the remaining solution.

[0276] With respect to temperature control, if there is a temperature requirement for the material to be filled, temperature control may be built in. In some embodiments, an enclosure is added to the necessary regions (e.g., the bulk reservoir and cassette, or the entire filling system). According to some embodiments, a temperature sensor in the enclosure measures the temperature and provides feedback to the control system. A heat pump, temperature control unit, Pelletier system, or other means of controlling temperature may be used to provide a modulated temperature which, combined with a fan for circulation within the enclosure, may control the temperature appropriately. In some embodiments, the temperature information is then made available in the automated historian and batch report.

[0277] With respect to oxygen sensitive liquids, the provided disclosure herein may provide for the ability to generate an overlay of inert gas for the desired effect of preventing oxygen exposureof the liquid. In some embodiments, the machine is provided with an integrity testing coupling and the fdling assembly is provided with an integrity testing coupling, and the device can also be provided with a vacuum pump, vacuum chamber, inert gas source (e.g., bottled or as a distributed utility system), and additional gas control valves which allow for sequencing the integrity testing port on the cassette between vacuum cycles and purge or overlay the gas source.

[0278] According to some embodiments, this configuration allows for the inert purge gas to be applied and the fill units drawn to their maximum fill. This configuration may allow for the purge gas to be shut off and the vacuum applied to the fill assembly. In some embodiments, this configuration allows for the fill units to be pushed to their minimum volume, which is nearly empty. According to some embodiments, this configuration allows these three steps to be performed in sequence multiple times as necessary to attain a desired overlay gas purity.

[0279] In some embodiments, the vacuum is not necessary to attain the desired concentration. In such cases, the venting of the purge gas may be performed by the syringe cycling with discharge applied to atmosphere instead of vacuum.

[0280] With respect to starting material requiring additional filtration or processing, the aforementioned systems and devices may have presumed the solution to be filled and already purified (e.g., sterile). In some embodiments, the filling assembly and machine may be expanded to include additional steps. According to some embodiments, this is the sterilization of the solution to be filled by means of filtration. However, the filtration may need not be for the purpose of sterilization, but may rather imbue another quality, such as uniformity, removal of contaminants, homogeneity, catalytic conversion, etc. In such embodiments, the machine and filling assembly are provided with a pump, a filter or other flow through unit, an auxiliary line for flush solution, and a vent filter or integrity test coupling.

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

[0282] According to some embodiments, the sequence of operations include stopping the pump when sufficient quantity has passed the filter. The sequence of operations may include disconnecting the flush solution from the filling assembly. In some embodiments, the sequence ofoperations includes using the pump to transfer any remaining flush solution such that none remains in the lines. According to some embodiments, the sequence of operations includes connecting the integrity test tube to the vent filter or integrity test coupling.

[0283] The sequence of operations may include performing the integrity test. In some embodiments, the sequence of operations includes disconnecting the integrity test tube. According to some embodiments, the sequence of operations includes closing off / clamping shut the vent filter or integrity test coupling and flush container. The sequence of operations may include connecting the unfiltered bulk reservoir to the filling assembly.

[0284] In some embodiments, the sequence of operations includes using the pump to transfer the unfiltered bulk through the filter and into the bulk reservoir. According to some embodiments, the sequence of operations includes performing filling operations as described above. Sterile filtration may typically be a critical operation. In some embodiments, it is common to have two filters in series with filter integrity testing of one or both individually or in series).Example Embodiments

[0285] Embodiment 1 : A system, including: a fluid source containing fluid; a plurality of filling units fluidly coupled with the fluid source; and an apparatus mechanically coupled to the one or more filling units; wherein the plurality of filling units is configured to draw the fluid therewithin substantially in parallel using the apparatus.

[0286] Embodiment 2: The system of Embodiment 1, wherein the system further including a distribution system fluidly coupling the fluid source with the plurality of filling units.

[0287] Embodiment 3: The system of Embodiment 1 or 2, wherein the fluid source, the distribution system, and the plurality of filling units define a closed containment for the fluid configured to maintain a sterility therewithin, the fluid source coupled to the distribution system via a first flow pathway.

[0288] Embodiment 4: The system of any one of Embodiments 1-3, wherein the distribution system includes a manifold configured to receive the fluid from the fluid source, and a plurality of second flow pathways each fluidly coupling the manifold with a corresponding filling unit of the plurality of filling units.

