WO2021119438A1 - Plate-forme de traitement parallèle à lignes multiples destinée à la fabrication de médicaments - Google Patents

Plate-forme de traitement parallèle à lignes multiples destinée à la fabrication de médicaments Download PDF

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Publication number
WO2021119438A1
WO2021119438A1 PCT/US2020/064528 US2020064528W WO2021119438A1 WO 2021119438 A1 WO2021119438 A1 WO 2021119438A1 US 2020064528 W US2020064528 W US 2020064528W WO 2021119438 A1 WO2021119438 A1 WO 2021119438A1
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Prior art keywords
line
processing unit
processing
drug
units
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PCT/US2020/064528
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English (en)
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Samer Banna
Amos Dor
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Applied Materials, Inc.
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Publication of WO2021119438A1 publication Critical patent/WO2021119438A1/fr

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    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
    • G06Q10/00—Administration; Management
    • G06Q10/06—Resources, workflows, human or project management; Enterprise or organisation planning; Enterprise or organisation modelling
    • G06Q10/063—Operations research, analysis or management
    • G06Q10/0631—Resource planning, allocation, distributing or scheduling for enterprises or organisations
    • G06Q10/06312—Adjustment or analysis of established resource schedule, e.g. resource or task levelling, or dynamic rescheduling
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
    • G06Q50/00—Systems or methods specially adapted for specific business sectors, e.g. utilities or tourism
    • G06Q50/04—Manufacturing
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P90/00—Enabling technologies with a potential contribution to greenhouse gas [GHG] emissions mitigation
    • Y02P90/30—Computing systems specially adapted for manufacturing

Definitions

  • the subject matter described herein relates to a multi -line parallel processing platform for manufacturing pharmaceutical drugs.
  • the process of manufacturing a drug requires several interacting processes that are performed serially. Often, each process is performed at one geographical location, and the output of that process is transferred to another geographical location such as another city, another country, or even another continent in some instances. Such actions can be time consuming, and it can take a long time to manufacture a drug.
  • Some pharmaceutical companies have conventionally reduced transportation delays by restricting the different processes to be in a same geographical location, such as a same city, or in a single manufacturing facility. In other instances, some pharmaceutical companies have increased the size of containers used to perform those processes to increase the quantity of the drug that can be manufactured in a single batch.
  • a multi-line parallel processing platform for drug manufacturing includes a plurality of parallel lines, each line of the plurality of parallel lines comprising a plurality of processing units that perform a plurality of processes for manufacturing a drug.
  • a plurality of sensors are coupled to at least one the of the plurality of parallel lines and the plurality of processing units, and the plurality of parameters are configured to detect one or more parameters.
  • a control system receives data from the plurality of sensors and is configured to disconnect a processing unit from a corresponding first line in response to the detection of the one or more parameters meeting a particular criterion and to connect a corresponding processing unit in a second line with at least one of a preceding processing unit in the first line and a succeeding processing unit in the first line.
  • Implementations may include one or more of the following features.
  • the particular criterion may indicates an abnormality in one or more chemical properties of content being processed by the processing unit.
  • the criterion may indicate an abnormality in a condition of one or more mechanical features of the processing unit.
  • the abnormality may indicate a malfunctioning of the processing unit.
  • the criterion may indicate a quantity of content being processed by the processing unit being lower than a threshold value.
  • the quantity may indicate whether the processing unit requires in-situ cleaning.
  • at least two of the processing units may be configured to perform the in-situ cleaning.
  • the multi-line parallel processing platform allows a quick modification of various pharmaceutical processes, thereby providing flexibility to the manufacturing process. Furthermore, the multi-line parallel processing platform permits operation of all the processing units of a line and the corresponding processes to be a single location, and avoids any delays due to malfunctioning of a processing unit within a single line. Further, the processing platform is easily and promptly scalable, by, for example, increasing a number of lines of processes that can run in parallel, which in turn reduces the time it takes for the drug to reach the market.
  • the multi-line parallel processing platform is a compact and a well -engineered system that provides a central and efficient control of the manufacturing of the drug, or at least several processes of the manufacturing of the drug.
