Systems, articles, and methods related to weight sensing

Abstract

In-situ residual moisture determination during lyophilization processes allows for the use of a release criteria to limit the time material spends in a freeze dryer; and such determination can be made by in-situ sensing of the weight of a vial containing the product to be lyophilized, wherein a spring supports a basket that holds the vial such that the vial center of mass is below the anchor point of the spring and as water sublimates from the product in the vial, the spring changes which changes the displacement and slope of targets which may be measured optically.

Description

[0001] MIT 26101

[0002] - 1 -

[0003] SYSTEMS, ARTICLES, AND METHODS RELATED TO WEIGHT SENSING

[0004] RELATED APPLICATIONS

[0005] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 703,089, filed on October 3, 2024, which is hereby incorporated by reference herein in its entirety.

[0006] GOVERNMENT SPONSORSHIP

[0007] This invention was made with government support under FD006755-01 awarded by the Food and Drug Administration. The government has certain rights in the invention.

[0008] TECHNICAL FIELD

[0009] The use of weight sensing system, articles, and methods for lyophilization applications is generally described.

[0010] BACKGROUND

[0011] Lyophilization has been an important step in pharmaceutical distribution for decades. The lyophilization process, or freeze-drying, removes water from an aqueous formulation, keeping the solution from degrading. This water removal reduces the need for freezers when storing and transporting such products, significantly reducing costs and risk of product loss. However, if the product retains too much or too little residual moisture, the resultant product cake will not remain stable, indicating the importance of ensuring appropriate moisture removal.

[0012] SUMMARY

[0013] In summary, the present disclosure describes systems, articles, and methods for sensing the weight of a vial containing liquid to be lyophilized comprising a supporting frame into which are anchored at their proximal ends, one or more flexible cantilever beams where at their distal end region is an attachment region for a hanging basket that extends below the cantilever(s) to hold a vial with product to be lyophilized such that the center of mass of the vial and contents is below the plane of attachment of the cantilever to the frame, and at the distal end of the cantilever(s) is an end member that is not loaded by the basket and vial weight, but deflects along with the cantilever such that as the lyophilization process takes place and the weight of the product decreases as liquid sublimates, the cantilever deflection changes. A target to be

[0014] #14460974v 1 MIT 26101 - 2 - optically viewed is attached to or part of the end member, and the viewed change in position and / or orientation of the end member with respect to the start-of-process indicates the change in weight and hence degree of lyophilization of the product in the vial. April tags containing QR- type code images are one example of a target to be viewed by a camera to detect motion of the end member when the end member extends from the end of the cantilever beam, where the longer the extension the greater the sensitivity. Another example is an end member with a mirror to reflect a laser beam onto a fixed sensing photodiode to serve as an optical lever for measuring change in slope and hence deflection of the end member of the cantilever beam with minimal extension required of the end member.

[0015] Systems, articles, and methods related to weight sensing of lyophilization samples are generally described. The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more systems and / or articles.

[0016] In one aspect, a weight sensing system is described. In some embodiments, the weight sensing system comprises at least two springs, wherein each spring comprises a spring body at least laterally extending from a first anchored end portion to an unloaded distal end portion, the first anchored end portion anchored to a base of the system; a receptacle configured to support a container disposed therein, wherein the receptacle is configured to be suspended from the at least two springs; and one or more optical targets, wherein each optical target of the one or more optical targets is associated with a separate spring of the at least two springs, and wherein displacement of the at least two springs by the receptacle causes a change in pose of the one or more optical targets.

[0017] In another aspect, a method of sensing a weight of a material disposed in a container is described. In some embodiments, the method comprises placing the container in a receptacle supported by at least two springs; deforming the at least two springs with the receptacle and the container disposed therein; changing a pose of one or more optical targets due to deforming the at least two springs; and determining a weight of the container and / or the material based at least in part on the pose of the one or more optical targets, wherein each spring comprises a spring body laterally extending from a first anchored end portion to an unloaded distal end portion, the first anchored end portion anchored to a base of the system.

[0018] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the disclosure when considered in conjunction with the accompanying figures. In cases where the present

[0019] #14460974v 1 MIT 26101 - 3 - specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale unless otherwise indicated. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0022] FIG. l is a schematic diagram that depicts a weight sensing system, according to some embodiments.

[0023] FIG. 2 is a schematic diagram depicting optical targets positioned on the distal ends of springs, according to some embodiments.

[0024] FIG. 3 is a schematic diagram of optical targets comprising a mirror positioned on a distal end of an arm, according to some embodiments.

[0025] FIG. 4 is an image depicting optical targets, in the form of April tags, of the weight sensing system, according to some embodiments, depicts April tags placed on the ends of the spring wire sensing arms, wherein the motion of the April tags is tracked by a camera to determine the mass change in the vial during sublimation, according to some embodiments.

[0026] FIG. 5 is a schematic diagram depicting the base and the location of the anchoring ends, according to some embodiments.

[0027] FIGS. 6A-6B are schematic diagrams of A) the anchored end between the base and the spring and B) the spring of the weight sensing system, according to some embodiments.

[0028] FIG. 7 is a schematic diagram of the springs of the weight sensing system and the associated geometry that allows the spring to be oriented substantially vertically when loaded with a container, according to some embodiments.

[0029] FIG. 8 is a schematic diagram describing various orientations of the spring that alters the sensitivity to load, according to some embodiments.

[0030] FIG. 9 is a schematic diagram depicting the receptacle having hooks that attach to the springs of the weight sensing system, according to some embodiments.

[0031] #14460974v 1 MIT 26101 - 4 -

[0032] FIGS. 10A-10C are schematic diagrams that show the rotational axis of a container placed in a receptacle, according to some embodiments.

[0033] FIGS. 11 A-l IB are plots describing the normalized tag motion against the normalized mass additions which show the linearity of the spring system response, according to some embodiments.

[0034] FIG. 12A is a diagram showing a curved cantilevered beam loaded perpendicular to the curvature plane, according to some embodiments. P is the out of plane force, D is the diameter of the cantilevered beam (assuming a circular cross section), alpha is the total angle of the wire arc, and r is the radius of curvature of the wire arc, according to some embodiments.

[0035] FIG. 12B is a diagram that describes how the extension (e.g., the sensing arm) of the spring moves both sideways and down as the spring wire deflects, according to some embodiments.

[0036] FIG 13 is a plot showing that the vial estimated mass flatlines when water is no longer sublimating out of the vial, according to some embodiments.

[0037] FIG. 14 is a plot showing that the remaining residual moisture in the vials at the endpoint detected by the weight sensing system is about 15wt%, corresponding to the end of primary drying, according to some embodiments.

[0038] FIG. 15 is an image depicting the elephant trunk that is used to pull the vial basket down for vial loading and unloading, according to some embodiments.

[0039] FIG. 16 shows that a two-part robotic arm cone mounted directly to the gripper fingers, according to some embodiments.

[0040] FIG. 17 is a diagram describing an alignment cone that serves to center the vial basket assembly during operations which involve vertically pushing down on the vial in the basket, such as capping and loading, according to some embodiments.

[0041] FIG. 18 is an image describing that the weight sensing systems can be assembled together onto a tray for motion through a continuous lyophilizer, according to some embodiments.

[0042] FIG. 19 is a plot showing that the average accuracy for the sensors is below 25 mg, according to some embodiments.

[0043] FIG. 20 is a plot showing the variation in coefficients for the fit models for the sensors, according to some embodiments.

[0044] FIG. 21 is a plot showing that the average accuracy for the sensors can be improved to below lOmg by using an initial mass and sensor measurement, according to some embodiments.

[0045] #14460974v 1 MIT 26101 - 5 -

[0046] DETAILED DESCRIPTION

[0047] Systems, articles, and methods related to weight sensing of lyophilization samples are generally described. Residual moisture is a measurement of interest during a lyophilization process. The residual moisture content indicates how far in the drying process the vial has progressed and when it has finished the lyophilization process. Current lyophilization systems either measure residual moisture content after a completed lyophilization cycle, interrupt the cycle to remove vials with a sample thief to test a representative sample, or measure the moisture in the system which is sublimating out of the samples. These systems do not provide individual vial, in-situ residual moisture measurements. As such, lyophilization processes measured with existing methods lack the ability to differentiate the process state of individual vials in their systems, delaying the process to accommodate the slowest-drying units. This distinction has less of an effect in existing batch lyophilizers, where the next process step for the batch cannot start until all units in the batch are finished. However, in continuous systems, these measurements may be insufficient to determine the state of specific vials or limit the production rate of the machine.

[0048] Standard direct residual moisture content measurement methods include Karl Fischer (KF) titration, thermal gravimetric analysis, moisture analysis devices, near-IR spectroscopy, a pressure differential measurement, and tunable diode laser absorption spectroscopy (TDLAS). KF titration is a destructive process, where the sample goes through an oxidation reaction to measure moisture. Thermal gravimetric analysis measures mass loss while heating the sample to drive out the remaining moisture, where the mass loss represents the remaining moisture. A moisture analysis device similarly heats the sample to evaporate water, then replaces the moist gas with a dry gas and uses a sensor to measure moisture loss. These methods both require sample destruction and are done off-line. Near-IR spectroscopy measures the water signal in the lyophilizer headspace in the infrared spectrum. The pressure differential measurement takes advantage of the water sensitivity of a Pirani pressure gauge. The Pirani gauge depends on the gas composition, while a capacitance manometer measures the inert pressure. When these two gauges read the same pressure value, it is an indication that there is no longer water vapor in the chamber. A lack of water vapor means that sublimation has finished, and thus the change in water in the system is measured non-invasively. TDLAS measures the concentration of various chemicals in a gas mixture, including water vapor, which can be used to identify the water content in the lyophilizer’s vacuum system. When this water vapor measurement is sufficiently low, it is indicative that the sublimation process has finished.

