Modular lyophilization system and related methods

Abstract

Continuous lyophilization can enable higher uniformity and throughput than existing systems by improving vial condition uniformity and using in-situ monitoring to release products as they finish freeze-drying. The present disclosure relates, in various aspects, to modular systems for lyophilization. In various aspects, a system provided herein separates lyophilization process chambers spatially rather than temporally so that all process operations may occur simultaneously. The system may be made up of reconfigurable modules and may be deterministically sized based on desired production rates and process times. The provided modularity allows a lyophilization system developed at benchtop scale to be scaled to a production scale using the same chamber geometry, which may advantageously reduce the complexity of scaling processes first identified at research scale.

Description

MIT 26102 - 1 - MODULAR LYOPHILIZATION SYSTEM AND RELATED METHODS RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63 / 703,155, filed on October 3, 2024, which is hereby incorporated by reference herein in its entirety. GOVERNMENT FUNDING

[0002] This invention was made with government support under U01 FD006755 awarded by the Food and Drug Administration. The government has certain rights in the invention. FIELD

[0003] The present disclosure relates, in various aspects, to pharmaceutical lyophilization of liquid medicines in a vial to form dry powder in the same vial for later reconstitution, to modular systems for lyophilization, and to associated methods. BACKGROUND

[0004] After a pharmaceutical product is synthesized, there is a complex supply chain required to deliver the product to the patients who need it. The product must be kept stable and viable as it moves through this supply chain such that it can provide the necessary medical benefits to patients. Unfortunately, many products do not have long term stability in their synthesized liquid state. These unstable products can be lyophilized to transition them into a stable dry state.

[0005] Existing pharmaceutical lyophilization systems suffer from three major limitations. The first limitation is the difficulty in translating processes between research scale systems and industrial scale systems. Because the research systems and the industrial systems have significantly differing geometries, the processes developed on research machines do not directly correspond to lyophilization processes that work on industrial equipment. Thus, when developing a lyophilization process for new formulations, the process must be developed on both the research equipment and then a second time on the industrial equipment. This delay can be costly, as it requires the industrial equipment to be taken offline 13178167 #14412969v1MIT 26102 - 2 - while it is testing lyophilization parameters for new formulations, and the long cycle time of lyophilization can cause this process to take days.

[0006] The second limitation is the non-uniformity in vial conditions within an industrial pharmaceutical lyophilizer. The internal volume of these lyophilizers is large enough to have significant variation in thermal and vacuum conditions between vials. This variation can be sufficiently large to cause some vials to not successfully lyophilize. The variation is tied to the distance of the vials from the vacuum system inlet and the proximity of the vials to the walls of the lyophilizer. The further the vials are from the vacuum system inlet, the higher the local pressure at the vial will be, which can slow down the sublimation rate. The closer the vials are to the machine walls, the more they are heated by the radiative heat emanating from those walls, increasing their temperature relative to other vials. These higher pressures and temperatures make the lyophilization process more prone to failure. Accordingly, machines can be run with empty vials around the outermost rows of shelves because any product in those vials would not successfully lyophilize. These vials represent lost productivity for this equipment, reducing their effective capacity.

[0007] The third limitation is the batched nature of industrial unit dose lyophilizers. Pharmaceutical production lines have been starting to evolve into continuous systems for improved production rates, flexibility, and quality. Lyophilization has similarly begun moving towards continuous manufacturing, but most work has been limited to bulk material processing. While unit dose lyophilizers have been proposed, the industry standard for unit dose freeze dryers remains batched systems. To match overall production rates, these machines have large batch sizes. This disconnect leads to a requirement for large buffers between the production line and the lyophilizers, which takes up space and increases the risk of vial contamination as they are waiting to be moved between factory subsystems. There have been preliminary investigations into continuous systems for unit dose pharmaceutical lyophilization, but fully functional systems are currently limited.

[0008] Addressing the third limitation requires a significant topological change to existing lyophilization systems. Continuous lyophilization exists in other industries, such as food production. These lyophilizers often operate on a bulk mass principle, where material is moved in large quantities through the system. This method does not have as precise control of unit quantities and sanitation as a unit vial system. In the food industry, for example, this loss 13178167 #14412969v1MIT 26102 - 3 - of precision is acceptable; however, in the pharmaceutical industry, this potential variation can be problematic. Thus, unit dose continuous lyophilizers would be desirable.

[0009] This document presents the design, manufacture, and evaluation of a continuous lyophilization system for unit-dose vial production. This system addresses the three existing lyophilizer limitations presented above. The translatability between the research system and the industrial system is addressed by using a modular geometry which is maintained between both a research and industrial scale system, ensuring that processes developed on the research system scale directly to the industrial system. The vial non- uniformity is addressed by using a smaller internal geometry and continuously moving trays ensuring that each vial is exposed to similar conditions throughout the lyophilization process. The continuous nature of the system addresses the existing unit dose batch process integration limitations, enabling more effective interfacing with the continuous nature of modern pharmaceutical production equipment. SUMMARY

[0010] In one aspect, a lyophilization module is provided. According to some embodiments, the lyophilization module comprises: a module housing including a base configured to be disposed on a supporting surface; a passage extending from a first side of the module housing to a second side of the module housing, wherein the passage includes a first opening and a second opening, wherein at least one selected from the first opening and the second opening are configured to form a seal with one or more adjacent lyophilization modules such that the passage of the module housing is aligned with a passage of the one or more adjacent lyophilization modules; and one or more stators supported in the base of the module housing, wherein the one or more stators are configured to magnetically levitate and control movement of one or more magnetic movers through the passage.

[0011] In another aspect, a lyophilization system is provided. According to some embodiments, the lyophilization system comprises: a plurality of lyophilization modules configured to be sequentially connected on a supporting surface, wherein each lyophilization module of the plurality of lyophilization modules includes: a module housing including a base configured to be disposed on the supporting surface; a passage extending from a first side of the module housing to a second side of the module housing, wherein the passage includes a first opening and a second opening, wherein at least one selected from the first 13178167 #14412969v1MIT 26102 - 4 - opening and the second opening are configured to form a seal with one or more adjacent lyophilization modules of the plurality of lyophilization modules such that the passage of the module housing is aligned with a passage of the one or more adjacent lyophilization modules; and one or more stators supported in the base of the module housing, wherein the one or more stators are configured to magnetically levitate and control movement of one or more magnetic movers through the passage.

[0012] In still another aspect, a method of lyophilizing material is provided. According to some embodiments, the method comprises: controlling movement of a magnetic mover through a passage extending through a plurality of lyophilization modules that are sequentially connected with a plurality of stators, wherein each lyophilization module of the plurality of lyophilization modules includes: a module housing sealed and connected to one or more adjacent lyophilization modules of the plurality of lyophilization modules, and one or more stators of the plurality of stators supported in a base of the module housing. It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying figures.

[0013] In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, then the document having the later effective date shall control. BRIEF DESCRIPTION OF DRAWINGS

[0014] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. It should be understood that the various systems, components, features, and methods described relative to these embodiments may be used either individually and / or in any desired combination as the disclosure is not limited to only the specific embodiments described herein. 13178167 #14412969v1MIT 26102 - 5 -

[0015] For purposes of clarity, not every component may be labeled in every drawing. In the drawings:

[0016] FIG.1A provides a perspective-view schematic illustration of a non-limiting stator, according to some embodiments;

[0017] FIG.1B provides a perspective-view schematic illustration of a non-limiting mover, according to some embodiments;

[0018] FIG.2. provides a schematic, top-view illustration of a non-limiting lyophilization system, according to some embodiments;

[0019] FIG.3 provides a schematic, top-view illustration of a non-limiting lyophilization system where drift has resulted from minor misalignments of modules, according to some embodiments;.

[0020] FIGS.4A-4B. Depict a schematic figure of a module include a machine body, a stator, and a base according to one embodiment.

[0021] FIGS.5A-5C show various schematic perspectives of a non-limiting first lyophilization module type, according to some embodiments;

[0022] FIGS.6A-6C show various schematic perspectives of a non-limiting second lyophilization module type, according to some embodiments;

[0023] FIGS.7A-7C show various schematic perspectives of a non-limiting third lyophilization module type, according to some embodiments;

[0024] FIGS.8A-8C show various schematic perspectives of a non-limiting fourth lyophilization module type, according to some embodiments;

[0025] FIG.9 shows a photograph of a pore defect in a non-limiting as-cast lyophilization module, according to some embodiments;

[0026] FIG.10 provides a photograph of a non-limiting, as-cast module and a non- limiting as-machined module for comparison, according to some embodiments; .

[0027] FIGS.11A-11B provide non-limiting, schematic illustrations of seals used to close a non-limiting lyophilization module against vacuum leakage, according to some embodiments;

[0028] FIG.12 provides a non-limiting schematic cross-section of the seal between a stator and the cavity, according to some embodiments; 13178167 #14412969v1MIT 26102 - 6 -

[0029] FIG.13 provides a non-limiting schematic illustration of tolerance of a stator cavity, according to a specific, non-limiting set of embodiments provided solely for the sake of illustration;

[0030] FIGS 14A provide a non-limiting schematic illustration of an exemplary stator for sealing onto the module, illustrating a non-limiting size of various stator features, according to some embodiments;

[0031] FIG.14B illustrates a non-limiting cross-section of a lyophilization module, showing the machined groove of the lyophilization module configured for sealing the stator of FIG.14A, according to some embodiments; FIGS.15A-15B show photographs of a non- limiting sandblasted lyophilization module surface, according to some embodiments

[0032] FIG.16 shows a non-limiting, schematic representation of a sealant injection fill path, according to some embodiments

[0033] FIGS.17A-17C provide illustrations and photographs of non-limiting fittings that may be used for sealant injection, according to some embodiments;

[0034] FIGS.18A-18B provide photographs of a non-limiting capping system for a lyophilization system, according to some embodiments.

[0035] FIG.19 provides a non-limiting schematic illustration of a gap resulting from a non-stiff support surface;

[0036] FIG.20 provides a non-limiting embodiment of a free body diagram showing a support surface with two supports experiencing uniform loading on its surface, according to some embodiments;

[0037] FIG.21 provides a non-limiting schematic plot showing the normalized slope change as a function of the normalized distance along the beam length, according to some embodiments;

[0038] FIG.22 shows a non-limiting schematic cross-section of the connection between the base plates and the rail slider system, according to some embodiments;.

[0039] FIG.23 provides a photograph of an assembled benchtop-scale lyophilization system comprising 28 lyophilization modules, according to some embodiments;

[0040] FIG.24 illustrates another photograph of a non-limiting lyophilization system, according to some embodiments, including a cooling module, a load lock and sensing module, a loading / unloading area, and a drying and capping module, according to some embodiments; 13178167 #14412969v1MIT 26102 - 7 -

[0041] FIG.25 presents a chromatogram produced by size exclusion chromatography of lyophilized myoglobin, according to some embodiments;

[0042] FIG.26 presents a chromatogram produced by size exclusion chromatography of lyophilized LDH according to some embodiments; and

[0043] FIG.27 illustrates the measured enzymatic stability of catalase both before and after freezing and full lyophilization using the lyophilization system of FIG.23, according to some embodiments. DETAILED DESCRIPTION

[0044] As discussed above, conventional pharmaceutical lyophilization systems suffer from major limitations, including the difficulty in translating processes between research scale systems and industrial scale systems as well as the non-uniformity of vial conditions in big batch processes causing efficiency losses due to lyophilizing vials non- uniformly in parallel. Further, large batch processes often require different freezing and drying conditions than small batch processes, e.g., because differences in system geometry result in inhomogeneous freezing and drying conditions that can limit standardization. This makes adaptation of benchtop processes to large-scale processes challenging. Furthermore large batch processes can be prone to contamination due to their size—and the associated risk of product loss is increased by the batch size.

[0045] The present disclosure is directed, in various aspects, towards systems and methods for rapid, serialized processes for industrial-scale lyophilization. In particular, some aspects of the disclosure relate to a modular system for lyophilization that can achieve industrial-scale throughput through the serialized processing of batches comparable to batches used at the research scale. The modular nature of the system can facilitate easy scale- up. The use of continuous lyophilization processes involving smaller numbers of vials reduces the non-uniformity of vial conditions because uniform processing in the serialized systems provided herein is easier than uniform processing of big batches, and can make processing more hygienic and less prone to large-scale product contamination. Also, the use of smaller-scale but continuously operating freezing and freeze-drying modules means that research-scale procedures do not need to be adapted for use with larger batches, simplifying and accelerating product development. Furthermore, the modularity of at least some of the systems and methods provided herein can, in some embodiments, facilitate easy 13178167 #14412969v1MIT 26102 - 8 - customization of a lyophilization system. These and other advantages of the provided systems and methods are detailed below.

[0046] In various aspects, the disclosure relates to a lyophilization module suitable for use in a modular lyophilization system. The module may be configured to connect to one or more additional modules to form the lyophilization system. Thus, a lyophilization system provided herein may comprise a plurality of lyophilization modules configured to be sequentially connected (e.g., on a supporting surface the lyophilization system is disposed on). According to some embodiments, the module comprises a module housing. The module housing may include an interior chamber disposed within the module housing. For example, a lyophilization module, in at least some embodiments, contains a passage extending from a first side of the module housing to the second side of the module housing. The passage may include a first opening and a second opening. In some embodiments, the passage extends through the interior chamber of the module, e.g., from a first opening to the second opening. According to some embodiments, the first opening is on an opposite side of the lyophilization module from the second opening of the lyophilization module, e.g., so that the passage extends linearly from the first opening to the second opening. However, other embodiments, e.g., where the first opening and the second opening are disposed on adjacent walls of a lyophilization module are also possible, as the disclosed lyophilization modules are not limited to any particular arrangement of openings and passageways. As elaborated on further below, to help facilitate the movement of materials through the lyophilization modules, in some embodiments, each lyophilization module may include a base formed in the associated module housing including one or more stators. The one or more stators may be configured to be appropriately aligned with one or more stators located in the bases of adjacent lyophilization modules such that the one or more stators may be configured to magnetically levitate and control movement of one or more magnetic movers through the passage of each module housing, and thus, through the combined passage of the overall lyophilization system. The one or more magnetic movers may be configured to hold materials for lyophilization thereon. For example, the one or more magnetic movers may include a vial holding product support rack attached thereto in some embodiments.

[0047] In some embodiments, it may be desirable to isolate the interior of the assembled lyophilization system from an exterior environment. Accordingly, at least one, and in some instances both, openings selected from the group of the first opening and the second 13178167 #14412969v1MIT 26102 - 9 - opening of a module housing of a lyophilization module is configured to form a seal with one or more adjacent lyophilization modules. Thus, in at least some embodiments, the lyophilization module can be a first lyophilization module of a modular lyophilization system, and the modular lyophilization system may comprise a second lyophilization module connected to the first lyophilization module. In at least some embodiments, the passage of the first lyophilization module may extend to and be connected with a passage of the second lyophilization to form an extended passage through both lyophilization modules. Thus, the sequentially connected lyophilization modules may be connected to form an overall system with any desired length. In some embodiments, a lyophilization module comprises a load lock (e.g., a gate) at one or both of the first opening and the second opening. Such a load lock may, in some embodiments, be used to separate the interior chamber of a first lyophilization module from the interior chamber of a second lyophilization module, thereby allowing different temperature and pressure conditions to be introduced at different portions of a lyophilization system. Thus, the extended passageway formed by connected modules may be subdivided, depending on the embodiment, to create an extended system where different stages of lyophilization may be simultaneously performed within separate isolated portions of the system.

