Patent Application
20240367829
The present disclosure relates to systems and methods for filling containers, such as pre-filled syringes.
Filling systems are often used to fill large numbers of relatively small containers, such as pre-filled syringes, with fluid from a relatively large reservoir. The filling system includes a pump fluidly coupled to the reservoir and to one or more filling nozzles. In large filling systems, the pump may connect to tens, 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 individual containers through the filling nozzle(s).
Embodiments of the present invention provide systems and methods that account for certain fluid dynamic behaviors in order to distribute filling fluid through a filling nozzle to a container in a manner that increases filling accuracy and prevents blockages. More particularly, embodiments distribute filling fluid in a manner that avoids overfilling and under filling containers while also accounting for fluid dynamic behaviors to avoid an unwanted drying of filling fluid within the filling nozzle that may lead to blockages or contamination. The systems and methods herein may be used for repetitive, accurate, high throughput manufacturing of combination pharmaceutical products, such as pharmaceutical liquids in delivery devices.
In one exemplary embodiment disclosed herein, a filling system includes: a reservoir holding a filling fluid for distribution; at least one filling nozzle fluidly coupled to the reservoir to distribute the filling fluid through a nozzle opening; a pump fluidly coupled to the reservoir and at least one filling nozzle configured to distribute the filling fluid through the filling nozzle and the nozzle opening; and at least one processor operatively coupled to the pump and a memory having a filling module stored therein. The at least one processor is configured to execute the filling module to: receive at least one fluid property of the filling fluid; generate, based at least partially on the at least one fluid property, at least one set of operating parameters for distributing the filling fluid through the nozzle opening such that a fluid interface with a stable resting profile forms in the filling fluid in the filling nozzle adjacent to the nozzle opening after the filling fluid is distributed from the at least one filling 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 distribute the filling fluid through the nozzle opening during a filling procedure.
In another exemplary embodiment disclosed herein, a filling system includes a reservoir holding a filling fluid for distribution and at least one filling nozzle fluidly coupled to the reservoir to distribute the filling fluid through a nozzle opening defining a nozzle radius (r). A stable fluid interface forms in the filling fluid adjacent to the nozzle opening after the filling fluid is distributed from the at least one filling nozzle. The stable fluid interface has a static interface and/or a controlled plug volume
In another embodiment a processor-implemented method of distributing a filling fluid from a reservoir holding the filling fluid to a container using at least one pump and at least one filling nozzle fluidly connected to the reservoir is disclosed. The at least one filling nozzle includes a nozzle opening and is configured to deliver the filling fluid through the nozzle opening to a container. The method includes receiving via an input mechanism an input specifying at least one fluid property of the filling fluid; generating, based at least partially on the at least one fluid property, at least one set of operating parameters for controlling the pump during a filling procedure to distribute the filling fluid through the nozzle opening such that a fluid interface with a stable resting profile forms in the filling fluid in the filling nozzle adjacent to the nozzle opening after the filling fluid is distributed from the at least one filling 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 distribute the filling fluid through the nozzle opening during a filling procedure.
The foregoing and other objects, features and advantages of the exemplary embodiments will be more fully understood from the following description when read together with the accompanying drawings, in which:
Embodiments of the present invention provide systems and methods for filling containers with filling fluid through a filling nozzle in ways that increase filling accuracy and prevent material blockages. More particularly, embodiments inhibit filling fluid flow towards the bottom of the filling nozzle where the fluid may impact filling accuracy by overfilling, or drip from the nozzle resulting in under filling. Additionally fluid at the end of the nozzle may dry within the filling nozzle causing a blockage. The filling fluid defines a density (ρ), a fluid surface tension (γ), and a net acceleration (a). Accordingly, in some embodiments, the filling system has a processor and a memory holding a filling module that, upon execution by the processor, generates one or more sets of operating parameters based on at least one input fluid property of the filling fluid. The one or more sets of operating parameters enable control of a pump, to distribute the filling fluid through the filling nozzle, in a manner that forms a fluid interface with a stable resting profile within the filling nozzle after the filling fluid is distributed from the filling nozzle.
Referring now to the drawings, and more particularly
The filling system 100 includes a processor 150 operatively coupled to the pump 130 and a memory 160. The memory 160 has a filling module stored therein, which is executed by the processor 150 and described further herein. The filling module may include one or more software components, programs, applications, or other units of code base or instructions configured to be executed by one or more processors including processor 150. In some embodiments, the processor 150 and the memory 160 are part of a computing device 170 that also includes an input 171, such as a keyboard, touchscreen, etc., for inputting data to the filling module. In some embodiments, the computing device 170 includes a display 172 operatively coupled to the processor 150 to display graphics for controlling functions of the filling system 100, as will be described further herein. The processor 150 may operatively couple to the pump 130 by a wireless or wired connection, either directly or indirectly through a network. In some embodiments, the processor 150 operatively couples to multiple pumps through a router or similar element to control multiple pumps simultaneously. In some embodiments, the pump 130 includes a pump memory 133 that stores pump operating instructions that originate from, for example, the processor 150.
