Systems and methods for filling containers

Abstract

Systems and methods for dispensing fill fluid are discussed. More specifically, an exemplary fill system may include a reservoir that holds the fill fluid for dispensing. The fill system may also include a pump and a fill nozzle fluidically coupled to the reservoir. A processor executes a fill module that, when executed, receives at least one input fluid characteristic of the fill fluid and generates, based at least in part on the fluid characteristic, at least one set of operating parameters for controlling operation of the pump during a fill operation. The generated set of operating parameters enables control of the pump to dispense the fill fluid through the fill nozzle, and after the fill fluid is dispensed from the fill nozzle, a fluid interface having a stable, stationary profile is formed in the fill fluid within the fill nozzle adjacent the nozzle opening. [Selection diagram] Figure 8

Description

[Technical Field]

[0001] The present disclosure relates to systems and methods for filling containers, such as pre-filled syringes. [Background technology]

[0002] Filling systems are often used to fill a large number of relatively small containers, such as prefilled syringes, with fluid from a relatively large reservoir. The filling system includes a pump fluidly coupled to the reservoir and one or more filling nozzles. In large-scale filling systems, the pump may be connected to dozens or even hundreds of filling nozzles to simultaneously fill a large number of individual containers with fluid from the reservoir. The pump may be automatically controlled by a controller to dispense fluid from the reservoir to the individual containers via the filling nozzle(s). Summary of the Invention

[0003] Cross-reference to related patent applications This application claims the benefit of U.S. Provisional Application No. 62 / 791,850, filed January 13, 2019, and U.S. Provisional Application No. 62 / 663,927, filed April 27, 2018, the contents of both of which are incorporated herein by reference in their entireties.

[0004] Embodiments of the present invention provide systems and methods that account for specific fluid dynamic behavior to dispense fill fluid into containers through a fill nozzle to increase filling accuracy and prevent clogging. More specifically, embodiments dispense fill fluid to avoid overfilling and underfilling of containers, while also considering fluid dynamic behavior to avoid undesirable drying of the fill fluid inside the fill nozzle, which can lead to clogging or contamination. The systems and methods herein can be used for repeatable, accurate, high-throughput manufacturing of combination formulations, such as pharmaceutical liquids, in delivery devices.

[0005] In one exemplary embodiment disclosed herein, a filling system includes a reservoir holding fill liquid for dispensing, at least one fill nozzle fluidly coupled to the reservoir and dispensing the fill liquid through a nozzle opening, a pump fluidly coupled to the reservoir and the at least one fill nozzle and configured to dispense the fill liquid through the fill nozzle and the nozzle opening, and at least one processor operably coupled to the pump, and a memory having a filling module stored therein. The at least one processor is configured to receive at least one fluid characteristic of the fill liquid, generate at least one set of operating parameters for dispensing the fill liquid through the nozzle opening based at least in part on the at least one fluid characteristic, such that a fluid interface of a stable, static profile is formed in the fill liquid in the fill nozzle adjacent the nozzle opening after the fill liquid is dispensed from the at least one fill nozzle, and output the at least one set of operating parameters. The at least one set of operating parameters enables control of the pump to dispense the fill liquid through the nozzle opening during a filling procedure.

[0006] In another exemplary embodiment disclosed herein, a filling system includes a reservoir that holds a fill liquid for dispensing, and at least one fill nozzle fluidly coupled to the reservoir for dispensing the fill liquid through a nozzle opening that defines a nozzle radius (r). After the fill liquid is dispensed from the at least one fill nozzle, a stable fluid interface is formed in the fill liquid adjacent the nozzle opening. The stable fluid interface has a static interface and / or a controlled plug volume.

[0007] In another embodiment, a processor-implemented method for dispensing fill fluid from a reservoir holding the fill fluid into a container is disclosed, the method using at least one pump and at least one fill nozzle fluidically coupled to the reservoir. The at least one fill nozzle includes a nozzle opening and is configured to deliver the fill fluid to the container through the nozzle opening. The method includes receiving, via an input mechanism, an input specifying at least one fluid characteristic of the fill fluid; generating, based at least in part on the at least one fluid characteristic, at least one set of operating parameters for controlling the pump during the filling procedure to dispense the fill fluid through the nozzle opening such that a stable, stationary profile fluid interface is formed in the fill fluid adjacent the nozzle opening after the fill fluid is dispensed from the at least one fill nozzle; and outputting the at least one set of operating parameters. The at least one set of operating parameters enables control of the pump to dispense the fill fluid through the nozzle opening during the filling procedure.

[0008] The foregoing and other objects, features, and advantages of the illustrative embodiments will be more fully understood from the following description when read in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a partial schematic view of an exemplary embodiment of a filling system. [Figure 2] 1 is a cross-sectional view of an exemplary pump and fill nozzle for filling a container with a fill liquid. [Figure 3] 3A-3C are schematic diagrams illustrating the movement of the fill nozzle shown in FIG. 2 at various times during the filling procedure. [Figure 4A] FIG. 1 is a side view of a capillary tube, such as a fill nozzle, showing a drip of liquid. [Figure 4B] 1 is a side view of a capillary tube, such as a filling nozzle, showing a liquid plug forming in the tube. [Figure 4C]FIG. 10 is a side view of a fill nozzle showing a formed gas bubble with a stable liquid interface to inhibit dripping and plug formation in an exemplary embodiment. [Figure 5] FIG. 1 is a side view of a pipette containing a formed gas bubble with a stable resting profile. [Figure 6] FIG. 1 is a side view of a pipette containing a formed air bubble with an unstable resting profile. [Figure 7] 4 is a flow chart illustrating an exemplary series of steps for operating a fill system in an exemplary embodiment. [Figure 8] 4 is a flow chart illustrating another exemplary series of steps for operating the fill system in an exemplary embodiment. [Figure 9] 10 is a flow chart illustrating a further series of steps for operating the filling system in an exemplary embodiment. [Figure 10A] To demonstrate the flow profiles resulting from different filler nozzle diameters, diagrams of fluid columns flowing from the openings of filler nozzles of different diameters are shown. [Figure 10B] To demonstrate the flow profiles resulting from different filling rates, diagrams of columns of fluid flowing from the opening of a filling nozzle are shown. [Figure 11] 1 is a flow chart illustrating an exemplary series of steps for designing a filling system in an exemplary embodiment. [Figure 12] 10 is a flow chart illustrating another exemplary series of steps for designing a filling system in an exemplary embodiment. [Figure 13] 1A and 1B are charts showing testing of two variations when filling a container in an exemplary embodiment. [Figure 14] 1 illustrates an exemplary computing device suitable for use with the embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0010] Embodiments of the present invention provide systems and methods for filling containers with fill fluid through a fill nozzle to improve fill accuracy and prevent material blockage. More specifically, embodiments inhibit the flow of fill fluid toward the bottom of the fill nozzle, where the fluid can affect fill accuracy by overfilling or drip out of the nozzle, resulting in underfilling. Additionally, fluid at the end of the nozzle can dry out within the fill nozzle and cause blockages. The fill fluid defines a density (ρ), a fluid surface tension (γ), and a net acceleration (a). Thus, in some embodiments, a filling system includes a processor and a memory holding a filling module that, when executed by the processor, generates one or more sets of operating parameters based on at least one input fluid characteristic of the fill fluid. The one or more sets of operating parameters enable control of a pump dispensing the fill fluid through the fill nozzle to form a fluid interface with a stable rest profile within the fill nozzle after the fill fluid is dispensed from the fill nozzle.

[0011] 1 and 2, an exemplary embodiment of a filling system 100 is shown. The filling system 100 includes a reservoir 110, shown as a break tank, that holds fill fluid for dispensing into containers such as, but not limited to, vials, cartridges, syringes, and pre-filled syringes. At least one fill nozzle 120, shown as a fill needle, is fluidly coupled to the reservoir 110 for dispensing the fill fluid through a nozzle opening 221 (shown in FIG. 2) formed in the fill nozzle 120. A pump 130 is fluidly coupled to the reservoir 110 and the fill nozzle 120 to force the fill fluid from the reservoir 110 through the nozzle opening 221 and dispense the fill fluid through the nozzle opening 221. In some embodiments, the fill nozzle 120 is fluidly coupled to the reservoir 110 through the pump 130 via nozzle tubing 122 that is fluidly coupled to a first connector 131 of the pump 130, shown as a Y-connector. Pump 130 may be fluidly coupled to reservoir 110 via first tubing 123, which couples reservoir 110 to a distributor 140, shown as a four-way distributor, and second tubing 124, which fluidly couples distributor 140 to a second connector 132 of pump 130, also shown as a Y-connector. Tubing 122, 123, 124 in system 100 may comprise silicone or other materials and may have variable tubing diameters depending on the fill liquid to be dispensed and the desired fill rate.

