Additive manufacturing system and method using an omnidirectional magnetic movement device

Abstract

A processing system and method for manufacturing articles using an omnidirectional magnetic motion system (20) having a transport surface, and a manufacturing module having a forming surface transportable omnidirectionally on the transport surface under the control of a motion controller. The article forming apparatus provides process unit operations for forming articles on the forming surface as the manufacturing module is moved asynchronously between a plurality of processing locations on the transport surface, and has a deposition device (40) for placing build material on the forming surface, and one or more processing systems (50, 60) for forming the build material into an article.

Description

[Technical field]

[0001] The present invention relates to the use of an omnidirectional magnetic appratus to form articles such as dosage forms using additive manufacturing techniques.

[0002] Industrial manufacturing of pharmaceutical dosage forms is well known in the art and has been practiced for over 100 years. The current state of the art in pharmaceutical unit operation manufacturing of oral solid dosage forms is to incorporate a series of independent activities that can be performed in batch mode or continuously, using various process unit operations including powder dispensing, powder mixing, powder milling, wet or dry granulation, compression or encapsulation, coating, and packaging of the dosage form. The process unit operations are performed in independently operated large scale equipment, often in large physical spaces located close to or far from each other, utilizing linear and / or circuitous, intermittent, or continuous processes. This traditional coordination or relationship between operations has resulted in the need to build separate equipment, rooms, and sometimes entire facilities for the manufacture of new or generic pharmaceutical dosage forms.

[0003] Magnetic transfer devices are well known in the art. For example, U.S. Pat. No. 9,202,719 (the disclosure of which is fully incorporated herein by reference) discloses the basic structure and operation mode of an omnidirectional magnetic transfer device, also known as a planar motor. An omnidirectional magnetic transfer device or system allows for asynchronous and / or random movement, positioning, and orientation of one or more shuttles by a guide system along or on a planar transport surface of a stator. WO 2018 / 176137 A1, the disclosure of which is incorporated by reference in its entirety, discloses magnetic transfer devices with shuttles and stators of many different designs and teaches how to fix the stator using a guideway in the transfer area between the stator of the magnetic transfer device and a statorless transport system (e.g., conveyor belt, robot gripper, etc.), where the shuttle is first floated from the stator onto the guideway, then slides on the guideway (e.g., on a roller), and is moved by the statorless transport system when it leaves the magnetic working area of ​​the stator. Summary of the Invention

[0004] The present invention provides a process system and method for forming an article or processing materials or components of an article, including but not limited to additive manufacturing (including three-dimensional printing, or "3DP") that includes one or more process unit operations, an omnidirectional magnetic motion device including a magnetic field generating stator having a planar transport surface, and one or more manufacturing modules incorporating one or more magnetic field actuated shuttles that move on the planar transport surface in six directions of motion including horizontal x- and y-axes and vertical z-axis by magnetic levitation. A motion controller having one or more processors and one or more sensors controls the omnidirectional motion of the one or more shuttles on the planar transport surface. The controller system provides a method for monitoring and controlling the processing of materials, including the quality of the process, the quality and characteristics of the build material input, and the quality and characteristics of the article produced by the unit operations and the process system.

[0005] Steering of one or more substrates carried by a manufacturing module and moved by one or more shuttles allows for asynchronous and / or selective movement, positioning, and orientation of one or more substrates relative to and between one or more process unit operations to allow for the formation or processing of one or more articles on the substrates. Incorporation of one or more, and typically multiple, process unit operations into an omnidirectional magnetic motion system can provide a means for optimizing size, production rate, and flexibility for producing individual articles, such as, by way of non-limiting example, pharmaceutical dosage forms, at speeds and volumes comparable to or greater than those achieved with conventional process unit operations.

[0006] In various aspects, the process unit operation system is designed and constructed to enable flexibility and optimize the number and type of individual process unit operations and operation equipment deployed with the omnidirectional magnetic movement system at a given time. As an example, the processing system can provide and incorporate multiple construction materials at once using material deposition modules. The modules function to deposit the same or similar construction materials, or different construction materials, which may change physical state from solid particles, semi-solid solutions or suspensions, liquids, or any combination thereof.

[0007] Similarly, the apparatus can be designed and constructed to employ a variety of liquid dispensing and / or printing techniques used to form the articles, such as piezo inkjet printing, material jetting, melt deposition, extrusion, and hot melt extrusion.

[0008] Similarly, the equipment can be designed and built to employ a variety of process analytical technologies, such as near-infrared (NIR) and shortwave infrared (SWIR) spectrometers, 2D and 3D cameras that can incorporate artificial intelligence (AI) and machine learning capabilities, used for instantaneous, continuous, or intermittent monitoring and control, including closed-loop feedback control, of the quality and consistency of, and output from, the process.

[0009] The modular design allows for rapid and immediate changes in the utilization, functionality, and maintenance of process unit operations without or with less time-consuming disassembly and reassembly of equipment and assemblies typically associated with conventional discrete, serial, and parallel processing technology product manufacturing assemblies. The modular design of the processing system of the present invention can also be used for development, simulation, testing, experimentation, and similar activities on a smaller, more efficient production scale, allowing for process qualification on equipment or equipment modules that may be the exact same equipment as the modules employed in pilot or commercial scale manufacturing. Modularity allows for thorough and systematic testing and development of the process and operating conditions of an equipment or equipment module before the same equipment or equipment module is installed in a GMP-rated pilot or production facility. Modularity also allows for an equipment or equipment module to be removed from a GMP-rated pilot or production facility and placed in a processing facility for dynamic simulation of the process on a smaller scale to aid in process adjustments and troubleshooting process anomalies, and for the same equipment or equipment module to be returned to the pilot or production facility.

[0010] Non-limiting versatility of the sub-processing systems can include systems that process gaseous, particulate, solid, or liquid materials and compositions by one or more of conveying, mixing, blending, dispensing, printing, leveling, irradiating, heating, boiling, cooling, freezing, evaporating, pressurizing, vacuuming, blanketing with gas, sealing (from one element to another), dehumidifying, venting or purging gas or vapor, and other process unit operations to form articles on or within a substrate.

[0011] In various embodiments, the one or more process unit operations include a deposition system for the build material and a phase modification system that forms the build material into an article. The one or more process unit operations include a three-dimensional printing (3DP) or other additive manufacturing process operation. The article can be any solid, semi-solid, semi-liquid, or liquid product, including pharmaceutical forms, pharmaceutical or drug dosage forms, and household, industrial, or commercial products.

[0012] Non-limiting examples of substrates upon which or within which articles may be formed include trays, containers, sheets, mold parts, and packaging materials, more specifically blister cards.

[0013] The present invention provides a processing system for manufacturing articles, the processing system having: i) an omnidirectional magnetic motion device having a transport surface; ii) one or more fabrication modules having a) at least one shuttle, and b) at least one substrate having one or more forming surfaces; iii) at least one deposition device that deposits a) a component material on at least one of the one or more forming surfaces when the shuttle is positioned at a deposition position on the transport surface, and b) at least one processing system that performs a process unit operation on the component material when the shuttle is positioned at a processing position on the transport surface; and iv) a motion controller that omnidirectionally and asynchronously controls transport of the one or more fabrication modules on the transport surface between at least the deposition position and the at least one processing position to form an article.

[0014] The present invention also provides one or more additional processes or procedures that efficiently and effectively form the articles of the present invention. In an embodiment, the processing system includes an inspection system disposed above one or more inspection stations, the one or more inspection systems including one or more sensors or detectors, each of which can be AI and / or machine learning based. The method of forming the article can include performing an in-line real-time analytical evaluation of the physical and / or chemical properties of the article (e.g., tablet form) and its intermediate forms to confirm the acceptability of the fully or partially formed article or product, or to determine the need for rework of the process or unit operation process of the fully or partially formed article to create an acceptable finished article or product. In an embodiment, the inspection method and system can detect the physical properties of the article, such as the article (e.g., tablet) or its intermediate forms, or can detect processing conditions and parameters, such as liquid deposition location, specific compound content or uniformity, individual layers or total dose space volume, residual solvent / moisture content, and broken or damaged dosage forms. Non-limiting examples of processing performed on the article or its intermediate forms can include tamping, compression, etching, engraving, labeling, coloring, and visible printing. Following inspection and evaluation of the inspection results, the manufacturing module with the substrate and processed article may be returned to one of the unit operation stations for further processing according to the inspection results, as an example of asymmetric processing.

[0015] Once the unit operation processing is fully completed, the manufacturing module with the substrate and article is moved under the control of both the process unit operation controller and the motion controller, out of the unit operation processing system, and removed from the magnetic motion device for further processing, inspection, packaging, handling, and shipping.

[0016] Omnidirectional magnetic transfer systems provide trackless transport systems that can flexibly integrate a series of process unit operations performed by devices and equipment. Omnidirectional magnetic transfer devices have multiple surface tile segments that are typically square in size and arranged side-by-side with one or more adjacent tile segments. Various layouts and patterns of tile segments of a magnetic transfer device provide flexible and immediate changes of process unit operations that are not available in linear track or conveyor systems. In some embodiments, the transport surface of a magnetic transfer device or system is an extended open area, such as a square or rectangle, circle or ellipse, and control of shuttle movement is controlled to restrict or prevent shuttle movement to certain areas on the actuation coil. In other embodiments, tile segments can be arranged in various patterns to provide islands or peninsulas of non-tiled areas within or within the perimeter of the tile pattern where shuttle movement is prohibited. For example, a tile pattern can include a main elongated zone and multiple tile segments extending laterally from the main elongated zone.

[0017] A motion controller of the omnidirectional magnetic motion system has one or more processors and one or more sensors that detect the real-time position of one or more shuttles, each having a unique identification address, move the one or more shuttles across a planar transport surface according to instructions provided by a process controller, and form articles on a substrate associated with the one or more shuttles.

[0018] Incorporating the dosage formation process unit operations of the component distribution system and phase correction system into an omnidirectional magnetic movement system provides a means to optimize size, production rate, and flexibility for manufacturing individual articles, e.g., pharmaceutical dosage forms, at speeds and volumes equal to or greater than those achieved with conventional process unit operations.

[0019] The processing system, under control of the process unit operation controllers and the motion controller of the omnidirectional magnetic motion system, intelligently and efficiently moves the forming substrate along with its constituent materials and / or intermediate articles, allowing asymmetric processing of the articles by shuttle movement that carries the substrate to the precise, sometimes asynchronous, location, position and orientation required for processing. The processing system and its controller operate multiple independent manufacturing modules through the process unit operation system while maintaining continuous and / or efficient utilization of the individual process unit operations. The processing system and its controller allow reworking of a particular article on a particular manufacturing module, if necessary, simultaneously with the programmed processing routines of other manufacturing modules.

[0020] The association of the manufacturing modules with the control system and each individual substrate (e.g., blister card) and / or forming surface (e.g., recess) with its respective shuttle allows the system sensors and controller to historically and accurately track and record the movement of the manufacturing modules and their respective shuttles, substrates, and forming surfaces from the transport surface to the equipment process locations and the process unit operations performed therein. The movement of the shuttles and each forming module is controlled to move independently between unit operation locations on the transport surface based on calculated available space around other manufacturing modules moving on the transport surface, the speed of movement, planned unit operation durations, and other factors, and via the movement controllers, determines and executes an optimal path from the transport surface to each process station while avoiding collisions with other shuttles and manufacturing modules to maximize article manufacturing throughput from the processing system.

[0021] The present invention also provides a manufacturing system having one or more, typically multiple, manufacturing modules, which utilize an omnidirectional magnetic motion system. One non-limiting example of a manufacturing module is a substrate forming system that forms a substrate from a stock material and places or positions the formed substrate on a carrier. Another non-limiting example of a manufacturing module is a packaging module that applies one or more packaging elements to an article-loaded substrate and / or places the article-loaded substrate in an outer packaging material. Another non-limiting example of a manufacturing module is a separate processing system that performs one or more process unit operations in conjunction with an article forming processing system, such as a system and method for printing or placing an identification mark on a substrate or a forming surface of a substrate.

[0022] The present invention also provides a containment system and associated equipment including a containment housing that provides a containment zone above the transport surface of the stator. The containment housing has one or more transport openings in a sidewall of the containment housing that provide ingress and / or egress of manufacturing modules into and out of the containment zone, and one or more sealable openings through a ceiling or sidewall of the containment housing that provide access of manufacturing systems and unit operation processing systems to the manufacturing modules in the containment zone. The containment housing can also have one or more vent openings that allow ambient air, or conditioned gas or air (hereinafter referred to as "outside air") from outside the containment housing to flow into and through the containment zone (referred to as "process air" within the containment housing). The one or more vent openings are positioned at various locations along the containment housing to control the location and amount of outside air that is drawn into the containment housing, and the location and manner in which the process air passes through the containment zone. An air handling and filtration system including an air handling and filtration device (hereinafter "air handling device") draws outside air into the containment zone and passes process air through the containment zone. The process air may include airborne particles, entrained particles, suspended particles, dust, and liquid droplets. The air handling device is constructed and operated to maintain a negative air pressure within the containment housing, thereby ensuring that air exchange occurs from the exterior of the containment housing to the interior of the containment housing and from the interior of the containment housing through the air handling device.

[0023] In various embodiments, the containment housing is designed and constructed to have sufficient vertical height to allow the manufacturing modules to travel above the transport surface and below the process unit operation equipment that penetrates the ceiling and / or side walls of the containment housing. In some embodiments, the airflow velocity within the containment zone, particularly the horizontal airflow velocity, is controlled within the containment housing to provide effective capture and collection of droplets, particulates, and mixtures thereof, without affecting the process unit operations or the articles being formed on the substrate of the formation module. In some embodiments, the ratio of the vertical height (or average vertical height) of the containment housing to the area of ​​the containment housing is typically at least 0.1 cm / m. 2 , up to 100cm / m 2 while the ratio of the vertical height (or average vertical height) to the width (shorter lateral dimension) of the containment housing is at least 0.5 cm / m and at most 20 cm / m.

[0024] <1a> A non-limiting aspect of the present invention provides a processing system for manufacturing an article having: i) an omnidirectional magnetic motion device having a transport surface and a stator disposed under the transport surface and having a plurality of actuating coils that exert a primary magnetic field through the transport surface in response to a controlled current through an actuation circuit; ii) one or more fabrication modules having: a) one or more magnetic components that levitate and transport at least one shuttle in an omnidirectional manner above the transport surface in response to a primary magnetic field exerted by a planar body and a plurality of actuating coils, and b) at least one substrate having one or more forming surfaces; iii) a motion controller that sends a controlled current through one or more of the plurality of actuating coils to control the levitation and transport of the one or more fabrication modules; and iv) an article formation system having: a) a deposition device that deposits a build material on at least one of the one or more forming surfaces when the fabrication module is positioned at a deposition position on the transport surface; and b) a phase modification device that forms at least a portion of the deposited build material into an article within the at least one of the one or more forming surfaces when the fabrication module is positioned at a phase modification position on the transport surface. In one embodiment, the motion controller is configured to include one or more steps of asynchronously transporting the one or more fabrication modules between at least the deposition location and the phase correction location to form an article.

[0025] <1b> A non-limiting aspect of the present invention provides a processing system for manufacturing articles comprising: i) an omnidirectional magnetic moving device having a transport surface and a stator disposed below the transport surface; ii) one or more fabrication modules having a) at least one shuttle, and b) at least one substrate having one or more forming surfaces; iii) a fabrication module having a) at least one deposition device that deposits build material on at least one of the one or more forming surfaces when the shuttle is disposed at a deposition location on the transport surface; and b) at least one processing system that performs a process unit operation on the build material when the shuttle is disposed at a processing location on the transport surface; and iv) a motion controller that asynchronously controls the transportation of the one or more fabrication modules on the transport surface between at least the deposition location and the at least one processing location to form an article. The stator has a plurality of actuation coils that generate the primary magnetic field through the transport surface in response to a control circuit current through an actuation circuit. The shuttle has one or more magnetic components that levitate and transport at least one shuttle omnidirectionally above the transport surface in response to a primary magnetic field generated by a planar body and a plurality of actuation coils.

[0026] <1c> A non-limiting aspect of the present invention is a processing system including: i) an omnidirectional magnetic moving device having a transport surface; ii) at least one shuttle having a planar body and one or more magnetic components that interact with the magnetic moving device to levitate and transport the at least one shuttle omnidirectionally above the transport surface; and b) one or more fabrication modules having at least one substrate having one or more forming surfaces; iii) a) a deposition device that deposits a component material on at least one of the one or more forming surfaces when the shuttle is placed at a deposition position on the transport surface; and b) a phase modification device that forms at least a portion of the deposited component material into an article within at least one of the one or more forming surfaces when the shuttle is placed at a phase modification position on the transport surface; iv) a control system that controls the deposition device and the phase modification device of the article forming system and the movement of the one or more fabrication modules on the transport surface of the omnidirectional magnetic moving device; wherein the motion controller is configured to have one or more steps of asynchronously transporting the one or more fabrication modules between at least the deposition position and the phase modification position to form an article.

[0027] <1d> In one aspect, the present invention provides a processing system for the manufacture of articles, including by one or more process unit operations, the AM system comprising: i) a horizontal planar transport surface having a perimeter extending in a first direction and a transverse second direction, and having an upper transport side and a lower side; ii) a stator disposed below the transport surface, the stator having a primary actuation circuit and a plurality of primary pairs of primary actuation coils that exert a primary magnetic field through the transport surface and on the upper transport side in response to controlled current through the actuation circuit; iii) one or more fabrication modules having: a) at least one shuttle having one or more magnetic components that interact with a planar body and the plurality of actuation coils to levitate and transport at least one shuttle in an omnidirectional manner above the transport surface; and b) at least one substrate having one or more forming surfaces; and iv) a motion controller that sends a controlled current through one or more of the plurality of actuation coils to control the levitation and transport of the one or more fabrication modules. the transport of the shuttle includes a) moving the shuttle in a first direction, a second direction, or a combination thereof between two or more positions on the transport surface, b) rotating the shuttle about at least one orthogonal axis of the shuttle, and c) combinations thereof; and v) an article formation system having a) a deposition device that deposits a build material on at least one of the one or more forming surfaces when the shuttle is positioned at the deposition position on the transport surface, and b) a phase modification device that forms at least a portion of the deposited build material within at least one of the one or more forming surfaces into the shape of an article when the shuttle is positioned at a phase modification position on the transport surface; and the motion controller is configured to include one or more steps of asynchronously transporting the one or more manufacturing modules at least between the deposition position and the phase modification position to form an article.

[0028] <1e> One aspect of the present invention is an omnidirectional magnetic moving device having: i) a transport surface and a stator disposed under the transport surface, the stator having a plurality of actuating coils that exert a primary magnetic field through the transport surface in response to a controlled current through an actuation circuit; ii) one or more fabrication modules having: a) at least one shuttle having one or more magnetic components that levitate and transport at least one shuttle in an omnidirectional manner above the transport surface in response to the primary magnetic field exerted by a planar body and the plurality of actuating coils, and b) at least one substrate including one or more forming surfaces; and iii) a magnetic actuator that controls the levitation and transport of the one or more fabrication modules through one or more of the plurality of actuating coils. and iv) an article formation system having: a) a deposition device that places a build material on the at least one forming surface when the fabrication module is positioned at a deposition position on the transport surface; and b) a phase modification device that forms at least a portion of the deposited build material in the at least one forming surface into an article when the fabrication module is positioned at a phase modification position on the transport surface; wherein the motion controller is configured to include one or more steps of asynchronously transporting the one or more fabrication modules between at least the deposition position and the phase modification position to form an article.

[0029] <1> The aspects of the present invention can include any one of features <1a> to <1e>.

[0030] <2> Features <1a>~ <2> In any of the embodiments, the motion controller is configured to include one or more steps of asynchronously transporting the one or more manufacturing modules between at least the deposition location and the phase correction location to form an intermediate product or a finished product.

[0031] <3> Features <1a>~ <3> In any of the embodiments, the transport surface comprises a continuously formed sheet that is non-conductive, and the sheet can be made of a material selected from the group consisting of polymer, glass, titanium, and stainless steel.

[0032] <4> Features <1a>~ <3> In any of the aspects, the transport surface is a rectangular region comprising a central region and a peripheral region, optionally the transport surface is a rectangular region comprising a central region and a peripheral region, the surface temperature of such region being controlled by circulation of a suitable heat transfer medium through an interior region of the stator to control and maintain the temperature of the transport surface, the peripheral region having a width dimension at least the width of the manufacturing module and the central region being at least the width of the manufacturing module.

[0033] Features <1a>~ <4> In any of the embodiments, the stator includes a second actuation circuit and a second set of multiple pairs of second actuation coils, the second actuation circuit and second actuation coils exerting a second magnetic field through the transport surface to an upper transport side in response to a controlled current through the actuation circuit, the force of the second magnetic field being greater than the force of the first magnetic field.

[0034] <5> Features <1a>~ <5> In any of the embodiments, the one or more fabrication modules further comprise a carrier that secures the substrate onto the at least one shuttle.

[0035] <6> Features <1a>~ <5> In any of the embodiments, the one or more forming surfaces have one or more recesses.

[0036] Features <1a>~ <6> In any of the embodiments, the step of transporting the shuttle further includes pivoting the shuttle about a horizontal axis through the shuttle, about a vertical axis through the shuttle, or about a combination of both horizontal and vertical axes sufficient to effect a change in the distribution of the deposited build material on the one or more build surfaces, preferably including planarizing the deposited build material to a uniform thickness by controlling at least one or more of the following factors: pivot angle, acceleration, and frequency.

