High-throughput and high-precision pharmaceutical additive manufacturing system

Abstract

To provide a high throughput and a high precision pharmaceutical additive manufacturing system.SOLUTION: An exemplary printing system includes: a material supply module for receiving a set of printing materials; a flow distribution module with a flow distribution plate, and the material supply module is configured to transport a single stream corresponding to the set of printing materials to the flow distribution plate with multiple channels for dividing the single stream into multiple streams; multiple nozzles with multiple needle valve mechanisms; one or more controllers for controlling the multiple needle valve mechanisms to dispense multiple streams based on multiple nozzle specific parameters; and a printing platform configured to receive multiple dispensed streams, and to move to form a batch of pharmaceutical product.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] The present disclosure relates generally to additive manufacturing technologies, and more specifically to high throughput and high precision 3D printing approaches for producing pharmaceutical dosage units (e.g., tablet caplets, printlets). [Background technology]

[0002] Additive manufacturing, also known as three-dimensional printing ("3D printing"), is a rapid prototyping technology that involves the process of bonding or solidifying materials to produce three-dimensional objects. Specifically, materials are added together (such as liquid molecules or powder particles fused together), usually layer by layer, based on a digital model. A computer system operates the additive manufacturing system to control the flow of material and the movement of the print nozzle until the desired shape is formed. Currently, 3D printing techniques include photocuring, powder bonding, and fused deposition modeling (FDM) methods.

[0003] In the FDM process, material in the form of a filament is fed through a heated nozzle, which melts the material onto a surface. Under the direction of a computer system, the surface or the heated nozzle can move to dispense the molten material into a set shape. Other additive manufacturing methods utilize non-filamentary materials that are melted and pressurized before being dispensed through a printing nozzle, but such methods often result in undesirable stringing from the printing nozzle, especially when the viscosity of the molten material is high.

[0004] There are several challenges in adapting techniques such as FDM for use in the manufacture of pharmaceutical dosage units (e.g., tablets, caplets, printlets): achieving high throughput, achieving high accuracy / consistency, and printing pharmaceutical dosage units with complex structures and compositions. For example, single-nozzle or multi-nozzle printing devices can only achieve relatively low throughput. On the other hand, systems that provide parallel printing by operating multiple printing devices simultaneously are also inadequate, as multiple printing devices result in inconsistencies and low accuracy (e.g., in volume, shape, weight, and / or composition) between the printed units. Such systems are also expensive to manufacture and maintain, as well as inefficient and complex to operate.

[0005] In particular, printing materials required in the pharmaceutical context tend to be highly viscous and associated with low printing pressures. Furthermore, when multiple types of printing materials are involved in the printing process, the nozzles dispensing these different types of printing materials need to operate in a coordinated manner (e.g., alternately open and close). Conventional 3D printing systems are unable to coordinate the operation of multiple nozzles or control the release of multiple types of materials in a precise and consistent manner. Thus, conventional 3D printing systems are unable to maintain a high level of consistency between pharmaceutical dosage units output by nozzles within the same batch or across multiple batches. The above challenges are further complicated when the pharmaceutical units being manufactured are composed of different materials arranged in a specific configuration (e.g., multiple inner parts coated with a shell).

[0006] Furthermore, configuring multiple 3D printers to work together to produce batches of pharmaceutical dosage units does not produce satisfactory results when using traditional 3D printing techniques. Specifically, inconsistencies between the multiple 3D printers (e.g., in both hardware and software configurations) can result in an end product that is inconsistent and does not meet quality standards. Moreover, systems that involve coordination between multiple 3D printers are generally inefficient to operate and expensive to maintain.

[0007] Thus, there is a need for a system and method for 3D printing pharmaceutical dosage units (e.g., tablet caplets, printlets) in an accurate, precise, and cost-effective manner while maintaining high throughput over time. There is also a need for a system that can coordinate the operation of multiple 3D printers to print batches of pharmaceutical dosage units. Summary of the Invention [Means for solving the problem]

[0008] An exemplary system for producing pharmaceutical products by additive manufacturing includes a material supply module for receiving a set of printing materials, a flow distribution module comprising a flow distribution plate, the material supply module configured to transport a single stream corresponding to the set of printing materials to the flow distribution plate, the flow distribution plate comprising a plurality of channels for splitting the single stream into multiple streams, a plurality of nozzles, and one or more controllers for controlling the plurality of nozzles to dispense the multiple streams based on nozzle-specific parameters.

[0009] In some embodiments, the system further comprises a print platform configured to receive the dispensed streams, the print platform configured to move to form a batch of the pharmaceutical product.

[0010] In some embodiments, the material supply module is configured to heat a received set of printing materials.

[0011] In some embodiments, the material supply module is configured to plasticize a received set of printing materials.

[0012] In some embodiments, the material supply module includes a piston mechanism, a screw mechanism, a screw pump mechanism, a gear mechanism, a plunger pump mechanism, or any combination thereof.

[0013] In some embodiments, the multiple channels form a first junction configured to split a single stream into two streams.

[0014] In some embodiments, the multiple channels form a second junction and a third junction configured to split the two streams into four streams.

[0015] In some embodiments, the first junction is positioned higher than the second junction and the third junction.

[0016] In some embodiments, the first junction, the second junction, and the third junction are positioned on the same plane.

[0017] In some embodiments, the flow distribution plate is separable into multiple components, and the multiple components are configured to be held together via one or more screws.

[0018] In some embodiments, one nozzle of the plurality of nozzles comprises a heater.

[0019] In some embodiments, one nozzle of the plurality of nozzles comprises a thermal isolation structure.

[0020] In some embodiments, the multiple nozzles comprise multiple needle valve mechanisms.

[0021] In some embodiments, a needle valve mechanism of the plurality of needle valve mechanisms comprises a feed channel extending through a respective nozzle, the feed channel tapering at a distal end of the nozzle, and a needle, the distal end of the needle configured to contact and seal with the feed channel when the needle valve mechanism is in a closed position, and the distal end of the needle configured to be retracted to enable dispensing of a flow of printing material.

[0022] In some embodiments, the movement of the needle is driven by one or more actuators.

[0023] In some embodiments, the one or more actuators include a linear motor.

[0024] In some embodiments, the movement of the needle is manually controlled.

[0025] In some embodiments, the needle is a first needle and the multiple nozzles include a single plate coupled to the first needle and the second needle, and movement of the single plate causes movement of the first needle and the second needle.

[0026] In some embodiments, a parameter of the plurality of nozzle-specific parameters includes an opening amount of each nozzle.

[0027] In some embodiments, the one or more controllers are configured to adjust the opening of each nozzle based on a weight of units in the batch that corresponds to each nozzle.

[0028] In some embodiments, the one or more controllers are configured to adjust the opening of each nozzle based on one or more machine learning algorithms.

[0029] In some embodiments, the one or more controllers are configured to control the temperature or pressure of the multiple nozzles.

[0030] In some embodiments, the temperature is controlled via a temperature control device that includes one or more heating devices, one or more cooling devices, or a combination thereof.

[0031] In some embodiments, the temperature of the plurality of nozzles is greater than the temperature of the material supply module.

[0032] In some embodiments, the temperature of the plurality of nozzles is greater than the temperature of the flow distribution plate.

[0033] In some embodiments, the one or more controllers are configured to control a feed rate of the sets of printing material.

[0034] In some embodiments, the plurality of nozzles is a first plurality of nozzles, and the printing system further comprises a second plurality of nozzles configured to dispense a different set of materials, and the printing system is configured to switch between the first plurality of nozzles and the second plurality of nozzles to print the batch.

[0035] In some embodiments, the pharmaceutical unit is a tablet.

[0036] An exemplary computer-enabled method for producing a pharmaceutical product by additive manufacturing includes receiving a plurality of unit measurements corresponding to a plurality of pharmaceutical dosage units, the plurality of pharmaceutical dosage units being produced using a plurality of nozzles of an additive manufacturing system; determining whether a sum of the plurality of unit measurements differs from a target batch measurement by more than a predefined threshold; adjusting one or more nozzles of the plurality of nozzles based on an average of the plurality of unit measurements in accordance with a determination that the sum differs from the target batch measurement by more than a predefined threshold; and adjusting one or more nozzles of the plurality of nozzles based on the target unit measurement in accordance with a determination that the sum does not differ from the target batch measurement by more than a predefined threshold.

[0037] In some embodiments, the multiple pharmaceutical units are multiple tablets.

[0038] In some embodiments, the unit measurement is a weight measurement of a multiple of a pharmaceutical dosage unit.

[0039] In some embodiments, the unit measurement is a volumetric measurement of a multiple of a pharmaceutical dosage unit.

[0040] In some embodiments, the unit measure is a composition measure of a multiple of a pharmaceutical dosage unit.

[0041] In some embodiments, the method further includes adjusting one or more operational parameters of the additive manufacturing system according to a determination that the sum differs from the target batch measurement by more than a predefined threshold.

[0042] In some embodiments, the one or more operating parameters include temperature.

[0043] In some embodiments, the one or more operating parameters include pressure.

[0044] In some embodiments, the one or more operating parameters include a speed at which the printing material is advanced.

[0045] In some embodiments, the predefined threshold is + / - 0.5% to + / - 5%.

[0046] In some embodiments, the method further includes printing a new batch after adjusting one or more nozzles of the plurality of nozzles based on the target unit measurement, determining whether a weight of a unit in the new batch differs from the target unit measurement by more than a second predefined threshold, and adjusting one or more operating parameters of the additive manufacturing system according to a determination that the weight of the unit in the new batch differs from the target unit measurement by more than the second predefined threshold.

[0047] In some embodiments, the one or more operating parameters include temperature.

[0048] In some embodiments, the one or more operating parameters include a nozzle opening.

[0049] In some embodiments, the second predefined threshold is less than 5%.

[0050] An exemplary method for producing a pharmaceutical product by additive manufacturing includes receiving a set of printing materials using a material supply module; transporting a single stream corresponding to the set of printing materials using the material supply module to a stream distribution plate, the stream distribution plate comprising a plurality of channels; splitting the single stream into multiple streams via the plurality of channels of the stream distribution plate; and dispensing the multiple streams to a plurality of nozzles based on a plurality of nozzle-specific parameters.

[0051] An exemplary non-transitory computer-readable storage medium stores one or more programs, the one or more programs including instructions that, when executed by one or more processors of an electronic device having a display, cause the electronic device to receive a plurality of weight measurements corresponding to a plurality of pharmaceutical dosage units produced using a plurality of nozzles of a 3D printing system, determine whether a sum of the plurality of weight measurements differs from a target batch weight by more than a predefined threshold, adjust one or more nozzles of the plurality of nozzles based on an average weight measurement of the plurality of weight measurements in accordance with a determination that the sum differs from the target batch weight by more than a predefined threshold, and adjust one or more nozzles of the plurality of nozzles based on the target weight measurement in accordance with a determination that the sum does not differ from the target batch weight by more than a predefined threshold.

[0052] In some embodiments, an exemplary system for producing a plurality of pharmaceutical products by additive manufacturing includes a first printing station, the first printing station comprising a first printing platform and a first plurality of nozzles; a second printing station, the second printing station comprising a second printing platform and a second plurality of nozzles; a plate transport mechanism; and a printing plate, wherein the system is configured to: determine whether printing of a first portion of each pharmaceutical product in the batch of pharmaceutical products is completed at the first printing station while the printing plate is positioned on the first printing platform; identify a second printing station according to a determination that printing of the first portion is completed at the first printing station; transport the printing plate from the first printing platform to the second printing platform via the plate transport mechanism; and cause printing of a second portion of each pharmaceutical product in the batch of pharmaceutical products at the second printing station.

[0053] In some embodiments, the system further comprises two conveyors, the system being configured to transport the printing plate along one of the two conveyors via the plate transport mechanism.

[0054] In some embodiments, the printing of the first portion at the first printing station is based on a first coordinate system associated with the first printing station, and the printing of the second portion at the second printing station is based on a second coordinate system associated with the second printing station.

[0055] In some embodiments, the system is configured to obtain a first relative positioning between the first printing platform and the first plurality of nozzles, obtain a second relative positioning between the second printing platform and the second plurality of nozzles, calculate a plurality of offset values ​​based on the first relative positioning and the second relative positioning, and determine at least one of the first coordinate system and the second coordinate system based on the plurality of offset values.

[0056] In some embodiments, the first relative positioning includes a first x-axis value and a first y-axis value, and the second relative positioning includes a second x-axis value and a second y-axis value.

[0057] In some embodiments, the multiple offset values ​​include a difference value between a first x-axis value and a second x-axis value, and a difference value between a first y-axis value and a second y-axis value.

[0058] In some embodiments, obtaining the first relative positioning includes measuring a first x-axis and a first y-axis value based on one or more retractable sensors located on the first printing station while the printing plate is positioned on the first printing platform.

[0059] In some embodiments, obtaining the first relative positioning includes measuring a first x-axis and a first y-axis value based on one or more laser sensors located on the first printing station while the printing plate is positioned on the first printing platform.

[0060] In some embodiments, obtaining the first relative positioning includes moving the first printing platform on the x-axis until it contacts a first sensor on the first printing station, and moving the second printing platform on the y-axis until it contacts a second sensor on the first printing station.

[0061] In some embodiments, determining the first coordinate system includes determining a zero point on a z-axis.

[0062] In some embodiments, the zero point comprises a z-axis position where a plate placed on the first printing platform contacts the first plurality of nozzles.

[0063] In some embodiments, determining the zero point is performed using a plug gauge.

[0064] In some embodiments, determining the zero point includes raising the first printing platform; determining whether a resistance force above a predefined threshold is detected using a sensor coupled to the first printing platform; pausing the raising of the first printing platform in accordance with a determination that a resistance force above the predefined threshold is detected and determining the zero point based on a current z-axis position of the first printing platform; and continuing the raising of the first printing platform in accordance with a determination that a resistance force above the predefined threshold is not detected.

[0065] In some embodiments, determining the zero point includes fixing a sensor having a retractable portion to the first printing platform, the retractable portion protruding from the first printing platform, placing an object on the sensor such that the protruding portion of the sensor is retracted, recording the retracted position of the sensor, determining whether the retracted position of the sensor is detected while the first printing platform is raised, and pursuant to a determination that the retracted position is detected, determining the zero point based on a current z-axis position of the first printing platform.