[0012] Filling system 100 includes a processor 150 and memory 160 operably coupled to pump 130. Memory 160 has a filling module stored therein that is executed by processor 150 and is described further herein. The filling module may include one or more software components, programs, applications, or other code-based units or instructions configured to be executed by one or more processors, including processor 150. In some embodiments, processor 150 and memory 160 are part of a computing device 170 that also includes an input 171, such as a keyboard, touchscreen, or the like, for entering data into the filling module. In some embodiments, computing device 170 includes a display 172 operably coupled to processor 150 for displaying graphics for controlling functions of filling system 100, as described further herein. Processor 150 can be operably coupled to pump 130 by a wireless or wired connection, directly or indirectly via a network. In some embodiments, processor 150 is operably coupled to multiple pumps via a router or similar element to simultaneously control multiple pumps. In some embodiments, pump 130 includes pump memory 133 that stores pump operating instructions, for example, from processor 150 .

[0013] 2 , pump 130 and fill nozzle 120 are shown in more detail. Pump 130 is shown as a peristaltic pump that rotates to dispense fill fluid through pump tubing 134 fluidly coupled to both first connector 131 and second connector 132 to pump the fill fluid to fill nozzle 120 for filling container 220, shown as a syringe reservoir. In some embodiments, pump 130 is configured to rotate in one direction, shown as arrow R, to dispense fill fluid through fill nozzle 120 and rotate in the opposite direction, shown as arrow O, to draw fill fluid back into fill nozzle 120. Such functionality is commonly known as a backflow or “suckback” functionality for drawing droplets of fill fluid, such as droplet 232, back into fill nozzle 120 and is described further herein. While pump 130 is shown as a peristaltic pump, other types of pumps, such as rotary pumps, may also be included in fill system 100.

[0014] In one exemplary embodiment, the exemplary pump head of the peristaltic pump has a diameter of 60 mm and consists of three equally spaced 10 mm cams per fluid path. The pump tubing follows the pump head at 130-140°. The combination of the rotation angle around the pump head and the tubing ID (indicating the inner diameter of the tube) determines the amount of liquid dispensed. Therefore, the tubing ID determines the volume per revolution. The larger the ID, the more liquid is dispensed per revolution. As a result, the same pump parameters can result in different flow rates when different tubing diameters are used. Exemplary programmable parameters are outlined in the table below. Pump Head Parameters JPEG0007792197000001.jpg140170

[0015] It is understood that the effect of these parameters on the fluid in the fill nozzle / needle is also a function of the fill nozzle / needle ID inner diameter, which refers to the diameter of the fill nozzle / needle (the larger the ID, the slower the fluid rate per revolution), the pump tubing ID, and the number of fluid paths / pump heads, and that the pump parameters described are added for illustrative purposes only. Embodiments of the invention are not limited to the described parameters, and pump and other operating characteristics should be considered within the scope of the invention.

[0016] 3 , the fill nozzle 120 is moved to different positions within the container 220 during filling by a nozzle actuator 310, which is also operably coupled to the processor 150. The nozzle actuator 310 may start, for example, at an initial fill position 311 above the container 220. Once the filling process begins, the nozzle actuator 310 moves the fill nozzle 120 to an initial fill point 312 within the container 220, which is the point closest to the closed end 321 of the container 220 that the fill nozzle 120 will reach during filling of the container 220. As fill fluid from the reservoir 110 fills the container 220 through the fill nozzle 120, the nozzle actuator 310 raises the fill nozzle 120 relative to the closed end 321 of the container 220. The nozzle actuator 310 raises the fill nozzle 120 within the container 220 to a final fill point 313 within the container 220. Once the filling procedure is complete and the container 220 is filled with filling liquid, the nozzle actuator 310 returns the nozzle actuator 310 to the initial filling position 311 above the container 220, and the empty container replaces the already full container 220 for filling by the filling system 100.

[0017] Processor 150 can execute a fill module stored in memory 160 to operate various elements of fill system 100, such as pump 130 and nozzle actuator 310, to automatically fill empty containers with fill fluid from reservoir 110 according to specified operating parameters as described herein. In some embodiments, the fill module is operatively coupled to other elements, such as a container conveyor, that moves the container for filling to a fill position beneath fill nozzle 120 and nozzle actuator 310 before initiating the filling procedure. Once the container is in the fill position, the fill module outputs one or more signals to nozzle actuator 310 to lower fill nozzle 120 into container 220 and rotate pump 130 so that fill fluid is dispensed into the container from nozzle opening 221. During the filling procedure, the fill module can also send a signal to nozzle actuator 310 to raise fill nozzle 120, as described above.

[0018] After the container 220 is filled with fluid, the fill module can signal the pump 130 to perform a suck-back function to draw any remaining fill fluid back through the nozzle opening 221 into the fill nozzle 120 to prevent dripping from the nozzle opening 221. The fill module can also signal the nozzle actuator 310 to return to the initial fill position 311 and cause the container conveyor to move a new container into the fill position before resuming the fill procedure. The fill procedure can be repeated in a loop as necessary, for example, until the reservoir 110 is empty or the desired number of containers have been filled with fill fluid.

[0019] Varying operating parameters of conventional filling systems can lead to wasted fill fluid and inconsistent filling of containers during the filling process. For example, fill fluid sometimes drips from the fill nozzle 120 and is wasted during the period between when a filled container leaves the fill position and when a new container is moved into the fill position.

[0020] A droplet 401 at the end of the filling nozzle 120 is shown in FIG. 4A. While this drip waste may be acceptable for inexpensive fill fluids, certain fill fluids, such as biological products, are so expensive that drip waste from multiple fill nozzles 120 in the filling system 100 can add up to significant revenue loss. Furthermore, splashing of the fill fluid on the container as it exits the fill nozzle 120 can lead to underfilling of the container. If the fill fluid is a formulation that is delivered to a prefilled syringe, a relatively small amount of underfilling of the prefilled syringe can be reason for the prefilled syringe to be rejected for dispensing, such as due to the risk of delivering an underdose to the patient.

[0021] To address drip waste, the suck-back function described above can be performed at the end of the fill procedure while a new container is moved to the fill position. The suck-back function draws droplets that may form at the nozzle opening 221 back into the fill nozzle 120, reducing drip waste. While the suck-back function reduces drip waste, it is not completely effective in eliminating drip waste.

[0022] Using the suck back feature also has drawbacks. As shown in Figure 4B, when the suck back feature is used, air can enter the fill nozzle 120 and form an air bubble 402 inside the fill nozzle 120. The air bubble 402 separates the liquid inside the fill nozzle 120 into a first portion 403A on one side of the air bubble 402 and a second portion 403B on the opposite side of the air bubble 402 adjacent the nozzle opening 221.

[0023] While second portion 403B may be a non-trivial amount of fill fluid dispensed into a container as it is being filled, a larger problem arises when operation of fill system 100 is interrupted for as little as two minutes. As can be seen from FIG. 4B , second portion 403B of fill fluid is exposed to the environment outside fill nozzle 120. If second portion 403B of fill fluid remains inside fill nozzle 120 for more than two minutes, as can occur in conventional systems, second portion 403B of fill fluid may dry out and form a solid plug inside fill nozzle 120, especially if the fill fluid contains a significant amount of dissolved solid active ingredients, such as one or more proteins, in a carrier fluid. When fill system 100 attempts to resume filling the container, the formed plug of solid material may clog fill nozzle 120, disrupting operation of fill system 100 and potentially leading to further fill system shutdowns.

