TECHNICAL FIELD

The current disclosure relates to manufacturing of personalized pills and in particular to systems devices and methods for three-dimensional (3D) printing of personalized pills.

BACKGROUND

Traditional pharmaceutical and nutraceutical tableting processes have been refined and optimized over decades. In order to cater for their dedication to volume and speed, product and process development for each tablet or pill account for a substantial period of development time & costs, and once fixed, are changed infrequently.

However, each patient rarely consumes a single pill. Multiple pills daily or polypharmacy add on to medication errors, lack of compliance and unnecessary burden on caretakers and healthcare professionals. The ability to combine and customize several pills into one pill for each customer has so far been unable to surpass the barrier of cost as each typical pill manufactured via the conventional tableting press is a result of lengthy process development, as well as heavy capital investment into the large-scale tableting press.

Systems, devices and methods for improving manufacturing of personalized pills are desirable.

SUMMARY

According to embodiments of the present disclosure, a three-dimensional (3D) printing node for manufacturing a personalized pill is provided. The 3D printing node may comprise: an axis frame, a print head movably mounted to the axis frame, the print head configured to extrude a controlled amount of paste having an active ingredient during manufacturing of a portion of a personalized pill, and a near infra-red (NIR) spectrophotometer arranged to image the portion of the personalized pill to verify the portion of the personalized pill that was printed. According to some embodiments, the 3D printing node may further comprise a communication module for communicating with a remote computer system, wherein the 3D printing node communicates with the remote computer system to receive instructions for controlling the print head to extrude the controlled amount of paste.

According to some embodiments, the NIR spectrophotometer may communicate with the remote computer system via the communication module to compare the image of the portion of the personalized pill to a library of spectra, thereby to perform real-time quality control of the portion of the personalized pill. According to some embodiments, the spectra generated by the NIR spectrophotometer may be stored in association with an identifier of the portion of the personalized pill.

According to some embodiments, the 3D printing node may be coupled to at least a second 3D printing node, each printing node configured to extrude a controlled amount of a single paste, each paste comprising different active ingredients and different release profiles.

According to some embodiments, the 3D printing node may further comprise a conveyor mechanism for moving a printing plate between the 3D printing node and the at least second 3D printing node; and a positioning sensor for determining a location of the printing plate along the conveyor mechanism.

According to some embodiments, the conveyor mechanism may comprise a conveyor belt.

According to some embodiments, the positioning sensor may comprise an imaging sensor configured to capture an image of a registration mark on the printing plate.

According to some embodiments, the registration mark may provide information on an x-y position of the printing plate.

According to some embodiments, the registration mark may further provide information identifying a composition of the personalized pill printed on the printing plate. According to some embodiments, the registration mark may comprise a quick response (QR) code.

According to some embodiments, the 3D printing node may further comprise at least one communication module for co-ordinating manufacturing of different portions of the personalized pill by the 3D printing node and the at least second 3D printing node.

According to some embodiments, the communication module may communicate between the at least second 3D printing node and a remote computing system.

According to some embodiments, the remote computing system may control operation of the 3D printing node.

According to some embodiments, the communication module may comprise a wireless connection for communicating with at least one of: the at least second 3D printing node; and the remote computing system.

According to some embodiments, the wireless connection may comprise a plurality of wireless connections each for communication with each of the 3D printing nodes.

According to some embodiments, the communication module may comprise at least one wired connection for communicating with at least one of: the at least second 3D printing node; and the remote computing system. According to some embodiments, the at least one wired connection may comprise a plurality of wired connections each for communicating with each of the 3D printing nodes.

According to some embodiments, the plurality of wired connections each for communicating with each of the printing nodes are each for communicating with adjacent 3D printing nodes.

According to some embodiments, the 3D printing node may further comprise a second print head moveably mounted to the axis frame, the second print head configured to extrude a controlled amount of paste having an active ingredient during manufacturing of a portion of a personalized pill.

According to some embodiments, the print head and second print head may each be configured to receive a removable syringe of paste for extruding the paste.

According to some embodiments, each of the removable syringes may comprise paste having the same composition.

According to some embodiments, the 3D printing node may further comprise a sensor for identifying a syringe identifier on each of the removable syringes to identify the paste in the syringe.

According to some embodiments, the 3D printing node may further comprise a sensor for detecting the amount of paste within each of the removable syringes.

According to some embodiments, the personalized pill may comprise a polypill comprising a plurality of active ingredients.

According to some embodiments, the active ingredient of the paste comprises at least one of: a medicinal composition; a supplement composition; a nutraceutical composition; an alternative medicine composition; or a complementary medicine composition.

According to some embodiments, the paste may comprise a specific dosage amount and release profile of the active ingredient.

According to some embodiments, there is provided a system for manufacturing personalized pills, the system may comprise: a plurality of three-dimensional (3D) printing nodes, each comprising: an axis frame and a print head movably mounted to the axis frame, the print head configured to extrude a controlled amount of paste having an active ingredient during manufacturing of a portion of a personalized pill; a positioning sensor for determining a location of a printing plate with respect to the plurality of 3D printing nodes; a conveyor mechanism for moving the printing plate between adjacent 3D printing nodes of the plurality of 3D printing nodes; and a computing system, which may comprise: at least one processor; and a memory for storing instructions, to be executed by the at least one processor, to configure the computing system to coordinate printing of each layer of a plurality of personalized pills by a respective print head with respect to the plurality of printing heads of the plurality of 3D printing nodes.

According to some embodiments, each of the plurality of 3D printing nodes may further comprise a near infra-red (NIR) spectrophotometer configured to image the portion of the personalized pill, and wherein the memory of the computing system further comprises instructions to compare the spectra image of the portion of the personalized pill generated by the NIR spectrophotometer to a library of spectra, thereby to perform real-time quality control of the portion of the personalized pill.

According to some embodiments, the memory of the computing system may further comprise instructions to: receive a pill profile comprising a plurality of pill components; and generate a printing profile for printing a plurality of pills according to the pill profile via the plurality of 3D printing nodes such that each of the plurality of 3D printing nodes is configured to extrude a respective paste comprising at least one of the pill components.