  • an individual processing unit can include sub-chambers that can be used for separate types of drugs (e.g., same drug with customized quantities of various constituents per the requirement of that type of patient), thereby offering personalized medication features while manufacturing different types of drugs at the same time without loss of throughput.
  • the processing platform allows cycling through different drugs more effectively than conventional designs.
  • the processing units can use smaller processing volumes, which enables in-situ cleaning (aka “wash in place”), modularity, simplification of the line, e.g., reduction of number of units required, and gravity feeding of the product from one process to the next.
  • output can be scaled out by increasing the number of processing lines.
  • FIG. 1 is a schematic diagram of a multi-line parallel processing platform that manufactures a drug, in accordance with some implementations of the current subject matter.
  • FIG. 2 illustrates one possible design of the multi-line parallel processing platform that implements a first set of non-limiting exemplary processes to manufacture a drug, in accordance with some implementations of the current subject matter.
  • FIG. 3 illustrates one possible design of pipes connecting processing units of different lines of the multi-line parallel processing platform, in accordance with some implementations of the current subject matter.
  • FIG. 4 illustrates a particular schematic of the multi-line parallel processing platform having multiple processing units and corresponding chambers, in accordance with some implementations of the current subject matter.
  • FIG. 5 illustrates another example of a multi-chamber processing unit within a line of the multi-line parallel processing platform, in accordance with some implementations of the current subject matter.
  • FIG. 6 illustrates a method performed by the controller for avoiding delays in manufacturing due to malfunctioning of one or more processing units within the lines, in accordance with some implementations of the current subject matter.
  • FIG. 7 illustrates a method performed by the controller for performing in-situ cleaning of a chamber during the manufacturing of the drug, in accordance with some implementations of the current subject matter.
  • the multi-line parallel processing platform (which can also be referred to as a multi-unit multi-line parallel processing platform) can address one or more of the problems of the conventional designs.
  • the multi-line parallel processing includes parallel lines, with each line including multiple processing units that are integrated (e.g., operationally and/or physically coupled with each other) in sequence and perform corresponding processes in sequence for manufacturing a drug. Some examples of such units and processes are described below.
  • processing unit (sometimes simply referred to as a “unit”) refers to particular equipment, e.g., a tool, for performing an operation in a manufacturing system that can be defined and physically separated from other operations.
  • each processing unit can be considered as a discrete component in that the corresponding process or set of processes is performed in a particular location before the material being processed is passed to the next location for processing.
  • processing units include feeders, mills, mixers, compactors, extruders, granulators, dryers, presses, mills, molds, chillers, filters, centrifuges, reactors, etc.
  • Each line — and the equipment (e.g., processing units) therein — is configured for continuous manufacturing with relatively low processing volumes, e.g., 1 ⁇ 2 kilogram to 3 kilogram per hour, as compared to 10 kg per hour for conventional bulk continuous processing for drug manufacturing (conventional bulk batch processing can typically handle up to 500 kg of material in a batch). These lower volumes permit the units to use smaller processing chambers and themselves be smaller.
  • each line including the processing units therein, can be a continuous processing line that is optimized for one or more of the above objectives.
  • FIG. 1 illustrates a schematic diagram of a multi-line parallel processing platform 102, in accordance with some implementations of the current subject matter.
  • the multi-line parallel processing platform 102 includes a controller 104 that controls operations of several parallel lines 106, each of which performs several processes for manufacturing a drug.
  • Such processes can include, in one non limiting example, feeding of an active pharmaceutical ingredient (API), feeding of an excipient, milling of large lumps of material, convective mixing of material via turbulence, tablet pressing (or alternately capsule filling), and coating of the tablet, as explained in greater detail by FIG. 2.
  • API active pharmaceutical ingredient
  • FIG. 2 tablet pressing
  • many other combinations of processes are possible, and not all of the processes noted above are necessary.
  • Each process can be performed by a separate unit that can encompass a corresponding chamber (not shown).
  • a separate unit that can encompass a corresponding chamber (not shown).
  • Some non-limiting configurations of the units and chambers are discussed below with respect to FIG. 2. Alternate non limiting configurations of the units and chambers are described below by FIGS. 4 and 5.
  • each unit can include one or more sensors to measure process control and/or product parameters, and a microcontroller to locally control operation of the unit, to transmit the data from the sensor to a line microcontroller, and to receive instructions from a line microcontroller.