[0024] Alternatively, a further problem exists in conventional systems: the first portion 403A of the filling liquid dispensed from the filling nozzle 120 may dissolve the formed film and carry the solid active ingredient into the filled container. This can significantly increase the amount of active ingredient dispensed into the container. Because dosages of formulations are subject to strict regulations regarding filling accuracy compared to the advertised dosage, increasing the amount of active ingredient in the prefilled syringe is also a reason to reject the prefilled syringe upon dispensing and represents significant product waste.

[0025] Attempts to address the aforementioned problems have focused on trial and error testing to find the proper operating parameters of the fill system. While trial and error testing has resulted in some improvements in the operation of the fill system, such testing does not address the root cause of the particular problem. Thus, each time a new fill fluid is dispensed from the fill system, extensive trial and error testing has been required to determine the acceptable operating parameters of the fill system. Additionally, trial and error testing is time-consuming and expensive. Not only does trial and error testing require a significant amount of time to determine acceptable operating parameters, but it also has other requirements that add to the expense, such as the formulation of surrogate fluids, a "test setup" for the fill system, etc.

[0026] To address the issues of wasteful dripping and inconsistent fill volumes during the filling procedure, as shown in FIGS. 1 and 4C , the fill system 100 disclosed herein is configured to account for the dynamic fluid behavior that causes dripping and inconsistent fill. With particular reference to FIG. 4C , it has been discovered that the formation of a fluid interface, which may be a gas bubble 411, having a stable, stationary profile adjacent the nozzle opening 221 of the fill nozzle 120 results in a stable fluid interface 412 that inhibits the formation of droplets of fill liquid outside the fill nozzle 120 as shown in FIG. 4A , and also inhibits the formation of a solid plug inside the fill nozzle 120 as shown in FIG. 4B . In some embodiments, the stable fluid interface 412 may be a fully formed, i.e., closed, gas bubble, or part of a partially formed, i.e., open to the atmosphere, gas bubble 411. Essentially, the gas bubble 411 has sufficient length to prevent fill liquid from dripping out of the nozzle opening 221, while not having excessive length that would result in the formation of a significant liquid plug inside the fill nozzle 120 at the nozzle opening 221. Thus, when a bubble 411 with a stable, resting profile is formed adjacent the nozzle opening 221, the fill liquid inside the fill nozzle 120 resists drying inside the fill nozzle 120 and dripping out of the nozzle opening 221 because the fill liquid is stably held inside the fill nozzle 120 and resists evaporation of the fluid components. In one embodiment, the fill liquid comprises a fluid profile that minimizes mass loss due to convective drying by creating a stable, resting profile that recedes from the fill needle opening. In one embodiment, the amount of retraction is due to the surrounding environmental fluid, e.g., air flowing around the fill nozzle.

[0027] It has been discovered that various fluid properties of the fill liquid and operating parameters of the fill system 100 can be controlled to form a bubble 411 with a stable resting profile. The Bond number (B o) is less than a value of 0.842, a bubble 411 with a stable, stationary profile can be achieved. It should be understood that although the Bond number of 0.842 for the fill liquid in the fill nozzle represents a theoretical limit beyond which the profile will not be stable, useful bubbles may be obtained in some circumstances even with Bond number values ​​slightly above 0.842.

[0028] The operating parameters of the filling system 100 to keep the Bond number (sometimes called the Eötvös number) (ratio of gravity to surface tension) below a critical value are given by the equation ρ a r 2 / γ<0.842, where ρ is the density difference of the fill liquid relative to the surrounding environmental fluid (air, inert gas, oil, alcohol, etc.), a where σ is the net acceleration of the fluid (equal to the acceleration of gravity when the fill nozzle 120 is not moving), r is the radius of the fill nozzle 120 (shown in FIG. 4C ), and γ is the fluid surface tension of the fill liquid relative to the surrounding environment fluid. For ease of explanation, it is assumed herein that the surrounding environment fluid is air, and that the fill liquid's density difference and effect on the fluid surface tension are negligible. In certain scenarios where the filling procedure is performed in an environment where the surrounding environment fluid has a non-negligible effect on the fill liquid's density difference and fluid surface tension, the effect of the surrounding environment fluid may need to be considered.

[0029] The density difference (p) of a particular fill liquid is generally constant regardless of the operating parameters of the fill system 100, the net acceleration of the fill liquid, the radius r of the fill nozzle 120, and the fluid surface tension between the fill liquid and the fill nozzle 120, and therefore may represent a controllable parameter for achieving a Bond number value of less than 0.842. The fluid surface tension of the fill liquid may be altered, for example, by adjusting the fluid surrounding the fill nozzle, i.e., the ambient fluid 120, as described above, which affects the fluid surface tension of the fill liquid. In some exemplary embodiments, the fluid surface tension of the fill liquid may be controlled, for example, by assuming that the material of the fill nozzle 120 does not change, i.e., the fluid surface tension of the fill liquid is also constant. In some embodiments, the fill nozzle 120 may comprise a metallic material such as stainless steel. As used herein, the density and fluid surface tension of the fill liquid may each be referred to as the “fluid properties” of the fill liquid and may be provided or measured according to methods known in the art. Other fluid properties of the fill liquid may include, but are not limited to, viscosity, compressibility, etc.

[0030] If the fluid surface tension is assumed to be constant, the only variables to control are the net acceleration of the fill fluid and the radius r of the fill nozzle 120, which may be referred to as operating parameters of the fill system 100, separate from the fluid properties of the fill fluid. In some exemplary embodiments, the net acceleration of the fill fluid and the radius r of the fill nozzle 120 are determined by the equation ( a *r 2 )<(0.842*γ / ρ). The net acceleration of the fill fluid can be, for example, a net acceleration as a result of gravity acting on the fill fluid, an opposing acceleration due to the reverse flow / suckback function of the pump 120, movement of the fill nozzle 120 and fill fluid by the nozzle actuator 310, or any combination of these forces. In some exemplary embodiments, the material of the fill nozzle 120, which can be stainless steel or plastic, can also be an operating parameter of the fill system 100, as the composition of the fill nozzle or a coating thereon can affect the velocity of the fluid.

[0031] To operate fill system 100, as shown in FIG. 7, processor 150 is configured to execute a fill module stored in memory 160 to perform method 700, including steps 701, 702, and 703, and in some embodiments, steps 704, 705, and 706. Step 701 includes inputting at least one fluid property of the fill fluid into fill system 100. In some embodiments, the at least one fluid property is the density of the fill fluid, as described above, and is input to computing device 170 via input 171, which may be a keyboard. In some embodiments, the fluid property is not input directly into the fill module by a user, but is received by the fill module from a database, which may be stored in memory 160 or communicated to the fill module from another element. For example, a user can select a graphic shown on display 172 that corresponds to a particular fluid, and the fill module then queries memory 160 to retrieve one or more fluid properties of the selected fluid from a database stored in memory 160 for input into the fill module.

[0032] Step 702 includes generating, based at least in part on at least one fluid characteristic, at least one set of operating parameters for dispensing fill fluid through the nozzle opening 221 such that a stable, stationary profile of gas bubbles is formed in the fill fluid in the fill nozzle 120 adjacent the nozzle opening 221 after the fill fluid is dispensed from the fill nozzle 120. In some embodiments, the set of operating parameters can be generated to establish a Bonds number less than the critical value of 0.842, as described above. For example, generating the one or more sets of operating parameters can be based on input of one or more fluid characteristics to identify a range of pump and other operating parameters required to establish a Bonds number less than 0.842. In some embodiments, the fill module is configured to establish the Bonds number indirectly from certain fluid characteristics or operating parameters. For example, the mass and volume of the fill fluid can be input into the fill module, and the density of the fluid can then be determined as part of establishing a Bonds number less than the critical value. In another embodiment, the density of the fill fluid can be input directly into the fill module.

[0033] Additionally, in some embodiments, one or more operating parameters may be input into the filling module to reduce the number of adjustable variable operating parameters. For example, the radius r of the fill nozzle 120 may be input as a constant, and the filling module then generates one or more sets of operating parameters based on the radius r being held constant. In such a scenario, the one or more sets of operating parameters may include, but are not limited to, possible materials of the fill nozzle 120, such as plastic, stainless steel, or coatings or structures thereon, that may be used (to control fluid surface tension), and operating parameters that affect the net acceleration of the fill fluid. In some embodiments, the at least one set of operating parameters may include only a single variable, such as the backflow rate, which may be referred to as the “suckback rate” of the pump 130, to establish a Bond number below a critical value of 0.842. Therefore, it should be understood that generating the at least one set of operating parameters may vary in many different ways depending on the at least one fluid characteristic input into the fill system 100 and the operating parameter(s), if any, that are held constant. For example, if surface tension is input as a fluid property, the system uses the Bond number relationship to determine density and then calculates the design space from these two values.