[0048] A lyophilization system may comprise a plurality of sequentially connected lyophilization modules configured to perform separate portions of a lyophilization process. For example, a lyophilization module may be a load lock module (e.g., which may include a load lock at both openings, thereby allowing it to act as an airlock), a preconditioning module, a nucleation module, a freezing module, a freeze-drying module (e.g., configured to maintain vacuum conditions on a freeze-dried sample). An advantage of the modular lyophilization systems provided herein is that, depending on the desired process, lyophilization modules with any or all of these functions can be connected (e.g., serially) so that process steps such as preconditioning, freezing, and freeze-drying can be performed by connected modules of the lyophilization system in sequence. As a non-limiting illustration, a lyophilization system may be configured to transport a sample between different lyophilization modules configured to perform the different portions of a lyophilization process. For example, the sequentially connected lyophilization modules in a lyophilization system may include lyophilization modules configured to transport a magnetic mover from load-lock chamber to a preconditioning chamber to a freezing chamber to a freeze-drying 13178167 #14412969v1MIT 26102 - 10 - chamber, and out of a downstream load lock in sequence using the electrodynamic suspension system of the lyophilization module. Another example is that the lyophilization system can be extended to arbitrary length to permit serial processing of lyophilization samples using serially connected modules with the functions described above. And, of course, these are mere examples; the lyophilization module design provided herein is highly customizable and the person of ordinary skill could readily prepare a lyophilization module configured to perform another function, depending on the unique needs of a given lyophilization scheme.

[0049] In some embodiments, a module housing of a lyophilization module includes a base configured to be disposed on a supporting surface such that the lyophilization module may be aligned with and connected to one or more other sequentially arranged and connected lyophilization modules. For example, in some embodiment, the module housing module includes a base configured to be disposed on a rail or a plurality of rails. A suitable supporting surface may be configured to support a plurality of modules. In some embodiments, the supporting surface is configured to help construct the lyophilization system and / or to help align lyophilization modules of the lyophilization system. For example, in some embodiments, the supporting surface comprises a rail or plurality of rails configured to help align adjacent modules (which may, e.g., be configured to slide or roll along the rail before being locked into a desired position for the modules). For example, the rail(s) may movably support the module housing of one or more lyophilization modules, according to some embodiments. Of course, it should be understood that any appropriate type of construction capable of appropriately aligning and supporting the lyophilization modules on a supporting surface may be used as the disclosure is not so limited (e.g., wheels, feet, appropriately sized and shaped bottom surfaces, etc.).

[0050] A lyophilization system may be configured to transport lyophilization samples through the lyophilization system (e.g., through a passageway of one or more lyophilization modules, and / or between adjacent lyophilization modules). Although any of a variety of methods may generally be used to transport the lyophilization sample, advantages have been recognized for the use of non-mechanical methods of moving a lyophilization sample. For example, by avoiding mechanical components, the risk of sample contamination or mechanical breakdown is significantly reduced. Thus, according to some embodiments, and as noted above, advantages have been recognized for the use of an electrodynamic suspension 13178167 #14412969v1MIT 26102 - 11 - system (e.g., a magnetic levitation system) configured to move a vial holding product support rack or other appropriate container support through a lyophilization system. The electromagnetic suspension system may be an electromagnetic levitation system configured to magnetically levitate and control movement of one or more magnetic movers through and between the passages of the sequentially arranged lyophilization modules. Advantageously, electromagnetic levitation may remove the risk of particulate generation (a common problem for mechanical movers) which could contaminate products. Electromagnetic levitation may help to ensure particulate generation remains within acceptable levels. One of the major benefits of a unit dose lyophilizer over a bulk product lyophilizer is the sanitation that is achieved, in some embodiments, by removing the direct contact between the product and the lyophilizer hardware, but contamination by airborne particulates can compromise that benefit, making electromagnetic suspension particularly useful.

[0051] In some embodiments, a lyophilization system provided herein comprises a plurality of stators configured to move a magnetic mover (e.g., which may be coupled to a vial holding product support rack, e.g., a lyophilization tray). In some embodiments, the plurality of stators is configured to move the magnetic mover through a passageway of the lyophilization system. The passageway may be at least partially defined by the interior chamber of the lyophilization module, depending on the embodiment. Thus, in some embodiments the plurality of stators is configured to guide a vial holding product support rack into or out of a lyophilization module.

[0052] Another advantage of magnetic levitation systems is that they are available in modular units that may be advantageous for use in concert with a modular lyophilization system. In some embodiments, a lyophilization system provided herein comprises a lyophilization module configured to admit integration of one or more stators. For example, a lyophilization module may comprise a base that is configured to support the one or more stators (e.g., by receiving the one or more stators into one or more cavities or other structures configured to receive and support the one or more stators in a desired location and orientation within the module housing). The one or more stators may be removably or permanently integrated into the lyophilization module, depending on the embodiment. In some embodiments the one or more stators integrated into the lyophilization module are configured such that the upper surface(s) (oriented into the passage) of the one or more stators form a 13178167 #14412969v1MIT 26102 - 12 - portion of the passage of a lyophilization module that is configured to be aligned with one or more stators disposed in adjacent connected lyophilization modules.

[0053] According to some embodiments, the one or more stators in the module are configured to magnetically levitate and control movement of one or more magnetic movers through the passageway. For example, in some embodiments, the one or more stators are configured to move the magnetic mover through the passageway of the lyophilization module by interaction with one or more magnets (e.g., permanent magnets, electromagnets, superconducting magnets) of the magnetic mover. A lyophilization system comprising a plurality of lyophilization modules is, in some embodiments, configured to transport a magnetic mover between modules of the lyophilization system. For example, in some embodiments, upper surfaces (oriented into the passage) of the separate stators positioned in the bases of separate lyophilization modules may be aligned when the modules are assembled, so that the stators form a substantially continuous supporting surface extending through the passage of the overall lyophilization system. According to some embodiments, the lyophilization system can be controlled to move a magnetic mover through a passage extending through a plurality of lyophilization modules that are sequentially connected and wherein at least some of the modules comprise one or more stators configured to move the magnetic mover. For example, the substantially continuous surface defined by the stators may provide a track configured to control the movement of the magnetic mover(s).

[0054] A magnetic mover may be used to move one or more lyophilization samples or other materials through the lyophilization system. For example, the magnetic mover may be configured to hold, couple to, and / or otherwise support a vial holding product support rack such that as the magnetic mover moves through a lyophilization system it moves the vial holding product support rack (e.g., a tray) through the lyophilization system. According to some embodiments, the magnetic mover actually forms a portion of the vial holding product support rack (e.g., such that the vial holding product support rack is integrally formed into the magnetic support rack). In some embodiments, a magnetic mover is attached to a fixture for holding one or more vials capable of holding liquid to be lyophilized. Of course, it should be understood that any appropriate type of arrangement capable of supporting and transporting a material for lyophilization through a lyophilization system as disclosed herein may be used with a magnetic mover (e.g., trays, receptacles, connections, etc.) as the disclosure is not limited in this fashion. 13178167 #14412969v1MIT 26102 - 13 -

[0055] Any of a variety of mag-lev systems may be used to provide non-contact motion. For example, according to some embodiments, the motion system developed by Planar Motors Inc. may be used. According to some embodiments, the lyophilization system is configured to move movers at relatively high speeds. The lyophilization system may be configured to lift movers with any of a variety of suitable carrying capacities, depending on the size and scale for the system. In some embodiments, the magnetic movers, the lyophilization modules, and / or the stator(s) are sterilizable (e.g., they may be configured for steam sterilization) to a level of sterility suitable for pharmaceutical manufacturing requirements. The lyophilization system (and the individual lyophilization modules thereof) may provide any appropriate number of degrees of freedom motion control (e.g., six degrees of freedom) for movers disposed therein, allowing a wide range of motion profiles. Control of high numbers of degrees of freedom may be particularly useful in sensor development, where the required motion profiles are not known a priori. Furthermore, as discussed above, in some embodiments, the electromagnetic levitation system is modular, simplifying its incorporation into the modular lyophilization systems provided herein.

[0056] Turning to the figures, specific non-limiting embodiments are described in further detail. It should be understood that the various systems, components, features, and methods described relative to these embodiments may be used either individually and / or in any desired combination as the disclosure is not limited to only the specific embodiments described herein.

[0057] The electromagnetic levitation system comprises one or more stators and one or more movers, according to some embodiments. FIG.1A provides a perspective-view schematic illustration of non-limiting stator 101, according to some embodiments. According to some embodiments, stator 101 comprises a plurality electromagnets (internal to the stator, not shown). The electromagnets, when energized, may be configured to move a mover across the stator, e.g., by magnetic levitation. For example, stator 101 is a rectangular stator having sides 111a, 111b, 111c, and 111d. The stator may be configured to levitate a mover between opposite sides of the stator (e.g., from side 111a to side 111c or from side 111b to side 111d). Such an arrangement may allow a plurality of adjacent stators 101 to transport a mover (via magnetic levitation) along a linear track comprising the plurality of stators. In some embodiments, a plurality of stators may be configured to transport a mover along a non- linear track. For example, a stator 111 may be configured to transport a mover between 13178167 #14412969v1MIT 26102 - 14 - adjacent sides of the stator (e.g., from side 111a to side 111b or to side 111d), e.g., in order to act as a corner connecting a first linear track to a second linear track perpendicular to the first linear track.

[0058] FIG.1B provides a perspective-view schematic illustration of non-limiting mover 103, according to some embodiments. Mover 103 comprises one or more magnets (e.g., permanent magnets) configured to interact with the electromagnets of the stator. For example, in some embodiments, the mover comprises magnets that permit the stator to levitate via magnetic repulsion of the mover against the electromagnets of a stator or stators disposed beneath it. In some embodiments, the mover has an orientation. For example, the mover may have a bottom surface configured to face the stators during use, and a top surface configured to oppose the stators during use. Mover 103, for example, comprises top surface 121 and a bottom surface (not shown) on the opposite side of mover 103 from top surface 121. Top surface 121 may be configured to hold a lyophilization tray, according to some embodiments. For example, top surface 121 may be sized appropriately to hold a lyophilization tray, and may comprise one or more features configured to retain the lyophilization tray. For example, mover 103 comprises bumper 123 and hole 125, which may be used to align the lyophilization tray with a desired position on top surface 121 of mover 103, and which may be used to help retain the lyophilization tray in a fixed position with respect to mover 103 during the mover’s motion.

[0059] To establish the electromagnetic levitation system, according to at least some embodiments, the stators can be arranged in a 2D layout (e.g., within the bases of a plurality of lyophilization modules, according to at least some embodiments), and the movers can be seamlessly passed between adjacent stators, in some embodiments.

[0060] The lyophilization modules provided herein may be configured to incorporate one or more stators into the base of the module housing of a lyophilization module. According to some embodiments, the stators can be added and removed from the electromagnetic levitation system, meaning that the lyophilization modules and stators can be easily integrated and moved within the larger system. This flexibility may allow for simple scaling of the machine size (and throughput), as well as simplified modification of a lyophilization system to change its throughput as production demands change.

[0061] Stators and movers may be chosen to have any of a variety of appropriate sizes, depending on the embodiments. According to some embodiments, it is advantageous 13178167 #14412969v1MIT 26102 - 15 - for stators of a modular lyophilization system to be uniformly sized, e.g., because uniformly sized stators may improve the modularity of the system. Likewise, in at least some embodiments, it is advantageous for movers of a modular lyophilization system to be uniformly sized.

[0062] A mover provided herein may have any of a variety of suitable thicknesses (e.g., average or maximum differences between the top surface and the bottom surface of the mover, e.g., as indicated by thickness T in FIG.1B). In some embodiments, a mover has a thickness of greater than or equal to 10 mm, greater than or equal to 20 mm, greater than or equal to 30 mm, greater than or equal to 40 mm, greater than or equal to 50 mm, greater than or equal to 60 mm, greater than or equal to 70 mm, greater than or equal to 80 mm, greater than or equal to 90 mm, greater than or equal to 100 mm, greater than or equal to 110 mm, greater than or equal to 120 mm, greater than or equal to 130 mm, greater than or equal to 140 mm, greater than or equal to 150 mm, greater than or equal to 160 mm, greater than or equal to 170 mm, greater than or equal to 180 mm, or greater than or equal to 190 mm. In some embodiments, a mover has a thickness of less than or equal to 200 mm, less than or equal to 190 mm, less than or equal to 180 mm, less than or equal to 170 mm, less than or equal to 160 mm, less than or equal to 150 mm, less than or equal to 140 mm, less than or equal to 130 mm, less than or equal to 120 mm, less than or equal to 110 mm, less than or equal to 100 mm, less than or equal to 90 mm, less than or equal to 80 mm, less than or equal to 70 mm, less than or equal to 60 mm, less than or equal to 50 mm, less than or equal to 40 mm, less than or equal to 30 mm, or less than or equal to 20 mm. Combinations of these ranges are also possible (e.g., greater than or equal to 10 mm and less than or equal to 200 mm, greater than or equal to 10 mm and less than or equal to 70 mm, or greater than or equal to 10 mm and less than or equal to 20 mm). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0063] A mover may have a length dimension perpendicular to the thickness dimension (e.g., length L in FIG.1B). A mover provided herein may have any of a variety of suitable lengths. In some embodiments, a mover has a length of greater than or equal to 50 mm, greater than or equal to 100 mm, greater than or equal to 150 mm, greater than or equal to 200 mm, greater than or equal to 250 mm, greater than or equal to 300 mm, greater than or equal to 350 mm, greater than or equal to 400 mm, greater than or equal to 450 mm, greater than or equal to 500 mm, greater than or equal to 550 mm, greater than or equal to 600 mm, 13178167 #14412969v1MIT 26102 - 16 - greater than or equal to 650 mm, greater than or equal to 700 mm, greater than or equal to 750 mm, greater than or equal to 800 mm, greater than or equal to 850 mm, greater than or equal to 900 mm, or greater than or equal to 950 mm. In some embodiments, a mover has a length of less than or equal to 1000 mm, less than or equal to 950 mm, less than or equal to 900 mm, less than or equal to 850 mm, less than or equal to 800 mm, less than or equal to 750 mm, less than or equal to 700 mm, less than or equal to 650 mm, less than or equal to 600 mm, less than or equal to 550 mm, less than or equal to 500 mm, less than or equal to 450 mm, less than or equal to 400 mm, less than or equal to 350 mm, less than or equal to 300 mm, less than or equal to 250 mm, less than or equal to 200 mm, less than or equal to 150 mm, or less than or equal to 100 mm. Combinations of these ranges are also possible (e.g., greater than or equal to 50 mm and less than or equal to 1000 mm, or greater than or equal to 100 mm and less than or equal to 500 mm). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0064] A mover may have a width dimension perpendicular to the thickness dimension and the length dimension (e.g., width W in FIG.1B). A mover provided herein may have any of a variety of suitable widths. In some embodiments, a mover has a width of greater than or equal to 50 mm, greater than or equal to 100 mm, greater than or equal to 150 mm, greater than or equal to 200 mm, greater than or equal to 250 mm, greater than or equal to 300 mm, greater than or equal to 350 mm, greater than or equal to 400 mm, greater than or equal to 450 mm, greater than or equal to 500 mm, greater than or equal to 550 mm, greater than or equal to 600 mm, greater than or equal to 650 mm, greater than or equal to 700 mm, greater than or equal to 750 mm, greater than or equal to 800 mm, greater than or equal to 850 mm, greater than or equal to 900 mm, or greater than or equal to 950 mm. In some embodiments, a mover has a width of less than or equal to 1000 mm, less than or equal to 950 mm, less than or equal to 900 mm, less than or equal to 850 mm, less than or equal to 800 mm, less than or equal to 750 mm, less than or equal to 700 mm, less than or equal to 650 mm, less than or equal to 600 mm, less than or equal to 550 mm, less than or equal to 500 mm, less than or equal to 450 mm, less than or equal to 400 mm, less than or equal to 350 mm, less than or equal to 300 mm, less than or equal to 250 mm, less than or equal to 200 mm, less than or equal to 150 mm, or less than or equal to 100 mm. Combinations of these ranges are also possible (e.g., greater than or equal to 50 mm and less than or equal to 1000 mm, or greater than or equal to 100 mm and less than or equal to 500 mm). Other ranges, 13178167 #14412969v1MIT 26102 - 17 - both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0065] In a set of non-limiting embodiments, a stator may have the shape of a 240mm x 240mm x 70mm box. In another set of non-limiting embodiments, a mover may have a size ranging from 120mm x 120mm x 10mm to 450mm x 450mm x 16mm.