[0037] Features <1a>~ <6> In any of the embodiments, movement of each of the multiple manufacturing modules to and from each of the deposition positions and the phase modification positions is independent and selective, providing the ability to asynchronously form a dosage form on the at least one substrate in two different manufacturing modules.

[0038] Features <1a>~ <6> In any of the embodiments, the deposition device places the build material on the one or more build surfaces based on at least one of volume and mass.

[0039] <7> Features <1a>~ <6> In any of the embodiments, the one or more manufacturing modules include a plurality of manufacturing modules, each of which is independent and selective in movement to and from each of the deposition positions and the phase correction positions, providing the ability to asynchronously form an article on at least one of the substrates in two different manufacturing modules.

[0040] <8> Features <1a>~ <7> In any of the embodiments, the processing system or sub-processing system further comprises means for planarizing the deposited component material to a uniform thickness.

[0041] <9> Features <1a>~ <8> In any of the embodiments, the processing system or sub-processing system further comprises one or more additional processing equipment selected from the group consisting of a drying equipment, a component leveling equipment, a surface finishing equipment, a substrate loading equipment, a substrate unloading equipment, and combinations thereof.

[0042] <10> Features <1a>~ <9> In any of the embodiments, the processing system or sub-processing system further includes a surface finishing device that surfaces at least one upper surface of the deposited build material or solid dosage form in the forming surface when the shuttle is positioned in a surface finishing position on the transport surface.

[0043] <11> Features <1a>~ <10> In any of the embodiments, the processing system or sub-processing system further comprises a deposition detection device that detects the uniformity of distribution of the deposited component material on the one or more build surfaces.

[0044] <12> Features <1a>~ <11> In any of the embodiments, the building material may comprise an ingestible powder material; the building material or the ingestible powder material may comprise an active agent, non-limiting examples of which include an API, a biological material, or a drug. The article may be a solid dosage form, and the phase modifying device may comprise a means for dispersing a binding liquid that forms the ingestible powder material into a bound powder material having an interconnected matrix of the ingestible powder material. The building powder material may comprise a particulate binder. The binding liquid may comprise an active agent, non-limiting examples of which include an API or a drug. The binding liquid may comprise a soluble binder material. The interconnected matrix of the building powder material may be porous and, in some embodiments, rapidly disperses in the oral cavity. The building material may comprise at least one heat-fusible powder material, and the phase modifying device may comprise a means for at least partially melting the heat-fusible material.

[0045] Features <1a>~ <11> In any of the embodiments, the processing system or sub-processing system further comprises a device, apparatus, or subsystem that stores, delivers, and / or deposits a co-active agent on the component or phase-modifying component. Non-limiting examples of active agents include APIs or drugs, and / or materials with specific functionality designed to impart targeting sites or release rates of biologically active agents. The co-active agent can be in particulate or liquid form, optionally in solid, particulate, or liquid form, together with one or more optional solvents, free-flowing adjuvants, diluents, and carrier materials.

[0046] The invention also provides a method of transporting a shuttle or shuttles on a stator using a guide system with an omnidirectional magnetic transport system that provides synchronous and / or asynchronous movement of the shuttle or shuttles to transport and optimize positional orientation of the shuttle or shuttles transporting the substrates to and between unit operation processing equipment that, in an example of asynchronous processing, performs corresponding process unit operations on the substrates in series, parallel, and / or simultaneously to optimize processing efficiency and process utilization.

[0047] Methods and systems for omnidirectional, asynchronous movement of substrates to and between processing equipment provide for selectively processing one or more articles simultaneously through one or more process unit operations, within a small space, and in less time than conventional processing systems for the same articles.

[0048] <13> Aspects of the invention provide methods of using a planar motor system to transport one or more manufacturing modules through multiple process unit operations utilized in the additive manufacturing of a dosage form, where the transport is controlled (either explicitly or via machine learning, artificial intelligence, or other position scheduling approaches) to achieve asynchronous, synchronous, and random positioning and orientation, thereby achieving asynchronous and simultaneous utilization of process unit operations in forming the dosage form.

[0049] <14> Features <13> In one embodiment, the plurality of process unit operations include dispensing a quantity of building material onto one or more forming surfaces of a manufacturing module, and modifying the quantity of building material disposed on the one or more forming surfaces of the manufacturing module into a solid dosage form.

[0050] <15> Features <13> or <14> In any of the embodiments, the plurality of process unit operations further comprises one or more process unit operations selected from the group consisting of mixing two or more different components, planarizing a top surface of the bulk components, finishing an exterior surface of the solid dosage form, inspecting one or more physical properties of a material, and cleaning contaminated equipment or devices used in the method.

[0051] <16> Features <13> ~ <15> In any of the aspects, the build material is an ingestible powder material and the phase modification comprises printing a liquid material having a solvent or other volatile compound onto a layer of the ingestible powder material, and optionally drying excess of the solvent or other volatile compound from the wet powder layer.

[0052] <17> Features <13> ~ <16> In any of the embodiments, the plurality of process unit operations include dispensing a bulk of ingestible powder onto one or more forming surfaces of a manufacturing module, planarizing a top surface of the bulk of ingestible powder disposed on the one or more forming surfaces of the manufacturing module to form a powder layer, printing a liquid material including a solvent or other volatile compound onto the top surface of the disposed bulk of powder to form a wet powder layer on the one or more forming surfaces of the manufacturing module, and optionally drying excess of the solvent or other volatile compound from the wet powder layer.

[0053] <18> Features <13> ~ <17> In any of the embodiments, the method further comprises a process unit operation of printing a liquid material having a solvent onto one or more forming surfaces of the substrate prior to dispensing the ingestible powder.

[0054] <19> Features <13> ~ <18> In any of the embodiments, said additive manufacturing of the dosage form is selected from the group consisting of binder jetting, material jetting, stereolithography, fused deposition, laser sintering, and extrusion.

[0055] <20> Features <13> ~ <19> In any of the embodiments, cleaning the device or equipment comprises positioning a cleaning substrate in sufficient proximity to a particular process unit operation and spatially manipulating the cleaning substrate and at least one of the contaminated device or equipment to clean one or more surfaces of the contaminated device or equipment. [Brief description of the drawings]

[0056] [Figure 1] FIG. 1 illustrates a processing system having an omnidirectional magnetic transfer device, a containment system, and multiple process unit operation systems for forming articles on a transport module. [Diagram 2] FIG. 2 shows a containment housing having access ports for placing process equipment on the transport surface. [Diagram 3] FIG. 3 shows a plan view of the transport surface of an omnidirectional magnetic transfer device, illustrating the individual tile segments and unit operation processing stations between which groups of transport modules can be moved and positioned. [Figure 4] FIG. 4 shows a bottom perspective view of a fabrication module including a shuttle, carrier, and substrate. [Diagram 5] FIG. 5 shows a top perspective view of the fabrication module of FIG. 4 and a mask that can be placed on a substrate. [Figure 6] FIG. 6 shows an exploded view of the elements of the manufacturing module of FIG. [Figure 7] 7A and 7B show an air treatment and filtration device that provides air treatment and separation of airborne particles and droplets. [Figure 8A] FIG. 8A shows a top perspective view of a powder dosing device dispensing powder material onto an individual forming surface of a substrate. [Figure 8B] FIG. 8B shows an exploded view of the elements of the powder dosing device of FIG. 8A. [Figure 9A] FIG. 9A shows a partial cutaway perspective view of the powder leveling device in a raised position. [Figure 9B] FIG. 9B shows the powder leveling device of FIG. 9A in a lowered position. [Figure 10] FIG. 10 shows a bottom perspective view of a liquid printing device. [Figure 11A] FIG. 11A shows a bottom perspective view of a surface finishing apparatus for finishing a top surface of an article formed on a substrate. [Figure 11B] FIG. 11B shows a top perspective view of the surface finishing apparatus of FIG. 11A. [Figure 12] 12A and 12 show an imaging device scanning the surface contour of a substrate and the build material deposited within recesses in the substrate. [Figure 13] FIG. 13 shows a top front perspective view of a print nozzle cleaning apparatus for use with the shuttle. [Figure 14] FIG. 14 is a perspective view of the print nozzle cleaning device of FIG. 13 as seen from the top rear. [Figure 15] FIG. 15 shows an exploded view of the elements of the print nozzle cleaning device of FIG. [Figure 16A] FIG. 16A shows a top front perspective view of a finish cleaning apparatus for use with a shuttle. [Figure 16B] FIG. 16B shows a bottom front perspective view of the finish surface cleaning apparatus of FIG. 16A. [Figure 16C] FIG. 16C shows an exploded view of the elements of the finish cleaning apparatus of FIG. 16A. [Figure 17A] FIG. 17A shows a perspective view of a mask lifting device that lifts and removes a mask from a manufacturing module. [Figure 17B] FIG. 17B shows a perspective view of the manufacturing module of FIG. 17A, where a mask lifting device lifts the mask in a hinged manner. [Figure 18] FIG. 18 illustrates in plan view a processing system including a transport surface, a containment system, and a multiple process unit operation system disposed within the containment system and above the transport surface to form tablet shapes. [Figure 19A] FIG. 19A shows a top perspective cross-sectional view of a typical recess in a blister card passing through a laser stripe plane to generate a first laser stripe image along the contour surface of the blister card. [Figure 19B]FIG. 19B shows a cross-sectional side view of the corrected elevation profile of the contoured surface of the blister card determined from the laser stripe image generated in FIG. 19A. [Figure 20A] FIG. 20A is a top perspective cross-sectional view of the blister card of FIG. 19A showing the laser stripe surface passing through a second portion of the blister card to create a second laser stripe image along the contoured surface of the blister card. [Figure 20B] FIG. 20B shows a cross-sectional side view of the corrected elevation profile of the contoured surface of the blister card determined from the laser stripe image generated in FIG. 20A. [Figure 21A] FIG. 21A shows a top perspective cross-sectional view of a partially filled recess in the blister card of FIG. 19A, passing through the laser stripe plane to generate a laser stripe image along the contour surface of the blister card. [Figure 21B] FIG. 21B shows a cross-sectional side view of the corrected elevation profile of the contoured surface of a blister card having a partially filled recess, as determined from the laser stripe image generated in FIG. 21A. [Figure 22A] FIG. 22A is a top perspective cross-sectional view of the blister card of FIG. 20A showing how the laser stripe surface passes through a second portion of the blister card having partially filled recesses to generate a laser stripe image along the contour surface of the partially filled recesses. [Figure 22B] FIG. 22B shows a cross-sectional side view of the corrected elevation profile of the contour surface of a partially filled recess of a blister card, as determined from the laser stripe image generated in FIG. 22A. Detailed Description of the Invention

[0057] Definition: "Active agents" include, but are not limited to, one or more of drugs, active pharmaceutical agents (APIs), nutrients, pharma- ceutically acceptable agents, bioactive agents, therapeutic agents, diagnostic agents, and preservatives or bactericides. Active agents include compounds or compositions that provide biological activity in a mammalian or non-mammalian species; e.g., pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affecting the structure and function of a mammalian or non-mammalian species. Diagnostic agents include imaging agents and / or radiolabeled compounds. Active agents can be small molecule therapeutics, peptides, and / or proteins.

[0058] As used herein, an "article" is an object or composition of matter. Non-limiting examples of objects include tablets or implants. Non-limiting examples of compositions of matter include liquids, semi-solids, or solid materials.

[0059] As used herein, a "component" is a material (solid, semi-solid, liquid, or liquefied gas) that is a part or portion of an article or composition, or a portion thereof, or any intermediate thereof.

[0060] As used herein, a "process unit operation" includes, but is not limited to, a process involving the physical change or chemical transformation of a material or composition involved in the supply, delivery and distribution of a component or intermediate product for an article, or the processing of an article or intermediate product, or a compound, composition or material including a component, and may further include the unit operations described below.

[0061] <Omnidirectional magnetic moving device> 1, an omnidirectional magnetic moving device 20 has a horizontal and planar (xy coordinate) transport surface 16 along and above which one or more transport units having permanent magnets (or electromagnets), referred to herein as shuttles, are transported in a horizontal plane in the xy direction to designated xy locations in designated xy directions. Drive coils located below the transport surface, referred to as stators, are controlled by a control unit to generate alterable and adjustable magnetic fields through the transport surface to levitate and move one or more shuttles in desired horizontal directions on the transport surface. Details of the design and construction of omnidirectional magnetic moving devices and systems are described in International Patent Publications WO2018 / 176137, WO2020 / 073118, WO2020 / 243814, and WO2021 / 119819, the disclosures of which are incorporated by reference in their entirety.

[0062] Alternatively, the stator may consist of permanent magnets and the shuttle may be equipped to generate a controlled magnetic field that levitates and moves over the stator. However, in the context of this disclosure, regardless of the mode of operation, the stator shall be referred to as an assembly of fixed and controllable electromagnets, and the transport unit shall be referred to as a permanent (or electromagnetic) magnet shuttle that is movable over the stator.

[0063] 1-3 show a process facility 10 including an omnidirectional magnetic transfer device 20 (hereinafter also referred to as process transfer device 20) integrated with one or more, typically multiple, process unit operations. The process facility 10 includes a process platform 12 that includes or houses the omnidirectional magnetic transfer device 20, as well as electronic and electrical connections and process utilities for operation of the process facility including the process transfer device. The process facility 10 also includes a platform surface 13 that covers the process platform 12. A portion of the platform surface 13 includes a transport surface 16 beneath which the omnidirectional magnetic transfer device 20 resides.

[0064] The process transfer device 20 includes a magnetic transfer stator 21 that includes a plurality of magnetic transfer subunits, or tile segments 22, each of which consists of a stator or a single group of stators housed within a housing. The tile segments 22 are joined end to end and integrated to form a matrix of tile segments, each of which is approximately 9 inches (22 cm) square, or approximately 1 foot (30 cm) square. The integrated tile segments 22 can be oriented in a wide variety of configurations. In the illustrated embodiment, the integrated tile segments are arranged 2 tile segments wide by 12 tile segments long. The platform surface 13 is disposed on the top surface of the housing of the integrated tile segments 22, a portion of which is disposed directly above the integrated tile segments that provide the transport surface 16. The platform surface 13, particularly the portion above the integrated tile segments, is a thin non-magnetic sheet, such as a non-magnetic stainless steel plate. In the embodiment shown in FIG. 1, the platform surface 13 has a rectangular area that is 4 feet wide and 13 feet long.

[0065] The transport surface 16 can have one or more processing stations and one or more inspection stations, unit operation processing equipment can be located at and above the one or more processing stations, and inspection equipment can be located at and above the one or more inspection stations. As described herein, the shuttle can travel to a processing station to be positioned and oriented below the processing equipment, or can travel to an inspection station to be positioned and oriented below the inspection equipment.

[0066] <Shuttle> A number of drive magnets (permanent or electromagnets) are positioned within the plane of the shuttle's planar body and are covered or encased in stainless steel, durable plastic, or similar continuous material. The magnetic field of the on-board drive magnets interacts with the generated and controlled magnetic field of the stator, exerting a drive force on the shuttle in an intended and directed direction to move the shuttle along the transport surface and to move the shuttle itself on the transport surface. The shuttle can move on the transport surface in three position rotations (pitch, roll, yaw) and in three orthogonal directions of movement (including horizontal directions x and y and vertical direction z).

[0067] In this manner, the multiple drive coils in the stator and the multiple drive magnets in the shuttle are arranged to allow the shuttle to move in all six degrees of motion, achieving the simplest to most complex movements of the shuttle with high precision.

[0068] The omnidirectional magnetic motion system may also include one or more sensors that transmit the position of the shuttle. In one embodiment, the motion controller uses the real-time position of the shuttle to activate one or more stator drive circuits to drive actuation coil assemblies, thereby interacting with one or more magnets of the shuttle to move the shuttle over the transportation surface.

[0069] Each shuttle in the omni-directional magnetic transfer system is provided with a unique shuttle identification code. The shuttle (magnetic transfer device) also has at least one shuttle identification device, while the stator has at least one stator identification device that can interact with the at least one shuttle identification device to associate a unique shuttle identification code with that particular shuttle, and one or more sensors that sense the position of the particular shuttle. A control system can continuously track the position of the stator and the magnetic field it generates to move, position, and orient the shuttle as directed.

[0070] The present invention provides a processing system and method that uses an omnidirectional magnetic (process) motion device as a means for transporting substrates through a manufacturing process that employs one or more, preferably multiple, process unit operations. Figures 4-6 show a fabrication module 70 incorporating a shuttle for positioning and moving the fabrication module on the transport surface 16 of the omnidirectional magnetic motion device 20. The 24 tile segments 22 shown (segments A1-A12 and B1-B12) are integrated into a unitary stator 21 that underlies and forms part of the unitary transport surface 16 of the platform surface 13.

[0071] The shuttle typically has a square planar shape (other shapes are possible) with a perimeter and has a hard durable plastic cover. Alternatively, the shuttle may have a continuous stainless steel cover with no seams. A feature of the shuttle allows for a carrier to be attached to the top or perimeter of the shuttle, which allows the shuttle to transport the carrier and any material or object placed on the carrier.

[0072] In various aspects, the system may include subsystems and processes performed to deliver a shuttle to a process mover device and associate the shuttle with a unique identification address to the process mover device.

[0073] <Transportation and manufacturing modules> A transport module is a magnetically movable device that includes at least one shuttle and, in various embodiments, a carrier. The carrier is a structural device that has a lower portion configured to be attached to the surface of the shuttle in a predetermined orientation, and an upper portion that supports or is attached to a substrate. Typically, the carrier is fixed or secured to the shuttle. A transport module can have a single shuttle, but two or more shuttles can also be combined into a single transport module. The structural device of the carrier can be any suitable material of construction, such as plastic, ceramic, metal, or composites thereof. The carrier connects the substrate with at least one shuttle.

[0074] A fabrication module as described herein is a transport module having a substrate attached or secured to a carrier. The substrate can be any device or material upon which a component material of an article, such as a solid, solid particle, semi-solid, or liquid, or a raw material, component, or reactant of a process or unit operation that produces the article, is placed or deposited. An example of a fabrication module 70 is shown in Figures 4-6.

[0075] The movement and positioning of the manufacturing module by the process movement device is important to the operation of the process unit operation device associated with or interacting with the manufacturing module. For example, after a manufacturing module is moved to a component material distribution device and properly positioned and oriented, the movement controller can send a command to the process unit operation controller notifying or confirming that the particular manufacturing module is properly positioned and oriented, so that the process unit operation controller can continue to control the process unit operation and the unit operation device or devices. In some process unit operations, the process proceeds while the manufacturing module is fixed in position and orientation, while in other process unit operations, the process unit operation proceeds while the manufacturing module is moved. In some embodiments, the manufacturing module moves in any one or combination of the sixth degrees of freedom of movement along with the movement of the shuttle, for example, horizontal (x,y) directions, vertical (z) directions, rotational movement through a vertical axis perpendicular to the plane of the shuttle, or combinations thereof. In some embodiments, the shuttle can oscillate in either or both horizontal axes through the plane of the shuttle, causing an oscillatory movement of the shuttle and a vibration at the same frequency of the manufacturing module secured thereto.

[0076] A process movement controller tracks the movement and position of manufacturing modules through one or more unit operations, allowing the product manufacturing process to be fully controlled to individually manufacture an individual or multiple products for a single unique customer or patient.

[0077] <Substrate> A substrate is a device or molded material onto which component materials of an article or reactants for a process unit operation that produces an article are placed or deposited. Non-limiting examples of component materials include solid, solid particulate, semi-solid, liquid, or liquefied gas components of the article produced in process facility 10.

[0078] The substrates may be formed in an integrated substrate forming system and process, or more generally, may be formed at a separate and remote location from the processing system where the article or intermediate of the article is processed and formed. The formed substrates are then sent to an omnidirectional magnetic transfer system and / or a containment system for further processing. The substrate forming system may include a substrate forming device that forms the substrate from a stock material (e.g., a thermoplastic film), a stock film feeder that feeds the stock material to the substrate forming device, and a loading system that positions and deposits the formed substrates onto a carrier of a transport module. The substrates may be formed on demand as needed, or may be preformed and stacked or grouped for use. In the latter aspect, the processing system may include a substrate staging area and a device that uses a combination of a vertical lift arm and a destacking mechanism (separating a single top substrate from a stack of substrates) to remove stacked substrates and place non-stacked substrates onto the transport module, more specifically, onto the carrier of the transport module.

[0079] In some embodiments, the substrate can be a flat surface and one or more articles can be formed on the flat surface. In other embodiments, the substrate can be a container for one or more materials. In some embodiments, the container can be a mold having one or more recesses in which the articles are produced by process unit operations and then released or ejected from the one or more recesses. In some embodiments, the recesses in the mold have the shape of a tablet or other dosage form, including, but not limited to, cylindrical or oval.

[0080] In one particular embodiment, and in various embodiments of the process for forming articles on a substrate using processing equipment 12, the substrate is a blister card in which one or more, usually a plurality of, recesses are arranged, providing both a molded form for processing the article and packaging for the article.

[0081] Blister cards can have any usable surface shape or size and number of blister recesses as desired or needed. In various embodiments, a blister card having a single forming surface formed as a recess can be at least 1 centimeter (cm) in length and width, and up to several centimeters. A blister card typically has several, up to dozens or more forming surfaces formed as recesses, and can have length and width dimensions of about 5 cm to 20 cm each. A stock roll of blister cards that is typically divided into a number of individual blister cards can have hundreds, thousands, or more forming surfaces formed as recesses. In one non-limiting example, a blister card is about 10-15 cm wide, about 16-20 cm long, and has 2-40 forming surfaces formed as recesses. In one embodiment, a blister card is about 20 cm long, 13 cm wide, and has 24 preformed recesses (6x4 layout). In another embodiment, a blister card is about 13 cm long, 10 cm wide, and has 12 preformed recesses (6x2 layout). An example of a blister card 80 is shown in FIG.