[0066] In some embodiments, the first plurality of nozzles is configured to dispense a first type of printing material and the second plurality of nozzles is configured to dispense a second type of printing material.

[0067] In some embodiments, the batch of pharmaceutical products comprises a batch of tablets, wherein the first portion of each pharmaceutical product comprises an outer portion of each tablet and the second portion of each pharmaceutical product comprises an inner portion of each tablet.

[0068] In some embodiments, the batch of pharmaceutical products comprises a batch of tablets, wherein the first portion of each pharmaceutical product comprises a bottom portion of each tablet and the second portion of each pharmaceutical product comprises an upper portion of each tablet.

[0069] In some embodiments, determining whether printing of a first portion of each pharmaceutical product in a batch of pharmaceutical products is completed at a first printing station includes receiving, at a plate transport mechanism, a status of the first printing station, and determining, at the plate transport mechanism, whether printing is completed based on the status of the first printing station.

[0070] In some embodiments, the system is further configured to record progress data associated with the printing plate after printing of the first portion of each pharmaceutical product is completed.

[0071] In some embodiments, the progress data includes a current height of a batch of pharmaceutical product.

[0072] In some embodiments, the progress data includes the identified second print station.

[0073] In some embodiments, the system is configured to transmit the recorded progress data from the first printing station to a plate transport mechanism.

[0074] In some embodiments, identifying the second printing station is based on a set of printing instructions associated with the pharmaceutical product.

[0075] In some embodiments, identifying the second print station is based on the second portion being printed.

[0076] In some embodiments, identifying the second printing station is based on a printing material associated with the second portion to be printed.

[0077] In some embodiments, identifying the second printing station is based on a status of the second printing station.

[0078] In some embodiments, transporting the printing plate from the first printing platform to the second printing platform via the plate transport mechanism includes removing the printing plate from the first platform, moving the printing plate onto the plate transport mechanism, and moving the plate transport mechanism along a channel based on a location associated with the second printing station.

[0079] In some embodiments, removing the printing plate from the first platform includes deactivating the electromagnetic component.

[0080] In some embodiments, causing the printing of the second portion of each pharmaceutical product in the batch of pharmaceutical products at the second printing station includes updating a status of the second printing station as busy.

[0081] In some embodiments, causing printing of a second portion of each pharmaceutical product in the batch of pharmaceutical products at the second printing station includes identifying a portion of the printing instruction based on progress data associated with the printing plate.

[0082] In some embodiments, the progress data includes a current height of a batch of pharmaceutical product on a printing plate.

[0083] In some embodiments, the progress data is transmitted from the plate transport mechanism to the second printing station.

[0084] In some embodiments, the system further comprises a controller associated with the first print station, a controller associated with the second print station, or any combination thereof.

[0085] In some embodiments, the system further comprises a controller associated with the plate transport mechanism.

[0086] In some embodiments, the system further comprises a third printing station. The present invention provides, for example, the following: (Item 1) 1. A system for making a pharmaceutical product by additive manufacturing, comprising: a material supply module for receiving a set of printing materials; 1. A flow distribution module comprising a flow distribution plate, the material supply module is configured to deliver a single stream corresponding to the set of printing materials to the stream distribution plate; a flow distribution module, the flow distribution plate comprising a plurality of channels for dividing the single flow into a plurality of flows; A plurality of nozzles; and one or more controllers for controlling the plurality of nozzles to dispense the plurality of streams based on a plurality of nozzle-specific parameters. (Item 2) 2. The system of claim 1, further comprising a printing platform configured to receive the dispensed multiple streams, the printing platform configured to move to form a batch of the pharmaceutical product. (Item 3) 3. The system of claim 1 or 2, wherein the material supply module is configured to heat the received set of printing materials. (Item 4) 4. The system of any one of items 1 to 3, wherein the material supply module is configured to plasticize the received set of printing materials. (Item 5) The system of any one of items 1 to 4, wherein the material supply module includes a piston mechanism, a screw mechanism, a screw pump mechanism, a gear mechanism, a plunger pump mechanism, or any combination thereof. (Item 6) 6. The system of any one of claims 1 to 5, wherein the plurality of channels form a first junction configured to split the single stream into two streams. (Item 7) 7. The system of claim 6, wherein the plurality of channels form a second junction and a third junction configured to split the two streams into four streams. (Item 8) 8. The system of claim 7, wherein the first junction is positioned higher than the second junction and the third junction. (Item 9) 8. The system of claim 7, wherein the first joint, the second joint, and the third joint are positioned on the same plane. (Item 10) 10. The system of any one of claims 1 to 9, wherein the flow distribution plate is separable into a plurality of components, and the plurality of components are configured to be held together via one or more screws. (Item 11) 11. The system of any one of claims 1 to 10, wherein one nozzle of the plurality of nozzles is equipped with a heater. (Item 12) 12. The system of any one of claims 1 to 11, wherein one nozzle of the plurality of nozzles is provided with a thermal isolation structure. (Item 13) Item 13. The system of any one of items 1 to 12, wherein the plurality of nozzles comprises a plurality of needle valve mechanisms. (Item 14) One of the plurality of needle valve mechanisms is a feed channel extending through each nozzle, said feed channel tapering at a distal end of said nozzle; and

[0023] A needle is provided. a distal end of the needle configured to seal against the feed channel when the needle valve mechanism is in a closed position; Item 14. The system of item 13, wherein the distal end of the needle is configured to retract to enable dispensing of a stream of printing material. (Item 15) Item 15. The system of item 14, wherein the movement of the needle is driven by one or more actuators. (Item 16) Item 16. The system of item 15, wherein the one or more actuators include a linear motor. (Item 17) Item 15. The system of item 14, wherein the movement of the needle is manually controlled. (Item 18) Item 15. The system of item 14, wherein the needle is a first needle, and the plurality of nozzles includes a single plate coupled to the first needle and a second needle, and movement of the single plate causes movement of the first needle and the second needle. (Item 19) 19. The system according to any one of claims 1 to 18, wherein one parameter of the plurality of nozzle-specific parameters includes an opening amount of each nozzle. (Item 20) 20. The system of claim 19, wherein the one or more controllers are configured to adjust the opening amount of each nozzle based on a weight of units in the batch that corresponds to the respective nozzle. (Item 21) 20. The system of claim 19, wherein the one or more controllers are configured to adjust the opening amount of the respective nozzles based on one or more machine learning algorithms. (Item 22) 22. The system of any one of items 1 to 21, wherein the one or more controllers are configured to control a temperature or pressure of the plurality of nozzles. (Item 23) 23. The system of claim 22, wherein the temperature is controlled via a temperature control device including one or more heating devices, one or more cooling devices, or a combination thereof. (Item 24) 24. The system according to any one of claims 1 to 23, wherein a temperature of the plurality of nozzles is higher than a temperature of the material supply module. (Item 25) 25. The system of any one of claims 1 to 24, wherein a temperature of the plurality of nozzles is higher than a temperature of the flow distribution plate. (Item 26) 26. The system of any one of items 1 to 25, wherein the one or more controllers are configured to control a feed speed of the set of printing materials. (Item 27) 27. The system of any one of items 1 to 26, wherein the plurality of nozzles is a first plurality of nozzles, and the printing system further comprises a second plurality of nozzles configured to dispense a different set of materials, and the printing system is configured to switch between the first plurality of nozzles and the second plurality of nozzles to print the batch. (Item 28) 28. The system according to any one of items 1 to 27, wherein the pharmaceutical unit is a tablet. (Item 29) 1. A computer-enabled method for making a pharmaceutical product by additive manufacturing, the method comprising: receiving a plurality of unit measurements corresponding to a plurality of pharmaceutical dosage units, the plurality of pharmaceutical dosage units being produced using a plurality of nozzles of an additive manufacturing system; determining whether a sum of the plurality of unit measurements differs from a target batch measurement by more than a predefined threshold; adjusting one or more nozzles of the plurality of nozzles based on an average of the plurality of unit measurements in response to a determination that the sum differs from the target batch measurement by more than the predefined threshold; and adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement in accordance with a determination that the sum does not differ from the target batch measurement by more than the predefined threshold. (Item 30) 30. The method of claim 29, wherein the plurality of pharmaceutical units is a plurality of tablets. (Item 31) 31. The method of claim 29 or 30, wherein the unit measurement is a weight measurement of the plurality of pharmaceutical dosage units. (Item 32) 32. The method of any one of items 29 to 31, wherein the unit measurement is a volumetric measurement of the plurality of pharmaceutical dosage units. (Item 33) 33. The method of any one of items 29 to 32, further comprising adjusting one or more operational parameters of the additive manufacturing system in accordance with a determination that the sum differs from the target batch measurement by more than the predefined threshold. (Item 34) Item 34. The method of item 33, wherein the one or more operating parameters include temperature. (Item 35) Item 34. The method of item 33, wherein the one or more operating parameters include pressure. (Item 36) Item 34. The method of item 33, wherein the one or more operating parameters include a speed at which the printing material is fed. (Item 37) Item 34. The method of item 33, wherein the one or more operating parameters include a nozzle opening amount. (Item 38) 38. The method according to any one of items 29 to 37, wherein the predefined threshold value is between + / - 0.5% and + / - 5%. (Item 39) printing a new batch after adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement; determining whether weights of units in the new batch differ from the target unit measurement by more than a second predefined threshold; 39. The method of any one of items 29 to 38, further comprising: adjusting one or more operating parameters of the additive manufacturing system in accordance with a determination that the weight of the units in the new batch differs from the target unit measurement by more than the second predefined threshold. (Item 40) 40. The method of claim 39, wherein the one or more operating parameters include temperature. (Item 41) 40. The method of claim 39, wherein the one or more operating parameters include a nozzle opening. (Item 42) 40. The method of claim 39, wherein the second predefined threshold is less than 5%. (Item 43) 1. A method for producing a pharmaceutical product by additive manufacturing, comprising: receiving a set of printing materials using a material supply module; using the material supply module to deliver a single stream corresponding to the set of printing materials to a flow distribution plate, the flow distribution plate comprising a plurality of channels; splitting the single stream into multiple streams via the multiple channels of the flow distribution plate; and dispensing the multiple streams to a plurality of nozzles based on a plurality of nozzle-specific parameters. (Item 44) A non-transitory computer-readable storage medium storing one or more programs, the one or more programs including instructions that, when executed by one or more processors of an electronic device having a display, cause the electronic device to: receiving a plurality of weight measurements corresponding to a plurality of pharmaceutical dosage units produced using a plurality of nozzles of the 3D printing system; determining whether a sum of the plurality of weight measurements differs from a target batch weight by more than a predefined threshold; adjusting one or more nozzles of the plurality of nozzles based on an average weight reading of the plurality of weight readings in response to a determination that the sum differs from the target batch weight by more than the predefined threshold; and adjusting one or more nozzles of the plurality of nozzles based on the target weight measurement in accordance with a determination that the sum does not differ from the target batch weight by more than the predefined threshold. (Item 45) 1. A system for producing a plurality of pharmaceutical products by additive manufacturing, the system comprising: a first printing station, A first printing platform; and a first printing station including a first plurality of nozzles; a second printing station, A second printing platform, and a second print station comprising a second plurality of nozzles; A plate transport mechanism; A printing plate; The system comprises: determining whether printing of a first portion of each pharmaceutical product in the plurality of pharmaceutical products is completed at the first printing station while the printing plate is positioned on the first printing platform; identifying the second printing station in response to determining that the printing of the first portion is completed at the first printing station; transporting the printing plate from the first printing platform to the second printing platform via the plate transport mechanism; The system is configured to cause printing of a second portion of each pharmaceutical product in the plurality of pharmaceutical products at the second printing station. (Item 46) Item 46. The system of item 45, further comprising two conveyors, the system being configured to transport the printing plate along one of the two conveyors via the plate transport mechanism. (Item 47) the printing of the first portion at the first print station is based on a first coordinate system associated with the first print station; Item 46. The system of item 45, wherein the printing of the second portion at the second print station is based on a second coordinate system associated with the second print station. (Item 48) The system comprises: obtaining a first relative positioning of the first printing platform and the first plurality of nozzles; obtaining a second relative positioning of the second printing platform and the second plurality of nozzles; calculating a plurality of offset values ​​based on the first relative positioning and the second relative positioning; Item 48. The system of item 47, configured to determine at least one of the first coordinate system and the second coordinate system based on the plurality of offset values. (Item 49) 49. The system of claim 48, wherein the first relative positioning includes a first x-axis value and a first y-axis value, and the second relative positioning includes a second x-axis value and a second y-axis value. (Item 50) The offset values ​​are a difference value between the first x-axis value and the second x-axis value; 50. The system of claim 49, further comprising: a difference value between the first y-axis value and the second y-axis value. (Item 51) Obtaining the first relative positioning includes: The system described in items 48 to 50, further comprising measuring the first x-axis and the first y-axis values ​​based on one or more retractable sensors located on the first printing station while the printing plate is positioned on the first printing platform. (Item 52) Obtaining the first relative positioning includes: The system described in items 48 to 50, further comprising measuring the first x-axis and the first y-axis values ​​based on one or more laser sensors positioned on the first printing station while the printing plate is positioned on the first printing platform. (Item 53) Obtaining the first relative positioning includes: moving the first printing platform on the x-axis until it contacts a first sensor on the first printing station; 53. The system of any one of claims 47 to 52, further comprising: moving the second printing platform on the y-axis until it contacts a second sensor on the first printing station. (Item 54) Item 48. The system of item 47, wherein determining the first coordinate system includes determining a zero point on the z-axis. (Item 55) Item 55. The system of item 54, wherein the zero point comprises a z-axis position where a plate placed on the first printing platform contacts the first plurality of nozzles. (Item 56) Item 55. The system of item 54, wherein determining the zero point is performed using a plug gauge. (Item 57) Determining the zero point comprises: raising the first printing platform; determining, using a sensor coupled to the first printing platform, whether a resistive force above a predefined threshold is detected; interrupting raising the first printing platform in response to a determination that the resistance force exceeding the predefined threshold is detected and determining the zero point based on a current z-axis position of the first printing platform; and continuing to raise the first printing platform in accordance with a determination that the resistance force is not detected above the predefined threshold. (Item 58) Determining the zero point comprises: securing a sensor to the first printing platform, the sensor having a retractable portion protruding from the first printing platform; placing an object on the sensor such that the protruding portion of the sensor is retracted; recording a retracted position of the sensor; determining whether the retracted position of the sensor is detected while the first printing platform is elevated; Item 55. The system of item 54, further comprising: determining the zero point based on a current z-axis position of the first printing platform in accordance with a determination that the retracted position has been detected. (Item 59) 59. The system of any one of items 45 to 58, wherein the first plurality of nozzles is configured to dispense a first type of printing material and the second plurality of nozzles is configured to dispense a second type of printing material. (Item 60) the plurality of pharmaceutical products comprises a plurality of tablets; the first portion of each pharmaceutical product comprises an outer portion of the respective tablet; 60. The system of any one of items 45 to 59, wherein the second portion of each pharmaceutical product comprises an inner portion of the respective tablet. (Item 61) the plurality of pharmaceutical products comprises a plurality of tablets; the first portion of each pharmaceutical product comprises a lower portion of the respective tablet; 61. The system of any one of items 45 to 60, wherein the second portion of each pharmaceutical product comprises an upper portion of the respective tablet. (Item 62) Determining whether printing of the first portion of each pharmaceutical product in the plurality of pharmaceutical products is completed at the first printing station includes: receiving a status of the first printing station at the plate transport mechanism; 62. The system of any one of items 45 to 61, further comprising: in the plate transport mechanism, determining whether the printing is complete based on the status of the first printing station. (Item 63) The system comprises: 63. The system of any one of items 45 to 62, further configured to record progress data associated with the printing plate after printing of the first portion of each pharmaceutical product is completed. (Item 64) Item 64. The system of item 63, wherein the progress data includes a current height of the plurality of pharmaceutical products. (Item 65) Item 64. The system of item 63, wherein the progress data includes the identified second printing station. (Item 66) 66. The system of any one of items 63 to 65, wherein the system is configured to transmit the recorded progress data from the first printing station to the plate transport mechanism. (Item 67) 67. The system of any one of claims 45 to 66, wherein identifying the second printing station is based on a set of printing instructions associated with the pharmaceutical product. (Item 68) Item 68. The system of any one of items 45 to 67, wherein identifying the second printing station is based on the second portion being printed. (Item 69) Item 68. The system of any one of items 45 to 67, wherein identifying the second printing station is based on a printing material associated with the second portion to be printed. (Item 70) Item 68. The system of any one of items 45 to 67, wherein identifying the second printing station is based on a status of the second printing station. (Item 71) transporting the printing plate from the first printing platform to the second printing platform via the plate transport mechanism; Removing the printing plate from the first platform; moving the printing plate onto the plate transport mechanism; Item 68. The system of any one of items 45 to 67, further comprising: moving the plate transport mechanism along a channel based on a location associated with the second printing station. (Item 72) Item 72. The system of item 71, wherein removing the printing plate from the first platform includes deactivating an electromagnetic component. (Item 73) 73. The system of any one of items 45 to 72, wherein causing the printing of the second portion of each pharmaceutical product in the plurality of pharmaceutical products at the second printing station includes updating the status of the second printing station as busy. (Item 74) The system of any one of items 45 to 73, wherein causing printing of the second portion of each pharmaceutical product in the plurality of pharmaceutical products at the second printing station includes identifying a portion of a printing instruction based on progress data associated with the printing plate. (Item 75) Item 75. The system of item 74, wherein the progress data includes a current print height of the plurality of pharmaceutical products on the printing plate. (Item 76) Item 75. The system of item 74, wherein the progress data is transmitted from the plate transport mechanism to the second printing station. (Item 77) 77. The system of any one of claims 45 to 76, further comprising a controller associated with the first printing station, a controller associated with the second printing station, or any combination thereof. (Item 78) 78. The system of any one of items 45 to 77, further comprising a controller associated with the plate transport mechanism. (Item 79) Item 79. The system of any one of items 45 to 78, further comprising a third printing station. [Brief description of the drawings]