[0034] Step 703 includes outputting at least one set of operating parameters. The set of output operating parameter(s) enables control of the pump 130 when dispensing fill fluid through the nozzle opening 120 during a filling procedure, such as the filling procedures described above. In some exemplary embodiments, the set of operating parameters includes at least pump operating parameters of the pump 130, including, for example, forward rotation speed, suck-back speed of the suck-back function, acceleration (forward / reverse), deceleration (forward / reverse), timing parameters for actuation of the pump 130, etc. In some embodiments, the set of operating parameters includes nozzle movement parameters of the nozzle actuator 310, including, for example, nozzle actuator 310 movement speed to impart to the fill nozzle 120, timing parameters for actuation of the nozzle actuator 310, diving needle movement, etc. Other operating parameters that may be controlled include the diameter of the fill nozzle 120, the composition of the fill nozzle, etc. It should be appreciated, therefore, that the set(s) of output operating parameters may be output to enable automatic control of some or all components of fill system 100, for example, to fill a container such that a stable, static profile of gas bubbles is formed in the fill liquid after dispensing the fill liquid if the fill procedure is interrupted. Alternatively, the set(s) of output operating parameters may be displayed to a user for manual control of some or all components of fill system 100.

[0035] In some exemplary embodiments, the generated set(s) of operating parameters are output to aid in the selection of operating parameters for the filling system 100. For example, the set(s) of operating parameters may be output to the display 172 of the computing element 170 to display a visual element indicative of the generated operating parameters. Such output may be required, for example, if the filling system 100 has certain parameters controlled by the filling module, such as parameters of the pump 130 and nozzle actuator 310, and other parameters that must be manually adjusted, such as the radius r or the composition of the filling nozzle 120, which can be adjusted by manually replacing the filling nozzle 120. In some embodiments, the filling module only generates and outputs at least one set of operating parameters and does not control other functions of the filling system. For example, the filling module may output the set(s) of operating parameters to another computing device at a remote location over a network or otherwise enable control of an off-site pump or other components of the filling system. Thus, it should be understood that the filling system 100 may include multiple processors.

[0036] Step 704 includes processor 150 executing a filling module to control pump 130 according to at least one set of operating parameters to fill at least one container, such as container 220, with filling fluid. In some embodiments, the filling module continuously controls pump 130 during the filling procedure. In some embodiments, the filling module outputs some or all of a set(s) of operating parameters to pump 130, which then automatically operates according to the operating parameters until otherwise directed by the filling module. Similarly, the filling module can output some or all of a set(s) of operating parameters to nozzle actuator 310, which may be continuously controlled by the filling module or may automatically operate according to the operating parameters until otherwise directed by the filling module. While pump 130 and nozzle actuator 310 are described as receiving operating parameters and being controlled by the filling module, it should be understood that other components of filling system 150, such as the container conveyor, may similarly be controlled by the filling module.

[0037] Step 705 includes receiving at least one additional system parameter and generating at least one set of operating parameters based at least in part on the at least one additional system parameter. In some embodiments, the at least one additional system parameter is one or more operating parameters of the fill system 100, such as the radius r of the fill nozzle 120, the composition of the fill nozzle 120, the net acceleration of the fill nozzle 120, the fluid fill during the fill procedure, etc. In some embodiments, the at least one additional system parameter is a different parameter that affects the operation of the fill system 100, such as the model of the pump 130 and / or the composition of one or more of the tubings 122, 123, 124, etc. For example, the model of the pump 130 affects the possible suckback rates that can be achieved by the fill system 100 during operation, which may affect other operating parameters of the system. Thus, it should be understood that the at least one additional system parameter does not directly affect the fluid movement of the fill liquid, but rather affects the possible operating parameters that can be generated. It should further be understood that many different additional system parameters can be received for use in generating the at least one set of operating parameters.

[0038] As previously mentioned, forming a gas bubble 411 with a stable, resting profile in the fill liquid within the fill nozzle inhibits dripping of the fill liquid from the nozzle opening 221 and drying of the fill liquid inside the fill nozzle 120. However, forming a gas bubble 411 with a stable, resting profile only serves to prevent the liquid plug from expanding during rest, such as when the fill system 100 is not operating. Because the gas bubble 411 (or stable fluid interface 412) rises slightly faster than the fill liquid during suck-back, a liquid plug may still form in the fill nozzle 120 during the suck-back function. This mismatch in the rising speed of the gas bubble compared to the fill liquid may lead to some fill liquid escaping from the gas bubble 411 and forming a film on the walls of the fill nozzle 120, which may dry out and form a relatively small liquid plug.

[0039] 8 illustrates a method 800 for operating the filling system 100 to minimize film thickness. Method 800 includes steps 701, 702, and 703 of method 700, and in some embodiments, steps 704 and 705, as well as an additional step 806. Step 806 involves solving the modified Taylor's Law equation: h / r such that h / r is less than a predetermined maximum value. h / r=1.34*Ca 2 / 3 / (1+1.34*2.5Ca 2 / 3 ) where Ca = μV / γ, h / r is the thickness of the film formed inside the filling nozzle 120 divided by the radius of the filling nozzle 120, μ is the viscosity of the filling liquid, V is the velocity of the filling liquid, and γ is the fluid surface tension. The predetermined maximum value of h / r can depend on the acceptable variability of the filling procedure, for example, the maximum allowable overfill or underfill of the filling liquid into the container, or the minimum volume of a formed plug that clogs the filling nozzle 120. The volume of the formed plug can be calculated as the volume of the annulus, which is equal to the integral of h / r multiplied by the height of the suck-back of the filling liquid. In some embodiments, the predetermined maximum value of h / r is between 0.01 and 0.05. In some embodiments, the predetermined maximum value of h / r is less than 0.10, e.g., less than 0.05.

[0040] In some embodiments, the velocity of the fill liquid is the suckback velocity, and is the only operating parameter in the modified Taylor's Law equation that can be adjusted by the fill module. In some embodiments, the fill module outputs at least one set of operating parameters that establish a Bond number less than a critical value of 0.842 (“Condition 1”) and h / r satisfies the modified Taylor's Law equation and is less than a predetermined maximum (“Condition 2”), corresponding to a formed film thickness that is less than or equal to 10% of the radius r of the fill nozzle 120. It should be understood that the exemplary 10% thickness limit is not absolute; the thickness limit is imposed by either the acceptable variability of the fill (from a safety or efficacy standpoint) and / or limitations on the duration of the fill process. In some embodiments, the at least one set of operating parameters is a range of operating parameters that can be varied within a range to simultaneously satisfy both Condition 1 and Condition 2, enabling the fill system 100 to fill a container such that a bubble of a stable, stationary profile is formed adjacent the nozzle opening 221 and a thin film thickness develops inside the fill nozzle 120 following the dispensing of the fill liquid. The filling module may also receive one or more additional system parameters, as described above, and generate at least one set of operating parameters that simultaneously satisfy both condition 1 and condition 2 based at least in part on the received one or more fluid characteristics and one or more additional system parameters.

[0041] In some embodiments, the fill nozzle 120 may be a tapered nozzle having a first radius and a second radius smaller than the first radius adjacent the nozzle opening 221. In some embodiments, the fill nozzle 120 has a narrow portion of the second radius. The narrow portion may be between the body of the fill nozzle 120, which has the first radius, and the nozzle opening 221, which also has the first radius, resulting in a narrower portion or other constriction at the bottom of the fill nozzle above the nozzle opening. Such an embodiment may have a narrow portion due to the air interface formed in the fill nozzle 120, while the first radius of the nozzle opening 120 and the body of the fill nozzle reduce the risk of a thin film, as described by the modified Taylor's Law equation, from completely clogging the fill nozzle 120.