[0082] Non-limiting examples of substrates include blister trays and 3D printing support structures having connecting members that removably connect to a planar structure and a 3D printing tablet, as described in U.S. Patent Application Publication No. 2021 / 0205228, the disclosure of which is incorporated by reference in its entirety.

[0083] In certain embodiments, the substrate forming system and process includes a marking system that marks (e.g., by printing) a unique identification code, such as a lot number, digital address code, 2D barcode, data matrix, or QR ("quick response") code, on the substrate, including the forming surface of the substrate. The marking can be a visible marking or an invisible marking that is not visible to the naked eye, using suitable visible or invisible inks. In various embodiments, the marking is formed on one or more surfaces of the substrate (e.g., the top and bottom surfaces of a blister card), or on each forming surface (e.g., the top surface of the recess bottom and / or the bottom or underside of the recess bottom of each blister recess). The marking can be detected and read by a scanner or imaging system, and the unique identification code is communicated and input to a controller of a process control system. The process control system associates the unique identification code of the physical substrate with the unique shuttle identification code of the particular shuttle that transports the fabrication module to which the physical substrate is transported. When the manufacturing model carrying the substrate is moved to a unit operation processing station under the control of the motion controller, the process unit operation controller associates the substrate's unique identification code with the unit operation process and creates a record of the execution and completion of the unit operation process using the same substrate's unique identification code. This control and recording process can be repeated at each unit operation processing station and inspection station used in the manufacture of the product.

[0084] In some aspects, the substrate forming system and process also includes a substrate transfer system consisting of an omnidirectional magnetic transfer system dedicated to the substrate forming system. The substrate forming system, including the substrate forming apparatus, the stock film supply apparatus, and the loading system, is disposed on a transport surface of the substrate transfer apparatus. A transport module (shuttle with carrier) can be disposed adjacent to the loading system, which positions and places the formed substrate on the carrier and provides the fabrication module. A marking system is also included to mark the formed substrate as described above. A scanning system is also included to detect the identification code of the marked substrate and the carrier of the transport module. The fabrication module can then be moved along the transport surface of the substrate transfer apparatus to an exit under the control of the motion controller. In various aspects, the substrate transfer apparatus can be integrated with the process transfer apparatus for seamless movement between the transport module and the fabrication module.

[0085] <Substrate mask> A mask having one or more openings can be placed on the top surface of the substrate, with the one or more openings aligned with one or more forming surfaces of the substrate. In one embodiment, the mask is a sheet having a perimeter shape and size that overlaps or aligns with the perimeter of the blister card substrate, and the mask sheet has a plurality of openings that align with the openings corresponding to the recesses of the blister card. In an embodiment, the mask sheet can have one or more openings of any regular, irregular, or geometric shape as desired or required, including, as non-limiting examples, circular, elliptical, and oval, that may be required to achieve the functional performance or design aesthetic of the article. Conventional blister cards usually have circular recesses and openings, so a typical mask has a plurality of circular openings that align with the circular openings of the recesses.

[0086] In one embodiment, the mask can remove one or more portions of the sheet, typically along the edge of the substrate (blister card), to form an opening or window that matches a unique identification code printed on the substrate, thereby exposing the substrate's unique identification code for scanning and / or imaging, identifying and registering the specifically identified substrate with the processing and motion control systems, and allowing the blister card to be moved, tracked, and positioned throughout subsequent unit operation processing.

[0087] In various embodiments, the mask includes a means for removably attaching to the top surface or portion of the carrier, inhibiting or preventing the blister card from moving or separating from the carrier, covering the planar surface of the top surface of the film of the blister card in a continuous area surrounding the recess, and inhibiting and preventing the deposition of construction materials and phase-modifying fluids on the top surface of the film that is then contacted and sealed with the sealing film. An example of a mask 90 is shown in FIG.

[0088] The manufacturing module shown in Figures 4-6 includes a transport module consisting of a shuttle 75, which can be moved on a transport plane by a stator, a carrier 72, and a substrate 80. The carrier 72 has a base 73 with a planar cavity into which the shuttle 75 fits snugly. The base 73 is oriented over the shuttle 75 by a pair of fasteners, shown as screws 76, which pass through holes 77 disposed in adjacent side walls of the base 73 and strike the sides of the shuttle 75. Four posts 173 extend vertically from the four corners of the base 73. The carrier 72 also has an upper portion, called the nest 74, which has four support retainers 174, which consist of a short hollow cylinder into which the upper ends of the four posts 173 extend to form the semi-rigid structure of the carrier, and between each post 173 and the support retainer 174 is a spring 175. Spring 175 is selected to provide flexibility so that a portion of the spring "flexes" as nest 74 passes under equipment in the containment zone. One function of the spring is to suspend nest 74 above post 173 so that the upper end of post 173 maintains a clearance space with support retainer 174 of nest 74 and does not come into contact with support retainer 174 of nest 74 and dead-end.

[0089] The nest 74 has a number of openings 78 formed in its top surface to align and receive all of the recesses of the blister cards. The substrate 80 is a dual tray blister card having blister cards 82a and 82b with first and second six recesses in a blister frame 81. The blister frame 81 has a common retaining pin at each corner of the blister frame 81 such that any orientation of the blister frame 81 will align with a corresponding common retaining slot 182 in the top surface of the nest 74. The nest 74 and blister frame 81 also have a means for positioning the blister frame 81 in only one orientation on the nest 74. The blister frame includes a pair of closely spaced orientation pins 186 at opposite longitudinal (or lateral) ends and a pair of spaced apart orientation pins 187 at one longitudinal (or lateral) end. The adjacent orientation pins 186 of the blister frame 81 align and fit only with the adjacent orientation slots 183 of the nest 74, and the spaced apart orientation pins 187 of the blister frame 81 align and fit only with the spaced apart orientation slots 184 of the nest 74.

[0090] The mask 90 is placed on the blister frame 81 to prevent the unformed film portions of the blister card 82 (those portions of the film surrounding the recesses) from contacting or contaminating the construction or processing materials. Excessive spray of printing fluid on the outside of the recesses or on the unformed film portions may prevent the sealing film from being properly secured over the formed dosage forms of the blister card. As shown in Figures 5 and 6, the mask 90 has a planar frame 91 with a plurality of circular openings 92 that correspond to and align with the openings of the plurality of recesses 84 of the blister cards 82a, 82b when oriented toward the nest 74. The mask includes hinge members shown as a pair of lift pins 94 extending from opposite sides of the frame 91 at the front end of the mask, and a pair of hinge pins 99 extending from opposite sides of the frame 91 at the rear end of the mask, and includes hinge members shown as a pair of clamps 99 that engage with a pair of hinge members on opposite sides of the frame 91 at the rear end of the nest 74 and have slots that respectively receive the pair of hinge pins 99 to form a pair of hinges, thereby allowing the front end of the mask 90 to rotate upwardly and away from the nest 74.

[0091] The nest 74 also has a leading edge with a recess 188 having an undercut pattern at the leading edge of the blister card 80 such that a user's finger or other instrument can be aligned with the recess to lift the leading edge of the blister card 80 when removing the blister card 80 from the nest 74. Similar recesses 88 are formed in the side edges of the nest 74 and have an undercut pattern at the leading edge of the blister card 80 such that a user's finger or other instrument can be aligned with the recess to lift the leading edge of the blister card when removing the blister card 80 from the nest 74.

[0092] <Module movement> Each independent transport or manufacturing module can move independently of the other transport or manufacturing modules and can move in a different direction and pattern than the other transport or manufacturing modules. A transport or manufacturing module can move on the transport surface at a speed of up to 2 m / s, typically 0.1 to 0.75 m / s, and can move at a speed of up to 5 m / s. 2 It can accelerate up to

[0093] The shuttle movement can be configured to operate under control of the motion controller with the substrate secured to the carrier and the carrier secured to the shuttle, and once the substrate is removed from the carrier, the shuttle can be automatically moved under control of the motion controller to a staging area remote from the dosage formation system.

[0094] The shuttle is typically magnetically levitated above the transport surface to a height of about 4 mm, more typically to a height of about 3.5 mm, and can be controlled to a height of about 0.1-3.5 mm. More specifically, the planar underside of the shuttle is elevated above and parallel to the planar transport surface. After the fabrication modules are positioned and oriented at the process station, the shuttle can be vertically raised to raise the substrates secured to the carriers transported by the shuttle into contact with the unit operation equipment or devices, or into a closer non-contact position, improving processing accuracy and efficiency and reducing loss of powder or droplet material into the air space of the containment zone.

[0095] Each shuttle includes a plurality of motion signaling devices in communication with one or more of a plurality of static detectors in the stator to communicate the position and orientation of the shuttle and its movement along the transportation surface at any time. The accuracy resolution is typically about 0.2 mm or less (including about 0.02 or less), e.g., about 5 microns, with a refresh interval (or delay) of less than 100 milliseconds.

[0096] Each independent manufacturing module can be independently moved and positioned at a processing station or inspection station of the processing platform 12, thereby allowing the substrate and its one or more formed surfaces to be positioned and / or oriented accordingly under or relative to the processing equipment or inspection equipment, respectively.

[0097] <Containment System> The processing system may include a containment system having a volumetric air space bounded by and between an upper surface of the transport face of the stator and a containment housing, typically providing a containment zone consisting of the volumetric air space, the containment housing including one or more transport openings and one or more sealable openings.

[0098] The transport opening may include an opening or port through the sidewall of the containment housing, extending from the transport surface to the sidewall, providing entrance and / or exit of the fabrication module to and from the containment zone. The lateral and height dimensions of the transport opening are sufficient and typically sized to allow one or more shuttles (including their respective substrates and articles formed thereon) to pass through the transport opening simultaneously. The transport opening may also be used to provide an entrance for airflow to enter the containment zone from the outside. When exiting the fabrication module, the inflow of air over and through the fabrication module aids in the removal of loose particles. In some embodiments, a temporary closure may be placed over the transport opening to close it, and the closure may be hinged or removable.

[0099] The sealable opening includes an opening or port through a ceiling panel or a side wall of the containment housing, and is typically sealed during operation of the processing system or sub-processing system. The unit operation processing device is placed in one of the sealable openings in the containment housing to process the unit operation in the containment zone. Typically, the sealable openings are of similar or uniform size. The unit operation processing device typically has a processing portion that extends vertically into the containment zone and an external portion that extends outside the containment zone and can be accessed or controlled from outside the containment housing. The processing portion that extends into the containment zone can be an element that dispenses a compound or processing material, such as a powder dosing port or liquid nozzle, a texturing element that compacts or manipulates the construction material or phase modifying material, and an instrument such as a probe element that contacts the construction material or substrate to manipulate or move the construction material and / or phase modifying material or processed material. Each unit operation processing device can optionally be fitted with a seal adapter plate having an inner seal portion sealably attached to the processing device and an outer seal portion sealably positionable within a sealable opening using, for example, conventional fasteners or quick disconnect fasteners.

[0100] The containment housing also has one or more vents that allow air from the outside, such as conditioned air or ambient air, to pass through the containment housing and into the containment zone, and optionally includes a closure to seal the vents. The vents can be located at various locations along the containment housing, which allows for better control of the location and amount of air drawn into the containment housing.

[0101] The containment system includes an air treatment and filtration device, such as a high efficiency particulate air (HEPA) filter device that treats the air and separates particles and droplets in the air. An example of a commercially available HEPA filter device 18 is shown in Figures 7A and 7B. One of the sealable openings 34 can be configured to accommodate a HEPA filter that includes a support 140 that attaches to the ceiling panel 33 of the containment housing, an air inlet port 141 disposed within the containment housing, a particle separation means (e.g., a filter and / or a cyclone separator), and an air exhaust port. The HEPA filter device 18 is configured to draw a flow of outside air, typically a predetermined flow of outside air and / or a continuous flow of outside air, into the containment zone and into and through a particulate collector, preventing the escape of the pharmaceutical or active particulates and droplets from the containment zone and into the outside environment. Air within the containment zone, which may contain airborne particles and / or liquid droplets, is drawn into the air inlet port 141 by the blower of the HEPA filter device, filtered to separate and isolate the particles and / or liquid droplets, and exhausted to the atmosphere as filtered air. Outside air is drawn into the containment housing through the transport openings 36 and flows along or through the containment zone, past areas of the process unit operations and equipment (e.g., powder material deposition equipment and / or phase modification equipment).

[0102] In various embodiments, the containment system, including the containment housing design and HEPA filter system, is configured to maintain a constant negative air pressure within the containment housing relative to the environment outside the containment housing, ensuring that air exchange occurs from outside the containment housing to inside the containment housing and that air passing from inside the containment housing to outside passes through a HEPA filter device.

[0103] An example of a containment system is shown in Figure 2. The containment housing 30 includes a plurality of fixed panels, typically transparent panels, and optionally a support frame. The plurality of panels includes one or more upper ceiling panels 33, and a plurality of sidewall panels, typically a series of sidewall panels including a first sidewall panel 31 and a second sidewall panel 32 on opposite sides of the containment housing 30, which provide a perimeter boundary. A transport opening 36 of the perimeter boundary is located at the front end of the containment housing 30. The transport opening 36 extends from the transport surface 16 to the ceiling panel 33 and is bounded by an opposing panel 35. The transport opening 36 provides both an inlet and an outlet for movement of manufacturing modules into and out of the containment zone, as described herein, and also provides an inlet for airflow.

[0104] The ceiling panels 33 and sidewall panels 31, 32, 35 are typically transparent or translucent, preferably transparent, and may be constructed of sheets of transparent polymeric material such as polycarbonate (Lexan®), acrylic (Plexiglas®), tempered glass, sapphire, or polyvinyl chloride (PVC) of sufficient thickness to allow viewing from outside the containment system of the movement of the manufacturing modules in and between the processing stations, and to provide stability and support. The framework of the ceiling and sidewall panels may be made of conventional frame materials, non-limiting examples of which include aluminum or thermoplastics, by conventional frame construction. In some embodiments, the framework provides rigidity and support to the ceiling and sidewall panels. In various embodiments, the equipment supports that support the process unit operation equipment on the transport surface 16 and on the containment housing 30 may include lateral equipment supports 15 spanning the width of the containment housing, elevated by support brackets 14.

[0105] In various aspects, the containment housing is configured to minimize the number of pieces of equipment within the space and to minimize the exposure of the components of the equipment within the space, which also helps reduce airflow velocity by reducing obstacles for the airflow to flow around, and can increase the airflow velocity as it passes around obstacles.

[0106] In various aspects, the containment housing is designed to provide a containment zone of minimal volume sufficient to perform some or all of the process unit operations on the components deposited and / or phase modified on or within the substrate.

[0107] In various embodiments, the vertical height of the containment housing is minimized to a height sufficient to move the substrate and its deposition surface above the transport surface and below the components of the apparatus that perform a series of process unit operations. The process unit operation apparatus communicates with the fabrication modules through the ceiling and / or sidewall panels of the containment housing to transfer or deposit construction materials and / or perform phase modification operations. For example, the powder deposition apparatus and binder dispenser can each place corresponding amounts of powder and binder liquid through an exhaust nozzle, print head, or port that penetrates the ceiling and / or sidewall panels of the contaminant housing.

[0108] In various aspects, only the portions or components of the unit operation necessary to perform the process unit operation extend vertically through the top (ceiling) panel of the containment housing into its volume, thereby minimizing or limiting contact between airborne particles and the remaining portions or components of the unit operation. As an example, a powder deposition device that deposits a build material, such as a bondable powder material, onto a top deposition surface of a substrate, e.g., into recesses in a blister sheet, is configured such that only the outlet or deposition port at the bottom end of the device extends through the ceiling panel of the containment housing into its volume. By minimizing the vertical height and volume of the containment housing, less mass or volume of air is required to efficiently and effectively collect and draw airborne particles and droplets from within the containment zone.

[0109] The openings in the containment housing and the location of the process unit operation apparatus within the containment housing are designed, positioned, and oriented to avoid excessive containment airflow velocities, particularly horizontal airflow velocities, that may affect the effectiveness of the unit operations performed by the apparatus on the articles being formed on the substrate.

[0110] In some embodiments, the lateral air flow velocity within the containment housing is up to 10 m / sec. The minimum air flow velocity into the air inlet opening is controlled to at least 0.5 m / sec so that particles within the containment zone cannot migrate or escape the containment zone through the opening. In various embodiments, the design of the containment system and the location of the process unit operation equipment results in an average air flow through the containment system of less than 5 m / sec, more typically less than 2 m / sec, in the air spaces immediately surrounding and adjacent the unit operation process, particularly the powder deposition equipment and binder fluid printing system.

[0111] For example, when depositing certain build materials onto a substrate, air may flow horizontally between a deposition device (e.g., a powder deposition device) and the substrate onto which the build material (e.g., a dosed powder) is deposited, or in phase modification of build materials by a phase modification device (e.g., deposition of a binder liquid onto a dosed powder disposed on a substrate), air may flow horizontally between a liquid dispensing nozzle and the powder material disposed on the substrate. Excessive air flow through the containment system and directed between the unit process device and the substrate may affect the placement of the powder on the substrate and / or the precision and accuracy of the placement of the powder and / or liquid on the substrate.

[0112] In particular, errors in the placement accuracy of the liquid ejected from the printing nozzles can be affected by the linear velocity at which the transport module carries the substrate (and the article formed thereon) under the stationary printing nozzle. Typically, a linear airflow velocity of 1.0 meters / second (m / s) or less, preferably 0.6 m / s or less, is used to minimize errors in the position and phase correction quality of the droplets used. Droplet placement accuracy can also be improved by shortening the clearance distance between the printing nozzle plate and the substrate and / or increasing the droplet velocity to minimize the flight time of the droplets. The clearance distance between the printing nozzle plate and the substrate, such as the blister card described herein or the protective mask covering the blister card, is less than 1 cm, more typically about 8 mm or less, or 6 mm or less, for example about 5-8 mm, and can be controlled stepwise and / or infinitely by the motion controller.

[0113] In an embodiment, to prevent or limit air flow interference during deposition of the powder material on the substrate and printing of the binding liquid onto the layer of powder material, barriers such as one or more baffles, internal walls, or air curtains can be installed around the printing nozzle or apparatus and / or powder deposition apparatus to reduce or prevent air flows and air vortexes across the surface of the substrate and between the surface of the substrate and the process apparatus.

[0114] In various embodiments, the ratio of the vertical height (or average vertical height) of the containment housing to the area of ​​the containment zone (usually determined by the peripheral side walls of the containment housing) is between 0.1 and 100 cm of height per square meter (cm / m 2 ), more typically between 0.5 and 20 cm / m 2 , more typically 5.0 to 10.0 cm / m 2 In one non-limiting example, the containment housing is 20 square feet (approximately 1.8 m 2 ) and the internal height is about 12.5cm, the ratio is about 7cm / m 2 It becomes.

[0115] In other embodiments, the ratio of the vertical height (or average vertical height) to the width (shorter lateral dimension) of the containment zone is between 0.5 and 20 cm / m, more typically between 2 and 10 cm / m, even more typically between 4 and 8 cm / m. The height of the containment housing from the transport surface of the stator to the ceiling panel is preferably less than 50 cm, more preferably less than 15 cm.

[0116] Within the volumetric space of the containment housing are fabrication modules that float above the transport surface of the stator and "float" through the space within the containment housing. Typically, the height of the carriers and substrates moving and operating within the containment housing is less than the height of the containment system within the operating space. In a typical arrangement, the bottom of the shuttle of the fabrication module floats above the transport surface of the stator by about 1-5 mm, for example about 1.5-3.5 mm. The shuttle is typically 1-2 cm thick. The carriers secured to the shuttle and transported by it can have a vertical height of at least 1 cm, preferably at least 5 cm, up to about 20 cm, preferably about 10 cm, above the top surface of the shuttle. In some circumstances, the carriers can have a higher vertical height when in the containment housing, provided they operate with sufficient headspace. To optimize the amount of airflow required for the control of airborne particles, the vertical height of the containment housing can be minimized, typically about 20-30 cm in height, preferably about 15 cm or less, for example about 10 cm or less.

[0117] <Process unit operation> The present invention also provides that an omnidirectional magnetic transfer system, including an omnidirectional magnetic transfer device, a shuttle, a carrier associated with the shuttle, and a substrate, can be used to interactively perform one or more process unit operations, which can be coordinated multiple unit operations.

[0118] Each process unit operation is located near, and typically directly above, a corresponding unit operation station. This unit operation station is comprised of an area of ​​the process mover apparatus designated for positioning and orientation of a fabrication module that performs a unit operation process at or on a given one or more forming surfaces of a substrate. Under the control of a motion controller, each fabrication module can be precisely positioned and oriented so that each fabrication surface of the fabrication module is located under a processing device to begin a given process operation. In one embodiment, a given process operation can be performed while the fabrication module and one or more forming surfaces thereon are fixed and stationary in a given position on the process mover apparatus, e.g., in a stationary position and / or orientation for stationary processing while floating above a transport surface. Alternatively, the same fixed and stationary fabrication module can be lowered to a physical platform surface (non-floating) during the execution of a process operation. In another embodiment, a given process operation can be performed while the fabrication module moves horizontally under the control of a motion controller along the upper surface of a transport surface in a unit operation station during the execution of a process operation, e.g., changing position and / or orientation for dynamic processing while floating above the transport surface.