[0289] Embodiment 5: The system of Embodiment 4, wherein the manifold includes a first channel having a first inlet opening fluidly coupled to the first flow pathway, and a plurality ofopenings fluidly coupled with a corresponding second flow pathway of the plurality of second flow pathways.

[0290] Embodiment 6: The system of any one of Embodiments 1-5, wherein the apparatus is configured to interact with the plurality of filling units so as to i) pull at least a partial vacuum within the plurality of filling units to draw the fluid therewithin, ii) expel at least some of the fluid from within the plurality of filling units, or iii) both.

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

[0292] Embodiment 8: The system of Embodiment 7, wherein the apparatus includes a lower rack configured to couple with a distal portion of the plurality of syringes, wherein the lower rack is configured to move longitudinally so as to correspondingly move a respective plunger rod of the plurality of syringes, thereby being configured to pull the at least partial vacuum to draw the fluid within the syringes, expel the at least some of the fluid, or both.

[0293] Embodiment 9: The system of Embodiment 8, wherein the lower rack is moveable via a linear actuator.

[0294] Embodiment 10: The system of Embodiment 8 or 9, wherein the lower rack is in operative communication with one or more processors, such that the lower rack is moveable to draw in fluid to within the syringes, expel fluid from the syringes, or both, based on instructions received from the one or more processors.

[0295] Embodiment 11 : The system of any one of Embodiments 8-10, wherein the lower rack includes a plurality of lower rack segments, each lower segment configured to individually move the plunger rod of a respective syringe of the plurality of syringes, thereby enabling for selective i) drawing in of fluid within a desired syringe, ii) expelling of fluid from within the desired syringe, or iii) both.

[0296] Embodiment 12: The system of any one of Embodiments 1-11, wherein the apparatus is configured to seal the plurality of filling units from the distribution system.

[0297] Embodiment 13: The system of any one of Embodiments 1-12, wherein the apparatus is configured to separate the plurality of filling units from the distribution system.

[0298] Embodiment 14: The system of Embodiment 13, wherein the apparatus is configured to seal and separate the plurality of filling units substantially simultaneously.

[0299] Embodiment 15: The system of any one of Embodiments 1-15, the apparatus further including a first beam having a first side, and a second beam having a second side, wherein the first and second beams are configured to be aligned and spaced apart from each other, such that the first side faces towards the second side.

[0300] Embodiment 16: The system of Embodiment 15, wherein each of the first side and second side includes a groove configured to receive at least a portion of each filling unit of the plurality of filling units, such that the plurality of filling units is configured to slideably engage with the first and second beams so as to be disposed therebetween.

[0301] Embodiment 17: The system of Embodiment 15 or 16, wherein: the first beam includes a first component at least partially defining the first side; and the second beam includes a second component at least partially defining the second side; wherein one or both of the first component and second component are configured to be moveable towards the other.

[0302] Embodiment 18: The system of Embodiment 17, wherein when the plurality of filling units are disposed between the first and second beams, the corresponding second flow pathways are disposed between the first and second components, wherein the corresponding second flow pathways each include a tubing.

[0303] Embodiment 19: The system of Embodiment 18, wherein i) the first component defines a first profile having a raised first valley portion about the first side, and a raised first plateau about the first valley portion, and ii) wherein the second component defines a second profile having a raised second valley portion about the second side, and a raised second plateau about the second valley portion, such that a first portion of the tubing of the plurality of filling units is configured to be pinched by the first and second plateaus when one or both of the first component and the second component are moved towards each other.

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

[0305] Embodiment 21 : The system of Embodiment 20, wherein the apparatus is configured to heat the first portion of the tubing when pinched between the first and second plateaus, 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 be to at least partially pushed from the first portion to a second portion of the tubing of the plurality of filling units, thereby reducing the tubing material at thefirst portion of the plurality of filling units, the second portion of the tubing of the plurality of filling units disposed between the respective first and second valley portions distal to the first and second plateaus.

[0306] Embodiment 22: The system of Embodiment 21, wherein the apparatus is configured to split the tubing at the first portion for the plurality of filling units, wherein the second portion remains physically coupled to the respective filling unit and separated from the distribution system.

[0307] Embodiment 23: The system of Embodiment 22, wherein the second portion is configured to be sealed via bonding of the tubing material to close a channel therewithin.