[0087] [Figure 1A] FIG. 1 illustrates a schematic diagram of an exemplary additive manufacturing system, according to some embodiments of the present invention. [Figure 1B] FIG. 1 illustrates a schematic diagram of an exemplary additive manufacturing system, according to some embodiments of the present invention. [Figure 1C] 1 illustrates an exemplary additive manufacturing system including a piston mechanism, according to some embodiments of the present invention. [Figure 1D] 1 illustrates an exemplary additive manufacturing system, according to some embodiments of the present invention. [Figure 2A] 1 illustrates a side cross-sectional view of an exemplary flow distribution module, according to some embodiments of the present invention. [Figure 2B] 1 illustrates a top cross-sectional view of an exemplary flow distribution module, according to some embodiments of the present invention. [Figure 2C] 1 illustrates an exemplary flow distribution module configuration, according to some embodiments of the present invention. [Figure 2D] 1 illustrates a bottom perspective view of a flow distribution module according to some embodiments of the present invention. [Diagram 3] 1 illustrates a cross-sectional view of a distal end of an exemplary nozzle, according to some embodiments of the present invention. [Figure 4] FIG. 1 illustrates a cross-sectional view of an exemplary additive manufacturing system, according to some embodiments of the present invention. [Diagram 5] 1 illustrates an example pressure curve for dispensing printing material at a nozzle, according to some embodiments of the present invention. [Figure 6A] 1 illustrates an exemplary process for 3D printing pharmaceutical dosage units, according to some embodiments of the present invention. [Figure 6B] 1 illustrates an exemplary process for 3D printing pharmaceutical dosage units, according to some embodiments of the present invention. [Figure 7] 1 illustrates an exemplary electronic device according to some embodiments. [Figure 8A] 1 illustrates an example layout of a standardized multi-station printing system for pharmaceutical units, according to some embodiments. [Figure 8B] 8 illustrates a partial side view of an exemplary multi-station system 800 according to some embodiments. [Figure 9] 1 illustrates an exemplary process for initializing a multi-station printing system having a first print station and a second print station, according to some embodiments. [Figure 10A]1 illustrates an example architecture for a multi-station 3D printing system according to some embodiments. [Figure 10B] 1 illustrates an exemplary process for 3D printing pharmaceutical dosage units using a multi-station system, according to some embodiments. [Figure 10C] 1 illustrates an exemplary process for 3D printing pharmaceutical dosage units using a multi-station system, according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] Described herein are apparatus, devices, systems, methods, and non-transitory storage media for additively manufacturing (e.g., 3D printing) pharmaceutical dosage units (e.g., tablet caplets, printlets) in an accurate, precise, and cost-effective manner while maintaining high throughput over time. According to some embodiments, the printing system utilizes a flow distribution module to split a single flow of printing material into multiple flows. The multiple flows are dispensed by multiple nozzles in a precisely controlled manner to 3D print a batch of pharmaceutical dosage units (e.g., tablet caplets, printlets). This achieves unit-to-unit consistency within a single batch and across multiple batches while maintaining high throughput.

[0089] Further, the printing system comprises an environment (e.g., a closed environment such as a thermostatic oven, an open environment such as a printing platform) for additive manufacturing (e.g., 3D printing) of pharmaceutical dosage units. A number of closed-loop control systems are used to control the temperature, pressure, flow rate, weight, volume, and other related parameters within the environment at multiple stages of the manufacturing process. In particular, control systems and methods are implemented to precisely adjust the nozzle opening, specifically the opening of the nozzle needle valve mechanism, in a precise manner to ensure consistency between the nozzle output. In some embodiments, the unit weight inconsistency (i.e., inconsistency between the weights of units within the same batch) is less than 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%). In some embodiments, the batch weight inconsistency (i.e., inconsistency between the weights of batches) is less than 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%).

[0090] Based on different types of printing materials and required compositions, the system can adjust the control parameters. In this way, the printing system can be used to produce a variety of high quality pharmaceutical dosage units.

[0091] In some embodiments, the material is non-filamentary (e.g., powder, pellet, or liquid). In some embodiments, the material has a viscosity of 0.01 to 10,000 Pa·s when dispensed from the system. For example, the material has a viscosity of about 100 Pa·s or greater when dispensed from the device. In some embodiments, the material has a viscosity of about 400 Pa·s or greater when dispensed from the device. In some embodiments, the material melts at about 50° C. to about 400° C. In some embodiments, the material is dispensed from the nozzle at a temperature of about 50° C. to about 400° C. In some embodiments, the material is dispensed from the nozzle at a temperature of about 90° C. to about 300° C.

[0092] In some embodiments, the printing system comprises multiple printing stations. Each printing station can be used to print a portion of a batch of pharmaceutical dosage units (e.g., shell, bottom half, top half). Additionally, multiple printing stations can be operated in parallel, so that multiple batches of pharmaceutical dosage units can be printed simultaneously. In some embodiments, a single FDM multi-station system can produce 3,000-5,000 pharmaceutical units (e.g., tablets) per day. In some embodiments, the system minimizes inconsistencies between pharmaceutical units in the same patch and different patches to ±2.5% (e.g., in weight, volume). In some embodiments, the multi-station system is easy to clean and maintain, thus complying with the requirements for standardized production of pharmaceutical products.

[0093] The following description is presented to enable those skilled in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those skilled in the art, and the general principles defined herein can be applied to other implementations and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described and shown herein, but should be accorded the scope consistent with the claims.

[0094] In the following description, terms such as "first" and "second" are used to describe various elements, but these elements should not be limited by these terms. These terms are used only to distinguish one element from another. For example, a first nozzle may be referred to as a second nozzle, and similarly, a second nozzle may be referred to as a first nozzle without departing from the scope of the various embodiments described. A first nozzle and a second nozzle are both nozzles, but are not the same nozzle.

[0095] The terms used in the description of the various embodiments described herein are intended to describe particular embodiments only and are not intended to be limiting. As used in the description of the various embodiments described and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. It will also be understood that the term "and / or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms "includes," "including," "comprises," and / or "comprising," as used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0096] The term "if" is, depending on the context, optionally interpreted to mean "when" or "upon" or "in response to determining" or "in response to detecting." Similarly, the phrase "when determined" or "when [described condition or event] is detected" is, depending on the context, optionally interpreted to mean "when determined" or "in response to determining" or "when [described condition or event] is detected" or "in response to detecting [described condition or event]."

[0097] FIG. 1A shows a schematic diagram of an exemplary additive manufacturing system (e.g., 3D printing system) 100, according to some embodiments of the present invention. The system 100 comprises a material supply module 102 for transporting a set of printing materials to a stream distribution module 104. The stream distribution module 104 comprises a stream distribution plate having branching channels (not shown) configured to split a single stream of printing material (e.g., supplied by the material supply module) into multiple streams. In some embodiments, the stream distribution module 104 can split the single stream into two streams, two streams are split into four streams, four streams are split into eight streams, eight streams are split into sixteen streams, and sixteen streams are split into thirty-two streams. In some embodiments, the stream distribution module can directly split the single stream into two streams, three streams, four streams, five streams, ..., or n streams. In some embodiments, the stream distribution module can split the single stream into three streams, three streams are split into nine streams, and nine streams are split into twenty-seven streams. Referring to FIG. 1B, the multiple streams can each be dispensed by an array of nozzles 106 of the system 100 to generate 3D printed pharmaceutical dosage units (e.g., tablet caplets, printlets) on the printing platform 110.

[0098] The material supply module 102 is configured to pre-treat a set of printing material before transporting it to the flow distribution module 104. In some embodiments, the pre-treatment includes melting and pressurizing the printing material (e.g., to a target temperature range, to a target pressure range) based on a predetermined setting. The pre-treated material is then transported to the flow distribution module 104 via the supply channel 108. In some embodiments, a continuous flow of printing material is supplied to the flow distribution module 104 via the supply channel 108.

[0099] In some embodiments, the material supply module 102 includes one or more heaters configured to melt the printing material. In some embodiments, the material supply module includes one or more temperature sensors configured to detect a temperature of the melted printing material in the material supply module 102. In some embodiments, the one or more temperature sensors are connected to a computer system that operates the one or more heaters in response to temperatures reported by the one or more temperature sensors.

[0100] In some embodiments, one or more pressure sensors are connected to a computer system that operates the material supply module to pressurize the printing material to a desired pressure in response to the pressure reported by the pressure sensor. In some embodiments, the printing pressure is within about 0.05 MPa of the desired pressure. In some embodiments, the material supply module includes a piston mechanism, a screw mechanism (single screw, double screw, three screw, four screw, five screw, eight screw), a screw pump mechanism, a gear mechanism, a plunger pump mechanism (e.g., a valveless metering pump mechanism), or any combination thereof. Additional details of the material supply module and many other features of the printing system are found in "PRECISION PHARMACEUTICAL 3D Printing System" (2013) and ...). No. 6,399,413, entitled "3D PRINTING DEVICE AND METHOD," and PCT / CN2018 / 071965, entitled "3D PRINTING DEVICE AND METHOD," the contents of which are incorporated in their entireties.

[0101] FIG. 1C illustrates an exemplary additive manufacturing system including a piston mechanism, according to some embodiments of the present invention. In the illustrated example, a piston 122 is driven in the z-direction by one or more motors 120. As the piston is driven downward, it pushes the printing material down the barrel 124, the feed channel 108, and the flow distribution module 104, altering the pressure of the printing material in the system. Opening the distal outlet of the printing nozzle can dispense the printing material in a precisely controlled manner. The amount of printing material dispensed can be controlled by controlling the position of the piston, the speed at which the piston moves, the acceleration at which the piston moves, or a combination thereof. In some embodiments, the motor 120 is a stepper motor, a servo motor, a hydraulic control, or a combination thereof.