[0119] For example, in a powder dosing (unit operation) station, a levitated production module and one or more forming surfaces (such as a blister card and its recesses) can be positioned and oriented (in the x, y plane) such that the recesses are located directly below and coaxial with the outlets of the powder dosing device, and the blister card surface is spaced below the outlets of the powder dosing device by a minimum vertical clearance distance, within a range of up to 10 mm, for example about 6 mm. With the production module fixed and levitated in place, the powder dosing device can deposit a dose of powder material downwards from each outlet into a corresponding recess in the blister card substrate. The minimum vertical clearance minimizes the vertical fall distance of the powder doses and therefore the risk of dust cloud formation or powder scattering outside the recesses. An example of a powder dosing device is shown in Figures 8A and 8B.

[0120] In another example, in a powder leveling (unit operation) station, a production module, its one or more forming surfaces, and the doses of powder component material (e.g., blister cards containing dose piles of powder material and their recesses) can be positioned and oriented (in the x, y plane) under a powder leveling device. With the production module fixed and grounded (not levitated) on a transport surface, one or more vibrating probes of the vibrating leveling device are lowered until their distal ends contact the top surface of the production module and / or the substrate (e.g., the blister film web between adjacent recesses), and energy waves (e.g., sound waves) of a predetermined frequency and amplitude are passed axially from the distal ends of the probes onto and into the substrate, thereby dispersing and diffusing the dose piles of powder material within the cavities of the recesses, reducing the surface irregularities of the powder material and forming a powder layer with a flatter surface.

[0121] In another example, in a liquid printing (unit operation) station, a floating manufacturing module, its one or more forming surfaces, and the building materials therein (e.g., blister cards and their recesses containing layers of powder material) can be initially positioned and oriented (in the x, y plane) such that the forming surfaces are located outside the target lines of one or more rows of printing nozzles. Each printing nozzle selectively and independently dispenses printing liquid at a predetermined volumetric rate within the unit target area under the nozzle. The floating manufacturing module then passes under the printing nozzles and into and through the target lines of one or more rows of printing nozzles. Meanwhile, each printing nozzle independently dispenses a curtain of printing liquid onto the powder material layer in a predetermined printing pattern under the control of a process controller, but not onto the substrate area outside the powder layer.

[0122] The process unit operations include, in no particular order or priority, delivery and association of a shuttle to an omnidirectional magnetic moving device; delivery, association, and orientation of a carrier with a shuttle; formation of a substrate from a stock material, including formation of formed surfaces such as wells, cavities, penetrations, protrusions, or other geometric modifications onto which the build material may be deposited; delivery, association, and orientation of a substrate with a carrier; delivery and dispensing of build materials to the substrate, which may include powder or granular materials and liquid materials; planarization of powder or granular build materials on the substrate; delivery and dispensing of treatment materials to the substrate for phase modification or treatment of the build material; sanitization or sterilization of the substrate or its stock materials, build materials, treatment or phase modification liquids, and products and their intermediates using electromagnetic spectrum emissions or chemical reactants; surface modification of articles formed from build materials or their intermediates, such as removal of excess solidified material, including subtractive manufacturing methods; electromagnetic (EM) irradiation; thermal phase change; evaporation and drying; disinfection; article and process inspection and quality control; marking and identification of articles; unloading of finished products from the substrate; and post-formation handling and packaging of the substrate including the articles to form integral primary packaging units.

[0123] The use of an omnidirectional movement system for moving multiple manufacturing modules between two, and typically more, unit operation stations as described herein allows for asymmetric processing of intermediate and finished products, providing either functionality or advantages that are impractical, if not impossible, with conventional processing systems. In one example, the asynchronous movement of multiple manufacturing modules allows each manufacturing module to remain at a particular unit operation station only for the time required to perform a unit operation process without preventing other manufacturing modules from moving to other unit operation stations.

[0124] In another example, the ability to independently adjust the position, orientation, and motion of each fabrication module allows the unit operation processing of a particular fabrication module to be adjusted completely independent of other fabrication modules. In one non-limiting example, the passage of a substrate under a liquid spray unit operation that wets a layer of powder material disposed within one or more recesses of the substrate can be changed with each successive pass by changing the orientation of the fabrication module such that the dispersion of liquid is applied to the next powder layer at a different angle (e.g., 90 degrees or sideways) than was applied to the previous powder layer. This is not known or feasible with conventional transport systems.

[0125] In another example, an inspection system may include one or more inspection devices that detect a particular defect or error in an intermediate or finished product on a particular manufacturing module, or in a particular manufacturing location on a particular manufacturing module, and may direct the particular manufacturing module to return to one of the unit operation stations for further processing to fix the defect or error preferentially, and may even temporarily interrupt the unit operation processes scheduled to be performed on other manufacturing modules. This is particularly important when a series of manufacturing modules are processed as a particular unique batch, and in a conventional production system, the required further processing would require inserting the particular manufacturing module into a queue of a transport system before other manufacturing modules in the queue, prior to the unit operation process, and then removing the same manufacturing module from the transport system after the unit operation and returning the same manufacturing module to its batch mates.

[0126] <Constituent materials> A building material includes any liquid, liquefied gas, semi-solid, or solid material that can be formed, transformed, reacted, mixed, or combined into an article. A building material can be an ingredient that includes one of two or more components of an article. A building material can be an intermediate (solid, semi-solid, or liquid) or unfinished product (e.g., a tablet body) that is preformed in a processing system and further processed to form a finished product or product. A solid building material can be a powder that includes one or more particulate compounds or compositions. Non-limiting examples of powder forms can include amorphous or crystalline particulates, granules, powders, agglomerates, coated (shell and core) particles, and nuggets.

[0127] Liquid building materials can be free-flowing liquids, including substances that contain suspensions or dispersions of solid or fine particles, or viscous or gel materials. Non-limiting examples of liquid building materials can include aqueous and non-aqueous liquids, organic and inorganic liquids, creams, lotions, pastes, gels, and monomeric compounds.

[0128] The component may be one or more components, may be a single compound or composition, may be two or more separate compounds or compositions, or may be a blend or mixture of two or more compounds and / or compositions.

[0129] In some embodiments, a material or a component of a material (e.g., one or more component compounds of a composition) may be not only a constituent material, but also an element or component of a phase modification system. In a non-limiting example, the binding liquid of the base powder can have a binding material and a solvent (non-limiting examples are water or alcohols such as ethanol or isopropanol), and the binding material and a portion of the water or other solvent can become component compounds of the resulting bound powder dosage form, and can become components of the phase modification system of the base powder that are bound by both the binding material and the wetting of the base powder to form the bound powder matrix of the dosage form.

[0130] In various embodiments, the material of construction can have an active agent, an API, by way of non-limiting example, in powder or particle form, or in liquid form.

[0131] The components of the building blocks or their components, or the components of the processing materials, can be functional components of the resulting article. Non-limiting examples of functional components include, for example, in the case of tablets or pharmaceuticals, fillers, diluents, binders, suspending agents, viscosity agents, polymers including release positioning or modified polymers, coatings, flavorings, disintegrants, sweeteners, preservatives, colorants, lubricants and glidants. Non-limiting examples of compounds or ingredients of such components include inorganic salts, acidic compounds, organic compounds such as sugars and sugar alcohols, modified starches and starches, cellulose ethers and esters, microcrystalline cellulose, carboxymethylcellulose, croscarmellose sodium, glycols such as polyethylene glycol and propylene glycol, povidone, mineral hydrocarbons, and oleochemicals such as fatty alcohols, mineral stearates, glycerol, and lipids.

[0132] In various embodiments, the construction material or its components can be altered into a different form by a mechanical process (by way of non-limiting examples, compression, grinding, or dissolving or suspending in a second liquid material) and / or transformed into a different physical state or phase (e.g., heating or cooling of the material resulting in evaporation, or sublimation, solidification, freezing, melting, spray drying, spray solidification, or condensation), and / or transformed into a different chemical structure by chemical reaction with another compound, or irradiation, curing, or polymerization. One or more of these process unit operations may require the use of process equipment integrated into a processing system that includes an omnidirectional magnetic movement system and controller, a containment system, and a process unit operation controller.

[0133] In some embodiments, the powder material comprises a thermoformable powder that softens and / or melts when exposed to heat and high temperatures and solidifies the build material when cooled. Non-limiting examples of thermoformable powder materials and processes, apparatuses and systems for producing dosage forms are described in U.S. Patent 2009 / 0060983 (Bunick et al.), U.S. Patent No. 6,258,381 (Luber et al.), U.S. Patent No. 8,313,768 (Kriksunov et al.), U.S. Patent No. 9,511,028 (Chen et al.), U.S. Patent No. 10,493,026 (Koll et al.) and WO2018 / 096363 (UCL Business PLC), the disclosures of which are incorporated by reference in their entirety. Thermoformable powder materials, including thermoformable compounds or materials, can be deposited in a recess and flattened into a single layer of uniform thickness. Typically, the leveling process comprises moving the powder material deposited in the recess to form a layer of powder material with a uniform or flat top surface. The variation in height of the upper surface is less than 20% of the diameter of the recess, more preferably less than 10%, or less than 5%, and even more preferably less than 2%. After the layer of powder material is formed, it is exposed to a phase modification system to form a solidified porous or non-porous solid article, such as a dosage form. The phase modification system can include thermal heating by conduction, convection, or radiation using an electromagnetic (EM) spectrum system, as described below. The thermoformable material in the powder material softens and partially melts, adhering to other particles of the powder material. After cooling, the attached thermoformable material solidifies and bonds the particles of the powder material to form a bonded powder material.

[0134] In other embodiments, the thermoformable powder can be deposited, flattened, and thermoformed into the recesses two or more times as described above to form a multi-layer article. Each layer of the thermoformable powder can have the same composition and ingredients, optionally including an active agent, or a different composition, optionally including an active agent.

[0135] <Distribution of constituent materials> In various embodiments, the building materials are delivered and stored in the processing system, particularly the omnidirectional magnetic transfer system and / or the containment system, by conventional means including pumps, conveyors, tanks, and bins depending on their form (e.g., liquid or solid). The building materials can be dispensed or deposited on the substrates of the fabrication modules by known means depending on the chemical type of the building materials and their state.

[0136] Typical types of equipment for distributing or depositing construction materials or materials used in phase modification systems. Powder construction materials can be stored in bulk in tanks or other containers and can be delivered to the processing system by air conveying or gravity feed through fixed or flexible piping, tubes, or hoses. Equipment for distributing or depositing powders and other powder materials can include iris valves, rotary valves, butterfly valves, augers, screw conveyors, belt conveyors, tubular drag conveyors (e.g., U.S. Patent Application Publication No. 2022-0184891 to Hewlett-Packard Development Corporation, LP, the disclosure of which is incorporated by reference in its entirety), and powder dosators. In various embodiments, equipment for feeding and distributing deposited powder materials can include a modular container of powder material with a feedback-controlled instantaneous and continuous mixing system, allowing for easy and rapid changes in the supply of powder material to process equipment.

[0137] As previously described herein, the components in liquid form can be stored in bulk in tanks or other containers and can be delivered to the processing system by gravity feed, pumps, hydraulics and pneumatics, and via fixed or flexible piping, tubes, or hoses.

[0138] In various embodiments, the component dispensing module can include probes for continuous and / or intermittent sampling of the component to measure, record and report the compositional uniformity of the component. The controller system can include processes incorporating intelligent data processing algorithms, including artificial intelligence (AI) as needed, to analyze and evaluate whether the phase correction dispensing process is in control and can implement corrective actions or other controls.

[0139] <Powder dispenser> In one embodiment, the component dispensing device is a powder dispenser that delivers a predetermined mass or volume or "dose" of flowable powder material to a deposition site or sites of a substrate. The substrate can be a blister card, and the deposition site or sites can be one or more recesses formed in the blister card. The powder dispenser delivers a predetermined mass (or volume) of flowable powder material to one, more, or all of the recesses of the blister card. In various embodiments, the predetermined mass of powder material deposited in any one recess can be about 1 mg or less, or at least about 1 mg, preferably about 15 mg to about 375 mg, and up to about 5 gm. Non-limiting examples of dispensers are described in PCT Publications WO2020 / 081561 and WO2021 / 21189, the disclosures of which are incorporated by reference in their entireties.

[0140] In various aspects, the dispenser dispenses or is configured to dispense a fixed amount of powder material. Dispensing a fixed amount of powder material preferably provides a uniform volumetric density of powder material to achieve uniform and repeatable mass dosing.

[0141] In various embodiments, multiple doses of powder material are distributed simultaneously and separately to corresponding multiple deposition surfaces, particularly multiple recesses. Ideally, the respective volume amounts of powder material deposited in all of the multiple recesses are the same or at least have a statistically narrow variance. For example, the variance is about 3% or less, about 2% or less, or 1% or less. Assuming that the mass density of the powder filled in each recess is constant and the same, the mass dose of powder deposited in each recess is the same or within a statistically narrow variance.

[0142] In various embodiments, the dosator system can include an integrated near-infrared (NIR) spectral sensor. NIR spectroscopy utilizes light transmission and absorption to measure various components of sample materials, such as moisture, starch, protein, fat, and oil. NIR can be used to detect these specific elements, understand the concentration of elements, and / or detect changes in overall composition. NIR penetrates deeper into bulk materials than mid-infrared, providing better and more reliable measurements on the production line. In one embodiment, the NIR sensor can emit electromagnetic waves in the range of, but not limited to, 780-2500 nanometers. The NIR light waves illuminate the surface of the powder material as it passes through a passage in the dosator assembly.

[0143] The NIR sensor can be used to detect and monitor the uniformity of one or more compounds, including one or more active agents and pharmaceutical ingredients mixed with other excipient powders, detect variations in the amount of the compound within the powder material, and accordingly detect variations in the compound within the volume of the powder material dispensed onto the substrate surface or recesses, including, but not limited to, detecting and monitoring that the concentration of the compound, such as one or more active agents and pharmaceutical ingredients, is too high or too low and the processing system can be programmed to terminate or modify the process if it is outside of a target tolerance range.

[0144] In other embodiments, the dispenser deposits or is configured to deposit a consistent mass or a statistically narrowly varying mass of powder material. Various means of controlling the mass of powder material can be used. In various embodiments, a weigh scale (load cell) can be placed under the bulk powder hopper or intermediate bulk powder feeder to measure or monitor the weight of the powder dispensed onto the substrate. In some embodiments, a weigh scale can be placed in the carrier or under the substrate to detect the absolute or differential mass of powder material dispensed onto a particular forming surface (recess) or across the substrate (blister card). In some embodiments, a controlled weigh scale that ensures a consistent mass of powder material is prepared for deposition into a particular recess.

[0145] In various embodiments, the dispenser provides an assembly of components that deliver a predetermined dosage of powder material onto (or into) one or more or all of the deposition surfaces of the substrate. When multiple dispensers are arranged in parallel, each independent dispenser can be assembled with components that deliver a different predetermined dosage of powder material onto (or into) one or more or all of the deposition surfaces of the substrate, and the combination of these one or more dispensers provides greater and nearly infinite control over the amount of powder material dispensed onto (or into) one or more or all of the deposition surfaces of the substrate.

[0146] The underside of the deposition portion of the dispenser is positioned to provide a clearance above the substrate of 1 cm or less, preferably 6 mm or less, more preferably 3 mm or less.

[0147] Typically, the bulk density of the powder is between 0.2 and 1.5 gm / cm 3 , more typically 0.4 to 1.0 gm / cm 3 which can be determined by well known methods.

[0148] A typical deposition of powder from a supply vessel includes a means to assist or maintain the flow of powder from the supply vessel through an outlet to maintain a constant powder density. A non-limiting example of such a means is a volumetric feeder, such as a metering screw feeder. Another non-limiting example of such a means is a vibrating device that must be separate from the supply vessel. Additionally, powder agitators and / or spreaders can be utilized and can include rollers, blades, or other types of material spreading and agitating devices.

[0149] In various embodiments, powder flow aids can be used to improve the processability of powder materials when used at a mass level of about 0.05-5%. Examples of powder flow aids include fumed silica, stearates, tricalcium phosphate, calcium silicate, aluminum oxide, magnesium oxide, and zinc oxide. In one example, fumed silica is supplied by Degussa AG under the trademark AEROSILR.

[0150] 8A and 8B show a non-limiting example of a volumetric powder dosing device, or powder dosator 40, configured to deposit equal amounts of powder material with minimal deviation into each recess of a blister tray. Build powder material from a supply container (not shown) is fed into a metering screw feeder 41, which is connected to a respective connection port 42b of a supply base 42a. The supply base 42a is fixed to a frame 43 having a cylindrical cavity. A circular distribution plate 44 is rotatably disposed within the cylindrical cavity, has a number of openings extending around its circumference, and distributes the powder into the dosing fill cavities below. Directly below the distribution plate 44 is disposed a stock plate 45a having a number of conical stock ports 45b that hold a fixed amount of material. The number of the conical ports 45b is selected and arranged in an array to match the recesses of the production surface of the substrate, e.g., a blister card. An electric drive 46 rotates the distribution plate within the cavity of the frame. Mounted beneath the frame 43 are an upper dose-filling frame 47a and a lower dose-ejecting frame 49a. The upper dose-filling frame 47a has three parallel-arranged dose-filling plates 47b, each with a row of precisely machined and formed dose-filling cavities 47c. The upper dose-filling frame 47a is driven by a drive 48a between a filling position, in which the dose-filling cavities 47c are aligned with the stock ports 45b in the stock plate 45a, and a feed position, in which the dose-filling cavities 47c are filled with powder.

[0151] The lower dose ejection frame 49a has three dose distribution plates 49b arranged in parallel alignment with the three dose filling plates 47b of the upper dose filling frame 47a. Each dose distribution plate 49b has a row of distribution ports 49c. The lower dose ejection frame 49a is driven by the drive 48b between a filling position, in which the dose distribution plates 49b block the bottom openings of the dose filling cavities 47c of the upper dose filling frame 47a, and a dispensing position, in which the distribution ports 49c are axially aligned with the dose filling cavities 47c to dispense powder from the dose filling cavities 47c into the recesses of the blister card.

[0152] <Leveling> Leveling is a process unit operation that moves a batch or batch of particles of build material deposited on or in a recess of a substrate to a flatter powder layer, preferably a powder layer having a flat surface. In one aspect, the powder layer provides a build material layer with an upper flat surface. The leveled build material layer is then treated by a phase modification process to form a solidified monolayer of build material.

[0153] In one aspect, the build material can be a powder, particulate, or powder material, followed by a phase modification process to form an integral bonded powder matrix having an upper planar surface.

[0154] In various embodiments, leveling can be accomplished with the movement of the manufacturing module by vibrating or pitching the shuttle about an axis passing through the shuttle, or accelerating the shuttle laterally above and along the transport surface. Under control of the motion controller of the omnidirectional magnetic motion device, the motion stator can be actuated to vibrate and / or oscillate the shuttle to the manufacturing module via the magnetic forces on the shuttle to form the deposited powder into a powder layer having a substantially uniform thickness and a substantially uniform and flat top surface in the recess. In some embodiments, the vibration or oscillation cycle can rotate the body of the shuttle about a vertical axis passing through the shuttle, and / or angle or pitch motion about a horizontal axis or line passing through the shuttle. The cycle time required for powder dose leveling is, for example, less than 10 seconds, typically less than 5 seconds, or 2 seconds or less, more typically 1 second or less.

[0155] In various aspects, leveling of the powder doses on or within the cavities of the substrate can be accomplished in a separate processing station that includes a means for vibrating the substrate, e.g., a blister card having a plurality of recesses, to level the doses of loose powder dispensed therein. In one aspect, the powder leveling device vibrates the blister card with an amplitude and frequency to convert the pile of powder dispensed within the cavities of the blister card into a layer of powder having a horizontal or more horizontal top surface, more preferably a flat surface. A non-limiting example of a vibrating leveling device uses a voice coil actuator to generate vibrations that are transmitted to the blister card and cause movement of the powder material disposed in the recesses.

[0156] 9A and 9B show a vibratory leveling device 52 useful for leveling powder material on or in a substrate, such as recesses in a blister card, by transmitting vibrations to the blister card to move powder material disposed in the recesses. The vibratory leveling device 52 includes a base 53 and an activator manifold 54 supporting positioned voice coil actuators (VCAs) 55. Each actuator 55 includes an elongated rigid probe 56 that extends axially below the actuator and reciprocates axially when actuated by the VCA. The rigid probes 56 have a tip made of a resilient material that transmits vibrations of the probes 56 to the substrate. The base 53 is configured for sealable mounting to the ceiling panel 33 of the containment housing and easy removal. The vibratory leveling device 52 includes a lift mechanism 57 that is rigidly attached to the activator manifold 54, which vertically lowers and raises the activator manifold 54. In the raised position, shown in FIG. 9A, the distal end of the probe 56 is raised up to a collar 58 on the base 53 to protect the probe 56 when the vibration leveling device 52 is installed or removed from the containment housing and to prevent the probe from extending into the containment zone. In the lowered position, shown in FIG. 9B, the activator manifold 54 is lowered and the distal end of the probe 56 is lowered to extend below the ceiling 33 and into the containment zone. In the lowered position, the distal end of the probe contacts the top surface of a fabrication module 70 (shown in FIG. 4) that is positioned and oriented below the vibration leveling device 52, and more specifically, contacts a substrate 80 (blister card) or a mask 90 that is placed on the substrate or other portion of the nest that is in direct contact with the substrate. In various embodiments, two or more VCAs are positioned on the activator manifold 54 such that the distal end of the probe 56 contacts the top surface of the substrate at a symmetrical location to the top surface of the substrate or mask. After the probe contacts the substrate (or mask), the VCA is activated to transmit vibrations to the body substrate. In one embodiment, the VCA transmits vibrations in a frequency range of about 1-100 Hz with an amplitude of 1-10 volts (e.g., 40 Hz with an amplitude of 1 volt).Vibrating a mask in contact with the top surface of a substrate, such as a blister card or substrate, vibrates the powder material in the recesses, forming a powder layer in the recesses with uniform thickness and a uniform, level top surface, which takes less than 1 second, typically 0.1 seconds or less.