[0049] #14460974v 1 MIT 26101

[0050] - 6 -

[0051] In addition to the above, lyophilization of a sample generally involves exposing the sample to relatively low temperatures and pressures such that excess moisture content may be removed. Lyophilization may increase the shelf-life of a variety of materials, such as pharmaceuticals, so that they can be stored and eventually used in a reconstituted form. To sufficiently lyophilize a sample, it is desirable to monitor the moisture content of the sample so that the duration of the lyophilization process may be suitable to drive away excess moisture. However, in large-scale lyophilization systems, the residual moisture content in each sample may vary on a sample-to-sample basis, and accordingly, while one sample may be sufficiently lyophilized after undergoing a lyophilization process, another sample may be insufficiently lyophilized. Some samples may then be exposed to lyophilization conditions for durations that are longer than necessary, thereby increasing processing times, while other samples may be exposed to lyophilization conditions that are shorter than necessary thereby reducing the effectiveness of the lyophilization process. While invasive measurement devices may be able to determine the moisture content of samples relatively accurately, such devices may contaminate samples. Moreover, moving parts that are involved in typical measurement systems may generate particulates that may also contaminate samples. In contrast, in-situ product state measurement during lyophilization processes allows for the use of release criteria to optimize the time material spends in a freeze-dryer. This specification increases the machine’s production rate and, with sufficiently accurate state measurements, ensures product quality. This measurement may occur non-invasively, within a vacuum, and without introducing contaminants to the lyophilized product.

[0052] In view of the above, the inventors have recognized a need for systems that monitor the moisture content in lyophilization samples on a sample-to-sample basis without risking sample contamination. Further, in some embodiments of a lyophilization system, product may pass through the system continuously, or at least semi-continuously. In such embodiments, it may be desirable to provide nondestructive, in-situ, individual vial information to distinguish finished products ready to exit from new products entering each process chamber. The current methods for residual moisture measurement are either destructive and not in-situ or they conflate the residual moisture measurements for all vials in the system. The in-situ full system measurement methods which are based on identifying when no more water vapor is being produced by vials in the system are not viable for a continuous system, where new products entering the system would ensure there is always water being sublimated within the system. To address these limitations, the present disclosure describes a measurement system that is able to obtain

[0053] #14460974v 1 MIT 26101

[0054] - 7 - measures directly related to individual product mass and / or containers of the product or other material being lyophilized as a proxy for residual moisture. Thus, the disclosed systems and methods may be used to provide information for each vial or other container within the system rather than grouping information about all vials together. In some embodiments, a measurement system may be configured to function within a vacuum system and does not interfere with the lyophilization process, allowing it to be used in-situ.

[0055] In view of the above, the Inventors have recognized the benefits associated with an in- situ residual moisture sensing method that may allow for more efficient lyophilization processes using continuous freeze-driers. Specifically, in some embodiments, a weight of each vial (e.g., sample) or other container within a portion of a lyophilization system may be directly measured to determine a residual moisture content based on water mass removal during sublimation. As described in the present disclosure, each vial, or other container, may be suspended by two or more compliant springs such that an appropriate sensor, such as a camera or other photosensitive detector, may be used to detect a change in pose of one or more optical targets (e.g., computer vision targets such as April Tags and other appropriate optical targets) attached to the springs to assess spring deflection and hence changes to the mass of the vial or other container.

[0056] Weight sensing systems and methods are provided. In some embodiments, a weight sensing system comprises optical targets positioned on springs (e.g., sensing wires) which provide the deflection motion as the system mass changes, a base into which the springs are mounted, a receptacle (e.g., a basket) which holds a container (e.g., a vial) suspended from the springs, and an optical detector (e.g., a camera) which records the change in pose of the optical targets. The change in pose of the optical targets may correspond to a change in weight of the material being lyophilized within the container.

[0057] In view of the above, in some embodiments, a weight sensing system may include at least two springs configured to suspend a receptable. For example, as shown in FIG. 1, weight sensing system 100 comprises first spring 102A and second spring 102B. First spring 102A and second spring 102B suspend receptacle 205. The springs may extend laterally, and in some instances vertically as well, from a first anchored end portion of each spring to an unloaded distal end portion of the spring relative to a direction of gravity during use. The springs may also extend vertically as well in some embodiments as elaborated on below. For example, as shown in FIG. 1, first spring 102A comprises first anchored end portion 106A that is anchored to base 110 and second spring 102B comprises second anchored end portion 106B that is anchored to base 110. First spring 102A then extends laterally in a partial arc, as described elsewhere in this

[0058] #14460974v 1 MIT 26101

[0059] - 8 - disclosure, forming first spring body 104A. First spring body extends vertically to first unloaded distal end portion 108 A of first spring 102A. The receptacle may be attached to the at least two springs at a location between the first anchored end portion and unloaded distal end portion of each spring. For example, receptacle 205 is suspended at the location of hook 215A between first unloaded distal end portion 108A of first spring 102A and first anchored end portion 106A. The receptacle may be configured to support a container. For instance, as shown in FIG. 1, receptacle 205 supports container 210. Depending on the embodiment, the container may, for example, be a vial or other container configured to contain a material that is to be lyophilized in an internal volume of the container. In some embodiments, one or more optical targets may be associated with the at least two springs. For instance, each optical target may be attached to a separate unloaded distal end portion of the associated spring. For example, as shown in FIG. 1 and described elsewhere in this disclosure, first unloaded distal end portion 108 A of first spring 102A comprises first optical target 112A. The unloaded distal end portions and the associated one or more optical targets may change pose when a weight of the container is altered. For example, during lyophilization, as moisture is removed from material within the container, the weight of the receptacle and the container may change causing a corresponding change in pose of the unloaded distal end portion of each spring, and thus, a change in the pose of the one or more attached optical targets as well. In some embodiments, an absolute weight and / or changes in the weight of the container and / or material in the internal volume of the container may be determined based at least in part on a detected pose of the one or more optical targets. The change in pose of the optical targets may be detected by an optical detector (e.g., a camera and / or laser detector). For example, as shown in FIG. 1, optical detector 114 detects the change in pose of first optical target 112A and / or second optical target 112B.

[0060] Certain aspects of the present disclosure generally related to methods of implementing a weight sensing system. In some embodiments, the method can be implemented using one or more processers configured to determine a weight of a container and / or the material disposed in the container based at least in part on an absolute pose and / or a change in the pose of the one or more optical targets detailed above. In some embodiments, the one or more processors may determine the change in pose of the optical targets over a duration of time to determine whether the lyophilization process is complete and / or sufficient. For instance, as shown in FIG. 1, processor 116 receives information (e.g., images, numerical data, or other forms of data) from optical detector 114. When container 210 has a first weight at the beginning of the lyophilization process, optical detector 114 may capture images of first optical target 112A and second optical

[0061] #14460974v 1 MIT 26101

[0062] - 9 - target 112B. Optical detector 114 may then send the images to process 116 to determine the first weight of container 210. Throughout the lyophilization process, optical detector 114 may continue to capture images of first optical target 112A and second optical target 112B and send the images to processor 116. When container 210 is at a second weight that is different than the first weight, the orientation (e.g., pose) of first optical target 112A and second optical target 112B may change. Processor 116 may then compare the change of pose of first optical target 112A and second optical target 112B when container is at the first weight to the pose of first optical target 112A and second optical target 112B when container 210 is at the second weight. Processor 116 may then determine the change in pose of first optical target 112A and second optical target 112B and correlate such change to the weight of container 210. This correlation may be influenced by the stiffness of the springs.

[0063] In some embodiments, a weight sensing system comprises springs. In some embodiments, the weight sensing system comprising at least two springs (e.g., a first spring, a second spring, a third spring, or more). In some embodiments, at least some of the springs of the weight sensing system comprises a spring body. The spring body may laterally extend from a first anchored end portion to an unloaded distal end portion. For example, as shown in FIG. 1, weight sensing system 100 comprises first spring 102A having first spring body 104A laterally extending from first anchored end portion 106A anchored to a suitable support (e.g., base 110) to first unloaded distal end portion 108 A and second spring 102B has second spring body 104B laterally extending from second anchored end portion 106B anchored to the support to second unloaded distal end portion 108B. In some embodiments, the first and / or second anchored end portions are anchored to any suitable support including, for example, a base of the system and / or any other appropriate structure. For example, as shown in FIG. 1, first anchored end portion 106A and second anchored end portion 106B are anchored to base 110 of system 100.

[0064] In some embodiments, the springs may deform in response to changes in weight of the container. For example, as shown in FIG. 2, container 210 has a first weight at the beginning of the lyophilization process, which deforms first spring 102 A and second spring 102B. This results in first optical target 112A to be separated by distance dl from second optical target 112B. At the end of the lyophilization process, container 210 may have a second weight that is less than the first weight. Container 210 having a second weight may then deform first spring 102 A and second spring 102B less than when container 210 is at the first weight. This may be indicated by a change in the z-direction (Az as shown in FIG. 2). The reduced weight of container 210 results

[0065] #14460974v 1 MIT 26101 - 10 - in the distance between first optical target 112A and second optical target 112B to decrease from dl to d2.

[0066] In some embodiments, each of the springs have a spring body. In some embodiments, the one or more springs comprise a spring body that extends laterally (e.g., axially) and / or vertically from an anchored end portion to an unloaded distal end portion of the spring relative to a direction of gravity when a base of the frame is disposed on level ground during operation of the system. The spring body may extend to a distal end portion of the spring. In some embodiments, the spring body extends in a helical manner (e.g., helically, in a helical shape, and / or along a helical path) to a distal end portion of the spring. In some embodiments, the spring body extends in a partial-arc having a central angle less than 360 degrees, less than or equal to 300 degrees, less than or equal to 240 degrees, less than or equal to 180 degrees, less than or equal to 120 degrees, and / or greater than or equal to 10 degrees, greater than or equal to 20 degrees, or greater than or equal to 30 degrees. For example, as shown in FIG. 1, first spring body 104A has a partial arc that is less than 180 degrees. In some embodiments, the one or more springs each are cantilevered springs. In some embodiments, the one or more spring each are subject to bending and / or torsion in response to the weight and / or a change in the weight of the containers thereby changing the pose of the one or more optical targets.

[0067] In some embodiments, the lateral stiffness of the spring is greater than the vertical stiffness of the spring. In some embodiments, the relatively low vertical stiffness may allow for a change in pose of the optical targets with relatively small change in weight of the container. However, the spring may be relatively stiff laterally such that vibrations (e.g., those that may occur during the lyophilization process) do not significantly destabilize (e.g., tilt) the container.