Referring specifically now to
In one exemplary embodiment, an exemplary pump head for a peristaltic pump has a diameter of 60 mm and consists of three evenly spaced 10 mm cams per fluid path. The pump tubing follows the pump head for 130-140°. The degrees of rotation around the pump head in combination with the tubing ID (which indicates the tube internal diameter) determines the amount of fluid dispensed. The tubing ID thus determines the volume in one revolution. The larger the ID, the more fluid is dispensed per revolution. As a result, the same pump parameters can result in different flow rates when different tubing diameters are used. Exemplary parameters which can be programmed are outlined in the table below.
It should be appreciated that the fluid impact of these parameters at the filling nozzle/needle is also a function of: a filling nozzle/needle ID internal diameter indicative of filling nozzle/needle diameter (the larger the ID, the slower the fluid velocity is per revolution), pump tubing ID, and number of fluid paths/pump head and that the described pump parameters are added only for illustration purposes. Embodiments of the present invention are not limited to the described parameters and pumps and other operating characteristics should be considered to be within the scope of the present invention.
In some embodiments, and referring now to
Processor 150 may execute the filling module stored in the memory 160 to operate various elements of the filling system 100, such as the pump 130 and the nozzle actuator 310, to automatically fill empty containers with filling fluid from the reservoir 110 in accordance with identified operating parameters as described herein. In some embodiments, the filling module is operatively coupled to other elements, such as a container conveyor, that move containers for filling to a filling position under the filling nozzle 120 and nozzle actuator 310 prior to starting the filling procedure. Once the container is in the filling position, the filling module outputs one or more signals to the nozzle actuator 310 to lower the filling nozzle 120 into the container 220 and to the pump 130 to rotate so filling fluid is distributed from the nozzle opening 221 into the container. During the filling procedure, the filling module can also signal the nozzle actuator 310 to raise the filling nozzle 120, as previously described.
After the container 220 is filled with the fluid, the filling module may signal the pump 130 to perform the suck-back function to pull back any remaining filling fluid from the nozzle opening 221 into the filling nozzle 120 in order to prevent drips from the nozzle opening 221. The filling module may also signal the nozzle actuator 310 to return to the initial filling position 311 and the container conveyor to move a new container to the filling position before restarting the filling procedure. The filling procedure can be repeated in a loop as necessary until, for example, the reservoir 110 is empty or a desired number of containers have been filled with the filling fluid.
Various operating parameters of conventional filling systems lead to waste of filling fluid and inconsistent filling of containers during the filling procedure. For example, filling fluid sometimes drips from the filling nozzle 120 and is wasted during the period between the filled container leaving the filling position and a new container moving to the filling position.
A liquid drop 401 at the end of the filling nozzle 120 is illustrated in
To address drip waste, the previously described suck-back function can be performed at the end of the filling procedure while a new container moves to the filling position. The suck-back function pulls liquid droplets that may form at the nozzle opening 221 back into the filling nozzle 120 to reduce drip waste. While the suck-back function reduces drip waste, it is not completely effective to eliminate drip waste.
Use of the suck-back function can also have drawbacks. When the suck-back function is used, air can enter the filling nozzle 120 and form a bubble 402 within the filling nozzle 120, as shown in
While the second portion 403B can be a non-trivial amount of filling fluid that will be distributed into a container when the container is filled, a bigger issue arises when operation of the filling system 100 is interrupted for as little as two minutes. As can be appreciated from
Alternatively, an additional issue presents in a conventional system as the first portion 403A of filling fluid distributed from the filling nozzle 120 may dissolve the formed film to carry the solid active ingredient into the container being filled. This may significantly increase the amount of active ingredient distributed into the container. Because drug product dosages are subject to strict regulations concerning fill accuracy compared to the advertised dosage, having an increased amount of active ingredient in a pre-filled syringe is also grounds for rejecting a pre-filled syringe for distribution and represents significant product waste.
Attempts to address the previously described issues have focused on trial and error tests to find suitable operating parameters of filling systems. While the trial and error tests have produced some improvements to operation of filling systems, such testing does not address the underlying causes of the specific issues. Thus, extensive trial and error testing was needed to determine acceptable operating parameters of a filling system whenever a new filling fluid was to be distributed from the filling system. Trial and error testing is also time-consuming and expensive. Trial and error testing not only requires a significant amount of time to determine acceptable operating parameters, but also has other requirements adding to the expense such as formulating surrogate fluids, a filling system “test setup,” etc.
