阅读说明：本技术 高通量和高精度的药物增材制造系统 (High-throughput and high-precision drug additive manufacturing system ) 是由 刘海利 邓飞黄 吴伟 李人杰 成森平 李霄凌 于 2020-07-30 设计创作，主要内容包括：本发明总体上涉及使用增材制造技术来制造药物产品。一种示例性打印系统包括：供料模块,所述供料模块用于接收一组打印材料；分流模块,所述分流模块包括分流板,其中,所述供料模块被配置成将与所述一组打印材料相对应的单个流输送到所述分流板；其中,所述分流板包括：多个通道,所述多个通道用于将所述单个流分成多个流；多个喷嘴,其中,所述多个喷嘴包括多个针阀机构；一个或多个控制器,所述一个或多个控制器用于基于多个喷嘴特定参数来控制所述多个针阀机构以分配所述多个流；以及打印平台,所述打印平台被配置成接收所分配的所述多个流,其中,所述打印平台被配置成运动以形成一批所述药物产品。(The present invention generally relates to the manufacture of pharmaceutical products using additive manufacturing techniques. An exemplary printing system includes: a feeding module for receiving a set of printing materials; a diverter module comprising a diverter plate, wherein the feeder module is configured to deliver a single stream corresponding to the set of printing materials to the diverter plate; wherein the flow distribution plate comprises: a plurality of channels for dividing the single stream into a plurality of streams; a plurality of nozzles, wherein the plurality of nozzles comprises a plurality of needle valve mechanisms; one or more controllers for controlling the plurality of needle valve mechanisms to distribute the plurality of flows based on a plurality of nozzle-specific parameters; and a printing platform configured to receive the dispensed plurality of streams, wherein the printing platform is configured to move to form a batch of the pharmaceutical product.)

1. A system for manufacturing a pharmaceutical product by additive manufacturing, the system comprising:

a feeding module for receiving a set of printing materials;

a splitter module comprising a splitter plate,

wherein the feed module is configured to deliver a single stream corresponding to the set of printing materials to the diverter plate;

wherein the diverter plate comprises a plurality of channels for dividing the single stream into a plurality of streams;

a plurality of nozzles; and

one or more controllers to control the plurality of nozzles to dispense the plurality of streams based on a plurality of nozzle-specific parameters.

2. The system of claim 1, further comprising a printing platform configured to receive the dispensed plurality of streams, wherein the printing platform is configured to move to form a batch of the pharmaceutical product.

3. The system of any of claims 1-2, wherein the feed module is configured to heat the received set of printing materials.

4. The system of any of claims 1-3, wherein the feed module is configured to plasticize the received set of printing material.

5. The system of any of claims 1-4, wherein the feed module comprises a piston mechanism, a screw pump mechanism, a gear pump mechanism, a plunger pump mechanism, or any combination thereof.

6. The system of any of claims 1-5, wherein the plurality of channels form a first junction configured to split the single flow into two flows.

7. The system of claim 6, wherein the plurality of channels form a second junction and a third junction configured to split the two flows into 4 flows.

8. The system of claim 7, wherein the first engagement portion is positioned higher than the second engagement portion and the third engagement portion.

9. The system of claim 7, wherein the first joint, the second joint, and the third joint lie on a same plane.

10. The system of any of claims 1-9, wherein the diverter plate is detachable into multiple components, wherein the multiple components are configured to be fixedly held together by one or more screws.

11. The system of any of claims 1-10, wherein a nozzle of the plurality of nozzles comprises a heater.

12. The system of any of claims 1-11, wherein a nozzle of the plurality of nozzles comprises a thermally insulating structure.

13. The system of any of claims 1-12, wherein the plurality of nozzles comprises a plurality of needle valve mechanisms.

14. The system of claim 13, wherein a needle valve mechanism of the plurality of needle valve mechanisms comprises:

a feed channel extending through the respective nozzle, wherein the feed channel tapers at a distal end of the nozzle; and

a needle is provided with a needle head and a needle head,

wherein the distal end of the needle is configured to contact and seal the feed passage when the needle valve mechanism is in the closed position, an

Wherein a distal end of the needle is configured to retract to allow a flow of printing material to be dispensed.

15. The system of claim 14, wherein the movement of the needle is driven by one or more actuators.

16. The system of claim 15, wherein the one or more actuators comprise linear motors.

17. The system of claim 14, wherein the movement of the needle is manually controlled.

18. The system of claim 14, wherein the needle is a first needle, wherein the plurality of nozzles comprises a single plate coupled to the first and second needles, and wherein movement of the single plate causes movement of the first and second needles.

19. The system of any of claims 1-18, wherein a parameter of the plurality of nozzle-specific parameters comprises an opening amount of a respective nozzle.

20. The system of claim 19, wherein the one or more controllers are configured to adjust the opening amount of the respective nozzle based on a weight of a unit in the batch corresponding to the respective nozzle.

21. The system of claim 19, wherein the one or more controllers are configured to adjust the opening amounts of the respective nozzles based on one or more machine learning algorithms.

22. The system of any of claims 1-21, wherein the one or more controllers are configured to control a temperature or a pressure at the plurality of nozzles.

23. The system of claim 22, wherein the temperature is controlled by a temperature control device comprising one or more heating components, one or more cooling components, or a combination thereof.

24. The system of any of claims 1-23, wherein a temperature at the plurality of nozzles is higher than a temperature at the feed module.

25. The system of any of claims 1-24, wherein a temperature at the plurality of nozzles is higher than a temperature at the diverter plate.

26. The system of any of claims 1-25, wherein the one or more controllers are configured to control a feed speed of the set of printing materials.

27. The system of any of claims 1-26, wherein the plurality of nozzles is a first plurality of nozzles, the printing system further comprising a second plurality of nozzles configured to dispense different sets of materials, wherein the printing system is configured to switch between the first and second plurality of nozzles to print the batch.

28. The system of any one of claims 1-27, wherein the drug unit is a tablet.

29. A computer-implemented method of manufacturing a pharmaceutical product by additive manufacturing, the method comprising:

receiving a plurality of unit measurements corresponding to a plurality of drug dosage units, wherein the plurality of drug dosage units are generated using a plurality of nozzles of an additive manufacturing system;

determining whether a difference between a sum of the plurality of unit measurements and a target lot measurement exceeds a predetermined 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 of whether a difference between the sum and the target lot measurement exceeds the predetermined threshold;

in accordance with a determination that the sum and the target batch measurement differ by no more than the predetermined threshold, adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement.

30. The method of claim 29, wherein the plurality of drug units are a plurality of tablets.

31. The method of any of claims 29-30, wherein the unit measurement is a weight measurement of the plurality of drug dosage units.

32. The method of any of claims 29-31, wherein the unit measurement is a volume measurement of the plurality of drug dosage units.

33. The method according to any one of claims 29-32, further comprising:

adjusting one or more operating parameters of the additive manufacturing system based on a determination that a difference between the sum and the target lot measurement exceeds the predetermined threshold.

34. The method of claim 33, wherein the one or more operating parameters include temperature.

35. The method of claim 33, wherein the one or more operating parameters include pressure.

36. The method of claim 33, wherein the one or more operating parameters include a speed at which the printing material is fed.

37. The method of claim 33, wherein the one or more operating parameters include an opening amount of a nozzle.

38. The method of any of claims 29-37, wherein the predetermined threshold is between +/-0.5% to +/-5%.

39. The method according to any one of claims 29-38, further comprising:

printing a new batch after adjusting one or more of the plurality of nozzles based on the target cell measurements;

determining whether the difference between the weight of the units in the new lot and the target unit measurement is greater than a second predetermined threshold;

adjusting one or more operating parameters of the additive manufacturing system based on a determination that a difference between the weight of the units in the new lot and the target unit measurement exceeds the second predetermined threshold.

40. The method of claim 39, wherein the one or more operating parameters comprise temperature.

41. The method of claim 39, wherein the one or more operating parameters comprise an opening amount of a nozzle.

42. The method of claim 39, wherein the second predetermined threshold is less than 5%.

43. A method of manufacturing a pharmaceutical product by additive manufacturing, the method comprising:

receiving a set of printing materials using a feeding module;

delivering a single stream corresponding to the set of printing materials to a manifold using the feed module, wherein the manifold includes a plurality of channels;

dividing the single flow into a plurality of flows through the plurality of channels of the diverter plate;

causing a plurality of nozzles to dispense the plurality of streams based on a plurality of nozzle-specific parameters;

44. a non-transitory computer readable storage medium storing one or more programs, the one or more programs comprising instructions, which when executed by one or more processors of an electronic device with a display, cause the electronic device to:

receiving a plurality of weight measurements corresponding to a plurality of drug dosage units, wherein the plurality of drug dosage units were generated using a plurality of nozzles of a 3D printing system;

determining whether a difference between a sum of the plurality of weight measurements and a target batch weight is greater than a predetermined threshold;

in accordance with a determination that the difference between the sum and the target batch weight is greater than the predetermined threshold, adjusting one or more nozzles of the plurality of nozzles based on an average weight measurement of the plurality of weight measurements;

adjusting one or more nozzles of the plurality of nozzles based on a target weight measurement in accordance with a determination that the difference between the sum and the target batch weight does not exceed the predetermined threshold.

45. A system for manufacturing a plurality of pharmaceutical products by additive manufacturing, the system comprising:

a first printing workstation 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 board conveying mechanism;

printing a plate;

wherein the system is configured to:

determining whether printing of a first portion of each of the plurality of pharmaceutical products is completed at the first printing station while the print plate is positioned on the first printing deck;

identifying the second print workstation based on a determination that printing of the first portion is complete at the first print workstation;

transporting the print plate from the first print station to the second print station by the plate transport mechanism; and

causing printing of a second portion of each of the plurality of pharmaceutical products at the second printing station.

46. The system of claim 45, further comprising two conveyors, wherein the system is configured to convey the print plate along one of the two conveyors by the plate transport mechanism.

47. In accordance with the system set forth in claim 45,

wherein printing of the first portion at the first printing workstation is based on a first coordinate system associated with the first printing workstation, and

wherein printing of the second portion at the second printing station is based on a second coordinate system associated with the second printing station.

48. The system of claim 47, wherein the system is configured to:

obtaining a first relative position between the first print deck and the first plurality of nozzles;

obtaining a second relative position between the second printing platform and the second plurality of nozzles;

calculating a plurality of offset values based on the first relative position and the second relative position;

determining at least one of the first coordinate system and the second coordinate system based on the plurality of offset values.

49. The system of claim 48, wherein the first relative position comprises a first x-axis value and a first y-axis value, and wherein the second relative position comprises a second x-axis value and a second y-axis value.

50. The system of claim 49, wherein the plurality of offset values comprises:

a sum of differences between the first x-axis value and the second x-axis value

A difference between the first y-axis value and the second y-axis value.

51. The system of claims 48-50, wherein obtaining the first relative position comprises:

measuring the first x-axis value and the first y-axis value based on one or more retractable sensors placed on the first printing station while positioning the print plate on the first printing platform.

52. The system of claims 48-50, wherein obtaining the first relative position comprises:

measuring the first x-axis value and the first y-axis value based on one or more laser sensors placed on the first printing station while positioning the print plate on the first printing platform.

53. The system of any one of claims 47-52, wherein obtaining the first relative position comprises:

moving the first print platform in the x-axis until the first print platform contacts a first sensor on the first print workstation; and

moving the second printing platform in the y-axis until the second printing platform contacts a second sensor on the first printing workstation.

54. The system of claim 47, wherein determining the first coordinate system comprises: a zero point on the z-axis is determined.