[0157] In various embodiments, the spring provides a spring constant k that supports the weight of the nest 74, substrate 80 (e.g., blister card 82) and any build materials (e.g., build powder and binder liquid), and mask 90, and its natural frequency is matched or estimated to the vibration frequency transmitted by the VCA.

[0158] In various embodiments, once a manufacturing module is positioned at the leveling station, the motion controller lowers the shuttle element of the manufacturing module to lock onto the process surface 16 where it remains while the vibratory leveling device lowers the probe and during the leveling process. After actuation of the VCA and the leveling process are complete, the vibratory leveling device lifts the probe back to the raised position and the manufacturing module is lifted off the process surface 16 and moved out of the leveling station under the control of the motion controller.

[0159] In various embodiments, a leveling means can be used simultaneously to deposit a dose of powdered build material.

[0160] Non-limiting examples of devices for controlling the volumetric level of powder material within a recess of a blister tray are described in PCT Publications WO2020 / 081561 and WO2021 / 211898, the disclosures of which are incorporated by reference in their entireties.

[0161] <Liquid distribution> Equipment for dispensing or dispersing liquids, including aqueous and non-aqueous liquids, organic and inorganic liquids, solutions, suspensions, creams, lotions, pastes, gels, and monomeric compounds, can include pumps (including piston pumps, gear pumps, positive displacement pumps, peristaltic pumps, and progressive cavity pumps), gravity-fed dispensing valves, spray nozzles (including single-fluid, dual-fluid, ultrasonic atomizers, and printing nozzles). The type of equipment used for liquids can be selected based on the type of liquid, dosage amount, and properties including temperature, density, viscosity, vapor pressure, and surface tension. The equipment can deliver components to a substrate to form a single article (e.g., a single dosage form) or to form multiple articles sequentially or simultaneously.

[0162] The liquid make-up material can be stored in bulk in a tank or other container and can be pumped or gravity fed to the processing system via fixed or flexible piping, tubes, or hoses. In one aspect, the make-up liquid or other processing liquid can be stored in a modular container. The modular container has an interior space that holds a volume of liquid and includes a fill port for filling the interior space with a volume of liquid, and a dispense port for draining the liquid from the interior space. The drain port typically includes a quick-connect feature, such as a bayonet-type connector and sealing element that mates with a corresponding receiving port of a liquid dispensing device, allowing for the rapid replacement of used or empty liquid containers or the replacement of different liquid materials.

[0163] The liquid can contain an active agent or compound. In some embodiments, the liquid is an aqueous liquid containing the API. In some embodiments, the active agent-containing liquid is dispensed onto a powder component in a process that phase modifies the powder into a solid form. In some embodiments, the active agent-containing liquid is dispensed onto an intermediate or unfinished product (e.g., a tablet body) and further processed, for example, by drying the volatile components of the liquid to leave the API and form a finished product or product.

[0164] <Liquid spraying and printing> Water-based liquids and solvents are dispersed as multiple streams or droplets by a liquid printing device, typically by a nozzle, which can dispense the liquid onto a substrate or apply the liquid onto a mass or layer of powder material. Non-limiting examples of nozzles that form liquid streams or droplets include single or dual fluid nozzles, ultrasonic atomizers, thermal inkjet nozzles, and piezoelectric inkjet nozzles. Large droplets can be dispensed by nozzles on the order of milliliters and microliters. Printheads or printhead nozzles can dispense liquids with droplet sizes on the order of microliter, nanoliter, or picoliter droplet volumes. One skilled in the art can select a printhead or printhead nozzle based on process parameters including liquid dosage, temperature, and pressure, and liquid properties including density, viscosity, vapor pressure, and surface tension.

[0165] An example of a liquid printing device is shown in Figures 10A and 10B. The liquid printing device 50 includes a printer housing 551 and a pair of printer nozzles 552 mounted on a bottom surface 556 of the printer housing 551. Each printer nozzle 552 is comprised of an elongated series of nozzle ports. The printer nozzles 552 of a pair are arranged in parallel, axially displaced, and laterally offset, such that the last nozzle port at one end of one nozzle 552 axially overlaps at least one nozzle port at the other end of the other nozzle 552. The printing device 50 also includes a support frame 553 and a lift mechanism 555 for vertically raising and lowering the housing 551. The lift mechanism 555 raises and lowers the housing 551 vertically between a lowered position in which the bottom surface 556 and the printer nozzle 552 extend below the ceiling panel 33 of the storage housing 30 into the storage zone, and an elevated position in which the housing 551 and the bottom surface 556 are raised above the storage housing 30 to provide access to and allow removal of the printer housing 551 from the storage housing.

[0166] Other non-limiting examples of printheads or printhead nozzles are described in U.S. Pat. Nos. 4,825,227, 4,875,619, 4,883,219, 4,937,598, 5,659,346, 5,757,391, 5,781,212, 9,217,700, 9,381,154, 10,562,059, 10,850,236, 10,889,133, and 10,933,636, and U.S. Patent Application Publication No. 2012 / 0092416, the disclosures of which are incorporated by reference in their entireties.

[0167] In an embodiment, a pattern of jetted liquid can be formed on the substrate or mass of powder material by jetting liquid from selected jets of a fixed nozzle to emit one or more curtains of jetted liquid aligned with the plane of the printing nozzle and advancing the substrate or mass of powder material beneath the one or more curtains of jetted liquid. The speed of the advancing substrate and the selection of jets for droplet emission are controlled to emit droplets only from jets directly above the lateral strip of the substrate or mass of powder material to be wetted. This process is well known in the art.

[0168] In an aspect, the article can be a drug dosage form, the constituent material of which comprises a powder material, and the phase modification system can include a binder fluid printing system and a wet powder material drying system.

[0169] When printing liquid onto either the deposition surface of a substrate or onto a layer of powder or other build material, the resolution and accuracy of the deposition of the printed liquid is improved by limiting the flight path of the liquid from the nozzle to the top surface of the powder layer, the diameter or size of the droplets, and the linear velocity of the extruded droplets. Preferably, the substrate is controlled so that the minimum clearance under the printing nozzle is 2.5 cm (1 inch) or less, more typically less than 1 cm.

[0170] Non-limiting examples of binding liquids that can be dispensed onto a layer of powder or other component material are known and are described in PCT Publications WO2020 / 081561 (Aprecia Pharmaceuticals LLC) and WO2021 / 211898 (Aprecia Pharmaceuticals LLC), the disclosures of which are incorporated by reference in their entireties.

[0171] <Co-activator> In any of the embodiments described herein above, the system may further include a device, apparatus, or subsystem that stores, delivers, and / or deposits a co-active agent, such as an API or drug, on the component or phase-modifying component. The co-active agent may be in the form of either a particulate material, or other solid material, or a liquid material, or a liquid with one or more solvents. In various embodiments, a mass or volume amount of the co-active agent may be deposited on the component (e.g., an ingestible powder material) or phase-modifying component. Examples of devices, apparatus, or subsystems that store, deliver, and / or deposit a co-active agent, such as an API or drug, on the component or phase-modifying component are described in U.S. Pat. No. 8,252,234 and U.S. Pat. No. 8,101,244 (both to SmithKline Beecham Corporation), the disclosures of which are incorporated by reference in their entirety.

[0172] <Surface modification> In various aspects, the process unit operations can provide surface modification of the article or intermediate article. In various aspects, the surface finishing apparatus can include a surface finishing body having a bottom finishing surface. The finishing surface is configured to extend the bottom finishing surface onto the powder layer or the wet powder layer in the recess to change or modify the surface roughness of either the powder layer or the wet powder layer. In some aspects, the finishing surface provides a consistent contour and texture to the top surface of the intermediate article and / or the finished product. In some aspects, the contour of the top surface can be rounded or slightly domed. The finishing surface can also provide a means to remove particles of powder material that are attached to the top of the recess sidewall. In some aspects, the powder of the powder layer can be a dry, as-deposited, or leveled powder layer, while in other aspects, the powder of the powder layer can be a wet or partially wet powder layer.

[0173] In some aspects, the finishing surface contacts the powder layer at a portion higher than the profile of the finishing surface, reducing the elevated portion of the powder layer. The finishing surface is lowered until the profile surface of the finishing surface contacts the entire top surface of the powder layer, forming a surface profile on the top surface of the powder layer that matches the surface profile of the finishing surface. In various aspects, the finishing surface is lowered over the top surface of the powder layer, compacting or compressing the powder material in the powder layer. In various aspects, the material of the facing that forms the finishing surface is a solid material made of a metal or alloy, or a solid thermoplastic material. In preferred aspects, the material of the facing resists or prevents adhesion of wet or dry particles of the wet or dry powder material. In various aspects, the facing and the finishing surface can extend to the depth of the recess. Non-limiting examples of solid thermoplastic materials include, but are not limited to, polyethylene, particularly ultra-high molecular weight polyethylene (UHMWPE, or simply UHMW), nylon, and polypropylene.

[0174] In various aspects, the surfacer may also rotate about an axis of the surfacer and surface, rotate in an arc, oscillate, or rotate at a constant speed to improve the surface smoothness of the powder layer. In some aspects, the surfacer may rotate in one direction of rotation or in both directions of rotation.

[0175] 11A and 11B show a surface finishing apparatus 60 useful for top surface finishing of articles formed on a substrate, particularly medication tablets formed within recesses 84 of a blister card 82 of a substrate 80. The surface finishing apparatus 60 includes a base 61 and a tamp manifold 62 including a plurality of tamps having tamp stems 67 and tamp heads 68. The upper ends of the tamp stems 67 are vertically actuated by a corresponding plurality of solenoids 65 disposed on the tamp manifold 62 on the upper surface of the base 61. The tamp stems 67 extend through openings 66 on the underside of the manifold 62. The base is configured for sealable attachment and easy removal from the containment housing's top panel 33, and the plurality of tamp stems 67 and tamp heads 68 extend through open ports 34d in the containment housing's top panel 33. A lift bracket 63, which is rigidly attached to the tamp manifold 62, is vertically movable by a hoist or lift 64 to lift the tamp manifold 62, solenoids, and tamp head 68 upwardly through an open port 34d in the ceiling panel for removal, cleaning, or repair. The plurality of tamp heads each have a head diameter and a lower surface that extends at least partially over the top of the recess to contact the build material, powder layer, or wet powder layer. As shown in FIG. 11A, the plurality of tamp heads 68 are arranged to provide a first plurality of six heads 68a that are positioned to align with the six recesses corresponding to the first blister card 82a, and a second plurality of six heads 68b that are positioned to align with the six recesses corresponding to the second blister card 82b.

[0176] <Melted filament manufacturing> Fused Filament Fabrication (FFF) is a three-dimensional printing (3DP) process that uses a continuous filament of thermoplastic material. The filament is fed from a large spool to a heated extrusion head, which deposits the molten thermoplastic onto a workpiece placed on a worktable. Upon cooling, the thermoplastic hardens (changes phase) into the finished product. The extrusion head or worktable, or both, move under computer control to define the printed shape, layer by layer. In some embodiments, the extrusion head moves in two lateral directions (xy) to deposit a horizontal layer of thermoplastic at a time, then moves the worktable or extrusion head vertically a short distance to start a new layer. The speed of the extrusion head can also be controlled to stop and start the deposition to form interrupted planes without stringing or dripping between sections. A variety of materials can be formed into filaments and extruded, including thermoplastics such as polylactic acid (PLA), acrylonitrile butadiene styrene (ABS), polyethylene terephthalate glycol (PETG), polyethylene terephthalate (PET), high impact polystyrene (HIPS), thermoplastic polyurethane (TPU), and aliphatic polyamides (nylons).

[0177] The FFF device can be positioned to extend the heated extrusion head above the transport surface of the omnidirectional magnetic moving device. In an embodiment, the FFF device is configured to raise and lower the heated extrusion head vertically (±z direction), and the substrate on which the molten thermoplastic material is deposited is moved in fine incremental movements in the x,y horizontal plane under the control of both the extrusion / printing operation (process unit operation) controller and the motion controller. The article is built by extruding a first layer (or subsequent layer) of extruded thermoplastic material and then raising the heated extrusion head an incremental height before extruding the next layer of extruded thermoplastic material on top of the first layer (or preceding layer). In an embodiment, the heated extrusion head is fixed vertically and moves in the x,y horizontal plane, while the substrate on which the molten thermoplastic material is deposited can move vertically (±z direction).

[0178] In various embodiments, an active agent-containing article, such as a pharmaceutical dosage form or an active agent-containing medical device, can be manufactured in a processing system with a process unit operation including fused filament manufacturing. One or more portions of the incremental volume of the extruded thermoplastic material contain an active agent that is compatible with the melt temperature at which the thermoplastic material is melted and extruded from a heated extrusion head, thereby forming a pharmaceutical dosage form containing one or more active agents, including two or more. Examples of dosage forms containing active agents manufactured using FFF processing are described in International Patent Publications WO2016 / 038356 (University of Central Lancashire), WO2018 / 206497 (Pharmaprint), WO2020 / 240028, WO2020 / 240029, WO2020 / 240030, WO2021 / 115887, and WO2021198308 (Dihesys Digital Health Systems GMBH), the disclosures of which are incorporated by reference in their entirety. An FFF printer device of this type is described in US Pat. Nos. 6,070,107 and 10,259,164, the disclosures of which are incorporated by reference in their entireties.

[0179] In some embodiments, an intermediate or unfinished FFF formed article can be formed and a separate, predetermined mass or volume of an active agent-containing powder or active agent-containing liquid can be dispensed onto or into a cavity of the unfinished FFF formed article to provide a dose of the active agent in the resulting finished article.

[0180] <Electromagnetic wave irradiation> Several bands of the electromagnetic spectrum are useful in performing numerous process unit operations, including X-ray, ultraviolet (UV), infrared (IR), and microwave wavelengths. Each wavelength spectrum can provide useful process unit operation functions. These EM radiations can be generated by a variety of devices. Microwaves can be generated by electron tubes called magnetrons to heat articles or intermediate forms of moisture for phase change and evaporation processes. UV light (wavelengths from 10 nm to 400 nm) can be generated by lamps, light emitting diodes (LEDs), and lasers to polymerize or cure monomer resins for inks, coatings, and adhesives, and to disinfect and sterilize surfaces and clear liquids (water). IR light covers a broad wavelength range from about 0.78 to 1000 microns, can be generated by lamps, light emitting diodes (LEDs), and lasers, and can be used to heat compounds for evaporation and drying processes. In some embodiments, radiation can be used to heat energy absorbing compounds in the composition to raise the temperature, softening or melting the compounds in situ and acting as a binding material in the composition, for example, a thermoformable powder composition. Examples of processes and systems are described in U.S. Pat. Nos. 9,511,028 (J&J), 11,229,577 (Merck Patent GmbH), U.S. Patent Application Publications US2007 / 0238056 (DeGussa AG), US2009 / 0060983 (J&J), US2015 / 0333291 (TNO) and US2019 / 0374471 (UCL Business PLC), and International Patent Publications WO2015 / 143553 (Orthopaedic Innovation Centre, Inc), WO2017 / 190994 (Merck Patent GmbH), and WO2018 / 096363 (UCL Business PLC), the disclosures of which are incorporated by reference in their entireties.

[0181] In an embodiment, the powder material includes a fusible material and an active ingredient, and when a liquid with an energy absorbing material is sprayed or jet printed onto the powder in a predetermined pattern, for example, the pattern of a tablet, the powder material can be spread in one or a series of incremental layers to form an article such as a tablet. The fusible material is a material that melts and fuses when heated and then solidifies when cooled, and can be one or a mixture of sugar alcohols such as mannitol, polymers, polyvinylpyrrolidone (PVP), and the like. The energy absorbing material can be any material that absorbs IR, NIR, visible, UV, or microwave radiation and converts the radiation into heat, examples of which include water itself, carbon black, pigments, inorganic salts, and the like. The radiation heats the energy absorbing material, melting the fusible material at least partially and fusing the powder layers. Upon cooling, an integrated bonded powder layer is formed. Alternatively, the melting material can be included in the liquid printed onto the powder layer. Examples of such processes are described in U.S. Pat. No. 11,229,577 and U.S. Patent Application Publication Nos. 2007 / 0238056, 2019 / 0374471, 2021 / 0196572, 2021 / 0205176, and 2021 / 0213678, the disclosures of which are incorporated by reference in their entireties.

[0182] <Phase changes of materials> In various embodiments, a change in temperature of a component material or intermediate article can change the material from one phase (liquid, solid, or gas) to another, for example, by heating or cooling the material to cause evaporation, sublimation, solidification, freezing, melting, or condensation. Cooling (removing energy) a vaporous compound or composition can cause the compound or compounds in the composition to condense into a liquid form (e.g., vapor or water vapor into liquid water); or solidify (freeze) a liquid compound or compounds in the composition into a solid form (e.g., water into ice, or a molten thermoplastic polymer into a solid). Heating (energy input) a liquid compound or composition can cause the compound or compounds in the composition to evaporate into gas form (e.g., water or a solvent to vapor); or melt a solid compound or compound in the composition into a liquid (e.g., ice to water, solid thermoplastic polymer to molten liquid, or laser sintered metal particles to molten metal and then solidify back into solid metal); or sublimate water or moisture in the composition into vapor (e.g., freeze drying under sufficient vacuum conditions, or die ice).

[0183] Energy removal or energy input can be affected by any one or more of conduction, convection, or irradiation.

[0184] In various embodiments, chemical reactions on the building blocks or intermediate articles can affect the phase change of the material. For example, monomers and polymer liquids such as epoxies, silicones, and other adhesives can be polymerized and solidified using chemical reactants such as pH changes, saponification, amination; or irradiation at specific wavelengths in the EM spectrum such as UV, IR, microwave, etc.

[0185] <Evaporation and drying> The step of drying the wet powder layers can occur after each wet layer, after two or more wet layers, after all wet layers, or after shaping and surfacing.

[0186] In some embodiments, the drying station is constructed within the containment system and the manufacturing modules can be moved to the drying station within the containment system for processing. In other embodiments, the manufacturing modules are transported out of the containment system, processed at the remote drying station, and returned as needed. A drying station constructed outside the containment system separates the wet layer drying system and solvent processing system of the drying station from the containment system of the dosage formation system.

[0187] The first surface of the drying station is a means for moving a substrate that includes a wet powder layer on one or more forming surfaces (e.g., in a recess). In various embodiments, the substrate is separated from the carrier and manually or mechanically transported to the drying station. In some embodiments, the carrier to which the substrate is secured is manually or mechanically removed from the shuttle and again manually or mechanically transported to the drying station. In other embodiments, the entire fabrication module is manually or mechanically transported to the drying station.

[0188] The drying station includes a device that evaporates excess water or other solvents from the printing liquid in the wet powder material. The evaporation device can use one or more of infrared, microwave, ultrasonic energy, radiant heat, and convection (hot air) heating to increase the vapor pressure of the solvent, including water, to evaporate it. In some embodiments, the surface temperature of the wet powder material during drying can reach up to 90° C. or higher.

[0189] The drying station also includes a solvent removal system that transports the solvent vapor from the evaporator to a solvent condensation and collection system. When printing liquids that contain only water as a solvent or liquids that contain small amounts of organic solvent, the solvent vapor from the evaporator can be vented to the atmosphere, for example to a fume hood.

[0190] After drying the wet powder material, the dry powder layer contained on or within the substrate can be returned to the containment system for further processing of the dosage form. In various embodiments, the substrate is re-secured to the carrier and / or shuttle (the same carrier and / or shuttle from which the particular substrate was removed for drying) and returned to the transport surface and / or containment housing for further processing.

[0191] <Sterilization and Sanitation> The processing system may include systems and methods for sterilization and / or sanitization of articles and objects introduced into or onto a transport surface or into a containment housing, including materials of construction, processing materials, substrates, carriers, shuttles, transport modules, manufacturing modules, inspection devices, processing devices, and sampling devices. Depending on the type of contaminant, the article being formed, and other processes performed in the processing system, the sanitizing agent or germicide may be an EM spectrum emitter or a chemical compound or composition. Non-limiting examples of sanitizing agents or germicides include UV light, e.g., UV-C light, bleach, peracid, and the like.

[0192] <Item inspection and marking> Aspects of the process method or system of the present invention may include process analytical technology (PAT), an overview and examples of which are described in https: / / en.wikipedia.org / wiki / Process_analytical_technology, the disclosure of which is incorporated by reference in its entirety. The process method or system may include one or more inspection devices, inspection systems, and inspection processes for one or more process unit operations and / or one or more intermediate or final articles, improving control of the processing system and the quality of the intermediate or final articles. The inspection system may provide real-time monitoring of the process, the equipment during operation, and the intermediate and final articles, and may include one or more cameras and other digital imaging devices, process parameter sensors, and intermediate and final product parameter sensors. The inspection system may provide real-time feedback of the real-time monitoring system to a process unit operation controller, with or without process control, improving control and efficiency of the process and minimizing or eliminating offline quality control inspection and equipment. In an aspect, the inspection system enables real-time release of one or more final articles. Non-limiting examples of inspection devices, inspection systems, and inspection processes are described in US Pat. Nos. 8,252,234 and 8,101,244 (both to SmithKline Beecham Corporation), the disclosures of which are incorporated by reference in their entireties.