[0068] In some embodiments, the weight sensing system comprises a receptacle. In some embodiments, the receptacle is configured to support a container disposed and / or placed therein. For example, as shown in FIGS. 1 and 9, receptacle 205 is configured to support container 210 disposed and / or placed therein. In some embodiments, the receptacle is configured to be suspended from the at least two springs. For example, as shown in FIG. 9, receptacle 205 is configured to be suspended from the at least two springs from hooks 215 A and 215B or other appropriate connection to the springs. Thus, the weight of the container may be supported by the springs thereby deforming (e.g., via a bending force or torsional force) the springs. FIG. 9 is a model depicting the receptacle 205 (e.g., a wire basket assembly) is used to hold containers. In some embodiments, the receptacle comprises elastically averaging arms 305 hold the vial in the center of the basket, a support ring 310 that helps the system resist the forces created by vial

[0069] #14460974v 1 MIT 26101

[0070] - 11 - loading, spring holding features 315, container posts 320 locate and connect the support ring to the basket base, a basket base 325 that connects the other main parts of the basket, and the basket wire which connects the basket to the sensing wires, according to some embodiments.

[0071] In some embodiments, the weight sensing system comprises one or more optical targets. As described above, the one or more optical targets may be attached to separate unloaded distal end portions of the springs. Thus, a change in pose of the springs as a result of a change in weight of the container and / or material within the interior volume of the container causes a corresponding change in pose of the one or more optical targets. For example, in some embodiments, each optical target of the one or more optical targets is associated with a separate spring of the at least two springs. One such embodiment is shown in FIG. 1 where first optical target 112A is associated with spring 102A and an optical target 112B is associated with spring 102B. The one or more optical targets may be coupled to one or more associated springs using any appropriate type of connection including adhesives, mechanical fasteners, welds, mechanically interlocking features, and / or any other appropriate type of direct and / or indirect connection. In the depicted embodiment, the displacement of the at least two springs by the receptacle causes a change in the relative pose of the two illustrated optical targets. However, instances in which an absolute pose of the one or more targets and / or a relative change in pose of the one or more targets over time may be used to determine a weight of the container and / or a material disposed therein are contemplated.

[0072] As noted above, in some embodiments, each of the one or more optical targets are disposed on an unloaded distal end portion of the associated spring. For example, as shown in FIGS. 1-4., first optical target 112A and second optical target 112B are disposed on first unloaded distal end portion 108 A and second unloaded distal end portion 108B of springs 102A and 102B. However, depending on the geometry of the springs, the associated change in pose may be relatively small. Accordingly, it may be desirable to increase (e.g., amplify) a corresponding change in pose of the one or more optical targets based on a given change in pose of an associated spring. Thus, in some embodiments, a distal end portion of a spring may include an extension extending from the unloaded distal end portion of a spring that an associated optical target may be attached to. For example, as shown in FIG. 1, first spring 102A comprises extension 118A having first unloaded distal end portion 108A with first optical target 112A attached thereto. Second 102B comprises extension 118B having second unloaded distal end portion 108B with optical target 112B attached thereto. The extension may be configured to increase the change in pose of the one or more optical targets relative to a change in pose of the

[0073] #14460974v 1 MIT 26101

[0074] - 12 - unloaded distal end portion the associated spring. In some embodiments, the extension can be an arm, an attachment, and / or other structure extending at least partially vertically out from the unsupported distal end portion of the spring relative to a direction of gravity during operation of the system. In some embodiments the extension can be an arm, attachment, and / or other structure extending at least partially horizontally out of the unsupported distal end portion of the spring. For example, as shown in FIG. 3, first spring 102 A comprises extension 118A extending horizontally outward therefrom. A portion of extension 118A comprises first optical target 112 A. However, it should be noted that extensions having excessively large lengths may increase the geometric volume of the system. As lyophilization systems operate in vacuum environments, large system volumes may be undesirable. Accordingly, it may be desirable to increase the change in pose of the optical targets relative to the change in weight of the containers while maintaining a relatively low system volume in some embodiments. An example of optical target in the form of April tags are shown in FIG. 4.

[0075] In some embodiments, a change in pose of the one or more optical targets may involve displacement of the one or more optical targets laterally and / or vertically. As used herein, “pose” may generally refer to a position and angular orientation of an optical target in three-dimensional space. In some embodiments, the change in pose of the one or more optical targets involves a change in position and / or a change in angular orientation of the one or more optical targets in response to changes in the weight of the container. That is, when the container has a first weight, the one or more optical targets may have a first pose. During the lyophilization process, moisture may be removed from the material in the internal volume of the container thereby reducing the weight of the container to a second weight. When the container is at the second weight, the optical targets may be in a different, second pose than the first pose of the optical targets when the container was at the first weight. As described above, the angular orientation of the optical target may change as the weight of the container changes. For example, as shown in FIGS. 7-8, first spring 102 A may be anchored by first anchored end portion 106 A and deform, thereby changing the orientation of first unloaded distal end portion 108 A by angle 0o. Moreover, first spring 102 A may deform and bend at first anchored end portion 106 A, thereby changing the effective length of first spring body 104 A.

[0076] In some embodiments, the springs are positioned to allow for desirable deflection of the optical targets when under load. In some embodiments, the springs are positioned such that the springs are bent to an angle offset from perpendicular to the spring body (e.g., the curved beam deflecting arm), according to some embodiments. An example of this position is shown in FIG.

[0077] #14460974v 1 MIT 26101

[0078] - 13 -

[0079] 7. This offset sets a preload angle for the spring (e.g., the wire), which is calculated based on the predicted deflection of the curved beam given an empty container (e.g., a vial and cap) load, such that when an empty container (e.g., a vial) is loaded to deflect this spring, the line connecting the beginning and the end of the curved beam section is parallel to the base. FIG. 8 is a diagram depicting the spring at various angles and the resulting change in length of the moment arm thereby decreasing the system sensitivity to load, according to some embodiments. The initial angle is set such that the preload mass of an empty container and cap loads the container to its horizontal position, where the measurement is most sensitive.

[0080] In view of the above, in some embodiments, a change in pose of the one or more optical targets is a change in an orientation of the one or more optical targets. For example, one or more optical targets may be tilted at an initial pose (e.g., a first orientation) of the optical targets prior to a change in weight of the container and may be tilted at a second pose (e.g., a second orientation) after a change in weight of the container. Alternatively, in other embodiments, the change in the pose of the one or more optical targets is a change in a distance between two or more optical targets. For example, as described above and as shown in FIG. 2, the distance between first optical target 112A and second optical target 112B may change in response to the weight of container 210. As the weight of container 210 decreases, the distance between first optical target 112A and second optical target 112B may change from distance dl to distance d2 that is less than distance dl. For instance, a distance between the two or more optical targets may change in response to a change in weight of the container due to the corresponding change in pose of the two or more optical targets. In some embodiments, the distance between optical targets of the weight sensing system may change from the beginning of a lyophilization process to the end of the lyophilization process by at least 0.1 mm, at least 0.2 mm, at least 0.5 mm, at least 1 mm, at least 1.5 mm, or more. In yet other embodiments, a change in pose of the one or more optical targets is a change in the distance between the optical targets and a change in the angular orientation of the optical targets. In some embodiments, the angle between the vertical axis of the spring parallel to the extension of the spring and the base is within 0.5 degrees, within 1 degree, within 2 degrees, within 3 degrees, within 4 degrees, within 5 degrees, within 10 degrees, and / or within 30 degrees of a right angle (e.g., 90 degree angle). Thus, it should be understood that the disclosed systems and methods are not limited to a specific type of pose and / or change in pose for determining a weight and / or change in weight of a container and / or a material disposed within the container.

[0081] #14460974v 1 MIT 26101

[0082] - 14 -

[0083] As described above, a system may comprise one or more optical targets according to some embodiments. FIG. 2 is a schematic diagram that depicts April tags placed on the ends of the springs (e.g., wire sensing arms), wherein the motion of the April tags is tracked by a camera to determine the mass change in the vial during sublimation, according to some embodiments. In some embodiments, the one or more optical targets are capable of being identified within an image acquired by a photosensitive detectors (e.g., a camera) and one or more associated processors. It may be advantageous for the one or more optical targets to be relatively distinguishable (e.g., optically distinguishable) from the surrounding environment. In some embodiments, the one or more optical targets have geometric patterns (e.g., stripes, dots, checkers), textures, and / or colors that distinguish the optical target from the surrounding environment when viewed through a photosensitive detector (e.g., a camera). In some embodiments, the one or more optical targets each comprise a QR code. In some embodiments, the one or more optical targets comprise one or more reflective targets. For example, as shown in FIG. 3, first optical target 112A and second optical target 112B are reflective. Optical detector 114 emits light (e.g., a laser) from emitter 114B, through window 304 of chamber 302, onto first optical target 112 A. The light reflects off first optical target 112A at a first angle when container 210 is at a first weight. The reflected light is then received by receiver 114A at a first angle. When container 210 has a second weight that is different (e.g., less) than the first weight, the reflected light may be received by receiver 114A at a second angle that is different than the first angle. The processor (not shown in FIG. 3) may than determine the difference between the first weight and the second weight based on the difference of the first angle and the second angle. In some embodiments, the one or more reflective targets are configured to reflect light incident from a light source (e.g., a laser) to a photosensitive detector. Based, at least in part, on the angle, absolute position, and / or changes in the absolute position of the reflected light, the photodetector and one or more associated processors may be capable of determining the change in pose of the one or more optical targets comprising the one or more reflective targets.

[0084] In some embodiments, to determine the change of pose of the optical targets, a photosensitive detector (e.g., a camera) with a known frame of reference relative to the one or more optical targets may capture one or images. The one or more images may then be evaluated by one or more processors to determine the change in pose of the one or more optical targets over a period of time. In some embodiments, one or more images may be acquired in a relatively short period of time such that the pose of each optical target can be averaged. By averaging the pose of the optical targets over a relatively short period of time, incidental vibrations (e.g.,

[0085] #14460974v 1 MIT 26101 - 15 - imparted by the lyophilization system and / or process) may be discounted from the moisture content determination.