55. The system of claim 54, wherein the zero point comprises a z-axis position at which a plate placed on the first printing platform is in contact with a first plurality of nozzles.

56. The system of claim 54, wherein the determination of the zero point is performed using a plug gauge.

57. The system of claim 54, wherein the determination of the zero point comprises:

lifting the first printing platform;

determining, using a sensor coupled to the first printing platform, whether a resistance force above a predetermined threshold is detected;

in accordance with a determination that a resistance force above the predetermined threshold is detected, pausing lifting the first printing platform and determining the zero point based on a current z-axis position of the first printing platform;

in accordance with a determination that no resistance above the predetermined threshold is detected, continuing to lift the first printing deck.

58. The system of claim 54, wherein the determination of the zero point comprises:

securing a sensor having a telescoping portion to the first printing platform, wherein the telescoping portion protrudes beyond the first printing platform;

placing an object over the sensor such that the protrusion of the sensor is retracted;

recording a retracted position of the sensor;

determining whether a retracted position of the sensor is detected while lifting the first printing deck; and

in accordance with a determination that the retracted position is detected, determining the zero point based on a current z-axis position of the first printing platform.

59. The system of any one of claims 45-58, wherein the first plurality of nozzles is configured to dispense a first type of printing material, and wherein the second plurality of nozzles is configured to dispense a second type of printing material.

60. The system of any one of claims 45-59,

wherein the plurality of pharmaceutical products comprises a plurality of tablets;

wherein the first portion of each pharmaceutical product comprises an exterior of the respective tablet; and is

Wherein the second portion of each pharmaceutical product comprises an interior of the respective tablet.

61. The system of any one of claims 45-60,

wherein the plurality of pharmaceutical products comprises a plurality of tablets;

wherein the first portion of each pharmaceutical product comprises a lower portion of the respective tablet; and

wherein the second portion of each pharmaceutical product comprises an upper portion of the respective tablet.

62. The system of any of claims 45-61, wherein determining whether printing of the first portion of each of the plurality of pharmaceutical products at the first printing workstation is complete comprises:

receiving a status of the first print station at the plate transport mechanism; and

determining, at the plate transport mechanism, whether the printing is complete based on a status of the first printing station.

63. The system of any one of claims 45-62, wherein the system is further configured to:

upon completion of printing of the first portion of each pharmaceutical product, recording progress data associated with the print plate.

64. The system of claim 63, wherein the progress data includes current heights of the plurality of pharmaceutical products.

65. The system of claim 63, wherein the progress data includes the identified second print workstation.

66. The system of any of claims 63-65, wherein the system is configured to transmit the recorded progress data from the first printing workstation to the plate transport mechanism.

67. The system of any of claims 45-66, wherein identifying the second printing workstation is based on a set of printing instructions associated with the pharmaceutical product.

68. The system of any of claims 45-67, wherein identifying the second printing workstation is based on the second portion to be printed.

69. The system of any of claims 45-67, wherein identifying the second printing workstation is based on printing material associated with the second portion to be printed.

70. The system of any of claims 45-67, wherein identifying the second printing workstation is based on a status of the second printing workstation.

71. The system of any of claims 45-67, wherein transporting the print plate from the first printing station to the second printing station by the plate transport mechanism comprises:

removing the print plate from the first platform;

moving the print plate onto the plate transport mechanism; and

moving the plate transport mechanism along a lane based on a position associated with the second print station.

72. The system of claim 71, wherein detaching the print plate from the first platform comprises deactivating an electromagnetic component.

73. The system of any one of claims 45-72, wherein causing printing of the second portion of each of the plurality of drug products at the second printing workstation comprises: updating the status of the second print workstation to busy.

74. The system of claims 45-73, wherein causing printing of the second portion of each of the plurality of drug products at the second printing workstation comprises: a portion of a print order is identified based on progress data associated with the clapper.

75. The system of claim 74, wherein the progress data includes a current print height of the plurality of pharmaceutical products on the print plate.

76. The system of claim 74, wherein the progress data is transmitted from the plate transport mechanism to the second print workstation.

77. The system of any one of claims 45-76, further comprising: a controller associated with the first printing workstation, a controller associated with the second printing workstation, or any combination thereof.

78. The system of any one of claims 45-77, further comprising: a controller associated with the plate transport mechanism.

79. The system of any of claims 45-78, further comprising a third print workstation.

Technical Field

The present invention relates generally to additive manufacturing techniques and more particularly to high throughput and high precision 3D printing techniques for manufacturing pharmaceutical dosage units (e.g., tablets, printed sheets).

Background

Additive manufacturing, also known as three-dimensional printing ("3D printing"), is a rapid prototyping technique that involves the process of joining or curing materials to produce a three-dimensional object. In particular, based on digital modeling, materials are typically added together layer by layer (such as fusing liquid molecules or powder particles together). The computer system operates the additive manufacturing system and controls the flow of material and the movement of the print nozzle until a desired shape is formed. Currently, 3D printing techniques include photo-curing techniques, powder bonding techniques, and Fused Deposition Modeling (FDM) techniques.

In the FDM process, material in the form of a filament is fed through a heated nozzle that melts the material onto a surface. The surface or heated nozzle may be moved to dispense the molten material into a fixed shape as directed by the computer system. Other additive manufacturing methods utilize a non-linear material that is melted and pressurized prior to being dispensed through a print nozzle, but such methods often result in undesirable stringing from the print nozzle, particularly when the melted material has a high viscosity.

Adaptive techniques such as FDM present several challenges when used to manufacture pharmaceutical dosage units (e.g., tablets, caplets, printed tablets): high throughput, high precision/consistency, and printing of drug dosage units with complex structures and compositions. For example, a single nozzle printing device or a multi-nozzle printing device can only achieve relatively low throughput. On the other hand, systems that provide parallel printing by operating multiple printing devices simultaneously are also deficient because the multiple printing devices create inconsistencies and low precision between printing units (e.g., in volume, shape, weight, and/or composition). Such systems are also expensive to manufacture and maintain, inefficient and complex to operate.

In particular, the printing materials required in the pharmaceutical field tend to have high viscosities and are associated with low printing pressures. Furthermore, when multiple types of printing material are involved in the printing process, the nozzles that dispense these different types of printing material 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 and to control the release of multiple types of materials in an accurate and consistent manner. Thus, conventional 3D printing systems fail to maintain a high degree of consistency between the drug dosage units delivered by the nozzles in the same batch or in multiple batches. The above challenges are further compounded if the drug units to be manufactured are composed of different materials arranged in a specific configuration (e.g., a plurality of inner core portions are coated with an outer shell).

Furthermore, configuring multiple 3D printers to work together to produce a batch of pharmaceutical dosage units does not produce satisfactory results when conventional 3D printing techniques are used. In particular, inconsistencies between multiple 3D printers (e.g., in terms of hardware and software configurations) may result in end product inconsistencies that fail to meet quality standards. Furthermore, systems involving coordination between multiple 3D printers are typically inefficient to operate and costly to maintain.

Accordingly, there is a need for such systems and methods: the system and method are used for 3D printing of pharmaceutical dosage units (e.g., tablets, caplets, printed tablets) 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 a batch of pharmaceutical dosage units.

Disclosure of Invention

An exemplary system for manufacturing a pharmaceutical product by additive manufacturing, the system comprising: a feeding module for receiving a set of printing materials; a diverter module comprising a diverter plate, wherein the feeder module is configured to deliver a single stream corresponding to the set of printing materials to the diverter plate; wherein the diverter plate comprises a plurality of channels for dividing the single stream into a plurality of streams; 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.

In some embodiments, the system further comprises a printing platform configured to receive the dispensed plurality of streams, wherein the printing platform is configured to move to form a batch of the pharmaceutical product.

In some embodiments, the feed module is configured to heat the received set of printing materials.

In some embodiments, the feed module is configured to plasticize the received set of printing material.

In some embodiments, the feed module comprises a piston mechanism, a screw pump mechanism, a gear pump mechanism, a plunger pump mechanism, or any combination thereof.

In some embodiments, the plurality of channels form a first junction configured to split the single flow into two flows.

In some embodiments, wherein the plurality of channels form a second junction and a third junction, the second junction and the third junction configured to split the two streams into 4 streams.

In some embodiments, the first engagement portion is positioned higher than the second engagement portion and the third engagement portion.

In some embodiments, the first joint, the second joint, and the third joint are located on the same plane.

In some embodiments, the diverter plate is detachable into multiple components, wherein the multiple components are configured to be fixedly held together by one or more screws.

In some embodiments, a nozzle of the plurality of nozzles includes a heater.

In some embodiments, a nozzle of the plurality of nozzles comprises a thermally insulating structure.

In some embodiments, the plurality of nozzles comprises a plurality of needle valve mechanisms.

In some embodiments, a needle valve mechanism of the plurality of needle valve mechanisms comprises: a feed channel extending through the respective nozzle, wherein the feed channel tapers at a distal end of the nozzle; and a needle, wherein a distal end of the needle is configured to contact and seal the feed channel when the needle valve mechanism is in a closed position, and wherein the distal end of the needle is configured to retract to allow a flow of printing material to be dispensed.

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

In some embodiments, the one or more actuators comprise linear motors.

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

In some embodiments, the needle is a first needle, the plurality of nozzles comprises a single plate coupled to the first and second needles, and wherein movement of the single plate causes movement of the first and second needles.

In some embodiments, a parameter of the plurality of nozzle-specific parameters includes an opening amount of the respective nozzle.

In some embodiments, the one or more controllers are configured to adjust the opening amount of the respective nozzle based on a weight of a unit in the batch corresponding to the respective nozzle.

In some embodiments, the one or more controllers are configured to adjust the opening amounts of the respective nozzles based on one or more machine learning algorithms.

In some embodiments, the one or more controllers are configured to control a temperature or pressure at the plurality of nozzles.

In some embodiments, the temperature is controlled by a temperature control device comprising one or more heating elements, one or more cooling devices, or a combination thereof.

In some embodiments, the temperature at the plurality of nozzles is higher than the temperature at the feed module.

In some embodiments, the temperature at the plurality of nozzles is higher than the temperature at the diverter plate.

In some embodiments, the one or more controllers are configured to control a feed speed of the set of printing materials.

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

In some embodiments, the pharmaceutical unit is a tablet.

A computer-implemented exemplary method of manufacturing a pharmaceutical product by additive manufacturing, the method comprising: receiving a plurality of unit measurements corresponding to a plurality of drug dosage units, wherein the plurality of drug dosage units are generated using a plurality of nozzles of an additive manufacturing system; determining whether a difference between a sum of the plurality of unit measurements and a target lot measurement exceeds a predetermined 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 of whether a difference between the sum and the target lot measurement exceeds the predetermined threshold; in accordance with a determination that the sum and the target batch measurement differ by no more than the predetermined threshold, adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement.

In some embodiments, the plurality of drug units is a plurality of tablets.

In some embodiments, the unit measurement is a weight measurement of the plurality of drug dosage units.

In some embodiments, the unit measurement is a volume measurement of the plurality of drug dosage units.

In some embodiments, the unit measure is a compositional measure of the plurality of drug dosage units.

In some embodiments, the method further comprises: adjusting one or more operating parameters of the additive manufacturing system based on a determination that a difference between the sum and the target lot measurement exceeds the predetermined threshold.

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

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

In some embodiments, the one or more operating parameters include a speed at which the printing material is fed.

In some embodiments, the predetermined threshold is between +/-0.5% to +/-5%.

In some embodiments, the method further comprises: printing a new batch after adjusting one or more of the plurality of nozzles based on the target cell measurements; determining whether the difference between the weight of the units in the new lot and the target unit measurement is greater than a second predetermined threshold; adjusting one or more operating parameters of the additive manufacturing system based on a determination that a difference between the weight of the units in the new lot and the target unit measurement exceeds the second predetermined threshold.