[0193] In various aspects, the processing system can include a visual sensor or camera that intermittently or continuously monitors the volume of the material deposited on the substrate. The mass and total mass of the material deposited individually in the cavity can be determined by a determined or measured volume of the material times a known or determined density of the material.

[0194] In one aspect, the processing system can employ a PAT system that includes a spectroscopic sensor, a non-limiting example of which is a near-infrared sensor, to intermittently or continuously monitor the uniformity of the material deposited within one or more individual cavities to determine the accuracy and efficacy of the amount of component material.

[0195] In one embodiment, the processing system can employ a PAT system that includes a sensor, a non-limiting example of which is a microwave resonant sensor, to intermittently or continuously monitor the density of the material deposited within one or more individual cavities and determine the mass of the volume of constituent material.

[0196] In an embodiment, the processing system can employ a PAT system including spectroscopic and visual sensors and cameras to intermittently or continuously monitor the position of the build material deposited and / or repositioned in one or more individual cavities to determine the accuracy of the dispensing device in dispensing a predetermined amount of the build material. In an embodiment, as described herein, the PAT system can be used to monitor, evaluate, and control a leveling process that moves the powder build material deposited in a cavity or recess to form a layer of powder material having a uniform or flat top surface.

[0197] In one embodiment, the PAT system and / or device can provide a means to detect the outer surface, particularly the outer top surface, of a particulate or viscous material or molded article and determine its shape, texture, and dimensions in three-dimensional coordinates (hereinafter referred to as "3D coordinates"). Additionally, the system and / or device can determine the 3D coordinates of an inner surface within a confined space of a known or determined shape (e.g., a cavity of a recess in a blister card) of a substrate or other surface. From the 3D coordinates of the top surface of the particulate or viscous material, or the cavity surface of a substrate, the system can determine or calculate the actual volume of the particulate or other material (which may include liquids, suspensions, semi-solids, etc.) deposited in the cavity by a volume difference determined between the 3D coordinates of the top surface of the material in the cavity before and after the particulate or other material is deposited.

[0198] In an embodiment, the granular material is a powder material, and the process for forming the article is a binder jetting process in which a binder liquid is dispensed into a layer of the powder material to form a wet-bound powder material, and a subsequent dose or layer of powder material is deposited on the top surface of the wet-bound powder material. The PAT system detects the 3D coordinates of the top surface of the wet-bound powder material in the cavity, and then detects the 3D coordinates of the top surface of the powder material deposited on the wet-bound powder material. The top outer surface of the deposited powder material or the wet-bound powder material may be flat and planar, or may be contoured with curves and slopes on the top surface. Based on the respective 3D coordinates of the top surfaces of the deposited powder material and the wet-bound powder material, a volumetric difference can be determined. The volume of the dose of powder material recently deposited in the cavity can be determined by the determined volumetric difference of the total material in the cavity before and after deposition into the cavity.

[0199] An example of a device for detecting the 3D coordinates of the top surface of the powder material in the cavity space is a three-dimensional (3D) laser camera. An example of a 3D laser camera 95a is shown in FIG. 1 and FIG. 12A and FIG. 12B. The 3D laser camera 95a is mounted on the overhead frame 19 directly above the containment housing 30 to photograph the containment zone and the manufacturing modules through the transparent ceiling panel 33. An example of such a 3D laser camera is the model In Sight® 3D-L4000 series manufactured by Cognex Corporation.

[0200] The 3D laser camera includes a laser 295 (FIGS. 12A and 12B) and represents a means for directing a plane of laser light onto the contoured surface of the cavity, or possibly the material within the cavity. A laser light detector 296 of the 3D laser camera views the contoured surface at perspective angles relative to the laser plane and captures images detecting where the laser plane hits the contoured surface (called a laser stripe). The captured laser stripe images are then correlated taking into account the perspective angle of the laser light plane relative to a true vertical plane, and the perspective angle of the laser light detector relative to the laser light plane, to generate a corrected elevation profile of the laser stripe along the contoured surface.

[0201] When an empty recess of a blister card is scanned, each corrected elevation profile generated provides a true reference profile of the empty recess surface taken along the laser plane, and the cumulative series of corrected elevation profiles provides 3D coordinates of the recess's bottom and sidewalls, as well as the 3D coordinates of the recess's surfaces, including the top sheet of the blister card. Similarly, when a recess contains powdered and / or wetted binding powder material and passes under the 3D laser camera, each corrected elevation profile generated provides a true reference profile of the recess and the powder material surface taken along the laser plane, and the corresponding cumulative series of corrected elevation profiles provides 3D coordinates of the recess, the contoured surface of the powder material within the recess, and the top sheet of the blister card.

[0202] The volume of the powder material below or above the contour surface can be determined by one of several calculation methods. In one common method, the width space between each incremental laser stripe is multiplied by the area below or above the curve of the incremental laser stripe to obtain an incremental volume, and the sum of the incremental volumes provides the cumulative volume of the material below or above the 3D contour surface of the powder material. By predetermining the total volume of the material below the contour surface of the material in the cavity before depositing the powder material, the volume of the deposited powder material is determined by the difference between the volume below the deposited powder material. Similarly, by predetermining the total volume of the space above the contour surface of the material in the cavity (up to the opening of the recess) before depositing the powder material, the volume of the deposited powder material is determined by the difference between the space above the deposited powder material and in the cavity up to the opening of the recess.

[0203] Once the volume of the deposited powder material is determined, the volume can be multiplied by the density of the powder material to determine the mass of the deposited powder material. The density of the powder material can be determined by one or more methods, including continuous measurements by microwave resonance or similar measurements, for example, as described in U.S. Patent No. 5,977,780, the disclosure of which is incorporated by reference in its entirety, or by a predetermined density value based on empirical data, which can be measured independently or simultaneously.

[0204] In one aspect, the 3D coordinates of the contour surface of the material are divided into a regular matrix of two horizontal unit areas, and the elevation of each unit area is defined by one, multiple, or all elevation measurements found within that unit area. The average elevation of the contour surface of the material, represented as a horizontal plane, is the average elevation of the total unit area found on the contour surface of the material.

[0205] In a non-limiting example, the detection device and method can be used during the article formation process to determine the volume of an incremental dose or layer of powder material deposited in one or more cavities of a blister card. As shown in FIG. 19A, a typical recess 84 of a blister card 82 has slightly tapered sidewalls 86 and a flat bottom 87, providing a circular cavity in the shape of a truncated cone. The dimensions of the blister cavity, including the nominal depth hc of the bottom, the lower cavity radius rc of the bottom 87, and the upper cavity radius Rc of the upper opening of the recess 84 in the sheet 85 of the blister card 82, can be determined by the 3D scanning method described above. As the blister card passes a stationary laser plane 96 emitted by a laser 295 of a 3D laser camera 95a, each blister recess 84 is illuminated by the laser plane 96 including the top surface, sidewalls 86, and bottom 87 of the blister card 82 of the sheet 85, and an imaging component of the 3D laser camera (e.g., imaging camera 95 shown in FIG. 1 ) consisting of a laser light detector 296 captures a sequence of multiple images of the laser stripe illuminated on the blister card 82 and each recess 84. FIG. 19A shows a first laser stripe 97 illuminated along a first lateral portion of the blister recess, including a portion 97a along the bottom 87, a portion 97b along the inner wall, and a portion 97c along the sheet 85, and FIG. 20A shows a second laser stripe 97' illuminated along a second lateral portion of the blister recess, including a portion 97'a along the bottom 87a of the blister recess, a portion 97'b along the inner wall, and a portion 97c' along the sheet 85 of the recess 84. The PAT system then generates a corresponding sequence of corrected elevation profiles of the laser stripe along the contoured surface. The two corrected elevation profiles corresponding to the two captured images of the laser stripes 97 and 97' are the first corrected elevation profile 197 shown in FIG. 19B and the second corrected elevation profile 197' shown in FIG. 20B.

[0206] The PAT system uses the sequence of corrected elevation profiles to generate 3D coordinates of the surface features and contours of the cavity of the recess 84, from which the PAT system can calculate or determine the initial volume V0 of the empty recess 84 using the floor 87 as a first reference distance representing the bottom elevation h0, and the top surface of the sheet 85 of the blister card 82 as a second reference elevation representing the top elevation hmax.

[0207] After the powder material has been deposited within the circular cavity of the recess 84 and / or flattened within the recess 84, the partially filled recess 84 can be passed again under the stationary laser plane 96, exposing the top surface of the sheet 85, a portion of the sidewall 86, and the top surface of the layer of powder material P disposed within the cavity of the recess 84 to the laser plane 96. The imaging component of the 3D laser camera captures a new sequence of multiple images of the laser stripe as the same blister card 82 and each partially filled recess 84 passes progressively under the laser plane 96. FIG. 21A shows a first laser stripe 98 exposed along a first lateral portion of the partially filled blister recess, including a portion 98a along the bottom 87, a portion 98b along the inner wall, and a portion 98c along the sheet 85. FIG 22A shows a second laser stripe 98' exposed along a second lateral portion of the partially filled blister recess, including portion 98'a along the bottom 87a, portion 98'b along the inner wall, and portion 98c' along the seat 85 of the recess 84. The PAT system then generates a corresponding sequence of corrected elevation profiles of the laser stripe along the contour surface of the partially filled recess. Two of the corrected elevation profiles corresponding to the two captured images of the laser stripes 98 and 98' are the first corrected elevation profile 198 shown in FIG 21B, and the corrected elevation profile 198' shown in FIG 22B.

[0208] The PAT system uses the sequence of corrected elevation profiles to generate 3D coordinates of the surface features and contours of the partially filled recess 84, from which the PAT system can calculate or determine the initial volume Vo of the empty recess 84 using the floor 87 as a first reference distance representing the bottom elevation h0 and the top surface of the sheet 85 of the blister card 82 as a second reference elevation representing the top elevation hmax.

[0209] The PAT system uses the new sequence of corrected elevation profiles to generate 3D coordinates of the surface features and contours of the partially filled recess, including the exposed portion of the recess and the layer of powder material P disposed within the cavity of the recess 84. The PAT system determines an average elevation (average top surface elevation, hp) of the contour surface of the powder material, which can be depicted as a horizontal plane, based on the average of the elevations of the corrected elevation profiles of the top surface or portion of the layer of powder material P.

[0210] The volume of the powder material P is the volume of the truncated cone (V tc ) can be calculated based on the formula: V tc =(1 / 3)*π*Δh*(r 2 +r*R+R 2 ) (1)

[0211] Here, Δh is the distance between the base and top of the truncated cone, r is the radius of the base of the truncated cone, and R is the top plane of the truncated cone.

[0212] The height of the bottom of the recess in a commercially available blister card is h0, and the height of the top of the recess wall is h r , the external angle θ of the recess wall from the horizontal, the radius r0 of the bottom of the recess, and the radius R of the top of the recess. r The dimensions and physical parameters of the blister recess can be measured using the scanning system or can be determined in advance from the manufacturing process of the blister card itself. r Either radii r0 and R rIf both are known, then from the detected total depth of the empty recess, the empty volume from the bottom to the top of the recess can be determined.

[0213] After depositing the first dose of powder material at the bottom of the empty recess, and optionally, preferably after leveling the powder material to the first incremental layer of powder, the average elevation of the contour surface of the dose or incremental layer of powder is detected as described above and designated as the average top surface elevation hp of the powder. p1 The exterior angle θ and radius r can also be estimated. p1 or radius R r Either the radius r p1 and R r Knowing the average top elevation of the detected first incremental layer of powder, the volume of the first incremental layer of powder can be determined. In one method, the average top elevation of the first incremental layer of powder is a bottom plane surface for calculating the empty volume above the first incremental layer, and the volume of the first incremental layer of powder is the difference with the empty volume of the recess. In another method, the average top elevation of the first incremental layer of powder is a top plane surface for calculating the volume of the first incremental layer of powder above the bottom of the recess.

[0214] After the binder liquid is printed onto the first incremental layer of powder, the average ripper surface elevation of the wetted first layer of powder can optionally be detected and determined.

[0215] After depositing the second dose of powder material on the first layer of wetted powder, and optionally, but preferably after leveling the powder material to the second incremental layer of powder, the average elevation of the contour surface of the second dose or incremental layer of powder is detected as described above and designated as the average top surface elevation hp of the second layer of powder. p2 The exterior angle θ and radius r can also be estimated. p2 or radius Rr, or radius r p2 Once Rr and Rr are known, the volume of the second incremental layer of powder can be determined from the detected average top surface elevation of the second incremental layer of powder by any of the methods described above. The procedure and determination of the volumes of subsequent incremental layers of powder proceed in the same manner.

[0216] The detected elevation measurements of the blister recesses and other dimensions of the recesses such as top radius, bottom radius, wall angle, etc. are automatically and instantly transmitted to a controller operating one or more software systems (e.g., KAX Group software ProaXesS), which uses the 3D coordinates of the generated surface features to calculate the average top surface elevation of the powder layer and the incremental powder layer volume below or above the calculated average top surface elevation.

[0217] In various embodiments, the controller uses the entire scanned surface of the deposited or planarized powder to determine the average top surface elevation and volume of the powder layer. In some embodiments, the controller uses an area of ​​20% or more, more typically 50% or more, and preferably 75% or more of the scanned surface of the deposited or planarized powder. In other embodiments, the controller selects a single or more target areas of 20% or more, more typically 50% or more, and preferably 75% or more of the scanned surface of the deposited or planarized powder. In some embodiments, the selected area of ​​the scanned surface of the deposited or planarized powder used to calculate the average top surface elevation is about 25 square millimeters (mm ) selected from a predetermined location on the scanned surface of the deposited or planarized powder. 2 ) or more. Depending on the total area (size) of the blister depression, the area of ​​the selected area is 25 mm 2 From about 100 mm 2 up to 20%, more typically 50% or more, and preferably 75% or more of the scanned surface of the deposited or planarized powder.

[0218] <Material placement> In an embodiment of the process, one or more measurement devices, such as a shortwave IR camera, are used to monitor the quality and accuracy of the deposition of the printing fluid.

[0219] The PAT system can include a subsystem that monitors and evaluates the effectiveness of the liquid dispensing process. The subsystem can include a non-contact spectral imaging camera configured to use one or more serial or parallel bandpass filters. In an embodiment, the device accurately detects and records position data of individual dispensed or printed droplets and / or deposition patterns formed from multiple droplets deposited on a substrate or construction material. The PAT system can then compare the position data in real time with the printed image and / or concentration specifications used by the processing system to control the droplet dispensing rate and pattern and the amount of one or more API compounds deposited in one or more individual cavities during article formation. The subsystem provides a means to continuously measure, record, and report the quality and consistency of the prescribed printing process. The camera system can incorporate intelligent data processing algorithms, including artificial intelligence where appropriate, to evaluate and determine whether an article passed inspection or failed inspection and requires rework or quarantine in the process.

[0220] In various embodiments, the aforementioned means for continuously measuring, recording, and reporting the quality and consistency of a given printing process may consist of an integrated short-wave infrared (SWIR) imaging sensor. The SWIR sensor may operate in the range of 550-2500 nanometers (nm), typically in the range of 1,050-2500 nm, and more commonly in the range of 1,400-1650 nm, i.e., in the region of light waves beyond the visible and NIR ranges, but not limited to this. The surface of the material to be processed may be illuminated with light in the SWIR range of known wavelength and intensity emitted from a separate SWIR light source or from the SWIR sensor device itself. Depending on the composition of the material on or near the surface (SWIR wavelengths can penetrate deep into many materials), some of the emitted SWIR light waves are absorbed by compounds of the composition, and in combination with a bandpass filter, an image is constructed based on the SWIR light waves reflected by the object and absorbed by the SWIR sensor. This image may be interpreted to identify the location of the material or composition, and one or more components of the material. In one non-limiting example, in a process where an aqueous binding liquid is dispersed as multiple droplets onto the surface of a powder material disposed within a blister cavity, a SWIR imaging sensor can monitor the effectiveness of the liquid dispensing process and dispense known amounts of binding liquid to predetermined target areas. A control system can interpret the actual dispensing pattern, compare it to the predetermined target areas, and instruct the processing system to take the next action.

[0221] In various embodiments, the SWIR imaging sensor can measure that the liquid dispensing process failed to dispense a droplet of liquid from one of the dispensing nozzles (also called jets), for example due to a clogged jet, resulting in an unprinted portion of the expected print pattern of liquid that the liquid dispensing system was programmed to take, leaving an unprinted area on the build material. In a binder jet process, there may be unintended overlapping lines of unwetted or weakly wetted powder in a series of wetted, bound powder layers. However, as a result of the detected error in the actual dispensing pattern, the processing system can be programmed to take one or more further processing steps or reprocessing steps to avoid the adverse effects of the dispensing error appearing in the processed article.

[0222] In one example, when a dispensing error is detected, the control system can generate new commands using normally operating print nozzles to print a corrective pattern of fluid only in the unprinted areas, thereby dispensing fluid in the previously missing areas and correcting the printed areas to match the originally commanded print pattern.

[0223] In another example, the processing system can be programmed to instruct the transport system to pass the fabrication module, as well as the substrate and the build material thereon (powder material) under the array of printing nozzles along modified laterally offset paths using a different set of printing nozzles to print predetermined target areas in the next layer of powder material. In this process, if a jet is clogged and cannot dispense the binding liquid as instructed, the PAT system recognizes the linear pattern of missing liquid on the wetted powder surface, but when the next layer of powder material is printed, a modified laterally offset path is taken and the unprinted areas are moved to another position in the wetted bound powder layer, thereby laterally shifting the lines of missing liquid in a series of progressively wetted bound powder layers.

[0224] Additionally, when an unprinted line of build material is detected, the printing program can be instructed to dispense additional binder liquid from a nozzle or two nozzles adjacent to the failed jet to place additional liquid in the vicinity of the unprinted line of powder material, which can then move laterally to fill the powder material with enough liquid to fully bind the powder material and avoid the adverse effects of the dispensing error. Alternatively, the processing system can instruct the liquid dispensing system to deposit a larger amount of liquid in a subsequent liquid print pattern along the line or area observed to be deficient in the amount of liquid detected by the SWIR image sensor to make up for the deficient binder liquid of the previous layer.

[0225] In another example, when an unprinted line of build material is detected, the processing system can be programmed to instruct the transport system to pass the manufacturing module, and the substrate and build material (powder material) thereon, under another row of printing nozzles in the array of printing nozzles to avoid passing the area of ​​printed build material under the clogged jet until the clogged jet is cleaned or removed or replaced.

[0226] Alternatively, the system may be programmed to determine, based on the printed fluid pattern detected by the SWIR imaging camera, that a critical fault has occurred in the printing system, requiring further processing to be stopped and printing nozzles repaired or replaced, correct operating conditions to be restored, or the article being produced to be quarantined.

[0227] <Qualification of finished product> In various embodiments, the control or PAT process can include an aesthetic evaluation method for an article, comprising acquiring a number of digital images of the processed article or one or more intermediate forms of the article. The number of images can be classified into one or more article (or intermediate form) image classes, the image classes being selected from the group consisting of acceptable images and unacceptable images, the unacceptable images including at least one of rework images and quarantine images. Predefined and stored images of articles (e.g., dosage forms) of acceptable quality are accumulated and assembled into a class of acceptable images. Predefined and stored images of articles (e.g., dosage forms) that are not of acceptable quality are accumulated and assembled into a class of unacceptable images. The unacceptable images can be further classified as rework images and quarantine images based on whether the article in the image can be reworked to acceptable quality or cannot be reworked and requires quarantine. The method comprises using the number of acceptable images to create an algorithm that can distinguish real-time article images into acceptable and unacceptable images. The process further includes using the plurality of reworked images to create an algorithm capable of distinguishing the real-time article image as a reworked image or a non-reworked image, or as a reworked image or a quarantine image. The process includes acquiring a digital image of the article in real-time, and analyzing the real-time article image with one or more algorithms to distinguish the live article image as at least one of an acceptable image, an unacceptable image, a reworked image, and a quarantine image. The process includes further processing the real-time article based on the analysis of the real-time article image, and if the real-time article image is determined to be an acceptable image, the real-time article advances to a next processing step. If the real-time article image is determined to be a reworked image, the real-time article advances to a rework processing step where one or more previous processing steps performed on the article are repeated. Also, if the real-time article image is determined to be a quarantine image, the article advances to a quarantine processing step where the real-time article is removed from the processing system and quarantined.A method for assessing the aesthetics of an article can be built from a database of images that is continually updated with additional images of articles produced by the processing system and having exterior surfaces of acceptable quality and appearance, and can continually reduce false negatives or false positives over time as articles are produced in the processing system.

[0228] In various embodiments, a two-dimensional (2D) camera imaging system, such as a Cognex Insight 9000 series camera, can be used to inspect the finished product after all processing is complete. In some embodiments, the 2D camera images the surface of the build material or processed build material (e.g., the wet binding powder layer), and the aesthetic evaluation of the article described above can be used to determine the surface quality of the top surface layer of the binding powder matrix.

[0229] In various embodiments, the aforementioned two-dimensional camera imaging system can be installed and used to monitor the top surface quality of the workpiece, for example, but not limited to, the control system can be programmed to execute subsequent processing operations depending on the results of the evaluation by the 2D camera imaging system. For example, if the 2D camera determines that the image of the top surface of the workpiece is a reject image and a rework image, the process control system can command the workpiece to be reprocessed (reworked) through a top surface smoothing / tamping unit operation of the workpiece and then re-image the top surface of the reworked item to inspect and determine if the reject surface finish has been corrected. The process control system can be configured to command the reprocessing of the workpiece one or more times until a satisfactory result is obtained or until quarantined. Alternatively, if the 2D camera image determines that the image of the top surface of the workpiece is a quarantine image, the process control system can command the item to be quarantined. If the workpiece is determined to be excessively reworked and / or quarantined, the control system can stop further processing operations until the operation of the system is inspected and corrective action is taken.