[0042] In some embodiments, the composition of the fill nozzle 120 is selected to control the contact angle θ between the fill liquid and the fill nozzle 120. A relatively high contact angle θ, i.e., close to or greater than 90°, can alter the behavior of the fill liquid inside the fill nozzle 120. This change in fill liquid behavior was observed by Alexandru Herescu in a paper titled “Two-Phase Flow in Microchannels: Morphology and Interface Phenomena” published by Michigan Technological University in 2013 (hereinafter “Herescu”), which is incorporated herein by reference in its entirety. For example, a high contact angle θ can induce the formation of a non-wetting film, as shown by Herescu, in addition to the “Bretherton film” that forms adjacent to the meniscus upon impact with a fluid at high fluid velocities, e.g., high suck-back velocities. At very high fluid velocities, multiple plugs may form in the fill liquid, as shown by Herescu. Thus, in some embodiments, one controlled parameter of the fill system 100 is the composition of the fill nozzle 120 to control the contact angle θ formed between the fill nozzle 120 and the fill liquid. A large contact angle results in a hydrostatic jump and an increase in film thickness. Thus, in some embodiments, a contact angle of less than 90 degrees is selected.

[0043] 9, another sequence of steps for a method of operating fill system 100 is shown in an exemplary embodiment. Method 900 includes steps 701, 702, and 703 of method 700 and, in some embodiments, steps 704 and 705 and step 806 of method 800, as well as an additional step 907. Step 907 includes generating at least one set of operating parameters for dispensing fill fluid through nozzle opening 221 based, at least in part, on at least one fluid characteristic, such that a stable jet of fill fluid dispensed through the nozzle opening does not collapse during filling. A stable jet of fill fluid reduces the risk of fill fluid forming droplets between nozzle opening 221 and the material of the container being filled or fluid already dispensed into the container, reducing the risk of fill fluid splattering. Reducing the risk of fill fluid splattering during the filling process reduces the risk of splattered fill fluid drying on the outside of fill nozzle 120 and any associated stoppering device.

[0044] In some embodiments, at least one set of operating parameters is generated to determine the Ohnesorge number (OhMS) at which a stable jet of fill liquid is dispensed from the nozzle opening 221. R ) is generated. The Ohnesorge number is given by the formula 0h2 / R=2μ 2 / ργR, where μ is the dynamic viscosity of the fill liquid, ρ is the density of the fill liquid, γ is the surface tension of the fill liquid, and R is the radius r of the fill nozzle 120. Various Ohnesorge numbers and associated critical lengths are described in an article titled "Stability of viscous long liquid filaments" by Driessen et al., published in "Physical Fluids" in 2013 (hereinafter "Driessen et al."), which is incorporated herein by reference in its entirety. For a particular critical length (Γ), representing the distance (in units of the fill needle radius) over which the jet remains stable, in some embodiments, an associated Ohnesorge number that results in a stable jet of fill liquid can be generated based on previously determined stable and unstable experimental points. For ease of explanation, fill liquid dispensed from the fill nozzle 120 as a stable jet may be referred to as "Condition 3."

[0045] As can be appreciated, the filling module can generate at least one set of operating parameters to simultaneously satisfy conditions 1, 2, and 3, as described above. When fill fluid is dispensed from the filling system according to one or more sets of operating parameters that simultaneously satisfy conditions 1, 2, and 3, consistent filling of containers can be achieved with a reduced risk of the fill fluid drying out, clogging, or otherwise adversely affecting the operation of the filling system 100. It should be appreciated that the set(s) of operating parameters can satisfy only one of consistent filling of containers and reducing drying out and clogging by the fill fluid, achieved by establishing one or more sets of operating parameters that account for the previously described hydrodynamic behavior. Accordingly, the filling systems 100 and methods 700, 800, 900 described herein can be utilized to establish operating parameter constraints for operating the filling system 100 that account for the aforementioned hydrodynamic behavior. Taking the aforementioned hydrodynamic behavior into account can increase fill volume consistency, reduce downtime caused by clogging, and increase active ingredient distribution consistency.

[0046] In some exemplary embodiments, for example, when the filling fluid contains a biological agent that is susceptible to damage from shear stress, at least one set of operating parameters can be generated to avoid damage to one or more components of the filling fluid. For example, the at least one set of operating parameters can be generated at a filling fluid flow rate that limits the fluid shear stress of the filling fluid to less than a maximum allowable shear value to limit damage to one or more components of the filling fluid. The maximum allowable shear value can vary for different filling fluids. In some exemplary embodiments, the filling fluid contains a biological agent, including, but not limited to, at least one of a protein, an antibody, a sugar, one or more nucleic acids, one or more cells, and one or more tissues. The filling fluid also contains other substances associated with the biological agent, including, but not limited to, at least one of a carrier fluid, one or more additional active ingredients, a surfactant, a stabilizer, an adjuvant, an encapsulating particle, and a buffer.

[0047] To test the ability of the filling system 100 to accurately dispense fluids as described above, various tests were performed to determine whether bubbles with stable resting profiles were formed with various fluids. The fluids and the fluid densities and surface tensions of each fluid are listed below in Table 1. The fluids were tested with various pipettes having various radii, as listed below in Table 2.

[0048] One exemplary fill fluid is an aluminum hydroxide suspension, representative of vaccine / suspension formulations, which is presented in the table below with two different fluid properties due to the addition of surfactant to Formulation B.

[0049] Another exemplary loading solution comprises Antibody A with inactive ingredients including a surfactant, which has the properties set forth in Table 1. For example, Antibody A may be a humanized antibody that specifically binds to human α4β7 integrin and is also known as "vedolizumab."

[0050] Various methods can be used to generate the anti-α4β7 antibody vedolizumab or antibodies containing the antigen-binding region of vedolizumab. Vedolizumab is also known under the trademark ENTYVIO® (Takeda Pharmaceutical Company). Vedolizumab is a humanized antibody containing a human IgG1 framework and constant region and the antigen-binding CDRs of the murine antibody Act-1. Vedolizumab CDRs, variable regions, and mutated Fc regions (mutated to eliminate Fc effector function) are described in U.S. Patent No. 7,147,851, which is incorporated herein by reference in its entirety. Vedolizumab formulations are also described in U.S. Patent No. 9,764,033 and U.S. Patent Application Publication No. 20140341885, which are also incorporated herein by reference in their entirety.

[0051] While antibody A is one of only two biological preparations listed in Table 1, it should be understood that other biological preparations, such as other antibodies, therapeutic proteinaceous substances, cell suspensions, liposomes, vaccines, or nucleic acid materials, can be filled into containers according to the present disclosure. Other biological preparations may have densities of, for example, 0.8 g / mL to 1.2 g / mL and surface tensions of 35 mN / m to 75 mN / m. For example, antibody B was formulated without surfactant and exhibited static fluid properties at a wider diameter filling nozzle (or pipette) than antibody A, which contained surfactant. Similarly, a sample of aluminum hydroxide (a vaccine preparation) differed in the presence of surfactant in formulation B, which exhibited lower surface tension than formulation A without surfactant. This static fluid properties were also observed at a wider diameter nozzle than formulation B.