[0102] In some embodiments, the diameter D of the barrel is between 5 and 20 mm. In preferred embodiments, D is about 10 mm. In some embodiments, the diameter d of the nozzle outlet is between 0.1 and 2 mm. In preferred embodiments, d is about 0.4 mm. In some embodiments, a ratio parameter is calculated that indicates the ratio between the cross-sectional area of ​​the nozzle outlet and the cross-sectional area of ​​the barrel. The ratio can also be calculated as D 2 Square of and d 2 In some embodiments, the ratio is calculated as:

number

[0103] Returning to FIG. 1B, the flow distribution module 104 includes a flow distribution plate 114, a number of nozzles 106, a temperature control mechanism, a pressure sensor, a temperature sensor, or any combination thereof. As an example, FIG. 2A illustrates a cross-sectional view of an exemplary flow distribution plate. The flow distribution plate includes a single channel 210 connected to a supply channel of the material supply module for receiving a single flow of printing material. The flow distribution plate includes a number of branching channels configured to split the single flow into multiple flows that are respectively dispensed through a number of nozzles. Each nozzle is configured to dispense a flow of printing material in a controlled manner through a needle valve mechanism. As shown, the nozzle 206a operates in conjunction with a needle 220a that is driven by a motor 212a to move in the Z direction. The operation of the needle valve mechanism is described in more detail below.

[0104] 2B shows a top view of the flow distribution plate shown in FIG. 2A, according to some embodiments. As shown, branching channels in the flow distribution plate separate the single stream of printing material into two streams, then into four streams, then into eight streams. The eight streams of printing material are then dispensed by the eight nozzles, respectively.

[0105] FIG. 2C shows exemplary configurations of channels in a flow distribution plate according to some embodiments. In each configuration, a single stream can be split into multiple streams, which are dispensed equally (e.g., in terms of weight) at multiple nozzles. Due to the arrangement of channels and junctions in the flow distribution plate, each of the multiple streams traverses a unique flow path that begins, for example, at a top inlet for receiving the single stream from the feed channel into the flow distribution plate and extends to the distal end of the nozzle. In some embodiments, the flow paths of the multiple streams are geometrically symmetric (e.g., equal length, equal geometric shape). In some embodiments, the flow paths of the multiple streams are not geometrically symmetric, but equal distribution is achieved by adjusting the diameter of the flow paths along different portions of the flow paths. In some embodiments, some or all of these junctions are positioned on the same or substantially the same plane (e.g., the same XY plane). In some embodiments, some or all of these junctions are positioned on different planes (e.g., different XY planes).

[0106] In some embodiments, the flow distribution plate can be separated into multiple components (e.g., horizontally, vertically, and / or diagonally). The multiple components can be held together with screws. When disassembled, each individual component exposes the inner surface of one or more channels and joints in the flow distribution plate, facilitating cleaning of the channels and joints of the flow distribution plate.

[0107] In some embodiments, during operation, the pressure in the channels of the flow distribution plate can be 0-20 MPa (e.g., 0-5 MPA, 0-10 MPA, 0-20 MPA). The time required for material to traverse the flow distribution plate can be 5 minutes to 5 hours. In some embodiments, the dispense rate at the nozzle can be 0.1-10 μL / s (e.g., 2-3 μL / s).

[0108] 1B, the flow distribution plate includes a temperature control mechanism for maintaining the temperature of the flow distribution plate at a desired level. In some embodiments, the temperature control mechanism includes one or more heaters and one or more coolers configured to operate in conjunction to maintain an internal temperature of the flow distribution plate.

[0109] One or more heaters can be located within the flow distribution plate or in close proximity to the flow distribution plate 114. For example, the flow distribution plate includes internal slots to accommodate one or more heaters (e.g., wires, plates) made of a material with high thermal conductivity. One or more heating wires extend through the internal slots on the inside of the flow distribution plate 114, for example, as shown in the bottom perspective view of the flow distribution plate in FIG. 2D. The flow distribution plate can include multiple rows and columns of internal slots to allow for even distribution of the heating wires throughout the plate such that the temperature inside the plate is maintained in a consistent manner.

[0110] One or more coolers can be located within the flow distribution plate or adjacent to the flow distribution plate 114. In some embodiments, the temperature control device achieves cooling via water flow. As shown in FIG. 1B, a pair of cooling plates, each having an internal channel for flowing water, are positioned above and below the flow distribution plate 114, thus allowing water flow, air, coolant, etc. to occur adjacent to the flow distribution plate 114 to regulate the temperature of the plate. In some embodiments, the flow distribution plate includes internal slots for accommodating one or more coolers within the flow distribution plate. As shown in FIG. 1A, the flow distribution plate 114 and the cooling plates above and below the flow distribution plate 114 all include an inlet 105 for receiving coolant.

[0111] In some embodiments, the flow distribution plate includes one or more temperature sensors connected to a computer system that operates one or more heaters and coolers in response to temperatures reported by the one or more temperature sensors. Figure 2D shows a bottom perspective view of a flow distribution plate and illustrates an example placement of temperature sensors, according to some embodiments.

[0112] In some embodiments, the flow distribution plate includes one or more pressure sensors 130 configured to detect the pressure of the printing material in the channels of the flow distribution plate. In some embodiments, the pressure sensors are positioned proximate to the flow distribution plate (e.g., around the corners, around the periphery, around the center) or within the channels of the flow distribution plate. In some embodiments, small range strain gauge sensors are used.

[0113] FIG. 3 illustrates an exemplary needle valve mechanism 300 for dispensing printing material at a printing nozzle 302, according to some embodiments. A feed channel 304 is formed along the inside of the nozzle 302 to transport the printing material to a distal outlet of the nozzle. The feed channel includes a tapered (e.g., conical) chamber to serve as a dispensing outlet for the printing material. A sealing needle 306 extends through the feed channel and is driven by a motor system (not shown) to move along the feed channel. When the needle valve mechanism is in a closed position, the needle is extended to contact the tapered distal end of the feed channel, sealing the outlet or extrusion port, thus preventing the printing material from being dispensed. Retracting the needle unseals the outlet, so that the printing material can be dispensed. To regulate the temperature of the distal end of the printing nozzle, a number of heating devices 308 and a thermal isolation structure 310 can be placed around the distal end of the nozzle 302. The print nozzle 302 may further include one or more temperature and / or pressure sensors 312.

[0114] In some embodiments, the tapered end of the sealing needle comprises a sharp tip. In some embodiments, the tapered end of the sealing needle is frustoconical. In some embodiments, the tapered inner surface of the feed channel has a first taper angle and the tapered end of the sealing needle has a second taper angle. The second taper angle is the same as or less than the first taper angle. In some embodiments, the second taper angle is about 60° or less. In some embodiments, the second taper angle is about 45° or less. In some embodiments, the ratio of the first taper angle to the second taper angle is about 1:1 to about 4:1.

[0115] In some embodiments, the extrusion port has a diameter of about 0.1 mm to about 1 mm. In some embodiments, the tapered end has a maximum diameter of about 0.2 mm to about 3.0 mm. In some embodiments, the extrusion port has a diameter and the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion port is about 1:0.8 to about 1:0.1.

[0116] In some embodiments, the motion system of the needle valve mechanism includes one or more motors, one or more sensors, one or more drivers, and one or more controllers. The sensor may be an encoder. In some embodiments, the controller includes a programmable logic controller ("PLC"). In some embodiments, the diver includes a bus driver.

[0117] In some embodiments, the motion system that drives the needles to regulate the flow at the nozzle is controlled manually or by a computer controller. The motion system can include multiple motors or actuators, each coupled to a corresponding needle. The motors can be mechanical motors (which can include a screw), hydraulic motors, pneumatic motors (which can include a pneumatic valve), or electromagnetic motors (which can include a solenoid valve). The motors that drive the needles can be linear motors, fixed shaft type motors, non-captive type motors, or combinations thereof.

[0118] In some embodiments, a non-captive type linear motor is used in conjunction with an anti-backlash nut and a ball spline. Ball splines generally operate with lower friction, allowing the motor to operate with greater precision (e.g., ±0.003 mm). Additionally, the motor is relatively small (e.g., 20-42 mm), allowing nozzle-to-nozzle spacing of 20-50 mm in some embodiments. Alternatively, a screw linear motor is used.

[0119] In some embodiments, each of the multiple needles is driven by a respective motor. For example, if there are 32 nozzles, there are 32 motors controlling the 32 needles respectively. Further, the motors are each connected to a bus driver (e.g., CAN-open, Modbus).

[0120] In some embodiments, the system uses a method of stall detection to find the zero position of the distal end of each needle. During the configuration phase to identify the zero position of the needle, the system configures the corresponding motor to operate at a low power level (e.g., 400-1200 mA) and drive the needle slowly toward the distal outlet of the nozzle. This is done to ensure that the distal end of the needle does not deform when the needle is driven against the distal outlet of the nozzle. When the distal end of the needle is in contact with the distal outlet of the nozzle, the needle cannot move any further despite continued driving of the motor. When the encoder no longer detects movement of the needle, the system determines that the needle is at the true zero position. Following the determination that the needle is at the true zero position, the system stops the motor, retracts the needle by 0.003-0.01 mm, and then sets the position of the needle as the configured zero position. The use of a configured zero position ensures that the distal end of the needle is not driven against the distal outlet of the nozzle during operation of the needle valve mechanism, thus improving the life of both the needle and nozzle. During normal operation, the motor runs at a higher electrical level (e.g., 1600-1800 mA) and at a higher speed (e.g., 0.3-15 mm / s) to ensure rapid opening and closing of the valve.

[0121] In an alternative embodiment, the motion system may include a single plate coupled to multiple needles such that needle retraction, and therefore nozzle dispense flow, is uniformly controlled as shown in FIG.

[0122] In some embodiments, the distal ends of the plurality of nozzles form a plane. In some embodiments, the plane is configured to deviate from the XY plane by no more than ±0.01 (±0.005 to ±0.02). In some embodiments, the plane is configured to have a flatness within ±0.005 to ±0.02 MM.

[0123] The motion system may be activated by a mechanical braking mechanism, a hydraulic braking mechanism, a pneumatic braking mechanism, an electromagnetic braking mechanism, a linear motor, or any combination thereof.

[0124] The distal end of the nozzle includes a heater and insulating material to maintain a temperature of the distal end. Additionally, the distal end of the nozzle includes one or more pressure sensors (see also pressure sensor 132 in FIG. 1B) and temperature sensors that are configured to directly measure the temperature and pressure of the printing material within the nozzle. In some embodiments, the one or more pressure sensors include small range strain gauge sensors.

[0125] In some embodiments, the diameter of the channel in the flow distribution plate is 1-16 mm. In some embodiments, the diameter of the feed channel in the nozzle is 0.1-1.0 mm. In some embodiments, the diameter of the needle is 0.1-6 mm. In some embodiments, the diameter of the distal outlet of the nozzle is 0.05-3.0 mm. In some embodiments, the spacing between each nozzle is 8-50 mm. In a preferred embodiment, the spacing between two nozzles is 20-50 mm and the diameter of the nozzle outlet is 0.05-0.8 or 0.8-1.0 mm.

[0126] In some embodiments, the system includes multiple needle valve mechanisms, a push plate, a flow distribution plate, and a needle valve adjustment system. The needle valve adjustment system includes a first elastic component, a second elastic component, a push plate actuator, and a locking mechanism, as described below. The needle valve adjustment system allows the opening of each needle valve mechanism to be precisely adjusted so that the needle valve mechanisms all operate uniformly (e.g., dispensing print material). The push plate allows all the needle valve mechanisms to open and close simultaneously.

[0127] The proximal ends of the needles can be coupled to a push plate such that vertical movement of the push plate can cause vertical movement of the needles. In some embodiments, multiple needles can be coupled to the same push plate such that movement of the push plate can move multiple needles simultaneously. The push plate can be driven using any motion system such as a wedge mechanism, a cam mechanism, etc. In some embodiments, the push plate is placed above the flow distribution plate.

[0128] In some embodiments, the hub of the needle at the proximal end of the needle is housed within the sleeve component. The sleeve component includes an upper ceiling and a lower floor. The lower floor includes a hole large enough for the stem portion of the needle to pass through, but small enough to hold the hub of the needle within the sleeve. The first elastic component can be disposed above the hub of the needle and is sandwiched between the hub of the needle and the upper ceiling of the sleeve component. In some embodiments, the first elastic component is a coil (e.g., a spring). Thus, the first elastic component can push the hub of the needle downward, resulting in the hub contacting the lower floor of the sleeve.

[0129] In operation, as the push plate transitions downward to close the needle valve, the first resilient component can be retracted so that the hub of the needle has room to move upward within the sleeve, which creates a cushioning effect and reduces the force on the distal tip of the needle when it contacts the nozzle. When multiple needles are coupled to the push plate, and each needle has a corresponding sleeve, this mechanism allows all of the needles to uniformly close their corresponding nozzles.

[0130] In some embodiments, the push plate includes a recess on the upper surface of the push plate. Furthermore, at least a lower portion of the sleeve can be disposed within the recess. The upper portion of the sleeve can be coupled to a support structure via a locking mechanism, and the support structure is fixed to the push plate. In some embodiments, the locking mechanism comprises a horizontal plate having a hole that allows the sleeve to pass through. The locking mechanism can be adjusted (e.g., the size of the hole can be adjusted) to clamp the sleeve via the hole. Thus, the sleeve can be fixed to the push plate (i.e., via the locking mechanism and the support), such that the sleeve does not move relative to the push plate during printing. In some embodiments, the second elastic component is placed within the recess below the sleeve, and the second elastic component can be retracted such that the sleeve has room to move within the recess below the sleeve. For example, the second elastic component can be a coil (e.g., a spring) sandwiched between the bottom of the recess and the bottom of the sleeve.

[0131] During the initialization phase, the vertical position of the sleeve can be adjusted manually or automatically to adjust the vertical position of the needle via deformation of the second elastic component. For example, the vertical position of the sleeve can be adjusted depending on where the sleeve is clamped by the locking mechanism. By adjusting the vertical position of the sleeve, and therefore the needle, the nozzle opening can be adjusted accordingly. Adjustments can be made during the initialization phase to ensure that the needle is uniformly controlled (e.g., the same amount of transitional displacement) to dispense the same amount of printing material during printing.

[0132] In some embodiments, the motion system that drives the push plate includes an actuator. In some embodiments, the actuator is disposed on the sleeve component. The actuator can be a pneumatic actuator, a mechanical actuator, an electromagnetic actuator, a hydraulic actuator, or an electric motor. The motion system can be coupled to the push plate, for example, via the support structure described above.