[0308] Embodiment 24: The system of Embodiment 23, wherein the splitting of the tubing and the sealing of the second portion occurs substantially simultaneously or at least partially sequentially.

[0309] Embodiment 25: The system of any one of Embodiments 20-24, wherein the heating element includes a recirculated heating fluid, an electric resistive heater, or both.

[0310] Embodiment 26: The system of any one of Embodiments 17-25, wherein one or both of the first component and second component are moveable pneumatically, hydraulically, magnetically, electrically, or any combination thereof.

[0311] Embodiment 27: The system of any one of Embodiments 1-26, further including a sample unit fluidly coupled with the fluid source, the sample unit configured to draw the fluid therewithin in parallel with the plurality of filling units drawing the fluid therewithin.

[0312] Embodiment 28: The system of any one of Embodiments 4-27, further including one or more additional subset of filling units, each subset of filling units including an equal number of filling units to the plurality of filling units, wherein the distribution system includes one or more additional manifolds corresponding to each additional subset of filling unit.

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

[0314] Embodiment 30: The system of Embodiment 29, wherein the apparatus is configured to seal the plurality of filling units and the filling units of the one or more additional subset of filling units from the distribution system.

[0315] Embodiment 31 : The system of any one of Embodiments 29-30, wherein the apparatus is configured to separate the plurality of filling units and the filling units of the one or more additional subset of filling units from the distribution system.

[0316] Embodiment 32: The system of Embodiment 31, wherein the apparatus further includes one or more additional pairs of the first and second beams of any one of Embodiments 17-24 configured to seal and split the filling units of the one or more additional subset of filling units.

[0317] Embodiment 33: The system of any one of Embodiments 1-31, further including an integrity test assembly, the integrity test assembly configured to perform an integrity test on the system or at least a component thereof.

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

[0319] Embodiment 35: A method including: fluidly coupling a plurality of filling units with a fluid source, the fluid source containing a fluid; and drawing the fluid into the plurality of filling units simultaneously, wherein the plurality of filling units are fluidly coupled with the fluid source in a closed configuration, thereby configured to maintaining a segregation of the fluid from a surrounding environment.

[0320] Embodiment 36: The method of Embodiment 35, wherein drawing the fluid into the plurality of filling units is at least partially based on the plurality of filling units pulling at least a partial vacuum therewithin.

[0321] Embodiment 37: The method of Embodiment 35-36, wherein fluidly coupling the plurality of filling units to the fluid source including fluidly coupling a distribution system of any one of Embodiments 1-28 to the plurality of filling units, and fluidly coupling the distribution system to the fluid source.

[0322] Embodiment 38: The method of any one of Embodiments 35-37, further including degassing or at least partially degassing the fluid drawn into the plurality of filling units.

[0323] Embodiment 39: The method of Embodiment 38, wherein degassing includes performing sequential steps of i) expelling the fluid from the within the plurality of filling units, and ii) drawing the fluid into the plurality of filling units, one or more times.

[0324] Embodiment 40: The method of Embodiment 39, wherein performing the sequential steps includes using the apparatus of any one of Embodiments 6-11, wherein expelling the fluid from within 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 to extend i) to a maximum position outside of the syringe, or ii) to a target position corresponding to a desired fill volume of the fluid drawn into the syringe.

[0325] Embodiment 41 : The method of any one of Embodiments 35-40, further including sealing the plurality of filling units.

[0326] Embodiment 42: The method of Embodiment 41, wherein sealing the plurality of filling units includes: moving one or both of the first and second components of any one of Embodiments 17-26 towards each other, thereby pinching the tubing of the plurality of filling units at the first portion; applying heat to the tubing of the plurality of filling units, so as to at least partially melt or soften the respective tubing material at least at the first portion, so as to be at least partially flowable; and optionally increasing a pressure between the first and second components; wherein the at least partially flowable tubing material is configured to pushed to a second portion of the respective tubing of the plurality of filling units.

[0327] Embodiment 43: The method of Embodiment 41 or 42, further including splitting the respective tubing at the first portion of the plurality of filling units, via pressure applied between the first and second plateaus, thereby separating the plurality of filling units from the fluid source.

[0328] Embodiment 44: The method of Embodiment 43, wherein sealing the plurality of filling units and splitting the respective tubing of the plurality of filling units occurs substantially simultaneously or substantially sequentially.