[0066] In some embodiments, the width of the mover is less than or equal to the length of the mover. In some embodiments, the thickness of the mover is less than or equal to the width of the mover and the length of the mover. Stators (e.g., stator 101) may be larger than the mover, depending on the embodiment. For example, length L and width W of mover 103 shown in FIG.1B may be less than or equal to the length of side 111a, side 111b, side 111c, and / or side 111d of stator 101 as shown in FIG.1A.

[0067] According to some embodiments, a mover serves as a tray that carries a batch of vials through the system. Without wishing to be bound by any particular theory, according to some embodiments, smaller batch sizes may be associated with more continuous lyophilization systems. Thus, according to some embodiments, the use of smaller movers is advantageous. However, larger movers may, in some embodiments, more easily traverse gaps between stators, and may be advantageous for at least this reason. Movers may be sized to cross any of a variety of suitable gap sizes. In some embodiments, a mover is sized to cross a gap between stators of greater than or equal to 0 mm, greater than or equal to 1 mm, greater than or equal to 2 mm, greater than or equal to 3 mm, greater than or equal to 4 mm, greater than or equal to 5 mm, greater than or equal to 6 mm, greater than or equal to 7 mm, greater than or equal to 8 mm, or greater than or equal to 9 mm. In some embodiments, a mover is sized to cross a gap between stators of less than or equal to 10 mm, less than or equal to 9 mm, less than or equal to 8 mm, less than or equal to 7 mm, less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm, less than or equal to 2 mm, or less than or equal to 1 mm. Combinations of these ranges are also possible (e.g., greater than or equal to 0 mm and less than or equal to 10 mm, or greater than or equal to 5 mm and less than or equal to 10 mm). For example, in some embodiments, movers are sized to traverse gaps of up to 10mm. Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0068] Movers may be operated serially or in parallel, depending on the embodiment. For example, in some embodiments, two movers can fit on a single stator side by side within 13178167 #14412969v1MIT 26102 - 18 - a lyophilization module provided herein. Accordingly, in some embodiments, the system can have multiple (e.g., two) rows of trays moving through the lyophilization system in parallel.

[0069] Depending on the embodiment, movers may hold any of a variety of appropriate numbers of lyophilization samples. In some embodiments, a mover is configured to hold greater than or equal to 1 sample, greater than or equal to 10 samples, greater than or equal to 20 samples, greater than or equal to 30 samples, greater than or equal to 40 samples, greater than or equal to 50 samples, greater than or equal to 60 samples, greater than or equal to 70 samples, greater than or equal to 80 samples, greater than or equal to 90 samples, greater than or equal to 100 samples, greater than or equal to 110 samples, greater than or equal to 120 samples, greater than or equal to 130 samples, greater than or equal to 140 samples, greater than or equal to 150 samples, greater than or equal to 160 samples, greater than or equal to 170 samples, greater than or equal to 180 samples, or greater than or equal to 190 samples. In some embodiments, a mover is configured to hold less than or equal to 200 samples, less than or equal to 190 samples, less than or equal to 180 samples, less than or equal to 170 samples, less than or equal to 160 samples, less than or equal to 150 samples, less than or equal to 140 samples, less than or equal to 130 samples, less than or equal to 120 samples, less than or equal to 110 samples, less than or equal to 100 samples, less than or equal to 90 samples, less than or equal to 80 samples, less than or equal to 70 samples, less than or equal to 60 samples, less than or equal to 50 samples, less than or equal to 40 samples, less than or equal to 30 samples, less than or equal to 20 samples, or less than or equal to 10 samples. Combinations of these ranges are also possible (e.g., greater than or equal to 1 sample and less than or equal to 200 samples, greater than or equal to 10 samples and less than or equal to 100 samples, or greater than or equal to 20 samples and less than or equal to 80 samples). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited. The samples may be held in one or a plurality of trays disposed on the mover. For example, the mover may be configured to hold 1, 2, 3, 4, 5, or more lyophilization trays, and each of those trays may be configured to hold some or all of the samples held by the mover. For example, in some embodiments, a mover can hold 5520mm vials in 11 rows of 5. In some embodiments, the vials are be spaced apart on the trays, e.g., to create room for convective cooling and / or vial state sensing. For example, in some embodiments, an arrangement of 3 rows of 4 vials with a 20mm diameter may be used, giving a total of 12 vials per tray. Table 1 provides a non-limit example of 13178167 #14412969v1MIT 26102 - 19 - lyophilization system sizing that may be appropriate for such an arrangement. Table 1.

[0070] According to some embodiments, the stators and movers are used in a modular lyophilization system. The modular lyophilization system may comprise a plurality of modules. Each module may be equipped with one or more stators, e.g., disposed in a base of the module. The stators may be configured to move one or more movers through the module. The following sections elaborate on specific details and provide specific examples to illustrate the advantages and flexibility of the lyophilization modules and systems provided herein. The disclosure provides, in some embodiments, a system for continuous unit dose lyophilization of vials containing liquid to be lyophilized in the vial comprising 13178167 #14412969v1MIT 26102 - 20 - reconfigurable modules which are attached together to create a tunnel through which the vials on trays are moved into process sections separated by load-locks. The shared core geometry of the lyophilization modules may allow the modules to link together and form a vacuum sealed system with an integrated tray motion system. Each module can then be customized to fit the needs of a given process section, depending on the embodiment. The number of modules needed for each process section may be determined by the intended process time, e.g., to facilitate continuous motion of vials through the system. The modules may be assembled on a rail system. The rail system may be configured to control the relative position of the lyophilization modules with high accuracy. For example, in some embodiments, the rail(s) are built on a stiff structure that limits the variation in orientation of lyophilization modules, thereby limiting misalignment (e.g., that might otherwise result from structural deformation). The system can be built at a production scale (e.g., using comparatively many lyophilization modules) or at a research scale (e.g., using a comparatively limited number of modules). In some embodiments, a lyophilization system comprises at least four modules (e.g., a load lock module, a preconditioning module, a freezing module, and a freeze-drying module) And an advantage of the modular lyophilization system is that scaling a process developed at the research scale does not require a change in internal geometry of the modules, simplifying scale-up.

[0071] The lyophilization systems provided herein may provide a number of advantages. In some embodiments, a lyophilization system provided herein may be used for continuous flow-through of vials containing liquid to be lyophilized from vials entering the system to vials containing dry powder leaving the system. According to some embodiments, the lyophilization systems are, advantageously, modular, and hence reconfigurable / expandable to accommodate production needs. Modules for filling vials in trays may be moved through the system, according to some embodiments. And in some embodiments, the lyophilization system provided herein can, advantageously, include load locks (e.g., gates) for separating modules to allow modules to be operated simultaneously, even under distinct thermal and pressure conditions. Still another example of an advantage of the lyophilization modules provided herein is that, according to some embodiments, they may be used to monitor the state of product in a vial to assess amount of liquid v. dry product and hence lyophilization progress. And a final advantage is that in some embodiments, small- scale lyophilization systems for benchtop analysis mimics the process full scale continuous 13178167 #14412969v1MIT 26102 - 21 - flow through system, to allow manual or automated research-scale development of drug product and processes.

[0072] Without wishing to be bound by any particular theory, in a manufacturing line, the system production rate is related to the number of units within the system and the time spent in the system, as shown by Little’s Law in Equation 1: ^= ^^ (1)where L is the total number of units in the system, ^ is the average rate of units entering the system, and W is the amount of time spent in the system. The time spent in the system corresponds, in some embodiments, to the process time plus the time required to move between process stations. In a lyophilizer, the time spent in the system is relatively fixed, according to some embodiments, because, in at least some embodiments, the total time is dominated by the process time required to freeze-dry samples. Thus, without wishing to be bound by any particular theory, to a first approximation W can be treated as a constant for the relationship between L and ^.

[0073] In a fully continuous system, according to some embodiments, the rate at which units enter the system remains constant and is equivalent to the average speed of individual elements moving through the system. Under conditions where the sample exit rate equals the sample entry rate (to prevent system emptying or accumulation), the overall machine production rate is given by ^, according to some embodiments. Given a desired production rate and total process time, the number of units needed in the system at any given time can be calculated from Little’s Law, as shown above in Equation 1.

[0074] According to some embodiments, the lyophilization system provided herein separates each process step in the lyophilization process spatially. The physically separated process steps may allow all operations to occur simultaneously. To ensure product is consistently moving through the system, the process sections may be sized relative to an amount of time appropriate to complete each process. According to some embodiments, process section sizing may be determined from Little’s Law, where the total process time is separated into distinct process sections which all share the same rate of units entering and exiting their subsystems. Table 2 shows a non-limiting example illustrating how the relative 13178167 #14412969v1MIT 26102 - 22 - process time lengths are translated into machine section lengths in a particular, non-limiting set of embodiments. Table 2. The relative amount of time required for each process translates directly into a relative process section length in the lyophilizer through using the relationship given by Little’s Law, according to some embodiments.

[0075] Using calculated machine section lengths, an appropriate number and variety of lyophilization modules can be assembled to make an appropriately designed lyophilization system. In addition to the process sections, the system includes load-locks, according to some embodiments, which may separate lyophilization modules for each process from each other. According to some embodiments, one end of a lyophilization system is configured to interface with equipment that adds vials to the lyophilization system. According to some embodiments, one end of a lyophilization system is configured to interface with equipment that removes vials from the system. Sections for interfacing with equipment that adds and / or removes vials may add length to the overall machine sizing, depending on the embodiment. According to some embodiments, the modules are arranged to produce a rectangular passage. 13178167 #14412969v1MIT 26102 - 23 - A gap may be left in the center of the rectangular layout to leave room for process chamber equipment, such as piping and / or chamber bodies.

[0076] FIG.2 provides a schematic, top-view illustration of a non-limiting lyophilization system 201 where individual lyophilization modules 203 (coded as 203a, 203b, 203c, 203d, 203e, and 203f and patterned based on their role within system 201) are represented as individual squares. A series of arrows 205 and illustrations of movers 207 illustrates the transportation of a tray of vials through the system, according to some embodiments. The transportation of the mover is described in detail below. Lyophilization system 201 of FIG.2 may be configured to achieve a throughput of about 100 vials / hour.

[0077] Lyophilization system 201 of FIG.2 includes 6 different types of process stations, each of which may include one or more appropriately chosen lyophilization modules, distinguished visually by patterns in the modules. The first station, loading (modules 203a), is where the schematized system interfaces with other elements of a production line. This station is connected to both the entrance and exit of the machine, according to some embodiments. The vials are carried by movers 207, which do not leave the machine, according to some embodiments. For example, loading modules 203a are configured to loop the beginning of a lyophilization pathway 217a to the end of a lyophilization pathway 217 so that within loading modules 203a, lyophilized vials are removed and fresh vials are added.

[0078] Vials may be added to movers 207, e.g., by adding equipment located in one of loading modules 203a. While the term “vials” is used throughout to refer to sample holders for lyophilization modules, it should, of course, be understood that one of ordinary skill in the art would be familiar with any of a variety of sample holders (e.g., flasks, centrifuge tubes, cylinders) that could be used and that the disclosure is not limited to the use of any particular type of sample holder.

[0079] Sample vials may be added to lyophilization system 201 at one or more of modules 203a, e.g., via the entrance of the machine, to start the lyophilization process at the beginning 217a of a lyophilization pathway. The vials may be lyophilized by passing them along the lyophilization pathway described below until they reach the end 217b of the lyophilization pathway, also located in modules 203a, where lyophilized vials are removed. Thus, the system is looped to return movers to the vial adding equipment to receive new vials once the lyophilized product is removed. Movers 207 then proceed to beginning 217a while 13178167 #14412969v1MIT 26102 - 24 - they are reloaded with fresh sample vials, and the process is continued. Connecting the entry and the exit of the system ensures that movers will follow a continuous looping motion to maintain operation through this loading and unloading of vials.

[0080] From beginning position 217a, mover 207 proceeds through a second type of station connecting the loading station to an adjacent station. The second type of station is the load lock (modules 203b), which may separate each process station, or which may separate at least one processing station from another. For example, modules 203b, represented in FIG.2 as white boxes, are load lock modules disposed between various stations of lyophilization system 201. Unlike most other station types in the represented system, load lock modules (modules 203b) are not positioned adjacent to one another, in most cases. Rather, they are distributed throughout the system, configured to act as airlocks between adjacent modules on either side, according to some embodiments. Load lock modules (modules 203b) may be useful for isolating the conditions created in each process station from their neighboring process stations.

[0081] The load lock module may be configured to be sealed off from adjacent modules, e.g., using one or more load locks (e.g., gates). The mover may enter load-lock module 203b through a first opening into the load module, after which a first load lock (e.g., a first gate) seals the first opening. Within the load lock module, the ambient conditions (e.g., the pressure, the temperature) of the mover may be changed. Then, a second load lock (e.g., a second gate) may be opened to reveal a second opening in the module through which the mover is passed by the stator. The change in ambient conditions may be configured to match ambient conditions within the load lock module prior to ambient conditions beyond the second load lock module, so that when the second load-lock is opened, the mover may seamlessly pass through the second opening and out of the load lock module.

[0082] It should, of course, be appreciated that while adjacent stations in lyophilization system 201 are separated by at most one load lock module 203b, this is not required of all lyophilization systems. The person of ordinary skill in the art could easily, for example, design a system comprising multiple adjacent load lock modules, e.g., so that multiple samples can be introduced to load lock modules and adjusted to new ambient conditions simultaneously. For example, in some embodiments, a first sample and a second sample are both passed from the loading station into load lock modules, the first sample passing into the first load lock module and the second sample passing through the first load 13178167 #14412969v1MIT 26102 - 25 - lock module and into the second load lock module. The pair of load lock modules may be sealed away from the first station in order to allow a change in ambient conditions; the first load lock module and the second load lock module may remain connected or may be separated by a load lock, as the disclosure is not limited to either possibility. Finally, the second sample may pass out of the second load lock module, and the first sample may pass out of the first load lock module, through the second load lock module, and into the station beyond.