According to some embodiments, the printing profile may be generated based on a volume and geometry of the personalized pill and a print sequence.

According to some embodiments, the printing profile may comprise a computer aided design (CAD) drawing.

According to some embodiments, the plurality of 3D printing nodes may be arranged along a printing line having a first 3D printing node and a last 3D printing node, the system may further comprise a conveyor loop for moving printing plates from the first 3D printing node to adjacent printing nodes until the printing plates reach the last 3D printing node to allow further pill layers to be printed by the plurality of 3D printing nodes.

According to some embodiments, the memory of the computing system may further comprise instructions to: display pill components capable of being printed by the plurality of 3D printing nodes; receive a selection of one or more of the displayed components, an associated amount for each of the selected components and a release profile for one or more of the selected components; generate a printing pill profile; and provide the printing pill profile to the computing system.

According to some embodiments, the active ingredient of the paste of each of the 3D printing nodes may comprise at least one of: a medicinal composition; a supplement composition; a nutraceutical composition; an alternative medicine composition; or a complementary composition.

According to some embodiments, the paste of each of the 3D printing nodes may comprise a respective dosage amount and release profile of the active ingredient. According to some embodiments, the personalized pills may be manufactured by the system in a standard pill shape or in a user-specified shape.

According to some embodiments, there is provided a method for manufacturing personalized pills using a plurality of three-dimensional (3D) printing nodes. The method may comprise: at a first one of the plurality of 3D printing nodes: identifying a location of a moveable printing plate; and printing a first portion of each of a plurality of pills on the printing plate using a first paste having a first composition; automatically moving the printing plate from the first one of the plurality of 3D printing nodes to a second one of the plurality of 3D printing nodes;

at the second one of the plurality of 3D printing nodes: identifying a location of the moveable printing plate; and printing a second portion of each of the plurality of pills on the printing plate using a second paste having a different composition from the composition of the first paste; and automatically moving the printing plate from the second one of the plurality of 3D printing nodes to a undergo a subsequent manufacturing operation.

According to some embodiments, the subsequent manufacturing operation may comprise at least one of: printing a further portion of the pills at a third 3D printing node; printing a further portion of the pills at the first 3D printing node; post processing the plurality of pills printed on the printing plate; or destroying the plurality of pills printed on the printing plate.

According to some embodiments, the method may further comprise: subsequent to printing the first portion of each of the plurality of pills and before automatically moving the printing plate: generating a near infra-red (NIR) spectra of the first portion; comparing the generated NIR spectra of the first portion to existing spectra; and based on the comparison, determining if the first portion of each of the plurality of pills was printed correctly.

According to some embodiments, the method may further comprise: subsequent to printing the second portion of each of the plurality of pills and before automatically moving the printing plate: generating a near infra-red (NIR) spectra of the second portion; comparing the generated NIR spectra of the second portion to existing spectra; and based on the comparison, determining if the second portion of each of the plurality of pills was printed correctly.

According to some embodiments, the generated NIR spectra of the first portion and the generated NIR spectra of the second portion may be stored in association with an identifier of the pills being printed. According to some embodiments, the first paste and the second paste may each comprise at least one of: a medicinal composition; a supplement composition; a nutraceutical composition; an alternative medicine composition; or a complementary composition.

According to some embodiments, the first paste and the second paste may each comprise a specific dosage amount and release profile of an active ingredient.

According to some embodiments, the method may further comprise: detecting when one of the first and second 3D printing nodes is low on paste; and providing a feedback signal to a central controller indicative of the low paste condition.

According to some embodiments, the method may further comprise providing a visual signal indicative of the amount of paste within each 3D printing node.

According to some embodiments, the visual signal may comprise a light system using a green light to indicate that the 3D printing node is full, an amber light to indicate that the 3D printing node is near empty and a red light to indicate that the 3D printing node is empty.

According to some embodiments, there is provided a personalized pill manufactured according to the method described hereinabove.

According to some embodiments, there is provided a 3D printed pill comprising: a plurality of individual components formed separately into a single pill, each of the individual components comprising a respective formulation having one or more active ingredients.

According to some embodiments, each of the individual components may have a wedge shape or a disk shape.

According to some embodiments, the pill may comprise a plurality of different wedge shaped components.

According to some embodiments, the pill may comprise a stack of a plurality of different disk shaped components.

According to some embodiments, there is provided a computer system comprising: at least one processor; and a memory for storing instructions, to be executed by the at least one processor, to configure the computing system to: display components capable of being printed by a plurality of 3D printing nodes; receive a pill profile comprising a selection of one or more of the displayed components, an associated amount for each of the selected components and a release profile for one or more of the selected components; generate a printing profile for printing a plurality of pills according to the received pill profile using the plurality of 3D printing nodes; and coordinate printing of a plurality of personalized pills according to the printing profile among the plurality of 3D printing nodes. BRIEF DESCRIPTION OF THE DRAWINGS

Features, aspects and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings in which:

FIG. 1 depicts a process of manufacturing personalized pills, in accordance with embodiments of the present disclosure;

FIG. 2 depicts details of the process for manufacturing personalized pills, in accordance with embodiments of the present disclosure;

FIG. 3A depicts a schematic 3D printing line for manufacturing personalized pills, in accordance with embodiments of the present disclosure;

FIG. 3B depicts a 3D entire production line for manufacturing personalized pills, in accordance with embodiments of the present disclosure;

FIGs. 4A-4B depict a 3D printing node with two printing heads for use in the 3D printing line of FIGs. 3A-3B, in accordance with embodiments of the present disclosure;

FIG. 4C depicts a 3D printing node with one printing head for use in the 3D printing line of FIGs. 3A-3B, in accordance with embodiments of the present disclosure;

FIG. 4D depicts an exploded view of a 3D printing node with one printing head, in accordance with embodiments of the present disclosure;

FIG. 4E depicts bottom, front and side views of the 3D printing node of FIG. 4A, in accordance with embodiments of the present disclosure;

FIGS. 5A-5B depict two printing modules, each of the two printing modules comprising two printing heads and each of the two printing modules comprising one printing head, respectively, in accordance with embodiments of the present disclosure;

