U.S. patent application number 17/592441 was filed with the patent office on 2022-07-07 for high-throughput and high-precision pharmaceutical additive manufacturing system.
The applicant listed for this patent is Triastek, Inc.. Invention is credited to Senping CHENG, Feihuang DENG, Renjie LI, Xiaoling LI, Haili LIU, Wei WU.
Application Number | 20220212404 17/592441 |
Document ID | / |
Family ID | 1000006213250 |
Filed Date | 2022-07-07 |
United States Patent
Application |
20220212404 |
Kind Code |
A1 |
LIU; Haili ; et al. |
July 7, 2022 |
HIGH-THROUGHPUT AND HIGH-PRECISION PHARMACEUTICAL ADDITIVE
MANUFACTURING SYSTEM
Abstract
The present disclosure relates generally to manufacturing
pharmaceutical products using additive manufacturing technology. An
exemplary printing system comprises: a material supply module for
receiving a set of printing materials; a flow distribution module
comprising a flow distribution plate, wherein the material supply
module is configured to transport a single flow corresponding to
the set of printing materials to the flow distribution plate;
wherein the flow distribution plate comprises a plurality of
channels for dividing the single flow into a plurality of flows; 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 dispense
the plurality of flows based on a plurality of nozzle-specific
parameters; and a printing platform configured to receive the
dispensed plurality of flows, wherein the printing platform is
configured to move to form a batch of the pharmaceutical
product.
Inventors: |
LIU; Haili; (Nanjing,
CN) ; DENG; Feihuang; (Nanjing, CN) ; WU;
Wei; (Nanjing, CN) ; LI; Renjie; (Nanjing,
CN) ; CHENG; Senping; (Nanjing, CN) ; LI;
Xiaoling; (Dublin, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Triastek, Inc. |
Nanjing |
|
CN |
|
|
Family ID: |
1000006213250 |
Appl. No.: |
17/592441 |
Filed: |
February 3, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17180565 |
Feb 19, 2021 |
11292193 |
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17592441 |
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PCT/CN2020/105868 |
Jul 30, 2020 |
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17180565 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B29C 64/245 20170801;
B33Y 80/00 20141201; B33Y 70/10 20200101; B33Y 30/00 20141201; B33Y
10/00 20141201; B29C 64/209 20170801; A61K 9/2095 20130101 |
International
Class: |
B29C 64/209 20060101
B29C064/209; B33Y 10/00 20060101 B33Y010/00; B33Y 30/00 20060101
B33Y030/00; B33Y 80/00 20060101 B33Y080/00; B29C 64/245 20060101
B29C064/245; B33Y 70/10 20060101 B33Y070/10; A61K 9/20 20060101
A61K009/20 |
Claims
1.-44. (canceled)
45. A system for creating pharmaceutical products by additive
manufacturing, comprising: a first printing station comprising: a
first flow distribution module; and a first plurality of nozzles; a
second printing station comprising: a second flow distribution
module; and a second plurality of nozzles; a plate transport
mechanism; a printing plate; and one or more controllers for
controlling the plate transport mechanism to transport the printing
plate between the first printing station and the second printing
station; wherein the first flow distribution module comprises a
first flow distribution plate, the first flow distribution plate is
configured to receive a first single flow corresponding to a first
set of printing materials, and divide the first single flow into a
first plurality of flows; wherein the second flow distribution
module comprises a second flow distribution plate, the second flow
distribution plate is configured to receive a second single flow
corresponding to a second set of printing materials, and divide the
second single flow into a second plurality of flows; wherein the
first plurality of nozzles is configured to dispense the first
plurality of flows on the printing plate to create a first portion
of the pharmaceutical products, and the second plurality of nozzles
is configured to dispense the second plurality of flows on the
printing plate to create a second portion of the pharmaceutical
products.
46. The system of claim 45, further comprising two conveyors,
wherein the system is configured to transport the printing plate
via the plate transport mechanism along one of the two
conveyors.
47.-58. (canceled)
59. The system of claim 45, 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.-61. (canceled)
62. The system of claim 45, wherein the system is configured to
determine whether creating of the first portion of each
pharmaceutical product in the plurality of pharmaceutical products
is complete at the first printing station, comprising: receiving,
at the plate transport mechanism, a status of the first printing
station; and determining, at the plate transport mechanism, whether
the printing is complete based on the status of the first printing
station.
63. The system of claim 45, wherein the system is configured to:
after creating of the first portion of each pharmaceutical product
is complete, recording progress data associated with the printing
plate.
64.-70. (canceled)
71. The system of claim 45, wherein the system is configured to
transport the printing plate from the first printing station to the
second printing station via the plate transport mechanism,
comprising: demounting the printing plate from the first printing
station; moving the printing plate onto the plate transport
mechanism; and moving the plate transport mechanism along a channel
based on a location associated with the second printing
station.
72.-73. (canceled)
74. The system of claim 45, wherein creating of the second portion
of each pharmaceutical product in the plurality of pharmaceutical
products at the second printing station comprises: identifying a
portion of printing instructions based on progress data associated
with the printing plate.
75.-79. (canceled)
80. A method for additive manufacturing pharmaceutical products
using a multi-station system, wherein the multi-station system
comprises: a first printing station; a second printing station; a
plate transport mechanism; a printing plate; and one or more
controllers; wherein the method comprises: printing, by the first
printing station, a first set of printing materials on the printing
plate to create a first portion of the pharmaceutical products;
determining, by the one or more controllers, whether printing is
complete at the first printing station; controlling the plate
transport mechanism to transport the printing plate from the first
printing station to the second printing station based on a
determination that printing is complete at the first printing
station; and printing, by the second printing station, a second set
of printing materials on the printing plate to create a second
portion of the pharmaceutical products.
81. The method of claim 80, wherein: the first printing station
comprises: a first flow distribution module; and a first plurality
of nozzles; the second printing station comprises: a second flow
distribution module; and a second plurality of nozzles; and the
first flow distribution module comprises a first flow distribution
plate, the first flow distribution plate is configured to receive a
first single flow corresponding to the first set of printing
materials, and divide the first single flow into a first plurality
of flows; the second flow distribution module comprises a second
flow distribution plate, the second flow distribution plate is
configured to receive a second single flow corresponding to the
second set of printing materials, and divide the second single flow
into a second plurality of flows; the printing, by the first
printing station, the first set of printing materials on the
printing plate comprises dispensing, by the first plurality of
nozzles, the first plurality of flows on the printing plate layer
by layer to create the first portion of the pharmaceutical
products; and the printing, by the second printing station, the
second set of printing materials on the printing plate comprises
dispensing, by the second plurality of nozzles, the second
plurality of flows on the printing plate layer by layer to create
the second portion of the pharmaceutical products.
82. The method of claim 80, wherein the determination is made based
on a status of the first printing station or based on signals
transmitted from the first printing station.
83. The method of claim 80, wherein the controlling the plate
transport mechanism to transport the printing plate from the first
printing station to the second printing station comprises:
determining, by the one or more controllers, whether the printing
plate is placed onto the plate transport mechanism; moving, by the
plate transport mechanism, the printing plate along a first axis
until beside the second printing station; determining, by the one
or more controllers, whether the second printing station is idle;
and moving, by the plate transport mechanism, the printing plate
along a second axis toward the second printing station based on a
determination that the second printing station is idle.
84. The method of claim 80, further comprising determining, by the
one or more controllers, whether printing is complete at the second
printing station.
85. The method of claim 84, further comprising: recording progress
data associated with the printing plate, wherein the progress data
comprises a current height of pharmaceutical dosage units on the
printing plate, an identifier of printing station, or a combination
thereof.
86. The method of claim 85, further comprising: identifying a
portion of printing instructions based on the progress data
associated with the printing plate, wherein the printing
instructions comprise one or more indicators marking a beginning
and an end to be performed by the second printing station; and
determining whether printing is complete based on detecting the one
or more indicators marking the end of the portion of printing
instructions.
Description
FIELD OF INVENTION
[0001] The present disclosure relates generally to additive
manufacturing technology, and more specifically to high-throughput
and high-precision 3D printing techniques for manufacturing
pharmaceutical dosage units (e.g., tablets caplets, printlets).
BACKGROUND
[0002] Additive manufacturing, also referred to as
three-dimensional printing ("3D printing"), is a rapid prototyping
technology involving processes in which material is joined or
solidified to manufacture a three-dimensional object. Specifically,
materials are added together (such as liquid molecules or powder
grains being fused together), typically layer by layer, based on a
digital model. A computer system operates the additive
manufacturing system, and controls material flow and movement of a
printing nozzle until the desired shape is formed. Currently, 3D
printing technology includes photocuring techniques, powder bonding
techniques, and fused deposition modeling (FDM) techniques.
[0003] In an FDM process, material in the form of a filament is fed
through a heated nozzle, which melts the material onto a surface.
The surface or the heated nozzle can move to dispense the molten
material into a set shape, as instructed by the computer system.
Other additive manufacturing methods utilize non-filamentous
materials that are molten and pressurized before being dispensed
through a printing nozzle, but such methods often result in
undesirable stringing from the printing nozzle, particular when the
molten material is of high viscosity.
[0004] There are several challenges with adapting techniques such
as FDM for the use of manufacturing pharmaceutical dosage units
(e.g., tablets, caplets, printlets): achieving high throughput,
achieving high precision/consistency, and printing pharmaceutical
dosage units having 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 providing parallel printing by running multiple
printing devices simultaneously are also deficient, as the multiple
printing devices introduce inconsistency and low precision among
the printed units (e.g., in volume, shape, weight, and/or
composition). Such systems are also expensive to manufacture and
maintain, as well as inefficient and complex to operate.
[0005] In particular, the printing materials required in the
pharmaceutical context tend to be of high viscosity and are
associated with low printing pressure. Further, when multiple types
of printing material are involved in the printing process, nozzles
dispensing these different types of printing material need to be
operating in a coordinated manner (e.g., opened and closed
alternately). Traditional 3D printing systems cannot coordinate the
operation of multiple nozzles and control the release of multiple
types of material in a precise and consistent manner. Thus,
traditional 3D printing systems cannot maintain a high level of
consistency among the pharmaceutical dosage units outputted by the
nozzles, in the same batch or across multiple batches. The
above-described challenges are compounded if the pharmaceutical
unit to be manufactured is composed of different materials arranged
in a particular structure (e.g., multiple inner parts coated with a
shell).
[0006] Further, 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. Specifically, inconsistencies among the multiple 3D printers
(e.g., in both hardware configuration and software configuration)
can cause the end product to be inconsistent and thus fail to meet
the quality standards. Further, system involving the coordination
among multiple 3D printers are generally inefficient to operate and
expensive to maintain.
[0007] Thus, there is a need for systems and methods for 3D
printing pharmaceutical dosage units (e.g., tablets caplets,
printlets) in an accurate, precise, and cost-efficient manner,
while maintaining high throughput over time. There is also a need
for a system that can coordinate the operations of multiple 3D
printers to print a batch of pharmaceutical dosage units.
BRIEF SUMMARY
[0008] An exemplary system for creating pharmaceutical products by
additive manufacturing, comprises: a material supply module for
receiving a set of printing materials; a flow distribution module
comprising a flow distribution plate, wherein the material supply
module is configured to transport a single flow corresponding to
the set of printing materials to the flow distribution plate;
wherein the flow distribution plate comprises a plurality of
channels for dividing the single flow into a plurality of flows; a
plurality of nozzles; and one or more controllers for controlling
the plurality of nozzles to dispense the plurality of flows based
on a plurality of nozzle-specific parameters.
[0009] In some embodiments, the system further comprises a printing
platform configured to receive the dispensed plurality of flows,
wherein the printing platform is configured to move to form a batch
of the pharmaceutical product.
[0010] In some embodiments, the material supply module is
configured to heat the received set of printing materials.
[0011] In some embodiments, the material supply module is
configured to plasticize the received set of printing
materials.
[0012] In some embodiments, the material supply module comprises a
piston mechanism, a screw mechanism, a screw pump mechanism, a
cogwheel mechanism, a plunger pump mechanism or any combination
thereof.
[0013] In some embodiments, the plurality of channels forms a first
juncture configured to dividing the single flow into two flows.
[0014] In some embodiments, wherein the plurality of channels forms
a second juncture and a third juncture configured to divide the two
flows into 4 flows.
[0015] In some embodiments, the first juncture is positioned higher
than the second juncture and the third juncture.
[0016] In some embodiments, the first juncture, the second
juncture, and the third juncture are positioned on a same
plane.
[0017] In some embodiments, the flow distribution plate is
split-table into a plurality of components, wherein the plurality
of components are configured to be held together via one or more
screws.
[0018] In some embodiments, a nozzle of the plurality of nozzles
comprises a heater.
[0019] In some embodiments, a nozzle of the plurality of nozzles
comprises a thermal isolation structure.
[0020] In some embodiments, the plurality of nozzles comprises a
plurality of needle-valve mechanisms.
[0021] 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
is tapered at a distal end of the nozzle; and a needle, wherein a
distal end of the needle is configured to be in 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
be retracted to allow a flow of printing materials to be
dispensed.
[0022] In some embodiments, movement of the needle is driven by one
or more actuators.
[0023] In some embodiments, the one or more actuators include a
linear motor.