[0052] It should be understood that the foregoing values ​​are merely exemplary, and that in accordance with the present disclosure, containers, e.g., tubes, vials, cartridges, syringes, capsules, can be filled with many different types of biological products. The system and method can be used in the manufacture of biological products, such as antibodies, enzymes, blood factors, or vaccines, by improving accuracy and line throughput in filling containers with liquid biological products. JPEG0007792197000002.jpg251122Table 1 JPEG0007792197000003.jpg23170Table 2

[0053] The fluid properties of the fluids listed in Table 1 and the pipette dimensions listed in Table 2 generated predicted Bond Number values ​​as shown below in Table 3. Predicted Bond Numbers below the aforementioned value of 0.842 are shown in the shaded cells. JPEG0007792197000004.jpg185170JPEG0007792197000005.jpg186170Table 3

[0054] After predicting the Bond number, an experiment was conducted to determine whether a stable, resting profile, i.e., a static profile, bubble (or other fluid interface) would form in the fluid after being dispensed from the corresponding pipette. To determine whether a stable, resting profile bubble would form, a serological pipette was attached to a pipette gun. The pipette gun aspirated various liquids into the pipette, which was then placed on a burette stand for 5 minutes to equilibrate. Following the 5-minute equilibration period, qualitative observations were made to determine whether the bubble formed was static, as shown in Figure 5, or moving, as shown in Figure 6. If the Bond number was greater than 0.842, it was predicted that an unstable, resting profile, i.e., a moving bubble, would form in the fluid after being dispensed from the corresponding pipette. The results of this test are shown in Table 4 below. JPEG0007792197000006.jpg233144Table 4

[0055] As can be seen, all fluids in pipettes with Bond numbers below 0.842 formed bubbles with a stable, stationary profile after dispensing the fluid from the pipette. Surprisingly, certain fluids (water, saline, dextrose, and high NaCl) were found to form quasi-static bubbles in the fill fluid after dispensing from the pipette. The bubbles formed were "quasi-static," meaning they would be stationary and not move; however, they could begin to move if a "shock" was delivered to the fluid, such as a pulling force that pulls the fluid away from the pipette opening, i.e., a reverse flow or "suckback" force. It should be noted that quasi-static bubbles formed in fluids with high contact angles to the pipette material may be associated with fill nozzles containing materials that do not meet other criteria for operating the fill system 100.

[0056] In one embodiment, a different approach is used that emphasizes three parameters that affect the breakup of a fluid jet: density, radius, and surface tension. This approach is similar to the Ohnesorge number described above, but assumes that the Reynolds number (the ratio of inertial to viscous forces) is negligibly high, and therefore does not capture viscous forces. This approach utilizes the following equation:

number

[0057] Therefore, in one embodiment, instead of using the Ohnesorge number, this characteristic collapse time equation can be used to use a high Reynolds number assumption to determine the minimum allowable fill needle radius for a stable liquid jet. It should be understood that this approach works when the fill time can be set for a sterilization line constrained by a maximum liquid velocity and a fixed distance from the fill needle to the bottom of the container. The maximum liquid velocity can be set by the maximum shear the fluid can withstand before the product's fluid quality attributes are affected due to shear from the mechanism of pump operation. In all cases, the maximum value is still set by a Bond number < 0.842.

[0058] Figures 10A and 10B illustrate the well-known effects of the Rayleigh-Plateau instability and show two engineering options for achieving longer stable profiles: by designing the system to use a larger fill nozzle diameter and / or higher fluid velocities.

[0059] FIG. 10A shows diagrams of columns of fluid flowing from filler nozzle openings of different diameters to demonstrate the flow profiles resulting from different filler nozzle diameters. A 10 millimeter diameter filler nozzle opening is shown at 1002. A 5 millimeter diameter filler nozzle opening is shown at 1004. A 3 millimeter diameter filler nozzle opening is shown at 1006. A 1.6 millimeter diameter filler nozzle opening is shown at 1008. As shown, larger diameter holes produce more stable columns.

[0060] Figure 10B shows a diagram of three fluid columns 1010, 1012, and 1014 flowing from the opening of a filling nozzle to demonstrate the flow profiles resulting from different filling rates. All columns are subjected to gravitational acceleration, which causes the column diameter to shrink until it becomes more susceptible to perturbations (due to conservation of mass). A faster-flowing column will travel further over the same period. The velocity is affected by the volumetric flow rate and the diameter of the filling needle outlet. For peristaltic pumps, volumetric flow is driven by the pump RPM and pump tubing diameter. In Figure 10B, the left column 1010 has the smallest hydrostatic head and therefore the slowest exit velocity, while the right column 1014 has the fastest exit velocity and therefore travels farther.

[0061] 11 is a flow chart illustrating an exemplary series of steps for a method for designing a filling system in an exemplary embodiment. In step 1102, the method includes calculating a maximum radius using measured fluid properties of the formulation and Bond number (including actuator acceleration and safety factors). In step 1104, the method includes determining the maximum forward volumetric flow rate (RPM and tubing size) that the protein can tolerate in terms of product quality attributes by initially characterizing these attributes before pumping. In step 1106, the method includes calculating the fill needle exit velocity and the length of steady fluid flow from the maximum radius and volumetric flow rate. In step 1108, the method includes reducing the reversal speed as reasonably as possible and setting a reversal distance of approximately three fill needle diameters, taking into account the economic constraints of operating the filling line and the limitations for maintaining a sterile environment as determined by the filling of the formulation medium. For example, diameter may be determined by techniques such as, but not limited to, the technique determined by Hanslip et al. (see, for example, J. Pharm Sci. 108:1130-1138, (2019)).

[0062] FIG. 12 is a flow chart illustrating another series of steps of a method for designing a filling system in an exemplary embodiment. In step 1202, the method includes determining the maximum fill needle radius with a Bond number < 0.842. In step 1204, the method includes using the determined radius to calculate the minimum volumetric flow rate required for a stable jet (either by Ohnesorge number or characteristic time requirement) throughout the filling process. The characteristic time is defined as a function of the initial fluid jet radius to determine the time required for the jet to break up, assuming maximum perturbation growth. The characteristic time must exceed the time required for the jet to traverse the distance between the fill needle and the bottom of the container. This is calculated by increasing or decreasing the exit velocity and any acceleration due to gravity (or any similar physical force). In step 1206, the method includes verifying that the maximum flow rate has no impact on product quality and / or determining the maximum flow rate with an acceptable impact on product quality. In step 1208, the method includes decreasing the fill needle radius until the maximum flow rate for product quality also meets the characteristic time requirement. In step 1210, the method includes minimizing h / r, where h / r is the formed film thickness divided by the radius of the nozzle opening, by changing the suck-back rate to the slowest allowable rate that satisfies either (a) a predetermined value (e.g., 10%) or (b) a predetermined total fill time (e.g., 5 seconds per fill).

[0063] In one exemplary embodiment for dispensing a fill solution according to the present disclosure, a fill solution containing antibody A having the fluid properties listed in Table 1 was dispensed into a 1 mL long (1 mL) ISO syringe with a target fill volume of 741 μL. Antibody A also had a viscosity of 15.75 cP at 20°C. When dispensed according to a set of operating parameters satisfying the aforementioned conditions 1, 2, and 3, the standard deviation of the fill volume, as a percentage of the fill volume, was found to be below the target of 2.000%. The standard deviation of the fill volume was found to be reliably within a 1% range. Furthermore, it was found that dispensing of antibody A from the test nozzle could be interrupted for 20 minutes without clogging the nozzle. Therefore, it was concluded that antibody A, as well as other fill solutions containing one or more biological agents, can be accurately and precisely filled into containers according to the present disclosure, resisting drying of the fluid after filling.

[0064] In one embodiment, a fill system can be designed and operated as described herein to include a stable resting profile, a stable retraction profile, and a stable flow profile. The pump speed can be controlled to reverse as slowly as possible (based on criteria predetermined from test results of various fluids) and to be as fast as possible during the fill operation while still meeting the constraints of these profiles. In some embodiments, a fill system designed to include a shorter fill needle radius and slower suck-back rate significantly increases accuracy (limiting fluid loss) and provides the ability to interrupt the fill line for longer periods of time, such as 20 minutes or more, without occlusion occurring.

[0065] Exemplary filling results can be seen in the results of the developmental pump / fill study attached as Exhibit A. Note that Variants #1 and #2 demonstrate no needle blockage when using a filling process constrained by these equations, and that Variant #1 has a smaller filling needle, which results in slightly higher consistency. In the study, the pump / fill settings for the Bosch™ pump were as follows: Variation #1 1.6mm ID filling needle (steel) Pump tube diameter of 1.2mm ID 365 RPM 0.5 accelerated filling 0.5 reduction filling 0.4 Acceleration Reverse 15 Reverse direction / backward suction Variation #2 2.5mm ID filling needle (steel) Pump tube diameter of 1.6mm ID 450 RPM 0.5 accelerated filling 0.5 reduction filling 0.4 Acceleration Reverse 15 Reverse direction / backward suction

[0066] Figures 13A and 13B each represent data collected for a different variation. The x-axis represents a time series of fill steps using the same fill needle, and the y-axis represents the measured fill weight (in grams) relative to the target weight. As noted above, using Taylor's Law, the variation from one fill step to the next closely matches the predicted film thickness for each profile. The degree of oscillation is determined by the amount required to form a liquid bridge on the fill needle.