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

In some embodiments, the one or more operating parameters include an opening amount of the nozzle.

In some embodiments, the second predetermined threshold is less than 5%.

An exemplary method of manufacturing a pharmaceutical product by additive manufacturing, the method comprising: receiving a set of printing materials using a feeding module; delivering a single stream corresponding to the set of printing materials to a manifold using the feed module, wherein the manifold includes a plurality of channels; dividing the single flow into a plurality of flows through the plurality of channels of the diverter plate; causing a plurality of nozzles to dispense the plurality of streams based on a plurality of nozzle-specific parameters.

An exemplary non-transitory computer readable storage medium storing one or more programs, the one or more programs comprising instructions, which when executed by one or more processors of an electronic device with a display, cause the electronic device to: receiving a plurality of weight measurements corresponding to a plurality of drug dosage units, wherein the plurality of drug dosage units were generated using a plurality of nozzles of a 3D printing system; determining whether a difference between a sum of the plurality of weight measurements and a target batch weight is greater than a predetermined threshold; in accordance with a determination that the difference between the sum and the target batch weight is greater than the predetermined threshold, adjusting one or more nozzles of the plurality of nozzles based on an average weight measurement of the plurality of weight measurements; adjusting one or more nozzles of the plurality of nozzles based on a target weight measurement in accordance with a determination that the difference between the sum and the target batch weight does not exceed the predetermined threshold.

In some embodiments, an exemplary system for manufacturing a plurality of pharmaceutical products by additive manufacturing, the system comprising: a first printing workstation 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 board conveying mechanism; printing a plate; wherein the system is configured to: determining whether printing of a first portion of each of the plurality of pharmaceutical products is completed at the first printing station while the print plate is positioned on the first printing deck; identifying the second print workstation based on a determination that printing of the first portion is complete at the first print workstation; transporting the print plate from the first print station to the second print station by the plate transport mechanism; and causing printing of a second portion of each of the pharmaceutical products in a batch at the second printing station.

In some embodiments, the system further comprises two conveyors, wherein the system is configured to convey the print plate along one of the two conveyors by the plate conveying mechanism.

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

In some embodiments, the system is configured to: obtaining a first relative position between the first print deck and the first plurality of nozzles; obtaining a second relative position between the second printing platform and the second plurality of nozzles; calculating a plurality of offset values based on the first relative position and the second relative position; determining at least one of the first coordinate system and the second coordinate system based on the plurality of offset values.

In some embodiments, the first relative position comprises a first x-axis value and a first y-axis value, and wherein the second relative position comprises a second x-axis value and a second y-axis value.

In some embodiments, the plurality of offset values comprises: a difference between the first x-axis value and the second x-axis value and a difference between the first y-axis value and the second y-axis value.

In some embodiments, obtaining the first relative position comprises: measuring the first x-axis value and the first y-axis value based on one or more retractable sensors placed on the first printing station while positioning the print plate on the first printing platform.

In some embodiments, obtaining the first relative position comprises: measuring the first x-axis value and the first y-axis value based on one or more laser sensors placed on the first printing station while positioning the print plate on the first printing platform.

In some embodiments, obtaining the first relative position comprises: moving the first print platform in the x-axis until the first print platform contacts a first sensor on the first print workstation; and moving the second printing platform in the y-axis until the second printing platform contacts a second sensor on the first printing station.

In some embodiments, determining the first coordinate system comprises: a zero point on the z-axis is determined.

In some embodiments, the zero point comprises a z-axis position at which a plate placed on the first printing deck is in contact with a first plurality of nozzles.

In some embodiments, the determination of the zero point is performed using a plug gauge.

In some embodiments, the determination of the zero point comprises: lifting the first printing platform; determining, using a sensor coupled to the first printing platform, whether a resistance force above a predetermined threshold is detected; in accordance with a determination that a resistance force above the predetermined threshold is detected, pausing lifting the first printing platform and determining the zero point based on a current z-axis position of the first printing platform; in accordance with a determination that no resistance above the predetermined threshold is detected, continuing to lift the first printing deck.

In some embodiments, the determination of the zero point comprises: securing a sensor having a telescoping portion to the first printing platform, wherein the telescoping portion protrudes beyond the first printing platform; placing an object over the sensor such that the protrusion of the sensor is retracted; recording a retracted position of the sensor; determining whether a retracted position of the sensor is detected while lifting the first printing deck; and in accordance with a determination that the retracted position is detected, determining the zero point based on a current z-axis position of the first printing platform;

in some embodiments, the first plurality of nozzles is configured to dispense a first type of printing material, and wherein the second plurality of nozzles is configured to dispense a second type of printing material.

In some embodiments, the batch of pharmaceutical products comprises a batch of tablets; the first portion of each pharmaceutical product comprises an outer portion of the respective tablet; and, the second portion of each pharmaceutical product comprises an interior of the respective tablet.

In some embodiments, the batch of pharmaceutical products comprises a batch of tablets; the first portion of each pharmaceutical product comprises a lower portion of the respective tablet; and, the second portion of each pharmaceutical product comprises an upper portion of the respective tablet.

In some embodiments, determining whether printing of the first portion of each drug product in the batch of drug products at the first printing workstation is complete comprises: receiving a status of the first print station at the plate transport mechanism; and determining, at the board conveying mechanism, whether the printing is completed based on a state of the first printing station.

In some embodiments, the system is further configured to: upon completion of printing of the first portion of each pharmaceutical product, recording progress data associated with the print plate.

In some embodiments, the progress data includes current heights of the plurality of pharmaceutical products.

In some embodiments, the progress data includes the identified second print workstation.

In some embodiments, the system is configured to transmit the recorded schedule data from the first printing workstation to the plate transport mechanism.

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

In some embodiments, identifying the second print workstation is based on the second portion to be printed.

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

In some embodiments, identifying the second print workstation is based on a status of the second print workstation.

In some embodiments, transporting the print plate from the first print station to the second print station by the plate transport mechanism comprises: removing the print plate from the first platform; moving the print plate onto the plate transport mechanism; and moving the plate transport mechanism along a lane based on a position associated with the second print station.

In some embodiments, detaching the print plate from the first platform comprises deactivating an electromagnetic component.

In some embodiments, causing printing of the second portion of each drug product in the batch of drug products at the second printing station comprises: updating the status of the second print workstation to busy.

In some embodiments, causing printing of the second portion of each drug product in the batch of drug products at the second printing workstation comprises: a portion of a print order is identified based on progress data associated with the clapper.

In some embodiments, the progress data includes a current print height of the batch of pharmaceutical products on the print plate.

In some embodiments, the schedule data is transmitted from the plate transport mechanism to the second print workstation.

In some embodiments, the system further comprises: a controller associated with the first printing workstation, a controller associated with the second printing workstation, or any combination thereof.

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

In some embodiments, the system further comprises a third print station.

Drawings

Fig. 1A depicts a schematic of an exemplary additive manufacturing system, according to some embodiments of the invention.

Fig. 1B depicts a schematic of an exemplary additive manufacturing system, according to some embodiments of the invention.

Fig. 1C depicts an exemplary additive manufacturing system including a piston mechanism, according to some embodiments of the invention.

Fig. 1D depicts an exemplary additive manufacturing system according to some embodiments of the invention.

Fig. 2A depicts a side cross-sectional view of an exemplary shunt module, according to some embodiments of the invention.

Fig. 2B depicts a top cross-sectional view of an exemplary diverter module according to some embodiments of the present invention.

Fig. 2C depicts a configuration of an exemplary offload module according to some embodiments of the invention.

Fig. 2D depicts a bottom perspective view of a diverter module according to some embodiments of the present invention.

Fig. 3 depicts a cross-sectional view of a distal end of an exemplary nozzle, according to some embodiments of the invention.

Fig. 4 depicts a cross-sectional view of an example additive manufacturing system, according to some embodiments of the invention.

Fig. 5 depicts an exemplary pressure profile for dispensing printing material at a nozzle, according to some embodiments of the invention.

Fig. 6A depicts an exemplary process for 3D printing of a drug dosage unit according to some embodiments of the present invention.

Fig. 6B depicts an exemplary process for 3D printing of drug dosage units, according to some embodiments of the present invention.

FIG. 7 depicts an exemplary electronic device, according to some embodiments.

Fig. 8A depicts an exemplary layout of a standardized multi-station printing system for drug units, according to some embodiments.

Fig. 8B depicts a partial side view of an exemplary multi-station printing system 800, according to some embodiments.

Fig. 9 depicts an exemplary process for initializing a multi-station printing system having a first print station and a second print station, according to some embodiments.

Fig. 10A depicts an exemplary architecture of a multi-station 3D printing system according to some embodiments.

Fig. 10B depicts an exemplary process for 3D printing of drug dosage units using a multi-station printing system, according to some embodiments.

Fig. 10C depicts an exemplary process for 3D printing of drug dosage units using a multi-station printing system, according to some embodiments.

Detailed Description

Described herein are devices, apparatuses, systems, methods, and non-transitory storage media for additive manufacturing (e.g., 3D printing) pharmaceutical dosage units (e.g., tablets, caplets, printed tablets) in an accurate, precise, and cost-effective manner while maintaining a high throughput over time. According to some embodiments, a printing system utilizes a diversion module to divide a single stream of printing material into multiple streams. The multiple nozzles dispense multiple streams in a precisely controlled manner to 3D print a batch of drug dosage units (e.g., tablets, caplets, printed tablets) to achieve consistency between units in a single batch as well as multiple batches while maintaining high throughput.

Further, the printing system comprises an environment (e.g. a closed environment such as an incubator, an open environment such as a printing platform) for additive manufacturing (e.g. 3D printing) of the drug dosage unit. Closed loop control systems are used to control temperature, pressure, flow, weight, volume, and other related parameters in an environment at various stages of a manufacturing process. In particular, control systems and methods are implemented to precisely adjust the opening of the nozzle, and in particular, the opening of the needle valve mechanism at the nozzle, to ensure consistency between nozzle outputs. In some embodiments, the inconsistency in the weight of units (i.e., the inconsistency between the weights of units in 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 inconsistency in the batch weights (i.e., the inconsistency between batch weights) is less than 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%).

The system can adjust the control parameters based on the different types of printing materials and compositions desired. In this way, the printing system may be used to manufacture a variety of high quality pharmaceutical dosage units.

In some embodiments, the material is non-linear (e.g., powder, granules, or liquid). In some embodiments, the viscosity of the material is 0.01 to 10000Pa · s when the material is dispensed from the system. For example, the viscosity of the material is about 100Pa · s or higher when the material is dispensed from the apparatus. In some embodiments, the viscosity of the material is about 400 Pa-s or higher when the material is dispensed from the apparatus. In some embodiments, the material melts at about 50 ℃ to about 400 ℃. In some embodiments, the material is dispensed from the nozzle at a temperature of about 50 ℃ to about 400 ℃. In some embodiments, the material is dispensed from the nozzle at a temperature of about 90 ℃ to about 300 ℃.

In some embodiments, the printing system includes a plurality of printing workstations. Each print station may be used to print a portion (e.g., housing, bottom half, top half) of a batch of drug dosage units. Furthermore, multiple print workstations may be operated in parallel, so that batches of pharmaceutical dosage units may be printed simultaneously. In some embodiments, a single FDM multi-station printing system can manufacture 3,000-5,000 drug units (e.g., tablets) per day. In some embodiments, the system minimizes inconsistencies between drug units in the same batch and different batches to ± 2.5% (e.g., in terms of weight, in terms of volume). In some embodiments, the multi-station printing system is easy to clean and maintain, thereby meeting the requirements of standardized production of pharmaceutical products.