[0086] In some embodiments, the optical targets may comprise identification information. For instance, optical targets having QR codes may not only serve as indicators for the optical detector to detect changes in pose, but they may also store information related to the identification of the sample in the container. For example, the QR codes, when scanned, may indicate whether the sample in the container is a reference (e.g., control) sample or particular known properties of the sample (e.g., concentration of an analyte, composition, particle size, among others).

[0087] In some embodiments, the spring may connect to the receptacle using any of a variety of connectors. In some embodiments, the spring is connected to the receptacle using one or more hooks, pin joints, other mechanically interlocking structures, and / or any other appropriate connection. In some embodiments, it may be advantageous to limit the friction between the spring and the receptacle. Friction may lead to hysteresis in the measurement. Accordingly, a rolling contact may be formed between the spring and the receptacle such that the spring may deform in response to changes in the weight of the container without being significantly inhibited by friction between the receptacle and the spring. For example, as shown in FIG. 9, hooks 215 A and 215B are used to create a rolling contact with springs 102 A and 102B shown in FIG. 1. In some embodiments, the hooks have a rounded cross-section such that the receptacle may be suspended by the springs while maintaining a rolling contact. In some embodiments, the rolling contact is positioned along the spring of the weight sensing system. For instance, in some cases, the rolling contact may be positioned along the spring and between the optical target and the spring body. For example, as shown in FIG. 1, first anchored end portion 106A having a rolling contact is positioned along first spring 102A and between first optical target 112A and first spring body 104 A.

[0088] In some embodiments, the system comprises a lyophilization tray. In some embodiments, the lyophilization tray comprises one or more weight sensing systems integrated with and supported by one or more corresponding bases associated with the lyophilization tray. Thus, the lyophilization tray may be configured to support one or more vials or other containers within one or more corresponding weight sensing systems integrated with the tray. This may allow for the construction and use of lyophilization trays with any appropriate number of weight sensing systems integrated therewith. This modularity provides flexibility in tray design and

[0089] #14460974v 1 MIT 26101 - 16 - geometry for different system configurations. An example of a lyophilization tray is shown in FIG. 18 and described below.

[0090] When a product is fully dried, the remaining water content in the dried cake accounts for 1% to 4% of the remaining mass. Given a 3mL aqueous solution of 5 wt% solute, the dried cake accounts for 5% of the original 3g mass, or 150 mg. Using a 1% to 4% target for the remaining water target gives a residual moisture content of 1.5 mg to 6 mg water. To measure 1.5 mg of water from a 3 g mass, a measurement system accurate to 1 part in 2000 is desirable. However, the 3g accounts for the solution mass, not necessarily the full system mass. Adding the mass of the vial and the cap of the vial adds about 12g to the system, creating an overall system mass of 15g. Thus, it may be desirable for the system to have measurements accurate to 1 part in 10,000 (or 1 part in 100,000, 1 part in 1,000,000, or 1 part in 10,000,000) for the desired measurable quantity compared to the total system mass. Details related to the accuracy of the weight sensing systems are further described below.

[0091] This system may be integrated into existing lyophilizer load systems to provide individualized vial state information in addition to their use in continuous unit dose lyophilization systems.

[0092] In some embodiments, the weight sensing system is configured to operate in a vacuum environment. In some embodiments, the vacuum environment is desirable for the lyophilization to occur via sublimation. It may be advantageous to limit the total volume of the weight sensing system, as large volumes may result in a need for larger vacuum chambers and additional energy used to maintain a vacuum. In some embodiments, the weight sensing system described herein is advantageously compact.

[0093] In some embodiments, the weight sensing system provides individual data regarding the lyophilization status of individual containers (e.g., vials). Typical lyophilization systems may measure the degree of lyophilization of samples at the machine-level, but do not provide sufficient information to distinguish between vials that are ready to move on to subsequent stages of the lyophilization process and vials that need additional time drying.

[0094] In some embodiments, the weight sensing system is capable of detecting relatively small changes in the weight and / or mass of the container. In some embodiments, the weight sensing system advantageously resolves less than or equal to 3 mg, less than or equal to 2.8 mg, less than or equal to 2.6 mg, less than or equal to 2.4 mg, less than or equal to 2.2 mg, less than or equal to 2.0 mg, less than or equal to 1.8 mg, less than or equal to 1.6 mg, less than or equal to 1.4 mg, less than or equal to 1.2 mg, less than or equal to 1.0 mg, and / or greater than or equal to 0.01

[0095] #14460974v 1 MIT 26101 - 17 - mg, greater than or equal to 0.05 mg, or greater than or equal to 0.1 mg. changes in the mass of the container.

[0096] In some embodiments, the weight sensing system is capable of accommodating any of variety of containers (e.g., vials) suitable for lyophilization applications. As lyophilization process may be used for a wide range of industries, including the pharmaceutical industry and the food industry, a wide range of vials or other containers having different shapes, volumes, and geometries may be desirable. Accordingly, the weight sensing systems described herein may advantageously accommodate a wide range of container geometries such that the system is capable of integrating with existing pharmaceutical production systems and / or production system of other industries. In some embodiments, the weight-sensing system is container (e.g., vial) agnostic.

[0097] In some embodiments, the weight sensing systems disclosed herein may be capable of determining the weight of the container in a nondestructive manner. In some embodiments, the weight sensing system does not destroy and / or contaminate the material within the container to determine the weight of the container and / or the residual moisture content of the material within the internal volume of the container. Invasive sensors and / or systems that rely on excessively moving parts that may produce particulates that contaminate samples may not be suitable for use in lyophilization systems. In some embodiments, the weight sensing system described herein advantageously may not include parts that move excessively and use invasive sensors.

[0098] In some embodiments, the weight sensing systems disclosed herein may be capable of operating in a wide variety of temperatures. In some embodiments, the weight sensing system is capable of operating in an environment having a temperature of greater than or equal to -80 degrees Celsius, greater than or equal to -75 degrees Celsius, greater than or equal to -70 degrees Celsius, and / or and less than or equal to 40 degrees Celsius, less than or equal to 37.5 degrees Celsius, or less than or equal to 35 degrees Celsius. It may be desirable for the disclosed weight sensing systems to operate throughout the entirety of the lyophilization process, and therefore, the weight sensing system may be capable of operating at relatively high and relatively low temperatures without experiencing significantly diminished performance.

[0099] In some embodiments, the weight sensing system may determine changes in weight of a wide variety of suitable materials. For example, materials that undergo lyophilization processes may be particularly suited for use in such systems. In some embodiments, the materials comprise therapeutic agents such as pharmaceutical agents and / or biological materials. Other materials may also be used.

[0100] #14460974v 1 MIT 26101

[0101] - 18 -

[0102] As described herein, any of a variety of spring deflection systems can be used to achieve the desired resolution, and in some embodiments, the spring deflection systems may use combinations of cantilevered and torsional beams to function as spring elements. Systems which incorporate torsional motion tend to deflect more than systems which rely primarily on bending deflections. The difference between torsional deflection and bending deflection, without wishing to be bound by any particular theory, is generally derived from the efficiency of stress distribution in the beam. In bending, the stress may be concentrated near the root of the beam, which generally limits most of the deflection to the root of the beam. However, in torsion, the stress is generally experienced over the full length of the beam, allowing a greater portion of the beam to contribute to the deflection.

[0103] In some embodiments, the weight sensing system may create a linear relationship with applied load which allows for single point calibration of the system in situ. If the linear slope is consistent, one data point may be needed to set the transformation between spring deflection measurements and vial mass. Cantilevered beams in deflection and torsion have a linear relationship between their load and motion, making them a desirable geometry. Non-linear relationships may also be employed, in some embodiments, with corresponding models.

[0104] Given the above considerations, in some embodiments, the weight sensing system involves a curved wire geometry deflecting under the vial mass load. As the mass inside the vial changes when the solvent sublimates, the wire deflection changes, providing a measurable system change according to some embodiments. Implementing this curved beam deflection system generally involves an integrated set of subsystems which mount the wires to a ground reference, connect the vial payload to the sensing wires, and a sensor for measuring the change in deflection.

[0105] The weight sensing system described in this example comprises four main subsystems. In some embodiments, the first subsystem is a curved wire which deflects based on the mass of the vial. In some embodiments, the second subsystem is the sensing system for measuring the curved wire’s change in deflection. The change in deflection (e.g., pose) of the wire as the vial mass changes is recorded by a camera, which measures the motion of extended sensing arms on the curved wire. The third subsystem, in some embodiments, is a fixed base into which the curved wires are mounted to provide resistive forces to the loaded payload. In some embodiments, the fourth subsystem is the suspended basket which carries the vial and connects the payload to the sensing curved wires. The assembly of these subsystems is shown in FIG. 1, according to some embodiments.

[0106] #14460974v 1 MIT 26101

[0107] - 19 -

[0108] In some embodiments, the sensing wire comprises a main deflecting section of the wire, an extended sensing arm used to amplify the spring deflection and change the motion plane to be parallel to the top of the chamber, a base crook comprising a 4mm nominal diameter semicircle and two 3mm substantially straight wire sections used to mount the spring wire to the wire base, and the curved interface for the basket wire, which may allow for a rolling contact between the basket wire and the spring wire. The rolling contact may limit sliding that could reduce repeatability and risk particulate generation.

[0109] To maintain the vial at a relatively level position while it is suspended by the curved beam, multiple curved beams may be used. If one beam is used, then the slope created by the beam’s deflection may lead to tilting of the vial. While this tilt could be mitigated by hanging the vial directly under the wire crook (e.g., like a bird feeder), doing so may limit access to the top of the vial. It may be undesirable for the top of the vial to be blocked because the vials may be capped while under vacuum in the system, and this can be done by keeping the area above the vial relatively clear. As long as at least two wires are used and the vial is supported between them, then the deflection may not necessarily tilt the vial. While more wires may improve vial stability, more wires may also distribute the load of the vial and will each deflect less. Thus, two wires may be used to meet the minimum number of wires needed for a desirable level of stability. These wires are positioned in axially symmetric positions to limit biasing the vial in any direction.