To address issues of waste drips and inconsistent fill volume during the filling procedure, and referring now to
To form the bubble 411 with the stable resting profile, it was discovered that various fluid properties of the filling fluid and operating parameters of the filling system 100 may be controlled. The bubble 411 with the stable resting profile can be achieved if the Bond number (Bo) of the filling fluid in the filling nozzle 120 is less than a value of 0.842, even if the bubble is not a fully formed bubble. It should be appreciated that a Bond number of 0.842 of the filling fluid in the filling nozzle represents a theoretical limit above which the profile is not stable but that Bond values only slightly exceeding 0.842 may still provide a useful bubble in some circumstances.
Operating parameters of the filling system 100 to keep the Bond number (which is also sometimes referred to as the Eötvös number)) (ratio of gravitational force to surface tension force) less than the critical value can be determined by the equation
where ρ is a density differential of the filling fluid relative to the surrounding environment fluid (e.g., air, inert gas, oil, alcohol), g is the net acceleration of the fluid (equal to the acceleration of gravity when the filling nozzle 120 is not moving), r is a radius of the filling nozzle 120 (shown in
Because the density differential (ρ) for a specific filling fluid will generally be constant regardless of the operating parameters of the filling system 100, the net acceleration of the filling fluid, the radius r of the filling nozzle 120, and fluid surface tension between the filling fluid and the filling nozzle 120 can represent controllable parameters to achieve a Bond number value of less than 0.842. The fluid surface tension of the filling fluid may be altered, for example, by adjusting the fluid surrounding the filling nozzle, i.e. the surrounding environment fluid 120, as described previously, which will affect the fluid surface tension of the filling fluid. In some exemplary embodiments, the fluid surface tension of the filling fluid may be controlled by, for example, assuming the material of the filling nozzle 120 will not change, i.e., the fluid surface tension of the filling fluid is also a constant. In some embodiments, the filling nozzle 120 may comprise a metal material such as stainless steel. As used herein, the density of the filling fluid and the fluid surface tension may each be referred to as a “fluid property” of the filling fluid and may be provided or measured according to methods known in the art. Other fluid properties of the filling fluid may include, but are not limited to, viscosity, compressibility, etc.
When the fluid surface tension is assumed to be constant, the only variables to control are the net acceleration of the filling fluid and the radius r of the filling nozzle 120, which may be referred to as operating parameters of the filling system 100 that are distinct from the fluid properties of the filling fluid. In some exemplary embodiments, the net acceleration of the filling fluid and the radius r of the filling nozzle 120 can be controlled to satisfy the equation (g*r2)<(0.842 * γ/ρ). The net acceleration of the filling fluid may be, for example, the net acceleration as a result of gravity acting on the filling fluid and an opposing acceleration due to the reverse flow/suck-back function of the pump 120, movement of the filling nozzle 120 and filling fluid by the nozzle actuator 310, or any combination of those forces. In some exemplary embodiments, a material of the filling nozzle 120, which may be stainless steel or plastic, may also be an operating parameter of the filling system 100 as the composition of the filling nozzle or coating thereon may affect the fluid velocity.
To operate the filling system 100, and referring now to
Step 702 includes generating, based at least partially on the at least one fluid property, at least one set of operating parameters for distributing the filling fluid through the nozzle opening 221 such that a bubble with a stable resting profile forms in the filling fluid in the filling nozzle 120 adjacent to the nozzle opening 221 after the filling fluid is distributed from the filling nozzle 120. In some embodiments, the set of operating parameters can be generated to establish a Bond number below the critical value of 0.842, as previously described. For example, generating the one or more sets of operating parameters may be based on the input of one or more fluid properties to identify a range of pump and other operating parameters needed to establish a Bond number less than 0.842. In some embodiments, the filling module is configured to establish a Bond number indirectly from certain fluid properties or operating parameters. For example, a mass and volume of the filling fluid may be input to the filling module, which can then determine the density of the fluid as part of establishing a Bond number below the critical value. In another embodiment, the density of the filling fluid may be input directly to the filling module.
In some embodiments, one or more operating parameters can also be input to the filling module to reduce the number of variable operating parameters that are adjustable. For example, the radius r of the filling nozzle 120 may be input as a constant, with the filling module then generating 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 possible materials such as, but not limited to, plastic, stainless steel, or coatings or constructs thereon, of the filling nozzle 120 that may be used (to control the fluid surface tension) and operating parameters that affect the net acceleration of the filling fluid. In some embodiments, the at least one set of operating parameters may include only a single variable, such as a reverse flow velocity, which may be referred to as a “suck-back velocity,” of the pump 130, to establish a Bond number below the critical value of 0.842. It should thus be appreciated that generating the at least one set of operating parameters can be varied in many different ways depending on the at least one fluid property input into the filling system 100 and the operating parameter(s), if any, that are held constant. For example, when surface tension is input as a fluid property, the system uses the Bond number relationship to determine the density, and then calculates a design space from those two values.