[0133] Referring to FIG. 4, the system includes a communication runner that connects the two nozzles. The pressure of the two nozzles can be automatically balanced and controlled via a closed-loop flow control system that includes a sensor and a motor. A switch is added to allow the printing material in the communication runner to be dispensed periodically to prevent the printing material from being held in the runner for too long and decomposing therein. In some embodiments, multiple sets of communication runners can be provided to connect multiple nozzles. Furthermore, both needles are coupled to a single plate, so that movement of the plate 402 (e.g., via manual control, via a motor) moves the needles uniformly.

[0134] Returning to FIG. 1A, the printing platform 110 is disposed on a stage drive mechanism. The stage drive mechanism can drive the printing platform 110 relative to the movement of the nozzle 106. In some embodiments, the stage drive mechanism can be a stepper motor, a linear motor, or a servo motor based on a Cartesian coordinate system, thereby driving the printing platform 110 along one or more of the X-axis, Y-axis, and Z-axis. In other embodiments, the printing apparatus 100 further includes a module drive mechanism for driving the movement of the printing platform module 110 relative to the nozzle 106. In yet other embodiments, the stage drive mechanism can be a transport track. The relative movement of the printing platform 110 and the nozzle 106 causes the printing material to be deposited on the printing platform 110 in a complex structure and desired configuration. It should be understood that other coordinate systems and / or movements can be used.

[0135] In some embodiments, multiple arrays of nozzles are used to print a single batch of pharmaceutical dosage units. For example, a first array of nozzles is configured to dispense a first type of printed material, and a second array of nozzles is configured to dispense a second type of printed material. By switching between multiple arrays of nozzles, each resulting tablet can include layers of different materials. As discussed, each nozzle includes a needle valve mechanism coupled to a corresponding motor 112 and a computer controller for controlling the output of the printed material, so that the resulting pharmaceutical dosage units are consistent in volume, weight, and / or composition within the same batch and across multiple batches.

[0136] FIG. 1D illustrates an exemplary system for printing pharmaceutical dosage units using multiple arrays of nozzles, according to some embodiments. In the illustrated example, the printed pharmaceutical dosage unit comprises four parts: inner part 1, inner part 2, inner part 3, and a shell. The printing process occurs in four phases. In the first phase, a first array of nozzles is configured to print a batch of inner part 1 units by dispensing material 1 based on a first set of instructions. In some embodiments, the set of instructions is implemented as an API. In the second phase, a second array of nozzles is configured to print a batch of inner part 2 units by dispensing material 2 based on API 2. In the third phase, a third array of nozzles is configured to print a batch of inner part 3 units by dispensing material 3 based on API 3. In the first, second, and third phases, the batches of parts are all printed on the same printing platform. Additionally, each inner part 1 unit has a corresponding inner part 2 unit and inner part 3 unit, and the three units are produced on the printing platform such that the relative arrangement of the three units matches the desired arrangement within the pharmaceutical dosage unit.

[0137] In a fourth phase, a fourth array of nozzles is configured to dispense material 4 to print a batch of shells based on API 4. Each shell is made to coat a unit of Inner Part 1 with a corresponding unit of Inner Part 2 and Inner Part 3 to form a final pharmaceutical unit.

[0138] The printing material comprises a viscous material. In some embodiments, it is a medicinal material or a thermoplastic material, or a combination thereof. In some embodiments, the material is dispensed from the nozzle at a temperature of about 25 degrees Celsius to about 400 degrees Celsius. In some embodiments, the viscosity of the material is 0.001 to 10,000 Pa·s.

[0139] In some embodiments, the material is a non-filamentary material, such as a powder, granule, gel, or paste. The non-filamentary material is melted and pressurized so that it can be dispensed through the extrusion port of the nozzle. As further described herein, the pressure, particularly for viscous materials, is carefully controlled to ensure precise and accurate deposition of the material. The material can be melted in the material supply module using one or more heaters disposed in the material supply module, such as in or around the barrel, feed channel, and / or nozzle containing the material. In some embodiments, the melt temperature of the material is about 30° C. or higher, such as about 60° C. or higher, about 70° C. or higher, about 80° C. or higher, about 100° C. or higher, about 120° C. or higher, about 150° C. or higher, about 200° C. or higher, or about 250° C. or higher. In some embodiments, the melting temperature of the material is about 400° C. or less, such as about 350° C. or less, about 300° C. or less, about 260° C. or less, about 200° C. or less, about 150° C. or less, about 100° C. or less, or about 80° C. or less. The material dispensed from the nozzle can be dispensed at a temperature equal to or greater than the melting temperature of the material. In some embodiments, the material is dispensed at a temperature of about 50° C. or greater, such as about 60° C. or greater, about 70° C. or greater, about 80° C. or greater, about 100° C. or greater, about 120° C. or greater, about 150° C. or greater, about 200° C. or greater, or about 250° C. or greater. In some embodiments, the material is dispensed at a temperature of about 400° C. or less, such as about 350° C. or less, about 300° C. or less, about 260° C. or less, about 200° C. or less, about 150° C. or less, about 100° C. or less, or about 80° C. or less.

[0140] The systems described herein are useful for accurately and precisely dispensing viscous materials. In some embodiments, the material has a viscosity of about 100 Pa·s or more when dispensed from the device, such as about 200 Pa·s or more, about 300 Pa·s or more, about 400 Pa·s or more, about 500 Pa·s or more, about 750 Pa·s or more, or about 1000 Pa·s or more. In some embodiments, the material has a viscosity of about 2000 Pa·s or less, such as about 1000 Pa·s or less, about 750 Pa·s or less, about 500 Pa·s or less, about 400 Pa·s or less, about 300 Pa·s or less, or about 200 Pa·s or less.

[0141] In some embodiments, the material is a medicamentically acceptable material. In some embodiments, the material is inert or biologically inert. In some embodiments, the material is an erodible or bioerodible material. In some embodiments, the material is a non-erodible or non-bioerodible material. In some embodiments, the material is a medicamentously acceptable material. In some embodiments, the material comprises one or more thermoplastic materials, one or more non-thermoplastic materials, or a combination of one or more thermoplastic materials and one or more non-thermoplastic materials. In some embodiments, the material is a polymer or copolymer.

[0142] In some embodiments, the material comprises a thermoplastic material. In some embodiments, the material is a thermoplastic material. In some embodiments, the material is or comprises an erodible thermoplastic material. In some embodiments, the thermoplastic material is edible (i.e., suitable for consumption by an individual). In some embodiments, the thermoplastic material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers (such as dissolving polymers), pH-sensitive polymers, natural polymers, wax-like materials, and combinations thereof. In some embodiments, the thermoplastic material is selected from the group consisting of cellulose ethers, cellulose esters, acrylics, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, C 12 ~C 30 Mono- or diglycerides of fatty acids, C 12 ~C 30Fatty alcohols, waxes, poly(meth)acrylic acid, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, vinyl pyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25 / 75, kollicoat IR-polyvinyl alcohol 60 / 40, polyvinyl alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, poly(dimethylaminoethyl methacrylate-co-methacrylic acid esters), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate) Poly(methacrylic acid-co-methacrylic acid) 7:3:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulose phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or hypromellose (HMPC), hydroxypropyl methylcellulose phthalate acetate succinate or hypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxylpropylcellulose (HPC), polyoxyl 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC), poloxamer, hydroxypropylmethylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil, hydrogenated soybean oil,Glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), polyvinyl acetate phthalate (PVAP), wax, beeswax, hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl acetal diethylaminolactate (AEA), paraffin, shellac, sodium alginate, cellulose acetate phthalate (CAP), gum arabic, xanthan gum, glyceryl monostearate, octadecanoic acid, thermoplastic starch, derivatives thereof (such as salts, amides, or esters thereof), or combinations thereof.

[0143] In some embodiments, the erodible material comprises a non-thermoplastic material. In some embodiments, the erodible material is a non-thermoplastic material. In some embodiments, the non-thermoplastic material is non-thermoplastic starch, sodium starch glycolate (CMS-Na), sucrose, dextrin, lactose, microcrystalline cellulose (MCC), mannitol, magnesium stearate (MS), powdered silica gel, titanium dioxide, glycerin, syrup, lecithin, soybean oil, tea oil, ethanol, propylene glycol, glycerol, Tween®, animal fat, silicone oil, cocoa butter, fatty acid glycerides, petrolatum, chitosan, cetyl alcohol, stearyl alcohol, polymethacrylic acid, non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, or combinations thereof.

[0144] Exemplary materials that can be used with the devices or methods described herein include, but are not limited to, poly(meth)acrylate copolymers (such as copolymers containing one or more of aminoalkyl methacrylates, methacrylic acid, methacrylic acid esters, and / or ammonioalkyl methacrylates, such as the copolymers sold under the trade name Eudragit® RSPO), and hydroxylpropylcellulose (HPC). In some embodiments, the material includes a drug. In some embodiments, the material is mixed with a drug.

[0145] 6A illustrates an exemplary process 600 for 3D printing pharmaceutical dosage units, according to some embodiments of the present invention. Process 600 is performed, for example, using printing system 100. In process 600, some blocks are optionally combined, some blocks are optionally reordered, and some blocks are optionally omitted. In some examples, additional steps may be performed in combination with process 600. Thus, the operations illustrated (and described in more detail below) are exemplary in nature, and thus should not be considered limiting.

[0146] In some embodiments, the printing system includes one or more computer controllers. The computer controller can be programmed based on a number of manufacturing parameters. The number of manufacturing parameters includes print speed, target temperature values ​​associated with different parts of the printing system (e.g., flow distribution plate, distal end of nozzle, material supply module, pump), and pressure curves. In some embodiments, some of the manufacturing parameters are specified by a user, and other parameters are automatically calculated by a computer. The manufacturing parameters can be determined based on desired metrics of the pharmaceutical dosage unit (e.g., volume, weight, composition, dimensions), printing materials, and / or settings of the printing system. In some embodiments, programming logic / code is generated based on the number of manufacturing parameters.

[0147] At block 602, the printing system performs an initialization step. The initialization step may include starting up the system, loading necessary data (e.g., 3D models) and programming logic, initializing parameters, or a combination thereof. The initialization step may further include a heating process to achieve a desired temperature in various components of the printing system (e.g., increasing the temperature of a heating wire). In some embodiments, the heating process is controlled by a proportional-integral-derivative controller ("PID controller"). Specifically, the PID controller may measure (e.g., periodically) the temperature of various components of the printing system and determine whether one or more target temperatures have been achieved. In accordance with a determination that one or more target temperatures have not been achieved, the PID controller continues the heating process. In accordance with a determination that one or more target temperatures have been achieved, the PID controller provides an output. In some embodiments, the output is a visual, audio, or tactile output to alert a human operator to add printing material. In some embodiments, the output is an output signal that triggers printing material to be automatically added to the printing system.

[0148] In block 604, the system receives and processes a set of printing materials. The printing materials can include active ingredients and / or excipients in a predefined composition. The printing materials can include medicinal materials, thermoplastic materials, and combinations thereof. In the material supply module, the printing materials are blended, plasticized, and melted. In block 606, the processed printing materials are transported as a single stream to a flow distribution module, for example, via a single screw pump (e.g., a gear pump or a screw valve).

[0149] At block 608, the flow distribution module splits the single stream of processed printing material into multiple streams. Specifically, the flow distribution plate includes multiple channels, such as those described with reference to FIGS. 2A-C. The multiple streams pass through the channels to the distal ends of multiple nozzles. When the printing system starts up, the needle valve mechanisms of the nozzles are in a closed position, thus preventing the multiple streams from being dispensed. In some embodiments, the needle valve mechanisms of the nozzles are not activated until a desired temperature is reached at the nozzles.

[0150] At block 610, the system performs a tuning step. Figure 5B shows an example process 550 for tuning a 3D printing system according to some embodiments.

[0151] At block 652, the system begins dispensing multiple streams with multiple nozzles to generate a first batch of test pharmaceutical dosage units (e.g., tablet caplets, printlets). Specifically, as each stream of printing material accumulates at the sealed distal end of the corresponding nozzle, a pressure sensor (e.g., in the stream distribution plate, at the distal end of the nozzle) begins to receive a higher pressure reading. When the pressure reading exceeds a predefined threshold, the needle valve mechanism can open to begin dispensing the multiple streams. Before the needle valve mechanism opens, the system maintains pressure of the printing material at the nozzle. The opening of the needle valve mechanism can be triggered at any time by one or more controllers.

[0152] Once the needle valve mechanism is open, the system begins to dispense multiple flows to 3D print a first batch of multiple test pharmaceutical dosage units (e.g., tablet caplets, printlets). The flow volume for 3D printing a single batch of units is controlled via a closed loop control system based on a predefined pressure curve. Figure 5 shows an example pressure curve, where each cycle represents a session of opening, printing, and closing the needle valve mechanism.

[0153] In blocks 654-662, the system iteratively adjusts the nozzle and material delivery module while improving the consistency between the weights of the test batch (e.g., consistency between the weights of 32 tablets) until the sum of the weights of the test batch (e.g., a batch of 32 tablets) falls within a predefined error range. In block 554, the system determines whether the sum of the weights of the test batch differs from the target total weight by a predefined amount (e.g., + / - 0.5%, + / - 1%, + / - 2%, + / - 3%, + / - 4%, + / - 5%).

[0154] In accordance with a determination that the difference in error is greater than a predefined amount at block 656, the system makes adjustments to reduce the error. In some embodiments, block 556 includes adjusting one or more nozzles (block 558) and adjusting a material supply module (block 560).

[0155] At block 658, the system adjusts one or more nozzles, specifically the opening of one or more nozzles, based on the average weight of the batch of test units. The goal is to reduce the difference between the output of the nozzles. For each nozzle, the adjustment is determined based on the following formula: H next =H c -α*(W A -W C ) (1)

[0156] In the above formula, H next represents the opening (in millimeters) of the needle valve mechanism of each nozzle in the next iteration, and H c represents the opening (in millimeters) of the needle valve mechanism of each nozzle at the current iteration, and W A represents the average weight (in milligrams) of the test batch in the current iteration, and W Crepresents the weight (in milligrams) of the test unit produced by the respective nozzle in the current iteration, and α represents the opening coefficient (in mm / mg), which may vary for different needle valve mechanisms. In some embodiments, a machine learning algorithm may be used to determine the opening amount for each nozzle. The opening amount of the needle valve is dictated in relation to the translation displacement of the needle. As the needle migrates upward, the opening amount increases. As the needle migrates downward, the opening amount decreases. The terms "opening amount" and "translation displacement" are used interchangeably herein.