[0110] In some embodiments, the motion of the tips of the wire are measured by a camera that captures the wire tip position change during the sublimation process. The reliability of the tip position measurements may depend on the ability to reliably measure the wire tip position in each image. Measuring positions in images can be challenging. AprilTags are a pattern developed to address and / or alleviate some of these challenges.

[0111] In some embodiments, an AprilTag is mounted at the end of each spring wire, as shown in FIG. 4, according to some embodiments. A printed plastic nub is coupled to the end of the wire, and the AprilTag is glued on top of this nub. The AprilTag allows for the camera to relatively accurately locate the sensing arm tip’s position in space, and such location may be advantageous for an accurate measurement of its motion. If the error in post position measurement is too large, it can drown out the actual measurement of interest, thus decreasing the system’s overall precision.

[0112] In some embodiments, the wire base is the mounting fixture for the spring wire. The spring wire, in some embodiments, is a “cantilever” subject to bending and torsion which may

[0113] #14460974v 1 MIT 26101 - 20 - help to increase the structural efficiency of the system (e.g., more deflection in less space and hence relatively greater sensitivity than a simple cantilever in bending only). It may therefore be advantageous for the mount to limit bending moments and torsion loads from the wire. This base provides the resistant forces and moments needed to keep one end of the wire fixed while the other end deflects under the vial and product weight. A diagram showing the wire base with certain features described is shown in FIG. 5, according to some embodiments. FIG. 5 depicts a top view of the wire base, wherein the wire base includes 2D features to improve manufacturability. In some embodiments, the base comprises a cutout for the ball plug press fit which holds the spring wires in the base, a central cutout through which the receptacle (e.g. a vial basket assembly) deflects vertically, cutouts used to attach individual wire base modules to a larger assembly, particularly during system development, and bolt hold cutouts, which are shared between consecutive base modules.

[0114] The base features can be designed in 2D to enable rapid and large-scale manufacturing with methods including but not limited to laser cutting.

[0115] The final wire mounting uses a press-fit ball mount to secure the wire to a unit base. This mounting feature is shown in FIGS. 6A-6B, according to some embodiments. FIGS. 6A-6B depict a diagram showing the ball plug press fit mounting used to mount the spring wires to the wire base which provides a rigid support for the deflecting spring wire, according to some embodiments. This feature comprises a circular hole for the ball and a slot to accommodate the wire. The slot is slightly undersized relative to the wire’s nominal dimensions to ensure that the wire will elastically deform the base, creating a clamping force on the wire. The base can have a lower elastic modulus than the wire so that the base elastically deforms to create the clamping force. Accordingly, since the wire is made from steel in example embodiments, the base in this embodiment is made from aluminum. Different material combinations can be used with similar considerations. In some embodiments, the slot width can be determined experimentally by cutting a series of different width slots and pressing the ball and wire into each to determine the fit. The overlap between the ball and the wire was found to be approximately 0.005in, or 0.14mm, on each side of the ball, in accordance with certain embodiments. The circular hole for the 3.5mm ball is slightly oversized to 3.6mm such that base deformation predominantly occurs where the base engages with the wire. However, it should be appreciated that the disclosure is not intended to be so limited as the hole in the base and the ball that is positioned in the hole may have any of variety of suitable sizes that allow the ball to secure springs.. The mounting features are positioned such that the distance between the basket hanger crook in the spring

[0116] #14460974v 1 MIT 26101 - 21 - wires is substantially equal to the diameter of the spring wire’s curved arc, and the line connecting the basket interface points is perpendicular to the basket hanger crook. These considerations allow the basket hanger to be positioned such that a rolling contact at this interface is present, as opposed to stochastic sliding. The mounting features are also positioned axisymmetric about the center of the wire base such that the vial is located centrally in the base.

[0117] The wire mounting crook that is pressed into the base is bent in a plane that is offset from perpendicular to the curved beam deflecting section, as shown in FIG. 7, according to some embodiments. The full mass of the vial plus the product may cause the beam to experience relatively large deflection, which, in some embodiments, is advantageous to achieve the desired sensitivity of the product mass. The sensing range is a subset of the total mass applied to the system, and accordingly, it may be useful to preload the wire such that the wire deflects in its most sensitive motion regime during measurement.

[0118] In some embodiments, the spring wire sensor is at a peak sensitivity when the curved arc section of the wire is parallel to the ground, as that is when the loading at the tip has the longest moment arm and will create the most deflection. This change in moment arm is shown in FIG. 8, according to some embodiments. Generally, greater precision is needed when the water has sublimated from the vial, leaving behind the product. At this point in the process, the system mass is dominated by the vial and its cap, so the masses of the vial and cap are used in calculating the wire preload angle.

[0119] In some embodiments, the vial basket holds the vials in the spring scale system. The basket holds the vial in place during use. This basket is shown in FIG. 9, according to some embodiments. The basket comprises elastically averaging arms which hold the vial in the center of the basket such that the vial is not positioned off-center. Such eccentricity caused by an off- center vial would create an artificial tilt in the sensing system.

[0120] In some embodiments, the vial basket hangs below the wire base plane to at least partially stabilize the system. The axial symmetry of the vial basket assembly allows for the center of mass of the vial basket to be located on its central axis, and the system is substantially upright when this axis is aligned vertically. In some embodiments, the pivot point for the vial basket system is the interface between the basket system and the spring wires. The line connecting these two points may serve as an axis of rotation for the basket assembly. The vial basket assembly may be stable if its center of mass is located vertically below this axis or is marginally stable if the center of mass is located vertically above this axis. If the basket assembly center of mass is located above, but not directly above, the rotational axis, then gravity

[0121] #14460974v 1 MIT 26101 - 22 - may induce a moment on the system about this axis causing the system to tip over. If the assembly center of mass is below the rotational axis, but not directly below the axis, then gravity may induce a moment on the system which tips the assembly back into a vertical state. This phenomenon is illustrated in FIG. 10A-10C, according to some embodiments. FIGS. 10A-10C show a model depicting the vial basket having a rotational axis which goes through the mounting points on the receptacle, according to some embodiments. When the center of mass of the receptacle (e.g., the vial basket assembly) is below this axis and the receptacle tilts, gravity creates a restoring moment which returns the vial basket assembly to an upright state. This hanging mounting also allows the system’s center of mass to be located below its center of stiffness. Conventional positioning of the center of mass above the center of stiffness leads to tilting motion and system instability. This motion results from the low stiffness of the sensing compliant elements. As the center of mass moves, if it does not have a restoring force recentering it within the assembly, the vial may continue to tilt and fall over. Keeping the center of mass below the system center of stiffness allows for the compliant element’s restoring force to stabilize the system similarly to gravity.

[0122] In some embodiments, this system uses an optical measurement system to record vial mass information from the vacuum chamber. The optical measurement, in some embodiments, does not involve any specialized vacuum pass-throughs, as an optical viewing window may be sufficient. Additionally, optical measurement generally may not interfere with the lyophilization process, nor does the optical measurement introduce potential contamination sources. This system comprises two reference markers, in some embodiments, which move based on the system weight and a series of fixed reference markers which are connected to the wire base. These reference markers may be 3mm edge length AprilTags, but other AprilTag sizes may be used. AprilTags are a standard computer vision target which are tracked in a camera image. Given a camera field of view covering 1 vial, the minimum field of view is expected to be around 40mm x 40mm. Using a standard camera HD resolution of 1920 x 1080 pixels, the camera can resolve distances at about 37pm / pixel. Accordingly, based on the range of travel needed for a 3g change in system mass, the desired motion of the optical measurement datum is 12pm / mg, or 12mm / g. However, in some embodiments, the position of the AprilTags can be identified to finer resolution than a single pixel by tracking the positions of its corners and using them to identify the tag centroid. This measurement method, in some embodiments, results in a lOx improvement in the optical measurement’s precision, such that the motion sufficient for measurement can be decreased to 1.2mm / g.

[0123] #14460974v 1 MIT 26101

[0124] - 23 -

[0125] In some embodiments, the final spring wire mass measurement system uses a portion of a helical spring as the primary deflecting arm and comprises an extended sensing arm to amplify and / or change the plane of the motion for the visual sensor. In some embodiments, the curved wire of the helical spring leverages torsional loading efficiency to increase system sensitivity while maintaining a relatively small footprint within the system. The curved wire of the helical spring is also simple to manufacture using conventional wire bending techniques. The expected deflection for this system, according to certain embodiments, is predicted using a model for the deflection of a curved beam experiencing out of plane bending. The problem setup appears in FIG. 12A

[0126] The strain energy for the curved beam can be found using the following relationship in

[0127] Equation 1 :

[0128] Where Mxis the bending moment, E is the beam’s Young’s Modulus, Ixis the beam’s second moment of inertia, Mzis the torsional moment, G is the beam’s torsional rigidity, and IPis the beam’s polar moment of inertia. These moment loads are functions of the distance between the root and the end of the beam, and they can be expressed by the relationships shown in Equation 2.

[0129] Mx= — Pr sin(<z — <p) , MZ= Pr[l — cos(<z — <p)] (2)

[0130] The strain energy can be separated into its bending (Ux) and torsional (Uz) components, shown in Equation 3.

[0131] Taking the partial derivative of strain energy with respect to the load, P, gives Equation

[0132] The explicit bending and torsional deflections can be split up as before, as seen in

[0133] Equation 5:

[0134] Using the choice of a circular wire geometry, the moments of inertia can be substituted in to get the final deflection relationships shown in Equation 6:

[0135] #14460974v 1 MIT 26101 - 24 -

[0136] Where r is the curvature radius of the beam, E is the beam’s elastic modulus, d is the wire diameter, G is the beam’s modulus of rigidity, P is the out of plane load on the end of the beam, and a is the total angle of the curved beam. These equations provide insight into the variables which influence the system performance by showing which variables have exponential effects on deflection.