Step 703 includes outputting the at least one set of operating parameters. The set of output operating parameter(s) enable control of the pump 130 when distributing the filling fluid through the nozzle opening 120 during a filling procedure, such as the previously described filling procedure. In some exemplary embodiments, the set of operating parameters includes, at least, pump operation parameters for the pump 130 including, for example, a forward rotation velocity, a suck-back velocity for the suck-back function, acceleration (forward/reverse), deceleration (forward/reverse), timing parameters for activation of the pump 130, etc. In some embodiments, the set(s) of operating parameters include nozzle movement parameters for the nozzle actuator 310 including, for example, a movement speed of the nozzle actuator 310 to carry the filling nozzle 120, timing parameters for activation of the nozzle actuator 310, diving needle motion, etc. Other operating parameters that may be controlled include a diameter of the filling nozzle 120, a filling nozzle composition, etc. It should thus be appreciated that the output set(s) of operating parameters may be output to enable automatic control of some, or all, components of the filling system 100 to fill containers such that a bubble with a stable resting profile is formed in the filling fluid after distributing the filling fluid when, for example, there is an interruption in the filling procedure. Alternatively, the output set(s) of operating parameters may be displayed to a user for manual control of some, or all, components of the filling system 100.
In some exemplary embodiments, the generated set(s) of operating parameters are output to assist in choosing operating parameters of the filling system 100. For example, the set(s) of operating parameters may be output to the display 172 of the computing element 170 for displaying visual elements that signify the generated operating parameters. Such output may be required, for example, when the filling system 100 has certain parameters controlled by the filling module, such as parameters of the pump 130 and the nozzle actuator 310, and other parameters that must be manually adjusted, such as the radius r and composition of the filling nozzle 120, which may be adjusted by manually replacing the filling nozzle 120. In some embodiments, the filling module only generates and outputs the at least one set of operating parameters but does not control other functions of a filling system. For example, the filling module may output the set(s) of operating parameters to a different computing device at a remote location via a network, or otherwise, to enable control of an off-site pump or other components of a filling system. It should therefore be appreciated that the filling system 100 may include multiple processors.
Step 704 includes the processor 150 executing the filling module to control the pump 130 in accordance with the at least one set of operating parameters and fill at least one container, such as the container 220, with the filling fluid. In some embodiments, the filling module continuously controls the pump 130 during the filling procedure. In some embodiments, the filling module outputs a portion or an entirety of the set(s) of operating parameters to the pump 130, which then automatically operates according to the operating parameters until instructed otherwise by the filling module. Similarly, the filling module may output a portion or an entirety of the set(s) of operating parameters to the nozzle actuator 310, which may be continuously controlled by the filling module or operate automatically according to the operating parameters until instructed otherwise by the filling module. While the pump 130 and the nozzle actuator 310 are described as receiving the operating parameters and being controlled by the filling module, it should be appreciated that other components of the filling system 150, such as the container conveyor, may also be controlled by the filling module in a similar fashion.
Step 705 includes receiving at least one additional system parameter and generating the at least one set of operating parameters based at least partially 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 filling system 100, such as the radius r of the filling nozzle 120, the composition of the filling nozzle 120, a net acceleration of the filling nozzle 120 and filling fluid during the filling procedure, etc. In some embodiments, the at least one additional system parameter is a different parameter that affects operation of the filling system 100, such as a model of the pump 130 and/or composition of one or more of the tubings 122, 123, 124, etc. For example, the model of the pump 130 may affect the possible suck-back velocities that can be achieved by the filling system 100 during operation and affect other operating parameters of the system. Thus, it should be appreciated that the at least one additional system parameter, while not directly affecting fluid motion in the filling fluid, has an impact on the possible operating parameters that can be generated. It should be further appreciated that many different additional system parameters can be received for use in generating the at least one set of operating parameters.
As previously described, forming the bubble 411 with a stable resting profile in the filling fluid in the filling nozzle inhibits dripping of the filling fluid from the nozzle opening 221 and drying of the filling fluid within the filling nozzle 120. However, forming the bubble 411 with the stable resting profile only acts to keep a liquid plug from expanding during rest, such as when the filling system 100 is not operating. A liquid plug may still form in the filling nozzle 120 during the suck-back function due to the bubble 411 (or stable fluid interface 412) rising slightly faster than the filling fluid during the suck-back. This disparity in the rising speed of the bubble compared to the filling fluid results in some filling fluid escaping the bubble 411 and forming a film on the wall of the filling nozzle 120, which may dry and form a relatively small liquid plug.
such that h/r is less than a predetermined maximum value where
h/r is a thickness of a formed film within the filling nozzle 120 divided by the radius of the filling nozzle 120, μ is a viscosity of the filling fluid, V is a velocity of the filling fluid, and γ is the fluid surface tension. The predetermined maximum value of h/r can depend on the acceptable variability of the filling procedure, e.g., the maximum allowed overfill or underfill of the filling fluid into a container or the minimum volume of a formed plug that clogs the filling nozzle 120. The volume of a formed plug may be calculated as an annulus volume, which is equal to an integration of h/r multiplied by a suck-back height of the filling fluid. 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, such as less than 0.05.