FIG. 6 depicts a printing plate, in accordance with embodiments of the present disclosure;

FIG. 7 depicts a control system for use in controlling the 3D printing line of FIG. 3A, in accordance with embodiments of the present disclosure;

FIGs. 8A and 8B depict illustrative 3D printed pills, in accordance with embodiments of the present disclosure;

FIGs. 9A and 9B are photographs of 3D printed pills, in accordance with embodiments of the present disclosure;

FIG. 10 depicts a dissolution profde for example pill components, in accordance with embodiments of the present disclosure; and

FIG. 11 depicts a 3D printing node for use in the 3D printing line of FIGs. 3A-3B, in accordance with embodiments of the present disclosure. DETAILED DESCRIPTION

A plurality of modular three-dimensional (3D) printing nodes, each capable of printing by controllably extruding a paste containing a particular composition for a portion of the pill, may be combined together in order to print pills having multiple different components. The different paste compositions, and so the pill components, may have different active ingredients. A profde of the personalized pills may be defined in a user interface and then converted to a printing profile that can be used by the individual printing nodes to print each portion of the personalized pill. Each of the printing nodes may include a conveyor belt or other mechanism for automatically moving the partially printed pills from one printing node to another. In order to align the partially printed pills to ensure that a subsequent portion of the pills is printed in the appropriate location, the pills may be printed on a printing plate whose position on the printing node can be accurately determined.

By comprising a plurality of modular 3D printing nodes, the system may enable a much faster manufacturing process compared to systems that comprise a single node used to print the different compositions required per pill. In the present disclosure, the printing process may begin at one node printing a first type of composition, then the printing plate may move on towards the next node comprising a second composition, thereby freeing the first node for the printing of another batch of the first composition, and so on, a printing plate moves from one node to the next until production of the batch of pills is complete, while additional printing plates may be part of consequent processes of 3D pill printing. This way, there is no need to wait for a batch production to complete before beginning the process of printing additional batches. That is, the present disclosure provides multiple printing heads printing multiple materials or compositions at the same time.

An example for how efficient and quicker the printing system of the present disclosure is, is illustrated in the following Table (I), with the following assumptions:

1) each of the active ingredients has the same volume;

2) no error or breakdown occurred during printing;

3) negligible time spent in movement of platform or print head to position before print start or restart;

4) negligible time spent in changing build platform for standalone printer;

5) each tablet of five different active ingredients has a total volume of 0.5 mL; and

6) extrusion speed is kept as lmL/min for both printers being compared below

As illustrated from Table I, as the number of pills increases, the time to completion of their printing is significantly shorter using the 3D printing system of the present disclosure, which comprises five modules each configured to print a different composition compared to a typical printer with five printing heads or a single nozzle printer with 5 different interchangeable cartridges of material.

A modularized 3D printing node and production line for fabrication of personalized pharmaceutical and nutraceutical products with real time quality control is described further below. The modularized 3D printing node and production line may be used to manufacture personalized pills without requiring heating or ultraviolet (UV) curing of the pill components as they are printed, and thus possible degradation of active ingredients by heat or UV radiation is mitigated.

The modularized 3D printing system of the present disclosure enables the printing of an expandable or changeable number of materials per print process. This allows more active ingredients to be incorporated into a single tablet or pill, and therefore, assists in sufficiently creating a personalised pill. Since the modularized 3D printing system of the present disclosure comprises only one material per one printing head, there is minimal risk of contamination of the nozzles of the printing head, compared to systems that use the same printing head to extrude several different materials.

Each 3D printing node uses paste extrusion technology for the printing of portions of the pills. The paste materials may include an active ingredient or ingredients, and can be blended with other materials or components that account for different release profdes such as immediate, delayed or sustained release profiles. The paste compositions may include one or more active ingredients of a pharmaceutical composition, a medicinal composition, a supplement composition, a nutraceutical composition, an alternative medicine composition, a complementary medicine composition, or other compositions that provide a desired characteristic to a portion of the pill. The particular characteristic of the portion of the pill may be characteristic related to medicines, supplements, nutraceuticals, alternative medicines, complementary medicines as well as other characteristics of the pill. For example, the one or more active ingredients of the paste composition may provide for disintegrant layers, shell layers, etc. or bulk material or placebo layers. The printer may also be used to print other dosage forms such as capsules, drops or fdms. Each 3D printing node in a production line is responsible for printing a single formulation. The 3D printing nodes are modular and so printing nodes can be added to a production line in order to allow new formulations to be printed. Each 3D printing node incorporates real time quality assurance control for each printed portion of the pills. The real-time quality assurance control may use a near infra-red (NIR) spectrophotometer. Real time quality assurance control ensures that time is not wasted on products destined to fail. Therefore, real-time quality assurance control increases the overall efficiency and production rate of the 3D printing system of the present disclosure.

The use of modular 3D printing nodes, each using a particular paste composition, allows for the expansion of the 3D printing production line as required by the demands or constraints of the manufacturer. The use of modular printing nodes may be desirable for businesses since the cost of each printing node is fixed and forecasting or budgeting for a production line can be done in advance, or amended accordingly based on changes in budget. Since each printing node prints a particular paste composition, the addition of additional printing nodes can expand the range of materials that can be printed, depending on the requirements of the manufacturer. Having a modular printing system can address the fast changing needs of the consumer, by providing the flexibility of assigning modules to other materials or adding more modules.

As the 3D printer includes the printing of pharmaceutical products, each printer is fitted with a NIR spectrophotometer behind the print nozzle. Each layer, after being printed, can be scanned and a spectra generated. This generated spectra can be compared to a library of spectra for the material being printed. Degradation of the paste, or an incorrect paste formulation, may be assumed when the two spectra deviate. Further real-time quality control may be provided using imaging techniques, for example to ensure that components of the pill are printed in the correct locations. This real-time quality assurance control allows a just-in-time control of materials, and where materials are found to be degraded, the printing process of the particular printer may be paused for investigation, saving material cost and unnecessary printing time. Alternatively, rather than pausing the printing, other personalized pills that do not use the possibly degraded paste composition may be printed while the cause of the degraded paste material is investigated. Additionally, the use of spectra, which may be stored in association with an identifier of the printed pills, generates an audit trail for each printed pill, adding an additional layer of accountability, particularly in the printing of pharmaceutical products.