[0157] At block 660, the system adjusts the material supply module, for example, by adjusting pressure and temperature (e.g., based on pressure readings at the nozzle, based on pressure readings at the flow distribution plate), by adjusting feed rate / amount, or any combination thereof. For example, if the total weight of the test batch exceeds the target batch weight, the system can reduce the pressure, reduce the temperature, reduce the feed rate / amount, or any combination thereof.

[0158] At block 662, after the adjustments are made, the system opens the needle valve mechanism to 3D print another batch of test units. At block 554, the system determines whether the sum of the weights of the new test batch differs from the target total weight by a predefined amount (e.g., + / -0.5%, + / -1%, + / -2%, + / -3%, + / -4%, + / -5%). If not, the system repeats the steps at 556 to continue adjusting the material supply module and nozzle.

[0159] In accordance with a determination that the sum of the weights of the new test batch does not differ from the target total weight by a predefined amount at block 664, the system adjusts one or more nozzles based on the target weight of the pharmaceutical units. In other words, after achieving the target batch weight while improving consistency between the nozzle outputs, the system adjusts the nozzles to ensure that each nozzle is able to achieve the target weight (e.g., the target weight of a particular tablet).

[0160] Specifically, the system adjusts one or more nozzles, specifically the opening of one or more nozzles, based on the target weight of the pharmaceutical unit. For each nozzle, the adjustment is determined based on the following formula: H next =H c -α*(W T -W C ) (2)

[0161] In the above formula, H next represents the opening (in millimeters) of the needle valve mechanism of each nozzle in the next iteration, and H c represents the opening (in millimeters) of the needle valve mechanism of each nozzle at the current iteration, and W T represents the target weight in milligrams, and W C where α represents the weight (in milligrams) of the test unit produced by the respective nozzle in the current iteration, and α represents the opening coefficient (in mm / mg), which may vary for different needle valve mechanisms. In some embodiments, a machine learning algorithm may be used to determine the opening amount for each nozzle.

[0162] The main difference between equations (1) and (2) is that W T and W A In some embodiments, the batch weight is first adjusted, for example, by adjusting the pressure and temperature in the system. When the batch weight is within the desired range, the unit weight is adjusted, for example, by adjusting the opening or closing of a needle valve.

[0163] At block 666, the system 3D prints the new test batch. At block 668, the system determines whether the weight of each test unit in the new test batch differs from the target unit weight by a predefined amount (e.g., + / -0.5%, + / -1%, + / -2%, + / -3%, + / -4%, + / -5%). In some embodiments, the predefined amount is + / -1.5%. If no, the initialization is complete. If yes, the system continues the tuning steps by repeating some or all of steps 654-664.

[0164] The above tuning steps are exemplary: parameters other than the weight of the pharmaceutical unit, such as the weight, volume, dimensions, and / or composition of the output deposit (e.g., extruded wire), can be used in the tuning step to achieve nozzle-to-nozzle and batch-to-batch consistency in these parameters.

[0165] The tuning step can be used in conjunction with a closed loop control system. In some embodiments, the system includes a temperature closed loop control system that adjusts heaters and temperature control devices based on temperature readings (e.g., from temperature sensors in the material feed module, flow distribution plate, or nozzle) to achieve and maintain a target temperature. In some embodiments, an average of temperature readings from multi-pole temperature sensors is used. For example, the temperature sensors can transmit the measured temperature to a computer system, which can operate one or more heaters to ensure a substantially constant temperature. A temperature sensor in the nozzle can operate with one or more heaters in the nozzle in a closed loop feedback system to ensure a substantially constant temperature of the material in the nozzle.

[0166] The temperature sensors described herein can include thermocouple sensors (e.g., type J, type K) or resistance thermometers. In some embodiments, the temperature sensors are configured to measure temperatures below 200° C. The pressure sensors described herein include piezoresistive type transducers or strain gauge sensors. In some embodiments, small range strain gauge sensors are used. Depending on the location of the temperature or pressure sensor (e.g., in or adjacent to the material supply module, flow distribution plate, or nozzle), different types of sensors can be used.

[0167] In some embodiments, one or more heaters in the system heat the material in the system to a temperature equal to or greater than the melting temperature of the material. In some embodiments, the one or more heaters heat the material to a temperature of about 60° C. or greater, such as about 70° C. or greater, 80° C. or greater, 100° C. or greater, 120° C. or greater, 150° C. or greater, 200° C. or greater, or 250° C. or greater. In some embodiments, the one or more heaters heat the material to a temperature of about 300° C. or less, such as about 260° C. or less, 200° C. or less, 150° C. or less, 100° C. or less, or 80° C. or less. In some embodiments, the one or more heaters heat the material to different temperatures at different locations of the device. For example, in some embodiments, the material is heated to a first temperature in the barrel, a second temperature in the feed channel, and a third temperature in the nozzle, each of which may be the same or different temperatures. In some embodiments, the temperature of the material at the nozzle is, for example, 0-10° C. or 0-20° C. higher than the feed channel and the channels in the flow distribution plate. As an example, the material may be heated to 140° C. in the barrel and feed channel, but 160° C. in the nozzle. A feedback control system allows for high precision of temperature. In some embodiments, the temperature is controlled to within 0.1° C. of the target temperature, within 0.2° C. of the target temperature, within 0.5° C. of the target temperature, within 1° C. of the target temperature, or within 10° C. of the target temperature.

[0168] In some embodiments, the system includes a pressure closed loop control system that adjusts the material delivery module (e.g., the rotational speed of a screw mechanism) based on pressure readings (e.g., from pressure sensors in the flow distribution plate or nozzles) to achieve and maintain a target pressure. In some embodiments, an average of the pressure readings from the multi-pole pressure sensors is used.

[0169] In some embodiments, the pressure sensor is configured to detect the pressure of the material in the nozzle or in the feed channel proximate to the nozzle. In some embodiments, the pressure sensor is positioned proximate to the nozzle, in the nozzle or adjacent to the feed channel. The pressure sensor can work with a pressure controller in a closed-loop feedback system to provide a substantially constant pressure to the material in the device. For example, when the pressure sensor detects a decrease in pressure, the feedback system can send a signal to the pressure controller to increase the pressure of the material (e.g., by lowering the piston, increasing the air pressure in the barrel, turning the pressure screw, etc.). Similarly, when the pressure sensor detects an increase in pressure, the feedback system can send a signal to the pressure controller to decrease the pressure of the material (e.g., by raising the piston, decreasing the air pressure in the barrel, turning the pressure screw, etc.). The constant pressure ensures that the molten material in the device is dispensed at a constant rate through the extrusion port of the nozzle when the sealing needle is in an open position. However, when the sealing needle is in a closed position, the constant increase in pressure (e.g., by raising the piston, decreasing the air pressure in the barrel, turning the pressure screw, etc.) can cause the molten material to leak through the nozzle. Also, the feedback system, including the pressure sensor and pressure controller, maintains a nearly constant pressure in the system when the sealing needle is repositioned from an open position to a closed position or from a closed position to an open position. This minimizes the "ramp-up" of the extrusion rate when the sealing needle is positioned from a closed position to an open position, since there is no need to ramp up the pressure of the material in the system. The feedback system can operate using a proportional-integral-derivative (PID) controller, a bang-bang controller, a predictive controller, a fuzzy control system, an expert system controller, or any other suitable algorithm. In some embodiments, the sample rate of the pressure sensor is about 20 ms or less, such as about 10 ms or less, about 5 ms or less, or about 2 ms or less.In some embodiments, the pressure is controlled to within 0.01 MPa of the target pressure, within 0.05 MPa of the target pressure, within 0.1 MPa of the target pressure, within 0.2 MPa of the target pressure, within 0.5 MPa of the target pressure, or within 1 MPa of the target pressure.

[0170] Returning to FIG. 6A, at block 612, the system prints one or more batches of pharmaceutical dosage units. In some embodiments, the system periodically performs a quality check of the pharmaceutical dosage units, for example, by measuring batch weights or unit weights and determining whether they are within a desired range. If the batch weights or unit weights fall outside of the desired range, the system can perform some or all of steps 654-664 to make adjustments and / or use any of the closed loop control systems described above.

[0171] In some embodiments, the system includes multiple arrays of nozzles for printing multiple layers of a pharmaceutical unit. Each of the arrays of nozzles can be tuned according to the steps above. The system can include a controller for coordinating the operation of the multiple arrays to 3D print a batch of pharmaceutical dosage units.

[0172] Various controllers used in the printing system may include programmable logic controllers (PLCs), including, for example, proportional-integral-derivative (PID) controllers, bang-bang controllers, predictive controllers, fuzzy control systems, expert system controllers, or any other suitable controller. Additionally, a bus structure may be used in some embodiments. Feedback systems may use proportional-integral-derivative control, bang-bang control, predictive control, fuzzy control systems, expert control, or any other suitable control logic.

[0173] The operations described above with reference to Figures 5A-B are optionally implemented by the components shown in Figure 6. It will be apparent to one skilled in the art how other processes can be implemented based on the components shown in Figure 6.

[0174] An exemplary system for producing pharmaceutical products by additive manufacturing includes a material supply module for receiving a set of printing materials, a flow distribution module comprising a flow distribution plate, the material supply module configured to transport a single stream corresponding to the set of printing materials to the flow distribution plate, the flow distribution plate comprising a plurality of channels for splitting the single stream into multiple streams, a plurality of nozzles, and one or more controllers for controlling the plurality of nozzles to dispense the multiple streams based on nozzle-specific parameters.

[0175] In some embodiments, the system further comprises a print platform configured to receive the dispensed streams, the print platform configured to move to form a batch of the pharmaceutical product.

[0176] In some embodiments, the material supply module is configured to heat a received set of printing materials.

[0177] In some embodiments, the material supply module is configured to plasticize a received set of printing materials.

[0178] In some embodiments, the material supply module includes a piston mechanism, a screw mechanism, a screw pump mechanism, a gear mechanism, a plunger pump mechanism, or any combination thereof.

[0179] In some embodiments, the multiple channels form a first junction configured to split a single stream into two streams.

[0180] In some embodiments, the multiple channels form a second junction and a third junction configured to split the two streams into four streams.

[0181] In some embodiments, the first junction is positioned higher than the second junction and the third junction.

[0182] In some embodiments, the first junction, the second junction, and the third junction are positioned on the same plane.

[0183] In some embodiments, the flow distribution plate is separable into multiple components, and the multiple components are configured to be held together via one or more screws.

[0184] In some embodiments, one nozzle of the plurality of nozzles comprises a heating device.

[0185] In some embodiments, the multiple nozzles comprise multiple needle valve mechanisms.

[0186] In some embodiments, a needle valve mechanism of the plurality of needle valve mechanisms comprises a feed channel extending through a respective nozzle, the feed channel tapering at a distal end of the nozzle, and a needle, the distal end of the needle configured to contact and seal with the feed channel when the needle valve mechanism is in a closed position, and the distal end of the needle configured to be retracted to enable dispensing of a flow of printing material.

[0187] In some embodiments, the movement of the needle is driven by one or more motors.

[0188] In some embodiments, the one or more motors include a linear motor.

[0189] In some embodiments, the movement of the needle is manually controlled.

[0190] In some embodiments, a parameter of the plurality of nozzle-specific parameters includes an opening amount of each nozzle.

[0191] In some embodiments, the one or more controllers are configured to adjust the opening of each nozzle based on a weight of units in the batch that corresponds to each nozzle.

[0192] In some embodiments, the one or more controllers are configured to adjust the opening of each nozzle based on one or more machine learning algorithms.

[0193] In some embodiments, the one or more controllers are configured to control the temperature or pressure of the multiple nozzles.

[0194] In some embodiments, the temperature is controlled via a heating device and a temperature control device.

[0195] In some embodiments, the temperature of the plurality of nozzles is greater than the temperature of the material supply module.

[0196] In some embodiments, the temperature of the plurality of nozzles is greater than the temperature of the flow distribution plate.

[0197] In some embodiments, the one or more controllers are configured to control a feed rate of the sets of printing material.

[0198] In some embodiments, the plurality of nozzles is a first plurality of nozzles, and the printing system further comprises a second plurality of nozzles configured to dispense a different set of materials, and the printing system is configured to switch between the first plurality of nozzles and the second plurality of nozzles to print the batch.

[0199] In some embodiments, the pharmaceutical unit is a tablet.

[0200] An exemplary computer-enabled method for producing a pharmaceutical product by additive manufacturing includes receiving a plurality of unit measurements corresponding to a plurality of pharmaceutical dosage units, the plurality of pharmaceutical dosage units being produced using a plurality of nozzles of an additive manufacturing system; determining whether a sum of the plurality of unit measurements differs from a target batch measurement by more than a predefined threshold; adjusting one or more nozzles of the plurality of nozzles based on an average of the plurality of unit measurements in accordance with a determination that the sum differs from the target batch measurement by more than a predefined threshold; and adjusting one or more nozzles of the plurality of nozzles based on the target unit measurement in accordance with a determination that the sum does not differ from the target batch measurement by more than a predefined threshold.

[0201] In some embodiments, the multiple pharmaceutical units are multiple tablets.

[0202] In some embodiments, the unit measurement is a weight measurement of a multiple of a pharmaceutical dosage unit.

[0203] In some embodiments, the unit measurement is a volumetric measurement of a multiple of a pharmaceutical dosage unit.

[0204] In some embodiments, the unit measure is a composition measure of a multiple of a pharmaceutical dosage unit.

[0205] In some embodiments, the method further includes adjusting one or more operational parameters of the additive manufacturing system according to a determination that the sum differs from the target batch measurement by more than a predefined threshold.

[0206] In some embodiments, the one or more operating parameters include temperature.

[0207] In some embodiments, the one or more operating parameters include pressure.