In some embodiments, the velocity of the filling fluid is the suck-back velocity and is the only operating parameter in the Modified Taylor's Law equation that may be adjusted by the filling module. In some embodiments, the filling module outputs the at least one set of operating parameters that both establishes a Bond number less than the critical value of 0.842 (“Condition 1”) and also satisfies the Modified Taylor's Law equation such that h/r is less than the predetermined maximum value (“Condition 2”), corresponding to a formed film thickness that is 10% or less of the radius r of the filling nozzle 120. It should be appreciated that the illustrative thickness limit of 10% is not absolute and the thickness limit can be driven by either acceptable variability in the fill (from a safety or efficacy perspective) and/or a limitation on the duration of the filling process. In some embodiments, the at least one set of operating parameters is a range of operating parameters that can be varied within the range to satisfy both Condition 1 and Condition 2 simultaneously, allowing the filling system 100 to fill containers such that the bubble with a stable resting profile is formed adjacent to the nozzle opening 221 and a thin film thickness develops within the filling nozzle 120 following filling fluid distribution. The filling module may also receive one or more additional system parameters, as previously described, and generate the at least one set of operating parameters satisfying both Condition 1 and Condition 2 simultaneously based at least partly on the received one or more fluid property and one or more additional system parameters.
In some embodiments, the filling nozzle 120 may be a tapered nozzle with a first radius and a second radius that is smaller than the first radius and is adjacent to the nozzle opening 221. In some embodiments, the filling nozzle 120 has a narrowed portion with the second radius. The narrowed portion may be between a body of the filling nozzle 120, which has the first radius, and the nozzle opening 221, which also has the first radius so as to provide a narrower portion or other constriction at bottom of the filling nozzle above the nozzle opening. Such an embodiment may have the narrowed portion for an air interface formed in the filling nozzle 120, while the first radius of the nozzle opening 120 and body of the filling nozzle reduces the risk of the thin film explained by the Modified Taylor's Law equation from fully clogging the filling nozzle 120.
In some embodiments, the composition of the filling nozzle 120 is selected to control a contact angle θ between the filling fluid and the filling nozzle 120. When the contact angle θ is relatively high, i.e., close to or greater than 90°, behavior of the filling fluid within the filling nozzle 120 may change. The change in behavior of the filling fluid was observed by Alexandru Herescu in a thesis entitled “Two-Phase Flow in Microchannels: Morphology and Interface Phenomena,” published by the Michigan Technological University in 2013 (hereafter “Herescu”), which is incorporated herein by reference in its entirety. For example, a high contact angle θ may induce the formation of a non-wetting film, as shown by Herescu, in addition to a “Bretherton film” formed adjacent to the meniscus due to shock that occurs in the fluid at high fluid velocities, e.g., high suck-back velocities. At very high fluid velocities, multiple plugs may be formed in the filling fluid, as shown by Herescu. Thus, in some embodiments, one controlled parameter of the filling system 100 is the composition of the filling nozzle 120 to control the contact angle θ formed between the filling nozzle 120 and the filling fluid. A high contact angle results in hydrostatic jumps and thicker films. Accordingly, in some embodiments a contact angle that is less than 90 degrees is selected.
Referring now to
In some embodiments, the at least one set of operating parameters is generated to produce an Ohnesorge number (OhR) that results in the stable jet of filling fluid being distributed from the nozzle opening 221. The Ohnesorge number may be determined from the equation
where μ is the dynamic viscosity of the filling fluid, ρ is the density of the filling fluid, γ is the surface tension of the filling fluid, and R is the radius r of the filling nozzle 120. Various Ohnesorge numbers and associated critical lengths are described by Driessen et al. in an article entitled “Stability of viscous long liquid filaments” published in “Physical Fluids” in 2013 (hereafter “Driessen et al”), which is incorporated in its entirety herein by reference. For a particular critical length (Γ) representing the distance the jet remains stable (in units of filling needle radius), the associated Ohnesorge number resulting in a stable jet of filling fluid can be generated, in some embodiments, based on previously determined stable and unstable experimental points. For convenience of description, the filling fluid being distributed from the filling nozzle 120 as a stable jet may be referred to as “Condition 3.”