[0329] Embodiment 45: The method of any one of Embodiments 35-44, further including performing an integrity test on the distribution system, the first flow pathway, or both.

[0330] Embodiment 46: The method of Embodiment 45, wherein the integrity test includes i) pressurizing the distribution system, the first flow pathway, or both, and ii) detecting for any leaks.

[0331] Embodiment 47: The method of Embodiment 46, wherein detecting for any leaks including i) monitoring for any pressure decay, ii) detecting a gas used for pressurization via a sniff test, or iii) both.

[0332] Embodiment 48: The method of any one of Embodiments 45-47, wherein performing the integrity test for the distribution system includes: pressurizing the distribution system, wherein the distribution system includes the syringes of any one of Embodiments 7-11 and is fluidly coupled thereto, wherein the plunger rod of the syringes are located at a first position; detecting for any leaks; optionally stroking the plunger rod to multiple positions to perform an integrity test at different fill volumes for the plurality of syringes.

[0333] Embodiment 49: For any one of Embodiments 1-48, the plurality of filling units includes a syringe, a bag, a vial, a container, a bottle, or any combination thereof.

[0334] Some of the components listed herein use the same number from figure to figure. It should be appreciated these components use the same numbers solely for ease of reference and to facilitate comprehension for the reader. While these components may use the same numbers, differences may be present in these components as illustrated in the various figures in which they appear and as described in the specification herein.

[0335] None of the steps described herein is essential or indispensable. Any of the steps can be adjusted or modified. Other or additional steps can be used. Any portion of any of the steps, processes, structures, and / or devices disclosed or illustrated in one embodiment, flowchart, or example in this specification can be combined or used with or instead of any other portion of any of the steps, processes, structures, and / or devices disclosed or illustrated in a different embodiment, flowchart, or example. The embodiments and examples provided herein are not intended to be discrete and separate from each other.

[0336] The section headings and subheadings provided herein are nonlimiting. The section headings and subheadings do not represent or limit the full scope of the embodiments described in the sections to which the headings and subheadings pertain. For example, a section titled “Topic 1” may include embodiments that do not pertain to Topic 1 and embodiments described in other sections may apply to and be combined with embodiments described within the “Topic 1” section.

[0337] The various features and processes described above may be used independently of one another, or may be combined in various ways. All possible combinations and subcombinations are intended to fall within the scope of this disclosure. In addition, certain method, event, state, or process blocks may be omitted in some implementations. The methods, steps, and processes described herein are also not limited to any particular sequence, and the blocks, steps, or states relating thereto can be performed in other sequences that are appropriate. For example, describedtasks or events may be performed in an order other than the order specifically disclosed. Multiple steps may be combined in a single block or state. The example tasks or events may be performed in serial, 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 than described. For example, elements may be added to, removed from, or rearranged compared to the disclosed example embodiments.

[0338] Conditional language used herein, such as, among others, "can," "could," "might," "may," “e.g.,” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements and / or steps. Thus, such conditional language is not generally intended to imply that features, elements and / or steps are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without author input or prompting, whether these features, elements and / or steps are included or are to be performed in any particular embodiment. The terms “comprising,” “including,” “having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations and so forth. Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not generally intended to imply that certain embodiments require at least one of X, at least one of Y, and at least one of Z to each be present.

[0339] The term “and / or” means that “and” applies to some embodiments and “or” applies to some embodiments. Thus, A, B, and / or C can be replaced with 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 can include A and B, some embodiments can include A and C, some embodiments can include B and C, some embodiments can only include A, some embodiments can include only B, some embodiments can include only C, and some embodiments can include A, B, and C. The term “and / or” is used to avoid unnecessary redundancy.

[0340] The term “substantially” refers to less than or equal to + / -!%, + / -2%, + / — 3%, + / -4%, + / -5%, + / — 6%, + / -7%, + / -8%, + / -9%, + / -10%, + / -11%, + / -12%, + / -14%, or + / -15% variation. As a non-limiting example, substantially parallel represents a range of -1 to 1 degree difference, -5 to 5 degree difference, or -15 degrees to 15 degrees of difference from being parallel, depending on the embodiments.

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

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

Claims

CLAIMSWe Claim:

1. A system, comprising: a fluid source containing fluid; a plurality of filling units fluidly coupled with the fluid source; and an apparatus mechanically coupled to the plurality of filling units; wherein the plurality of filling units is configured to draw the fluid therewithin substantially in parallel using the apparatus.