Each of the printing nodes may communicate with a central control system that controls the 3D printing nodes, which may include conveyor belts for moving partially printed pills to the next printing node. This allows the system to skip printers where the material to be printed is not selected, or to move onto redundant modules where a printer has either faced stoppages or depleted its print material. This central control system may also have the capacity to account for changes in the number and type of printing nodes as they are added or removed to the system.

The modular 3D printing nodes allow for personalization of pharmaceuticals and nutraceuticals required, or desired, by numerous individuals. The use of modular 3D printing nodes, may allow the unit costs of each pill to remain similar to other pill costs despite the ability to print a variety of ingredients. The production line of modular 3D printing nodes also allows for the large scale printing of pills, which may be valuable to pharmaceutical and nutraceutical companies as the trend towards personalization of healthcare product become increasingly widespread and demanded.

Polypharmacy relates to the use of multiple medicines or health products on a daily basis. This increases the risk of medication errors as well as unnecessary burden on both caregivers and healthcare professionals. The production line of modular 3D printing nodes may help mitigate these issues by attempting to combine all the medicines and health products required for the day into a single pill, or by reducing the number of pills required. As a result of polypharmacy, compliance to medications may be an issue. Patients may not consume their medicines in a timely manner or not consume the medicines at all. Simplifying the medication regimen could help reduce the risk of non-compliance for patients. This would be especially pertinent for high risk patients such as those with high medication load or psychiatric conditions. The production of personalized polypills comprising multiple medicines for an individual may be desirable to both patients as well as physicians, caregivers and healthcare professionals.

FIG. 1 depicts a process of manufacturing personalized pills. The process 100 includes receiving a pill profile from patients, consumers, physicians, caregivers etc. The pill profile may define the different components desired in a pill. The pill profile may be defined using a user interface 102. The pill profile may be converted to a printing profile that allows the different components of the pill to be printed using a production line 104 comprising a plurality of modular 3D printing nodes, each for printing one of the components from the pill profile. The 3D printed pills 106 may then be packaged to provide personalized pills. The personalized pill information, including, for example the pill profile, personal information for the individual the pills are for, printing information, including when the pills were printed along with quality control information, may be stored in an interface database 108. The information stored may be adjusted to comply with local regulations or requirements such as the Personal Data Protection Act (PDPA) in Singapore, the General Data Protection Regulation (GDPR) in Europe and the Health Insurance Portability and Accountability Act (HIPAA) in the United States.

FIG. 2 depicts details of the process for manufacturing personalized pills. The process 200 may be provided by three main stations, including a data acquisition & processing station 202, a 3D drug printing & fabrication station 204, and a post processing station 206. The data acquisition & processing station 202 may allow the pill profile to be defined and converted into a printing profile. The printing profile may be assigned to the 3D printing nodes of the 3D drug printing & fabrication station 204. The data acquisition & processing station 202 may coordinate the printing of multiple different printing profiles for different pills using the 3D printing nodes.

A password secured, user-specific interface may be used for the user to input their choice of supplement and their respective doses. Similarly, a password secured, patient-specific interface may be used for physicians to input their choice of drugs and their respective doses for patients.

The interface, e.g., user interface 102 (FIG. 1), whether it is user-specific or patient- specific can be accessed locally or through the internet and may be provided, for example in desktop and mobile versions. The data acquisition & processing station 202 may automatically convert the selection of ingredients, respective amounts and release rates (i.e. a pill profile) into a printing profile. The printing file may be a computer-aided design (CAD) file readable by the subsequent 3D drug printing & fabrication station 204. Converting the pill profile to the printing profile may take into account the concentration of active ingredients in the stock material (i.e. the printing paste) for 3D printing, choice of drug/supplement and also the doses of each drug/supplement. Once the conversion is completed, a user/patient-specific job order may be sent to the subsequent 3D drug printing & fabrication station 204. Various subtasks of the user/patient-specific job may be analyzed & distributed to the different modules of the 3D drug printing & fabrication station 204. The user may be the physician, who is prescribing on behalf of the patient. Alternatively, the patient can allow access to more than one physician to prescribe on their behalf. In the case of supplements, customers may select for supplements on their own.

The 3D printing & fabrication station 204, depicted in further detail in FIG. 3A, may comprise three lines within the station namely, a main fabrication line 302, a success line 304, and a failure line 306. The 3D printing & fabrication station 204 comprises a plurality of individual 3D printing nodes, for example, 310A, 310B, 3 IOC, 310D, 310E, 310F, 310G, 310H (referred to collectively as 3D printing nodes 310). The number of 3D printing nodes 310 participating in a specific 3D printing process may change based on the number of compositions required per pill, such that each single composition is to be extruded from a corresponding single node. In some embodiments, the compositions may be prepared offsite before use in the printing system. Preparing the compositions to be extruded offsite allows for additional quality control before use. The 3D printing nodes 310 may be located along the main fabrication line 302.

As depicted in FIG. 3 A the main fabrication line 302 may comprise a plurality of 3D printing nodes 310 arranged in a line. A number of printing plates, one of which is identified as 308, may be provided, and moved to the 3D printing nodes 310 on a conveyor system. Each of the printing plates, e.g., printing plate 308 may be associated with a respective job comprising one or more pills for a user. The conveyor system allows the printing plates to be moved from a first printing node depicted as 310A, to subsequent printing nodes. Printing plates from the last printing node, depicted as 31 OH may be moved by the conveyor system to the success line 304 if the printed pills on the printing plate pass the quality control process, to the failure line 306 if one or more of the pills on the printing plate fails the quality control process, or back to the first printing node 310A to print further layers of the pill if necessary.