As can be appreciated, the filling module may generate the at least one set of operating parameters to satisfy Condition 1 and Condition 2, as discussed previously, as well as Condition 3 simultaneously. When the filling fluid is distributed from the filling system according to one or more sets of operating parameters satisfying Condition 1, Condition 2, and Condition 3 simultaneously, consistent filling of containers may be achieved with a reduced risk of the filling fluid drying and clogging or otherwise detrimentally affecting operation of the filling system 100. It should be appreciated that the set(s) of operating parameters may satisfy only one of consistent filling of containers and inhibition of drying of and clogging by the filling fluid that is gained by establishing one or more sets of operating parameters that account for the previously described fluid dynamic behaviors. Thus, the filling system 100 and the methods 700, 800, 900 described herein may be utilized to establish operating parameters constraints for operating the filling system 100 that account for the previously described fluid dynamic behaviors. Accounting for the previously described fluid dynamic behaviors can increase fill volume consistency, reduce downtime caused by clogging, and increase active ingredient distribution consistency.
In some exemplary embodiments, such as when the filling fluid comprises a biologic drug product that is susceptible to damage from shear stress, the at least one set of operating parameters can be generated to avoid damaging one or more components of the filling fluid. For example, the at least one set of operating parameters can be generated with a flow velocity of the filling fluid that limits the fluid shear stress on the filling fluid below a maximum tolerable shear value to limit damaging one or more components of the filling fluid. The maximum tolerable shear value may vary for different filling fluids. In some exemplary embodiments, the filling fluid comprises a biologic drug product 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 may also comprise other substances accompanying the biologic drug product, including, but not limited to, at least one of a carrier fluid, one or more additional active ingredients, a surfactant, a stabilizer, an adjuvant, encapsulating particles, and a buffer solution.
To test the ability of the filling system 100 to accurately distribute fluid as previously described, various tests were performed to determine whether a bubble with a stable resting profile formed in various fluids. The fluids and the fluid density and surface tension of each fluid are shown in Table 1 below. The fluids were tested in a variety of pipettes having various radii, which are described in Table 2 below.
One exemplary filling fluid is an aluminum hydroxide suspension representative of a vaccine formulation/suspension formulation. This is provided in the tables below with two different fluid properties due to the addition of a surfactant to formulation B.
Another exemplary filling fluid comprises an antibody A with inactive ingredients including a surfactant, which has properties described in Table 1. For example, the antibody A may be a humanized antibody that specifically binds to human α4β7 integrin, and is also known as “vedolizumab.”
Various methods may be used to produce the anti-α4β7 antibody vedolizumab, or antibodies having antigen-binding regions of vedolizumab. Vedolizumab is also known by its trade name ENTYVIO® (Takeda Pharmaceuticals, Inc.). Vedolizumab is a humanized antibody that comprises a human IgG1 framework and constant regions and antigen-binding CDRs from the murine antibody Act-1. The vedolizumab CDRs, variable regions and mutated Fc region (mutated to eliminate Fc effector functions) are described in U.S. Pat. No. 7,147,851, which is incorporated in in its entirety by reference herein. Formulations of vedolizumab are also described in U.S. Pat. No. 9,764,033 and U.S. Patent Application Publication No. 20140341885, which are also incorporated in their entirety by reference herein.
It should be appreciated that while the antibody A is one of only two biologic drug products listed in Table 1, other biologic drug products, such as other antibodies, therapeutic proteinaceous material, cell suspensions, liposomes, vaccines or nucleic acid materials, can fill containers according to the present disclosure. Other biologic drug products may have, for example, densities between 0.8 g/mL and 1.2 g/mL and surface tensions between 35 mN/m and 75 mN/m. For example, antibody B was formulated without surfactant and shows static fluid properties in a wider diameter filling nozzle (or pipette) than antibody A, which had surfactant. Similarly, the aluminum hydroxide (vaccine formulation) samples differed in the presence of surfactant in formulation B, resulting in a lower surface tension than formulation A, without surfactant, which was static in wider diameter nozzles than formulation B.
It should be appreciated that the previously described values are exemplary only, and containers, e.g., tubes, vials, cartridges, syringes, capsules, may be filled with many different types of biologic drug products according to the present disclosure. The systems and methods may be used in manufacturing the biologic pharmaceutical products, such as antibodies, enzymes, blood factors or vaccines by improving the accuracy and line throughput when filling the liquid biologic formulations into the containers.
From the fluid properties of the fluids described in Table 1 and the pipette dimensions described in Table 2, predicted Bond number values were generated, as shown in Table 3 below. The predicted Bond numbers below the previously described value of 0.842 are displayed in bold and italics within their cells.