[0083] After proceeding from loading modules 203a through the first load lock module 203b, the mover then proceeds to a third station, according to some embodiments. The third station (comprising modules 203c) is the conditioning station, according to some embodiments. In this station, the product may be subcooled to a designated temperature just below 0°C. This subcooling prepares the product for controlled nucleation, according to some embodiments. For example, the station may be configured to cool the sample to near- or below-freezing temperatures, in order to ensure that it is capable of nucleating solvent crystals without actually initiating uncontrolled nucleation. For example, a plurality of vials disposed on mover 207 may, in some embodiments, be cooled within modules 203c to a designated temperature just below 0°C to prepare the sample for nucleation, according to some embodiments. The length of the conditioning station may be determined based on the desired throughput and rate of cooling of the samples. For example, when the desired rate of throughput is high, the movers may be configured to move through the conditioning station more rapidly, and a longer conditioning station length (e.g., comprising more conditioning modules) may be more suitable. In contrast, where movers are configured to move more slowly, a smaller conditioning station length (e.g., comprising fewer conditioning modules) may be more suitable. An advantage of the modular system provided herein is that those of ordinary skill in the art may adjust the size of the conditioning station by the addition or removal of conditioning modules based on, e.g., the desired throughput, the composition of the lyophilization samples, without needing a major overhaul of the system design.

[0084] From the conditioning system (comprising modules 203c), mover 207 may proceed to a fourth station, according to some embodiments. The fourth station is the nucleation station (comprising module 203d), according to some embodiments. In this station, controlled nucleation may occur. For example, in some embodiments, nucleation of solvent crystals (e.g., nucleation of ice crystals in an aqueous sample) occurs in order to 13178167 #14412969v1MIT 26102 - 26 - initiate the freezing process. Any of a variety of suitable nucleation strategies can be implemented in the nucleation station, including but not limited to vacuum induced surface freezing or thermal quenching. Nucleation may be a relatively fast process, compared with conditioning, and may thus, in some embodiments, take place in a relatively shorter station (e.g., in a station comprising relatively fewer modules). In FIG.2, for example, the nucleation station comprises a single module 203d. However, it should, of course, be understood that larger nucleation stations may be used, e.g., to increase throughput.

[0085] As the mover passes from conditioning modules 203c to nucleation module 203d, it does not pass through a load lock module 203b. In some embodiments, including that represented in FIG.2, load locks are not needed between these modules, e.g., because nucleation and conditioning occur at the same pressure. It should further be understood that the nucleation station and the conditioning station could be separated by a load lock, depending on the embodiments, e.g., where it is advantageous for avoiding premature nucleation of a not-fully-conditioned sample.

[0086] From the nucleation station (comprising module 203d), mover 207 proceeds to a fifth station, in some embodiments. The fifth process station is the freezing station (comprising modules 203e), according to some embodiments. In the freezing station, the nucleated samples may be further cooled, e.g., to facilitate growth of nucleated solvent crystals formed in the nucleation system. The growth may be controlled, e.g., by controlling ambient temperature conditions, in order to facilitate homogeneous crystal growth. In the freezing station, the product may be cooled further down to a designated temperature. Any of a variety of designated freezing temperatures may be chosen. For example, in some embodiments the designated freezing temperature is greater than or equal to -70 °C, greater than or equal to -65 °C, greater than or equal to -60 °C, greater than or equal to -55 °C, greater than or equal to -50 °C, greater than or equal to -45 °C, greater than or equal to -40 °C, greater than or equal to -35 °C, greater than or equal to -30 °C, greater than or equal to - 25 °C, greater than or equal to -20 °C, greater than or equal to -15 °C, greater than or equal to -10 °C, or greater than or equal to -5 °C. In some embodiments, in some embodiments the designated freezing temperature is less than or equal to 0 °C, less than or equal to -5 °C, less than or equal to -10 °C, less than or equal to -15 °C, less than or equal to -20 °C, less than or equal to -25 °C, less than or equal to -30 °C, less than or equal to -35 °C, less than or equal to -40 °C, less than or equal to -45 °C, less than or equal to -50 °C, less than or equal to -55 °C, 13178167 #14412969v1MIT 26102 - 27 - less than or equal to -60 °C, or less than or equal to -65 °C. Combinations of these ranges are also possible (e.g., greater than or equal to -70 °C and less than or equal to 0 °C, or greater than or equal to -40 °C and less than or equal to -60 °C). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited. For example, in some embodiments, the temperature for freezing aqueous samples is between -40 and -60°C.

[0087] This freezing ensures the ice crystals fully solidify and that the product is well below the collapse temperature before entering the drying section, in some embodiments. Like the nucleation and conditioning stations, the length of the freezing station may be chosen to control for the desired throughput. For example, the freezing station may have a length (e.g., may comprise an appropriate number of modules) that depends, in some embodiments, on sample size, sample container, freezing module temperature, and desired throughput, since these factors can affect the freezing rate and / or the time a mover spends in the freezing station.

[0088] As the mover passes from nucleation module 203d to freezing modules 203e, it does not pass through a load lock module 203b. In some embodiments, including that represented in FIG.2, load locks are not needed between these modules, e.g., because freezing and nucleation occur at the same pressure. It should further be understood that the nucleation station and the freezing station could be separated by a load lock, depending on the embodiments, e.g., where it is advantageous for maintaining a temperature gradient between these molecules. But such an arrangement is not necessary—temperature gradients, e.g., between connected modules, may be maintained using controlled heating and / or cooling, depending on the embodiment, without the use of a load lock module physically separating modules of different temperatures.

[0089] From the freezing station (comprising modules 203e), the mover may pass through a load lock module 203b before passing into a sixth process station. The sixth process station is the drying station (comprising modules 203f), according to some embodiments. In this station, the water sublimates out of the product, leaving behind the lyophilized cake, according to some embodiments. Load lock module 203b may act as an airlock, allowing the module to pass from a first pressure of the freezing station modules 203e into a second pressure of the freeze-freeze-drying module 203f. In some embodiments, the drying station maintains a vacuum environment to drive this sublimation process. The 13178167 #14412969v1MIT 26102 - 28 - load lock module may be configured to change ambient conditions of the mover from those conditions ambient in the freezing station to those conditions ambient in the drying station, e.g., by reducing the pressure surrounding the mover to a vacuum pressure.

[0090] After passing into the drying station, the movers may be conveyed along the remainder of the course through lyophilization system 201 to another load lock module 203b, to change ambient conditions of the mover to those of the loading station. The mover then returns to position 217b, at the end of the lyophilization pathway, where the fully lyophilized sample may be removed from the mover. The mover then returns to position 217a for reloading and recycling through lyophilization system 201.

[0091] Like the nucleation, conditioning, and freezing stations, the length of the drying station may be chosen to control for the desired throughput. For example, the drying station may have a length (e.g., may comprise an appropriate number of modules) that depends, in some embodiments, on sample size, sample container, freeze-drying module temperature, and desired throughput, since these factors can affect the drying rate and / or the time a mover spends in the drying station. Drying is often, relative to freezing, conditioning, or nucleation, a relatively slow step. Accordingly, in some embodiments such as that of FIG. 2, the drying station is the longest station.

[0092] It should, of course, be understood that the lyophilization system of FIG.2 and the mover pathway through the lyophilization system is purely illustrative, and that those of ordinary skill in the art would appreciate that different arrangements are also possible. For example, as discussed above, the lengths of the various stations may, in some embodiments, be adjusted based on the specific process design for lyophilization. As another example, although the depicted modular system is looped, such an arrangement is not necessary; a lyophilization system could be linearized, e.g., by introducing a mover return external to the lyophilization system, which returned used movers from the end of the lyophilization path to its beginning. Additionally, multiple paths could be connected with central terminal stations that could be used to distribute movers to appropriate process sections, such as from one freezing station to one of two or more freeze-drying stations. Furthermore, it should be understood that lyophilization systems may be configured to operate at a uniform rate (e.g., so that the movers pass at relatively constant speed through the lyophilization system) or at a variable rate (e.g., so multiple movers can be processed in parallel, by passing them rapidly into positions within a new station but allowing them time to dwell for longer within that 13178167 #14412969v1MIT 26102 - 29 - station. For example, where multiple load lock modules are used, multiple movers may be rapidly moved into the adjacent load lock modules, but allowed to dwell there for extended periods of time to facilitate changes to ambient conditions—this motion profile may be alternated for more batched processing, as the disclosure is not so limited.

[0093] As another example, the lyophilization system may contain one or more additional modules, e.g., for performing additional functions, even if those modules are not specifically shown in FIG.2. An additional process section (not shown) can be added between the conditioning and freezing sections, e.g., if a user wants finer control over the ice crystal growth during the freezing process. Without wishing to be bound by any particular theory, the ice crystal growth rate may depend on the freezing temperature, and if the desired growth temperature is significantly higher than the freezing station setpoint, then an intermediary crystal growth station can be added before the freezing section to provide the desired growth temperature conditions, according to some embodiments.

[0094] The separation of these cooling stages and the nucleation control in the system may provide a high degree of control over the freezing process, improving vial uniformity and ice crystallization control. This control over freezing can reduce reconstitution times, as the ice crystals in the frozen product determine the pore sizes in the dried product cake, which in turn determines the surface area available for the reconstitution process, according to some embodiments.

[0095] The lyophilization systems provided herein may use a modular design to make it adjustable to different user needs. As Table 1 shows, the machine size can vary significantly depending on the desired production rate, vial size, and process time. The modular nature of the lyophilization system makes it reconfigurable as necessary to optimize its layout, according to some embodiments. This modularity may also help in system development, as the system can be assembled in subassemblies to validate performance.

[0096] One consideration that can affect a lyophilization system performance is module alignment. According to some embodiments, lyophilization modules provided herein work well when stators are positioned such that the movers can successfully traverse gaps between stator modules without losing levitation and dragging. If the movers drag, they may produce particulates due to frictional wear.

[0097] Another consideration is the sealing interface between adjacent modules. Positional constraints can lead to gaps between sealing surfaces. These gaps can limit the 13178167 #14412969v1MIT 26102 - 30 - ability of the modules to seal to one another, limiting vacuum performance in at least some cases.

[0098] Yet another consideration is the positioning of the stators within the bases of the lyophilization modules, and the mounting of the modules to a supporting surface. As more units are added to the table, misalignment between the consecutive unit positioning can accumulate, leading to a drift in the overall lyophilization system shape. Drift in the lyophilization system can prevent the system from forming a complete loop. FIG.3 provides a schematic, top-view illustration of a non-limiting lyophilization system where drift has resulted from minor misalignments of modules 303, represented as squares, according to a non-limiting embodiment. The drift of the modules is exaggerated for effect, but nonetheless illustrates the problems that can result from lyophilization module misalignment. Drift can be a particular problem in lyophilization systems that are looped, since significant drift can lead to a break in the loop which does not allow the system to connect its entrance and exit.

[0099] FIG.4A provides a perspective-view, schematic illustration of a non-limiting lyophilization module 400 configured for use in a lyophilization system provided herein. For example, lyophilization module 400 may be a freeze-drying module configured for use in a drying station (e.g., as one of modules 203f in FIG.2).

[0100] According to some embodiments, the lyophilization module is configured to be mounted on a supporting surface. As shown, lyophilization module 400 comprises module housing 401 comprising a base configured to be disposed on a supporting surface using mounts 421 configured to support the module housing on a plurality of rails of a supporting surface beneath the lyophilization module. Mounting the module housing to one or more rails may, advantageously allow modules to be moved relative to one another to permit reconfiguration of the modules. Any of a variety of mounting types of mounts 421 be used to mount lyophilization module 400 on a supporting surface. The mounts may be translatable mounts, configurable to allow the modules to slide or roll along the rail, relative to one another. For example, in some embodiments, the mounts are wheels, grooves, bearings, or sliders configured to support the module. As shown in FIG.4A, mounts 421 are sliders configured to interlock with a rail of a supporting surface. The mounts may be lockable, e.g., to fix their position; however, locking the mounts is not necessary, according to some embodiments. For example, in some embodiments, the position of the mounted lyophilization module is locked by securing it to an adjacent module (e.g., using a fastener). 13178167 #14412969v1MIT 26102 - 31 - According to some embodiments, the mounts are not translatable, e.g., and are instead configured to mount the modules to a fixed position.

[0101] Mounts 421 connect to base 403 of housing 401 via fasteners 425. The fasteners are represented as bolts; however, it should be understood that any of a variety of suitable fasteners (e.g., rivets, bolts, screws, nails, pins) or other connections (e.g., adhesives, welds) may be used to connect the mounts to the base, as the disclosure is not so limited. Housing 401 extends from base 403, at base 403’s outer edges, upwards to define vertical sides of the housing. The sides terminate at a roof of the housing located at the top of the module. The housing may be made from any of a variety of suitable materials; however, in some embodiments, it is made from a material configured to withstand relatively low pressures and / or temperatures, e.g., in order to provide improved performance during lyophilization operations. Thus, according to some embodiments the housing is made from a relatively strong material, such as a metal.

[0102] The housing is, in some embodiments, configured to permit the passage of a mover through the housing. For example, lyophilization module 400 further comprises a passage extending from first opening 405 of the passage on a first side of module housing 401 to second opening 407 of the passage on a second side of module housing 401. In lyophilization module 400, first opening 405 and second opening 407 are formed on opposite sides of housing 401, e.g., so that the passageway connecting them is a linear passageway that allows the mover to pass into lyophilization module 400 via first opening 405, to pass through the passageway in a straight line, and finally to pass out of lyophilization module 400 via second opening 407. Of course, this is not necessary—for example, looped lyophilization systems such as that shown in FIG.2 may include lyophilization modules configured to act as corners of the loop, e.g., by conveying the mover through a right angle or along a curved track within the lyophilization module. Thus, in some embodiments, first opening 405 and second opening 407 could be formed in adjacent sides of lyophilization module 400, e.g., to allow use of the module to change the direction at which movers travel through a modular lyophilization system, e.g., at corners of a looped lyophilization system.

[0103] In order to integrate module 400 into a modular lyophilization system, module 400 is configured to be sealed to an adjacent module, e.g., following alignment of an opening of module housing 401 with an opening of an adjacent module. For example, first opening 405 of lyophilization module 400 may be sealed to a second opening of another 13178167 #14412969v1MIT 26102 - 32 - lyophilization module, e.g., so that a mover can pass into lyophilization module 400 by passing out of the second opening of the other lyophilization module, across the seal between the other lyophilization module and lyophilization module 400, and into first opening 405. Likewise, another module may be sealed to second opening 407 so that the mover, as it exits lyophilization module 400, passes through second opening 407, across the adjacent seal, and into a first opening of an adjacent module.