[0137] These equations demonstrate that the system deflection has an exponential relationship with the wire diameter and the arc of curvature bent into the spring wire shape. Thus, these parameters serve as the main driving tools in designing the wires for these springs. Decreasing the wire diameter creates a relatively large potential increase in deflection, but it is limited by keeping the wire in its elastic deflection regime. Additionally, a thinner wire may be more challenging to mount rigidly into a fixed base, which may facilitate the creation of the cantilevered beam condition. The wire chosen for certain example embodiments has a ,014in diameter to balance this preference for a thinner wire and requirement for a thick enough wire for mounting system flexibility. The wire deflection and stress relationships can be evaluated to select wire parameters for manufacture.

[0138] Table 1. Example output from a spreadsheet used for engineering the system.

[0139] #14460974v 1 MIT 26101

[0140] Table 1 shows the z deflection calculation based on the theoretical deflection of a curved cantilever beam loaded perpendicularly to the plane of its curvature using the parameters

[0141] #14460974v 1 MIT 26101 - 26 - described herein. The calculation shown in Table 1 is based on 3 grams of mass change, representative of the 3 grams of water that is sublimated from a vial used during the development of the lyophilizer described herein.

[0142] The spring wire, in accordance with certain embodiments, is a .014 in diameter CH900 stainless steel wire with a 140 degree wire bend arc, 16mm wire arc radius of curvature. This wire may have a linear vertical deflection at the tip of 1.68mm for a 3 gram load split between two wires. Such deflection may result in a vertical deflection rate at the wire tip of 0.56mm / g. This deflection rate may be insufficient for practical application, so some form of amplification may be needed. This amplification can be done, in some embodiments, using extended sensing arms. In some embodiments, the tip of the curved beam is not only deflecting but also tilting. This angular motion may be amplified by the extended sensing arm. The slope of the curved wire at its tip can be calculated using curved wire under out of plane motion equations derived in Roark’s Formulas for Stress and Strain. This calculation provides the slope induced at the wire tip due to bending and torsion. These slope directions create motion perpendicular to each other, such that the resultant wire motion is the square root of the sum of the squares of the wire tip motion created by each slope term. An example of this calculation is shown in Table 2 below.

[0143] Table 2. Estimates of the wire tip slope.

[0144] #14460974v 1 MIT 26101

[0145] -27-

[0146] #14460974v 1 MIT 26101

[0147] - 28 -

[0148] According to the results shown in Table 2, adding a sensing arm provides about a 2x amplification in the motion from the wire tip deflection to the sensing arm tip motion.

[0149] The extended sensing arm is 50mm long, which provides about a 2x amplification to the measured motion, increasing the expected deflection rate for each wire to 1.21mm / g. The system is assembled such that there are two wires bearing the mass, and these wires are moving in opposite directions. Thus, the effective motion measured by the optical system is doubled, resulting in a deflection rate of 2.42mm / g. This result is about two times the required resolution for the system, providing some flexibility for parasitic errors such as friction.

[0150] EXAMPLE 1

[0151] In this example, a weight sensing system comprising two springs coupled to optical targets was constructed. The orientation of the optical targets was evaluated to determine the change in weight of material within containers (e.g., vials) positioned in the system. As the material within the containers experienced a decrease in weight (e.g., via lyophilization), the optical targets exhibited a change in pose that was detected by an optical detector. The change in pose was then correlated to a change in weight. Further details regarding this system and the performance of such system are described below.

[0152] Experimental Results

[0153] An automated offline testing setup was built to evaluate the spring wire system before implementing it on the lyophilization hardware. This setup uses an analytical balance to provide the ground truth measurements of mass changes. A mounted camera records the AprilTag

[0154] #14460974v 1 MIT 26101

[0155] - 29 - positions as the peristaltic pump intermittently adds water to change the mass in the vial. In this example, the spring wire system is placed on an analytical balance to directly measure the mass changes in the system. A peristaltic pump is used to periodically add mass to the system, and a Canon Rebel T7i with an 18-55mm lens is used to capture the tag positions during the tests. Because the springs are deforming elastically, the motion when adding or subtracting mass was expected to be symmetric, so adding mass was a reasonable method for running calibration experiments. Removing mass mechanically has a high risk of artificially agitating the vial, which can affect the tag motion measurements. Water’s rate of evaporation at atmospheric pressure and room temperature is slow, which would lead to long tests. Using a fluid like liquid nitrogen which can vaporize more quickly due to boiling is also undesirable, as this boiling process can also induce additional vibrations in the system which may obfuscate measurements.

[0156] During a calibration test, water was added to the vial in 500mg increments. The water was pumped using the peristaltic pump and dispensed through a needle which is positioned over the top of the vial. After each water addition, the system was left to settle for 4 minutes. The impact of the droplets dispensed by the needle impacting the fluid in the vial caused large vibrations in the system. The system does not have much damping because as the system is designed to have relatively minimal friction. These impacts are an artifact of the test setup with the water dispensing, so it is appropriate to remove their effects from the measurements. However, in the lyophilizer, these spring systems will be subjected to inertial loads as they move around, so they will still have some vibration in-situ. Accordingly, the tag positions were recorded in a 10 second video, and the average position was reported. This test was performed with 15 mass additions, providing a system response over a total range of 7.5g. While the mass change in the vial was expected to only be 3g, this extended test range verifies whether the performance stays sufficiently consistent to handle variation in vial, cap, and fill masses.

[0157] The spring system linearity is evaluated by plotting the normalized tag motion against the normalized mass added during an experiment. An example normalized dataset is shown in FIGS. 11 A-l IB. If the system is linear, then the data points should fall on a parity line that diagonally bisects the plot. As shown in FIGS. 11 A-l IB, the data points show a slight concavity. This result indicates a consistent nonlinear behavior, as the data follows a relatively smooth curve which is offset from the parity line. The curvature of the residual data when compared to a parity line shows a consistent, mildly nonlinear behavior in the response. This nonlinearity is on the same order of magnitude of the resolution desired by the sensor.

[0158] #14460974v 1 MIT 26101 - 30 -

[0159] Multiple potential sources of nonlinearity have been investigated to try to identify the source of this nonlinearity. One source could be sliding at the basket wire and spring wire interface. This motion could be addressed by gluing the wires together, in some embodiments, thereby removing system compliance from this interface, or by adding an additional link to the system, such that any sliding motion would instead result in motion of this link.

[0160] Another source of potential nonlinearity is deflection in the parts of the spring wire not initially included in the analysis. Thus, the deflection created by these wire components was also modeled. This wire section can be treated as a combined beam in torsion and a cantilevered beam with a moment load applied to its end. The resultant modeled deflection is shown in Equation 7.

[0161] Where Li, L2, L3, and P are shown in FIG. 6B. E and I are the elastic modulus and second moment of inertia of the spring wire, and 0o is the preload angle bent in the spring wire shown in FIG. 7.

[0162] Another approach to address this nonlinearity involves evaluating the 2D motion of the tag as seen from the side. As the wires deflect, the tag not only moves sideways, but down. This motion means that as the deflection angle increases, the corresponding motion seen by the camera can change. A diagram illustrating this motion appears in FIG. 12B. The transformation between the deflection of the deflection at the sensing arm tip and the curved arc section of the spring wire is shown in Equation 8.

[0163] Given that the previous modeling and hardware adjustment approaches do not address the curvature seen in the parity plot, a higher order model is used to fit the calibration data. When compared to the data within an experiment, these higher order models show very good fits, as the model can predict the mass measured in the vial based on the tag deflections with less than 5mg of error. Namely, orders greater than or equal to 3 can predict the mass measured in the vial with less than 5 mg of error. The fit coefficient variation up to third order are shown in FIG. 20, for some embodiments.

[0164] While these models show strong performance on their own calibration data sets, the nonlinear nature of these models increases the difficulty of applying them to data where the mass is not known. During the lyophilization process, these systems are the only form of mass feedback, so the models will not have multiple known data points which can be used to ensure

[0165] #14460974v 1 MIT 26101

[0166] - 31 - strong performance. To test the model transferability, the coefficients calculated from one calibration experiment using a sample spring wire assembly are used in combination with the deflection results from a second, separate calibration experiment on the same assembly, predicted results are then compared to the measured results from that initial experiment. The results, shown in FIG. 19, show higher errors, greater than 25mg, which are well above the target precision of 3 mg.

[0167] While these results do not show acceptable performance, the results are based on the assumption of having no known deflection and mass measurements which can be used to calibrate the system in-situ. However, there is one known data point which can be used for in- situ calibration. Before the vial is first inserted into the weight sensing assembly, the mass of the vial, product, and cap are measured, providing a known mass value. Once the vial is placed into the weight sensing assembly, the resultant deflection can be measured. This combination provides a single known data point for mass and deflection in the system. Using this data point to update the higher order model used to predict the system’s mass versus tag motion curve improves the system repeatability to 15mg or less, as shown in FIG. 21. This data point is incorporated by using a maximum a priori estimator for the model coefficients.

[0168] This system, as described in this example, is sufficiently accurate to identify when the vial has completed the primary drying phase of the sublimation process in the lyophilizer. When vials supported in the spring mass measurement system are subjected to the sublimation process in the system, mass measurements demonstrate a leveling phenomenon corresponding to the end of primary drying. This result indicates that the system can detect when the residual moisture in the vial is no longer changing by more than the 15mg resolution shown above. The mass no longer significantly changing indicates that the product can be removed from the system, as leaving it in the drying section longer will not change the product’s state. This release criterion improves system efficiency by ensuring vials are not left in the system longer than necessary. Example vial weight trajectories and their ability to identify the end of the drying process appear in FIG. 13. FIG. 13 shows that the difference between when the first and last vial finishes drying within a puck can serve as an indicator as to how uniformly the vials went through the lyophilization process. This flatlining agrees with other measurements, such as a pressure ratio test. These measurements show agreement with a conventional method for measuring moisture in a lyophilizer which is a pressure ratio test which compares measurements between water sensitive and water ambivalent pressure sensors. However, the mass sensors described herein

[0169] #14460974v 1 MIT 26101

[0170] - 32 - provide detailed information for each vial’s drying rate and drying finish time. Once the last vial on a puck finishes drying, the puck is ready to be released from the system.