[0024] In some embodiments, movement of the needle is controlled
manually.
[0025] In some embodiments, the needle is a first needle, the
plurality of nozzles comprises a single plate coupled to the first
needle and a second needle, and wherein movement of the single
plate causes movement of the first needle and the second
needle.
[0026] In some embodiments, a parameter of the plurality of
nozzle-specific parameters comprises an amount of opening of a
respective nozzle.
[0027] In some embodiments, the one or more controllers are
configured to adjust the amount of opening of the respective nozzle
based on a weight of a unit in the batch corresponding to the
respective nozzle.
[0028] In some embodiments, the one or more controllers are
configured to adjust the amount of opening of the respective nozzle
based one or more machine learning algorithms.
[0029] In some embodiments, the one or more controllers are
configured to control temperature or pressure at the plurality of
the nozzles.
[0030] In some embodiments, the temperature is controlled via a
temperature control device comprising one or more heating devices,
one or more cooling devices, or a combination thereof.
[0031] In some embodiments, a temperature at the plurality of the
nozzles is higher than a temperature at the materials supply
module.
[0032] In some embodiments, a temperature at the plurality of the
nozzles is higher than a temperature at the flow distribution
plate.
[0033] In some embodiments, the one or more controllers are
configured to control a feeding speed of the set of printing
materials.
[0034] In some embodiments, the plurality of nozzles is a first
plurality of nozzles, the printing system further comprising a
second plurality of nozzles configured to dispense a different set
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.
[0035] In some embodiments, the pharmaceutical unit is a
tablet.
[0036] An exemplary computer-enabled method for creating
pharmaceutical products by additive manufacturing, comprises:
receiving a plurality of unit measurements corresponding to a
plurality of pharmaceutical dosage units, wherein the plurality of
pharmaceutical dosage units are generated using a plurality of
nozzles of an additive manufacturing system; determining whether a
sum of the plurality of unit measurements differs from a target
batch measurement by more than a predefined threshold; in
accordance with a determination that the sum differs from the
target batch measurement by more than the predefined threshold,
adjusting one or more nozzles of the plurality of nozzles based on
an average of the plurality of unit measurements; in accordance
with a determination that the sum does not differ from the target
batch measurement by more than the predefined threshold, adjusting
one or more nozzles of the plurality of nozzles based on a target
unit measurement.
[0037] In some embodiments, the plurality of pharmaceutical unit is
a plurality of tablets.
[0038] In some embodiments, the unit measurements are weight
measurements of the plurality of pharmaceutical dosage units.
[0039] In some embodiments, the unit measurements are volume
measurements of the plurality of pharmaceutical dosage units.
[0040] In some embodiments, the unit measurements are composition
measurements of the plurality of pharmaceutical dosage units.
[0041] In some embodiments, the method further comprises: in
accordance with a determination that the sum differs from the
target batch measurement by more than the predefined threshold,
adjusting one or more operation parameters of the additive
manufacturing system.
[0042] In some embodiments, the one or more operation parameters
include temperature.
[0043] In some embodiments, the one or more operation parameters
include pressure.
[0044] In some embodiments, the one or more operation parameters
include a speed of feeding printing materials.
[0045] In some embodiments, the predefined threshold is between
+/-0.5% to +/-5%.
[0046] In some embodiments, the method further comprises, after
adjusting one or more nozzles of the plurality of nozzles based on
a target unit measurement, printing a new batch; determining
whether a weight of an unit in the new batch differs from the
target unit measurement by more than a second predefined threshold;
in accordance with a determination that the weight of the unit in
the new batch differs from the target unit measurement by more than
the second predefined threshold, adjusting one or more operation
parameters of the additive manufacturing system.
[0047] In some embodiments, the one or more operation parameters
include temperature.
[0048] In some embodiments, the one or more operation parameters
include an amount of opening of a nozzle.
[0049] In some embodiments, the second predefined threshold is less
than 5%.
[0050] An exemplary method for manufacturing pharmaceutical
products by additive manufacturing comprises: receiving, using a
material supply module, a set of printing materials; transporting,
using the material supply module, a single flow corresponding to
the set of printing materials to a flow distribution plate, wherein
the flow distribution plate comprises a plurality of channels;
dividing, via the plurality of channels of the flow distribution
plate, the single flow into a plurality of flows; causing a
plurality of nozzles to dispense the plurality of flows based on a
plurality of nozzle-specific parameters.
[0051] An exemplary non-transitory computer-readable storage medium
stores one or more programs, the one or more programs comprising
instructions, which when executed by one or more processors of an
electronic device having a display, cause the electronic device to:
receive a plurality of weight measurements corresponding to a
plurality of pharmaceutical dosage units, wherein the plurality of
pharmaceutical dosage units are generated using a plurality of
nozzles of a 3D printing system; determine whether a sum of the
plurality of weight measurements differs from a target batch weight
by more than a predefined threshold; in accordance with a
determination that the sum differs from the target batch weight by
more than the predefined threshold, adjust one or more nozzles of
the plurality of nozzles based on an average weight measurement of
the plurality of weight measurements; in accordance with a
determination that the sum does not differ from the target batch
weight by more than the predefined threshold, adjust one or more
nozzles of the plurality of nozzles based on a target weight
measurement.
[0052] In some embodiments, an exemplary system for manufacturing a
plurality of pharmaceutical products by additive manufacturing
comprises a first printing station comprising: a first printing
platform; and a first plurality of nozzles; a second printing
station comprising: a second printing platform; and a second
plurality of nozzles; a plate transport mechanism; a printing
plate; wherein the system is configured to: while the printing
plate is positioned on the first printing platform, determining
whether printing of a first portion of each pharmaceutical product
in the plurality of pharmaceutical products is complete at the
first printing station; in accordance with a determination that the
printing of the first portion is complete at the first printing
station, identifying the second printing station; transporting the
printing plate from the first printing platform to the second
printing platform via the plate transport mechanism; and causing
printing of a second portion of each pharmaceutical product in the
batch of pharmaceutical products at the second printing
station.
[0053] In some embodiments, the system further comprises two
conveyors, wherein the system is configured to transport the
printing plate via the plate transport mechanism along one of the
two conveyors.
[0054] In some embodiments, the printing of the first portion at
the first printing station is based on a first coordinate system
associated with the first printing station, and the printing of the
second portion at the second printing station is based on a second
coordinate system associated with the second printing station.
[0055] In some embodiments, the system is configured to: obtaining
a first relative positioning between the first printing platform
and the first plurality of nozzles; obtaining a second relative
positioning between the second printing platform and the second
plurality of nozzles; calculating a plurality of offset values
based on the first relative positioning and the second relative
positioning; determining at least one of the first coordinate
system and the second coordinate system based on the plurality of
offset values.
[0056] In some embodiments, the first relative positioning
comprises a first x-axis value and a first y-axis value, and
wherein the second relative positioning comprises a second x-axis
value and a second y-axis value.
[0057] In some embodiments, the plurality of offset values
comprises: a difference value between the first x-axis value and
the second x-axis value and a difference value between the first
y-axis value and the second y-axis value.
[0058] In some embodiments, obtaining the first relative
positioning comprises: while the printing plate is positioned on
the first printing platform, measuring the first x-axis and the
first y-axis value based on one or more retractable sensors placed
on the first printing station.
[0059] In some embodiments, obtaining the first relative
positioning comprises: while the printing plate is positioned on
the first printing platform, measuring the first x-axis and the
first y-axis value based on one or more laser sensors placed on the
first printing station.
[0060] In some embodiments, obtaining the first relative
positioning comprises: moving the first printing platform on the
x-axis until it comes in contact with a first sensor on the first
printing station; and moving the second printing platform on the
y-axis until it comes in contact with a second sensor on the first
printing station.
[0061] In some embodiments, determining the first coordinate system
comprises: determining a zero point on the z axis.
[0062] In some embodiments, the zero point comprises a z-axis
position where a plate placed on the first printing platform comes
in contact with first plurality of nozzles.
[0063] In some embodiments, determining the zero point is performed
using a plug gauge.
[0064] In some embodiments, determining the zero point comprises:
elevating the first printing platform; determining, using a sensor
coupled to the first printing platform, whether a resistance force
above a predefined threshold is detected; in accordance with a
determination that the resistance force above the predefined
threshold is detected, pausing elevating 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 the resistance force above the predefined
threshold is not detected, continuing elevating the first printing
platform.
[0065] In some embodiments, determining the zero point comprises:
affixing a sensor having a retractable portion to the first
printing platform, wherein the retractable portion is protruded out
of the first printing platform; placing an object over the sensor
such that the protruded portion of the sensor is retracted;
recording a retracted position of the sensor; while elevating the
first printing platform, determining whether the retracted position
of the sensor is detected; 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;
[0066] 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.
[0067] 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 inner portion of the respective tablet.
[0068] 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.
[0069] In some embodiments, determining whether printing of the
first portion of each pharmaceutical product in the batch of
pharmaceutical products is complete at the first printing station
comprises: receiving, at the plate transport mechanism, a status of
the first printing station; and determining, at the plate transport
mechanism, whether the printing is complete based on the status of
the first printing station.
[0070] In some embodiments, the system is further configured to:
after printing of the first portion of each pharmaceutical product
is complete, recording progress data associated with the printing
plate.
[0071] In some embodiments, the progress data comprises a current
height of the batch of pharmaceutical products.
[0072] In some embodiments, the progress data comprises the
identified second printing station.
[0073] In some embodiments, the system is configured to transmit
the recorded progress data from the first printing station to the
plate transport mechanism.
[0074] In some embodiments, identifying the second printing station
is based a set of printing instructions associated with the
pharmaceutical products.
[0075] In some embodiments, identifying the second printing station
is based the second portion to be printed.
[0076] In some embodiments, identifying the second printing station
is based printing material associated with the second portion to be
printed.
[0077] In some embodiments, identifying the second printing station
is based a status of the second printing station.
[0078] In some embodiments, transporting the printing plate from
the first printing platform to the second printing platform via the
plate transport mechanism comprises: demounting the printing plate
from the first platform; moving the printing plate onto the plate
transport mechanism; and moving the plate transport mechanism along
a channel based on a location associated with the second printing
station.
[0079] In some embodiments, demounting the printing plate from the
first platform comprises deactivating an electromagnetic
component.
[0080] In some embodiments, causing printing of the second portion
of each pharmaceutical product in the batch of pharmaceutical
products at the second printing station comprises: updating the
status of the second printing station as busy.
[0081] In some embodiments, causing printing of the second portion
of each pharmaceutical product in the batch of pharmaceutical
products at the second printing station comprises: identifying a
portion of printing instructions based on progress data associated
with the printing plate.
[0082] In some embodiments, the progress data comprises a current
height of the batch of pharmaceutical products on the printing
plate.
[0083] In some embodiments, the progress data is transmitted from
the plate transport mechanism to the second printing station.
[0084] In some embodiments, the system further comprises a
controller associated with the first printing station, a controller
associated with the second printing station, or any combination
thereof.
[0085] In some embodiments, the system further comprises a
controller associated with the plate transport mechanism.
[0086] In some embodiments, the system further comprises a third
printing station.
DESCRIPTION OF THE FIGURES
[0087] FIG. 1A depicts a schematic view of an exemplary additive
manufacturing system, according to some embodiments of a present
invention.
[0088] FIG. 1B depicts a schematic view of an exemplary additive
manufacturing system, according to some embodiments of a present
invention.
[0089] FIG. 1C depicts an exemplary additive manufacturing system
comprising a piston mechanism, according to some embodiments of a
present invention.
[0090] FIG. 1D depicts an exemplary additive manufacturing system,
according to some embodiments of a present invention.
[0091] FIG. 2A depicts a side cross-sectional view of an exemplary
flow distribution module, according to some embodiments of a
present invention.
[0092] FIG. 2B depicts a top cross-sectional view of an exemplary
flow distribution module, according to some embodiments of a
present invention.
[0093] FIG. 2C depicts configurations of an exemplary flow
distribution module, according to some embodiments of a present
invention.
[0094] FIG. 2D depicts a bottom perspective view of a flow
distribution module, according to some embodiments of a present
invention.
[0095] FIG. 3 depicts a cross-sectional view of the distal end of
an exemplary nozzle, according to some embodiments of a present
invention.
[0096] FIG. 4 depicts a cross-sectional view of an exemplary
additive manufacturing system, according to some embodiments of a
present invention.
[0097] FIG. 5 depicts an exemplary pressure curve for dispensing
printing material at a nozzle, according to some embodiments of a
present invention.
[0098] FIG. 6A depicts an exemplary process for 3D printing
pharmaceutical dosage units, according to some embodiments of a
present invention.
[0099] FIG. 6B depicts an exemplary process for 3D printing
pharmaceutical dosage units, according to some embodiments of a
present invention.
[0100] FIG. 7 depicts an exemplary electronic device in accordance
with some embodiments.
[0101] FIG. 8A depicts an exemplary layout of a standardized
multi-station printing system for pharmaceutical units, in
accordance with some embodiments.
[0102] FIG. 8B depicts a partial side view of the exemplary
multi-station system 800, in accordance with some embodiments.
[0103] FIG. 9 depicts an exemplary process for initializing a
multi-station printing system having a first printing station and a
second printing station, in accordance with some embodiments.