[0067] The embodiments described herein illustrate the use of a computing device with a processor that executes a filling module. FIG. 14 illustrates an exemplary computing device suitable for use with embodiments of the present invention. FIG. 14 is a block diagram of an exemplary computing device 1400 that can be used to implement an exemplary embodiment of the filling system 100 described herein. The computing device 1400 includes one or more non-transitory computer-readable media for storing one or more computer-executable instructions or software for implementing the exemplary embodiment. The non-transitory computer-readable media may include, but are not limited to, one or more types of hardware memory, non-transitory tangible media (e.g., one or more magnetic storage disks, one or more optical disks, one or more flash drives), etc. For example, the memory 1406 included in the computing device 1400 may store computer-readable and computer-executable instructions or software for the filling module used in implementing the exemplary embodiment of the filling system 100. Computing device 1400 also includes a configurable and / or programmable processor 1402 and associated core(s) 1404, and optionally one or more additional configurable and / or programmable processor(s) 1402′ and associated core(s) 1404′ (e.g., in the case of a computer system with multiple processors / cores), to execute computer-readable and computer-executable instructions or software stored in memory 1406 and other programs for controlling the system hardware. Processor 1402 and processor(s) 1402′ may each be a single-core processor or a multi-core (1404 and 1404′) processor.

[0068] Virtualization can be employed in computing device 1400 to dynamically share the infrastructure and resources of the computing device. Virtual machines 1414 can be provided to handle processes running on multiple processors, so that the processes appear to be using only one computing resource rather than multiple computing resources. Multiple virtual machines can also be used on a single processor.

[0069] The memory 1406 may include computer system memory or random access memory, such as DRAM, SRAM, EDORAM, etc. The memory 1406 may also include other types of memory, or combinations thereof.

[0070] A user can interact with computing device 1400 via a visual display device 1418, such as a computer monitor, that can display one or more graphical user interfaces 1422, which may be provided in accordance with an exemplary embodiment. Computing device 1400 may include other I / O devices for receiving input from a user, such as a keyboard or any suitable multi-point touch interface 1408, a pointing device 1410 (e.g., a mouse), a microphone 1428, and / or an image capture device 1432 (e.g., a camera or scanner). The multi-point touch interface 1408 (e.g., a keyboard, pin pad, scanner, touch screen, etc.) and the pointing device 1410 (e.g., a mouse, stylus pen, etc.) may be coupled to the visual display device 1418. Computing device 1400 may include other appropriate conventional I / O peripherals.

[0071] The computing device 1400 may also include one or more storage devices 1424, such as a hard drive, CD-ROM, or other computer-readable medium, for storing data and computer-readable instructions and / or software for implementing the exemplary embodiments of the fill system 100 described herein. The exemplary storage device 1424 may also store one or more databases for storing any suitable information necessary to implement the exemplary embodiments. For example, the exemplary storage device 1424 may store one or more databases 1426 for storing information regarding fluid characteristics, system characteristics, and / or any other information used by embodiments of the fill system 100. The databases may be updated manually or automatically at any suitable time to add, delete, and / or update one or more items in the databases.

[0072] Computing device 1400 may include a network interface 1412 configured to interface with one or more networks, such as a local area network (LAN), a wide area network (WAN), or the Internet via various connections, such as, but not limited to, a standard telephone line, a LAN or WAN link (e.g., 802.11, T1, T3, 56 kb, X.25), a broadband connection (e.g., ISDN, Frame Relay, ATM), a wireless connection, a controller area network (CAN), or a combination of any or all of the above, via one or more network devices 1420. In an exemplary embodiment, computing device 1400 may include one or more antennas 1430 to facilitate wireless communication between computing device 1400 and the network (e.g., via the network interface). Network interface 1412 may include a built-in network adapter, a network interface card, a PCMCIA network card, a card bus network adapter, a wireless network adapter, a USB network adapter, a modem, or any other device suitable for interfacing computing device 1400 to any type of network with which it can communicate and for performing the operations described herein. Furthermore, computing device 1400 may be any computer system such as a workstation, desktop computer, server, laptop, handheld computer, tablet computer, mobile computing or communication device such as a smartphone, an in-house device, or other form of computing or communication device capable of communications and having sufficient processor power and memory capacity to perform the operations described herein.

[0073] Computing device 1400 may execute operating system 1416, such as versions of the Microsoft® Windows® operating system, different releases of Unix and Linux operating systems, versions of MacOS® for Macintosh computers, embedded operating systems, real-time operating systems, open source operating systems, proprietary operating systems, or other operating systems capable of executing on a computing device and performing the operations described herein. In an exemplary embodiment, operating system 1416 may execute in native mode or in an emulated mode. In an exemplary embodiment, operating system 1416 may execute on one or more cloud machine instances.

[0074] In describing the exemplary embodiments, specific terminology is employed for the sake of clarity. For purposes of description, each specific term is intended to include, at a minimum, all technical and functional equivalents that operate in a similar manner to accomplish a similar purpose. Furthermore, in some instances where a particular exemplary embodiment includes multiple system elements or method steps, those elements or steps may be replaced with a single element or step. Similarly, a single element or step may be replaced with multiple elements or steps that serve the same purpose. Furthermore, when various characteristic parameters are specified herein for exemplary embodiments, those parameters may be adjusted up or down by 1 / 20, 1 / 10, 1 / 5, 1 / 3, 1 / 2, etc., or by rounding approximations thereof, unless otherwise specified. Furthermore, while exemplary embodiments have been shown and described with reference to specific embodiments thereof, those skilled in the art will recognize that various substitutions and changes in form and details can be made without departing from the scope of the invention. Furthermore, other aspects, features, and advantages are also within the scope of the invention. JPEG0007792197000008.jpg16146JPEG0007792197000009.jpg21146JPEG0007792197000010.jpg170170 JPEG0007792197000011.jpg252157 JPEG0007792197000012.jpg239139JPEG0007792197000013.jpg61170 JPEG0007792197000014.jpg87162

Claims

1. a reservoir for holding a fill fluid for dispensing; at least one fill nozzle fluidly coupled to the reservoir and configured to dispense the fill liquid through a nozzle opening defining a nozzle radius (r); a pump fluidly coupled to the reservoir and the at least one fill nozzle and configured to dispense the fill liquid to the at least one fill nozzle through the nozzle opening; 1. A filling system comprising: a memory having a filling module stored therein; and at least one processor operably coupled to the pump; The at least one processor receiving at least one fluid characteristic of the fill fluid; generating, based at least in part on the at least one fluid characteristic, at least one set of operating parameters for dispensing the fill liquid through the nozzle opening such that a stable, static profile fluid interface is formed in the fill liquid within the fill nozzle adjacent the nozzle opening after the fill liquid is dispensed from the at least one fill nozzle; and outputting the at least one set of operating parameters enabling control of the pump to dispense the filling liquid through the nozzle opening during a filling procedure; is configured to run the at least one fluid property includes a density difference (ρ) of the fill liquid relative to the surrounding environment fluid, a fluid surface tension (γ) of the fill liquid relative to the surrounding environment fluid, and a net acceleration (a) of the fill liquid; the at least one set of operating parameters are generated such that the nozzle radius, the density difference, the fluid surface tension, and the net acceleration satisfy the equation ((ρ*a*r 2 ) / γ)<0.842; Filling system.

2. The filling system of claim 1 , wherein the at least one set of operating parameters includes a backflow rate of the pump.

3. The backflow velocity is expressed as a modified Taylor's law equation [Equation 2] wherein h / r is less than 0.10, h / r is the formed film thickness divided by the radius of the nozzle opening, and Ca is equal to {(fluid viscosity of the fill liquid * the backflow rate) / fluid surface tension of the fill liquid relative to the ambient environment fluid}.

4. A filling system as described in claim 1 or 2, wherein the processor generates the at least one set of operating parameters for dispensing the filling liquid through the nozzle opening based at least in part on the at least one fluid characteristic so that a stable jet of filling liquid dispensed through the nozzle opening does not collapse during filling.

5. 5. The filling system of claim 4, wherein the at least one set of operating parameters generates an Ohnesorge number that results in the stable jet of filling liquid being dispensed through the nozzle opening and downward to the bottom of a filling container.