  • Each line can have one or more sensors to measure product parameters of the drug between processes, e.g., between units, and a microcontroller 150.
  • the line microcontroller 150 can receive data from the sensors in the individual units, receive data from the line sensors, transmit that data to a platform controller, and receive instructions from the platform controller 104.
  • the line microcontroller 150 can coordinate operation of multiple units, e.g., determine whether operation of one unit in a line should be modified based on operation of another unit in the line.
  • the line microcontroller 150 can control opening and closing of valves of pipes that route material from one unit to another unit, and can sent instructions to the microcontrollers for the individual units to control the corresponding processes in that line.
  • the platform controller 104 receives data from the line microcontrollers 150, and can coordinate operation of multiple lines, e.g., determine whether operation of one line should be modified based on operation of another line, and can sent instructions to the line microcontrollers 150 for the individual lines to carry out necessary changes in operation of the individual lines.
  • Such a ground-up control architecture is scalable so that units and lines can easily be added to the platform.
  • the units within the lines 106 can be connected to each other via pipes, as explained in greater detail below by FIG. 3.
  • Each unit in a line 106 e.g., first line
  • Each unit in a line 106 can be connected to a preceding and/or a subsequent unit in the same line 106 via pipes, and to a preceding and/or a subsequent unit in an adjacent line 106 (e.g., second line) via bypass pipes.
  • the material can move between the units of a line 106 (e.g., first line) via, for example, pipes connecting the units. For instance, the material between any two of the units can move within a pipe connecting those two units.
  • pipes and valves are described as means (e.g., way) for controllably moving material between the units, in other implementations, the material can controllably be moved between units via other means such as by at least one robot (a robot may be useful for transport of petri dishes or other containers used to grow sample biological materials), at least one conveyer belt, pipes with gravity, any other such means, and/or any combination thereof.
  • at least one robot a robot may be useful for transport of petri dishes or other containers used to grow sample biological materials
  • at least one conveyer belt pipes with gravity, any other such means, and/or any combination thereof.
  • the ends of the pipes can include, or alternately be connected to, control valves, which can be controlled by the microcontroller 150 of that line 106.
  • control valves which can be controlled by the microcontroller 150 of that line 106.
  • the microcontroller 150 of that line 106 can control the valves to reroute material to the corresponding (e.g., same) unit in another line 106 (e.g., second line) until the malfunctioning unit is repaired or replaced.
  • Each line 106 can have one or more sensors, which can in-line sensors and/or in-situ sensors placed within one or more units (and in some implementations, within every unit of one or more lines, such as every line in various implementations).
  • the sensors can detect various process control parameters, such as a rotational speed of a structural component (e.g., screw) within a unit, a flow rate of input of a unit, a flow rate of output of a unit, a temperature within a unit, a pressure within a unit, rate of addition of a material in a specific unit, liquid to solid ratio in a unit, shear rate within a particular unit, volume filled within a specific unit, force (e.g., compression force) applied by or within a unit, moisture content within a unit, and/or other suitable process control parameters.
  • a structural component e.g., screw
  • the measured process control parameters can be used in a feedback loop to drive the unit to operate at a desired control values for the parameters.
  • the sensors can also detect various product parameters, e.g., particle porosity, particle size for interim product during manufacturing of the drug, distribution of the particle size, particle size for a final form of the drug, strength (e.g., hardness) of the drug (e.g., coated tablet), API composition of the drug, weight of the drug, composition uniformity of the drug, dissolution time of the drug, ratio of the coating to the API and/or other suitable product parameters.
  • the processor, microcontroller 150 or controller 104 can provide, based on the detection by such one or more sensors, instructions to modify (e.g. optimize) such parameters. Some specific examples of sensors and such optimization is further described below by FIG. 2.
  • the controller 104 can have one or more processors.
  • the controller 104 can be a server, such as a cloud computing server.
  • the controller 104 can be communicatively coupled to a display device 107 via a wired connection or a wireless connection.
  • Such wireless connection can be over a communication network, such as a local area network, a wide area network, internet, intranet, Bluetooth network, infrared network, any other one or more networks, and/or any combination thereof.