[0104] FIG. 10A depicts an exemplary architecture of a
multi-station 3D printing system, in accordance with some
embodiments.
[0105] FIG. 10B depicts an exemplary process for 3D printing
pharmaceutical dosage units using a multi-station system, according
to some embodiments.
[0106] FIG. 10C depicts an exemplary process for 3D printing
pharmaceutical dosage units using a multi-station system, according
to some embodiments.
DETAILED DESCRIPTION
[0107] Described herein are apparatuses, devices, systems, methods,
and non-transitory storage media for additive manufacturing (e.g.,
3D printing) pharmaceutical dosage units (e.g., tablets caplets,
printlets) in an accurate, precise, and cost-efficient manner,
while maintaining high throughput over time. According to the some
embodiments, a printing system leverages a flow distribution module
for dividing a single flow of printing material(s) into a plurality
of flows. The plurality of flows are dispensed by a plurality of
nozzles in a precisely controlled manner to 3D print a batch of
pharmaceutical dosage units (e.g., tablets caplets, printlets),
thus achieving consistency among the units in a single batch and
across multiple batches, while maintaining high-throughput.
[0108] Further, the printing system comprises an environment (e.g.,
a closed environment such as a constant temperature oven, an open
environment such as a printing platform) for additive manufacturing
(e.g., 3D printing) pharmaceutical dosage units. A plurality of
close-loop control systems are used to control temperature,
pressure, flow, weight, volume, and other relevant parameters in
the environment in multiple stages of the manufacturing process. In
particular, control systems and methods are implemented to adjust
the opening of the nozzles, specifically, the opening of the
needle-valve mechanisms at the nozzles, in a precise manner to
ensure consistency among outputs of the nozzles. In some
embodiments, the inconsistency in unit weight (i.e., inconsistency
among weights of units in the same batch) are smaller than 10%
(e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%). In some
embodiments, the inconsistency in batch weight (i.e., inconsistency
among weights of batches) are smaller than 10% (e.g., 1%, 2%, 3%,
4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%).
[0109] Based different types of printing materials and the
compositions required, the system can adjust the control
parameters. This way, the printing system can be used to
manufacture a variety of high-quality pharmaceutical dosage
units.
[0110] In some embodiments, the material is non-filamentous (e.g.,
powder, pellet, or liquid). In some embodiments, the material has a
viscosity of 0.01-10000 Pas when dispensed from the system. For
example, the material has a viscosity of about 100 Pas or more when
dispensed from the device. In some embodiments, the material has a
viscosity of about 400 Pas or more when dispensed from the device.
In some embodiments, the material melts at about 50.degree. C. to
about 400.degree. C. In some embodiments, the material is dispensed
from the nozzle at a temperature of about 50.degree. C. to about
400.degree. C. In some embodiments the material is dispensed from
the nozzle at a temperature of about 90.degree. C. to about
300.degree. C.
[0111] In some embodiments, the printing system comprises multiple
printing stations. Each printing station can be used to print a
portion (e.g., the shells, the lower halves, the top halves) of a
batch of pharmaceutical dosage units. Further, the multiple
printing stations can work in parallel such that multiple batches
of pharmaceutical dosage units can be printed at the same time. In
some embodiment, a single FDM multi-station system can manufacture
3,000-5,000 pharmaceutical units (e.g., tablets) per day. In some
embodiments, the system minimizes inconsistencies among
pharmaceutical units in the same patch and in different patches to
.+-.2.5% (e.g., in weight, in volume). In some embodiments, the
multi-station system is easy to clean and maintain, thus in
compliance with requirements for standardization production of
pharmaceutical products.
[0112] The following description is presented to enable a person of
ordinary skill 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 herein and shown, but are to be accorded the scope
consistent with the claims.
[0113] Although the following description uses terms "first,"
"second," etc. to describe various elements, these elements should
not be limited by the terms. These terms are only used to
distinguish one element from another. For example, a first nozzle
could be termed a second nozzle, and, similarly, a second nozzle
could be termed a first nozzle, without departing from the scope of
the various described embodiments. The first nozzle and the second
nozzle are both nozzles, but they are not the same nozzle.
[0114] 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 will also be understood that the
term "and/or" as used herein refers to and encompasses any and all
possible combinations of one or more of the associated listed
items. It will be further understood that the terms "includes,"
"including," "comprises," and/or "comprising," 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.
[0115] The term "if" is, optionally, construed to mean "when" or
"upon" or "in response to determining" or "in response to
detecting," depending on the context. Similarly, the phrase "if it
is determined" or "if [a stated condition or event] is detected"
is, optionally, construed to mean "upon determining" or "in
response to determining" or "upon detecting [the stated condition
or event]" or "in response to detecting [the stated condition or
event]," depending on the context.
[0116] FIG. 1A depicts a schematic view of an exemplary additive
manufacturing system (e.g., 3D printing system) 100, according to
some embodiments of the present invention. The system 100 comprises
material supply module 102 for transporting a set of printing
material(s) to a flow distribution module 104. The flow
distribution module 104 comprises a flow distribution plate having
branched channels (not depicted) configured to divide a single flow
of the printing materials (e.g., supplied by the material supply
module) into a plurality of flows. In some embodiments, the flow
distribution module 104 can divide a single flow into 2 flows,
which are divided into 4 flows, which are divided into 8 flows,
which are divided into 16 flows, which are divided into 32 flows.
In some embodiments, the flow distribution module can divide a
single flow directly into 2 flows, 3 flows, 4 flows, 5 flows . . .
or n flows. In some embodiments, the flow distribution module can
divide a single flow into 3 flows, which are divided into 9 flows,
which are divided into 27 flows. With reference to FIG. 1B, the
plurality of flows can be dispensed by an array of nozzles 106 of
the system 100, respectively, to generate 3D-printed pharmaceutical
dosage units (e.g., tablets caplets, printlets) over the printing
platform 110.
[0117] The material supply module 102 is configured to preprocess
the set of printing material(s) before transporting it to the flow
distribution module 104. In some embodiments, the preprocessing
comprises melting and pressurizing the printing material(s) based
on predetermined settings (e.g., to a target range of temperature,
to a target range of pressure). The preprocessed material is then
transported via a supply channel 108 to the flow distribution
module 104. In some embodiments, a continuous flow of printing
material(s) is supplied to the flow distribution module 104 via the
supply channel 108.
[0118] In some embodiments, the material supply module 102
comprises one or more heaters configured to melt the printing
material(s). In some embodiments, the material supply module
comprises one or more temperature sensors configured to detect the
temperature of the melted printing material(s) within the material
supply module 102. In some embodiments, the one or more temperature
sensors are connected to a computer system that operates the one or
more heaters in response to a temperature reported by the one or
more temperature sensors.
[0119] In some embodiments, one or more pressure sensors are
connected to a computer system that operates the material supply
module to pressurize the printing material(s) to a desired pressure
in response to the pressure reported by the pressure sensors. In
some embodiments, the pressure of the printing is within about 0.05
MPa of the desired pressure. In some embodiments, the material
supply 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 cogwheel mechanism, a plunger pump
mechanism (e.g., a valve-less measuring pump mechanism), or any
combination thereof. Additional details of the material supply
modules and a number of other features of the printing system can
provided in PCT/CN2018/071965, titled "PRECISION PHARMACEUTICAL 3D
PRINTING DEVICE" and WO2018210183, titled "3D PRINTING DEVICE AND
METHOD," the content of which is incorporated in its entirety.
[0120] FIG. 1C depicts an exemplary additive manufacturing system
comprising a piston mechanism, in accordance with some embodiments
of the invention. In the depicted example, a piston 122 is driven
by one or more motors 120 in the z direction. When the piston is
driven downward, the piston pushes the printing material(s) down
the barrel 124, the supply channel 108, and the flow distribution
module 104, to alter the pressure of the printing material(s)
within the system. Upon opening of the distal outlets of the
printing nozzles, the printing material(s) can be dispensed in a
precisely controlled manner. The amount of the printing material(s)
dispensed can be controlled by controlling the position of the
piston, the speed at which the piston moves, the acceleration at
which the piston moves, or a combination thereof. In some
embodiments, the motor 120 is a stepper motor, server motor,
hydraulic control, or a combination thereof.
[0121] In some embodiments, the diameter of the barrel, D, is
between 5-20 mm. In a preferred embodiment, D is about 10 mm. In
some embodiments, the diameter of the nozzle outlet, d, is between
0.1-2 mm. In a preferred embodiment, d is about 0.4 mm. In some
embodiments, a ratio parameter, which is indicative of a ratio
between the cross-section area of the nozzle outlet and the
cross-section area of the barrel is calculated. The ratio can be
also expressed as the ratio between D.sup.2 squared and d.sup.2. In
some embodiments, the ratio is calculated as:
D 2 j = 1 n .times. d j 2 ##EQU00001##
[0122] Turning back to FIG. 1B, the flow distribution module 104
includes a flow distribution plate 114, a plurality of nozzles 106,
a temperature control mechanism, pressure sensors, temperature
sensors, or any combination thereof. As an example, FIG. 2A depicts
a cross-sectional view of an exemplary flow distribution plate. The
flow distribution plate comprises a single channel 210 connected to
the supply channel of the material supply module for receiving a
single flow of printing material(s). The flow distribution plate
comprises multiple branched channels configured to divide a single
flow into multiple flows, which are dispensed via multiple nozzles,
respectively. Each nozzle is configured to dispense a flow of
printing material(s) in a controlled manner via a needle-valve
mechanism. As depicted, nozzle 206a operates in conjunction with a
needle 220a, which 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.
[0123] FIG. 2B depicts a top view of the flow distribution plate
shown in FIG. 2A, in accordance with some embodiments. As depicted,
the branched channels within the flow distribution plate causes a
single flow of printing material(s) to be split into two flows,
then into four flows, and then into eight flows. The eight flows of
printing material(s) are then dispensed by eight nozzles,
respectively.
[0124] FIG. 2C depicts exemplary configurations of the channels
within a flow distribution plate, in accordance with some
embodiments. Each configuration can divide a single flow into
multiple flows, which are dispensed at multiple nozzles in an
evenly manner (e.g., in terms of weight). Due to the arrangement of
channels and junctures within the flow distribution plate, each of
the multiple flows traverses a unique flow path which, for example,
starts from the top inlet for receiving the single flow from the
supply channel into the flow distribution plate and extends to the
distal end of the nozzle. In some embodiments, the flow paths of
the multiple flows are geometrically symmetrical (e.g., of equal
length, of equal geometric shape). In some embodiments, the flow
paths of the multiple flows are not geometrically symmetrical, but
even distribution is achieved by adjusting the diameters of the
flow passage along different portions of the flow path. In some
embodiments, some or all of these junctures are positioned over the
same or substantially the same plane (e.g., a same X-Y plane). In
some embodiments, some or all of these junctures are positioned
over different planes (e.g., different X-Y planes).
[0125] In some embodiments, the flow distribution plate can be
split (e.g., horizontally, vertically, and/or diagonally) into a
plurality of components. The plurality of components can be held
together by screws. When taken apart, each individual component
exposes the inner surfaces of one or more channels and junctures in
the flow distribution plate, and thus allows for easier cleaning of
the channels and junctures of the flow distribution plate.
[0126] In some embodiments, in operation, the pressure within the
channels of the flow distribution plate can be between 0-20 MPa
(e.g., 0-5 MPa, 0-10 MPa, 0-20 MPa). The amount of time needed for
material to traverse the flow distribution plate can be between 5
minutes to 5 hours. In some embodiments, the dispensed volume at a
nozzle can be between 0.1-10 .mu.L/s (e.g., 2-3 .mu.L/s).
[0127] Turning back to FIG. 1B, the flow distribution plate
comprises a temperature control mechanism for maintaining the
temperature of the flow distribution plate at a desired level. In
some embodiments, the temperature control mechanism comprises one
or more heaters and one or more coolers, which are configured to
operate in conjunction to maintain the internal temperature of the
flow distribution plate.
[0128] The one or more heaters can be arranged within the flow
distribution plate or in proximity to the flow distribution plate
114. For example, the flow distribution plate comprises internal
slots for accommodating one or more heaters (e.g., wires, plates)
made of materials of high thermal conductivity. The one or more
heating wires extend through the internal slots inside the flow
distribution plate 114, for example, as shown in a bottom
perspective flow the flow distribution plate in FIG. 2D. The flow
distribution plate can comprise multiple rows and columns of
internal slots to allow for an even distribution of heating wires
throughout the plate such that temperature inside the plate is
maintained in a consistent manner.
[0129] The one or more coolers can be arranged within the flow
distribution plate or in proximity to the flow distribution plate
114. In some embodiments, the temperature control device achieves
cooling via water flow. As shown in FIG. 1B, a pair of cooling
plates, each having internal channels for running water, are
positioned above and below the flow distribution plate 114, thus
allowing water flow, air, coolant, etc., to occur in close
proximity to the flow distribution plate 114 to regulate the
temperature of the plate. In some embodiments, the flow
distribution plate comprises internal slots for accommodating one
or more coolers within the flow distribution plate. As shown in
FIG. 1A, the flow distribution plate 114 and the cooling plates
above and below the flow distribution plate 114 are all equipped
with inlets 105 for receiving coolant.