The following description is presented to enable any person 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 of ordinary skill in the art, and the general principles defined herein may be applied to other examples 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 illustrated herein, but are to be accorded the scope consistent with the claims.

Although the following description uses the terms "first," "second," etc. to describe various elements, these elements should not be limited by these terms. These terms are only used 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. The first nozzle and the second nozzle are both nozzles, but they are not the same nozzle.

The terminology used in the description of the various described embodiments herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in the description of the various described embodiments and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It is also to 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 "comprises," "comprising," "includes" and/or "including," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

The term "if" is optionally to be construed to mean "when … …" or "at … …" or "in response to a determination" or "in response to a detection", depending on the context. Similarly, the phrase "if it is determined" or "if [ said condition or event ] is detected" is optionally to be construed as meaning "upon determining" or "in response to determining" or "upon detecting [ said condition or event ] or" in response to detecting [ said condition or event ] ", depending on the context.

Fig. 1A depicts a schematic diagram of an exemplary additive manufacturing system (e.g., 3D printing system) 100, according to some embodiments of the invention. The system 100 includes a feeder module 102 for delivering a set of printing materials to a diversion module 104. The diversion module 104 includes a diversion plate having a branching channel (not depicted) configured to divide a single stream of printing material (e.g., supplied by a supply module) into multiple streams. In some embodiments, the splitting module 104 may split a single stream into 2 streams, the 2 streams being split into 4 streams, the 4 streams being split into 8 streams, the 8 streams being split into 16 streams, the 16 streams being split into 32 streams. In some embodiments, the split module may split a single stream directly into 2 streams, 3 streams, 4 streams, 5 streams, or n streams. In some embodiments, the splitting module may split a single stream into 3 streams, the 3 streams being split into 9 streams, the 9 streams being split into 27 streams. Referring to fig. 1B, multiple streams may be respectively dispensed by an array of nozzles 106 of the system 100 to produce 3D printed drug dosage units (e.g., tablets, caplets, printed tablets) on a printing platform 110.

The feed module 102 is configured to pre-process a set of printing materials before delivering it to the diversion module 104. In some embodiments, the pre-processing includes melting and pressurizing the printing material based on predetermined settings (e.g., to a target temperature range, to a target pressure range). The pretreated material is then conveyed to the diverter module 104 through the feed channel 108. In some embodiments, a continuous stream of printing material is supplied to the diversion module 104 through a feed channel 108.

In some embodiments, the feed module 102 includes one or more heaters configured to melt the printing material. In some embodiments, the feed module includes one or more temperature sensors configured to detect the temperature of the molten printing material within the feed 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.

In some embodiments, one or more pressure sensors are connected to a computer system that operates the feed module to pressurize the marking material to a desired pressure in response to the pressure reported by the pressure sensors. In some embodiments, the pressure of printing is within about 0.05MPa of the desired pressure. In some embodiments, the feed module comprises a piston mechanism, a screw mechanism (single screw, twin screw, 3 screw, 4 screw, 5 screw, 8 screw), a screw pump mechanism, a gear pump mechanism, a plunger pump mechanism (e.g., a valveless metering pump mechanism), or any combination thereof. Additional details of the feed module and many other features of the printing system may be provided in PCT/CN2018/071965 entitled "PRECISION PHARMACEUTICAL 3D printing device" and WO2018210183 entitled "3D PRINTING DEVICE AND METHOD", the contents of which are incorporated herein in their entirety.

Fig. 1C depicts an example additive manufacturing system including a piston mechanism, according to some embodiments of the invention. In the depicted example, the piston 122 is driven in the z-direction by one or more motors 120. As the piston is driven downward, the piston pushes the printing material along the cartridge 124, feed channel 108, and diverter module 104 to change the pressure of the printing material within the system. Upon opening the distal outlet of the printing nozzle, the printing material can be dispensed in a precisely controlled manner. The amount of printing material dispensed may be controlled by controlling the position of the piston, the speed of the piston movement, the acceleration of the piston movement, or a combination thereof. In some embodiments, the motor 120 is a stepper motor, a servo motor, a hydraulic control, or a combination thereof.

In some embodiments, the diameter D of the cartridge is between 5-20 mm. In a preferred embodiment, D is about 10 mm. In some embodiments, the diameter d of the nozzle outlet is between 0.1-2 mm. In a preferred embodiment, d is about 0.4 mm. In some embodiments, a ratio parameter is calculated that represents the ratio between the cross-sectional area of the nozzle outlet and the cross-sectional area of the barrel. This ratio can also be expressed as the ratio between the D2 squared and D2. In some embodiments, the ratio is calculated as:

returning to fig. 1B, the diverter module 104 includes a diverter plate 114, a plurality of nozzles 106, a temperature control mechanism, a pressure sensor, a temperature sensor, or any combination thereof. As an example, fig. 2A depicts a cross-sectional view of an exemplary diverter plate. The diverter plate includes a single channel 210 connected to the feed channels of the feed modules for receiving a single stream of printing material. The diverter plate includes a plurality of branch channels configured to divide a single stream into a plurality of streams that are respectively distributed through a plurality of nozzles. Each nozzle is configured to dispense a flow of printing material in a controlled manner through a needle valve mechanism. As depicted, the nozzle 206a operates 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.

Fig. 2B depicts a top view of the diverter plate shown in fig. 2A according to some embodiments. As depicted, the branching channels within the diverter plate divide a single stream of printing material into two streams, then four streams, then eight streams. Eight streams of printing material are then dispensed through eight nozzles, respectively.

Fig. 2C depicts an exemplary configuration of channels within a diverter plate according to some embodiments. Each configuration may divide a single stream into multiple streams that are distributed in a uniform manner (e.g., in terms of weight) at multiple nozzles. Due to the arrangement of the channels and junctions within the splitter plate, each of the plurality of streams flows through a unique flow path, for example extending from a top feed opening for receiving a single stream from a feed channel into the splitter plate to a distal end of the nozzle. In some embodiments, the flow paths of the multiple streams are geometrically symmetric (e.g., of equal length, of the same geometry). In some embodiments, the flow paths of the multiple streams are not geometrically symmetric, but rather a uniform distribution is obtained by adjusting the flow path diameters along different portions of the flow path. In some embodiments, some or all of the joints lie in the same or substantially the same plane (e.g., the same X-Y plane). In some embodiments, some or all of the joints are located on different planes (e.g., different X-Y planes).

In some embodiments, the diverter plate may be split (e.g., horizontally, vertically, and/or diagonally) into multiple components. The multiple components may be secured together by screws. When detached, each individual component exposes the inner surface of one or more channels and joints in the manifold, thus allowing the channels and joints of the manifold to be more easily cleaned.

In some embodiments, in operation, the pressure within the channels of the diverter plate can be between 0-20MPa (e.g., 0-5MPa, 0-10MPa, 0-20 MPa). The time required for the material to flow through the diverter plate may be between 5 minutes and 5 hours. In some embodiments, the dispense volume at the nozzle can be between 0.1-10 μ L/s (e.g., 2-3 μ L/s).

Returning to fig. 1B, the diverter plate includes a temperature control mechanism for maintaining the temperature of the diverter 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 together to maintain the internal temperature of the diverter plate.

The one or more heaters may be disposed within the diverter plate or near the diverter plate 114. For example, the diverter plate includes internal slots for receiving one or more heaters (e.g., wires, plates) made of a high thermal conductivity material. One or more heating wires extend through internal slots in the diverter plate 114, for example, as shown in the bottom perspective view of the diverter plate in fig. 2D. The diverter plate may include multiple rows and columns of internal slots to allow for uniform distribution of the heating wire throughout the plate so that the temperature within the plate is maintained in a consistent manner.

The one or more coolers may be disposed within the diverter plate or near the diverter plate 114. In some embodiments, the temperature control device achieves cooling by water flow. As shown in fig. 1B, a pair of cooling plates are positioned above and below the diverter plate 114, each cooling plate having an internal passage for tap water, allowing water flow, air, coolant, etc. to appear in the vicinity of the diverter plate 114 to regulate the temperature of the plate. In some embodiments, the diverter plate includes an internal slot for receiving one or more coolers within the diverter plate. As shown in fig. 1A, the distributor plate 114 and the cooling plates above and below the distributor plate 114 are each provided with an inlet opening 105 for receiving a coolant.

In some embodiments, the manifold includes one or more temperature sensors connected to a computer system that operates the one or more heaters and coolers in response to temperatures reported by the one or more temperature sensors. Fig. 2D depicts a bottom perspective view of a diverter plate and shows an exemplary arrangement of temperature sensors, according to some embodiments.

In some embodiments, the diverter plate includes one or more pressure sensors 130 configured to detect the pressure of the printing material within the channels of the diverter plate. In some embodiments, the pressure sensor is positioned near the diverter plate (e.g., around a corner, around a periphery, around a center) or within a channel of the diverter plate. In some embodiments, a small-range strain gauge sensor is used.

FIG. 3 depicts an example needle valve mechanism 300 for dispensing printing material at a print nozzle 302, according to some embodiments. A feed channel 304 is formed along the interior of the nozzle 302 to deliver printing material to the distal outlet of the nozzle. The feed channel includes a tapered chamber (e.g., tapered) to serve as a dispensing outlet for the printing material. The sealing needle 306 extends through the feed channel and is driven by a motor system (not depicted) to move along the feed channel. When the needle valve mechanism is in the closed position, the needle extends such that it contacts the tapered distal end of the feed channel and seals the outlet or extrusion port, thereby preventing dispensing of the printing material. When the needle is retracted, the outlet is not sealed so that printing material can be dispensed. To regulate the temperature at the distal end of the print nozzle, a plurality of heating elements 308 and thermal insulation structures 310 may be placed around the distal end of the nozzle 302. The print nozzle 302 may also include one or more temperature sensors and/or pressure sensors 312.

In some embodiments, the tapered end of the sealing needle comprises a pointed 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; and wherein the second taper angle is equal to 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.

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

In some embodiments, a motion system for a needle valve mechanism comprises: one or more motors, one or more sensors, one or more drivers, and one or more controllers. The sensor may comprise an encoder. In some embodiments, the controller comprises a programmable logic controller ("PLC"). In some embodiments, the driver comprises a bus driver.

In some embodiments, the motion system that drives the needle is manually controlled or controlled by a computer controller for regulating the flow at the nozzle. The motion system may include a plurality of motors or actuators, each coupled to a corresponding needle. The motor may be a mechanical motor (which may include a screw), a hydraulic motor, a pneumatic motor (which may include a pneumatic valve), or an electromagnetic motor (which may include a solenoid valve). The motor driving the needle may be a linear motor, a shaft-fixed motor, a non-fixed motor, or a combination thereof.

In some embodiments, a non-stationary linear motor is used in conjunction with an anti-backlash nut and a ball spline. The ball spline typically operates with lower friction, so the motor can operate with higher precision (e.g., ± 0.003 mm). Further, in some embodiments, the motor is relatively small (e.g., 20-42mm), thus allowing the spacing between the nozzles to be between 20-50 mm. Alternatively, a screw linear motor is used.

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

In some embodiments, the system uses a stall detection method to find a zero position for the distal end of each needle. During the configuration phase for identifying the zero position of the needle, the system configures the corresponding motor to operate at a low power level (e.g., 400-. This is done so that the distal end of the needle does not deform when 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 the continued actuation of the motor. When the encoder no longer detects needle movement, the system determines that the needle is in a true null position. Upon determining that the needle is in the true null position, the system stops the motor, retracts the needle 0.003-0.01mm, and then sets the position of the needle to the configured null position. The use of the 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, thereby extending the life of the needle and nozzle. During normal operation, the motor is operated at a higher power level (e.g., 1600-.