[0104] The seal may be configured to maintain appropriate conditions within the modules of the modular lyophilization system (e.g., to avoid pressure leaks). Any of a variety of appropriate seals may be used. For example, adjacent modules may be sealed using a gasket seal or an O-ring seal, depending on the embodiment. As shown in FIG.4A, first opening 405 is configured to form a seal with one or more adjacent lyophilization modules, in this case using an O-ring seal (not shown) disposed in groove 431 surrounding the opening. Seals between adjacent modules are shown in figures discussed elsewhere herein, and are discussed in greater detail in connection with those figures.

[0105] Although not visible in FIG.4A, a similar groove may surround second opening (407) so that the lyophilization module can be connected as part of a plurality of lyophilization modules configured to be sequentially connected on a supporting surface, wherein each lyophilization module of the plurality of lyophilization modules includes at least some of the features above. Thus, in some embodiments, the first opening is configured to be sealed to a first adjacent module and the second opening is configured to be sealed to a second adjacent module, e.g., to form an extended passage of a lyophilization system.

[0106] The seal may be formed by compressing the O-ring or gasket between adjacent modules. Pressure to compress the O-ring or gasket may be maintained by any of a variety of suitable methods (e.g., by using one or more fasteners such as a clamp, a bolt, a screw, an adhesive, etc). For example, housing 401 may be fastenable to an adjacent module using one or more fasteners 427, depicted in the form of bolts configured to pass through holes in an adjacent module. Housing 401 further comprises analogous holes 437, which are configured to receive bolts from an adjacent module.

[0107] To facilitate the sealing of adjacent modules, it may be advantageous for the housing to include one or more flanged edges (e.g., bolt flanges), e.g., to facilitate fastening of adjacent modules. For example, housing 401 comprises recesses 439, and flanged edges 443 in order to provide a convenient location for fasteners 427 and holes 437. However, this 13178167 #14412969v1MIT 26102 - 33 - is not strictly necessary, as other methods may be used to fasten adjacent modules, depending on the embodiment.

[0108] In some embodiments, the first adjacent module and the second adjacent module are configured to be sealed to openings on opposite sides of the module to form a linear extended passage. As shown, the passage is a rectilinear passage comprising an interior chamber of the lyophilization module in which one or more steps of a lyophilization process may be performed. But, as discussed above, some modules may comprise openings on adjacent sides of the housing. It should, of course, be understood that although the first opening and the second opening are opposite each other in the pictured embodiments, in at least some modules the openings may be formed in adjacent sides of the module, e.g., so that the module can define a corner of the passage. And it should further be understood that in at least some embodiments the lyophilization freezing module may have a non-rectilinear passage as the disclosure is not so limited.

[0109] The lyophilization system is, in some embodiments, configured to propel movers along an extended passageway formed by the sealing of adjacent modules (such as module 400). The propulsion of the mover may be electromagnetic. For example, the propulsion may be achieved using stators configured to levitate and propel the movers through an interior chamber of the module that forms part of the extended passageway as part of a magnetic levitation system. As shown, lyophilization module 400 further comprises a stator 411 disposed in base 403 of lyophilization freezing module. The stator may thus form part of an electromagnetic levitation system for moving lyophilization samples through the passage (e.g., by receiving the lyophilization samples through first opening 405 and subsequently transmitting the lyophilization samples through second opening 407 using one or more movers controlled by the stator). In some embodiments, each module comprises a stator in the base, so that beneath the extended passageway extending through adjacent modules, a plurality of stators are arranged to propel the mover through the passageway.

[0110] The stators of adjacent modules may be directly adjacent, e.g., so that there is substantially no gap between them, in order to provide uniformity to the motion of the movers through the extended path. However, in some embodiments, stators of adjacent modules are not directly adjacent. For example, lyophilization module 400 includes stator 411 supported on base 403 but secured in position by sides of module housing 401, which will necessarily space stator 411 from any module sealed to first opening 405 or second 13178167 #14412969v1MIT 26102 - 34 - opening 407, creating a gap between stator 411 and any stator of an adjacent module. The stators may be configured to propel a mover over the gap, e.g., by sizing the gap and the movers appropriately for a given modular design. Thus, in some embodiments, a minimum width of the stator is chosen to exceed a maximum width of a gap between stators of adjacent modules, in order to ensure that the mover remains supported as it crosses seals between adjacent modules.

[0111] While the features (e.g., the housing, the base, the housing, the openings, the stator, the mounts, the seals) described above are noted in the context of lyophilization module 400 as represented in FIG.4A, it should, of course, be understood that they may be used in the context of any of a variety of modules of the system, e.g., since a plurality of modules comprising these features may be sealed together to form an extended passageway through which the mover can move. For example, the system described in connection with FIG.2 comprises a plurality of modules 203 that perform various functions, but that are connected to form an extended passageway by sealing together openings of adjacent modules. Those modules (e.g., the conditioning modules, the nucleation module, the freezing module, the load lock modules, the lyophilization modules, and the loading station modules) may each comprise similar features, e.g., to provide an extended passageway through which the lyophilization system can propel the magnetic movers using the stators.

[0112] Modules may comprise one or more features relevant to the particular function intended for the module, depending on the embodiment. In some embodiments, the lyophilization module comprises one or more components useful for performing a lyophilization process. For example, as shown, lyophilization module 400 comprises an optically transparent window 441, e.g., which may be used to monitor a lyophilization process. But it should of course be understood that this is non-limiting and that, according to some embodiments, lyophilization modules may additionally or alternatively include one or more other features useful for lyophilization, including but not limited to, one or more fluid inlets, one or more fluid outlets, one or more sensors (e.g., temperature sensors, pressure sensors, optical sensors, gas sensors, particle sensors). An advantage of the lyophilization modules provided herein is that, according to some embodiments they are highly customizable, depending on the embodiment, allowing the simple integration of modules customized for particular functions. And it should, of course, be understood that the mere fact that a module is adapted to perform a particular function does not limit it to performance 13178167 #14412969v1MIT 26102 - 35 - of that function. For example, in some embodiments, a lyophilization module does not comprise a window, e.g., because the progress of lyophilization may be monitored using windows in some lyophilization modules without monitoring lyophilization using windows in all lyophilization modules.

[0113] It should further be understood that modules intended for use other than lyophilization modules, e.g., modules for conditioning, freezing, nucleation, loading, or load- locking, may comprise one or more features specifically suited for performing those functions. For example, loading modules may comprise entrances, exits, and sample loaders; freezing modules and conditioning modules may comprise coolers; lyophilization modules and / or load lock modules may provide connections to one or more vacuum pumps and / or atmosphere supplies, etc., and load lock modules or modules adjacent to load lock modules may comprise one or more load locks. Various types of these features are detailed further below; they are mentioned here merely to emphasize that they may be used in other modules in combination with the features of module 400, depending on the embodiment and the intended use of the module.

[0114] FIG.4B presents a photograph of a non-limiting lyophilization module similar to the lyophilization module illustrated in FIG.4A. The lyophilization modules are substantially similar, although the optical window is disposed in the side of the module housing of the lyophilization module of FIG.4B, whereas the optical window is disposed in the top of the module housing of the lyophilization module of FIG.4A. The optical window could, in some embodiments, be replaced with a gas inlet (e.g., for use in a freezing module).

[0115] According to some embodiments, each module of a lyophilization system comprises a stator, a module housing, and a base configured to connect the lyophilization module to the support surface.

[0116] In order to manage alignment of a plurality of lyophilization modules to form a lyophilization system, the opening seals and the placement of lyophilization modules on a supporting surface may be carefully controlled. Accordingly, in some embodiments, the opening-adjacent portions of the module housing may be manufactured for a relatively high degree of parallelism and flatness. And, according to some embodiments, during assembly, the modules are placed onto the rail system before being bolted together, so that the rail can help to align the openings of adjacent modules. The parallelism and flatness requirements on the machine body, coupled with rail-guided alignment, may be particularly advantageous for 13178167 #14412969v1MIT 26102 - 36 - limiting deflection of the lyophilization system, improving the quality of seals between adjacent lyophilization modules.

[0117] The overall lyophilization system may be built from an assembly of modules. Each module may share a core base geometry while also including corresponding features for its application within a lyophilization system. The matching core geometry between modules improves manufacturability, and it may help ensure proper sealing between any module pair.

[0118] FIGS.5A-8C provide schematic illustrations of other modules of lyophilization systems, illustrating that they can include both features in common with module 400 described above, as well as differences. The lyophilization system may comprise any of the four types of modules (500, 600, 700, and 800) shown in FIGS.5A-5C (showing various schematic perspectives of a non-limiting first lyophilization module type), 6A-6C (showing various schematic perspectives of a non-limiting second lyophilization module type), 7A-7C (showing various schematic perspectives of a non-limiting third lyophilization module type), and 8A-8C (showing various schematic perspectives of a non-limiting fourth lyophilization module type). The representations shown in FIGS.5C, 6C, 7C, and 8C show the parts as-cast, prior to machining of the various holes, groves, and other designs illustrated in FIGS.5A-5B, 6A-6B, 7A-7B, and 8A-8B.

[0119] As illustrated in FIGS.5A-8C, the modules all have common features (e.g., a module housing (501, 601, 701, 801), a first opening (505, 605, 705, 805), a second opening (507, 607, 707, 807), and a base comprising a cavity (503, 603, 703, 803) configured to receive a stator). However, the modules of FIGS.5A-7C are configured for use with load locks (e.g., gates), whereas FIGS.8A-8C are not configured for use with load locks. The load lock modules include features to accommodate the gates moving between their open and closed positions. For example, the lyophilization module of FIGS.5A-5C includes two gate housings 551, and an O-ring grove 531 completely enclosing the gate housing such that the gate can rest within a seal formed between adjacent lyophilization modules.

[0120] A load lock may be configured to change between an open configuration and a closed configuration. For example, referring to FIGS.5A-5C where the load lock is a gate, the gate may be lowered to close the gate (e.g., by sealing opening 505 or opening 507) or raised to open the gate (e.g., by raising the gate away from opening 505 or opening 507). Gate housings 551 enclose both an opening (e.g., first opening 505 or second opening 507), 13178167 #14412969v1MIT 26102 - 37 - which is covered by the gate when the gate is in the closed configuration, and a volume above the opening, where the gate is held when in the open configuration.

[0121] The gate housing may further contain a gate actuator, such as a pneumatic piston configured to use a dynamic rod seal to close the gate and maintain the vacuum environment. As shown in FIGS.5A-7C, openings configured for use with load-lock gates may be angled. For example, the opening may be angled so that a mover passing through the opening travels in a direction that is not perpendicular to the mover. In some embodiments, the angled openings may be angled in the same direction on both sides of a load lock based on the intended pressure differential across the load lock.

[0122] An asymmetry of the load lock may be formed by pairing two types of modules, one angled for interfacing with each side of the load lock. The angles of the load lock modules may be selected based on the intended pressure differential, which may vary depending on the position of the load lock module within the system.

[0123] In some embodiments, the module of FIG.5A-5C is a load lock module, while the modules of FIGS.6A-6C and 7A-7C are configured to serve as terminal modules for a product station and are therefore chosen to complement an appropriate side of the load lock module of FIG.5A-5C, which is used to separate adjacent product stations. A load lock module such as module 500 of FIGS.5A-5C may be paired with a matching, load-lock- adjacent module like modules 600 or 700 of FIGS.6A-7C, also referred to herein as a “terminal module”. Modules such as module 800 of FIG.8A-8C, which are not configured for use with a load lock, may thus be used for non-terminal modules within a product station. Extended load locks product stations could also be prepared, if desired, using modules of the types shown in FIGS.6A-7C to define the terminals of the load lock product stations.

[0124] The lyophilization modules may be made by any of a variety of appropriate methods. In some embodiments, advantages have been recognized for casting the lyophilization module(s) of a lyophilization system. For example, casting can be an inexpensive and efficient way to make large numbers of modules. However, casting can have drawbacks. In some embodiments, casting components for vacuum systems introduces porosity to cast parts. A casting with example porosity is shown in FIG.9, which shows a photograph of a pore defect in a non-limiting as-cast lyophilization module. This porosity may arise from impurities in the melted metal. The porosity can create a risk of internally linked pores that form leak paths through the walls, compromising the ability of the module 13178167 #14412969v1MIT 26102 - 38 - to hold a vacuum seal. Reducing the size of the pores may, in turn, reduce this risk. One option for mitigating pore leakage is vacuum impregnation of liquid polymer into the pores, which can seal leak paths and improve performance. The polymer may cures inside the pores, plugging them and thereby blocking any connected pores that could otherwise permit leaks through the lyophilization modules.

[0125] Another risk created by the casting porosity is that the pores could create a gap that spans another sealing interface, such as an O-ring seal, according to some embodiments. These pores could also create sharp edges, which can damage an O-ring when it deforms during the preloading or sealing processes, according to some embodiments. This risk may be mitigated by keeping the sealing path width much larger than the maximum pore diameter. The ratio between sealing path width and pore diameter can be increased by increasing the sealing path width and decreasing the maximum pore diameter, according to some embodiments.

[0126] In some embodiments, casting molds are purged with an inert gas (e.g., argon gas) to remove most of the oxygen in the mold before casting. Inert gas purging may, in some embodiments, minimize the oxides which are the primary cause of the porosity in the castings. The pour rate during casting can also be controlled to reduce oxide formation. Any of a variety of appropriate materials may be used, including, but not limited to, aluminum, steel, or any of a variety of other suitable metals. According to some embodiments, aluminum is used. The aluminum may be heat treated to improve the machinability of the units, e.g., by hardening the aluminum. According to some embodiments the T6 heat treatment is used to harden the aluminum, such that it machines cleanly and can achieve the required dimensional tolerance.

[0127] In some embodiments, cast modules may be machined to meet the final feature tolerances required for successful assembly and operation, to create smaller features or surface details, and / or to polish away casting defects. To achieve appropriate post- machining sizes, cast modules may be over-sized (e.g., may be designed to include an additional 10mm of material thickness that can be machined away during machining). This extra thickness may allow the machining process to compensate for possible module warping due to internal stresses created during casting. Also, the material as cast does not have a proper datum for the external geometry relative to the internal tunnel, so this material must be machined in multiple iterations to measure and verify the creation of corners which can be 13178167 #14412969v1MIT 26102 - 39 - used as machining datums. FIG.10 provides a photograph of a non-limiting, as-cast module 1001 and a non-limiting as-machined module 1003 for comparison.

[0128] As discussed above, any of a variety of appropriate methods may be used to seal openings of lyophilization modules together to form a lyophilization system. FIGS. 11A-11B provide non-limiting, schematic illustrations of seals used to close a non-limiting lyophilization module against vacuum leakage. In the figures, module 1101a is rendered transparent, to allow the seals to be viewed in their place between module 1101a and an adjacent module 1101b (FIG.11A) or between module 1101a and a stator 1111 (FIG.11B). A first seal 1141, illustrated in FIG.11A, seals the module 1101a to an adjacent module 1101b. A second seal 1141, illustrated in FIG.11B, seals of the lyophilization module housing to a stator inserted into a cavity at the bottom of the lyophilization module.

[0129] To simplify the sealing method, it may be advantageous to avoid having seal paths that cross multiple components. Sealing paths that cross seams can create additional possibilities for leaks, which can compromise conditions within the lyophilization module. Accordingly, the modules may have separate seals between consecutive modules and their stators. This separation requires the modules to extend into a gap between consecutive stators.