[0130] In some embodiments, the flow distribution plate comprises
one or more temperature sensors connected to a computer system that
operates the one or more heaters and coolers in response to a
temperature reported by the one or more temperature sensors. FIG.
2D depicts a bottom perspective view of a flow distribution plate
and shows an exemplary arrangement of the temperature sensors, in
accordance with some embodiments.
[0131] In some embodiments, the flow distribution plate comprises
one or more pressure sensors 130 configured to detect the pressure
of the printing materials within the channels of the flow
distribution plate. In some embodiments, the pressure sensors are
positioned in proximity to the flow distribution plate (e.g.,
around the corners, around the peripherals, around the center) or
within the channels of the flow distribution plate. In some
embodiments, small-range strain-gauge sensors are used.
[0132] FIG. 3 depicts an exemplary needle-valve mechanism 300 for
dispensing printing material at a printing nozzle 302, in
accordance with some embodiments. A feed channel 304 is formed
along the inside of the nozzle 302 to transport printing material
to the distal outlet of the nozzle. The feed channel comprises a
chamber that is tapered (e.g., in a cone shape) to serve as the
dispensing outlet for the printing material. A 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 a closed position, the needle is extended
such that it is in contact with the tapered distal end of the feed
channel and seals the outlet or extrusion port, thus preventing
printing material from being dispensed. When the needle is
retracted, the outlet is unsealed such that the printing material
can be dispensed. To regulate temperature at the distal end of the
printing nozzle, the plurality of heating devices 308 and a thermal
isolation structure 310 can be placed around the distal end of the
nozzle 302. The printing nozzle 302 can further include one or more
temperature sensors and/or pressure sensors 312.
[0133] 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 the same or smaller than the
first taper angle. In some embodiments, the second taper angle is
about 60.degree. or less. In some embodiments, the second taper
angle is about 45.degree. 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.
[0134] In some embodiments, the extrusion port has a diameter of
about 0.1 mm to about 1 mm. In some embodiments, the tapered end
has a largest diameter of about 0.2 mm to about 3.0 mm. In some
embodiments, the extrusion port has a diameter and the tapered end
has a largest diameter, and the ratio of the largest diameter of
the tapered end to the diameter of the extrusion port is about
1:0.8 to about 1:0.1.
[0135] In some embodiments, the motion system for the needle-valve
mechanism comprises: one or more motors, one or more sensors, one
or more drivers, and one or more controllers. The sensors can
comprise encoders. In some embodiments, the controllers comprises
programmable logic controllers ("PLC"). In some embodiments, the
divers comprise bus drivers.
[0136] In some embodiments, the motion system driving the needles
are controlled manually or by a computer controller for regulating
the flow at the nozzles. The motion system can comprise a plurality
of motors or actuators each coupled to a corresponding needle. The
motor may be a mechanical motor (which may comprise a screw), a
hydraulic motor, a pneumatic motor (which may comprise a pneumatic
valve) or an electromagnetic motor (which may comprise a solenoid
valve). Motors that drive the needles can be linear motors,
shaft-fixed type motors, non-captive type motors, or a combination
thereof.
[0137] In some embodiments, a non-captive type linear motor is used
in conjunction with anti-backlash nuts and ball spline. Ball spline
generally operates with lower friction and thus the motor can
operate with higher precision (e.g., .+-.0.003 mm). Further, the
motor is relatively small (e.g., 20-42 mm), thus allowing the
spacing between the nozzles to be between 20-50 mm, in some
embodiments. Alternatively, a screw linear motor is used.
[0138] In some embodiments, each of a plurality of needles is
driven by a respective motor. For example, if there are 32 nozzles,
there are 32 motors controlling the 32 needles respectively.
Further, the motors are each connected to a bus driver (e.g.,
CAN-open, Modbus).
[0139] In some embodiments, the system uses a method of stall
detection to find the zero position for the distal end of each
needle. During the configuration stage for identifying zero
position for a needle, the system configures the corresponding
motor to operate at a low electricity level (e.g., 400-1200 mA) and
drive the needle toward the distal outlet of the nozzle at a low
speed. This is done so that the distal end of the needle would not
deform when it is driven against the distal outlet of the nozzle.
When the distal end of the needle is in contact with the distal
outlet of the nozzle, the needle cannot move further despite the
continual driving of the motor. When the encoder no longer detects
movement of the needle, the system determines that the needle is at
the true zero position. In accordance with the determination that
the needle is at the true zero position, the system stops the
motor, retracts the needle by 0.003-0.01 mm, and then sets the
position of the needle as the configured zero position. Using the
configured zero position ensures that, during the operation of the
needle-valve mechanism, the distal end of the needle is not driven
against the distal outlet of the nozzle, thus improving the
longevity of both the needle and the nozzle. During normal
operation, the motor operates at a higher level of electricity
(e.g., 1600-1800 mA) and a higher speed (e.g., 0.3-15 mm/s) to
ensure swift opening and closing of the valve.
[0140] In alternative embodiments, the motion system can comprise a
single plate coupled to multiple needles such that the retraction
of the needles, and thus the dispensing flow of the nozzles are
controlled in a uniform manner, as shown in FIG. 4.
[0141] 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 no more than .+-.0.01
(.+-.0.005-.+-.0.02). In some embodiments, the plane is configured
to have a flatness within .+-.0.005-.+-.0.02 MM.
[0142] The motion system can be activated by a mechanical braking
mechanism, a hydraulic braking mechanism, a pneumatic braking
mechanism, an electromagnetic braking mechanism, a linear motor, or
any combination thereof.
[0143] The distal end of the nozzle comprises heaters and
insulating materials to maintain the temperature of the distal end.
Further, the distal end of the nozzle comprises one or more
pressure sensors (see also pressure sensors 132 of FIG. 1B) and
temperature sensors, which are configured to directly measure the
temperature and pressure of the printing material inside the
nozzle. In some embodiments, the one or more pressure sensors
include small-range strain-gauge sensors.
[0144] In some embodiments, the diameter of the channels within the
flow distribution plate is between 1-16 mm. In some embodiments,
the diameter of the feed channel within the nozzle is between
0.1-1.0 mm. In some embodiments, the diameter of the needle is
between 0.1-6 mm. In some embodiments, the diameter of the distal
outlet of the nozzle is 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 two nozzles is between 20-50 mm,
and the diameter of the outlet of a nozzle is between 0.05-0.8 or
between 0.8-1.0 mm.
[0145] In some embodiments, the system comprises a plurality of
needle-valve mechanisms, a push plate, a flow distribution plate,
and a needle-valve adjustment system. The needle-valve adjustment
system comprises a first elastic component, a second elastic
component, a push-plate actuator, and a locking mechanism, as
described below. The needle-valve adjustment system allows the
amount of opening of each needle-valve mechanism to be adjusted in
a precise manner such that the needle-valve mechanisms all operate
(e.g., dispense printing material) uniformly. The push plate allows
all needle-valve mechanisms to open/close simultaneously.
[0146] The proximal end of the needle can be coupled to a push
plate such that vertical movement of the push plate can cause
vertical movement of the needle. In some embodiments, multiple
needles are coupled to the same push plate such that the movement
of the push plate can cause multiple needles to move
simultaneously. The push plate can be driven using any motion
system, such as a wedge mechanism, a cam mechanism, etc. In some
embodiments, the push plate is placed above the flow distribution
plate.
[0147] In some embodiments, the hub of the needle at the proximal
end of the needle is housed within a sleeve component. The sleeve
component comprises an upper ceiling and a lower floor. The lower
floor comprises a hole that is large enough to allow the stem
portion of the needle to pass through but small enough to retain
the hub of the needle within the sleeve. A first elastic component
can be disposed above the hub of the needle and is sandwiched
between the hub of the needle and the upper ceiling of the sleeve
component. In some embodiments, the first elastic component is a
coil. Thus, the first elastic component can push the hub of the
needle downward such that the hub is in contact with the lower
floor of the sleeve.
[0148] In operation, when the push plate travels downward to close
the needle valve, the first elastic component can be retracted such
that the hub of the needle has room to move upward within the
sleeve, thus creating a buffering effect and reducing the force on
the distal tip of the needle as it comes into contact with the
nozzle. When multiple needles are coupled to the push plate and
each needle has a corresponding sleeve, this mechanism allows all
needles to close the corresponding nozzles in a uniform manner.
[0149] In some embodiments, the push plate comprises a recess on
the upper surface of the push plate. Further, at least the lower
portion of the sleeve can be disposed within the recess. The upper
portion of the sleeve can be coupled to a support structure via a
locking mechanism, and the support structure is affixed to the push
plate. In some embodiments, the locking mechanism comprises a
horizontal plate with a hole, which allows the sleeve to pass
through. The locking mechanism can be adjusted (e.g., the size of
the hole can be adjusted) such that the sleeve can be clamped via
the hole. Thus, the sleeve can be affixed to the push plate (i.e.,
via the locking mechanism and the support) such that the sleeve
does not move relative to the push plate during printing. In some
embodiments, a second elastic component is placed within the recess
below the sleeve. For example, the second elastic component can be
a coil sandwiched between the bottom of the recess and the bottom
of the sleeve.
[0150] During the initialization stage, the vertical position of
the sleeves can be manually or automatically adjusted to adjust the
vertical position of the needles. For example, the vertical
position of the sleeve can be adjusted depending on where the
sleeve is clamped by the locking mechanism. By adjusting the
vertical position of the sleeves and thus the needles, the amount
of opening at the nozzles can be adjusted accordingly. The
adjustment can be done during the initialization stage to ensure
that the needles can be controlled in a uniform manner (e.g., same
travel displacement) to dispense the same amount of printing
material during printing.
[0151] In some embodiments, the motion system that drives the push
plate includes an actuator. In some embodiments, the actuator is
disposed over the sleeve component(s). The actuator can be a
pneumatic actuator, a mechanical actuator, an electromagnetic
actuator, hydraulic actuator, or an electrical motor. The motion
system can be coupled to the push plate, for example, via the
support structure described above.
[0152] With reference to FIG. 4, the system comprises a
communicating runner connecting two nozzles. The pressure at the
two nozzles can be automatically balanced and controlled via a
close-loop flow control system that includes a sensor and a motor.
A switch is added to allow printing materials in the communicating
runners to be periodically dispensed to prevent the printing
materials from being held in the runner for an extended period of
time and breaking down in the runner. In some embodiments, multiple
sets of communicating runners can be provided to connect multiple
nozzles. Further, both needles are coupled to a single plate such
that the movement of the plate 402 (e.g., via manual control, via a
motor) causes the needles to move in a uniform manner.
[0153] Turing back to FIG. 1A, printing platform 110 is arranged on
a stage-driving mechanism. The stage-driving mechanism may drive
the printing platform 110 relative to the movement of the nozzles
106. In some embodiments, the stage-driving mechanism may be a
stepper motor, linear motor, or servo motor based on the Cartesian
coordinate system so that it can drive printing platform 110 along
the X-axis, one direction of the Y and Z axes or more direction. In
other embodiments, the printing apparatus 100 further includes a
module drive mechanism for driving movement of the printing
platform module 110 with respect to the nozzle 106. In still other
embodiments, the stage-driving mechanism may be a transfer track.
With the printing platform 110 and the relative movement of the
nozzles 106, the printing material is deposited into complex
structures and the desired configuration on the printing platform
110. It should be appreciated that other coordinate systems and/or
movement can be used.
[0154] 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 materials. By switching among
multiple arrays of nozzles, each resulting tablet can comprise
layers of different materials. As discussed, each nozzle comprises
a needle valve mechanism, which is coupled to a corresponding motor
112 and a computer controller for controlling the output of
printing material such that the resulting pharmaceutical dosage
units are consistent in the same batch and across multiple batches
in volume, weight, and/or composition.
[0155] FIG. 1D depicts an exemplary system for printing
pharmaceutical dosage units using multiple arrays of nozzles, in
accordance with some embodiments. In the depicted example, the
pharmaceutical dosage unit to be printed comprises four parts:
Inner Part 1, Inner Part 2, Inner Part 3, and a Shell. The printing
process occurs in four phases. In the first phase, a first array of
nozzles are configured to dispense Material 1 based on a first set
of instructions to print a batch of Inner Part 1 units. In some
embodiments, the set of instructions is implemented as an API. In
the second phase, a second array of nozzles are configured to
dispense Material 2 based on API 2 to print a batch of Inner Part 2
units. In the third phase, a third array of nozzles are configured
to dispense Material 3 based on API 3 to print a batch of Inner
Part 3 units. In the first, second, and third phases, the batches
of parts are all printed over the same printing platform. Further,
each Inner Part 1 unit has a corresponding Inner Part 2 unit and
Inner Part 3 unit, and the three units are generated on the
printing platform such that the relative placement of the three
units is consistent with the desired placement within a
pharmaceutical dosage unit.
[0156] In the fourth phase, a fourth array of nozzles are
configured to dispense Material 4 based on API 4 to print a batch
of shells. Each shell is created to coat over an Inner Part 1 unit
and the corresponding Inner Part 2 unit and the Inner Part 3 unit
to form a final pharmaceutical unit.