[0171] The specific endpoint identified by the current mass sensing system corresponds to the end of primary drying. The 15mg target does not identify the end of secondary drying, where the residual moisture mass is closer to 3mg. Once primary drying is complete, the vials are left in the system for a designated hold time to finish secondary drying. This result in the desired residual moisture water content of 2wt%. Residual moisture measurements obtained via Karl Fischer titration. The solutions lyophilized for this testing were 3mL 5wt% sucrose. A plot showing the residual moisture versus secondary drying hold time is shown in FIG. 14. The vials were removed from the system after different hold times for secondary drying to compare their residual water content, as measured by Karl Fischer titration. The vials released shortly after their end point identification measured 15wt% residual moisture, corresponding to the end of primary drying. When leaving the vials in the system for longer times to complete secondary drying, the residual moisture was reduced to the final target of 2wt%.

[0172] In a production setting, the weight sensors will interact with other pharmaceutical equipment rather than a manual operator. To validate this interface, a Dispenseworks automated vial filling machine is used to automatically fill vials, place them on the weight sensors for freeze-drying, and remove them from the system after they are dried. The Dispenseworks machine uses a robotic arm to transfer vials between the two systems. The vials are moved between the Dispenseworks machine and the lyophilizer using automated trays, herein referred to as “pucks.”

[0173] The robotic arm needs to reach past the sensing arms on the weight sensing system to be able to pick up or place vials on the pucks. The robotic arm head has a diameter of 40mm, which would contact the sensing arms when it tries to move the vials to and from the pucks. Thus, the sensing arms need to be moved out of the way of the robotic arm while it is interacting with the puck. This motion can be achieved through two elements: the elephant trunk and the robotic arm cone.

[0174] The elephant trunk is an extended arm which pulls the basket down in preparation for vial loading and unloading. An example trunk 405 is shown in FIG. 15. The trunk is mounted to the system table and extends over the surface of the primary loading stator, in a position aligned with the vial filling machine’s robotic arm track. The front edge of the trunk is positioned such that the bottom surface of the trunk is above the neutral hanging height of the vial basket once the product in the vial is fully lyophilized. The surface of the root of the trunk is at a height such

[0175] #14460974v 1 MIT 26101 - 33 - that when the basket is touching this surface, it is also pushed down into contact with the puck plate cone. The trunk profile follows an S-shaped curve to transition between these two surface heights. The trunk thickness is set to 2mm allowing the trunk to fit in the gap between the basket base and where the bottom of the vial sits when it is in the basket. The trunk width is set to 5mm so that it can fit between the vial holding posts where these posts are connected to the basket base. The trunk includes a semicircular area where it overhangs the stator to increase the overall stiffness of the elephant trunk system. Behind this semicircular area, the elephant trunk includes mounting holes to connect to a piece of 1.5in t-slotted framing.

[0176] In some embodiments, the puck moves in front of the elephant trunk in preparation for loading and unloading. The puck then moves towards the elephant trunk, causing it to engage with the vial basket. As the puck continues to move, the elephant trunk pulls the vial basket down to engage it with the puck centering cone. Pulling the basket down causes the sensing wires to deflect outwards from the vial, moving them away from where the robotic arm travels, as shown in FIG. 2. The sensing arms then get out of the way of the robotic arm used by the Dispenseworks machine to load and unload vials from each puck. While this motion helps move the sensing arms away from the robotic arm, the motion is not sufficient to prevent interference between these two system elements. Thus, the robotic arm cone is added to the robotic arm.

[0177] The robotic arm cone provides a smooth angled surface to redirect the ends of the sensing arms away from the robotic arm gripper. This motion is desirable as it allows the sensing arms in the vial weight sensing system to be pushed to the side more than they are pushed down. If the sensing arms are pushed downwards, the sensing arms can be pushed out of the basket wire, dislodging the vial basket from the sensing arms. If this detachment occurs, then the sensing wires will move away from the basket wire, limiting the basket wire from reconnecting after the robotic arm leaves. If instead the sensing arms are pushed to the side, the hook where it connects to the basket wire will remain engaged, ensuring the vial basket remains connected to the sensing wires after the robotic arm retracts.

[0178] In some embodiments, the robotic arm cone may function when the robotic arm gripper is in both its open and closed positions. The robotic arm gripper may approach the puck in its closed position when bringing a fresh vial to the tray, as it is holding the vial which it brings from the vail filling machine. The robotic arm may approach with the gripper in the open position when it is coming to the tray to pick up a vial which has completed the lyophilization process. The robotic cone system can be mounted directly on the gripper’s moving arms, mounted to the robotic arm, or mounted to the lyophilizer. Mounting to the lyophilizer reduces

[0179] #14460974v 1 MIT 26101

[0180] - 34 - the potential error between the vial positioning and the cone because they are both referenced to the stator. This mounting also allows for the cone to be independent from the vial filling system used. However, this system may involve movement of the vial tray thereby restricting its geometry. Mounting of the robotic cone system to the robotic arm ensures the cone will not change positions between the gripper’s open and closed positions, so if it works in one state then it may work in the other state. However, this mounting may result in the cone to be wider than the entire robotic arm, which would create undesirable deflection in the sensing wires. Mounting the cone directly to the gripper arms accommodates the gripper open and closed positions, as well as allow for the motion between these states. However, this mounting allows for a relatively small form factor for the robotic arm cone. Given the restricted geometry in the system, the mounting on the gripper arms is selected to have a relatively small geometry.

[0181] In some embodiments, the robotic arm gripper includes three arms. One of these arms may be perpendicular to the motion of the wires during loading and unloading, so it does not interfere with the sensing arms. The other two arms may be symmetrically at an angle relative to the sensing arm motion. However, the sensing arms themselves may be axisymmetric rather than planar symmetric. Thus, the properties of the cone on each side of the robotic arm are different. On one side of the gripper, the sensing arm may be positioned directly below one of the gripper’s fingers. On the other side of the gripper, the sensing arm may be positioned between two of the gripper’s fingers. In the first case, the cone may shift the sensing arm from below the gripper’s finger to the area between the fingers, then further to the side outside of the robotic arm diameter. In the second case, the cone may shift the sensing arm outside of the robotic arm diameter. These considerations led to the robotic arm cone geometry shown in FIG. 16 where the robotic arm cone comprises two parts mounted directly to the gripper fingers. These parts are shaped differently to account for the linear asymmetry in the interaction between the gripper fingers and the sensing wires on the puck. The angled surfaces move the sensing arms to the side without pushing them down so the wires do not dislodge from the vial basket. The reverse taper on the top part of the robotic arm cone components ensures these parts do not pull up on the underside of the April tag nubs on the sensing arms when the robotic arm pulls up and away from the puck.

[0182] The robotic arm cone geometry comprises a sharp angled section which is positioned within the gripper’s finger area and a conical sweep which fills the volume between neighboring gripper fingers. For example, as shown in FIG. 16, robotic arm cone 500 comprises finer 510 and conical sweep 505. The sharp angled section shifts the sensing arm into the region between

[0183] #14460974v 1 MIT 26101 - 35 - neighboring gripper fingers, where the conical sweep then guides the sensing arm out of the robotic arm’s path. This setup involves the sensing arms to start outside of the profile of the vial. The robotic arm cone may not infringe on the vial profile because that would block the robotic arm from picking up vials. The robotic arm cone also may not extend too far outside of the robotic arm profile because it would then risk pushing down sensing arms on consecutive weight sensing systems.

[0184] In some embodiments, the top outer edges of the robotic arm cone include a reverse taper. This reverse taper limits the AprilTag nubs from catching on the robotic arm cone when the robotic arm retracts. The AprilTag nubs also include a conical body to help them engage with and be pushed by this reverse taper.

[0185] In some embodiments, the vial basket comprises an alignment post and corresponding alignment cone under its base to keep the vial centered when vials are added to and removed from the weight sensing system. For example, as shown in in FIG. 17, receptacle 205 comprises alignment post 605 which is positioned in alignment cone 610. When the elephant trunk pulls the vial basket down to move the wires aside for access by the robotic arm, the alignment post on the vial basket engages with the tapered edge of the alignment cone. This engagement ensures that the alignment post and subsequently the vial basket ends up in a consistent, centered, vertical orientation when the robotic arm interacts with the system for loading and unloading. When the centering post engages with the conical surface in the furniture cone, the vertical force causes it to slide into a centrally located position.

[0186] The individual weight sensing systems can be assembled together to move through a continuous lyophilizer based on the size of the motion system. If the motion system is larger than a singular weight sensing system, then a combination of these weight sensors can be mounted to a single mover. This assembly is shown in FIG. 18. These assemblies include a series of fixed reference tags which can be used to measure the motion of individual sensing arms. These reference tags can also be used to remove nonlinearity from the camera measurements. The mounted assembly includes reference datums used to measure the motion of the sensing arms based on a fixed reference. When the weight sensor is moved around, the position under the camera where it is measured may change. These references allow the measurements to compensate for the relative motion of the mover carrying the weight sensing systems. Using multiple references also allows the system to compensate for the nonlinearity created by the camera lens in measuring distances across its full field of view. These reference markers are also AprilTags for robust camera tracking.

[0187] #14460974v 1 MIT 26101

[0188] - 36 -

[0189] Lyophilization system modules through which the vials travel may include windows on their ceilings to provide visual access into the chambers during the lyophilization process. These windows may be utilized for the weight sensing system which provides direct feedback on the sublimation process. This overhead measurement system can also be used as part of a global vial tracking system based on QR codes. In some embodiments, the vial caps could include QR codes which are linked to the data collected on its process through the lyophilizer. Because each vial’s position is known as it moves through the machine, the freezing protocol used and the resultant drying process data could be tied to a specific vial’s identifying marker for future reference. This system would involve, in some embodiments, custom vial caps for each vial which include these unique QR code identification tags.

[0190] The various embodiments of a mechanical weight sensing system allow for measurement precision of one part in 1000 for a vial in a vacuum system during lyophilization. The weight sensing system uses a curved wire deflecting in bending and torsion to achieve the required measurable motion for mass change identification. The slope of the deflecting wire tip is amplified by a sensing arm, and the sensing arm motion is recorded using a camera tracking AprilTags on the sensing arm tips. The system provides in-situ process data during the sublimation phase of lyophilization to provide insight on the vial’s progress. This insight can be used to determine a process-based release criteria, rather than a pure total time criteria used in current lyophilization systems. Vials lyophilized using this in-situ data based released criteria meet the desired residual moisture content target of 2wt% water for a lyophilized cake.