[0208] In some embodiments, the one or more operating parameters include a speed at which the printing material is advanced.

[0209] In some embodiments, the predefined threshold is + / - 0.5% to + / - 5%.

[0210] In some embodiments, the method further includes printing a new batch after adjusting one or more nozzles of the plurality of nozzles based on the target unit measurement, and determining whether a weight of a unit in the new batch differs from the target unit measurement by more than a second predefined threshold.

[0211] In some embodiments, the second predefined threshold is less than 5%.

[0212] An exemplary method for producing a pharmaceutical product by additive manufacturing includes receiving a set of printing materials using a material supply module; transporting a single stream corresponding to the set of printing materials using the material supply module to a stream distribution plate, the stream distribution plate comprising a plurality of channels; splitting the single stream into multiple streams via the plurality of channels of the stream distribution plate; and dispensing the multiple streams to a plurality of nozzles based on a plurality of nozzle-specific parameters.

[0213] An exemplary non-transitory computer-readable storage medium stores one or more programs, the one or more programs including instructions that, when executed by one or more processors of an electronic device having a display, cause the electronic device to receive a plurality of weight measurements corresponding to a plurality of pharmaceutical dosage units produced using a plurality of nozzles of a 3D printing system, determine whether a sum of the plurality of weight measurements differs from a target batch weight by more than a predefined threshold, adjust one or more nozzles of the plurality of nozzles based on an average weight measurement of the plurality of weight measurements in accordance with a determination that the sum differs from the target batch weight by more than a predefined threshold, and adjust one or more nozzles of the plurality of nozzles based on the target weight measurement in accordance with a determination that the sum does not differ from the target batch weight by more than a predefined threshold.

[0214] FIG. 7 illustrates an example of a computing device according to one embodiment. The device 700 may be a host computer connected to a network. The device 700 may be a client computer or a server. As illustrated in FIG. 7, the device 700 may be any suitable type of microprocessor-based device, such as a personal computer, a workstation, an embedded system, a PLC, an FPGA, a server, or a handheld computing device (portable electronic device) such as a phone or tablet. The device may include, for example, one or more of a processor 710, an input device 720, an output device 730, a storage 740, and a communication device 760. The input device 720 and the output device 730 may generally correspond to those described above and may be connectable or integrated with the computer.

[0215] The input device(s) 720 may be any suitable device that provides input, such as a touch screen, a keyboard or keypad, a mouse, or a voice recognition device. The output device(s) 730 may be any suitable device that provides output, such as a touch screen, a tactile device, or a speaker.

[0216] Storage 740 can be any suitable device that provides storage, such as RAM, a cache, a hard drive, or an electrical, magnetic, or optical memory, including a removable storage disk. Communications device 760 can include any suitable device that can send and receive signals over a network, such as a network interface chip or device. The components of a computer can be connected in any suitable manner, such as through a physical bus or wirelessly.

[0217] Software 750 that may be stored in storage 740 and executed by processor 710 may include, for example, programming that embodies functions of the present disclosure (e.g., as embodied in a device as described above).

[0218] The software 750 may also be stored and / or transported in any non-transitory computer-readable storage medium for use by or in connection with an instruction execution system, apparatus, or device that can fetch and execute instructions associated with the software from an instruction execution system, apparatus, or device, such as those described above. In the context of the present disclosure, a computer-readable storage medium may be any medium, such as storage 740, that can contain or store programming for use by or in connection with an instruction execution system, apparatus, or device.

[0219] The software 750 can also be propagated in any transport medium for use by or in connection with an instruction execution system, apparatus, or device that can fetch instructions associated with the software from and execute the instructions, such as those described above. In the context of this disclosure, a transport medium can be any medium that can communicate, propagate, or transport programming for use by or in connection with an instruction execution system, apparatus, or device. Transport-readable media can include, but are not limited to, electronic, magnetic, optical, electromagnetic, or infrared wired or wireless propagation media.

[0220] The device 700 may be connected to a network, which may be any suitable type of interconnected communication system. The network may implement any suitable communication protocol and may be secured by any suitable security protocol. The network may include any suitable arrangement of network links capable of implementing transmission and reception of network signals, such as wireless network connections, T1 or T3 lines, cable networks, DSL, or telephone lines.

[0221] Device 700 may implement any operating system suitable for operation over a network. Software 750 may be written in any suitable programming language, such as C, C++, Java, Python, etc. In various embodiments, application software embodying functionality of the present disclosure may be deployed in different configurations, such as, for example, in a client / server arrangement or via a web browser as a web-based application or web service.

[0222] FIG. 8A illustrates an exemplary layout of a standardized multi-station printing system for pharmaceutical units, according to some embodiments. Referring to FIG. 8, the multi-station printing system 800 includes multiple printing stations 802A, 802B, 802C, and 802D. The multiple printing stations are arranged in a linear fashion. In the top-down view illustrated in FIG. 8A, each of the stations 802A-802D includes a set of nozzles (32 nozzles) configured to dispense multiple streams of printing material onto a printing plate to print a batch of pharmaceutical dosage units (e.g., a batch of tablets).

[0223] In some embodiments, each of the printing stations 802A-802D is configured to move a printing plate along an x-axis, a y-axis, and a z-axis with reference to a corresponding coordinate system. In some embodiments, the coordinate systems of the printing stations 802A-D are different from one another, and thus the printing stations 802A-D can be controlled independently (e.g., via one or more controllers).

[0224] 8, the multi-station system 800 includes a plate transport mechanism 806. As shown, the plate transport mechanism 806 is configured to transition along channels 804A and 804B. The plate transport mechanism 806 is configured to operate with the printing stations to move a printing plate from one printing station (e.g., 802A) to one of two ends of the plate transport mechanism (as indicated by arrows 808A and 808B), transport the printing plate along either channel (as indicated by arrows 810A and 810B), and move the printing plate to another printing station. In some embodiments, the operation of the printing stations and the plate transport mechanism are coordinated to maximize production speed and minimize idle time of the printing stations.

[0225] The stations in the system 806 may be arranged in other layouts, in some embodiments, the stations may be arranged around a circle or a square.

[0226] In some embodiments, the plate transport mechanism may consist of one or more channels that are circular or square shaped to allow the printing plate to be transported from one printing station to another. In some embodiments, the plate transport mechanism comprises one or more grippers and / or robotic arms for picking up the printing plate from one printing station and moving the printing plate to another printing station.

[0227] FIG. 8B illustrates a partial side view of an exemplary multi-station system 800, according to some embodiments. The multi-station system 800 comprises multiple printing stations, including printing stations 802A and 802B. Printing station 802A comprises a printing platform 806A and a set of nozzles (e.g., an array of nozzles) disposed on the printing platform. In operation, the set of nozzles can simultaneously dispense a set of streams of printing material onto a printing plate disposed on the printing platform 806A to form a batch of pharmaceutical dosage units. Printing station 802B comprises a different set of one or more nozzles and operates in a similar manner to printing station 802B. In some embodiments, printing stations 802A and 802B operate in coordination to produce the same batch of pharmaceutical dosage units. For example, at t0, printing station 802A prints a batch of shells of pharmaceutical dosage units onto a plate disposed on the printing platform 806A. The plate is then transported (eg, via a plate transport mechanism) to print station 802B and placed on print platform 806B. At t1, print station 802B prints the interior components in a batch of shells.

[0228] In some embodiments, the relative positioning of the printing platform and the nozzle (e.g., in the x-axis, y-axis, z-axis directions) varies from printing station to printing station. This causes the relative positioning of the pharmaceutical dosage unit and the nozzle to vary from printing station to printing station. For example, the nozzle and printing platform 806A of printing station 802A may be center aligned, but the nozzle and printing platform 806B of printing station 802B may not be center aligned. In this scenario, when the plate is transported from printing station 802A to printing station 802B, the batch of shells is not perfectly aligned with the nozzle of printing station 802A, and the system must account for the misalignment in the printing instructions, thereby moving the printing platform accordingly to print the internal components in the batch of shells.

[0229] Therefore, to achieve high precision printing of the same batch of pharmaceutical dosage products across multiple printing stations, the system needs to collect the relative positioning of the printing platform and the nozzles at each printing station. Based on how the relative positioning differs between printing stations, the system can adjust the printing instructions at a given printing station and move the printing platform / printing plate accordingly so that a set of nozzles can dispense printing material at the appropriate locations on the printing plate.

[0230] 9 illustrates an exemplary process for initializing a multi-station printing system having a first print station and a second print station, according to some embodiments. In process 900, some blocks are optionally combined, some blocks are optionally reordered, and some blocks are optionally omitted. In some examples, additional steps may be performed in combination with process 900. Thus, the operations illustrated (and described in more detail below) are exemplary in nature and, therefore, should not be considered limiting.

[0231] A plate is placed on the printing platform (e.g., printing platform 806A) of the first printing station. In some embodiments, the plate is attached to the printing platform 806A via one or more pins to prevent relative movement between the plate and the printing platform 806A. In some embodiments, one or more magnetic components (e.g., electromagnetic components) of adjustable strength can be used to ensure that the plate is securely attached to the printing platform.

[0232] In block 902, after the plate is attached to the first printing platform (e.g., 806A), the system obtains a relative positioning between the first printing platform (e.g., 806A) and the nozzles of the first printing station (e.g., 802A). In some embodiments, the relative positioning includes a first value indicating the relative positioning on the x-axis and a second value indicating the relative positioning on the y-axis.

[0233] In some embodiments, obtaining the relative positioning includes moving the printing platform to measure the first value and the second value. Referring to FIG. 8B, the printing station 802A includes a sensor module 810A and a sensor module 812A, which are fixed to the chassis of the printing station 802A and therefore always remain stationary with respect to the nozzle. During the initialization process, the system can move the printing platform 806A on the x-axis until it contacts the sensor 810A (e.g., based on the output of the sensor 810A). According to the determination that the printing platform 806A contacts the sensor 810A, the system obtains the amount of movement (X1) of the printing platform 806A on the x-axis from the initial position.

[0234] The system may further move the printing platform 806A in the y-axis direction until it contacts the sensor 812A (e.g., based on the output of the sensor 812A). Following a determination that the printing platform 806A is in contact with the sensor 812A, the system obtains the amount of movement (Y1) of the printing platform 806A on the x-axis from the initial position. In some embodiments, the sensors 810A and 812A may be any type of suitable sensor, such as a position sensor or a displacement sensor.

[0235] In block 904, the system obtains the relative positioning of the second printing platform (e.g., 806B) and the nozzles of the second printing station (e.g., 802B). In some embodiments, the same plate used in block 902 is used in block 904. In some embodiments, a different plate is used. In some embodiments, no plate is placed on the first and second printing platforms.

[0236] 8B, the printing station 802B includes a sensor module 810B and a sensor module 812B, which are fixed to the chassis of the printing station 802B and therefore always remain stationary with respect to the nozzle. During the initialization process, the system can move the printing platform 806B on the x-axis until the platform (or a plate on the platform) contacts the sensor 810B (based on the output of the sensor 810A). Following the determination that the printing platform 806A is in contact with the sensor 810B, the system obtains the displacement (X2) of the movement of the printing platform 806A on the x-axis from the initial position.

[0237] The system can further drive the printing platform 806B to move on the y-axis until the platform (or a plate on the platform) contacts the sensor 812B (e.g., based on the output of the sensor 812B). Following a determination that the printing platform 806A is in contact with the sensor 812B, the system obtains a displacement (Y2) of the movement of the printing platform 806B on the x-axis from the initial position.

[0238] In some embodiments, instead of moving the printing platform to determine whether it is in contact with a sensor to determine the values ​​of X1, X2, Y1, and Y2, the system uses one or more retractable sensors to determine the above values ​​(e.g., retracting a portion of the sensor to measure the distance X1, X2, Y1, or Y2). In some embodiments, the system uses one or more laser sensors to determine the above values.

[0239] At block 906, the system calculates offset values ​​based on the relative positioning (between the print platform and the nozzles) at the first print platform and the relative positioning at the second print platform. In some embodiments, the offset values ​​include an x-axis offset value ΔX and a y-axis offset value ΔY. In some embodiments, ΔX is calculated as the difference between X1 and X2 (e.g., ΔX=X1-X2). In some embodiments, ΔY is calculated as the difference between Y1 and Y2 (e.g., ΔY=Y1-Y2).

[0240] At block 908, the offset values ​​are input to one or more controllers that are used to generate motion of the printing platforms of the printing stations such that the location of the printing platforms (and thus the batch of pharmaceutical dosage units) relative to the nozzles can be accurately determined as the plate is transported from station to station.

[0241] Blocks 902-908 are steps directed to initializing the printing station with respect to the x-axis and y-axis directions. In some embodiments, the system performs initialization with respect to the z-axis direction. In some embodiments, the initialization with respect to the z-axis includes identifying a zero point on the z-axis. The zero point is the z-axis position where the printing platform and / or printing plate contacts the nozzles, which is also where the printing of the first layer occurs.

[0242] Identification of the zero point can be done in several ways. In some embodiments, the zero point is measured using a plug gauge. In some embodiments, the zero point is determined by gradually raising the printing platform (e.g., at a lower speed, such as 20%-50% of the speed during normal operation, using a lower current, such as 20%-50% of the current level during normal operation) until the printing platform contacts the nozzle and cannot be raised any further. Following a determination that the printing platform is in contact with the nozzle (e.g., a resistance force above a predefined threshold is detected), the system stops raising the printing platform and sets the location of the printing platform as the zero point. In some embodiments, a sensor is fixed to the printing plate with a retractable portion of the sensor protruding from the printing platform on the z-axis. A block is placed on the printing plate over the sensor such that the protruding portion of the sensor is retracted. The retracted position of the sensor is recorded. During a future initialization, the printing platform is raised such that the nozzle contacts the protruding portion of the sensor and retracts the protruding portion of the sensor. When the previously recorded retract position is detected, the system sets the location of the printing platform as the zero point on the z-axis.

[0243] Thus, the initialization process is complete and the printing system is ready to start printing. For example, the system can drive a first printing station to print a portion of a batch of tablets (e.g., bottom portions of the tablets) onto a printing plate, transport the printing plate to a second printing station, and have the second printing station print another portion of the batch of tablets (e.g., top portions of the tablets) based at least in part on the offset value entered in block 908. For example, the system can move a second printing platform based on the offset value such that the top portions of the tablets are aligned with the bottom portions of the tablets.