[0230] <Unloading of finished products> In various embodiments, after forming the article on or in the substrate, the article is removed from the substrate for further processing, including packaging. Removal of the article from the substrate can be performed in the processing system, on the transport surface of the magnetic transfer device, and / or in the containment system, or can be performed at a remote location or system.

[0231] In various embodiments, the substrate can provide part of the packaging for the article, where the article remains in the substrate and is further processed, including further addition of components and / or phase modification (including drying and / or packaging). For example, once dosage formation in or on the forming surface is complete, the manufacturing module can move to an unloading station in the magnetic transfer system. In some embodiments, the substrate with the formed article disposed in the forming surface, such as a blister tray loaded with dosage forms, is manually or mechanically removed from the transport module, more specifically, from the carrier of the transport module.

[0232] In a mechanical removal embodiment, the device separates and lifts the loaded substrate from the carrier and transports the separated loaded substrate to an area external to the processing system, more specifically to a substrate or blister inspection apparatus, and then to a substrate or blister sealing apparatus to seal the dosage forms in the recesses from the environment for storage and transport.

[0233] In another embodiment, after the finished product is formed on the substrate (e.g., a blister card with a dosage form formed within a recess), the manufacturing module is controlled to exit the containment zone via a mask lifting device 190 located in the transport opening 36 of the containment housing. The mask lifting device 190 provides a vestibule through which the mask 90 of the manufacturing module can be lifted from the substrate 80 and nest 74 of the manufacturing module 70 for manual or mechanical removal. As shown in FIG. 17A, the mask lifting device 190 has a pair of side walls 191 forming a vestibule and laterally spaced apart to allow the manufacturing module to pass therebetween with close non-contact clearance to the side walls 191. The side walls 191 each have a narrow groove 192 formed on the inner surface in a mirror image pattern. Each manufacturing module 90 can be provided with a pair of pins 94 (FIG. 6) on opposite sides of the front end of the mask 90 that extend laterally outward from the side of the mask 90 and beyond the side of the nest 74. Each groove 192 has an entrance 193 at the leading edge of the sidewall at a height that coincides with the pins 94 of the mask 90. ​​As the manufacturing module 70 enters the antechamber, the pins 94 of the mask 90 enter and pass along a horizontal portion 195 of the groove 192 and are guided along the curve of the groove to a second angled portion 196 that is inclined at an angle of approximately 45 to 75 degrees from the horizontal. As the pins 94 ascend the angled portion 196, the leading end of the mask 90 rises and disengages from the nest 74. The mask then controllably hinges and controllably rises completely out of the blister card, exposing the blister card for inspection, as shown in FIG. 17B, and allowing the blister card to be manually or automatically removed from the carrier for further processing or handling. Inspection of the blister cards containing the finished dosage forms includes inspection for scratches and defects in the surface finish, as described herein. Once one or more blister cards are removed, the carrier is manually or automatically reloaded with new blister cards and the hinged mask element is controllably lowered into position to cover the newly placed blister cards.

[0234] <Packaging and sealing> After the final doses are formed, the completed substrate with one or more dosage forms disposed within the recesses of the blister sheet is moved to a blister card inspection apparatus and then to a sealing and cutting apparatus. Sealing and cutting of the blister sheet is well known in the art and can be constructed within the containment system, where the sealed blister sheet is either formed within the containment system or is transferred from the containment system and sealed and cut in a packaging system outside of the containment system.

[0235] <Repair device> The invention also includes a repair device capable of cleaning or repairing a deposition mechanism of a deposition device, or a phase correction mechanism of a phase correction device, to restore their performance during installation of the deposition device or phase correction mechanism or device. In one non-limiting example, the print nozzle cleaning device has a nozzle cleaning shuttle and a nozzle cleaning substrate secured to the nozzle cleaning shuttle and capable of passing under the print nozzles, the nozzle cleaning substrate configured to wipe and clean the print nozzles and restore printing performance.

[0236] An embodiment of a printing nozzle cleaning device 150 is shown in Figures 13-15. The device 150 includes a transport module consisting of a nozzle cleaning carrier 151 and a nozzle cleaning blade 155, and a shuttle 75 (described elsewhere herein) that moves the nozzle cleaning device 150 over the processing surface 16. The nozzle cleaning carrier 151 has a base 152 having a planar cavity into which the shuttle 75 fits, and a frame 153 to which the nozzle cleaning substrate 155 is fixed. The base 152 is oriented over the shuttle 75 by one or more fasteners, such as screws 76, which pass through holes disposed in the side walls of the base 152 and strike the sides of the shuttle 75. The frame 153 comprises an open-topped container having a container volume 154 of sufficient volume to contain and contain a quantity of printing liquid that may remain in the printer housing 551 and the printer nozzles 552 during maintenance or replacement of the liquid printing device 50, or to contain a quantity of printing liquid that may be dispensed from the printer nozzles 552 during a cleaning procedure. Frame 153 also includes a sidewall 156 that slopes upwardly and outwardly at an angle, and a fixed plate 157. Sloped sidewall 156 has a plurality of threaded holes 159 that align with a plurality of through holes 161 in fixed plate 157 and a plurality of through holes 160 in nozzle cleaning blade 155. Nozzle cleaning blade 155 is secured to sloped sidewall 156 by passing a set screw 158 through hole 161 in fixed plate 157 and hole 160 in nozzle cleaning blade 155, and threading set screw 158 into threaded hole 159 in sloped sidewall 156, as shown in FIG.

[0237] In the illustrated embodiment, the nozzle cleaning blade 155 has an upper end 165 along its length and is made of a resilient elastomeric material, including natural or synthetic rubber or silicone, typically with a low durometer value that gives the material flexibility. The upper end 165 engages the nozzle of the print head and wipes or squeegees away material that may accumulate at the nozzle and impede or block the delivery of droplets and / or streams. The design and construction of the frame 153 keeps the upper end 165 of the nozzle cleaning blade 155 at a height sufficient to allow the tip of the upper end 165 to flex slightly when it engages the printer nozzle 552 when the print nozzle cleaning device 150 is magnetically levitated above the process surface 16 by the process movement device 20. As the print nozzle cleaning device 150 moves under the printer housing 551, the opposite sidewall of the angled sidewall 156 extends in a direction perpendicular to the length of the print nozzle 552, causing the tip of the upper end 165 to rub along the printer nozzle 552. To avoid splashing liquid or debris as the deflected tip of top end 165 passes over the last printer nozzle 552, the flying height of print nozzle cleaning device 150 is slightly lowered as the blade leaves the print nozzle so that the tip of top end 165 deflects in contact with printer nozzle 552.

[0238] In another example, the surface finishing cleaning apparatus can have a shuttle and one or more tamp head cleaning substrates secured to the surface finishing cleaning shuttle and pass under the surface finishing apparatus (e.g., surface finishing apparatus 60 shown in Figures 11A and 11B), and the surface cleaning substrates are configured to wipe and clean the finishing surface of the tamp head of the surface finishing apparatus to remove debris and restore the finishing surface.

[0239] An embodiment of a surface cleaner 280 is shown in Figures 16A-16C. The surface cleaner 280 includes a transport module consisting of a cleaning carrier 281 and a cleaning substrate 285, and a shuttle 75 (described elsewhere herein) that moves the surface cleaner 280 over the processing surface 16. The cleaning carrier 281 includes a base 282 having a planar cavity into which the shuttle 75 fits, and a frame 283 to which the cleaning substrate 285 is secured. The base 282 is oriented over the shuttle 75 using one or more fasteners, such as screws 76, that pass through holes disposed in the sidewall of the base 282 and engage the sides of the shuttle 75. The frame 283 includes a pair of elongated rectangular pockets 289 shaped to receive the cleaning substrate 285, and a support retainer 288 that comprises a short hollow cylinder. Four posts 284 extend perpendicularly from the four corners of the base 282 to support retainers 288 of the frame 283, providing the frame 283 with sufficient height for the cleaning substrate 285 to engage the underside of the tamp head 68 of the surface finishing apparatus 60. Each post 284 has a spring 288 between each post 284 and the support retainer 288 to provide flexibility and some "flex" as the cleaning substrate 285 passes under the surface finishing apparatus 60 or other equipment in the containment zone. The frame 283 is secured to the posts 284 of the base 282 using fasteners such as screws.

[0240] In the illustrated embodiment, the pair of cleaning substrates 285 includes an elongated rectangular body that fits into the pockets 289, and blades 287 that taper along their length. The cleaning substrate is made of a resilient elastomeric material that may include natural or synthetic rubber or silicone, and is typically of low durometer that imparts flexibility to the material. The upper ends of the blades 287 engage the bottom surface of the tamp head 68 of the surface finishing device 60 to wipe or squeegee away any construction or processing material or other debris that may have accumulated on the bottom surface of the tamp head 68. Such debris may interfere with smoothing or otherwise finishing the surface of the powder layer.

[0241] Working Example: A processing system for producing a solid dosage form as shown in FIG. 1 and described herein is provided. The system includes an omnidirectional magnetic mover having a stator formed of 24 tile segments, each segment being approximately 1 foot square, arranged with 2 tiles wide and 12 tiles long, and a process mover consisting of a thin stainless steel plate having a rectangular area 4 feet wide and 13 feet long, placed on the stator of the process mover. A containment zone is formed by a containment housing having transparent side walls and a transparent ceiling panel made of Lexan (polycarbonate) placed on the stainless steel plate and laterally centered on the stator. The containment housing is 3 feet wide, approximately 10 feet long, approximately 5 inches high, and has an air inlet opening at its front end. A HEPA filter device, shown as element 18, is placed and sealed on the top surface of the ceiling panel 33, with the air inlet of the HEPA filter device 18 extending through an open port 34c (FIG. 2) in the ceiling panel 33. The HEPA filter apparatus is positioned and supported above the ceiling panel on an equipment support 15c that is elevated by a pair of support brackets 14c.

[0242] A plurality of manufacturing modules are movable under the control of an omnidirectional magnetic motion system to process unit operation stations located on or within a transport surface enclosed in a containment housing. Examples of manufacturing modules are shown in Figures 4-6 and described herein.

[0243] <Example 1> The process equipment 10 shown in Figure 1 provides process unit operation stations and processing systems including a pair of powder dispensers 40a, 40b, a pair of liquid printing devices 50, and a pair of surface finishing devices 60. As shown in Figure 3, the first powder dosing station was disposed on the stator tile segment B1, and the second powder dosing station was disposed on the stator tile segment A1. The first and second powder devices 40a, 40b were disposed and sealed on the upper surface of the ceiling panel 33, and their powder discharge ports extended through the open port 34b of the ceiling panel to discharge the powder in the recesses of the blister card.

[0244] <PATステーション> A first liquid printing device 50a at the first printing station was disposed on stator tile segment A3, and a second liquid printing device 50b at the second printing station was disposed on stator tile segment A7. The first and second liquid printing devices 50a, 50b were disposed on the upper surface of the ceiling panel 33 and were removably sealed, with their printing nozzles extending through the open port 34a in the ceiling panel.

[0245] A first surface finishing device 60a at the first finishing station was positioned above stator tile segments A5-A6, and a second surface finishing device 60b at the second finishing station was positioned above stator tile segment B7. The first and second surface finishing devices 60a, 60b were positioned on the upper surface of the ceiling panel 33 and were removable and sealed, with their finishing surfaces extending through the open port 34d in the ceiling panel.

[0246] The inspection station's first imaging device 95a was positioned above stator tile segment B4. Imaging device 95a is positioned above containment housing 30 for imaging of the blister cards and components through transparent ceiling panel 33. Imaging device 95a is a Cognex 3D camera capable of detecting the position of the periphery of the powder material within the recess of the blister card and estimating the volume of powder contained within the recess.

[0247] A second imaging device 95b is disposed at the second inspection station and is located above stator tile segment B4. Imaging device 95b is located above containment housing 30 to image the blister cards, build powder, and binder liquid through transparent ceiling panel 33. Imaging device 95b is a SWTR camera that detects the location and concentration of binder liquid applied to the layer of build powder in the recesses of the blister cards and identifies the pattern and concentration of the binder liquid, as well as the specifics of the water and / or one or more solvents contained therein. A process controller system can receive the images captured by imaging device 95b and perform real-time analysis of the accuracy of the printing operation.

[0248] A third imaging device 95c is located at a third inspection station located above stator tile segment A8. Imaging device 95c is located adjacent to the second liquid printing station on stator tile segment A7 and images the blister cards, build powder, and binder liquid through transparent ceiling panel 33. Imaging device 95c is a SWIR camera that detects the location and concentration of the second or top binder liquid applied to the top layer of powder in the recesses of the blister cards and identifies the pattern and concentration of the binder liquid, particularly the water and / or one or more solvents contained therein. A process controller system receives the images captured by imaging device 95b and can perform real-time analysis of the accuracy of the printing operation.

[0249] A fourth imaging device 95d is located at a fourth inspection station located on stator tile segment B10. Imaging device 95d is located at the outer entrance of the containment zone to detect and inspect manufacturing modules entering and exiting the containment housing 30. Imaging device 95d is a 2D imaging device or camera used to image the manufacturing modules and identification markers on the substrates (blister cards) to monitor, identify, monitor and control the movements and unit operations performed on the substrates within the containment zone. The 2D imaging device 95d also captures images of blank substrates (blister cards) entering the containment zone and processed substrates with completed dosage forms exiting the containment zone and transmits the images to the control system to analyze the completed dosages in real time and verify the accuracy of the printing operations.

[0250] <Blister card and manufacturing module> At a remote forming station or facility, the substrate film blank was thermoformed into a substrate having a blister card with first and second six recesses within a blister frame. The blister forming process also included printing a unique identification code, such as a lot number or a QR code, on both the top and bottom surfaces of the blister sheet and on the bottom (underside) of the bottom of each recess. The unique 2D barcode (shown in FIG. 6) of the blister card to be attached to the manufacturing module was scanned by 2D imaging device 95d through window 189 in hinged mask 90 and entered into the data storage of the process unit operations controller before the manufacturing module entered the containment zone.

[0251] The processing system includes a processor that controls the processing of six manufacturing modules at a time, each of which follows a build program, and the manufacturing modules move asynchronously through a number of different process unit operations until each build program is completed. The processing system can process one manufacturing module or up to 10, 15, or 30 manufacturing modules simultaneously. Each one of the six newly formed and identified substrates was placed in a corresponding nest of a carrier attached to a uniquely identifiable shuttle, forming six manufacturing modules. An operator placed a first manufacturing module 70a (see FIG. 3) in a loading zone located on a transport surface above one of the tile segments (e.g., B7) of the omnidirectional magnetic moving device outside the containment housing, and scanned the unique identification barcode of the first substrate (blister card) with the 2D camera 95d of the fourth inspection station to the process unit operation controller. The movement controller of the omnidirectional magnetic moving device detected that the shuttle of the first manufacturing module was placed in the loading zone and confirmed to the process unit operation controller that the uniquely identifiable shuttle was correctly placed in the loading zone. This associated the unique identification code of the first substrate with the uniquely identifiable shuttle. The process unit operations controller notified the operator that the first fabrication module was properly identified and informed the operator that the first fabrication module could be moved into the containment system under control of the movement controller.

[0252] <Asynchronous Movement and Unit Operation Processing> The motion controller moved the fabrication modules (shuttle with attached carriers and substrates) from the air inlet opening into the containment housing of tile segment A8-B8. The first fabrication module, under the control of both the process unit operations controller and the motion controller, first moved to the 3D imaging device 95a to detect, evaluate and determine the volume within the empty blister recesses.

[0253] The first manufacturing module was then moved to the first liquid printing station of stator tile segment A3. The first manufacturing module was then appropriately positioned and oriented by the motion controller at an initial registration position, which initiated a controlled linear movement at a programmable (and in some embodiments constant) linear velocity along the vertical axis toward stator tile segment A4, thereby passing through a plurality of recesses 83 in the substrate directly beneath the ejection nozzles of first liquid printing apparatus 50. The controlled movement of the manufacturing module shuttle includes incremental and / or continuous linear movements in the horizontal plane, including rotation of the manufacturing module about a vertical axis, to manipulate the manufacturing module from one process unit operation to the next, while simultaneously and independently maneuvering the other five manufacturing modules (FIG. 3, 70b-70f) from station to station and through various process unit operations via the same transport surface and accommodation space, without contact or collision with other manufacturing modules, or undue delays or "traffic jams." Under the control of the process unit operation controller, according to the dosage printing program, an appropriate pattern of printing fluid was deposited as a pre-binding fluid layer on the inner bottom surface of each recess of the blister substrate.

[0254] The first manufacturing module then moved to a first powder dosing station located on stator tile segment B1 and was properly positioned and oriented by the motion controller to an initial registration position. Under the control of the process unit operation controller and in accordance with a dosage printing program, a predetermined amount of powder material was dispensed by the dosator 40 and deposited as a first powder deposit in each recess of the blister substrate on top of the preliminary binding liquid layer, as shown in Figures 8A and 8B.

[0255] After depositing the volume of powder material, the first manufacturing module 70a then moved to a vibration leveling device 55 located adjacent to the tile segment A2. As described herein, the vibration leveling device 55 had a voice coil actuator (VCA) located vertically above the transport surface 16. When the first manufacturing module was positioned under the voice coil actuator, a probe 56 extending vertically from the actuator extended downward to contact the mask 90 of the carrier 72 (see FIG. 4 ) and transmit vibrations at a frequency of about 40 Hz and an amplitude of 1 volt to the nest 74, directly to and through the mask 90, and to the blister card 82 located below it. The vibration of the blister card 82 caused the first powder deposited in the recess to form into a powder layer with a uniform thickness and a uniform, flat top surface within the recess. Alternatively, the manufacturing module and its blister cards can be vibrated during deposition of powder at the first powder dosing station to dispense a dose of powder material into a recess having a horizontal surface using a vibration force used in the dosing device 40 that provides free flow of powder material to and through the dosing device.

[0256] Optionally, or in addition to the leveling provided by the vibration leveling device 52 of the leveling station, the motion controller of the omnidirectional magnetic motion device can actuate the motion stator to vibrate the first fabrication module (e.g., at a frequency of about 40 Hz with an amplitude of about 1 volt) via the magnetic forces on the shuttle. Each vibration cycle consists of a small angle rotation (pitch) through the longitudinal axis of the shuttle, which can vibrate the carrier and substrate until a substantially uniform layer of the first powder deposited in the cavities is formed within the recesses of the blister card.

[0257] The first manufacturing module then returns to the 3D imaging device 95a under control of both the process unit operations controller and the motion controller to detect, evaluate and determine the volume remaining in each of the empty blister recesses above the first leveled uniform layer of powder material.

[0258] The first manufacturing module was then moved to a first liquid printing station located on stator tile segment A3 under the control of both the process unit operation controller and the motion controller, and appropriately positioned and oriented in an initial registration position by the motion controller. The motion controller then initiated controlled linear movement along a longitudinal axis toward stator tile segment A4 at a constant linear velocity, preferably 0.25 meters per second (m / s) or less, thereby passing the multiple recesses of the substrate containing the first uniform layer of powder directly under the ejection nozzle of the first liquid printing device. Under the control of the process unit operation controller, an appropriate pattern and amount of printing fluid was deposited on the first uniform layer of powder according to a dosage printing program, thereby wetting the first uniform layer of powder and forming a first wetted powder layer within each recess of the blister substrate.

[0259] The first manufacturing module was moved to a first inspection station located above stator tile segment B4, and one or more images of the top surface of the manufacturing module were taken by SWIR imaging device 95b to detect and evaluate the volume and distribution of the layer of wet powder material within the blister recesses, and to detect the position or accuracy of printed droplets deposited on the first layer of powder in forming the wet powder layer.

[0260] The first manufacturing module then returned to the 3D imaging device 95a under the control of both the process unit operations controller and the motion controller to detect, evaluate and determine the volume remaining in each of the empty blister recesses above the first layer of moist powder material.

[0261] The first manufacturing module then (under control of both the process unit operations controller and the motion controller) returned to the first powder dosing station (or the second powder dosing station if another manufacturing module had already located it at the first powder dosing station) located on stator tile segment A1 and repeated depositing a second predetermined amount of powder material on top of the first wetted powder layer in each recess. The second powder deposit was flattened into a second uniform powder layer as had been done for the first powder deposit. The first manufacturing module then returned to the 3D imaging device 95a to detect, evaluate and determine the amount remaining in each of the empty blister recesses above the second flattened uniform layer of powder material.

[0262] The first production module was then moved to the first liquid printing station (or to a second liquid printing station located on stator tile segment A7 if another production module was already located at the first liquid printing station, although this is unlikely since the first liquid printing station is processed quickly). The first production module moved along its longitudinal axis at a constant linear velocity, preferably 0.25 m / s or less, past the plurality of recesses in the substrate containing the second uniform powder layer directly beneath the ejection nozzles of the first liquid printing device and deposited the appropriate pattern and amount of printing fluid for the second build layer onto the second uniform powder layer in accordance with the dosage printing program, thereby wetting the second uniform powder layer and forming a second wetted powder layer within each recess of the blister substrate.

[0263] The first production module was again moved to the inspection station and one or more images of the top surface of the production module were taken by SWIR imaging device 95b to detect and evaluate the position or accuracy of the printing droplets deposited on the second powder layer when forming the wet powder layer.

[0264] The first manufacturing module cycled through the first powder dosing station (or second powder dosing station), leveled, detected and determined the remaining volume in each of the empty blister recesses on the flattened layer of powder material with a 3D imaging device, printed liquid in a second uniform powder layer, and inspected the wet powder layer for positioning and accuracy of the printed liquid, repeating the cycle over the transport surface and through the process equipment to build and evaluate four additional wet powder layers.