In an alternative embodiment, the motion system may comprise a single plate connected to a plurality of needles such that the retraction of the needles and the dispensing flow of the nozzle are controlled in a uniform manner, as shown in fig. 4.

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- ± 0.02). In some embodiments, the plane is configured to have a flatness in the range of ± 0.005- ± 0.02 MM.

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

The distal end of the nozzle includes a heater and an insulating material to maintain the temperature of the distal end. In addition, the distal end of the nozzle includes one or more pressure sensors (see also pressure sensor 132 of fig. 1B) and temperature sensors configured to directly measure the temperature and pressure of the printing material within the nozzle. In some embodiments, the one or more pressure sensors comprise a small-range strain gauge sensor.

In some embodiments, the diameter of the channels within the diverter plate is between 1-16 mm. In some embodiments, the diameter of the feed passage in the nozzle is between 0.1 and 1.0 mm. In some embodiments, the diameter of the needle is between 0.1-6 mm. In some embodiments, the distal outlet of the nozzle has a diameter between 0.05-3.0 mm. In some embodiments, the spacing between each nozzle is between 8-50 mm. In a preferred embodiment, the spacing between the two nozzles is between 20-50mm and the diameter of the nozzle outlet is between 0.05-0.8 or 0.8-1.0 mm.

In some embodiments, a system comprises: a plurality of needle valve mechanisms; pushing the plate; a flow distribution plate; and a needle valve adjustment system. The needle valve adjustment system includes a first resilient member, a second resilient member, a push plate actuator, and a locking mechanism, as described below. The needle valve adjustment system allows for precise adjustment of the opening of each needle valve mechanism such that the needle valve mechanisms all operate uniformly (e.g., dispense printed material). The push plate allows all needle valve mechanisms to open/close simultaneously.

The proximal end of the needle may be coupled to the push plate such that vertical movement of the push plate may cause vertical movement of the needle. In some embodiments, multiple needles are coupled to the same pusher plate such that movement of the pusher plate can cause multiple needles to move simultaneously. Any motion system may be used to drive the push plate, such as a wedge mechanism, a cam mechanism, or the like. In some embodiments, a push plate is placed over the diverter plate.

In some embodiments, the hub of the needle at the proximal end of the needle is housed within the sleeve member. The sleeve member includes an upper top plate and a lower bottom plate. The lower plate includes an aperture that is large enough to allow the shaft portion to pass through, but small enough to retain the hub of the needle within the sleeve. The first resilient member may be disposed over the hub of the needle and sandwiched between the hub of the needle and the upper top plate of the sleeve member. In some embodiments, the first resilient member is a coil (e.g., a spring). Therefore, the first elastic member may push the needle holder of the needle downward such that the needle holder is in contact with the lower bottom plate of the sleeve.

In operation, when the push plate travels downward to close the needle valve, the first resilient member may retract such that the needle hub of the needle has room to move upward within the cannula, thereby creating a cushioning effect and reducing the force on the distal tip of the needle when the distal tip of the needle contacts the nozzle. When multiple needles are coupled to the push plate and each needle has a corresponding sleeve, the mechanism allows all the needles to close the corresponding nozzles in a uniform manner.

In some embodiments, the push plate includes a groove on an upper surface of the push plate. Further, at least a lower portion of the sleeve may be disposed within the groove. The upper portion of the sleeve may be coupled to a support structure by a locking mechanism, and the support structure is secured to the push plate. In some embodiments, the locking mechanism comprises a horizontal plate with a hole that allows the sleeve to pass through. The locking mechanism may be adjusted (e.g., the size of the aperture may be adjusted) so that the sleeve may be gripped through the aperture. Thus, the sleeve may be fixed to the push plate (i.e., by the locking mechanism and support) such that the sleeve does not move relative to the push plate during printing. In some embodiments, a second resilient member is placed in a groove below the sleeve, and the second resilient member can be retracted so that the sleeve has room to move in the groove below the sleeve. For example, the second resilient member may be a coil (e.g., a spring) sandwiched between the bottom of the groove and the bottom of the sleeve.

In an initialization phase, the vertical position of the sleeve can be adjusted manually or automatically to adjust the vertical position of the needle by deformation of the second elastic member. For example, the vertical position of the sleeve may be adjusted depending on the position at which the locking mechanism grips the sleeve. By adjusting the vertical position of the sleeve and thus the needle, the amount of opening at the nozzle can be adjusted accordingly. Adjustments may be made during the initialization phase to ensure that the needle may be controlled in a uniform manner (e.g., the same travel displacement) to dispense the same amount of printing material during printing.

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

Referring to fig. 4, the system includes a communicating flow path connecting two nozzles. The pressure at the two nozzles can be automatically balanced and controlled by a closed loop flow control system including sensors and motors. A switch is added to allow the printing material in the communicating flow path to be periodically dispensed to prevent the printing material from being held in the flow path for a long time and being decomposed in the flow path. In some embodiments, multiple sets of communicating flow passages may be provided to connect multiple nozzles. Further, both needles are coupled to a single plate such that movement of the plate 402 (e.g., by manual control, by a motor) moves the needles in a uniform manner.

Returning to fig. 1A, the printing platform 110 is disposed on a desktop drive mechanism. The table drive mechanism may drive the printing platform 110 relative to the movement of the nozzles 106. In some embodiments, the desktop drive mechanism may be a stepper motor, a linear motor, or a servo motor based on a cartesian coordinate system such that it may drive the printing platform 110 in one or more directions along the X-axis, Y-axis, and Z-axis. In other embodiments, printing device 100 further includes a module drive mechanism for driving movement of printing deck module 110 relative to nozzles 106. In other embodiments, the table drive mechanism may be a transfer rail. With the relative motion of the printing platform 110 and the nozzle 106, the printing material is deposited on the printing platform 110 in a complex structure and desired configuration. It should be understood that other coordinate systems and/or motions may be used.

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 printing material, while a second array of nozzles is configured to dispense a second type of printing material. Each resulting tablet may comprise a layer of a different material by switching between a plurality of arrays of nozzles. As discussed, each nozzle includes a needle valve mechanism coupled to a corresponding motor 112 and a computer controller for controlling the output of printed material such that the resulting drug dosage units are consistent in volume, weight, and/or composition in the same batch and in multiple batches.

Fig. 1D depicts an exemplary system for printing drug dosage units using multiple arrays of nozzles, according to some embodiments. In the depicted example, the drug dosage unit to be printed comprises four parts: inner part 1, inner part 2, inner part 3 and housing. The printing process is divided into four stages. In the first stage, the first array of nozzles is configured to dispense material 1 based on a first set of instructions to print a batch of interior portion 1 units. In some embodiments, the instruction set is executed as an API. In the second stage, the second array of nozzles is configured to dispense material 2 based on API 2 to print a batch of internal part 2 units. In a third phase, a third array of nozzles is configured to dispense material 3 based on API 3 to print a batch of internal portion 3 units. In the first, second and third stages, portions of all batches are printed on the same printing platform. Furthermore, each inner part 1 unit has corresponding inner part 2 and inner part 3 units, and the three units are produced on a printing platform such that their relative positions coincide with the desired positions within the drug dosage unit.

In a fourth stage, a fourth array of nozzles is configured to dispense material 4 based on API 4 to print a batch of shells. Each housing is created to cover the inner part 1 unit and the corresponding inner part 2 unit and inner part 3 unit to form the final drug unit.

The printing material includes a viscous material. In some embodiments, it is a pharmaceutical 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 between 0.001 and 10000Pa · s.

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

The system described herein can be used to accurately and precisely dispense viscous materials. In some embodiments, the viscosity of the material as dispensed from the apparatus is about 100 Pa-s or greater, such as about 200 Pa-s or greater, about 300 Pa-s or greater, about 400 Pa-s or greater, about 500 Pa-s or greater, about 750 Pa-s or greater, or about 1000 Pa-s or greater. In some embodiments, the viscosity of the material is about 2000Pa · s or less, such as about 1000Pa · s or less, about 750Pa · s or less, about 500Pa · s or less, about 400Pa · s or less, about 300Pa · s or less, or about 200Pa · s or less.

In some embodiments, the material is a pharmaceutically acceptable material. In some embodiments, the material is inert or biologically inert. In some embodiments, the material is an erodible material or a bioerodible material. In some embodiments, the material is a non-erodible material or a non-bioerodible material. In some embodiments, the material is a pharmaceutically 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.

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 includes an erodible thermoplastic material. In some embodiments, the thermoplastic material is edible (i.e., suitable for human consumption). 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 soluble polymers), pH sensitive polymers, natural polymers, waxy materials, and combinations thereof. In some embodiments, the thermoplastic material is a cellulose ether, cellulose ester, acrylic resin, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, mono-or diglycerides of C12-C30 fatty acids, C12-C30 fatty 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, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol graft copolymer (PVAc), 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-methacrylate), poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, poly (methacrylic acid-co-methyl methacrylate) 1:2, poly (methacrylic acid-co-ethyl acrylate) 1:1, poly (vinyl acetate-co-methyl methacrylate) 1:1, poly (methacrylic acid-co-ethyl acrylate) 1:1, poly (vinyl acetate-co-ethyl, Poly (methacrylic acid-co-methyl methacrylate) 1:1, poly (ethylene oxide) (PEO), poly (ethylene glycol) (PEG), hyperbranched polyesteramides, hydroxypropyl methylcellulose phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or Hypromellose (HMPC), hydroxypropyl methylcellulose succinate or hypromellose succinate (HPMCAS), poly (lactide-co-glycolide) (PLGA), carbomers, poly (ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymers, Polyethylene (PE) and Polycaprolactone (PCL), hydroxypropyl cellulose (HPC), polyethylene glycol 40 hydrogenated castor oil, Methyl Cellulose (MC), Ethyl Cellulose (EC), poloxamers, hydroxypropyl methylcellulose phthalate (HPMCP), Poloxamers, hydrogenated castor oil, hydrogenated soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose Acetate Butyrate (CAB), polyvinyl acetate phthalate (PVAP), waxes, beeswax, hydrogels, gelatin, hydrogenated vegetable oils, polyvinyl acetal diethylamino lactic acid (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.

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), silica gel powder, titanium dioxide, glycerol, 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, polymethacrylate, non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, or a combination thereof.

Exemplary materials that may be used with the apparatus described herein or the methods described herein include, but are not limited to, poly (meth) acrylate copolymers (such as copolymers comprising one or more of amino alkyl methacrylates, methacrylic acids, methacrylates, and/or ammonio alkyl methacrylates, such as under the trademark Polymethylacrylate (R))Sold as RSPO) and hydroxypropyl cellulose (HPC). In some embodiments, the material comprises a drug. In some embodiments, the material is mixed with a drug.

Fig. 6A depicts an exemplary process 600 for 3D printing of a drug dosage unit 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, the order of some blocks is optionally changed, and some blocks are optionally omitted. In some examples, additional steps may be performed in connection with process 600. Thus, the illustrated (and described in more detail below) operations are exemplary in nature, and thus should not be considered limiting.

In some embodiments, the printing system includes one or more computer controllers. The computer controller may be programmed based on a plurality of manufacturing parameters. The plurality of manufacturing parameters includes a print speed, target temperature values associated with different portions of the printing system (e.g., diverter plate, distal ends of nozzles, feed module, pump), and a pressure profile. In some embodiments, some manufacturing parameters are specified by a user, while other manufacturing parameters are automatically calculated by a computer. The manufacturing parameters may be determined based on desired metrics (e.g., volume, weight, composition, size) of the pharmaceutical dosage unit, the printed material, and/or settings of the printing system. In some embodiments, the programming logic/code is generated based on a plurality of manufacturing parameters.