Once the first printing node, for example printing node 310A, has completed its printing of the subtask (subtask being one of the printing steps or tasks of a complete 3D printing process of a pill, each subtask achieved by printing of a single composition via a single 3D printing node 310), the NIR spectrophotometer, which may have been previously calibrated for the specific active ingredient of the module, can scan each of the printed pills on the printing plate. The generated spectra may be compared to a corresponding spectra of properly printed material. Any pill that does not fall within allowable limits will be identified and subsequent printing tasks may be suspended for these identified pills, which may conserve the printing paste. If more than 50%, or some other desired limit, of the pills do not fall within the allowable limit, the entire batch of pills on the same printing plate will move to the failure line 306 to be discarded. The printing plate, e.g., printing plate 308 may move forward and stop at the second printing node 310B for the printing of the subsequent subtask, assuming that the pills being printed include the component printed by printing node 310B. If there is no subtask assigned for the second module, the printing plate may continue to move forward until the next assigned node. Once the printing job has completed, the printing plate 308 exits at the success line 304 to proceed downstream into the post processing station.

FIG. 3B depicts a 3D production line for manufacturing personalized pills, in accordance with embodiments of the present disclosure. FIG. 3B illustrates another configuration of an entire production line for manufacturing personalized pills, which is a bit different from that illustrated in FIG. 3A. In some embodiments, the entire system for manufacturing personalized pills using 3D printing, may comprise a plurality of 3D printing nodes 320, each for extruding a single type of composition, whereby any node may be located at any location along the production line 312, and a conveyer system 318, which may comprise a continuous moving band of fabric, rubber, or metal wrapped around two or more pulleys or any other means for moving a printing plate, e.g., printing plate 308 (FIG. 3A) along the entire line may be implemented. For example, in case the production line 312 is arranged as a closed loop, e.g., a square, the different 3D printing nodes 320 may be spread along each of the sides of the production line 312. The number of 3D printing nodes 320 may be determined according to the number of compositions required for each pill production. The order of the 3D printing nodes 320 along the production line 312 may be determined according to the proper manufacturing order of compositions, assuming there is one.

In some embodiments, production line 312 may comprise an entrance or beginning point 322, through which a new empty printing plate may be inserted to begin the entire production process. Production line 312 may further comprise a post print line 314 for successful pills to be sent to post processing station, e.g., packaging. In some embodiments, production line 312 may comprise recovery line 316, for failed pills to be removed from the system, e.g., to be discarded.

Each of the 3D printing nodes 310 (FIG. 3 A) or 320 (FIG. 3B) is depicted in further detail in FIGs. 4A-4E and may comprise an axis frame 402 with associated base 404. In some embodiments, base 404 may comprise all electronics required for operation of the printer. These electronics include the power supply, the printed circuit board, an LED screen for display 440 and an emergency stop button 442. Each 3D printing node may powered by an electrical power cable, e.g., electrical power cable 411. Each 3D printing node 310 or 320 may comprise one or more printing heads, e.g., printing heads 406a, 406b each loaded with the same active ingredient of a single release profde for backup, in case one printing head does not work properly, the second printing head would be used instead. In some embodiments, the printing heads 406a and 406b may be Vipro HEAD 3 or HEAD 5 by Viscotec, though other printing heads may be used. Each 3D printing node 310 or 320 may further comprise a NIR spectrophotometer 408 for generating a spectra of printed layers to provide real-time quality control. That is, quality control may be performed per each printing session of each single composition of the personalized pill. Each 3D printing node 310 or 320 may further include a conveyor system 410 or any other mechanism for supporting a movable printing plate 412 on which the pills 420 are printed. Each of the 3D printing nodes 310 or 320 may work either independently or in coordination with other printing nodes connected to it (FIGS. 5A-5B).

According to FIG. 4B, the printing paste materials loaded in the printing head, e.g., printing heads 406a, 406b may be prepared in various manners, including, for example, via pestle and mortar at a different site and loaded into a standard sterile, medical grade disposable 30 mL syringes 422. The 3D printing nodes 310 or 320 may include a mechanism for determining when syringes 422 are running low on paste. The particular level considered as being low may be set for all 3D printing nodes together or may be set per each of the individual 3D printing nodes. A threshold amount of paste remaining in the syringe 422, or similarly a threshold amount of paste that has been used from the syringe 422, may be used to determine when the syringe 422 is running low on paste. When a 3D printing node 310 or 320 is running low on the paste, a feedback signal may be provided to a central control that may take appropriate action. The appropriate action may include for example notifying an operator to switch or refill the syringe 422, order more syringes, order paste, etc. A light system, e.g., light indicator system on display 440 may be used to indicate the amount of paste within the syringes 422. Such a light indicating system may use, for example, green, amber, and red lights to indicate the fill state of the syringe. The coloured lights may be provided, for example, on the front or top of each of the 3D printing nodes 310 or 320. A green light may indicate that the syringe is full, an amber light may indicate that the syringe is nearly empty and a red light may indicate that the syringe is substantially empty. Additionally, the syringes 422 may include an identifier that can be used to identify characteristics of the syringe including, for example, a size of the syringe, the composition of the paste in the syringe, a date the syringe and paste were manufactured, an expiry date of the syringe and paste, etc. The 3D printing nodes 310 or 320 may include one or more sensors for reading or detecting the syringe identifier to ensure that the correct paste composition is provided.

At any one time, one printing head of the 3D printing nodes 310 or 320 may be extruding paste (i.e. printing a portion of the pills) according to distributed subtasks. The second printing head may provide redundancy to reduce any downtime of the production due to replacement of printing material.

As illustrated in FIG. 4B, the printing heads 406a and/or 406b may be connected to the axis frame 402 via movement guides 430. Movement guides 430 may comprise one or more guides along which printing heads 406a and 406b may move along linearly. For example, movement guides 430 may comprise a guide to enable movement along the horizontal axis of axis frame 402, and may further comprise a guide to enable movement along the longitudinal axis of axis frame 402, such to enable movement along these two axes. In some embodiments, axis frame 402 may move up and down along the‘z’ axis, e.g., via movement guide 431, thus 3D movement may be enabled per each of the printing heads.

In some embodiments, 3D printing nodes 310 or 320 may comprise a stepper motor 432, which may be configured to control the extrusion of print material from each printing head.