2. The system of Claim 1, wherein the system further comprising a distribution system fluidly coupling the fluid source with the plurality of filling units.

3. The system of Claim 2, wherein the fluid source, the distribution system, and the plurality of filling units define a closed containment for the fluid configured to maintain a sterility therewithin, the fluid source coupled to the distribution system via a first flow pathway.

4. The system of any one of Claim 3, wherein the distribution system comprises a manifold configured to receive the fluid from the fluid source, and a plurality of second flow pathways each fluidly coupling the manifold with a corresponding filling unit of the plurality of filling units.

5. The system of Claim 4, wherein the manifold comprises a first channel having a first inlet opening fluidly coupled to the first flow pathway, and a plurality of openings fluidly coupled with a corresponding second flow pathway of the plurality of second flow pathways.

6. The system of any one of Claim 4, wherein the apparatus is configured to interact with the plurality of filling units so as to i) pull at least a partial vacuum within the plurality of filling units to draw the fluid therewithin, ii) expel at least some of the fluid from within the plurality of filling units, or iii) both.

7. The system of Claim 6, wherein the plurality of filling units comprise a plurality of syringes.

8. The system of Claim 7, wherein the apparatus comprises a lower rack configured to couple with a distal portion of the plurality of syringes, wherein the lower rack is configured to move longitudinally so as to correspondingly move a respective plunger rod of the plurality of syringes, thereby being configured to pull at least the partial vacuum to draw the fluid within the syringes, expel the at least some of the fluid, or both.

9. The system of Claim 8, wherein the lower rack is moveable via a linear actuator.

10. The system of Claim 8, wherein the lower rack is in operative communication with one or more processors, such that the lower rack is moveable to draw in fluid to within the syringes, expel fluid from the syringes, or both, based on instructions received from the one or more processors.

11. The system of any one of Claim 8, wherein the lower rack comprises a plurality of lower rack segments, each lower segment configured to individually move the plunger rod of a respective syringe of the plurality of syringes, thereby enabling for selective i) drawing in of fluid within a desired syringe, ii) expelling of fluid from within the desired syringe, or iii) both.

12. The system of Claim 2, wherein the apparatus is configured to seal the plurality of filling units from the distribution system.

13. The system of Claim 12, wherein the apparatus is configured to separate the plurality of filling units from the distribution system.

14. The system of Claim 13, wherein the apparatus is configured to seal and separate the plurality of filling units substantially simultaneously.

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

16. The system of Claim 15, wherein each of the first side and second side comprises a groove configured to receive at least a portion of each filling unit of the plurality of filling units, such that the plurality of filling units is configured to slideably engage with the first and second beams so as to be disposed therebetween.

17. The system of Claim 15, wherein: the first beam comprises a first component at least partially defining the first side; and the second beam comprises a second component at least partially defining the second side; wherein one or both of the first component and second component are configured to be moveable towards the other.

18. The system of Claim 17, wherein when the plurality of filling units are disposed between the first and second beams, the corresponding second flow pathways are disposed between the first and second components, wherein the corresponding second flow pathways each comprise a tubing.

19. The system of Claim 18, wherein i) the first component defines a first profile having a raised first valley portion about the first side, and a raised first plateau about the first valley portion, and ii) wherein the second component defines a second profile having a raised second valley portion about the second side, and a raised second plateau about the second valley portion, such that a first portion of the tubing of the plurality of filling units is configured to be pinched by the first and second plateaus when one or both of the first component and the second component are moved towards each other.

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

21. The system of Claim 20, wherein the apparatus is configured to heat the first portion of the tubing when pinched between the first and second plateaus, such that at least some of a materialof the tubing material from the first portion of the plurality of filling units is at least partially flowable and configured to be to at least partially pushed from the first portion to a second portion of the tubing of the plurality of filling units, thereby reducing the material of the tubing at the first portion of the plurality of filling units, the second portion of the tubing of the plurality of filling units disposed between the respective first and second valley portions distal to the first and second plateaus.

22. The system of Claim 21, wherein the apparatus is configured to split the tubing at the first portion for the plurality of filling units, wherein the second portion remains physically coupled to the respective filling unit and separated from a distribution system.

23. The system of Claim 22, wherein the second portion is configured to be sealed via bonding of the material of the tubing to close a channel therewithin.