At block 602, the printing system performs an initialization step. The initializing step may include: start the system, load the necessary data (e.g., 3D model) and program logic, initialize parameters, or a combination thereof. The initialization step may also include a heating process to achieve a desired temperature (e.g., increase the temperature of the heating wire) on various components of the printing system. In some embodiments, the heating process is controlled by a proportional-integral-derivative controller ("PID controller"). In particular, 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. Upon determining that one or more target temperatures are not achieved, the PID controller continues the heating process. Upon determining that one or more target temperatures are achieved, the PID controller provides an output. In some embodiments, the output is a visual, audible, or tactile output to alert the worker to add printed material. In some embodiments, the output is an output signal that triggers printing material to be automatically added to the printing system.

At block 604, the system receives and processes a set of printed materials. The printing material may include an active ingredient and/or an excipient of a predetermined composition. The marking material may include pharmaceutical materials, thermoplastic materials, and combinations thereof. At the feeding module, the printing material is mixed, plasticized and melted. At block 606, the processed printing material is delivered to the diversion module as a single stream, such as by a single progressive cavity pump (e.g., a gear pump or a screw valve).

At block 608, the split module splits the single stream of processed printing material into multiple streams. In particular, the diverter plate includes a plurality of channels, such as those described with reference to fig. 2A-C. Through the channel, the plurality of streams reach the distal ends of the plurality of nozzles. When the printing system is started up, the needle valve mechanism of the nozzle is in a closed position, thereby preventing the multiple streams from being dispensed. In some embodiments, the needle valve mechanism of the nozzle is not opened until a desired temperature is reached at the nozzle.

At block 610, the system performs an adjustment step. Fig. 5B depicts an exemplary process 550 for adjusting a 3D printing system, according to some embodiments.

At block 652, the system begins dispensing multiple streams at multiple nozzles to produce a first batch of test drug dosage units (e.g., tablets, caplets, printed tablets). In particular, as each stream of printing material accumulates at the sealed distal end of the corresponding nozzle, the pressure sensor (e.g., at the distal end of the nozzle, at the diverter plate) begins to receive a higher pressure reading. When the pressure reading exceeds a predetermined threshold, the needle valve mechanism may be opened to begin dispensing multiple flows. The system maintains the pressure of the printing material at the nozzles prior to opening the needle valve mechanism. The opening of the needle valve mechanism may be triggered at any time by one or more controls.

Upon opening the needle valve mechanism, the system begins to dispense multiple streams to 3D print a first plurality of test drug dosage units (e.g., tablets, caplets, print tablets). The flow rate for 3D printing a single batch unit is controlled by a closed loop control system based on a predetermined pressure profile. FIG. 5 illustrates an exemplary pressure profile, where each cycle represents the process of opening, printing, and closing of the needle valve mechanism.

At block 654-. At block 554, the system determines whether the sum of the weights of the test batch differs from the target total weight by a predetermined amount (e.g.,

+/-0.5％、+/-1％、+/-2％、+/-3％、+/-4％、+/-5％)。

at block 656, based on a determination that the error is greater than the predetermined amount, the system adjusts to reduce the error. In some embodiments, block 556 includes adjusting one or more nozzles (block 558) and adjusting the feed module (block 560).

At block 658, the system adjusts one or more nozzles, and in particular the openings at one or more nozzles, based on the average weight of a batch of test cells. The objective is to reduce the difference between the nozzle outputs. For each nozzle, the adjustment amount is determined based on the following formula.

H_next＝H_C-α*(W_A-W_C) (1)

In the above formula, H_nextRepresents the opening amount (in millimeters) of the needle valve mechanism of each nozzle in the next iteration; hc represents the amount of opening of the needle valve mechanism (in millimeters) for each nozzle in the current iteration; w_ARepresents the average weight (in milligrams) of the test batch in the current iteration; w_CRepresents the weight (in milligrams) of the test cell produced by each nozzle in the current iteration; alpha represents the opening coefficient, which can be different for different needle valve machinesThe structure varies (in mm/mg). In some embodiments, a machine learning algorithm may be used to determine the opening amount at each nozzle. The opening amount of the needle valve is guided in relation to the travel displacement of the needle — the opening amount increases as the needle travels upward; as the needle travels downward, the amount of opening decreases. The terms "opening amount" and "travel displacement" are used interchangeably herein.

At block 660, the system adjusts the feed module, for example, by adjusting pressure and temperature (e.g., based on pressure readings at the nozzles, based on pressure readings at the manifold), adjusting feed speed/amount, or any combination thereof. For example, if the total weight of the test batch exceeds the target batch weight, the system may reduce the pressure, reduce the temperature, reduce the feed rate/amount, or any combination thereof.

At block 662, after making the adjustment, the system opens the needle valve mechanism to 3D print another batch of multiple test cells. At block 554, the system determines whether the weight sum of the new test batch differs from the target total weight by a predetermined amount (e.g., +/-0.5%, +/-1%, +/-2%, +/-3%, +/-4%, +/-5%). If not, the system repeats the steps in 556 to continue adjusting the feed modules and nozzles.

At block 664, 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 predetermined amount, the system adjusts one or more nozzles based on the target weight of the drug unit. In other words, after reaching the target batch weight while improving consistency between nozzle outputs, the system then adjusts the nozzles to ensure that each nozzle can reach the target weight (e.g., the target weight for a particular tablet).

In particular, the system adjusts the one or more nozzles, in particular the openings at the one or more nozzles, based on the target weight of the drug unit. For each nozzle, the adjustment amount is determined based on the following formula.

H_next＝H_C-α*(W_T-W_C) (2)

In the above formula, H_nextRepresenting needle valve mechanisms of individual nozzles in the next iterationOpening amount (in millimeters); hc represents the amount of opening of the needle valve mechanism (in millimeters) for each nozzle in the current iteration; w_TRepresents the target weight of the unit (in milligrams); w_CRepresents the weight (in milligrams) of the test cell produced by each nozzle in the current iteration; alpha represents the opening coefficient, which may vary (in mm/mg) from needle valve mechanism to needle valve mechanism. In some embodiments, a machine learning algorithm may be used to determine the opening amount at each nozzle.

The main difference between equations (1) and (2) is W_TAnd W_AThe difference between them. In some embodiments, the batch weight is first adjusted, for example by adjusting the pressure and temperature within the system. When the batch weight is within the desired range, the unit weight is adjusted, for example, by adjusting the opening and closing of a needle valve.

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 predetermined amount (e.g., +/-0.5%, +/-1%, +/-2%, +/-3%, +/-4%, +/-5%). In some embodiments, the predetermined amount is +/-1.5%. If not, the initialization is complete. If so, the system continues with the adjustment step by repeating some or all of steps 654-664.

The above adjustment steps are exemplary. Parameters other than the weight of the drug units, such as the weight, volume, size and/or composition of the output deposit (e.g., extruded strand) may be used in the adjustment step to achieve nozzle-to-nozzle and batch-to-batch consistency among these parameters.

The adjusting step may be used in conjunction with a closed loop control system. In some embodiments, the system includes a temperature closed loop control system that adjusts the heaters and temperature control devices based on temperature readings (e.g., from temperature sensors in the feed module, the splitter plate, or the nozzles) to achieve and maintain a target temperature. In some embodiments, an average of the temperature readings from the plurality of temperature sensors is used. For example, a temperature sensor may transmit a measured temperature to a computer system, and the computer system may operate the one or more heaters to ensure a substantially constant temperature. A temperature sensor in the nozzle may work in a closed loop feedback system with the one or more heaters in the nozzle to ensure a substantially constant material temperature within the nozzle.

The temperature sensors described herein may include thermocouple sensors (e.g., type J, type K) or resistance thermometers. In some embodiments, the temperature sensor is configured to measure a temperature below 200 ℃. The pressure sensors described herein include piezoresistive transducers or strain gauge sensors. In some embodiments, a small-range strain gauge sensor is used. Depending on the location of the temperature or pressure sensors (e.g., within or near the feed module, diverter plate, or nozzle), different types of sensors may be used.

In some embodiments, the one or more heaters in the system heat the material within 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 ℃ or greater, such as about 70 ℃ or greater, 80 ℃ or greater, 100 ℃ or greater, 120 ℃ or greater, 150 ℃ or greater, 200 ℃ or greater, or 250 ℃ or greater. In some embodiments, the one or more heaters heat the material to a temperature of about 300 ℃ or less, such as about 260 ℃ or less, 200 ℃ or less, 150 ℃ or less, 100 ℃ or less, or 80 ℃ or less. In some embodiments, the one or more heaters heat the material to different temperatures at different locations of the apparatus. For example, in some embodiments, the material is heated to a first temperature within the barrel, a second temperature within the feed channel, and a third temperature within the nozzle, each of which may be the same temperature or a different temperature. In some embodiments, the temperature of the material at the nozzle is higher than the temperature of the feed channels and the channels in the diverter plate, e.g., 0-10 ℃ or 0-20 ℃. For example, the material may be heated to 140 ℃ in the barrel and feed channel, but to 160 ℃ in the nozzle. The feedback control system allows a high accuracy of the temperature to be achieved. In some embodiments, the temperature is controlled to be within 0.1 ℃ of the target temperature, within 0.2 ℃ of the target temperature, within 0.5 ℃ of the target temperature, within 1 ℃ of the target temperature, or within 10 ℃ of the target temperature.

In some embodiments, the system includes a pressure closed loop control system that adjusts the feed module (e.g., the rotational speed of the screw mechanism) based on pressure readings (e.g., from a pressure sensor in the diverter plate or nozzle) to achieve and maintain a target pressure. In some embodiments, an average of pressure readings from a plurality of pressure sensors is used.

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

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 on the drug dosage units, for example, by measuring batch weights or unit weights and determining whether they are within a desired range. If the batch weight or unit weight is not within the desired range, the system may perform some or all of steps 654-664 to make adjustments and/or use any of the closed loop control systems described above.

In some embodiments, the system includes a nozzle for printing multiple arrays of multi-layer drug units. Each of the nozzle arrays may be adjusted according to the above steps. The system may include a controller to coordinate the operation of the plurality of arrays to 3D print a batch of drug dosage units.

The various controllers used in the printing system may include Programmable Logic Controllers (PLCs) including, for example, proportional-integral-derivative (PID) controllers, switch-mode controllers, predictive controllers, fuzzy control systems, expert system controllers, or any other suitable controllers. Further, a bus structure may be used in some embodiments. The feedback system may use proportional integral derivative control, on-off control, predictive control, fuzzy control systems, expert control, or any other suitable control logic.

The operations described above with reference to fig. 5A-B may optionally be implemented by the components depicted in fig. 6. It will be clear to one of ordinary skill in the art how to implement other processes based on the components depicted in fig. 6.

An exemplary system for manufacturing a pharmaceutical product by additive manufacturing, the system comprising: a feeding module for receiving a set of printing materials; a diverter module comprising a diverter plate, wherein the feeder module is configured to deliver a single stream corresponding to the set of printing materials to the diverter plate; wherein the diverter plate comprises a plurality of channels for dividing the single stream into a plurality of streams; 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.

In some embodiments, the system further comprises a printing platform configured to receive the dispensed plurality of streams, wherein the printing platform is configured to move to form a batch of the pharmaceutical product.

In some embodiments, the feed module is configured to heat the received set of printing materials.

In some embodiments, the feed module is configured to plasticize the received set of printing material.