[0265] After the final layer of powder material was deposited, planarized, and inspected by the 3D imaging device to determine the volume remaining in each empty blister recess above the final planarized layer of powder material, the first manufacturing module was moved under the control of both the process unit operations controller and the motion controller to a first surface finishing station positioned above stator tile segment A5-A6 and appropriately positioned and oriented by the motion controller to an initial registration position. For example, a tamping head of a surface finishing device shown in Figures 11A and 11B and described herein is lowered onto the dried, planarized top powder layer to smooth and shape the top surface into a slightly domed rounded profile.

[0266] The first manufacturing module was then moved to the finishing printing station of stator tile segment A7, where it was properly positioned and oriented in the initial registration position by the motion controller. The motion controller then initiated controlled linear movement along the longitudinal axis toward stator tile segment A8, at a constant linear velocity, preferably 0.25 meters / second (m / s) or less, thereby passing the multiple recesses of the substrate containing the fully formed wet dosage forms directly under the ejection nozzles of the second liquid printing device. Under the control of the process unit operation controller, a first portion of the amount and pattern of finishing fluid was deposited on the top surface of the fully formed dosage forms, forming a first layer of finishing coating (of different or same composition as the binding fluid applied by the first liquid printing device), according to the dosage printing program. The first manufacturing module was then moved to a third inspection station, where one or more images of the top surface of the manufacturing module were taken by SWTR imaging device 95b to detect and evaluate the position or accuracy of the printed droplets of finishing coating deposited on the final formed powder material layer.

[0267] The first production module then returned under control of the process unit operations controller to the same finishing printing station three more times, where three additional portions of the finishing fluid volume and pattern were deposited on top of the fully formed dosage form in accordance with the dosage printing program to form remaining layers of finishing coating (either of a different or same composition as the binding fluid applied by the first liquid printing device).The first production module then moved again to a third inspection station and SWIR imaging device 95c to detect and evaluate the position or accuracy of the printed droplets of the final finishing coating deposited.

[0268] The first manufacturing module with the final printed and completed dosage form in the recess was then moved to the second surface finishing station of stator tile segment B7, again similar to the apparatus shown in Figures 11A and 11B, and properly positioned and oriented in the initial registration position by the motion controller. Under the control of the process unit operation controller and according to the dosage printing program, two sets of surface finishing bodies (UHMWPE) of the surface finishing apparatus were slowly lowered while rotating into contact with the top surface of the top wet powder layer in the recess to reduce the surface roughness of the upper surface of the dosage form. Upon completion, the rotating finishing bodies were slowly lifted off the surface finishing.

[0269] The first manufacturing module having the blister substrate with the 12 completed and fully formed wet powder dosage forms is moved, under the control of both the process unit operations controller and the motion controller, through the transport opening 36 of the containment housing 30 to the tile segment B10 of the fourth inspection station outside the containment zone, where the fourth 2D imaging device 95d acquires one or more images of the top finished surface of the constructed dosage form to detect and evaluate the appearance and texture of the top surface of the constructed dosage form. The bar code of the blister card is also scanned by the 2D imaging device 95d to the process unit operations controller. The motion controller of the omnidirectional magnetic motion device also detects the same uniquely identifiable shuttle, and the process unit operations controller verifies that the shuttle remains associated with the same unique identification code of the first substrate. The process unit operations controller then notifies the operator that the dosage form building of the first manufacturing module has been properly identified and that the first manufacturing module is ready to be manually moved to the dosage form drying system to evaporate excess water and solvent within the wet dosage forms.

[0270] The other five manufacturing modules, each having a uniquely printed identification mark on its substrate and each associated with a uniquely identifiable shuttle, were run through the same process unit operations as the first manufacturing module, with each manufacturing module being processed asynchronously through the same process unit operation stations as the other manufacturing modules in the six module batch.

[0271] After all six production modules in a batch were processed out of their containment housing at the unload station, a drying operation was initiated. Optionally, a drying operation could be performed on each loaded substrate in a production module individually as the production module was processed out of its containment housing. Each substrate (blister tray) fully loaded with wet dosage form was removed (lifted) from the carrier and passed through the drying system. After drying, the loaded blister tray was separated from the carrier nest for further processing, including film sealing and packaging of the blister tray.

[0272] The modular design of the processing system of this embodiment can be used for small-scale development, simulation, testing, experimentation, and similar activities, and the formulation forming device or device module used can be deployed to pilot and commercial scale manufacturing. This modularity allows the process and operating conditions of the device and device module to be thoroughly and systematically tested and developed before the same device and device module is installed in a GMP-rated pilot or manufacturing facility. The modularity of the device and device module allows the device and device module to be removed from the GMP-rated pilot or manufacturing facility and placed in the processing facility for small-scale dynamic simulation of the process before the same device or device module is returned to the pilot or manufacturing facility, which can help with process adjustments and troubleshooting of process anomalies.

[0273] Example 2: Mask removal chamber In a second embodiment, the system and operation of embodiment 1 was used to form a first manufacturing module having a blister substrate with 12 completed, fully formed wet powder dosage forms. In this embodiment, as shown in Figures 1, 17A and 17B, a mask lifting device 190 was placed in the transport opening 36 of the containment housing. The mask lifting device 190 lifted the mask 90 of the manufacturing module from the substrate 80 and nest 74 of the manufacturing module 70 to provide an antechamber that can be removed manually or mechanically. When the front end of the mask 90 enters the antechamber opening between a pair of side walls 191, a pair of pins 94 of the mask 90 enters at the height of a narrow groove 192 on the inner surface of the antechamber, and as the manufacturing module advances through the antechamber, the pins 94 of the mask 90 pass upward along the curve of the groove, causing the mask 90 to rotate upward and away from the blister card. As pin 94a moves upward along horizontal portion 195, the tip of mask 90 is lifted up from nest 74 and the blister card is exposed to 2D imaging device 95d, the barcode is read, and the appearance and texture of the top surface of the constructed dosage form is inspected and evaluated.

[0274] Example 3: Active Loading Tablet System The active loading tablet system is configured with an omnidirectional magnetic transfer device for movement of a transport module to and between a group of process unit operation stations that form tablets having doses of an active agent.

[0275] The active loading tablet system 210 is shown in a plan layout in Figure 18 and includes a stator transport surface, containment system, and group of process unit operation stations including a base tablet feeding system 240, an activator dispensing system 250, a drying system 260, and an optional coating system 270, each system located above a portion of the stator transport surface 16 of the omnidirectional magnetic moving device and / or within the containment housing 30. The base tablets used in the active loading tablet system 210 can be pre-formed by other manufacturing means, such as a compression tablet manufacturing system, and fed to the base tablet loading system 240 of the active loading tablet system 210.

[0276] In this embodiment, the base tablet is a preformed compressed tablet. The tablet includes a first side, an opposing second side, and a periphery. At least one of the sides (both in this embodiment) has a concave recess extending from slightly inside the periphery of the tablet partially inward toward the central plane. The active agent is in the form of a liquid active agent comprising a liquid composition including the active agent with one or more solvents or diluents.

[0277] The base tablet placement and distribution system 240 is disposed above the tablet placement station on stator tile segment B1. The base tablet placement and distribution system 240 includes a loading container or hopper that contains base tablets that are gravity fed into a loading chute that delivers the base tablets to the holding system. The base tablet distribution system has an upper inlet end disposed outside (and above) the containment housing 30 and a tablet distribution end that extends through a sealable port (not shown) in the containment system ceiling panel. The base tablet distribution system includes a placement device that arranges a predetermined plurality of base tablets in a predetermined arrangement or array (e.g., a 3x4 or 4x6 array) in a horizontal plane, where some (e.g., halves or quarters) or all of the tablets are equally spaced in a rectangular pattern. In this embodiment, the array includes two sets of six base tablets arranged and dimensioned as shown in FIG. 6. The base tablet dispensing system also includes a tablet placement means that vertically lowers and places the placed base tablets on the upper surface of a substrate, preferably comprising a substrate with an array of concave recesses of the same dimensions and arrangement as the placement device, such that each base tablet in the placement device is placed in a corresponding (array location) recess in the substrate. In this embodiment, the substrate is a blister substrate that is positioned and oriented by a carrier element of a transport module as described herein and shown in Figures 4 and 6, providing a manufacturing module that controllably moves the transport module on a stator of an omnidirectional magnetic transfer device using a shuttle. The manufacturing module, under the control of both the process unit operation controller and the motion controller, first moves to a tablet placement station below the dispensing means of the base tablet placement and dispensing system 240, where one of a predetermined number of base tablets is placed in each recess of the blister substrate.

[0278] The activator dispensing system 250 is for adding a liquid dose of activator to each base tablet deposited on the blister substrate, including real-time monitoring, feedback, and adjustment of the dispensing of the liquid activator to each base tablet. The activator dispensing system has a top end disposed outside the containment system for receiving one or more supply units of liquid activator, and a liquid dispensing end extending through a sealable port (not shown) in the top panel of the containment housing 30.

[0279] The liquid dispensing end includes one or more dispensing modules that dispense a predetermined or desired mass or volume of active agent onto at least a first side of the base tablet. Each dispensing module can be connected to a respective active agent supply unit installed at the top end of the dispensing system 250. The supply unit can be a replaceable cartridge, container, or canister that is easily inserted or connected to the top end of the dispensing system. Using multiple dispensing modules increases the speed and efficiency of dispensing liquid doses of active agent and / or adding different active agents to the base tablet without the need to clean or replace the module. For example, on a layered or opposite outer surface, the carrier tablet is returned to the active agent dispensing system for reprocessing. Each dispensing module includes a pump with an inlet connected in liquid communication with the supply unit and an outlet connected in liquid communication with one or more dispensing nozzles. In this embodiment, the pump outlet is in liquid communication with a plurality of dispensing nozzles arranged in the same predetermined array as the substrate. The pump is preferably a metered positive displacement pump (e.g., a peristaltic pump, a rotary gear pump, or other pump type capable of providing equivalent precision and speed) capable of variably dispensing a predetermined mass or volume of liquid activator, including as little as one droplet, through a dispensing nozzle under the control of a control system. An example of an activator dispensing system 250 is described in U.S. Patent No. 8,252,234, the disclosure of which is incorporated by reference in its entirety.

[0280] The manufacturing module with the base tablet disposed within each recess of the blister substrate is moved to a dispensing station beneath the activator dispensing system and positioned and oriented relative to one or more dispensing nozzles under the control of both the process unit operations controller and the motion controller. Examples of manufacturing modules are shown in Figures 4-6 and described herein. When a single dispensing nozzle is used, the manufacturing module is controlled to position the recess and the base tablet contained therein beneath the single dispensing nozzle by moving the module under the control of the motion controller. The pump is then actuated to dispense a predetermined amount of liquid activator onto a first side of the positioned base tablet. The manufacturing module is then actuated, also under control, to position the next recess into which the liquid activator will be dispensed, and the pump is again actuated to dispense a predetermined amount of liquid activator onto a first side of the positioned base tablet. The positioning of the manufacturing module and dispensing of liquid activator continues until liquid activator is applied to each base tablet, thereby forming an activator-filled tablet.

[0281] When an array of dispensing nozzles is used, the manufacturing module is configured to position a plurality of recesses in alignment with the array of dispensing nozzles and simultaneously dispense liquid active agent through the dispensing nozzles onto a corresponding array of base tablets.

[0282] In some embodiments of the base tablet, the loaded liquid active agent can partially or completely penetrate or migrate into the solid matrix of the base tablet, while in other embodiments, the liquid active agent can form a pool of liquid within the concave first side of the loaded tablet.

[0283] When the liquid active agent is a liquid composition that includes one or more solvents, a drying system 260 is used to evaporate excess solvent from the filled tablets. The drying system 260 is located above the drying station in the stator tile segment A4. The drying system includes a drying device or drying monitor. The drying device provides heat and optionally air flow to the active agent filled tablets to evaporate excess solvent, leaving a solidified or immobile film of active agent on the first side of the filled tablet and / or partially migrated into the tablet. The drying system 260 is integrated into the containment housing, and can optionally be located outside the containment housing 30, but is accessible by an omnidirectional magnetic moving device by transporting the tablet-loaded manufacturing module from the containment zone to a remote drying system under the control of both the process unit operation controller and the movement controller. The drying device can include any one or combination of infrared (IR), convection, conduction, and / or microwave heating. The drying system 260 can include sensors to detect conditions such as tablet surface temperature, tablet surface moisture content, etc.

[0284] After drying of the filled tablets is complete, the same or a different liquid activator can be applied to the same tablets. The manufacturing module with the dried tablets is returned to the activator dispensing station 250 under the control of the process unit operations controller and the transfer controller, where another amount of liquid activator is applied, and optionally transferred to the drying system 260 to evaporate the solvent.

[0285] After a quantity of liquid active agent has been loaded onto the tablet and dried if necessary, a coating system 270 is positioned on the coating station at stator tile segment A6. The coating system 270 applies a coating to the amount of active agent loaded onto the tablet to prevent loss of active agent through wear during normal handling of the tablet. The coating may be a sealant, which may conceal or disguise the applied liquid dosage, thereby providing a uniform appearance to the pharmaceutical product. The coating system 270 preferably includes a pad printing device and a coating dryer positioned within the coating source. The pad printing device is advantageous because it transfers the coating to the top surface of the loaded tablet and can efficiently transfer the coating to the loaded tablet without waste, e.g., without overspray. The coating system may be integrated into the containment system by extending the pad printing device through a sealable port on the top surface of the containment system to provide a coating station, where a manufacturing module with tablets loaded at their bases within each recess of the blister substrate is moved to the coating station below the coating system under the control of the process unit operation controller and the motion controller, and positioned and oriented relative to the pad printing device. The manufacturing module is controlled to align and position each recess and the filled tablet contained therein beneath a pad printing device for applying a coating of coating material to a first side of the filled tablet, which is then repositioned to the next recess, where the coating material is applied to each filled tablet to form a coated tablet.

Claims

1. i) an omnidirectional magnetic moving device having a transport surface and a stator disposed beneath the transport surface and having a plurality of actuation coils that exert a primary magnetic field through the transport surface in response to controlled current through an actuation circuit; ii) a) at least one shuttle having one or more magnetic components responsive to the primary magnetic field exerted by a planar body and the plurality of actuation coils to levitate and transport the at least one shuttle above and in all directions above the transportation surface; and b) at least one substrate having one or more forming surfaces; one or more manufacturing modules having iii) a motion controller that sends a controlled current to one or more of the plurality of actuation coils to control the levitation and transportation of the one or more manufacturing modules; and iv) a) a deposition device that deposits build material onto at least one of the one or more formation surfaces when the fabrication module is positioned at a deposition location on the transport surface; and b) a phase modification device that forms at least a portion of the deposited build material on or within the at least one forming surface into an intermediate product or a finished product when the manufacturing module is positioned at a phase modification position on the transport surface; A processing system for manufacturing an article, comprising:

2. 2. The processing system of claim 1, wherein the motion controller is configured to include one or more steps of asynchronously transporting the one or more manufacturing modules at least between the deposition location and the phase correction location to form an intermediate product or a finished product.

3. 3. The treatment system of claim 1 or claim 2, wherein the transport surface comprises a continuously formed non-conductive sheet, the sheet being capable of being made of a material selected from the group consisting of polymer, glass, titanium, and stainless steel, preferably stainless steel sheet.

4. 4. The processing system of claim 1, wherein the transport surface is a rectangular region including a central region and a peripheral region, and optionally the transport surface includes a central region and a peripheral region, such region having a surface temperature controlled by circulation of a suitable heat transfer medium through an interior region of the stator to control and maintain the temperature of the transport surface, the peripheral region having a width dimension that is at least the width of the manufacturing module, and the central region being at least the width of the manufacturing module.

5. The processing system of any one of claims 1 to 4, wherein the one or more fabrication modules further comprise a carrier for fixing the substrate on the at least one shuttle.

6. The treatment system of any one of claims 1 to 5, wherein the one or more forming surfaces have one or more recesses.

7. The processing system of any one of claims 1 to 6, wherein the one or more fabrication modules comprises a plurality of fabrication modules, each of which is independently and selectively moved to and from the deposition position and the phase modification position, providing the capability of asynchronously forming an article on at least one substrate in two different fabrication modules.

8. The processing system according to any one of claims 1 to 7, further comprising means for planarizing said deposited component material to a uniform thickness.

9. The processing system according to any one of claims 1 to 8, wherein the processing system or sub-processing system further comprises one or more additional processing systems selected from the group consisting of a drying apparatus, a component material planarizing apparatus, a surface finishing apparatus, a substrate loading apparatus, a substrate unloading apparatus, and combinations thereof.

10. The processing system or sub-processing system according to any one of claims 1 to 9, further comprising a surface finishing device for surface finishing at least one upper surface of the deposited build material or solid dosage form in the forming surface when the shuttle is positioned at a surface finishing position on the transport surface.

11. The processing system according to any one of claims 1 to 10, wherein the processing system or sub-processing system further comprises a deposition detection device for detecting a uniformity of distribution of the deposited component material on the one or more build surfaces.

12. 12. The treatment system of any one of claims 1 to 11, wherein at least the building material can comprise an ingestible powder material; the building material or the ingestible powder material can comprise an active agent, non-limiting examples of which are an API, a bioactive substance or a drug; the article is a solid dosage form; the phase modifying device has means for dispersing a binding liquid forming the ingestible powder material into the bound powder material comprising an interconnected matrix of the ingestible powder material; the build powder material can comprise a particulate binder; the binding liquid can comprise an active agent, non-limiting examples of which are an active pharmaceutical ingredient (APT) or a drug; the binding liquid can comprise a soluble binder; the interconnected matrix of the building powder material can be porous and / or rapidly oral dispersible; and / or the building material can comprise at least one heat-fusible powder material; and the phase modifying device can have means for at least partially melting the heat-fusible material.

13. 1. A method of using a planar motor system to transport one or more manufacturing modules through a plurality of process unit operations utilized in the additive manufacturing of a dosage form, comprising: The above method, wherein the transport is controlled (explicitly or via machine learning, artificial intelligence or other position scheduling techniques) to perform asynchronous, synchronous and random positioning and orientation, thereby achieving asynchronous and simultaneous utilization of process unit operations in forming the dosage form.

14. 14. The method of claim 13, wherein the plurality of process unit operations includes dispensing a quantity of a component material on one or more forming surfaces of a manufacturing module, and modifying the quantity of a component material disposed on the one or more forming surfaces of the manufacturing module into a solid dosage form.

15. 15. The method of claim 13 or 14, wherein the plurality of process unit operations further comprises one or more process unit operations selected from the group consisting of mixing two or more different components, planarizing a top surface of the quantity of components, finishing an exterior surface of the solid dosage form, inspecting one or more physical properties of a material, and cleaning contaminated equipment or devices used in the method.

16. 16. The method according to any one of claims 13 to 15, wherein the build material is an ingestible powder material, and the phase modification comprises printing a liquid material having a solvent onto a layer of the ingestible powder material, and optionally drying excess solvent from the wet powder layer.

17. 17. The method of any one of claims 13 to 16, wherein the plurality of process unit operations comprises dispensing a quantity of ingestible powder on one or more building surfaces of a manufacturing module, planarizing a top surface of the quantity of the ingestible powder disposed on the one or more building surfaces of the manufacturing module to form a powder layer, printing a liquid material having a solvent on a top surface of the quantity of powder disposed to form a wet powder layer on the one or more building surfaces of the manufacturing module, and optionally drying excess solvent from the wet powder layer.

18. 18. The method of any one of claims 13 to 17, further comprising a process unit operation of printing a liquid material having a solvent onto the one or more forming surfaces of a substrate prior to dispensing the ingestible powder.

19. 19. The method of any one of claims 13 to 18, wherein the additive manufacturing of the dosage form is selected from the group consisting of binder jetting, material jetting, stereolithography, fused deposition, laser sintering, and extrusion.

20. 20. The method of any one of claims 13 to 19, wherein cleaning of the equipment or apparatus comprises positioning the cleaning substrate in a location sufficiently close to a particular process unit operation and spatially manipulating at least one of the cleaning substrate and the contaminated equipment or apparatus to clean one or more surfaces of the contaminated equipment or apparatus.

21. i) an omnidirectional magnetic moving device having a transport surface; ii) a) at least one shuttle; and b) one or more fabrication modules having at least one substrate having one or more forming surfaces; iii) a) at least one deposition device that deposits build material onto at least one of the one or more forming surfaces when the shuttle is positioned at a deposition location on the transport surface; and b) at least one processing system that performs a process unit operation on the component material when the shuttle is positioned at at least one processing location on the transport surface; and iv) a motion controller that asynchronously controls transport of the one or more manufacturing modules on the transport surface between at least a deposition location and at least one processing location for forming an article; A processing system for manufacturing an article, comprising:

22. a) one or more process unit operations; b) an omnidirectional magnetic moving device including a magnetic field generating stator having a planar transport surface; c) one or more manufacturing modules incorporating one or more magnetically actuated shuttles that move by magnetic levitation on a planar transport surface in six directions of movement, including horizontally in the x and y axes and vertically in the z axis; and d) a motion controller having one or more processors for controlling omnidirectional movement of one or more shuttles on a planar transportation surface; A processing system for forming an article or processing a material or component of an article, comprising:

23. 23. The processing system of claim 22, further comprising one or more sensors that monitor and control processing of materials including quality of the process, quality and characteristics of build material inputs, and quality and characteristics of unit operations and articles produced by the processing system.

Images