0.558866
0.28881
0.565245
0.292107
0.567056
0.293042
0.587517
0.303616
0.640022
0.330749
0.63795
0.330749
0.577808
0.580726
0.585545
0.751608
0.706421
0.520852
0.600561
0.696195
0.775917
0.572986
0.687191
0.356279
0.526836
After predicting the Bond numbers, an experiment was conducted to see if a bubble (or other fluid interface) with a stable resting profile, i.e., a static profile, would form in the fluids after distribution from the corresponding pipette. To determine whether a bubble with a stable resting profile would be formed, serological pipettes were attached to a pipette gun. The pipette gun aspirated the various fluids into the pipettes, which were then placed in a burette stand for a five-minute period to equilibrate. Following the five-minute equilibration period, a qualitative observation was made to determine whether the formed bubble was static, as shown in
As can be seen, the fluids in pipettes with a Bond number below 0.842 all formed a bubble with a stable resting profile after distribution of the fluid from the pipette. Surprisingly, it was found that certain fluids (water, saline, dextrose, and high NaCl) formed a quasi-static bubble in the filling fluid after distribution from the pipette. The formed bubble was “quasi-static” in the sense that the bubble would not move at rest, but could begin moving upon a “shock” being delivered to the fluid, such as a force pulling the fluid away from the pipette opening, i.e., a reverse flow or “suck-back” force. It was noted that the quasi-static bubbles formed in fluids having a high contact angle relative to the pipette material, which may be relevant to filling nozzles comprising materials that do not satisfy other criteria for operating the filling system 100.
In one embodiment, another approach is used that highlights three parameters that impact fluid jet break-up (density, radius, and surface tension). This approach is similar to the Ohnesorge number discussed above, but does not have the viscous forces captured as it assumes the Reynolds (ratio of inertial forces to viscous forces) number is high enough that it can be neglected. The approach utilizes an equation:
that comes from linearizing the governing equations assuming infinitesimal varicose perturbations on the interface. This can then be solved as a modified Bessel Equation, and the characteristic break-up time assumed to be the inversion of maximum growth rate (the fastest growing perturbation occurs when wavelength=9.02*Radius), an approach consistent with well-established fluid dynamics. In the equation, the break-up time (t) is approximated with r as a nozzle radius, ρ as a density defined by the filling fluid, and γ as a fluid surface tension. In some embodiments, this equation may be used as an alternate control option since the perturbations in filling line under nominally laminar flow can become complex due to the effects from other equipment in the line.
Accordingly, in one embodiment, this characteristic breakup time equation may be used instead of using the Ohnesorge number, using the assumption of high Reynolds number to determine minimum acceptable filling needle radius for a stable liquid jet. It should be appreciated that this approach will work if one can set a filling time on the sterile line constrained by a maximum liquid velocity and fixed distance from the filling needle to the bottom of the container. The maximum liquid velocity may be set by the maximum shear the fluid can withstand before a product quality attribute of the fluid is impacted due to shear from the mechanisms of pump operation. In all cases the maximum value is still set by Bond number<0.842.
In one exemplary embodiment for distributing filling fluid according to the present disclosure, the filling fluid comprising antibody A with fluid properties described in Table 1 was distributed into 1 mL Long (1 mLL) ISO syringes with a target fill volume of 741 μL. The antibody A also had a viscosity of 15.75 cP at 20° C. It was found that the standard deviation of fill volumes was below a target 2.000% as a percentage of fill volume, when distributed according to sets of operating parameters that satisfied the previously described Condition 1, Condition 2, and Condition 3. The standard deviation of fill volumes was reliably found to be within 1%. Further, it was found that the distribution of antibody A from the test nozzle could be interrupted for 20 minutes without clogging of the nozzle. Thus, it was concluded that antibody A, and other filling fluids that comprise one or more biologic drug products, can fill containers according to the present disclosure with high precision and accuracy in a manner that resists drying of the fluid after filling.
In one embodiment, a filling system may be designed and operated as described herein to include a stable resting profile, a stable retracting profile and a stable flowing profile. The pump speed may be controlled so that it is as slow as possible in reversing (based on pre-determined criteria from test results for different fluids) and as fast as possible during the filling operation while satisfying these profile constraints. In some embodiments, filling systems designed to include a smaller filling needle radius and a slower suck-back speed substantially increase accuracy (limiting fluid loss) and provide the ability to interrupt the filling line for longer periods of time up to and exceeding 20 minutes without clogs occurring.
Exemplary filling results may be seen in results of a development pump/fill study attached hereto as Exhibit A. It should be noted that Variants #1 and #2 demonstrate the lack of needle clogging when using the filling process constrained by these equations and that Variant #1 has a smaller filling needle and thus is slightly more consistent. In the study, the pump/fill settings for a Bosch™ pump were as follows:
Embodiments described herein have described the use of a computing device equipped with a processor executing a filling module.