In some embodiments, 3D printing nodes 310 or 320 may comprise an emergency stop button 442 to enable the stopping of the printing process in case of an emergency.

FIG. 4C illustrates an example of a printing node that comprises only one single printing head, e.g., a single printing head 406, which may comprise a single syringe 422. According to the present disclosure, a 3D pill printing system may comprise multiple 3D printing nodes, each comprising either a single printing head or two printing heads. It should be clear that a system with nodes comprising a single printing head is cheaper than one comprising two printing heads although it may be more inclined to operational dysfunctions compared to a system comprising two printing heads per node.

FIG. 4D illustrates an exploded view of a printing node. In this view, a second stepper motor 434 is present, which may be configured to move the conveyer system 410.

FIG. 4E illustrates different views of a printing node with two printing heads, i.e., bottom view 451, front view 452 and side view 453.

FIGS. 5A-5B depict two printing modules, each of the two printing modules comprising two printing heads and each of the two printing modules comprising one printing head, respectively, in accordance with embodiments of the present disclosure. As illustrated in FIG. 4B, a printing node or printing module may comprise two printing heads, whereas according to FIG. 4C, a printing node or module may comprise a single printing head. Accordingly, once an additional printing node is connected to a first printing node, each of the printing nodes may comprise either a single or two printing heads. In some embodiments, a printing node with a single printing head may be connected to a printing node with two printing heads, and vice versa. The number or printing nodes connected to one another and the number of printing heads per printing node may be a design choice. The design choice may depend on the characteristics of the paste to be extruded from each printing head, e.g., the viscosity of the paste, though the design choice may depend on other features.

Each of the plurality of printing nodes may comprise a NIR spectrophotometer 408 for generating a spectra of printed layers to provide real-time quality control. Accordingly, quality control may be performed per each printing session of each single composition of the personalized pill. Each of the printing nodes that form a module of a plurality of printing nodes may comprise a stepper motor 432 to control extrusion of paint or paste from extruder head(s) 406, and may comprise movement guides 430 to enable linear motion of the printing head(s) 406. In addition, each printing node may comprise a second stepper motor 434 to move the conveyer system 410, which may comprise a rubber timing belt, or any other moving mechanism that would enable movement of a printing plate, e.g., printing plate 412.

In some embodiments, the 3D printers may be mechanically connected to each other. In some embodiments, on each side of a printer module, there may be either a male end of the alignment port, e.g., rods 444 (FIG. 4B) or a female end of the alignment port. Each of the printer modules are connected to an adjacent module via these male-female alignment rods at the side of base 404 of the 3D printing node 310 or 320, connected to the corresponding female- male end of the alignment rod positioned at the side of the base of the 3D printing node 310 or 320. In terms of data, adjacent printing modules may be connected via USB cables. A central USB cable may then be fed to a central PC or laptop for any user initiated commands, e.g., control system 700 (described later with respect to FIG. 7). In other embodiments, a custom, elongated block may be 3D printed and two adjacent printing modules may be secured to opposite sides of the block, via bolts and nuts. Such two printing modules may have their own USB connection to a central PC or laptop.

As the printing plate 412 moves from one printing node to the next in the production line, it may be necessary to locate the printing plate to allow subsequent portions of the pills to be printed at the correct location. A printing plate 412 is depicted in FIG. 6. As depicted, the printing plate 412 may comprise a substrate 602 that allows pills to be printed on, and once dried, removed from. The substrate 602 may also provide strength and rigidity to the printing plate 412 to allow the printing plate 412 to be easily moved from one printing node to another, e.g., from one conveyer belt of one printing node to another conveyer belt of another printing node. In some embodiments, the substrate 602 may be a reusable substrate, such as a glass plate, or it may be a disposable substrate. Alternatively, the substrate 602 may comprise a reusable portion providing strength and rigidity and a disposable portion, such as a removable fdm or layer positioned on top of the reusable portion. Using a disposable portion of top of the reusable portion may avoid the need to clean the reusable portion between production of different batches of pills, and simple removal of the disposable portion may provide a clean reusable portion. In some embodiments, a new disposable portion may be applied onto the reusable portion prior to beginning of production of a new batch of different pills than the ones completed.

Each of the printing plates 412 may include a registration mark 604 that allows a positioning sensor, which may be incorporated within NIR spectrophotometer 408 (FIG. 4A- 4B) of each printing node to determine the precise location and orientation of the printing plate 412. The registration mark 604 may be an optical mark and the positioning sensor may comprise an imaging device or a visible light sensor that may scan the relative location of the registration mark 604, e.g., a quick read (QR) code present on each printing plate. The printing plate 412 may also include a unique identifier that can be detected by each printing node and used to identify the printing job associated with the printing plate 412. The registration mark 604 may be used to identify x-y coordinate position information of the printing plate 412 as well as information about the pills, such as the composition information being printed. The positional information and the identifying information may be provided separately or combined into a single marking such as a quick read (QR) code. Each printing plate may include a plurality of pill printing locations 606. The printing locations are depicted as being circular and arranged in an array, although any particular arrangement and shape may be used. The printing plate 412 may be a flat plate or may include wells, or other similar formations for each printed pill.

Once the pills have been printed, the printing plates, e.g., printing plates 412 may be moved from the 3D drug printing & fabrication station 204 (FIG. 2), to the post processing station 206 (FIG. 2). The printing plate, e.g., printing plate 412 exits the fabrication station through the success line 304 and into a desiccator box maintained at, for example, 20% relative humidity to dry the printed pills. Alternatively the pills may be dried via microwave. The paste of each of the printed pills loses its water content to the surrounding environment and shrinks to its final volume. The weight of the pills, and possibly the printing plate, e.g., printing plate 412, may be monitored and once no further change in weight is detected, the printing plate may be removed from the desiccator box. The successfully printed and dried pills may be removed from the printing plate and each of the pills is weighed individually to ensure they fall within the allowable limit for quality control. The pills that pass the quality control may then be packed into individual packaging for storage and/or delivery to the end user.