[0157] The printing material comprises viscous materials. In some
embodiments, it is medicinal material or thermoplastic material, or
a combination thereof. In some embodiments, the material is
dispensed from a nozzle at a temperature of about 25 degrees to
about 400 degrees Celsius. In some embodiment, the viscosity of the
material is between 0.001-10000 Pas.
[0158] In some embodiments, the material is a non-filamentous
material, such as a powder, granules, a gel, or a paste. The
non-filamentous material is melted and pressurized so that it can
be dispensed through an extrusion port of a nozzle. As described
further herein, pressure of particularly viscous materials is
carefully controlled to ensure precise and accurate depositing of
the material. The material can be melted within the material supply
module using one or more heaters disposed within the material
supply module, such as within or surrounding a barrel containing
the material, a feed channel, and/or a nozzle. In some embodiments,
the melting temperature of the material is about 30.degree. C. or
higher, such as about 60.degree. C. or higher, about 70.degree. C.
or higher, about 80.degree. C. or higher, about 100.degree. C. or
higher, about 120.degree. C. or higher, about 150.degree. C. or
higher, about 200.degree. C. or higher, or about 250.degree. C. or
higher. In some embodiments, the melting temperature of the
material is about 400.degree. C. or lower, such as about
350.degree. C. or lower, about 300.degree. C. or lower, about
260.degree. C. or lower, about 200.degree. C. or lower, about
150.degree. C. or lower, about 100.degree. C. or lower, or about
80.degree. C. or lower. Material dispensed from the nozzle can 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.degree. C. or higher, such as about
60.degree. C. or higher, about 70.degree. C. or higher, about
80.degree. C. or higher, about 100.degree. C. or higher, about
120.degree. C. or higher, about 150.degree. C. or higher, about
200.degree. C. or higher, or about 250.degree. C. or higher. In
some embodiments, the material is dispensed at a temperature of
about 400.degree. C. or lower, such as about 350.degree. C. or
lower, about 300.degree. C. or lower, about 260.degree. C. or
lower, about 200.degree. C. or lower, about 150.degree. C. or
lower, about 100.degree. C. or lower, or about 80.degree. C. or
lower.
[0159] The system described herein is useful for accurately and
precisely dispensing viscous materials. In some embodiments, the
material has a viscosity of about 100 Pas or more, such as about
200 Pas or more, about 300 Pas or more, about 400 Pas or more,
about 500 Pas or more, about 750 Pas or more, or about 1000 Pas or
more, when dispensed from the device. In some embodiments, the
material has a viscosity of about 2000 Pas or less, such as about
1000 Pas or less, about 750 Pas or less, about 500 Pas or less,
about 400 Pas or less, about 300 Pas or less, or about 200 Pas or
less.
[0160] 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
material, 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 a co-polymer.
[0161] In some embodiments, the material comprises a thermoplastic
material. In some embodiments, the material is a thermoplastic
material. In some embodiments, the material is or comprises an
erodible thermoplastic material. In some embodiments, the
thermoplastic material is edible (i.e., suitable for consumption by
an individual). In some embodiments, the thermoplastic material is
selected from the group consisting of a hydrophilic polymer, a
hydrophobic polymer, a swellable polymer, a non-swellable polymer,
a porous polymer, a non-porous polymer, an erodible polymer (such
as a dissolvable polymer), a pH sensitive polymer, a natural
polymer, a wax-like material, and a combination thereof. In some
embodiments, the thermoplastic material is a cellulose ether, a
cellulose ester, an acrylic resin, ethylcellulose,
hydroxypropylmethylcellulose, hydroxypropyl cellulose,
hydroxymethylcellulose, a mono- or diglyceride of C.sub.12-C.sub.30
fatty acid, a C.sub.12-C.sub.30 fatty alcohol, a wax,
poly(meth)acrylic acid, polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymer 57/30/13,
polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),
polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,
polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and
polyvinylpyrrolidone (PVP) 80/20, vinylpyrrolidone-vinyl acetate
copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft
copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl
alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl
methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl
methacrylate) 1:2:1,
poly(dimethylaminoethylmethacrylate-co-methacrylic esters),
poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride), poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic
acid-co-methylmethacrylate) 1:2, poly(methacylic acid-co-ethyl
acrylate) 1:1, poly(methacylic acid-co-methyl methacrylate) 1:1,
poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),
hyperbranched polyesteramide, hydroxypropyl methylcellulose
phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or
hypromellose (HMPC), hydroxypropyl methylcellulose acetate
succinate or hypromellose acetate succinate (HPMCAS),
poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl
acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and
polycaprolactone (PCL), hydroxyl propyl cellulose (HPC), polyoxyl
40 hydrogenerated castor oil, methyl cellulose (MC), ethyl
cellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate
(HPMCP), poloxamer, hydrogenated castor oil, hydrogenated soybean
oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA),
polyglycolic acid (PGA), cellulose acetate butyrate (CAB),
polyvinyl acetate phthalate (PVAP), a wax, beeswax, hydrogel,
gelatin, hydrogenated vegetable oil, polyvinyl acetal diethyl
aminolactate (AEA), paraffin, shellac, sodium alginate, cellulose
acetate phthalate (CAP), arabic gum, xanthan gum, glyceryl
monostearate, octadecanoic acid, thermoplastic startch, derivatives
thereof (such as the salts, amides, or esters thereof), or a
combination thereof.
[0162] 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 a non-thermoplastic starch, sodium
starch glycolate (CMS-Na), sucrose, dextrin, lactose,
microcrystalline cellulose (MCC), mannitol, magnesium stearate
(MS), powdered silica gel, titanium dioxide, glycerin, syrup,
lecithin, soybean oil, tea oil, ethanol, propylene glycol,
glycerol, Tween, an animal fat, a silicone oil, cacao butter, fatty
acid glycerides, vaseline, chitosan, cetyl alcohol, stearyl
alcohol, polymethacrylate, non-toxic polyvinyl chloride,
polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, or
a combination thereof.
[0163] Exemplary materials that may be used with the device
described herein or the methods described herein include, but are
not limited to, a poly(meth)acrylate co-polymer (such as a
co-polymer containing one or more of amino alkyl methacrylate,
methacrylic acid, metacrylic ester, and/or ammonioalkyl
methacrylate, such as a copolymer sold under the brand name
Eudragit.RTM. RSPO) and hydroxyl propyl cellulose (HPC). In some
embodiments, the material comprises a drug. In some embodiments,
the material is admixed with a drug.
[0164] FIG. 6A depicts an exemplary process 600 for 3D printing
pharmaceutical dosage units, according to some embodiments of a
present invention. Process 600 is performed, for example, using a
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 combination with the process 600.
Accordingly, the operations as illustrated (and described in
greater detail below) are exemplary by nature and, as such, should
not be viewed as limiting.
[0165] In some embodiments, the printing system comprises one or
more computer controllers. The computer controllers can be
programmed based on a plurality of manufacturing parameters. The
plurality of manufacturing parameters include printing speed,
target temperature values associated with different portions of the
printing system (e.g., the flow distribution plate, the distal end
of the nozzles, the material supply module, the pump), and pressure
curves. In some embodiments, some of the manufacturing parameters
are specified by the user, while others are automatically
calculated by a computer. The manufacturing parameters can be
determined based on desired metrics of the pharmaceutical dosage
units (e.g., volume, weight, composition, dimensions), the printing
materials, and/or the settings of the printing system. In some
embodiments, programming logic/code is generated based on the
plurality of manufacturing parameters.
[0166] At block 602, the printing system performs initialization
steps. The initialization steps can include starting up the system,
loading necessary data (e.g., 3D models) and programming logic,
initialize parameters, or a combination thereof. The initialization
steps can further comprises a heating process to achieve desired
temperatures at various components of the printing system (e.g.,
raising the temperature of the heating wires). In some embodiments,
the heating process is controlled by a
proportional-integral-derivative controller ("PID controller").
Specifically, the PID controller can measure (e.g., periodically)
temperatures of various components of the printing system and
determine whether one or more target temperatures are realized. In
accordance with a determination that the one or more target
temperatures are not realized, the PID controller continues the
heating process. In accordance with a determination that the one or
more target temperatures are realized, the PID controller provides
an output. In some embodiments, the output is a visual, audible, or
haptic output to alert a human worker to add printing materials. In
some embodiments, the output is an output signal that triggers the
printing materials to be added to the printing system
automatically.
[0167] At block 604, the system receives and processes a set of
printing materials. The printing materials can include active
ingredients and/or excipients in a predefined composition. The
printing materials can include medicinal material, thermoplastic
material, and a combination thereof. At the material supply module,
the printing materials are blended, plasticized, and melted. At
block 606, the processed printing materials are transported as a
single flow to the flow distribution module, for example, via a
single screw pump (e.g., gear pump or screw valve).
[0168] At block 608, the flow distribution module divides the
single flow of processed printing materials into a plurality of
flows. Specifically, the flow distribution plate comprises a
plurality of channels such as those described with reference to
FIGS. 2A-C. Through the channels, the plurality of flows reach the
distal ends of a plurality of nozzles. When the printing system
starts up, the needle-valve mechanisms of the nozzles are in closed
position, thus preventing the plurality of flows from being
dispensed. In some embodiments, the needle-value mechanisms of the
nozzles are not activated until a desired temperature is reached at
the nozzles.
[0169] At block 610, the system performs tuning steps. FIG. 5B
depicts an exemplary process 550 for tuning the 3D printing system,
in accordance with some embodiments.
[0170] At block 652, the system starts dispensing the plurality of
flows at the plurality of nozzles to produce a first batch of test
pharmaceutical dosage units (e.g., tablets caplets, printlets).
Specifically, as each flow of printing materials accumulates at the
sealed distal end of the corresponding nozzle, the pressure sensors
(e.g., at the distal end of the nozzle, at the flow distribution
plate) start receiving higher pressure readings. When the pressure
readings exceed a predefined threshold, the needle-valve mechanisms
may be opened to start dispensing the plurality of flows. Before
the needle-valve mechanisms are opened, the system maintains the
pressure of the printing materials at the nozzles. The opening of
the needle-valve mechanisms can be triggered by one or more
controllers at any time.
[0171] Upon opening of the needle-valve mechanisms, the system
starts dispensing the plurality of flows to 3D print the first
batch of plurality of test pharmaceutical dosage units (e.g.,
tablets caplets, printlets). The flow volume for 3D printing a
single batch of units is controlled via a closed-loop control
system based on a predefined pressure curve. FIG. 5 illustrates an
exemplary pressure curve, in which each cycle represents a session
of opening, printing, and closing of the needle-valve
mechanism.
[0172] At blocks 654-662, the system makes iterative adjustments to
nozzles and the material supply module until the sum of weights of
a test batch (e.g., a batch of 32 tablets) falls within a
predefined margin of error, while improving the consistency among
the weights of a test batch (e.g., the consistency among the
weights of 32 tablets). At block 554, the system determines whether
a sum of weights of the test batch differs from a target total
weight by a predefined amount (e.g., +/-0.5%, +/-1%, +/-2%, +/-3%,
+/-4%, +/-5%).
[0173] At block 656, in accordance with a determination that the
error difference is higher than the predefined amount, the system
makes adjustments to reduce error. In some embodiments, block 556
includes adjusting one or more nozzles (block 558) and adjusting
the material supply module (block 560).
[0174] At block 658, the system adjusts one or more nozzles,
specifically the openings at the one or more nozzles, based on an
average weight of the batch of test units. The goal is to reduce
the variance among the outputs of the nozzles. For each nozzle, the
adjustment is determined based on the formula below.
H.sub.next=H.sub.C-.alpha.*(W.sub.A-W.sub.C) (1)
[0175] In the formula above, H.sub.next represents the amount of
opening of the needle-valve mechanism of the respective nozzle in
the next iteration (in millimeter); H.sub.c represents the amount
of opening of the needle-valve mechanism of the respective nozzle
in the current iteration (in millimeter); W.sub.A represents the
average weight of the test batch in the current iteration (in
milligram); W.sub.C represents the weight of the test unit produced
by the respective nozzle in the current iteration (in milligram); a
represents an opening coefficient, which can vary for different
needle-valve mechanisms (in mm/mg). In some embodiments, a machine
learning algorithm can be used to determine the amount of opening
at each nozzle. The amount of opening of the needle-valve is
directed related to the travel displacement of the needle--as the
needle travels upward, the amount of opening increases; as the
needle travels downward, the amount of opening decreases. The terms
"amount of opening" and "travel displacement" are used
interchangeable herein.
[0176] At block 660, the system adjusts the material supply module,
for example, by adjusting the pressure and temperature (e.g., based
on the pressure readings at the nozzles, based on the pressure
readings at the flow distribution plate), adjusting the feeding
speed/amount, or any combination thereof. For example, if the total
weight of the test batch exceeds the target batch weight, the
system can reduce the pressure, reduce the temperature, reduce
feeding speed/amount, or any combination thereof.
[0177] At block 662, after the adjustments are made, the system
opens the needle-valve mechanisms to 3D print another batch of
plurality of test units. At block 554, the system determines
whether a sum of weights of the new test batch differs from a
target total weight by a predefined amount (e.g., +/-0.5%, +/-1%,
+/-2%, +/-3%, +/-4%, +/-5%). If not, the system repeats the steps
in 556 to continue adjusting the material supply modules and the
nozzles.