Virtualization may be employed in the computing device 1400 so that infrastructure and resources in the computing device may be shared dynamically. A virtual machine 1414 may be provided to handle a process running on multiple processors so that the process appears to be using only one computing resource rather than multiple computing resources. Multiple virtual machines may also be used with one processor.
Memory 1406 may include a computer system memory or random access memory, such as DRAM, SRAM, EDO RAM, and the like. Memory 1406 may include other types of memory as well, or combinations thereof.
A user may interact with the computing device 1400 through a visual display device 1418, such as a computer monitor, which may display one or more graphical user interfaces 1422 that may be provided in accordance with exemplary embodiments. The computing device 1400 may include other I/O devices for receiving input from a user, for example, 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 capturing device 1432 (e.g., a camera or scanner). The multi-point touch interface 1408 (e.g., keyboard, pin pad, scanner, touch-screen, etc.) and the pointing device 1410 (e.g., mouse, stylus pen, etc.) may be coupled to the visual display device 1418. The computing device 1400 may include other suitable conventional I/O peripherals.
The computing device 1400 may also include one or more storage devices 1424, such as a hard-drive, CD-ROM, or other computer readable media, for storing data and computer-readable instructions and/or software that implement exemplary embodiments of the filling system 100 described herein. Exemplary storage device 1424 may also store one or more databases for storing any suitable information required to implement exemplary embodiments. For example, exemplary storage device 1424 can store one or more databases 1426 for storing information regarding fluid properties, system properties and/or any other information to be used by embodiments of the filling 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.
The computing device 1400 can include a network interface 1412 configured to interface via one or more network devices 1420 with one or more networks, for example, Local Area Network (LAN), Wide Area Network (WAN) or the Internet through a variety of connections including, but not limited to, standard telephone lines, LAN or WAN links (for example, 802.11, T1, T3, 56 kb, X.25), broadband connections (for example, ISDN, Frame Relay, ATM), wireless connections, controller area network (CAN), or some combination of any or all of the above. In exemplary embodiments, the computing device 1400 can include one or more antennas 1430 to facilitate wireless communication (e.g., via the network interface) between the computing device 1400 and a network. The network interface 1412 may include a built-in network adapter, network interface card, PCMCIA network card, card bus network adapter, wireless network adapter, USB network adapter, modem or any other device suitable for interfacing the computing device 1400 to any type of network capable of communication and performing the operations described herein. Moreover, the 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, internal corporate devices, or other form of computing or telecommunications device that is capable of communication and that has sufficient processor power and memory capacity to perform the operations described herein.
The computing device 1400 may run operating system 1416, such as versions of the Microsoft® Windows® operating system, different releases of the Unix and Linux operating systems, versions of the MacOS® for Macintosh computers, embedded operating systems, real-time operating systems, open source operating systems, proprietary operating systems, or other operating systems capable of running on the computing device and performing the operations described herein. In exemplary embodiments, the operating system 1416 may be run in native mode or emulated mode. In an exemplary embodiment, the operating system 1416 may be run on one or more cloud machine instances.
In describing exemplary embodiments, specific terminology is used for the sake of clarity. For purposes of description, each specific term is intended to at least include all technical and functional equivalents that operate in a similar manner to accomplish a similar purpose. Additionally, in some instances where a particular exemplary embodiment includes a plurality of system elements or method steps, those elements or steps may be replaced with a single element or step. Likewise, a single element or step may be replaced with a plurality of elements or steps that serve the same purpose. Further, where parameters for various properties are specified herein for exemplary embodiments, those parameters may be adjusted up or down by 1/20th, 1/10th, ⅕th, ⅓rd, ½nd, and the like, or by rounded-off approximations thereof, unless otherwise specified. Moreover, while exemplary embodiments have been shown and described with references to particular embodiments thereof, those of ordinary skill in the art will understand that various substitutions and alterations in form and details may be made therein without departing from the scope of the invention. Further still, other aspects. functions and advantages are also within the scope of the invention.
This application is a continuation application of U.S. patent application Ser. No. 17/938,779, filed Oct. 7, 2022, which is a divisional application of U.S. patent application Ser. No. 17/051,004, filed Oct. 27, 2020, which is a U.S. National Phase Under 35 U.S.C. § 371 of International Application No. PCT/US2019/029722, filed Apr. 29, 2019, which claims priority to U.S. Provisional Application No. 62/791,850, filed on Jan. 13, 2019, and U.S. Provisional Application No. 62/663,927, filed on Apr. 27, 2018, the contents of both of which are hereby incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62791850 | Jan 2019 | US | |
| 62663927 | Apr 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17051004 | Oct 2020 | US |
| Child | 17938779 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17938779 | Oct 2022 | US |
| Child | 18432516 | US |