[0130] The interface between consecutive modules may be configured to facilitate sealing of the modules together. Two common seal methods are gaskets and O-rings. Gaskets can have looser surface flatness requirements and can cover large areas. O-rings may require specially machined grooves, but they take up a smaller area on the sealing surface. Gaskets may be cut specifically for their application shape, while O-rings may be obtained in standard or custom sizes. O-rings are advantageous, in at least some embodiments, because standardly sized O-rings can simplify module production and component sourcing. An O-ring groove can be made by any of a variety of appropriate methods, including machining. In some embodiments, an O-ring groove is machined using a dovetail tool, which holds the O-ring in place after installation. Having features which keep the sealing material in place during assembly can make the assembly of the lyophilization system easier.

[0131] An O-ring may be configured to be used with a crush that remains greater than 15%. Misalignment and / or module housing defects can limit O-ring performance, in some embodiments. The lyophilization modules and / or supporting surfaces can be designed to limit these risks to ensure appropriate O-ring performance. 13178167 #14412969v1MIT 26102 - 40 -

[0132] The normal force used to crush the O-rings may be applied using one or more fasteners (e.g., bolts) configured to tighten the connection between adjacent modules. The module housing can be configured to accommodate these fasteners. Discussion of these fasteners is provided in greater detail above. For example, referring again to FIG.4A, the module housing comprises bolt holes configured to tighten the lyophilization module against an adjacent lyophilization module when a bolt passing through the bolt hole is tightened. Any of a variety of appropriate bolts (e.g., a flange bolt) may be used. According to some embodiments, some or all of the lyophilization modules are compressed together using bolt flanges on the sides through which these bolts are connected.

[0133] A lyophilization module may likewise be configured to form a seal with a stator, as shown in FIG.11B, so that a top surface of the stator is exposed to a vacuum environment in the drying section, while the bottom of the stator is exposed to atmospheric conditions.

[0134] The seal between the stator and the lyophilization module may be formed in any of a variety of suitable ways. For example, the seal may be a temporary seal (e.g., an O- ring or gasket seal) or a permanent seal (e.g., an adhesive seal). The housing includes a cavity into which the stator is inserted, according to some embodiments (e.g., cavities 503, 603, 703, and 803 of FIGS.5A-8C).

[0135] According to some embodiments, the cavity includes a small lip that contacts the stator top surface. FIG.12 provides a non-limiting schematic cross-section of the seal between a stator and the cavity, according to some embodiments. In the figure, stator 1211 sits within a cavity of housing 1201. In some embodiments, the module is assembled by inserting stator 1211 into the cavity of housing 1201. The stator may comprise one or more features for aligning the stator within the cavity during its insertion. For example, stator 1211 may comprise protrusions or alignment holes in order to align it within the cavity.

[0136] The stator may be sealed in the cavity via any of a variety of appropriate methods. In some embodiments the stator is sealed in position permanently, e.g., using a sealant such as an epoxy. For example, housing 1201 comprises sealant grove 1265 configured to be filled with sealant in order to seal stator 1211 into housing 1201. Sealant grooves and sealing methods are described in greater detail below.

[0137] The stator may be positioned within the cavity in order to ensure the alignment of the stator with other stators of the lyophilization system. For example, an epoxy shim 13178167 #14412969v1MIT 26102 - 41 - layer may be added to the bottom of the stator on its bolting feet during assembly. This epoxy shim layer ensures that any mismatch in the tolerance directions of the stator and the cavity do not prevent the stator and walls of the housing from both bolting to the base of the housing, according to some embodiments. An epoxy shim may have advantages over a solid material shim, e.g., because it can better account for variations in the actual dimensions of each part due to their independent tolerances. This may help stators be interchangeable between lyophilization modules, so that modules do not need to be custom-machined to match particular stators. The housing bottom may include overflow grooves, according to some embodiments, to ensure any extra epoxy applied during the shimming process can flow out of the groove, preventing the risk of creating too thick of an epoxy shim layer. For example, housing 1201 comprises overflow groove 1269, which can receive excess sealant used during sealing and / or shimming the stator.

[0138] In FIG.12, 1263 is the cavity lip used to position the stator during assembly, 1231 is the O-ring groove used to seal consecutive modules, 1265 is the sealant groove for creating a vacuum seal between the cavity wall and the stator, 1267 is the epoxy shim used to ensure the baseplate and the stator are both bolted to the baseplate regardless of dimensional errors within their respective tolerances, and 1269 is the epoxy shim overflow groove used to ensure that any excess epoxy used in the shimming process can flow away from the stator and baseplate interface rather than create too thick of a shim, according to some embodiments

[0139] The stator cavity dimensions may be appropriate for the stators used in the lyophilization system. The maximum cavity dimensions can affect the possible offset between consecutive stators, in some embodiments. Because the cavity will be larger than the stator, the stator will likely rest against one or two walls, but that final position relative to the housing is not necessarily known before assembly. If this relative positioning is important for a given lyophilization system, then the stator and the housing walls can each be referenced to the base of the housing using features such as dowel pins to facilitate consistent stator placement.

[0140] However, precision stator placement is not necessary for all embodiments, and in some embodiments, the imprecision in stator placement may be relatively high (e.g., as much as 1mm of positional offset in any direction, relative to the center of the cavity. Without wishing to be bound by any particular theory, positional error can come from four main sources: 1) errors in the position of the stator relative to the cavity, 2) errors in the 13178167 #14412969v1MIT 26102 - 42 - cavity dimensions and position relative to the housing, 3) errors in the overall machine size, and 4) errors in the assembly of consecutive modules. Because the consecutive module faces serve as the assembly references, the fourth source of error is expected often negligible.

[0141] The first source of error has a minimum value which comes from the tolerancing on the stator dimensions. These units are machined by a commercial manufacturer, according to some embodiments, so their tolerances must be accepted as they are and designed around in this system. Appropriate tolerancing of the first source of error may be identified depending on the specific design of a lyophilization system. For example, in a non-limiting embodiment provided solely for the sake of illustration, the maximum negative tolerance on the stator dimension is 0.10mm. This tolerance means the smallest expected stator would be 239.6mm x 239.6mm. If two of these stators were to be placed in consecutive 240mm x 240mm cavities, then there could be a maximum error of 0.4mm between their nominal centers, as each could be offset from their corresponding cavity center by 0.2mm. Accordingly, only 0.6mm of positional tolerance remains to allocate to the stator cavity size, the relative cavity position, and the overall module size. This tolerance is evenly allocated to all three error sources, providing 0.2mm tolerance to each. For a part of this size, a 0.2mm machining tolerance is reasonable to achieve and does not require specialized machining capabilities. This tolerancing only considers linear offsets, not twisting between the stator and the housing. The potential for twisting is limited by setting a parallelism and perpendicularity requirement for the stator cavity, using a similar tolerance to the linear tolerances listed above. Using the parallelism and perpendicularity requirements ensures that the effective linear offsets between any points on the stators do not exceed the allowable offsets from the error budget. The fully toleranced drawing for a non-limiting stator cavity is shown in the non-limiting schematic of FIG.13. It should, of course, be understood that the foregoing tolerance discussion is specific to a particular set of embodiments, and that other tolerancing may be identified depending on the specific lyophilization module.

[0142] According to some embodiments, the sealing path between the stator and the housing goes around the sides of the stator because its top and bottom surfaces are exposed to different conditions. It may be advantageous not to seal to the top surface of the stator to maximize the available usable space on the stator. Likewise, it may be advantageous to avoid sealing the bottom surface to the electrical connections of the stator accessible without introducing vacuum passthroughs. 13178167 #14412969v1MIT 26102 - 43 -

[0143] Although O-rings could be used to seal the stator in some embodiments, it may be advantageous to avoid using O-rings for rectangular stators, such as those of FIG.1A. Accordingly, in some embodiments, the sealing strategy illustrated in FIG.12 may be particularly advantageous for stators with sharp corners that might damage O-ring seals.

[0144] In some embodiments, it is advantageous to add the stator to the cavity and add a sealing material afterwards. According to some embodiments, a groove is machined into the housing and filled with an injectable sealing material after the stator and the housing are assembled. The sealing groove may be machined into the housing or the stator. The sealing groove path may be located at the point where it can have the largest cross-sectional area, to minimize the resistance to sealant flow during injection. According to some embodiments, the sealing groove path is positioned to avoid any features on the sides of the stators, as these could risk compromising the seal integrity or serve as leak points, preventing the injection from completely filling the groove. FIGS 14A provide a non-limiting schematic illustration of an exemplary stator for sealing onto the module, illustrating a non-limiting size of various stator features. FIG.14B illustrates a non-limiting cross-section of a lyophilization module, showing the machined groove of the lyophilization module configured for sealing the stator of FIG.14A. The maximum sealing path depth is set by maintaining a minimum thickness of the walls around the stator, according to some embodiments. This minimum thickness is set at 1 / 16in to ensure material integrity during machining and assembly, in some embodiments.

[0145] Any of a variety of appropriate sealants may be used. The sealant may be a vacuum sealant (e.g., may be configured to maintain vacuum pressures within the chamber by barring the passage of fluid around the stator without sustaining damage to itself). In some embodiments, the sealant is an epoxy. In some embodiments, the sealant used is Self- leveling Green, produced by Av-DEC, or a generic version thereof. The sealant may be injected to form a gasket. According to some embodiments, a strongly adhesive sealant performs better, blocking off potential leak paths between the stator and the cavity that could form if a poorly adhesive sealant were used. When adhesion is weaker, the vacuum load can cause the sealant to deflect away from the walls, creating leak paths which compromise the vacuum seal, according to some embodiments. To improve adhesion, both the stator and the sealant groove on the machined housing may be sandblasted. This sandblasting may increase the surface area at the interface, improving the ability of the sealant to bond to the surface. 13178167 #14412969v1MIT 26102 - 44 - Photographs of a non-limiting sandblasted lyophilization module surface are shown in FIGS. 15A-15B.

[0146] The sealant, in some embodiments, completely surrounds the perimeter of the stator, so that the stator forms an airtight barrier between the interior of the module and the passage itself. The sealant may be added via injection of the sealant into a sealant groove after insertion of the stator (e.g., from an edge of the housing). The sealant may be injected into the groove from one side of the housing, where it then flows around the groove and exits from the other side of the housing. A non-limiting illustration of injection fill path 1665 (indicated as a dashed line superimposed on a cross-sectional schematic illustration of a module comprising stator 1611 and housing 1601) is shown in FIG.16. The arrows 1675 indicate the sealant flow direction. As shown, sealant enters housing 1601 before proceeding along sealant flow path 1665, which is defined by a sealant groove in housing 1601 (like sealant grove 1265 of FIG.12, but more difficult to visualize in this cross-section). The sealant may be injected through a tube which is joined to the housing wall (e.g., through a 1 / 8in NPT adapter that mounts to a corresponding 1 / 8in NPT threaded hole in the side of the housing), according to some specific, non-limiting embodiments. A matching assembly may be used on the opposite side of the system for the sealant outlet.

[0147] The sealant may be injected into the sealant path through an inlet and may be ejected from the sealant path through an outlet in the module housing, according to some embodiments. Illustrations and photographs of non-limiting fittings that may be used for sealant injection are shown in FIGS.17A-17C, according to some embodiments. FIG.17A shows a side-view illustration of a lyophilization module 1700 comprising housing 1701 with a sealant injection fitting in the form of sealant inlet 1781. FIG.17B shows another side- view schematic illustration of another side of lyophilization module 1700, showing injection fitting 1783, which comprises sealant outlet 1785 and plug holes 1787. The outlet may be monitored for air bubbles during sealing. During the initial injection, the sealant may trap air bubbles as it displaces the air in the sealant groove. As the injection continues, these air bubbles may be purged from the system. The outlet tube may be oriented upwards relative to gravity to help promote this purging process.

[0148] As illustrated in FIG.16, the sealant flow path may bifurcate within the cavity housing so that a flow of sealant through inlet 1781 bifurcates before reuniting at the sealant outlet 1785. In order to ensure that sealant completely surrounds the stator, it may therefore 13178167 #14412969v1MIT 26102 - 45 - be advantageous to strategically block the flow of sealant along at least a portion of the sealant flow path, to force sealant to travel along an alternate route around the stator. Plug holes 1787 may be used for this purpose. On the outlet side, there may be threaded holes that are used with corresponding threaded plugs to ensure the sealant fills the groove on both sides of the stator, according to some embodiments. During the initial injection, the plugs are left open until the sealant is seen from one side, according to some embodiments. The corresponding plug on that side is then inserted, increasing the flow resistance on that side and causing it to preferentially flow to the underfilled side. This strategy ensures that both sides of the stator are filled while using only one entrance and exit located opposite each other, according to some embodiments. It should, of course, be understood that other methods (aside from the use of plugs and plug holes) for increasing flow resistance along a particular sealant flow path are also possible, as the disclosure is not so limited.

[0149] The efficacy of this injected seal can be compromised by differential thermal expansion between the stator and the housing. In some embodiments, the stator and the housing comprise the same material, e.g., to avoid thermal expansion mismatch between the stator and the housing, so differential expansion is primarily caused by temperature difference between the two components. Both the stator and the housing are primarily made from aluminum, according to some embodiments, so differential expansion is primarily caused by temperature difference between the two components. When manufacturing this equipment with other materials such as stainless steel, it may be advantageous to either ensure both components use the same materials or that the temperature of both components is monitored to prevent differential thermal expansion from compromising the seal.

[0150] Cooling of the stators may be advantageous. During normal operation, the stators may be hotter than the housing because they generate heat while levitating the movers which carry vials through the system. However, the temperature of the system may be controlled to meter the power delivered to the vials during sublimation. This power delivery control can help prevent vial overheating, which can cause cake collapse during drying. Controlling this power delivery allows the drying process to operate close to the collapse temperature without exceeding it, according to some embodiments, which can facilitate faster drying while maintaining high product quality. Cooling the stators directly is the most efficient way to reduce the temperature in the chamber because they are the main source of heat generation, according to some embodiments. In some embodiments, it is advantageous 13178167 #14412969v1MIT 26102 - 46 - to keep the stators at a temperature higher than the module housing temperature, e.g., because if the stators are cooled to temperatures below that of the housing, then they could start to shrink away from the housing walls, straining the injected sealant and / or causing leakage. This potential leak path can be avoided, in some embodiments by cooling the housing (and thus indirectly cooling the stators) rather than directly cooling the stators. This method may help the housing remain cooler than the stator, reducing the risk of leakage in some embodiments. The modules can be cooled through cooling blocks placed on the outside of the housing, or cooling channels can be machined directly into the housing walls, in some embodiments.

[0151] The lyophilization system may be configured to cap (e.g., to stopper) one or more lyophilization vials (e.g., to reduce the risk of vial contamination that would result from exposing the vials to conditions outside the lyophilization system before capping them). Once the lyophilization process is complete, the vials may be capped while still within the vacuum environment. This capping can help ensure that the product in the vials does not reabsorb moisture from the air after it exits the vacuum chamber. According to some embodiments, capped vials may be sealed removed from the lyophilization system for packaging and distribution.

[0152] Any of a variety of appropriate capping systems may be used. In some embodiments, capping uses actuation of components to ensure the cap is fully seated in the top of the vial. According to some embodiments, use of an electromagnetic motion system for capping vials is advantageous, as it would rely on non-mechanical motion, reducing the risk of contamination discussed above. According to some embodiments, a pneumatic piston may be used to create a passthrough for a capping mechanism. Using the pneumatic piston provides moving component with more than sufficient travel to successfully cap the vials, according to some embodiments.