[0178] At block 664, in accordance with a determination that the
sum of weights of the new test batch does not differ from a target
total weight by the predefined amount, the system adjusts one or
more nozzles based on a target weight of the pharmaceutical unit.
In other words, after achieving a target batch weight while
improving the consistency among the nozzle outputs, the system then
makes adjustments to the nozzles to make sure each nozzle can
achieve the target weight (e.g., a target weight of a particular
tablet).
[0179] Specifically, the system adjusts one or more nozzles,
specifically the openings at the one or more nozzles, based on a
target weight of the pharmaceutical unit. For each nozzle, the
adjustment is determined based on the formula below.
H.sub.next=H.sub.C-.alpha.*(W.sub.T-W.sub.C) (2)
[0180] In the formula above, H.sub.next represents the amount of
opening of the needle-valve mechanism of the respective nozzle in
the next iteration (in millimeter); H.sub.c represents the amount
of opening of the needle-valve mechanism of the respective nozzle
in the current iteration (in millimeter); W.sub.T represents the
target weight of the unit (in milligram); W.sub.C represents the
weight of the test unit produced by the respective nozzle in the
current iteration (in milligram); a represents an opening
coefficient, which can vary for different needle-valve mechanisms
(in mm/mg). In some embodiments, a machine learning algorithm can
be used to determine the amount of opening at each nozzle.
[0181] The primary difference between formula (1) and (2) is the
difference between W.sub.T and W.sub.A. In some embodiments, the
batch weight is first adjusted, for example, by adjusting pressure
and temperature within the system. When the batch weight is within
a desirable range, the unit weight is adjusted, for example, by
adjusting the opening and closing of the needle valves.
[0182] At block 666, the system 3D prints a new test batch. At
block 668, the system determines whether the weight of each test
unit in the new test batch differs from the target unit weight by a
predefined amount (e.g., +/-0.5%, +/-1%, +/-2%, +/-3%, +/-4%,
+/-5%). In some embodiments, the predefined amount is +/-1.5%. If
no, the initialization is complete. If yes, the system continues
the tuning steps by repeated some or all of steps 654-664.
[0183] The tuning steps described above are exemplary. Parameters
other than weight of a pharmaceutical unit, such as weight of
output deposit (e.g., extruded wire), volume, dimension, and/or
composition, can be used in the tuning steps to achieve consistency
among the nozzles and across batches in these parameters.
[0184] The tuning steps can be used in conjunction with close-loop
control systems. In some embodiments, the system comprises a
temperature close-loop control system, which adjusts the heater and
the temperature control device based on temperature readings (e.g.,
from temperature sensors in the material supply module, the flow
distribution plate, or nozzle) to achieve and maintain the target
temperature. In some embodiments, average of temperature readings
from multipole temperature sensors is used. For example, a
temperature sensor can transmit a measured temperature to a
computer system, and the computer system can operate the one or
more heaters to ensure an approximately constant temperature. The
temperature sensor in the nozzle can operate with the one or more
heaters in the nozzle in a closed-loop feedback system to ensure
approximately constant temperature of the material within the
nozzle.
[0185] The temperature sensors described herein can comprise
thermocouple sensors (e.g., type J, type K) or resistance
thermometers. In some embodiments, the temperature sensors are
configured to measure temperature below 200.degree. C. The pressure
sensors described herein comprise piezo-resistance type transducers
or strain-gauge sensors. In some embodiments, small-range
strain-gauge sensors are used. Depending on the location of the
temperature or pressure sensor (e.g., within or in proximity to the
material supply module, flow distribution plate, or nozzle),
different types of the sensor can be used.
[0186] In some embodiments, the one or more heaters in the system
heat the material within the system to a temperature at or above
the melting temperature of the material. In some embodiments, the
one or more heaters heats the material to a temperature of about
60.degree. C. or higher, such as about 70.degree. C. or higher,
80.degree. C. or higher, 100.degree. C. or higher, 120.degree. C.
or higher, 150.degree. C. or higher, 200.degree. C. or higher, or
250.degree. C. or higher. In some embodiments, the one or more
heaters heats the material to a temperature of about 300.degree. C.
or lower, such as about 260.degree. C. or lower, 200.degree. C. or
lower, 150.degree. C. or lower, 100.degree. C. or lower, or
80.degree. C. or lower. In some embodiments, the one or more
heaters heat the material to different temperatures at different
locations of the device. For example, in some embodiments, the
material is heated to a first temperature within the barrel, a
second temperature within the feed channel, and a third temperature
within the nozzle, each of which may the same temperature or
different temperatures. In some embodiments, the temperature of the
material at the nozzle is higher than the feed channel and the
channels in the flow distribution plate, for example, by
0-10.degree. C. or 0-20.degree. C. By way of example, a material
may be heated to 140.degree. C. in the barrel and the feed channel,
but to 160.degree. C. when in the nozzle. The feedback control
system allows high precision of the temperature. In some
embodiments, the temperature is controlled within 0.1.degree. C. of
the target temperature, within 0.2.degree. C. of the target
temperature, within 0.5.degree. C. of the target temperature,
within 1.degree. C. of the target temperature, or within 10.degree.
C. of the target temperature.
[0187] In some embodiments, the system comprises a pressure
close-loop control system, which adjusts the material supply module
(e.g., the rotation speed of the screw mechanism) based on pressure
readings (e.g., from pressure sensors in the flow distribution
plate or nozzle) to achieve and maintain the target pressure. In
some embodiments, average of pressure readings from multipole
pressure sensors is used.
[0188] In some embodiments, the pressure sensors are configured to
detect pressure of the material within the nozzle or the feed
channel proximal to the nozzle. In some embodiments, pressure
sensors are positioned within the nozzle or adjacent to the feed
channel and proximal to the nozzle. The pressure sensors can
operate with the pressure controller in a closed-loop feedback
system to provide approximately constant pressure to the material
in the device. For example, when a pressure sensor detects a
decrease in pressure, feedback system can signal the pressure
controller to increase pressure of the material (e.g., by lowering
the piston, increasing air pressure in the barrel, turning the
pressure screw, etc.). Similarly, when the pressure sensor detects
an increase in pressure, the feedback system can signal the
pressure controller to decrease pressure of the material (e.g., by
raising the piston, decreasing air pressure in the barrel, turning
the pressure screw, etc.). Constant pressure ensures that the
melted material in the device is dispensed through the extrusion
port of the nozzle at a constant rate when the sealing needle is in
the open position. However, when the sealing needle is in a closed
position, constant pressure increase (e.g., by raising the piston,
decreasing air pressure in the barrel, turning the pressure screw,
etc.) may cause leakage of the melted material through the nozzle.
Additionally, the feedback system including the pressure sensor and
pressure controller keeps an approximately constant pressure in the
system when the sealing needle is repositioned from the open
position to the closed position, or from the closed position to the
open position. This minimizes a "ramp up" in extrusion rate when
the sealing needle is positioned in the open position from the
closed position because there is no need to ramp up pressure of the
material in the system. The feedback system can be operated using a
proportional-integral-derivative (PID) controller, a bang-bang
controller, a predictive controller, a fuzzy control system, an
expert system controller, or any other suitable algorithm. In some
embodiments, the sample rate of the pressure sensor is about 20 ms
or less, such as about 10 ms or less, about 5 ms or less, or about
2 ms or less. In some embodiments, the pressure is controlled
within 0.01 MPa of the target pressure, within 0.05 MPa of the
target pressure, within 0.1 MPa of the target pressure, within 0.2
MPa of the target pressure, within 0.5 MPa of the target pressure,
or within 1 MPa of the target pressure.
[0189] Turning back to FIG. 6A, at block 612, the system prints one
or more batches of pharmaceutical dosage units. In some
embodiments, the system periodically conducts quality checks on the
pharmaceutical dosage units, for example, by measuring the batch
weights or the unit weights and determining whether they are within
desirable ranges. If the batch weights or the unit weights fall out
of the desirable ranges, the system can perform some or all of
steps 654-664 to make adjustments and/or use any of the close-loop
control systems described above.
[0190] In some embodiments, the system comprises multiple arrays of
nozzles for printing multiple layers of a pharmaceutical unit. Each
of the arrays of nozzles can be tuned in accordance with the steps
described above. The system can comprise a controller to coordinate
the operation of the multiple arrays to 3D print a batch of
pharmaceutical dosage units.
[0191] The various controllers used in the printing system can
comprise programmable logic controllers (PLC) which, for example,
comprise a proportional-integral-derivative (PID) controller, a
bang-bang controller, a predictive controller, a fuzzy control
system, an expert system controller, or any other suitable
controller. Further, bus structure can be used in some embodiments.
The feedback system can use proportional integral differential
control, bang-bang control, predictive control, fuzzy control
systems, expert control, or any other appropriate control
logic.
[0192] The operations described above with reference to FIGS. 5A-B
are optionally implemented by components depicted in FIG. 6. It
would be clear to a person having ordinary skill in the art how
other processes are implemented based on the components depicted in
FIG. 6.
[0193] An exemplary system for creating pharmaceutical products by
additive manufacturing, comprises: a material supply module for
receiving a set of printing materials; a flow distribution module
comprising a flow distribution plate, wherein the material supply
module is configured to transport a single flow corresponding to
the set of printing materials to the flow distribution plate;
wherein the flow distribution plate comprises a plurality of
channels for dividing the single flow into a plurality of flows; a
plurality of nozzles; and one or more controllers for controlling
the plurality of nozzles to dispense the plurality of flows based
on a plurality of nozzle-specific parameters.
[0194] In some embodiments, the system further comprises a printing
platform configured to receive the dispensed plurality of flows,
wherein the printing platform is configured to move to form a batch
of the pharmaceutical product.
[0195] In some embodiments, the material supply module is
configured to heat the received set of printing materials.
[0196] In some embodiments, the material supply module is
configured to plasticize the received set of printing
materials.
[0197] In some embodiments, the material supply module comprises a
piston mechanism, a screw mechanism, a screw pump mechanism, a
cogwheel mechanism, a plunger pump mechanism or any combination
thereof.
[0198] In some embodiments, the plurality of channels forms a first
juncture configured to dividing the single flow into two flows.
[0199] In some embodiments, wherein the plurality of channels forms
a second juncture and a third juncture configured to divide the two
flows into 4 flows.
[0200] In some embodiments, the first juncture is positioned higher
than the second juncture and the third juncture.
[0201] In some embodiments, the first juncture, the second
juncture, and the third juncture are positioned on a same
plane.
[0202] In some embodiments, the flow distribution plate is
split-table into a plurality of components, wherein the plurality
of components are configured to be held together via one or more
screws.
[0203] In some embodiments, a nozzle of the plurality of nozzles
comprises a heating device.
[0204] In some embodiments, the plurality of nozzles comprises a
plurality of needle-valve mechanisms.
[0205] 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
is tapered at a distal end of the nozzle; and a needle, wherein a
distal end of the needle is configured to be in 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
be retracted to allow a flow of printing materials to be
dispensed.
[0206] In some embodiments, movement of the needle is driven by one
or more motors.
[0207] In some embodiments, the one or more motors include a linear
motor.
[0208] In some embodiments, movement of the needle is controlled
manually.
[0209] In some embodiments, a parameter of the plurality of
nozzle-specific parameters comprises an amount of opening of a
respective nozzle.
[0210] In some embodiments, the one or more controllers are
configured to adjust the amount of opening of the respective nozzle
based on a weight of a unit in the batch corresponding to the
respective nozzle.
[0211] In some embodiments, the one or more controllers are
configured to adjust the amount of opening of the respective nozzle
based one or more machine learning algorithms.
[0212] In some embodiments, the one or more controllers are
configured to control temperature or pressure at the plurality of
the nozzles.
[0213] In some embodiments, the temperature is controlled via a
heating device and a temperature control device.
[0214] In some embodiments, a temperature at the plurality of the
nozzles is higher than a temperature at the materials supply
module.
[0215] In some embodiments, a temperature at the plurality of the
nozzles is higher than a temperature at the flow distribution
plate.
[0216] In some embodiments, the one or more controllers are
configured to control a feeding speed of the set of printing
materials.
[0217] In some embodiments, the plurality of nozzles is a first
plurality of nozzles, the printing system further comprising a
second plurality of nozzles configured to dispense a different set
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.
[0218] In some embodiments, the pharmaceutical unit is a
tablet.
[0219] An exemplary computer-enabled method for creating
pharmaceutical products by additive manufacturing, comprises:
receiving a plurality of unit measurements corresponding to a
plurality of pharmaceutical dosage units, wherein the plurality of
pharmaceutical dosage units are generated using a plurality of
nozzles of an additive manufacturing system; determining whether a
sum of the plurality of unit measurements differs from a target
batch measurement by more than a predefined threshold; in
accordance with a determination that the sum differs from the
target batch measurement by more than the predefined threshold,
adjusting one or more nozzles of the plurality of nozzles based on
an average of the plurality of unit measurements; in accordance
with a determination that the sum does not differ from the target
batch measurement by more than the predefined threshold, adjusting
one or more nozzles of the plurality of nozzles based on a target
unit measurement.
[0220] In some embodiments, the plurality of pharmaceutical unit is
a plurality of tablets.
[0221] In some embodiments, the unit measurements are weight
measurements of the plurality of pharmaceutical dosage units.