FIG. 7 depicts a control system for use in controlling the 3D printing line of FIGS. 3A- 3B. The control system 700 is depicted as being provided by a single server, however, it may be provided by multiple servers or computing systems. The control system 700 may comprise one or more central processing units 702 capable of executing instructions to configure the control system 700 to provide various functionalities. The control system 700 may comprise one or more input/output interfaces 704 for connecting the control system 700 to input and output devices. The control system 700 may further comprise non-volatile storage 706 and memory 708 storing instructions, which when executed configure the control system 700 to provide 3D pill printing functionality 710. The pill printing functionality 710 includes displaying to a user available pill components 712 that can be printed by the production line. The available pill components may be displayed to the user in a graphical user interface 714. As depicted a plurality of pill components may be displayed and selected along with the dosage amount 716. The release profde of the selected components, e.g., Caffeine, Vitamin C, Folic Acid and Melatonin, may also be displayed, for example, as a graphic or graphics 718a, 718b depicting when the different pill components will be released, and if possible be modified by the user. The graphical user interface 714 may allow the user to confirm the pill profile by clicking a selection button 720. The pill printing functionality 710 may receive the selection of the components 722 along with the dosage amounts and generates a printing profile 724 for the pill. The printing profile may then be assigned to the production line and the functionality 710 may coordinate the printing of the pills by the production line 726, including the real-time quality control of the pills as they are printed, e.g., via the NIR spectrophotometer, e.g., NIR spectrophotometer 408 (FIG. 4B).

FIGs. 8A and 8B depict illustrative 3D printed pills. As depicted in FIG. 8A the printed pills may have a round shape with the different pill components printed as individual circular layers. The layers may be printed on top of each other and may include layers related to medicines, supplements, nutraceuticals, alternative medicines, complementary medicines, etc. as well as disintegrant layers that may allow the different layers to be separated when the pill is consumed. As depicted in FIG. 8B the pills may have a round shape with the different pill components printed as individual pizza slices, or wedges. The individual components may be separated by a disintegrant layer or wall. Further, although not depicted, the pills may be printed as a combination of the slices and layers. Further, the pills may be printed with a shell or similar layer. FIGs. 9A and 9B are photographs of 3D printed pills. The pills of FIG. 9A comprise a single active ingredient with single release profile and were printed on a standard glass printing plate. The pills of FIG. 9B comprise two active ingredients with two different release profiles on a standard 24 well plate. The individual pills of FIG. 9B have different amounts of the two active ingredients illustrated by the different sizes of pizza slices of one of two different colors.

FIG. 10 depicts a dissolution profile of, for example, pill components. As depicted, a pill may be printed with two components, namely nicotinic acid and caffeine, although other active ingredients may be implemented as part of the printed pill. The different components of the pill may have different release profiles. As per the current example, all of the nicotinic acid is released when the pill is consumed, and the caffeine is slowly released over four hours, or 240 minutes, after consuming the pill.

FIG. 11 depicts a 3D printing node for use in the 3D printing line of FIGs. 3A-3B, in accordance with embodiments of the present disclosure. According to FIG. 11, a printing node 1100 may comprise an axis frame 1102, which may differ from the axis frame 402 in that axis frame 1102 is positioned vertically with respect to its base 1104, whereas axis frame 402 is positioned horizontally or parallel to its base 404. However, similarly to the printing nodes illustrated in FIGs. 4A-4E, printing node 1100 comprises at least one movement guides 1130. In some embodiments, printing node 1100 may comprise one horizontal movement guide to enable movement along the‘x’ axis, and one longitudinal movement guide to enable movement along the‘z’ axis. Different numbers of guides may be used per each axis. For example, printing node 1100 may be moved along two guides at the‘x’ axis. In some embodiments, printing node 1100 may also be able to move along the‘y’ axis, if, for example, axis frame 1102 could move back and forth along base 1104.

In some embodiments, printing node 1100 may comprise at least one printing head 1106, which carries the paste or composition that is to be extruded from the printing head 1106. In some embodiments, printing node 1100 may comprise a print head holder 1132 or stepper motor configured to control extrusion of paint or paste from printing head(s) 1106.