[0153] In some embodiments, the piston moves between two set positions, fully opened and fully closed. A shaft collar may be used to limit the retraction distance of the pneumatic piston. When the piston retracts, the shaft collar may contact the piston body, preventing the piston from fully retracting into its cylinder. The piston may be mounted such that its full extension corresponds to the displacement required to fully cap the vial, so its motion is only limited in one direction. 13178167 #14412969v1MIT 26102 - 47 -

[0154] In some embodiments, a compliant element is added to the end of the capping piston to reduce the risk of damage due to overextension of the piston. The compliant element is, in some embodiments, a spring with a pusher connected at the bottom. According to some embodiments, as the piston extends, the pusher engages with the cap, and the compression of the spring provides the force required to cap the vial. The spring may provide some flexibility in the specific piston displacement, loosening the strictness on its specific mounting height. The pusher is, in some embodiments, a 3D printed piece with a textured surface and an aluminum foil coating. The textured surface and foil coating may be used to ensure the pusher does not stick to the vial cap during the capping operation. The capping system demonstrates high reliability, successfully capping hundreds of vials successfully without capping or vacuum environment failure. The capping system is shown in FIGS.18A-18B.

[0155] The supporting surface (e.g., machine table) for the lyophilization system may use a generally stiff structural system to keep overall deflections on the surface and resultant angular amplifications small while incorporating a module orientation adjustability feature to enable minor adjustments to compensate for this table structure deflection during assembly. Without wishing to be bound by any particular theory, the general table stiffness requirement comes from understanding the effect of the structural deflection on the system built on top of it. This effect is shown in FIG.19, which provides a non-limiting schematic illustration of a gap between lyophilization modules and resulting from a non-stiff support surface. When there is a difference in the angular orientation of consecutive modules created by a changing slope on the table surface, this angular difference results in a growing gap between the mating planes of consecutive modules, according to some embodiments. This gap is at its largest at the furthest point from the point at which the two modules are touching, which can be either the top or the bottom of the modules depending on the concavity of the structure’s bending shape, in some embodiments. If this gap is sufficiently large, it can prevent consecutive modules from mating closely enough to generate sufficient sealing force, which would compromise their vacuum seal. While the difference in slope may be small, the angular difference may be amplified, as described by Abbe errors, creating a leak risk if this angular difference is not managed. The linear gap width created by a change in slope along the deflected table length is given, according to some embodiments, by the following Equation 2:^ = ^|^^ − ^^| (2)13178167 #14412969v1MIT 26102 - 48 - where G is the gap length, H is the height of the furthest sealing interface from the modules’ edges in contact, and θ is the relative angle to horizontal of each unit. The height value comes from the module geometry. According to some embodiments, the maximum acceptable slope difference between any two points on the machine base structure surface. In some embodiments, the supporting surface is configured to keep that slope difference below or equal to 0.00056 radians.

[0156] The support structure (e.g., machine table) is built using two supports (e.g., rails), according to some embodiments, to ensure that the support engagement does not depend on the flatness of the surface on which the table is built. Depending on the support positions, the resultant beam deflection can vary widely, in some embodiments. The optimal support positioning can be determined by modeling the physical state of the structure using singularity loading modeling, according to some embodiments. In some embodiments, the loading modeling method uses singularity functions to represent changes in the loading conditions for the beam over its length. The structure built for this system can be modelled as a beam with a distributed weight load on top representing the system weight and two point loads on the bottom representing the supports. The free body diagram for this loading appears in FIG.20, according to some embodiments. The point load locations are assumed to be symmetric. While the support locations do not necessarily need to be located symmetrically, this alignment is expected to minimize the maximum slope variation across the structure surface. While the system weight is not necessarily fully symmetric, for modeling purposes, it is not expected to vary sufficiently to require analyzing the parameter space including asymmetric support locations. Equations 3-5 shows the singularity modeling for this system, according to some embodiments:

[0157] Assuming the supports are equally spaced and the load of the machine is evenly distributed, the reaction forces at the supports should be equal to each other. This means each support is expected to bear half of the total machine weight load, as shown in Equation 6: 13178167 #14412969v1MIT 26102 - 49 -^ = ^ = "#^ ^ ^ (6)

[0158] Additionally, because the supports are symmetrically located about the table center, the positionsand ^^can be written in terms of a single variable, S, representing the spacing between the two supports. The value of S can range from 0 to L, where L is the full length of the system. These boundary conditions represent when there is effectively a singlesupport in the center of the system, $ = 0, and when the supports are at each end of thesystem, $ = ^. Using this term, ^^and ^^ can be rewritten as the following:^ = #^&^ , ^ =#(& ^^ ^(7)

[0159] As expected for symmetrically located supports, theis equal to L. Substituting these relationships into Equation 5 above gives the following relationship:

[0160] Integrating this equation with respect to x gives the equation for the slope at any point across the beam, as shown in Equation 10.

[0161] To determine the value of the integration constant, a point with a known slope is needed. For a symmetric beam, the slope at the center will be zero, so the equation can beevaluated at ^ = #^:

[0162] A reasonable choice of support spacing is to use the Airy points. The Airy points are the support locations that cause the angular deflection at the ends of the beam to be zero. This deflection profile ensures that the system is flat at the end where it is interfacing 13178167 #14412969v1MIT 26102 - 50 - with other equipment in the production process. The Airy points for a beam supported at two ^ positions are separated by a distance S equal to√.^. To ensure that this support spacing is acceptable, the Airy points spacing can be plugged into Equation 9 to set the requirement for beam stiffness:

[0163] Once the support beam locations are selected, the maximum slope change in the beam under load needs to be found. Due to the singularity functions included in this equation, it is simplest to find the maximum slope change positions graphically. Because most of the parameters other than x, the position along the length of the beam, serve primarily as scaling parameters, they can all be normalized to 1 to find the value of x which maximizes the slope change. Accordingly, the following Equation 17 is plotted in FIG.21 to find the maximum slope change position.

[0164] The normalized plot shows that the maximum absolute slope change occurs at the support locations. Because the beam is symmetric, only one of these positions is needed for evaluating this maximum slope change. Using the support location for x in Equation 16 creates a relationship between the beam stiffness and the deflection requirement. :^ #^&#^√=^ = = :# .^√. ^^ ^=8^ (18)13178167 #14412969v1MIT 26102

[0165] With the general relationship between maximum slope change and table parameters determined, the next step is to start determining the values for these parameters. The first requirement is the maximum allowable slope change, which comes from the gap tolerance between consecutive modules. According to some embodiments, this model implies that for a maximum gap tolerance of 0.003in, an acceptable maximum slope difference of 0.00056 radians. (Though it should, of course, be understood that this is entirely system dependent and these values are taken solely for the purpose of illustration.) This value can then be inserted into Equation 23, providing the following relationship between table length and required stiffness, shown in Equation 24:^^ = − 3^^√.4"#^^^F.8H^-^ (24)^^ = −14932 − √34^^^ (25)

[0166] The structure length comes from the system layout calculated in Table 2. The distributed load can be estimated by assuming an approximate module volume and preliminary material selection. Using a single module as a basis, given an aluminum structure with 1” wall thickness, 5” tall interior chamber height, and a factor of safety of 1.5 to account for additional hardware (such as vacuum and sensing equipment), the chamber contribution to w can be estimated as 728 N / m. The stators weigh approximately 6.6kg, which over a module unit length of 250mm contributes 259 N / m. The structure itself will have some weight, which must be included.

[0167] The general structural support material selected for the table may be extruded aluminum rectangular tubing, though of course any of a variety of materials may generally be used. Extruded aluminum rectangular tubing may be advantageous because it may have flat and squared sides and a good strength to weight ratio, and because can be sourced relatively easily. Using tubing rather than solid beams may maintains much of the beam’s stiffness while removing a significant amount of the beam’s weight. Without wishing to be bound by any particular theory, the beam weight per unit length and the bending stiffnesses can be estimated as follows (using appropriate parameters for aluminum):13178167 #14412969v1MIT 26102 - 52 -

[0168] Given the estimates for system weight and the selection of aluminum extrusion for the table structure, Equation 25 can be re-written to depend on the aluminum extrusion height, width, and wall thickness. Because this equation will still provide 3 free parameters, there remains flexibility to accommodate other considerations that may affect final design decisions. Given the ability to choose multiple parameters, these relationships can be used to identify an acceptable beam stiffness and structural deflection is achieved. These relationships are summarized in Table 3. As a specific, non-limiting example, in some embodiments a 3in beam width is chosen to match with a standard 2x1 t-slotted aluminum extrusion which will create rails for moving modules on top of the built system. A beam height of 6in is also chosen to provide a 2:1 ratio of beam height to width. Using these values in the design spreadsheet built using the above equations results in a wall thickness of 0.25in. Accordingly, the structural rails used to create the basis for the machine structure are made from 3in x 6in x 0.25in extruded aluminum beams. Table 3 provides the associated analysis, though it should of course be understood that Table 3 provides a solely illustrative example and that other configurations are also possible. Table 3. The relationships derived between the beam parameters and the structure stiffness are added to a design spreadsheet to calculate the resultant maximum expected deflection between two consecutive modules, according to a specific, non-limiting embodiment used solely to illustrate the interrelation between the calculations discussed above. This table illustrates how changing the beam geometry affects the resultant deflection, enabling parameter selection, according to some embodiments.13178167 #14412969v1MIT 26102 - 53 -13178167 #14412969v1MIT 26102 - 54 -13178167 #14412969v1MIT 26102 - 55 -

[0169] Because the machine components are aligned relative to each other, according to some embodiments, constraining them to specific positions on the base structure can create some risks during assembly. For example, in some embodiments, if there is a difference between the distance between consecutive module centers due to their own machined geometry compared to alignment features built into the machine base, these constraints can be in conflict. These conflicts can, in some embodiments, damage or deform lyophilization modules. If the constraint positioning the modules on the supporting surface is stiffer, then the modules could either be forced to deform or have gaps between them. If these stiffnesses are similar, then both the modules and the base structure could be stressed or deformed. These risks can be mitigated by loosening the constraints on one set of features; in this case, the constraint to the base structure is loosened to ensure the vacuum seal between module faces is not compromised.

[0170] Additionally, given the modular nature of the system, it is beneficial, according to some embodiments, to include a feature which makes it easier to reconfigure the system. This reconfigurability also makes assembly easier. According to some embodiments, the modules are mounted onto the machine base on linear rails to allow them to slide back and forth. This sliding makes it easy to install and move modules around on each side of the system, and it does not strictly constrain the module positions, according to some embodiments. In some embodiments, the rails do not require the precision of commercial linear bearings, which can more tightly constrain their slider positions.

[0171] In some embodiments, the lyophilization modules are mounted to the support surface using a rail slider system. This system may allow the lyophilization modules to move into their final positions after being placed on the support surface. This system may also advantageously simplify separation of the modules for smaller sample set testing in both development and debugging. The sliders on the rails additionally provide accommodation for system expansion and contraction as it heats and cools without creating thermal stresses on the individual components, according to some embodiments. FIG.22 shows a non-limiting schematic cross-section of the connection between the base plates and the rail slider system, according to some embodiments. 13178167 #14412969v1MIT 26102 - 56 -

[0172] The slider assembly on the baseplates serves two functions, according to some embodiments. Firstly, the assembly attaches the linear plastic sliders onto the baseplate, which may allow the module to mount on the table rail system. This assembly also includes a locking bolt to fix the module in place as necessary, according to some embodiments. Secondly, the slider assembly includes a jack screw for module orientation adjustments, in some embodiments. These adjustments can help compensate for angular misalignment between consecutive modules, whether those come from the modules themselves after manufacturing or from the table deflecting under load. As a non-limiting example provided solely for the sake of illustration, in the system tabulated in Table 3 above, these jack screws can compensate for up to 0.25in vertical displacement, which translates to 2 degrees of angular misalignment parallel to the tunnel structure and 1.1 degrees of angular misalignment perpendicular to the tunnel structure. This adjustability in the direction parallel to the tunnel can account for angular misalignment created by deflection in the table, relaxing the requirement on the table stiffness. The 2 degrees of adjustability corresponds to 15.7mm of gap width at the top of a door unit seal. Because the slope differential may need to be made up over multiple consecutive units, this full width cannot be used to relax the table stiffness requirement. Thus, only 10% of this adjustability is allotted to the stiffness requirement, loosening the gap tightness by 1.57mm (or 0.06in). It should, of course, be understood that the numerical values in the foregoing paragraph are solely illustrative and can be different depending on the specifics of the rail system used.

[0173] The hardware used for the continuous lyophilization equipment can be assembled in a smaller benchtop system. This fully automated system includes freezing, drying, and sensing capabilities. The smaller benchtop system is built from the same modules used in the larger continuous system which includes these capabilities consists of four connected units: one loading and unloading, one cooling, one load-lock, and one drying / sensing chamber. FIG.23 provides a photograph of an assembled benchtop-scale lyophilization system comprising four lyophilization modules, according to some embodiments. The labeled components are: 1. Load-lock station for moving between process chambers.2. Conditioning station comprising a cooling chamber for subcooling vials.3. Control valve for cooling chambers.4. Freezing station for nucleating and freezing vials. This module uses the same chamber hardware as the cooling chamber but with a lower temperature setpoint.5. Drying modules for sublimating solvent from the vials.6. Vacuum 13178167 #14412969v1MIT 26102 - 57 - connections for maintaining the vacuum environment in the drying chambers.7. Pressure sensor connection for monitoring the vacuum system.8. Sensing station for monitoring the in-situ drying progress.9. Capping system for sealing the vials for release.10. Commercial vial filling machine for placing fresh vials on the system and removing used vials after they finish lyophilizing.11. Table structure supporting the system. The lyophilization system includes 28 modules. This lyophilization system was configured to lyophilize 15 vials per hour.

[0174] The system of FIG.23 can be used as follows: a sample may be added to load lock module 1, e.g., on a tray of a magnetic mover, after being filled by commercial vial filling machine 10. The load lock module may be sealed by closing an outer load lock, and its pressure and temperature may be adjusted. In the load lock module. Once ambient conditions are appropriate and the sample is sealed, a second, inner load lock of the load lock module may open and admit the mover to conditioning module 2, where the sample is subcooled inside the conditioning chamber. The stator may be propelled out of the load lock chamber and into the conditioning chamber along an extended passageway formed by the sealing of modules 1-2 and 5 together using O-ring seals. During subcooling, the temperature in conditioning module 2 is controlled using control valve 3. Once adequately subcooled, the sample is moved by the stators into freezing chamber 4, where ice crystals are nucleated and the sample is frozen. Finally, the stators move the mover into drying chambers 5, which are placed under vacuum conditions using vacuum connections 6 and which are monitored using pressure sensor connection 7. Drying is monitored using sensing station 8. Once dry, the sample is moved by the stators to capping station 9, which seals the sample in its vial for subsequent release from the lyophilization system.