24. The system of Claim 23, wherein the splitting of the tubing and the sealing of the second portion occurs substantially simultaneously or at least partially sequentially.

25. The system of Claim 20, wherein the heating element comprises a recirculated heating fluid, an electric resistive heater, or both.

26. The system of Claim 17, wherein one or both of the first component and second component are moveable pneumatically, hydraulically, magnetically, electrically, or any combination thereof.

27. The system of Claim 1, further comprising a sample unit fluidly coupled with the fluid source, the sample unit configured to draw the fluid therewithin in parallel with the plurality of filling units drawing the fluid therewithin.

28. The system of Claim 4, further comprising one or more additional subset of filling units, each subset of filling units comprising an equal number of filling units to the plurality of filling units, wherein the distribution system comprises one or more additional manifolds corresponding to each additional subset of filling unit.

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

30. The system of Claim 29, wherein the apparatus is configured to seal the plurality of filling units and the filling units of the one or more additional subset of filling units from the distribution system.

31. The system of Claim 30, wherein the apparatus is configured to separate the plurality of filling units and the filling units of the one or more additional subset of filling units from the distribution system.

32. The system of Claim 31, wherein the apparatus further comprises one or more additional pairs of the first and second beams of any one of Claims 17-24 configured to seal and split the filling units of the one or more additional subset of filling units.

33. The system of Claim 1, further comprising an integrity test assembly, the integrity test assembly configured to perform an integrity test on the system or at least a component thereof.

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

35. A method comprising: fluidly coupling a plurality of filling units with a fluid source, the fluid source containing a fluid; and drawing the fluid into the plurality of filling units simultaneously, wherein the plurality of filling units are fluidly coupled with the fluid source in a closed configuration, thereby configured to maintaining a segregation of the fluid from a surrounding environment.

36. The method of Claim 35, wherein drawing the fluid into the plurality of filling units is at least partially based on the plurality of filling units pulling at least a partial vacuum therewithin.

37. The method of Claim 36, wherein fluidly coupling the plurality of filling units to the fluid source comprising fluidly coupling a distribution system of Claim 3 to the plurality of filling units, and fluidly coupling the distribution system to the fluid source.

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

39. The method of Claim 38, wherein degassing comprises performing sequential steps of i) expelling the fluid from the within the plurality of filling units, and ii) drawing the fluid into the plurality of filling units, one or more times.

40. The method of Claim 39, wherein performing the sequential steps comprises using the apparatus of Claim 6, wherein expelling the fluid from within the plurality of filling units comprises 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 comprises optionally moving the plunger rod to extend i) to a maximum position outside of the syringe, or ii) to a target position corresponding to a desired fill 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 of Claim 41, wherein sealing the plurality of filling units comprises: moving one or both of the first and second components of Claim 19 towards each other, thereby pinching the tubing of the plurality of filling units at the first portion; applying heat to the tubing of the plurality of filling units, so as to at least partially melt or soften a material of the respective tubing at least at the first portion, so as to be at least partially flowable; and optionally increasing a pressure between the first and second components;wherein the at least partially flowable tubing material is configured to pushed to a second portion of the respective tubing of the plurality of filling units.

43. The method of Claim 42, further comprising splitting the respective tubing at the first portion of the plurality of filling units, via pressure applied between the first and second plateaus, thereby separating the plurality of filling units from the fluid source.

44. The method of Claim 43, wherein sealing the plurality of filling units and splitting the respective tubing of the plurality of filling units occurs substantially simultaneously or substantially sequentially.

45. The method of Claim 35, further comprising performing an integrity test on a distribution system, a first flow pathway, or both.

46. The method of Claim 45, wherein the integrity test comprises i) pressurizing the distribution system, the first flow pathway, or both, and ii) detecting for any leaks.

47. The method of Claim 46, wherein detecting for any leaks comprising i) monitoring for any pressure decay, ii) detecting a gas used for pressurization via a sniff test, or iii) both.

48. The method of Claim 45, wherein performing the integrity test for the distribution system comprises: pressurizing the distribution system, wherein the distribution system comprises the syringes of Claim 7 and is fluidly coupled thereto, wherein plunger rods of the syringes are located at a first position; detecting for any leaks; and optionally stroking the plunger rods to multiple positions to perform an integrity test at different fill volumes for the plurality of syringes.

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