In some embodiments, printing node 1100 may comprise a conveyer system 1110 or any other type of mechanism that enables the transportation or the movement of a printing plate, e.g., printing plate 1112, along a printing node and between one printing node to a subsequent printing node along the production line. In such case, instead of a standard conveyer belt system, conveyer system 1110 may comprise a flat surface moving along two parallel rods. The printing plate, e.g., printing plate 1112 may be placed onto the flat surface and moved along the conveyer system 1110 while pills 1120 are being printed on top of the printing plate. The above described disclosure is a fully integrated, automatic and high- volume facility for the production of personalized, multiple drug/supplement pill for individual users or patients, which may minimise manpower usage due to automation. The production line described above provides for mass customization of pills, such that each patient may have their own single dedicated pill mix of medicines, supplements or nutraceuticals, whether prescribed by the physician or selected for by the consumer. The unit economics of printing each pill is the same, as the same production line is capable of printing multiple materials. This may be contrasted with the conventional tableting process, where substantial costs are involved for each material change. Lead time for process development may also be considerably shortened compared to the traditional process of tableting. The cost per printing node may also be significantly lower than a large scale tableting press. Each 3D printer is termed a node. The production line may consist of either one or several printing nodes, connected together either through a wired connection or wireless connection. The printing nodes may be able to communicate with other printing nodes using the wired or wireless connections either directly or through a central control system, e.g., control system 700 (FIG. 7). Each printing node prints a single material, and the summation of multiple nodes allows for the printing of a single polypill, which stands for a pill comprising of several compositions. Additional printing nodes may be added or removed as needed, depending on financial and space constraints. Each printing node may be connected to another via a conveyor belt system or other movement mechanisms. System integration may be conducted via either physical wiring or through wireless network. Each 3D printing node may be fitted with a conveyor belt and connected to the adjacent 3D printing nodes via a conveyor belt. The pills are printed on a printing plate that lies on top of the conveyor belt. After printing the first layer of material, the pills are moved to the next subsequent 3D printing node via the conveyor belt. This process may be repeated until the polypill is complete. In the event that a particular material is not selected, the 3D printing node may be skipped. Each 3D printing node may also have a near infra-red (NIR) spectrophotometer fitted, that allows for real-time detection of the layer that is being printed. The generated spectra may be compared to a library of spectra to allow real-time determination of the quality of the printed product. In the event that the two spectra do not match, the operator may be alerted and appropriate actions may be taken such as discarding the pills. Additionally or alternatively, the appropriate actions may be taken automatically. Alerting the operator that degraded, or possibly incorrect, material was printed may allow the cause of the problem to be quickly investigated and corrected. Comparing the NIR spectra of printed layers to known spectra for the layer that is supposed to be printed can help detect problems such as degraded paste material or incorrect syringes being inserted. Each of the 3D printing nodes follow a 3D printing profile, which may be termed computer aided drawing (CAD). As described above, the conversion of patient preferences or doctor’s prescription may be converted from a pill profile into a CAD drawing of a polypill in real-time and be assigned to the production line. This dynamic process takes into account which pill components are of immediate release, sustained release, or delayed release formulations and which medicines should not be compartmentalized together. The generation of the printing profile, which may be a CAD drawing, specifies the geometry and volume of the pill and its components which are to be printed by the 3D printing nodes. Additionally, the printing profile may be generated to provide a printing sequence based on an arrangement of the 3D printing nodes in the production line . For example, if there are no restrictions on the ordering of different component layers in the pill, the first component layer printed would be the first 3D printing node in the production line, the second component layer would be the second 3D printing node in the production line, etc., which can reduce the time required for printing the pill. The 3D printing nodes may be dedicated to 3D printing of pills of specific geometries. As opposed to other 3D printers available, there are no specific 3D printers for printing of pills. As a result, certain parameters such as volume of print along the z-axis and the print resolution can be relaxed, resulting in a more simplified print process for the 3D printer by reducing the requirement along the z-axis. The geometry of the printed pill may be in the general form of a “pizza” slice structure, with each slice lying adjacent to other slices to form a fully formed circular pill. Alternatively, the printed structure may be in the general form of a circular disc printed on top of a previously printed circular disc. Each slice or circular disc may consist of one or more active ingredient. In another form, each circular disc may be interspersed by a circular disc that is of a fast disintegrant with no active ingredient, allowing the printed pill to be broken up into several discs once ingested into the stomach, as if each active ingredient were consumed separately.

According to some embodiments, the process of manufacturing personalized pills according to the present disclosure may comprise the following operations:

(a) A CAD file for the different materials required for pill production may be generated, based on the dose of each active ingredient required.

(b) The CAD file may be sliced into g-codes to be input into the printing system.

(c) The required print materials may be prepared offsite into a syringe of semi-solid paste.

The syringes, e.g., syringes 422 (FIG. 4B) may be inserted into the respective print heads, e.g., printing heads 406, before printing begins.

(d) Compressed air is used to maintain a constant pressure in the syringe to allow continuous feed of print material into the print head. Subsequently, the print head piston will turn in the number of revolutions as determined by the g-codes to print out the desired volume of material in the desired pattern.

(e) A first printing plate enters into Module A, e.g., 3D printing node 310A (FIG. 3A) and Print Head A, e.g., printing head 406a (FIG. 4A) begins to extrude Material A. In one configuration, the print head A may move in both the X and Y direction. The printing plate, together with the conveyor system, moves in the Z direction. In an alternative configuration, Print Head A may move in all X, Y and Z directions. The printing plate, together with the conveyor system, will remain at the same height and may only move when it is triggered to transfer the printing plate to the adjacent subsequent Module.

(f) Once the total volume of Material A has been printed in the pre-determined pattern, a quality control component using NIR sensors may scan each printed part to ensure the right quantity of active ingredient has been printed. Prior to printing, a data library of active ingredients and their respective NIR absorbance spectrum will be kept in house. At each scan, the NIR sensor may generate an absorbance spectrum that may be compared to the library. Based on a pre-calibrated standard curve, the quantity of active ingredient may be calculated to determine if the printed layer passes or fails the quality control test. Software alerts may be generated to encourage user actions should the quantity fall below or above stipulated limits.

(g) The conveyor system may then transfer the printing plate to an adjacent subsequent Module B, e.g., 3D printing node 310B and Print Head B may begin to extrude Material B. There may be various markings and QR code on each build/printing plate to ensure accurate transfer of the printing plate from one module to the other. QR code may also provide information about the print job, such as customer details, dose requirement and type of active ingredient requirement.

(h) When the first printing plate is moving into Module B, a new printing plate begins to enter Module A to start another print job.

(i) Operations (e) to (h) repeat, each time, with the printing plate transferring into the adjacent subsequent Module.

(j) In some embodiments, there may typically be eight Modules in an assembly line, though other numbers of modules are possible. In case the print process uses all eight materials, by the time a printing plate reaches Module H, all eight Modules will be occupied by printing plates and will be printing concurrently. This is when the production rate is the highest.

(k) When the printing plate has finally completed all the printing at the various Modules, it will be sent via the conveyor system into the post processing station. (1) If a print process does not involve any particular material, e.g. Print Job 11 does not involve Material C, the printing plate demarcated for Print Job 11, will wait at Module C, without any printing done. Subsequently, an escape conveyor or other scheduling of print jobs can be added to optimise the use of all Modules at any one time.

Although certain components and steps have been described, it is contemplated that individually described components, as well as steps, may be combined together into fewer components or steps or the steps may be performed sequentially, non-sequentially or concurrently. Further, although described above as occurring in a particular order, one of ordinary skill in the art having regard to the current teachings will appreciate that the particular order of certain steps relative to other steps may be changed. Similarly, individual components or steps may be provided by a plurality of components or steps. One of ordinary skill in the art having regard to the current teachings will appreciate that the components and processes described herein may be provided by various combinations of software, firmware and/or hardware, other than the specific implementations described herein as illustrative examples.

Numerous additional variations on the methods and apparatus of the various embodiments described above will be apparent to those skilled in the art in view of the above description. Such variations are to be considered within the scope.