[0175] FIG.24 illustrates another photograph of a non-limiting lyophilization system, according to some embodiments, including a cooling chamber, a load lock and sensing chamber, a loading / unloading area, and a drying and capping chamber, according to some embodiments. demonstrates a research-scale system which can be used for further evaluating the lyophilization of new formulations. For very small benchtop setups, according to some embodiments, the loading and unloading module could be removed by placing a door directly on the rear of the cooling module. This system is much smaller than the continuous lyophilizer, but it includes the same module geometry as the larger continuous system. Thus, lyophilization processes developed on the four-stator research unit can translate directly to 13178167 #14412969v1MIT 26102 - 58 - the production system. This translatability resolves one of the existing problems in current lyophilization systems, where the processes developed in research must be re-determined on the production equipment due to the differences in their geometries. Accordingly, a four- stator system is both a developmental tool for learning more about lyophilization process and an evaluation tool for determining optimal freeze drying parameters in a smaller scale environment before moving to larger production runs on the continuous lyophilization system.

[0176] The above describes the design of a modular continuous lyophilizer which can be sized based on lyophilization process parameters. This system separates the lyophilization process spatially rather than temporally, such that different vials are experiencing each part of the lyophilization process simultaneously to maintain a constant throughput. This system enables a smaller internal geometry for lyophilization while maintaining high throughputs, improving system uniformity and decreasing total process time. The modular nature enables the system to be built at both production sizes and research scale sizes while utilizing the same internal geometry so that process development on the research scale system translates directly to the production level system. Accordingly 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. EXAMPLES Example 1: Non-Limiting Modular Lyophilization System

[0177] This example describes the design of a non-limiting, exemplary lyophilization system as photographed in FIG.23 (described above) and illustrates how a system can be designed using an exemplary stator / mover system sold by Planar Motors. As discussed above, a small mover was advantageous and therefore Planar Motors mover capable of crossing a 10mm gap between stators (formed between the stators of adjacent lyophilization 13178167 #14412969v1MIT 26102 - 59 - modules) was chosen. A 120mm x 180mm x 10mm mover was chosen. The stators had a nominal length and width of 239.7 mm with a maximum positive tolerance of 0.30 mm. This measurement meant that the maximum potential stator dimensions were 240 mm x 240mm.

[0178] Each standard module mounted to a single stator. The module geometry include proper tolerancing to ensure that any given stator can fit into any given module. Because this system requires numerous modules, attempting to machine each module to match a pre-assigned stator would create significant additional assembly burden. Additionally, a vacuum seal must be formed between the stator and the chamber. Accordingly, the minimum dimensions for the lyophilization module stator cavity were be no less than 240 mm x 240 mm.

[0179] O-rings are a standard gland sealing method for plugs inserted into housings. However, when going around the side of the plug, the O-rings have a minimum recommended corner radius to avoid overstressing the O-ring before vacuum load compression. This recommended corner radius is at least 3 times the diameter of the O-ring. The commercial stators had a corner radius of only 3mm, which means they would require a 1mm O-ring diameter. The smallest commonly available O-ring diameter was 1.5mm, which is larger than this specification. Additionally, stator cavity tolerancing used to ensure the stators fit in the housing would not have been able to guarantee sufficient crush on such a small O-ring diameter to ensure an effective seal. Thus, the stator was sealed into the module using injectable adhesive.

[0180] An epoxy shim layer was added to the bottom of the stator on its bolting feet during assembly. This epoxy shim layer ensured that any mismatch in the tolerance directions of the stator and the cavity did not prevent the stator and walls of the housing from both bolting to the base of the housing. This epoxy shim layer was nominally 0.005in thick, which was larger than the total potential oversizing of the stator and undersizing of the cavity depth.

[0181] The photograph of FIG.4B (discussed above) shows an exemplary, non- limiting lyophilization module used for the lyophilization system. The module housing created the main vacuum seal between consecutive modules, and it connected to auxiliary components as needed for the purpose of a given module. Each lyophilization module included features that were specific to that lyophilization module’s function and features that were shared amongst all lyophilization modules. Because each lyophilization module connects to a Planar Motors stator, a base, and a consecutive module, all modules could be 13178167 #14412969v1MIT 26102 - 60 - used for these interfaces. These features covered the bottom surface and two sides of each module. The top surface and two other sides then have features specific to each module’s purpose.

[0182] When setting up the modular system, the elements of the modules acted to constrain system assembly. As more modules were added to the system, misalignment between consecutive units could have accumulated and result in large shifts across the system. Some features were used as constraints to align consecutive modules to ensure the total misalignment does not prevent full system assembly. The effects of variation in these alignment features varied depending on which features are used for this alignment. The features that were not used as constraints for alignment suffered from the tolerance error accumulation of not only themselves, but also those of the features used for alignment. Accordingly, the features most sensitive to misalignment were used for constraining consecutive modules to each other.

[0183] Modules were cast from aluminum. Castings were made in four versions (as illustrated in FIGS.5C, 6C, 7C, and 8C), matching the four types of modules used in the final system. The shared geometry between all four versions was chosen to make the molding process easier, as elements of the core could be added or removed to change between modules, rather than requiring completely new cores for each version. The modules that transitioned between load locks and standard tunnel units were created from a casting that included material for door features on both sides by removing the extra material from the door features that was not required. While this methodology resulted in higher material costs, it introduced additional flexibility on the manufacturing side by preventing an accumulation of transition units that did not need to be utilized.

[0184] The in-gates for the cast pour were reduced from a 1.5” x 1.5” gate to a .75” x .75” gate to reduce the velocity of the metal moving through the filters, limiting the amount of oxides entering the castings. The units were cast from Aluminum 356-T6, but they could easily have been made from other materials such as stainless steel.

[0185] Based on the size of the stators and movers, the maximum allowable gap between stators was determined to be 10 mm. Most of the gap was allotted to modules with angled door features, when present, in order to accommodate the load-lock door’s extension into the gap, resulting in asymmetry for load-lock modules. The asymmetry also provided space for sealing features to be machined on the thicker side, while the thinner side remained 13178167 #14412969v1MIT 26102 - 61 - flat to interface with a sealing material. This machining choice helped ensure that the minimum thickness of any part of the wall in the gap was no less than 1.5mm.

[0186] Modules were sealed together using O-rings. A nominal 1 / 8” O-ring was used because it was the largest size which did not require cutting more than half of the material depth into the material in the gap between stators. The recommended O-ring groove parameters in the Parker handbook were used for the dovetail groove profile. The geometric errors which could create a potential gap between consecutive module faces were designed to be limited, to ensure appropriate crush was maintained on the O-ring. Without good design, geometric errors could have arisen from the module face flatness and the relative positioning between consecutive faces during assembly. The assembly error could have come from deflections in the supporting surface structure under loading and positioning of the modules on the rails. Given a nominal O-ring crush of 20%, a minimum O-ring crush of 15%, and an O-ring diameter of 0.139in, the total error allowed was calculated to be 0.007in. The flatness of the module face with the O-ring groove was allotted 0.002in of this total error. Correspondingly, the parallelism of opposite face was specified to 0.004in. The parallelism requirement also ensured that the modules’ potential offset relative to the rails could be accommodated by the sliders in the t-slotted aluminum. Thus, the positioning of the modules on the rails did not affect O-ring crush. The parallelism error apportionment was split between the seals on each face of the module, leaving 0.003in available for supporting surface deflection under load. This allocation was used in the machine table design to ensure the table structure was built sufficiently stiffly to maintain the O-ring vacuum seal. A supporting surface was chosen to keep the maximum acceptable slope difference between any two points on the machine base structure surface at this value. In this case, the supporting surface was configured to keep that slope difference below or equal to 0.00056 radians.

[0187] As established above, including this tight constraint could lead to any error propagation creating stress on the linear bearings and degrading their life. A relatively cheap linear sliding system with extruded t-slotted aluminum with Teflon sliders was used to allow modules to slide on rails on the supporting surface. The Teflon sliders had about .4mm clearance between the slider width and the corresponding slot width on the extruded t-slotted aluminum, accommodating minor positional offsets between modules.

[0188] Bolts and flanges were used to tighten the connection between adjacent lyophilization modules. These flanges had the same thickness as the tunnel walls. Bolt holes 13178167 #14412969v1MIT 26102 - 62 - were clearance holes for simplicity and to provide flexibility for minor misalignments between consecutive chamber positioning. The modules were connected using 5 / 16-18 machine screws. The bolt holes were positioned such that a standard 5 / 16 washer had a 2mm clearance from the wall. The bolt holes were spaced 1.75 inches apart from each other. These dimensions were varied based on the required spacing for ensuring the appropriate preload force on the full length of the sealing O-ring given different potential chamber dimensions.

[0189] The lyophilizer elements which incorporate vertical motion in the load lock chambers, namely, pneumatic pistons, to move load lock gates. A similar pneumatic piston was used for vial capping within the lyophilization system. The pistons used in the load-lock doors had more travel than was required for the vial capping. The load lock doors needed to move about 5in vertically, while the capping piston only needed to travel about 0.25in. If the capping piston was allowed to move over its full travel length when mounted to the roof of a chamber, it would either exit the chamber when retracting or drive through the vial during extension. Exiting the chamber would break the vacuum seal, and driving through the vial would shatter the vial and ruin the product, so the capping piston travel length was shortened. The displacement based capping strategy included a risk of imprecision of the piston displacement used to cap the vials. If the displacement set was too large, then the piston could have risked breaking a weight sensing system of the vials, or the vials themselves. If the displacement was set is too small, then the vial caps would not have been fully seated, which would prevented them from sealing the product inside the vials.

[0190] Initial testing showed that the printed surface on the pusher could sometimes generate some suction adhesion to the vial cap when it would press down, causing the system to pull the cap back up off the vial during the capping operation. Once the surface texture and foil coating were added, the pusher no longer stuck to the vial cap. Example 2: Validation of exemplary non-limiting system

[0191] FIGS.25-26 illustrate the results of size exclusion chromatography runs for myoglobin and LDH, respectively, for samples lyophilized using the lyophilization system of FIG.23. The chromatograms indicate that no major aggregation occurred after lyophilization, demonstrating that the lyophilization system worked as designed.

[0192] FIG.27 illustrates the measured enzymatic stability of catalase both before and after freezing and full lyophilization using the lyophilization system of FIG.23. The consistent stability demonstrates that the lyophilization system worked as designed. 13178167 #14412969v1MIT 26102 - 63 -

[0193] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. Accordingly, the foregoing description and drawings are by way of example only.

[0194] While several embodiments of the present disclosure 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 disclosure. 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 disclosure 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 disclosure 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 disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present disclosure. 13178167 #14412969v1

Claims

MIT 26102 - 64 - CLAIMS What is claimed is:

1. A lyophilization module comprising: a module housing including a base configured to be disposed on a supporting surface; a passage extending from a first side of the module housing to a second side of the module housing, wherein the passage includes a first opening and a second opening, wherein at least one selected from the first opening and the second opening are configured to form a seal with one or more adjacent lyophilization modules such that the passage of the module housing is aligned with a passage of the one or more adjacent lyophilization modules; and one or more stators supported in the base of the module housing, wherein the one or more stators are configured to magnetically levitate and control movement of one or more magnetic movers through the passage.

2. The lyophilization module of claim 1, wherein the first and second sides are opposite from each other.

3. The lyophilization module of any one of the preceding claims, wherein the passage is a rectilinear passage.

4. The lyophilization module of any one of the preceding claims, wherein the first opening is configured to be sealed to a first adjacent module and the second opening is configured to be sealed to a second adjacent module.

5. The lyophilization module of any one of the preceding claims, further comprising: a first magnetic mover of the one or more magnetic movers, and a fixture attached to the first magnetic mover for holding one or more vials capable of holding liquid to be lyophilized, wherein the first magnetic mover forms a portion of a lyophilization tray.

6. The lyophilization module of any one of the preceding claims, wherein the module housing includes one or more rails configured to moveably support the module housing. 13178167 #14412969v1MIT 26102 - 65 - 7. The lyophilization module of any one of the preceding claims, wherein the module housing includes an optically transparent window.

8. The lyophilization module of any one of the preceding claims, wherein the lyophilization module is at least one selected from a load lock, a preconditioning chamber, a nucleation and freezing chamber, and a freeze-drying chamber.

9. A lyophilization system comprising: a plurality of lyophilization modules configured to be sequentially connected on a supporting surface, wherein each lyophilization module of the plurality of lyophilization modules includes: a module housing including a base configured to be disposed on the supporting surface; a passage extending from a first side of the module housing to a second side of the module housing, wherein the passage includes a first opening and a second opening, wherein at least one selected from the first opening and the second opening are configured to form a seal with one or more adjacent lyophilization modules of the plurality of lyophilization modules such that the passage of the module housing is aligned with a passage of the one or more adjacent lyophilization modules; one or more stators supported in the base of the module housing, wherein the one or more stators are configured to magnetically levitate and control movement of one or more magnetic movers through the passage.

10. The lyophilization system of claim 9, further comprising one or more movers within the lyophilization system, and further comprising a vial holding product support rack attached to one or more movers.

11. The lyophilization system of any one of the preceding claims, wherein the first and second sides are opposite from each other. 13178167 #14412969v1MIT 26102 - 66 - 12. The lyophilization system of any one of the preceding claims, wherein the passage is a rectilinear passage.

13. The lyophilization system of any one of the preceding claims, wherein the first opening is configured to be sealed to a first adjacent module and the second opening is configured to be sealed to a second adjacent module.

14. The lyophilization system of any one of the preceding claims, further comprising: a first magnetic mover of the one or more magnetic movers, and a fixture attached to the first magnetic mover for holding one or more vials capable of holding liquid to be lyophilized, wherein the first magnetic mover forms a portion of a lyophilization tray.

15. The lyophilization system of any one of the preceding claims, wherein the module housing includes one or more rails configured to moveably support the module housing.

16. The lyophilization system of any one of the preceding claims, wherein the module housing includes an optically transparent window.

17. The lyophilization system of any one of the preceding claims, wherein the lyophilization module is at least one selected from a load lock, a preconditioning chamber, a nucleation and freezing chamber, and a freeze-drying chamber.

18. A method of lyophilizing a material, the method comprising: controlling movement of a magnetic mover through a passage extending through a plurality of lyophilization modules that are sequentially connected with a plurality of stators, wherein each lyophilization module of the plurality of lyophilization modules includes: a module housing sealed and connected to one or more adjacent lyophilization modules of the plurality of lyophilization modules, and one or more stators of the plurality of stators supported in a base of the module housing. 13178167 #14412969v1MIT 26102 - 67 - 19. The method of claim 18, wherein the passage is a rectilinear passage.

20. The method of any one of the preceding claims, wherein the first opening is configured to be sealed to a first adjacent module and the second opening is configured to be sealed to a second adjacent module.

21. The method of any one of the preceding claims, further comprising: a first magnetic mover of the one or more magnetic movers, and a fixture attached to the first magnetic mover for holding one or more vials capable of holding liquid to be lyophilized, wherein the first magnetic mover forms a portion of a lyophilization tray.

22. The method of any one of the preceding claims, wherein the module housing includes one or more rails configured to moveably support the module housing.

23. The method of any one of the preceding claims, wherein the module housing includes an optically transparent window.

24. The method of any one of the preceding claims, wherein the lyophilization module is at least one selected from a load lock, a preconditioning chamber, a nucleation and freezing chamber, and a freeze-drying chamber. 13178167 #14412969v1

Images