6. The filling system of claim 5 , wherein the at least one set of operating parameters enables control of the pump to fill at least one container with the filling liquid.

7. The fill system of claim 5 , wherein the at least one set of operating parameters comprises a range of operating parameters.

8. The filling system of claim 4, wherein the processor is configured such that the filling module receives at least one additional system parameter and generates the at least one set of operating parameters based at least in part on the at least one additional system parameter.

9. The at least one additional system parameter is: a nozzle material for the at least one fill nozzle; and a contact angle between the at least one filling nozzle and the filling liquid; 9. The filling system of claim 8, wherein the filling system is selected from the group consisting of at least one of:

10. The filling system of claim 1 or 2, wherein the at least one fluid characteristic further comprises a composition of the filling liquid.

11. A filling system as described in claim 1 or 2, further comprising an input device operably coupled to at least one of the processor and the memory and configured to receive input of the at least one fluid characteristic.

12. The filling system of claim 1 or 2, wherein the at least one set of operating parameters includes a time parameter for performing the filling operation.

13. A reservoir for holding a fill liquid for dispensing; and at least one filling nozzle fluidly coupled to the reservoir for dispensing the fill liquid through a nozzle opening defining a nozzle radius (r), the at least one filling nozzle forming a stable fluid interface in the fill liquid adjacent the nozzle opening after the fill liquid is dispensed from the at least one filling nozzle, the stable fluid interface having a static interface and / or a controlled plug volume; 1. A filling system comprising: the fill system generates at least one set of operating parameters for dispensing the fill liquid through the nozzle opening based at least in part on at least one fluid characteristic; the at least one fluid property includes a density difference (ρ) of the fill liquid relative to the surrounding environment fluid, a fluid surface tension (γ) of the fill liquid relative to the surrounding environment fluid, and a net acceleration (a) of the fill liquid; the at least one set of operating parameters are generated such that the nozzle radius, the density difference, the fluid surface tension, and the net acceleration satisfy the equation ((ρ*a*r 2 ) / γ)<0.842; Filling system.

14. 14. The system of claim 13, wherein the fill liquid has a fluid profile that minimizes mass loss due to convective drying within the at least one fill nozzle when forming the stable fluid interface.

15. 15. The system of claim 1, wherein the net acceleration is the acceleration of gravity.

16. 16. The system of claim 1, wherein the at least one filling nozzle is a filling needle.

17. The system of claim 16 , wherein the filling needle comprises stainless steel.

18. The system of claim 13 , further comprising a pump fluidly coupled to the reservoir to dispense the fill liquid through the nozzle opening.

19. 20. The system of claim 18, further comprising a controller operatively coupled to the pump and configured to maintain a fluid interface at a stable quiescent profile by adjusting at least one pump parameter of the pump.

20. 20. The system of claim 19, further comprising a nozzle actuator coupled to the at least one fill nozzle and operably coupled to the controller, the controller configured to maintain the fluid interface at the stable quiescent profile by adjusting an actuator parameter of at least one of the nozzle actuators.

21. 14. The system of claim 13, wherein the at least one fill nozzle defines a first radius and a second radius smaller than the first radius, the at least one fill nozzle having a narrow portion having the second radius formed between the nozzle opening and a body of the at least one fill nozzle, the body and the nozzle opening of the at least one fill nozzle having the first radius.

22. A method of dispensing fill liquid from a reservoir holding fill liquid to a container, comprising: at least one pump and at least one fill nozzle fluidly coupled to said reservoir, said at least one pump configured to dispense said fill liquid to said at least one fill nozzle, said at least one fill nozzle including a nozzle opening configured to deliver said fill liquid to said container; The method is executed by a processor, receiving an input via an input device specifying at least one fluid characteristic of the fill liquid; generating, based at least in part on the at least one fluid characteristic, at least one set of operating parameters for controlling the pump during a filling procedure to dispense the fill liquid through the nozzle opening such that a fluid interface of a stable, static profile is formed in the fill liquid adjacent the nozzle opening after the fill liquid is dispensed from the at least one fill nozzle; and outputting the at least one set of operating parameters; the nozzle opening defines a nozzle radius (r); the at least one fluid property includes a density difference (ρ) of the fill liquid relative to the surrounding environment fluid, a fluid surface tension (γ) of the fill liquid relative to the surrounding environment fluid, and a net acceleration (a) of the fill liquid; The method, wherein the at least one set of operating parameters are defined such that the nozzle radius, the density difference, the fluid surface tension, and the net acceleration satisfy the equation ((ρ*a*r 2 ) / γ)<0.

842.

23. 23. The method of claim 22, wherein the at least one set of operating parameters comprises a backflow rate of the pump.

24. The backflow velocity is expressed as a modified Taylor's law equation [Equation 3] wherein h / r is less than 0.10, h / r is the formed film thickness divided by the radius of the nozzle opening, and C is equal to {(fluid viscosity of the fill liquid * the backflow rate) / fluid surface tension of the fill liquid relative to the surrounding environment fluid}.

25. 25. The method of claim 24, further comprising generating the at least one set of operating parameters for dispensing the fill liquid through the nozzle opening based at least in part on the at least one fluid characteristic, such that a stable jet of fill liquid dispensed through the nozzle opening does not collapse during filling.

26. 26. The method of claim 25, wherein the at least one set of operating parameters is generated to generate an Ohnesorge number that results in the stable jet of fill liquid being dispensed through the nozzle opening and falling to the bottom of a container being filled.

27. controlling the pump in accordance with the at least one set of operating parameters and filling at least one container with the fill liquid; 27. The method of claim 26, further comprising:

28. 28. The method of claim 27, wherein the at least one set of operating parameters comprises a range of operating parameters.

29. receiving at least one additional system parameter, wherein the at least one set of operating parameters is generated at least in part based on the at least one additional system parameter; 26. The method of claim 25, further comprising:

30. The at least one additional system parameter is: a nozzle material for the at least one fill nozzle; and a contact angle between the at least one filling nozzle and the filling liquid; and 30. The method of claim 29, comprising at least one of:

31. 31. The method of any one of claims 22 to 30, wherein the at least one fluid property further comprises a composition of the fill liquid.

32. 32. The method of any one of claims 22 to 31, wherein the at least one set of operating parameters includes a time parameter for performing a filling operation.

33. 13. Use of the system according to any one of claims 1 to 12 in the manufacture of a liquid formulation of antibody A, wherein said antibody A is vedolizumab.

34. 33. A method of filling a container with a liquid formulation of antibody A, comprising the method of any one of claims 22 to 32, wherein said antibody A is vedolizumab.

35. The system of claim 14 , wherein the stable fluid interface recedes from the nozzle opening.

36. 14. The system of claim 13, wherein the loading solution comprises a liquid formulation of antibody A, wherein the antibody A is vedolizumab.

37. The system of claim 13 , wherein the at least one set of operating parameters further comprises a contact angle between the at least one fill nozzle and the fill liquid.

38. 38. The system of claim 37, wherein the contact angle is less than 90 degrees.

39. The system of claim 18 , wherein the at least one set of operating parameters further includes a time parameter for performing a filling operation.

40. The at least one set of operating parameters includes a backflow rate of the pump, and the backflow rate is determined by a modified Taylor's law equation: [Equation 4] wherein h / r is less than 0.10, h / r is the formed film thickness divided by the radius of the nozzle opening, and C is equal to {(fluid viscosity of the fill liquid * the backflow rate) / fluid surface tension of the fill liquid with respect to the ambient fluid}.

41. 20. The system of claim 18, wherein the at least one set of operating parameters is generated to generate an Ohnesorge number that results in the stable jet of fill liquid being dispensed through the nozzle opening and falling to the bottom of a container being filled.

42. 20. The system of claim 18, wherein the at least one set of operating parameters enables control of the pump to fill at least one container with the fill liquid.

43. 14. The system of claim 13, wherein the at least one set of operating parameters is generated to cause gas bubbles to form in the fill liquid in the at least one fill nozzle at the stable fluid interface.

44. a steady jet of filler liquid is dispensed through the at least one nozzle opening; [Equation 5] The system of claim 13, wherein the system does not collapse during filling at a time t calculated by:

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