[0222] In some embodiments, the unit measurements are volume
measurements of the plurality of pharmaceutical dosage units.
[0223] In some embodiments, the unit measurements are composition
measurements of the plurality of pharmaceutical dosage units.
[0224] In some embodiments, the method further comprises: in
accordance with a determination that the sum differs from the
target batch measurement by more than the predefined threshold,
adjusting one or more operation parameters of the additive
manufacturing system.
[0225] In some embodiments, the one or more operation parameters
include temperature.
[0226] In some embodiments, the one or more operation parameters
include pressure.
[0227] In some embodiments, the one or more operation parameters
include a speed of feeding printing materials.
[0228] In some embodiments, the predefined threshold is between
+/-0.5% to +/-5%.
[0229] In some embodiments, the method further comprises, after
adjusting one or more nozzles of the plurality of nozzles based on
a target unit measurement, printing a new batch; determining
whether a weight of an unit in the new batch differs from the
target unit measurement by more than a second predefined
threshold.
[0230] In some embodiments, the second predefined threshold is less
than 5%.
[0231] An exemplary method for manufacturing pharmaceutical
products by additive manufacturing comprises: receiving, using a
material supply module, a set of printing materials; transporting,
using the material supply module, a single flow corresponding to
the set of printing materials to a flow distribution plate, wherein
the flow distribution plate comprises a plurality of channels;
dividing, via the plurality of channels of the flow distribution
plate, the single flow into a plurality of flows; causing a
plurality of nozzles to dispense the plurality of flows based on a
plurality of nozzle-specific parameters.
[0232] An exemplary non-transitory computer-readable storage medium
stores one or more programs, the one or more programs comprising
instructions, which when executed by one or more processors of an
electronic device having a display, cause the electronic device to:
receive a plurality of weight measurements corresponding to a
plurality of pharmaceutical dosage units, wherein the plurality of
pharmaceutical dosage units are generated using a plurality of
nozzles of a 3D printing system; determine whether a sum of the
plurality of weight measurements differs from a target batch weight
by more than a predefined threshold; in accordance with a
determination that the sum differs from the target batch weight by
more than the predefined threshold, adjust one or more nozzles of
the plurality of nozzles based on an average weight measurement of
the plurality of weight measurements; in accordance with a
determination that the sum does not differ from the target batch
weight by more than the predefined threshold, adjust one or more
nozzles of the plurality of nozzles based on a target weight
measurement.
[0233] FIG. 7 illustrates an example of a computing device in
accordance with one embodiment. Device 700 can be a host computer
connected to a network. Device 700 can be a client computer or a
server. As shown in FIG. 7, device 700 can 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 phone or
tablet. The device can include, for example, one or more of
processor 710, input device 720, output device 730, storage 740,
and communication device 760. Input device 720 and output device
730 can generally correspond to those described above, and can
either be connectable or integrated with the computer.
[0234] Input device 720 can be any suitable device that provides
input, such as a touch screen, keyboard or keypad, mouse, or
voice-recognition device. Output device 730 can be any suitable
device that provides output, such as a touch screen, haptics
device, or speaker.
[0235] Storage 740 can be any suitable device that provides
storage, such as an electrical, magnetic or optical memory
including a RAM, cache, hard drive, or removable storage disk.
Communication device 760 can 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
can be connected in any suitable manner, such as via a physical bus
or wirelessly.
[0236] Software 750, which can be stored in storage 740 and
executed by processor 710, can include, for example, the
programming that embodies the functionality of the present
disclosure (e.g., as embodied in the devices as described
above).
[0237] Software 750 can also be stored and/or transported within
any non-transitory computer-readable storage medium for use by or
in connection with an instruction execution system, apparatus, or
device, such as those described above, that can fetch instructions
associated with the software from the instruction execution system,
apparatus, or device and execute the instructions. In the context
of this disclosure, a computer-readable storage medium can be any
medium, such as storage 740, that can contain or store programming
for use by or in connection with an instruction execution system,
apparatus, or device.
[0238] Software 750 can 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 instructions associated with the software from the
instruction execution system, apparatus, or device and execute the
instructions. In the context of this disclosure, a transport medium
can be any medium that can communicate, propagate or transport
programming for use by or in connection with an instruction
execution system, apparatus, or device. The transport readable
medium can include, but is not limited to, an electronic, magnetic,
optical, electromagnetic or infrared wired or wireless propagation
medium.
[0239] Device 700 may be connected to a network, which can be any
suitable type of interconnected communication system. The network
can implement any suitable communications protocol and can be
secured by any suitable security protocol. The network can comprise
network links of any suitable arrangement that can implement the
transmission and reception of network signals, such as wireless
network connections, T1 or T3 lines, cable networks, DSL, or
telephone lines.
[0240] Device 700 can implement any operating system suitable for
operating on the network. Software 750 can 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 disclosure can be deployed in
different configurations, such as in a client/server arrangement or
through a Web browser as a Web-based application or Web service,
for example.
[0241] FIG. 8A depicts an exemplary layout of a standardized
multi-station printing system for pharmaceutical units, in
accordance with some embodiments. With reference to FIG. 8, the
multi-station printing system 800 comprises a plurality of printing
stations 802A, 802B, 802C, and 802D. The plurality of printing
stations are arranged in a linear fashion. In the top-down view
depicted in FIG. 8A, each of stations 802A-802D comprises a set of
nozzles (32 nozzles), which are configured to dispense multiple
flows of printing materials over a printing plate to print a batch
of pharmaceutical dosage units (e.g., a batch of tablets).
[0242] In some embodiments, each of the printing stations 802A-802D
is configured to move a printing plate along a x-axis, a y-axis,
and a z-axis with reference to a corresponding coordinate system.
In some embodiments, the coordinate systems of printing stations
802A-D are different from each other, thus allowing the printing
stations 802A-D to be controlled independently (e.g., via one or
more controllers).
[0243] Further with reference to FIG. 8, the multi-station system
800 comprises a plate transport mechanism 806. As depicted, the
plate transport mechanism 806 is configured to travel along the
channels 804A and 804B. The plate transport mechanism 806 is
configured to operate with the printing stations to move a printing
plate off one printing station (e.g., 802A) onto one of the two
ends of the plate transport mechanism (as shown by arrows 808A and
808B), transport the printing plate along either channel (as shown
by arrows 810A and 810B), and move the printing plate onto another
printing station. In some embodiments, the operations of the
printing stations and the plate transport mechanisms are
coordinated to maximize manufacturing rate and minimize idle time
of the printing stations.
[0244] The multiple stations in the system 806 can be arranged in
other layouts. In some embodiments, the multiple stations can be
arranged around a circle or a square.
[0245] In some embodiments, the plate transport mechanism can
comprise of one or more channels that are of a circular shape or
square shape such that it can transport printing plates from one
printing station to another. In some embodiments, the plate
transport mechanism comprises one or more grippers and/or robotic
arms for picking up a printing plate from one printing station and
moving the printing plate to another printing station.
[0246] FIG. 8B depicts a partial side view of the exemplary
multi-station system 800, in accordance with some embodiments. The
multi-station system 800 comprises multiple printing stations,
including printing station 802A and 802B. Printing station 802A
comprises a printing platform 806A and a set of nozzles (e.g., an
array of nozzles) placed over the printing platform. During
operation, the set of nozzles can simultaneously dispense a set of
flows of printing material onto a printing plate placed on the
printing platform 806A to form a batch of pharmaceutical dosage
units. Printing station 802B comprises a different set of one or
more nozzles and operates in a similar manner as the printing
station 802B. In some embodiments, the printing stations 802A and
802B work in concert to manufacture the same batch of
pharmaceutical dosage units. For example, at t0, the printing
station 802A prints a batch of shells of the pharmaceutical dosage
units over a plate placed on the printing platform 806A. The plate
is then transported to the printing station 802B (e.g., via a plate
transport mechanism) and placed onto the printing platform 806B. At
t1, the printing station 802B prints the inner components within
the batch of shells.
[0247] In some embodiments, the relative positioning (e.g., in the
x-axis direction, in the y-axis direction, in the z-axis direction)
between the printing platform and the nozzles varies from printing
station to printing station. This causes the relative positioning
between the pharmaceutical dosage units and the nozzles to vary
from printing station to printing station. For example, the nozzles
of the printing station 802A and the printing platform 806A may be
centrally aligned, while the nozzles of the printing station 802B
and the printing platform 806B may not be centrally aligned. In
this scenario, when the plate is transported from printing station
802A to printing station 802B, the batch of shells are not
perfectly aligned with the nozzles of the printing station 802A,
and the system needs to account for the misalignment in the
printing instructions in order to move the printing platform
accordingly to print the inner components within the batch of
shells.
[0248] Thus, in order to achieve high-precision printing of the
same batch of pharmaceutical dosage products across multiple
printing stations, the system need to acquire the relative
positioning between the printing platform and the nozzles for each
printing station. Based on how the relative positioning differs
among the printing stations, the system can adjust the printing
instruction on a given printing station to move the printing
platform/printing plate accordingly such that the set of nozzles
can dispense printing material at the appropriate position on the
printing plate.
[0249] FIG. 9 depicts an exemplary process for initializing a
multi-station printing system having a first printing station and a
second printing station, in accordance with 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 combination with the process 900. Accordingly, the
operations as illustrated (and described in greater detail below)
are exemplary by nature and, as such, should not be viewed as
limiting.
[0250] A plate is placed onto the printing platform of the first
printing station (e.g., printing platform 806A). In some
embodiments, the plate is attached to the printing platform 806A
via one or more pins to prevent relative movement between the plate
and the printing platform 806A. In some embodiments, one or more
magnetic components (e.g., electromagnetic components) of
adjustable strength can be used to ensure that the plate is
securely attached to the printing platform.
[0251] At block 902, after the plate is attached onto the first
printing platform (e.g., 806A), the system obtains the relative
positioning between the first printing platform (e.g., 806A) and
the nozzles of the first printing station (e.g., 802A). In some
embodiments, the relative positioning comprises a first value
indicative of the relative positioning on the x-axis and a second
value indicative of the relative positioning on the y-axis
value.
[0252] In some embodiments, obtaining the relative positioning
comprises moving the printing platform to measure the first value
and the second value. With reference to FIG. 8B, the printing
station 802A comprises a sensor module 810A and a sensor module
812A, which are affixed to the chassis of the printing station 802A
and thus always remain stationary with respect to the nozzles.
During the initialization process, the system can cause the
printing platform 806A to move on the x-axis until it is in contact
with the sensor 810A (e.g., based on the output of the sensor
810A). In accordance with a determination that the printing
platform 806A is in contact with the sensor 810A, the system
obtains the amount of movement (X1) of the printing platform 806A
on the x-axis from its initial position.
[0253] The system can further cause the printing platform 806A to
move on the y-axis direction until it is in contact with the sensor
812A (e.g., based on the output of the sensor 812A). In accordance
with a determination that the printing platform 806A is in contact
with the sensor 812A, the system obtains the amount of movement
(Y1) of the printing platform 806A on the x-axis from its initial
position. In some embodiments, the sensor 810A and the sensor 812A
can be any type of suitable sensor, such as a position sensor or a
displacement sensor.
[0254] At block 904, the system obtains the relative positioning
between the second printing platform (e.g., 806B) and the nozzles
of the second printing station (e.g., 802B). In some embodiments,
the same plate used in block 902 is used in block 904; in some
embodiments, a different plate is used. In some embodiments, no
plates are placed on the first and second printing platforms.
[0255] With reference to FIG. 8B, the printing station 802B
comprises a sensor module 810B and a sensor module 812B, which are
affixed to the chassis of the printing station 802B and thus always
remain stationary with respect to the nozzles. During the
initialization process, the system can cause the printing platform
806B to move on the x-axis until the platform (or the plate on the
platform) is in contact with the sensor 810B (based on the output
of the sensor 810A). In accordance with a determination that the
printing platform 806A is in contact with the sensor 810B, the
system obtains the displacement of movement (X2) of the printing
platform 806A on the x-axis from its initial position.
[0256] The system can further drive the printing platform 806B to
move on the y-axis until the platform (or the plate on the
platform) is in contact with the sensor 812B (e.g., based on the
output of the sensor 812B). In accordance with a determination that
the printing platform 806A is in contact with the sensor 812B, the
system obtains the displacement of movement (Y2) of the printing
platform 806B on the x-axis from its initial position.
[0257] In some embodiments, instead of moving the printing platform
and determining whether it is contact with a sensor to determine
the values of X1, X2, Y1, and Y2, the system uses one or more
retractable sensors to determine the above values (e.g., retracting
the a portion of the sensor to measure the distance X1, X2, Y1, or
Y2). In some embodiments, the system uses one or more laser sensors
to determine the above values.
[0258] At block 906, the system calculates the offset values based
on the relative positioning (between the printing platform and the
nozzles) in the first printing platform and the relative
positioning in the second printing platform. In some embodiments,
the offset values includes an x-axis offset value .DELTA.X and a
y-axis offset value .DELTA.Y. In some embodiments, .DELTA.X is
calculated as the difference between X1 and X2 (e.g.,
.DELTA.X=X1-X2). In some embodiments, .DELTA.Y is calculated as the
difference between Y1 and Y2 (e.g., .DELTA.Y=Y1-Y2).