[0191] In some embodiments, increasing the sensing arm length may lead to greater precision, further amplifying the measurement motion. While this sensing arm length could be directly increased, this length change would require increasing the system’s internal volume, which in turn would decrease its vacuum performance. In some embodiments, the sensing arm could be effectively lengthened by replacing the straight wire with an optical lever system. An optical lever system could be implemented by replacing the extended straight section of the wire with the AprilTag mounted on its end with a relatively shorter arm that has a mirror mounted instead. A laser from outside of the system could then be directed at the mirror, and its reflected image could be measured to track the spring motion. In this case, the sensing arm length becomes the total laser path length, which is decoupled from the chamber geometry. Thus, this system can significantly increase the sensing arm amplification and resultant measurement resolution. A diagram illustrating this optical lever concept is shown in FIG. 3. The mass of the system would be recorded based on the reflection of a directed light beam which reflects off of a mirror

[0192] #14460974v 1 MIT 26101

[0193] - 37 - mounted to the end of the sensing arm. As the sensing arm tilt and its slope changes, the laser position would move, and this change in position corresponds to a change in mass. The sensing arm length in this method is the full distance from the emitter to the mirror and back to the receiver, whereas the physical amplification arm is limited to the length of wire extending from the sensing wire. This optical system can significantly increase the effective length of the sensing amplification, improving the measurement resolution.

[0194] It will be appreciated that the methods and systems described above are set forth by way of example and not of limitation. Numerous variations, additions, omissions, and other modifications will be apparent to one of ordinary skill in the art. In addition, the order or presentation of method steps in the description and drawings above is not intended to require this order of performing the recited steps unless a particular order is expressly required or otherwise clear from the context. Thus, while particular embodiments have been shown and described, it will be apparent to those skilled in the art that various changes and modifications in form and details may be made therein without departing from the scope of the disclosure.

[0195] While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, and / or methods, if such features, systems, articles, materials, and / or methods are not mutually inconsistent, is included within the scope of the present invention.

[0196] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0197] #14460974v 1 MIT 26101 - 38 -

[0198] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0199] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0200] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements

[0201] #14460974v 1 MIT 26101 - 39 - other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0202] As used herein, “wt%” is an abbreviation of weight percentage. As used herein, “at%” is an abbreviation of atomic percentage.

[0203] Some embodiments may be embodied as a method, of which various examples have been described. The acts performed as part of the methods may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include different (e.g., more or less) acts than those that are described, and / or that may involve performing some acts simultaneously, even though the acts are shown as being performed sequentially in the embodiments specifically described above.

[0204] Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

[0205] The above-described embodiments of the technology described herein can be implemented in any of numerous ways. For example, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the software code can be executed on any suitable processor or collection of processors, whether provided in a single computing device or distributed among multiple computing devices. Such processors may be implemented as integrated circuits, with one or more processors in an integrated circuit component, including commercially available integrated circuit components known in the art by names such as CPU chips, GPU chips, microprocessor, microcontroller, or co-processor. Alternatively, a processor may be implemented in custom circuitry, such as an ASIC, or semicustom circuitry resulting from configuring a programmable logic device. As yet a further alternative, a processor may be a portion of a larger circuit or semiconductor device, whether commercially available, semi-custom or custom. As a specific example, some commercially available microprocessors have multiple cores such that one or a subset of those cores may constitute a processor. Though, a processor may be implemented using circuitry in any suitable format.

[0206] Further, it should be appreciated that a computing device may be embodied in any of a number of forms, such as a rack-mounted computer, a desktop computer, a laptop computer, or a

[0207] #14460974v 1 MIT 26101 - 40 - tablet computer. Additionally, a computing device may be embedded in a device not generally regarded as a computing device but with suitable processing capabilities, including a Personal Digital Assistant (PDA), a smart phone, tablet, or any other suitable portable or fixed electronic device.

[0208] Also, a computing device may have one or more input and output devices. These devices can be used, among other things, to present a user interface. Examples of output devices that can be used to provide a user interface include display screens for visual presentation of output and speakers or other sound generating devices for audible presentation of output. Examples of input devices that can be used for a user interface include keyboards, individual buttons, and pointing devices, such as mice, touch pads, and digitizing tablets. As another example, a computing device may receive input information through speech recognition or in other audible format.

[0209] Such computing devices may be interconnected by one or more networks in any suitable form, including as a local area network or a wide area network, such as an enterprise network or the Internet. Such networks may be based on any suitable technology and may operate according to any suitable protocol and may include wireless networks, wired networks or fiber optic networks.

[0210] Also, the various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. Additionally, such software may be written using any of a number of suitable programming languages and / or programming or scripting tools, and also may be compiled as executable machine language code or intermediate code that is executed on a framework or virtual machine.

[0211] In this respect, the embodiments described herein may be embodied as a computer readable storage medium (or multiple computer readable media) (e.g., a computer memory, one or more floppy discs, compact discs (CD), optical discs, digital video disks (DVD), magnetic tapes, flash memories, RAM, ROM, EEPROM, circuit configurations in Field Programmable Gate Arrays or other semiconductor devices, or other tangible computer storage medium) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments discussed above. As is apparent from the foregoing examples, a computer readable storage medium may retain information for a sufficient time to provide computer-executable instructions in a non-transitory form. Such a computer readable storage medium or media can be transportable, such that the

[0212] #14460974v 1 MIT 26101 - 41 - program or programs stored thereon can be loaded onto one or more different computing devices or other processors to implement various aspects of the present disclosure as discussed above.

[0213] As used herein, the term "computer-readable storage medium" encompasses only a non- transitory computer-readable medium that can be considered to be a manufacture (i.e., article of manufacture) or a machine. Alternatively or additionally, the disclosure may be embodied as a computer readable medium other than a computer-readable storage medium, such as a propagating signal.

[0214] The terms “program” or “software” are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computing device or other processor to implement various aspects of the present disclosure as discussed above. Additionally, it should be appreciated that according to one aspect of this embodiment, one or more computer programs that when executed perform methods of the present disclosure need not reside on a single computing device or processor, but may be distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present disclosure .

[0215] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically the functionality of the program modules may be combined or distributed as desired in various embodiments.

[0216] The embodiments described herein may be embodied as a method, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0217] Further, some actions are described as taken by a “user.” It should be appreciated that a “user” need not be a single individual, and that in some embodiments, actions attributable to a “user” may be performed by a team of individuals and / or an individual in combination with computer-assisted tools or other mechanisms.

[0218] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed

[0219] #14460974v 1 MIT 26101 transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0220] #14460974v 1

Claims

MIT 26101- 43 -CLAIMSWhat is claimed is:

1. A weight sensing system comprising: at least two springs, wherein each spring comprises a spring body at least laterally extending from a first anchored end portion to an unloaded distal end portion, the first anchored end portion anchored to a base of the system; a receptacle configured to support a container disposed therein, wherein the receptacle is configured to be suspended from the at least two springs; and one or more optical targets, wherein each optical target of the one or more optical targets is associated with a separate spring of the at least two springs, and wherein displacement of the at least two springs by the receptacle causes a change in pose of the one or more optical targets.

2. The weight sensing system of claim 1, further comprising one or more processers configured to determine, based at least in part on the change in the pose of the one or more optical targets, a weight of the container and / or a weight of a material in the container.

3. The weight sensing system of any one of claims 1-2, wherein the change in the pose is a change in an orientation of the one or more optical targets4. The weight sensing system of any one of claims 1-3, wherein the one or more optical targets are two or more targets, and wherein the change in the pose is a change in a distance between the two or more targets.

5. The weight sensing system of any one of claims 1-4, wherein each spring comprises a partial-arc having a central angle less than 360 degrees and at least a partial helical shape.#14460974v 1MIT 26101- 44 -6. The weight sensing system of any one of claims 1-5, further comprising a rolling contact formed between one or more connections of the receptacle and the unloaded distal end portions of the at least two springs.

7. The weight sensing system of any one of claims 1-6, wherein each optical target of the one or more optical targets is disposed on an unloaded distal end portion of the associated spring.

8. The weight sensing system of any one of claims 1-7, wherein the distal end portion includes an extension configured to increase the change in pose of the associated optical target relative to a change in pose of a portion of the at least two springs configured to support the receptacle.

9. The weight sensing system of any one of claims 1-8, wherein the one or more optical targets are one or more reflective targets10. A lyophilization tray comprising one or more of the weight sensing systems of any one of claims 1-9.

11. The weight sensing system of any one of claims 1-10, wherein each spring extends laterally and axially away from a first anchored position.

12. The weight sensing system of any one of claims 1-11, wherein each spring extends helically away from a first anchored position.

13. A method of sensing a weight of a material disposed in a container, the method comprising: placing the container in a receptacle supported by at least two springs; deforming the at least two springs with the receptacle and the container disposed therein; changing a pose of one or more optical targets due to deforming the at least two springs; and#14460974v 1MIT 26101- 45 - determining a weight of the container and / or the material based at least in part on the pose of the one or more optical targets, wherein each spring comprises a spring body laterally extending from a first anchored end portion to an unloaded distal end portion, the first anchored end portion anchored to a base.

14. The method of claim 13, wherein the deforming is due to bending and / or torsion of the at least two springs.

15. The method of any one of claims 13-14, wherein the change in the pose is a change in an orientation of the one or more optical targets16. The method of any one of claims 13-15, wherein the one or more optical targets are two or more targets, and wherein the change in the pose is a change in a distance between the two or more targets.

17. The method of any one of claims 13-16, wherein each spring comprises a partialarc having a central angle less than 360 degrees and at least a partial helical shape.

18. The method of any one of claims 13-17, wherein each optical target of the one or more optical targets is disposed on an unloaded distal end portion of the spring.

19. The method of any one of claims 13-18, wherein each spring extends laterally and axially away from a first anchored position.

20. The method of any one of claims 13-18, wherein each spring extends helically away from a first anchored position.#14460974v 1

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