In some embodiments, the feed module comprises a piston mechanism, a screw pump mechanism, a gear pump mechanism, a plunger pump mechanism, or any combination thereof.

In some embodiments, the plurality of channels form a first junction configured to split the single flow into two flows.

In some embodiments, wherein the plurality of channels form a second junction and a third junction, the second junction and the third junction configured to split the two streams into 4 streams.

In some embodiments, the first engagement portion is positioned higher than the second engagement portion and the third engagement portion.

In some embodiments, the first joint, the second joint, and the third joint are located on the same plane.

In some embodiments, the diverter plate is detachable into multiple components, wherein the multiple components are configured to be fixedly held together by one or more screws.

In some embodiments, one of the plurality of nozzles includes a heating component.

In some embodiments, the plurality of nozzles comprises a plurality of needle valve mechanisms.

In some embodiments, a needle valve mechanism of the plurality of needle valve mechanisms comprises: a feed channel extending through the respective nozzle, wherein the feed channel tapers at a distal end of the nozzle; and a needle, wherein a distal end of the needle is configured to contact and seal the feed channel when the needle valve mechanism is in a closed position, and wherein the distal end of the needle is configured to retract to allow a flow of printing material to be dispensed.

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

In some embodiments, the one or more motors comprise linear motors.

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

In some embodiments, a parameter of the plurality of nozzle-specific parameters includes an opening amount of the respective nozzle.

In some embodiments, the one or more controllers are configured to adjust the opening amount of the respective nozzle based on a weight of a unit in the batch corresponding to the respective nozzle.

In some embodiments, the one or more controllers are configured to adjust the opening amounts of the respective nozzles based on one or more machine learning algorithms.

In some embodiments, the one or more controllers are configured to control a temperature or pressure at the plurality of nozzles.

In some embodiments, the temperature is controlled by a heating element and a temperature control device.

In some embodiments, the temperature at the plurality of nozzles is higher than the temperature at the feed module.

In some embodiments, the temperature at the plurality of nozzles is higher than the temperature at the diverter plate.

In some embodiments, the one or more controllers are configured to control a feed speed of the set of printing materials.

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

In some embodiments, the pharmaceutical unit is a tablet.

A computer-implemented exemplary method of manufacturing a pharmaceutical product by additive manufacturing, the method comprising: receiving a plurality of unit measurements corresponding to a plurality of drug dosage units, wherein the plurality of drug dosage units are generated using a plurality of nozzles of an additive manufacturing system; determining whether a difference between a sum of the plurality of unit measurements and a target lot measurement exceeds a predetermined 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 of whether a difference between the sum and the target lot measurement exceeds the predetermined threshold; in accordance with a determination that the sum and the target batch measurement differ by no more than the predetermined threshold, adjusting one or more nozzles of the plurality of nozzles based on a target unit measurement.

In some embodiments, the plurality of drug units is a plurality of tablets.

In some embodiments, the unit measurement is a weight measurement of the plurality of drug dosage units.

In some embodiments, the unit measurement is a volume measurement of the plurality of drug dosage units.

In some embodiments, the unit measure is a compositional measure of the plurality of drug dosage units.

In some embodiments, the method further comprises: adjusting one or more operating parameters of the additive manufacturing system based on a determination that a difference between the sum and the target lot measurement exceeds the predetermined threshold.

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

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

In some embodiments, the one or more operating parameters include a speed at which the printing material is fed.

In some embodiments, the predetermined threshold is between +/-0.5% to +/-5%.

In some embodiments, the method further comprises: printing a new batch after adjusting one or more of the plurality of nozzles based on the target cell measurements; determining whether a difference between the weight of the cells in the new lot and the target cell measurement is greater than a second predetermined threshold.

In some embodiments, the second predetermined threshold is less than 5%.

An exemplary method of manufacturing a pharmaceutical product by additive manufacturing, the method comprising: receiving a set of printing materials using a feeding module; delivering a single stream corresponding to the set of printing materials to a manifold using the feed module, wherein the manifold includes a plurality of channels; dividing the single flow into a plurality of flows through the plurality of channels of the diverter plate; causing a plurality of nozzles to dispense the plurality of streams based on a plurality of nozzle-specific parameters.

An exemplary non-transitory computer readable storage medium storing one or more programs, the one or more programs comprising instructions, which when executed by one or more processors of an electronic device with a display, cause the electronic device to: receiving a plurality of weight measurements corresponding to a plurality of drug dosage units, wherein the plurality of drug dosage units were generated using a plurality of nozzles of a 3D printing system; determining whether a difference between a sum of the plurality of weight measurements and a target batch weight is greater than a predetermined threshold; in accordance with a determination that the difference between the sum and the target batch weight is greater than the predetermined threshold, adjusting one or more nozzles of the plurality of nozzles based on an average weight measurement of the plurality of weight measurements; adjusting one or more nozzles of the plurality of nozzles based on a target weight measurement in accordance with a determination that the difference between the sum and the target batch weight does not exceed the predetermined threshold.

FIG. 7 illustrates an example of a computing device, according to one embodiment. The device 700 may be a host connected to a network. The device 700 may be a client computer or a server. As shown in fig. 7, device 700 may be any suitable type of microprocessor-based device, such as a personal computer, workstation, embedded system, PLC, FPGA, server, or handheld computing device (portable electronic device), such as a cell 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 memory 740, and a communication device 760. The input device 720 and the output device 730 may generally correspond to the devices described above, and may be connectable or integrated with a computer.

The input device 720 may be any suitable device that provides input, such as a touch screen, keyboard or keys, mouse, or voice recognition device. Output device 730 may be any suitable device that provides output, such as a touch screen, a haptic device, or a speaker.

The memory 740 may be any suitable device that provides storage, such as an electrical, magnetic, or optical memory including RAM, cache, a hard drive, or a removable storage diskette. The communication device 760 may include any suitable device capable of transmitting and receiving signals over a network, such as a network interface chip or device. The components of the computer may be connected in any suitable manner, such as by a physical bus or wirelessly.

Software 750, which may be stored in memory 740 and executed by processor 710, may include, for example, programs embodying the functionality of the present invention (e.g., as embodied in the devices described above).

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

Software 750 may also be propagated within any transport medium for use by or in connection with an instruction execution system, apparatus, or device, such as those described above, that can fetch the instructions associated with the software from the instruction execution system, apparatus, or device and execute the instructions. In the context of the present invention, a transmission medium may be any medium that can communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. Readable transmission media can include, but are not limited to, an electronic, magnetic, optical, electromagnetic, or infrared wired or wireless propagation medium.

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 protected by any suitable security protocol. The network can include network links in any suitable arrangement that can enable transmission and reception of network signals, such as wireless network connections, T1 or T3 lines, cable networks, DSL or telephone lines.

Device 700 may implement any operating system suitable for running on a network. Software 750 may be written in any suitable programming language, such as C, C + +, Java, or Python. In various embodiments, application software embodying the functionality of the present invention may be in different configurations, such as in a client/server arrangement or through a Web browser as a Web-based application or Web service.

Fig. 8A depicts an exemplary layout of a standardized multi-station printing system for drug units, according to some embodiments. Referring to fig. 8, a multi-station printing system 800 includes a plurality of printing stations 802A, 802B, 802C, and 802D. The plurality of printing stations are arranged in a linear manner. In the top view depicted in fig. 8A, each of the workstations 802A-802D includes a set of nozzles (32 nozzles) configured to dispense multiple streams of printing material on a print plate to print a batch of drug dosage units (e.g., a batch of tablets).

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

With further reference to fig. 8, the multi-station printing system 800 includes a plate transport mechanism 806. As depicted, the plate transport mechanism 806 is configured to travel along the rails 804A and 804B. The plate transport mechanism 806 is configured to: operate in conjunction with the print stations to move the print plate from one print station (e.g., 802A) to one of the two ends of the plate transport mechanism (as indicated by arrows 808A and 808B), transport the print plate along either track (as indicated by arrows 810A and 810B), and move the print plate to the other print station. In some embodiments, the operation of the printing station and the plate transport mechanism are coordinated to maximize the manufacturing rate and minimize the idle time of the printing station.

The multiple workstations in the system 806 may be arranged in other configurations. In some embodiments, the plurality of workstations may be arranged around a circle or a square.

In some embodiments, the plate transport mechanism may include one or more circular or square channels such that the plate transport mechanism can transport a print plate from one print station to another. In some embodiments, the plate transport mechanism includes one or more grippers and/or robotic arms for picking up a print plate from one print station and moving the print plate to another print station.

Fig. 8B depicts a partial side view of an exemplary multi-station printing system 800, according to some embodiments. The multi-station printing system 800 includes a plurality of print stations, including print stations 802A and 802B. The print station 802A includes a print platform 806A and a set of nozzles (e.g., an array of nozzles) disposed on the print platform. During operation, the set of nozzles may simultaneously dispense a set of streams of printing material onto a print plate placed on the print platform 806A to form a batch of drug dosage units. Print station 802B includes a different set of one or more nozzles and operates in a similar manner as print station 802B. In some embodiments, the print stations 802A and 802B work in concert to manufacture the same batch of pharmaceutical dosage units. For example, at t0, print workstation 802A prints a batch of drug dosage unit enclosures on a plate that is placed on print platform 806A. The plate is then transported to the print station 802B (e.g., by a plate transport mechanism) and placed on the print platform 806B. At t1, print station 802B prints the core portion within the batch of shells.

In some embodiments, the relative positioning between the print platform and the nozzles (e.g., in the x-axis direction, in the y-axis direction, in the z-axis direction) differs between print stations. This causes the relative positioning between the drug dosage unit and the nozzle to vary from print station to print station. For example, the nozzles of print station 802A and print platform 806A may be centrally aligned, while the nozzles of print station 802B and print platform 806B may be non-centrally aligned. In this scenario, when the plate is transported from print station 802A to print station 802B, the batch of shells is not perfectly aligned with the nozzles of print station 802A, and the system needs to account for misalignment in the print instructions in order to move the print platform accordingly to print the core portion within the batch of shells.

Therefore, in order to achieve high precision printing of the same batch of pharmaceutical dosage product on multiple printing stations, the system needs to acquire the relative positioning between the printing platform and the nozzle for each printing station. Based on what the relative positions between the print stations differ, the system can adjust the print instructions for a given print station to move the print platform/print plate accordingly so that the set of nozzles can dispense the printing material at the appropriate location on the print plate.

Fig. 9 depicts 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, the order of some blocks is optionally changed, and some blocks are optionally omitted. In some examples, additional steps may be performed in connection with process 900. Thus, the illustrated (and described in more detail below) operations are exemplary in nature, and thus should not be considered limiting.

The plate is placed on a print platform (e.g., print platform 806A) of the first print workstation. In some embodiments, the plate is attached to the printing platform 806A by 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) with adjustable strength may be used to ensure that the plate is securely attached to the printing platform.

At block 902, after the plate is attached to a first printing platform (e.g., 806A), the system obtains a relative positioning between the nozzles of the first printing platform (e.g., 806A) and a first printing workstation (e.g., 802A). In some embodiments, the relative positioning comprises a first value representing the relative positioning on the x-axis and a second value representing the relative positioning on the y-axis value.

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 print station 802A includes a sensor module 810A and a sensor module 812A that are fixed to the frame of the print station 802A and thus remain stationary with respect to the nozzles at all times. During initialization, the system may move printing platform 806A in the x-axis until the printing platform is in contact with sensor 810A (e.g., based on the output of sensor 810A). Based on the determination that printing platform 806A is in contact with sensor 810A, the system obtains the amount of movement of printing platform 806A in the X-axis from its initial position (X1).