[0259] At block 908, the offset values are inputted into one or
more controllers. The controllers are used to generate the motion
of the printing platforms of the printing stations. The offset
values are used such that when the plate is transported from
station to station, the location of the printing platform (and thus
the batch of pharmaceutical dosage units) relative to the nozzles
can be accurately determined.
[0260] Blocks 902-908 are steps directed to initializing the
printing stations with respect to the x-axis and the y-axis
direction. 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 comprises identifying the
zero point on the z-axis. The zero point is the z-axis position
where the printing platform and/or the printing plate comes in
contact with the nozzles, which is also where the printing of the
first layer occurs.
[0261] The identification of the zero point can be performed in a
number of ways. In some embodiments, the zero point is measured
using a plug gauge. In some embodiments, the zero point is
determined by elevating the printing platform in small increments
(e.g., using lower currents such as 20%-50% of the current level
during normal operation, at a lower speed such as 20%-50% of the
speed during normal operation) until the printing platform comes in
contact with the nozzles and can no longer be elevated further. In
accordance with a determination that the printing platform is in
contact with the nozzles (e.g., a resistance force above a
predefined threshold is detected), the system stops elevating the
printing platform and sets the location of the printing platform as
the zero point. In some embodiments, a sensor is affixed to the
printing plate with a retractable portion of the sensor protruded
out of the printing platform on the z-axis. A block is placed on
the printing plate over the sensor, such that the protruded portion
of the sensor is retracted. The retracted position of the sensor is
recorded. During future initializations, the printing platform is
elevated such that the nozzles come in contact with the protruded
portion of the sensor and cause the protruded portion of the sensor
to retract. When the previously recorded retracted position is
detected, the system sets the location of the printing platform as
the zero point on the z-axis.
[0262] Accordingly, the initialization process is complete and the
printing system is ready to start printing. For example, the system
can drive the first printing station to print a portion of a batch
of tablets (e.g., the bottom portions of the tablets) over a
printing plate, transport the printing 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 portions of the
tablets) based at least partially on the offset values inputted at
block 908. For example, the system causes the second printing
platform to move based on the offset values such that the top
portions of the tablets are aligned with the bottom portions of the
tablets.
[0263] In some embodiments, using the techniques described herein,
the derivations among the nozzles at each printing station can be
within 0.01 mm (e.g., 0.02-0.05 mm) on the x-axis, within 0.01 mm
(e.g., 0.02-0.05 mm) on the y-axis, and within 0.005 mm (e.g.,
0.01-0.05 mm) on the z-axis. This ensures that, when a batch of
pharmaceutical dosage units is transported and printed across
multiple printing stations, the nozzles at each printing station
can line up with the batch of pharmaceutical dosage units in an
accurate manner.
[0264] In some embodiments, multiple printing plates can be used in
the multi-station printing system. In some embodiments, each
printing plate is placed on all printing stations to obtain a
plurality of X-values (e.g., n X-values corresponding to the n
printing stations), a plurality of Y-values (e.g., n Y-values
corresponding to the n printing stations), and/or a plurality of
Z-values (e.g., n Z-values corresponding to the n printing
stations) associated with the plate. This way, the offset values
between any two printing stations for the plate can be obtained
such that, when the plate is moved from a first printing station to
a second printing station, the offset values can be used to
determine the location of the plate (and thus the batch of
pharmaceutical dosage units) relative to the nozzles of the second
printing station. Thus, the nozzles of the second printing station
can be moved accordingly to continue printing the batch of
pharmaceutical dosage units on the plate.
[0265] FIG. 10A depicts an exemplary architecture of a
multi-station 3D printing system, in accordance with some
embodiments. The 3D printing system 1000 comprises a plurality of
hardware components and software components, all of which can be
communicatively coupled together (e.g., via communication protocols
such as modbus, via one or more networks such as P2P networks) to
provide a high-speed and high-throughput printing system. With
reference to FIG. 10A, the system 1000 comprises a plurality of
controllers 1002A-1002N, which are configured to control the
movements of N printing stations, respectively. Each controller can
be coupled to a set of actuator(s) and motor(s) 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 can be used to control the movements of multiple
printing platforms of multiple printing stations.
[0266] The system 1000 further comprises a controller 1004, which
is configured to control the movement of a plate transport
mechanism (e.g., 806 depicted in FIG. 8A). The controller 1004 can
be coupled to a set of actuator(s) and motor(s) for moving a
printing plate (e.g., along a conveyor or channel, via a gripper
loader).
[0267] The system 1000 further comprises one or more controllers
1006 configured to control the feeding of the printing materials by
the material supply modules (e.g., 102 depicted in FIG. 1A). The
system further comprises one or more controllers 1008 configured to
control the needle valves at the printing nozzles. For example, the
one or more controllers 1008 can be coupled to actuator(s) and
motor(s) driving the movements of the needles. The system further
comprises temperature controller 1010, which is configured to
control temperature at various portions of the system (e.g., flow
distribution plate).
[0268] The system 1000 further comprises 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 analytic module, a
speed control module, or any combination thereof.
[0269] In some embodiments, the system 1000 is communicatively
coupled to one or more networks, such that it can rely on the cloud
for data storage, data management, and data analytics. In some
embodiments, the system 1000 is communicatively coupled to one or
more mobile devices such that the printing processes 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
processes, as well as to enter and modify printing parameters
(e.g., temperature, pressure, speed, needle positions and
movements). In some embodiments, the system provides real-time
monitoring of various parameters of the printing processes at all
printing stations and all printing plates.
[0270] In some embodiments, the system 1000 comprises a quality
control system for testing the printed dosage units against various
metrics (e.g., shape, size, composition, consistency). In some
embodiments, the system 1000 comprises additional hardware
components such as sensors, cameras, and alert systems.
[0271] FIGS. 10B-C depict exemplary processes for 3D printing
pharmaceutical dosage units using a multi-station system, according
to some embodiments. Processes 1030 and 1060 can be part of the
software modules 1012 depicted in FIG. 10A. In each process, 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 combination
with each process. Accordingly, the operations as illustrated (and
described in greater detail below) are exemplary by nature and, as
such, should not be viewed as limiting.
[0272] Process 1030 can be performed at a printing station of the
multi-station system. At block 1032, the system mounts a printing
plate onto a printing platform of the printing station. Optionally,
at block 1034, the system moves the printing platform to a
receiving position (e.g., by lowering the printing platform along
the z-axis) such that the printing plate can be moved from the
plate transport mechanism onto the printing platform (e.g., along
the y-axis direction by the plate transport mechanism).
[0273] At block 1036, the system determines whether the plate
aligned with the platform. In some embodiments, the system makes
the determination based on inputs from one or more sensors. In some
embodiments, the system determines that the plate is placed onto
the platform if a proper alignment between components of the plate
and components of the platform (e.g., pins) is detected.
[0274] At block 1038, in accordance with a determination that the
plate is placed onto the platform, the system couples the plate and
the platform. In some embodiments, the system performs the coupling
by raising the printing platform along the z-axis such that the
printing plate comes in contact with the printing platform. In some
embodiments, the system activates one or more electromagnetic
components to ensure that the plate is securely attached or coupled
to the platform.
[0275] At block 1040, the system identifies a portion of printing
instructions based on progress data associated with the printing
plate. In some embodiments, each printing station of the system has
access to a copy of the same printing instructions for printing a
pharmaceutical dosage unit. As such, each printing station needs to
identify the portion of the printing instructions before commencing
printing. In some embodiments, the progress data comprises a
current height of the pharmaceutical dosage units (i.e., along the
z axis), an identifier of the printing station, or a combination
thereof. In some embodiments, the progress data is provided to the
printing station by the plate transport mechanism.
[0276] At block 1042, the system performs 3D printing based on the
identified portion of printing instructions. In some embodiments,
the printing is performed based on the coordinate system associated
with the current printing station, which can be obtained as
discussed above with reference to FIG. 9.
[0277] In some embodiments, the system identifies the plate by
scanning a code (e.g., an RFID code) on the plate. In some
embodiments, the identity of the plate can be used to identify
printing instructions and the coordinate system.
[0278] At block 1044, the system determines whether printing is
complete based on the identified portion of printing instructions.
In some embodiments, the printing instructions include one or more
indicators marking the beginning and/or end of a portion of
printing instructions to be performed by a particular printing
station. As such, the system can determine that printing is
complete upon detecting the one or more indicators marking the end
of the portion of printing instructions.
[0279] At block 1046, in accordance with a determination that
printing is complete at the current printing station, the system
records progress data associated with the printing plate. In some
embodiments, the progress data includes an identifier of the next
printing station (e.g., based on the printing instructions), a
current height of the pharmaceutical dosage units, or a combination
thereof. In some embodiments, the current printing station records
the progress data and transmits the progress data to the plate
transport mechanism.
[0280] At block 1048, the system unloads the printing plate from
the printing platform. In some embodiments, this includes lowering
the printing platform and deactivating the electromagnetic
components such that the plate transport mechanism can pick up the
printing plate. In some embodiments, the current printing station
is marked as idle by the station itself and/or by the system.
[0281] FIG. 10C depicts an exemplary process for 3D printing
pharmaceutical dosage units using a multi-station system, according
to some embodiments. Process 1060 can be performed by the plate
transport mechanism. In order to coordinate the operations of
multiple printing stations and the plate transport mechanism, the
multi-station system tracks the status of its various components
via a plurality of parameters such as: identifiers of the printing
stations, locations of the printing stations, whether each printing
station is busy or idle, the locations of all printing plates, the
progress data (e.g., current height) associated with each printing
plate, the location of the plate transport mechanism (e.g.,
coordinates on the channels), the coordinate systems of the
printing stations, the height of all of the components (e.g.,
printing platforms, printing plates, plate transport mechanism), or
any combination thereof. These parameters, or multiple versions of
these parameters, can be store at a single location or distributed
across multiple components.
[0282] At block 1062, the system determines whether printing is
complete at a first printing station. The determination can be made
based on the status of the first printing station (e.g., busy or
idle) or based on signals transmitted from the first printing
station to the plate transport mechanism.
[0283] At block 1064, in accordance with a determination that
printing is complete at the first printing station, the system
determines whether the printing plate is placed onto the plate
transport mechanism. As discussed above with respect to FIG. 10B,
after the printing is complete, the printing station can decouple
the printing plate from the printing platform. Subsequently, the
plate transport mechanism can pick up the printing plate and move
the printing plate off the printing platform.
[0284] At block 1066, the system moves the printing plate along a
first axis (e.g., the x-axis). For example, as depicted in FIGS. 8A
and 8B, the system can move the printing plate along a conveyor
along the x-axis until the printing plate is beside the second
printing station. In some embodiments, the second printing station
is determined by the plate transport mechanism based on the
progress data generated in block 1046. In some embodiments, the
second printing station is determined by the system based on the
status and the printing materials at each printing station (e.g.,
selecting an idle station that can dispense the current printing
materials needed for the products on the printing plate).
[0285] At block 1068, the system determines whether the second
printing station is idle, for example, based on the status
parameter of the second printing station (e.g., stored on the
second printing station, stored on system-wide memory). At block
1070, in accordance with a determination that the second printing
station is idle, the system moves the printing plate along a second
axis (e.g., the y-axis) toward the second printing station. In some
embodiments, the plate transport mechanism notifies the second
printing station, which proceeds to mount the printing plate onto
its printing platform as discussed above. In some embodiments, the
second printing station is marked as busy. The status of the second
printing station can be stored locally at the second printing
station, at the plate transport mechanism, and/or at a system-wide
memory.
[0286] At block 1072, the system causes the second printing station
to perform 3D printing over the printing plate. The second printing
station can perform the process 1030, including receiving progress
data (e.g., from the plate transport mechanism and identifying a
portion of printing instructions).
[0287] At block 1074, the system determines whether printing is
complete at the second printing station. The determination can be
made based on the status of the second printing station (e.g., busy
or idle) or based on signals transmitted from the second printing
station to the plate transport mechanism. In accordance with a
determination that printing is complete at the second printing
station, the system determines whether the printing plate is placed
onto the plate transport mechanism. As discussed above with respect
to FIG. 10B, after the printing is complete, the second printing
station can decouple the printing plate from the printing platform.
Subsequently, the plate transport mechanism can pick up the
printing plate and move the printing plate off the printing
platform.
[0288] At block 1076, the system records progress data associated
with the printing plate. Progress data can comprise the current
height of the pharmaceutical dosage units on the printing plate. In
some embodiments, the progress data is determined by the second
printing station based on the printing instructions, and
transmitted from the second printing station to the plate transport
mechanism. In some embodiments, the plate transport mechanism can
transmit the progress data to the next printing station. In some
embodiments, the entire multi-station system stores one copy of the
progress data associated with the printing plate, and various
components of the system (e.g., plate transport mechanism,
stations) have access to the progress data.
[0289] Although the disclosure and examples have been fully
described with reference to the accompanying figures, 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 disclosure
and examples as defined by the claims.
[0290] 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 view of the above
teachings. The embodiments were chosen and described in order to
best explain the principles of the techniques and their practical
applications. Others skilled in the art are thereby enabled to best
utilize the techniques and various embodiments with various
modifications as are suited to the particular use contemplated.
* * * * *