[0244] In some embodiments, using the techniques described herein, the lead-in between nozzles at each printing station can be within 0.01 mm (e.g., 0.02-0.05 mm) on the x-axis, within 0.01 mm (e.g., 0.02-0.05 mm) on the y-axis, and within 0.005 mm (e.g., 0.01-0.05 mm) on the z-axis, allowing the nozzles at each printing station to be precisely aligned with a batch of pharmaceutical dosage units as they are transported and printed across multiple printing stations.

[0245] In some embodiments, multiple printing plates can be used in a multi-station printing system. In some embodiments, each printing plate is placed at every printing station to obtain multiple X values ​​(e.g., n X values ​​corresponding to n printing stations), multiple Y values ​​(e.g., n Y values ​​corresponding to n printing stations), and / or multiple Z values ​​(e.g., n Z values ​​corresponding to n printing stations) associated with the plate. In this way, an offset value between any two printing stations for the plate can be obtained, so that when the plate is moved from a first printing station to a second printing station, the offset value can be used to determine the location of the plate (and thus the batch of pharmaceutical dosage units) relative to the nozzles of the second printing station. The nozzles of the second printing station can then be moved accordingly to continue printing the batch of pharmaceutical dosage units on the plate.

[0246] FIG. 10A illustrates an exemplary architecture of a multi-station 3D printing system, according to some embodiments. The 3D printing system 1000 includes multiple hardware and software components, all of which can be communicatively coupled together (e.g., via a communication protocol such as modbus, via one or more networks such as a P2P network) to provide a high speed and high throughput printing system. With reference to FIG. 10A, the system 1000 includes multiple controllers 1002A-1002N configured to respectively control the movement of N printing stations. Each controller can be coupled to a set of actuators and motors for moving a respective printing platform of the respective printing station along the x-axis, y-axis, and z-axis. In some embodiments, a single controller can be used to control the movement of multiple printing platforms of multiple printing stations.

[0247] The system 1000 further comprises a controller 1004 configured to control movement of a plate transport mechanism (e.g., 806 shown in FIG. 8A). The controller 1004 can be coupled to a set of actuators and motors for moving the printing plate (e.g., via a gripper loader, along a conveyor or channel).

[0248] The system 1000 further comprises one or more controllers 1006 configured to control the feeding of printing material by a material supply module (e.g., 102 shown in FIG. 1A). The system further comprises one or more controllers 1008 configured to control needle valves of the printing nozzles. For example, the one or more controllers 1008 can be coupled to actuators and motors that drive the movement of the needles. The system further comprises a temperature controller 1010 configured to control the temperature of various parts of the system (e.g., the flow distribution plate).

[0249] The system 1000 further includes a number of software modules 1012. In some embodiments, the number of software modules include a file management module, a process monitoring module, a modeling module, a post-processing module, a process optimization module, a simulation module, an analysis module, a rate control module, or any combination thereof.

[0250] In some embodiments, the system 1000 is communicatively coupled to one or more networks, such that it can rely on the cloud for data storage, data management, and data analysis. In some embodiments, the system 1000 is communicatively coupled to one or more mobile devices, such that the printing process can be monitored and controlled remotely. In some embodiments, the system provides a user interface (e.g., one or more graphical user interfaces) to allow a user to control and monitor the printing process, as well as to input and modify printing parameters (e.g., temperature, pressure, speed, needle position and movement). In some embodiments, the system provides real-time monitoring of various parameters of the printing process at all printing stations and all printing plates.

[0251] In some embodiments, the system 1000 comprises a quality control system for testing the printed dosage units for various metrics (e.g., shape, size, composition, consistency). In some embodiments, the system 1000 comprises additional hardware components such as sensors, cameras, and alarm systems.

[0252] 10B-C illustrate exemplary processes for 3D printing pharmaceutical dosage units using a multi-station system, according to some embodiments. Processes 1030 and 1060 may be part of software module 1012 shown in FIG. 10A. In each process, some blocks are optionally combined, some blocks are optionally reordered, and some blocks are optionally omitted. In some examples, additional steps may be performed in combination with each process. Thus, the operations illustrated (and described in more detail below) are exemplary in nature and, therefore, should not be considered limiting.

[0253] Process 1030 may be performed at a printing station of a multi-station system. In block 1032, the system loads a printing plate onto a printing platform of the printing station. Optionally, in block 1034, the system moves the printing platform to a receiving position (e.g., by lowering the printing platform along the z-axis) so that the printing plate can be moved from a plate transport mechanism onto the printing platform (e.g., along the y-axis by the plate transport mechanism).

[0254] At block 1036, the system determines whether the plate is aligned with the platform. In some embodiments, the system makes the determination based on input from one or more sensors. In some embodiments, the system determines that the plate is placed on the platform when proper alignment of components of the plate with components of the platform (e.g., pins) is detected.

[0255] In accordance with the determination that the plate is placed on the platform at block 1038, the system couples the plate to the platform. In some embodiments, the system performs the coupling by raising the printing platform along the z-axis so that the printing plate contacts the printing platform. In some embodiments, the system activates one or more electromagnetic components to ensure that the plate is securely attached or coupled to the platform.

[0256] At block 1040, the system identifies a portion of the print instructions based on progress data associated with the printing plate. In some embodiments, each printing station in the system has access to a copy of the same print instructions for printing pharmaceutical dosage units. As such, each printing station must identify a portion of the print instructions before it can begin printing. In some embodiments, the progress data includes the current height of the pharmaceutical dosage units (i.e., along the z-axis), an identifier for the printing station, or a combination thereof. In some embodiments, the progress data is provided to the printing stations by a plate transport mechanism.

[0257] At block 1042, the system performs 3D printing based on the identified portion of the printing instructions. In some embodiments, the printing is performed based on a coordinate system associated with the current printing station, which can be obtained as discussed above with reference to FIG.

[0258] In some embodiments, the system identifies the plate by scanning a code on the plate (e.g., an RFID code). In some embodiments, the identity of the plate can be used to identify the printing instructions and coordinate system.

[0259] At block 1044, the system determines whether printing is complete based on the identified portion of the print instructions. In some embodiments, the print instructions include one or more indicators that mark the beginning and / or end of a portion of the print instructions to be performed by a particular print station. Thus, the system can determine that printing is complete upon detecting one or more indicators that mark the end of a portion of the print instructions.

[0260] In accordance with a determination that printing is completed at the current print station, at block 1046, the system records progress data associated with the print plate. In some embodiments, the progress data includes an identifier for the next print station (e.g., based on the print command), the current height of the pharmaceutical dosage unit, or a combination thereof. In some embodiments, the current print station records the progress data and transmits the progress data to a plate transport mechanism.

[0261] At block 1048, the system unloads the printing plate from the printing platform. In some embodiments, this includes lowering the printing platform and deactivating the electromagnetic components to allow the plate transport mechanism to pick up the printing plate. In some embodiments, the current printing station is marked as idle by the station itself and / or by the system.

[0262] FIG. 10C illustrates an exemplary process for 3D printing pharmaceutical dosage units using a multi-station system, according to some embodiments. Process 1060 can be performed by a plate transport mechanism. To coordinate the operation of multiple printing stations and plate transport mechanisms, the multi-station system tracks the status of various components through multiple parameters, such as the identifiers of the printing stations, the locations of the printing stations, whether each printing station is busy or idle, the locations of all printing plates, progress data associated with each printing plate (e.g., current height), the location of the plate transport mechanism (e.g., coordinates on the channel), the coordinate system of the printing station, the height of all components (e.g., printing platform, printing plate, plate transport mechanism), or any combination thereof. These parameters, or multiple versions of these parameters, can be stored in a single location or distributed across multiple components.

[0263] At block 1062, the system determines whether printing is complete at the first print station. The determination can be made based on the status of the first print station (e.g., busy or idle) or based on a signal sent from the first print station to the plate transport mechanism.

[0264] In accordance with a determination that printing is completed at the first printing station, in block 1064, the system determines whether a printing plate is placed on the plate transport mechanism. As discussed above with respect to FIG. 10B, after printing is completed, the printing station can uncouple the printing plate from the printing platform. The plate transport mechanism can then pick up the printing plate and move it from the printing platform.

[0265] In block 1066, the system moves the printing plate along a first axis (e.g., the x-axis). For example, as shown in FIGS. 8A and 8B, the system can move the printing plate along a conveyor along the x-axis until the printing plate is next to a second printing station. In some embodiments, the second printing station is determined by the plate transport mechanism based on the progress data generated in block 1046. In some embodiments, the second printing station is determined by the system based on the status and printing material of each printing station (e.g., select an idle station that can dispense the current printing material required for the product on the printing plate).

[0266] In block 1068, the system determines whether the second printing station is idle, for example, based on a status parameter of the second printing station (e.g., stored in the second printing station, stored in a system-wide memory). In block 1070, in accordance with the determination that the second printing station is idle, the system moves the printing plate along a second axis (e.g., the y-axis) toward the second printing station. In some embodiments, the plate transport mechanism notifies the second printing station, which proceeds to load the printing plate onto its printing platform as discussed above. In some embodiments, the second printing station is marked as busy. The status of the second printing station can be stored locally in the second printing station, the plate transport mechanism, and / or in a system-wide memory.

[0267] At block 1072, the system causes the second printing station to 3D print on the printing plate. The second printing station can perform process 1030, including receiving progress data (e.g., from a plate transport mechanism and identifying a portion of the printing instructions).

[0268] In block 1074, the system determines whether printing is completed at the second printing station. The determination can be made based on the status of the second printing station (e.g., busy or idle) or based on a signal sent from the second printing station to the plate transport mechanism. According to the determination that printing is completed at the second printing station, the system determines whether a printing plate is placed on the plate transport mechanism. As discussed above with respect to FIG. 10B, after printing is completed, the second printing station can uncouple the printing plate from the printing platform. The plate transport mechanism can then pick up the printing plate and move the printing plate from the printing platform.

[0269] At block 1076, the system records progress data associated with the printing plate. The progress data can include a current height of the pharmaceutical dosage unit on the printing plate. In some embodiments, the progress data is determined by the second printing station based on the printing instructions and transmitted from the second printing station to a plate transport mechanism. In some embodiments, the plate transport mechanism can transmit the progress data to the next printing station. In some embodiments, the entire multi-station system stores one copy of the progress data associated with the printing plate, and various components of the system (e.g., plate transport mechanism, stations) have access to the progress data.

[0270] Although the present disclosure and examples have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications should be understood as being included within the scope of the disclosure and examples as defined by the claims.

[0271] For purposes of explanation, the foregoing description has been described with reference to specific embodiments. However, the illustrative discussion above is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments were chosen and described in order to best explain the principles of the techniques and their practical application. This will enable those skilled in the art to best utilize the techniques and various embodiments with various modifications as suited to the particular use contemplated.

Claims

1. 1. A computer-enabled method for producing a pharmaceutical product by an additive manufacturing system, the method comprising: receiving a plurality of unit measurements corresponding to a plurality of pharmaceutical dosage units, the plurality of pharmaceutical dosage units being produced using a plurality of nozzles of the additive manufacturing system; determining whether a sum of the plurality of unit measurements differs from a target batch measurement by more than a predefined threshold; adjusting one or more nozzles of the plurality of nozzles based on an average of the plurality of unit measurements in accordance with a determination that the sum differs from the target batch measurement by more than the predefined threshold; adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement in accordance with a determination that the sum does not differ from the target batch measurement by more than the predefined threshold; A method comprising:

2. 10. The method of claim 1, wherein the multiple pharmaceutical dosage units are multiple tablets.

3. The method of claim 1 , wherein the unit measurements are weight measurements of the plurality of pharmaceutical dosage units.

4. The method of claim 1 , wherein the unit measurement is a volume measurement of the plurality of pharmaceutical dosage units.

5. The method of claim 1, further comprising adjusting one or more operating parameters of the additive manufacturing system in accordance with a determination that the sum differs from the target batch measurement by more than the predefined threshold.

6. The method of claim 5 , wherein the one or more operating parameters include a temperature.

7. The method of claim 5 , wherein the one or more operating parameters include pressure.

8. The method of claim 5 , wherein the one or more operating parameters include a speed at which the printing material is advanced.

9. The method of claim 5 , wherein the one or more operating parameters include a nozzle opening.

10. The method of claim 1 , wherein the predefined threshold is between + / −0.5% and + / −5%.

11. The method comprises: printing a new batch after adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement; determining whether weights of units in the new batch differ from the target unit measurement by more than a second predefined threshold; adjusting one or more operating parameters of the additive manufacturing system in accordance with a determination that the weight of the units in the new batch differs from the target unit measurement by more than the second predefined threshold; The method of claim 1 further comprising:

12. The method of claim 11 , wherein the one or more operating parameters include a temperature.

13. The method of claim 11 , wherein the one or more operating parameters include a nozzle opening.

14. The method of claim 11 , wherein the second predefined threshold is less than 5%.

15. The additive manufacturing system comprises: a material supply module for receiving a set of printing materials for producing the pharmaceutical product; a flow distribution module; One or more controllers Equipped with the flow distribution module comprises a flow distribution plate and the plurality of nozzles; the material supply module is configured to deliver a single stream corresponding to the set of printing materials to the stream distribution plate; the flow distribution plate includes a plurality of channels for distributing the single flow into a plurality of flows; 15. The method of any one of claims 1 to 14, wherein the one or more controllers are configured to control the plurality of nozzles to distribute the plurality of streams out of the plurality of nozzles based on the plurality of nozzle-specific parameters for making the pharmaceutical product.

16. The method of claim 15 , wherein a nozzle of the plurality of nozzles comprises a heater or a nozzle of the plurality of nozzles comprises a thermal isolation structure.

17. 16. The method of claim 15, wherein the temperature of the plurality of nozzles is greater than a temperature of the material supply module, or the temperature of the plurality of nozzles is greater than a temperature of the flow distribution plate.

18. The method of claim 15 , wherein the one or more controllers are configured to control a temperature or pressure of the plurality of nozzles.

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