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

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

Referring to fig. 8B, the print station 802B includes a sensor module 810B and a sensor module 812B that are fixed to the frame of the print station 802B and thus remain stationary with respect to the nozzles at all times. During initialization, the system may move printing platform 806B in the x-axis until the platform (or a plate on the platform) comes into contact with sensor 810B (based on the output of sensor 810A). Based on the determination that print platform 806A is in contact with sensor 810B, the system obtains the amount of displacement of the print platform's movement in the X-axis from the initial position of print platform 806A (X2).

The system may also drive the print platform 806B to move in the y-axis until the platform (or a plate on the platform) comes into contact with the sensor 812B (e.g., based on the output of the sensor 812B). Based on the determination that print platform 806A is in contact with sensor 812B, the system obtains the amount of displacement of the print platform's movement in the x-axis from the initial position of print platform 806B (Y2).

In some embodiments, instead of moving the print platform and determining whether the print platform is in contact with the sensors to determine the values of X1, X2, Y1, and Y2, the system uses one or more retractable sensors to determine the values (e.g., retract a portion of the sensors to measure distances X1, X2, Y1, or Y2). In some embodiments, the system uses one or more laser sensors to determine the above values.

At block 906, the system calculates an offset value based on the relative positioning in the first printing deck (between the printing deck and the nozzles) and the relative positioning in the second printing deck. In some embodiments, the offset values include an X-axis offset value Δ X and a Y-axis offset value Δ Y. In some embodiments, Δ X is calculated as the difference between X1 and X2 (e.g., Δ X ═ X1-X2). In some embodiments, Δ Y is calculated as the difference between Y1 and Y2 (e.g., Y1-Y2).

At block 908, the offset value is input into one or more controllers. The controller is for generating movement of a print platform of the print workstation. The offset value is used so that the position of the printing platform (and the batch of drug dosage units) relative to the nozzles can be accurately determined as the plate is transported between the workstations.

Block 902-. 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 print platform and/or print plate is in contact with the nozzle, which is also the position where first layer printing occurs.

The identification of the zero point may be performed in a variety of ways. In some embodiments, the zero point is measured using a plug gauge. In some embodiments, the zero point is determined by: the print deck is raised in small increments (e.g., using a lower current, such as 20% -50% of the current level during normal operation, and at a lower speed, such as 20% -50% of the speed during normal operation) until the print deck is in contact with the nozzles and can no longer be raised any further. Upon determining that the printing platform is in contact with the nozzle (e.g., a resistance above a predetermined threshold is detected), the system stops lifting the printing platform and sets the position of the printing platform to a zero point. In some embodiments, the sensor is fixed to the print plate with the retractable portion of the sensor protruding out of the print deck in the z-axis. The block is placed on the print plate over the sensor such that the tabs of the sensor are retracted. The retracted position of the sensor is recorded. During future initialization, the printing platform is raised so that the nozzle comes into contact with and causes the protrusion of the sensor to retract. When the previously recorded retracted position is detected, the system will set the position of the printing platform to zero on the z-axis.

Thus, the initialization process is complete and the printing system is ready to begin printing. For example, the system may drive the first printing station to print a portion of a batch of tablets (e.g., the bottom of a tablet) on a print plate, transport the print plate to the second printing station, and cause the second printing station to print another portion of the batch of tablets (e.g., the top of a tablet) based at least in part on the offset value input at block 908. For example, the system moves the second printing platform based on the offset value such that the top of the tablet is aligned with the bottom of the tablet.

In some embodiments, using the techniques described herein, the derivative between nozzles at each print station may be in the range of 0.01mm (e.g., 0.02-0.05mm) on the x-axis, 0.01mm (e.g., 0.02-0.05mm) on the y-axis, and 0.005mm (e.g., 0.01-0.05mm) on the z-axis. This ensures that when a batch of drug dosage units is transported and printed between the plurality of printing stations, the nozzles at each printing station can be accurately aligned with the batch of drug dosage units.

In some embodiments, multiple printing plates may be used in a multi-station printing system. In some embodiments, each print plate is placed on all of the print stations to obtain a plurality of X values (e.g., n X values corresponding to n print stations), a plurality of Y values (e.g., n Y values corresponding to n print stations), and/or a plurality of Z values (e.g., n Z values corresponding to n print stations) associated with the plate. In this way, an offset value between any two print stations of the plate may be obtained, such that when the plate is moved from a first print station to a second print station, the offset value may be used to determine the position of the plate (and the batch of drug dosage units) relative to the nozzles of the second print station. Thus, the nozzles of the second printing station may be moved accordingly to continue printing the batch of drug dosage units on the plate.

Fig. 10A depicts an exemplary architecture of a multi-station 3D printing system according to some embodiments. The 3D printing system 1000 includes a number of hardware and software components, all of which may 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. Referring to FIG. 10A, the system 1000 includes a plurality of controllers 1002A-1002N configured to control the movement of N print workstations, respectively. Each controller may be coupled to a set of actuators and motors for moving the respective printing platform of the respective printing station along the x-axis, y-axis, and z-axis. In some embodiments, a single controller may be used to control the movement of multiple printing platforms of multiple printing workstations.

The system 1000 also includes a controller 1004 configured to control the motion of the plate transport mechanism (e.g., 806 depicted in fig. 8A). The controller 1004 may be coupled to a set of actuators and motors for moving the print plate (e.g., by a gripper along a conveyor belt or path).

The system 1000 also includes one or more controllers 1006 configured to control the feeding of the printing material by a feeding module (e.g., 102 depicted in fig. 1A). The system also includes one or more controllers 1008 configured to control needle valves at the print nozzles. For example, the one or more controllers 1008 can be coupled to actuators and motors that drive movement of the needles. The system also includes a temperature controller 1010 configured to control the temperature of various portions of the system (e.g., the manifold).

The system 1000 also includes a plurality of software modules 1012. In some embodiments, the plurality of software modules comprises: 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 speed control module, or any combination thereof.

In some embodiments, system 1000 is communicatively coupled to one or more networks such that the system may rely on the cloud for data storage, data management, and data analysis. In some embodiments, system 1000 is communicatively coupled to one or more mobile devices so 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 and to input and modify printing parameters (e.g., temperature, pressure, speed, needle position and motion). In some embodiments, the system provides real-time monitoring of various parameters of the printing process on all print workstations and all print plates.

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

Fig. 10B-C depict an exemplary process for 3D printing of drug dosage units using a multi-station printing system, according to some embodiments. Processes 1030 and 1060 may be part of software module 1012 depicted in fig. 10A. In each process, some blocks may optionally be combined, some blocks may optionally be changed in order, and some blocks may optionally be omitted. In some examples, additional steps may be performed in conjunction with each process. Thus, the illustrated (and described in more detail below) operations are exemplary in nature, and thus should not be considered limiting.

Process 1030 may be performed at a print station of a multi-station printing system. At block 1032, the system mounts the print plate to a print platform of a print workstation. Optionally, at block 1034, the system moves the print deck to a receiving position (e.g., by lowering the print deck along the z-axis) such that the print plate can be moved from the plate transport onto the print deck (e.g., along the y-axis direction by the plate transport).

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, if proper alignment between a component of the plate and a component of the platform (e.g., a pin) is detected, the system determines that the plate is placed on the platform.

At block 1038, the system couples the board and the platform according to a determination that the board is placed on the platform. In some embodiments, the system performs this coupling by raising the print platform along the z-axis such that the print plate is in contact with the print platform. In some embodiments, the system turns on one or more electromagnetic components to ensure that the plate is securely attached or coupled to the platform.

At block 1040, the system identifies a portion of the print instructions based on the progress data associated with the print plate. In some embodiments, each print workstation of the system may have access to a copy of the same print instructions for printing the pharmaceutical dosage units. Thus, each print station needs to identify a portion of the print instruction before starting printing. In some embodiments, the progress data includes a current height of the medication dosage unit (i.e., along the z-axis), an identifier of the printing workstation, or a combination thereof. In some embodiments, the progress data is provided to the print workstation by the plate transport mechanism.

At block 1042, the system performs 3D printing based on the identified portion of the print instruction. In some embodiments, printing is performed based on a coordinate system associated with the current print workstation, which may be obtained as discussed above with reference to FIG. 9.

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

At block 1044, the system determines whether printing is complete based on the identified print instruction portion. 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 executed by a particular print workstation. In this way, the system may determine that printing is complete upon detecting one or more indicators marking the end of the print instruction portion.

At block 1046, the system records progress data associated with the print plate in accordance with the determination that printing is complete at the current print workstation. In some embodiments, the progress data includes an identifier of the next print workstation (e.g., based on the print instructions), the current height of the medication dosage unit, or a combination thereof. In some embodiments, the current print workstation records and transmits the progress data to the plate transport mechanism.

At block 1048, the system unloads the print plate from the print platform. In some embodiments, this includes lowering the printing platform and deactivating the electromagnetic component so that the plate transport mechanism can pick up the print plate. In some embodiments, the current print workstation is marked as idle by the workstation itself and/or by the system.

Fig. 10C depicts an exemplary process for 3D printing of drug dosage units using a multi-station printing system, according to some embodiments. Process 1060 may be performed by a plate transport mechanism. To coordinate the operation of multiple print stations and the plate transport mechanism, the multi-station printing system tracks the status of its various components through a number of parameters, such as: an identifier of the print workstation, a location of the print workstation, whether each print workstation is busy or idle, a location of all print plates, progress data associated with each print plate (e.g., a current height), a location of the plate transport mechanism (e.g., coordinates on the lane), a coordinate system of the print workstation, a height of all components (e.g., print platform, print plate, plate transport mechanism), or any combination thereof. These parameters, or multiple versions of these parameters, may be stored in a single location or may be distributed among multiple components.

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

At block 1064, the system determines whether the print plate is placed on the plate transport mechanism based on a determination that printing is complete at the first print station. As discussed above with respect to fig. 10B, after printing is completed, the print workstation may separate the print plate from the print deck. Subsequently, the plate transport mechanism may pick up the print plate and move the print plate out of the print station.

At block 1066, the system moves the print plate along a first axis (e.g., the x-axis). For example, as depicted in fig. 8A and 8B, the system may move the print plate along the transport belt along the x-axis until the print plate is beside the second print station. In some embodiments, the second print workstation is determined by the plate transport mechanism based on the progress data generated in block 1046. In some embodiments, the second print workstation is determined by the system based on the status and printed materials at each print workstation (e.g., selecting a free workstation that can dispense the current printed materials needed to print the product on the board).

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

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

At block 1074, the system determines whether printing is complete at the second print station. The determination may be made based on the status of the second print station (e.g., busy or idle) or based on a signal transmitted from the second print station to the plate transport mechanism. In accordance with a determination that printing is complete at the second print station, the system determines whether a print plate is placed on the plate transport mechanism. As discussed above with respect to fig. 10B, after printing is completed, the second printing station may separate the printing plate from the printing platform. Subsequently, the plate transport mechanism may pick up the print plate and move the print plate out of the print station.

At block 1076, the system records progress data associated with the print plate. The progress data may include the current height of the medication dosage unit on the print plate. In some embodiments, the progress data is determined by the second printing station based on the print instructions and transmitted from the second printing station to the plate transport mechanism. In some embodiments, the plate transport mechanism may transmit the schedule data to the next print workstation. In some embodiments, the entire multi-station printing system stores one copy of the schedule data associated with the print plates, and the schedule data is accessible to various components of the system (e.g., plate transport mechanisms, workstations).

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

The foregoing description, for purpose of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the technology and its practical applications. To thereby enable others skilled in the art to best utilize the technology and various embodiments with various modifications as are suited to the particular use contemplated.