  • the display device 107 can execute, for example, a software application that can display the current status (e.g., functioning or malfunctioning) and related parameters for all components within each line 106.
  • such software application can be interactive, such that an authorized user (e.g., information technology administrator) can add, remove or modify instructions by the controller 104 to the microcontroller of each line 106 so as to manage the architecture of the drug manufacturing process (e.g., manage physical connections of each line 106).
  • an authorized user e.g., information technology administrator
  • Each line 106 can have a microcontroller 150, and such microcontroller 150 can control (a) the physical connections between the units 122- 132, (b) the physical connections between the units for each of the processes 108, (c) the flow rate at various points in the line 106 by, for example, controlling valves that allow passage of the material through the line 106, and/or (d) other parameters for each process as noted above.
  • the controller 104 can be communicatively coupled to the microcontroller of each line 106 via a wired connection or a wireless connection.
  • Such wireless connection can be over a communication network, such as a local area network, a wide area network, internet, intranet, Bluetooth network, infrared network, any other one or more networks, and/or any combination thereof.
  • the microcontrollers of the lines 106 can enable modification of the material flow paths between the units 122-132.
  • Such rerouting can advantageously avoid delays when a unit — for example, one of the units 122-132 — within a particular line 106 (e.g., first line 106, which is the top line in FIG. 1) malfunctions, as in such case the process performed by that unit can be rerouted to a corresponding unit in another line 106 (e.g., second line 106, which is the line below the top line in FIG. 1), as described in further detail below by FIG. 6.
  • such rerouting can beneficially allow in-situ cleaning without delays in the manufacturing, as described in greater detail below by FIG. 7.
  • Such rerouting can advantageously enable the multi-line parallel processing platform 102 to quickly add, remove or modify various pharmaceutical processes, thereby providing flexibility to the manufacturing process.
  • N can be any integer value, ranging from 2 to a threshold integer value.
  • the threshold integer value can be 2 in one implementation, 5 in another implementation, 10 in yet another implementation, 15 in a further implementation, 50 in another implementation, and 100 in a further implementation.
  • FIG. 2 illustrates one possible non-limiting design of a multi-line parallel processing platform 102, in accordance with some implementations of the current subject matter.
  • the processes 108 can include feeding 110 of an active pharmaceutical ingredient (API), feeding 112 of an excipient, milling 114 of large lumps of material, convective mixing 116 of material via turbulence, tablet pressing (or alternately capsule filling) 118, and coating 120 of the tablet.
  • FIG. 2 illustrates a horizontal layout of the units, the units can instead be vertically stacked. This permits gravity feed to transport the product from process to process.
  • Each process 108 can be performed by a separate unit that can encompass a corresponding chamber (not shown).
  • the unit for feeding 110 can include an API feeder 122 to perform such feeding 110.
  • the unit for feeding 112 can include an excipient feeder 124 to perform such feeding 112.
  • the unit for milling 114 can include a mill 126 to perform such milling 114.
  • the unit for convective mixing 116 can include a convective mixer 128 to perform such mixing 112.
  • the unit for tablet pressing 118 can include a tablet press 130 to perform such pressing 118.
  • the unit for coating 120 can include a coater 132 to perform such coating 120.
  • the units 122-132 of the lines 106 can be connected to each other via pipes, as explained in greater detail below by FIG. 3.
  • Each unit in a line 106 e.g., first line
  • Each unit in a line 106 can be connected to a preceding and/or a subsequent unit in the same line 106 via pipes, and to a preceding and/or a subsequent unit in an adjacent line 106 (e.g., second line) via bypass pipes.
  • the material can move between the units 122- 132 of a line 106 (e.g., first line) via, for example, pipes connecting the units.
  • pipes and valves are described as a technique for controllably moving material between the units 122-132, in other implementations, the material can controllably be moved between units via other means such as by at least one robot, at least one conveyer belt, pipes with gravity, any other such means, and/or any combination thereof.
  • the ends of the pipes can include, or alternately be connected to, control valves, which can be controlled by the microcontroller 150 of that line 106.
  • control valves which can be controlled by the microcontroller 150 of that line 106.
  • the microcontroller! 50 of that line 106 can control the valves to reroute material to the corresponding (e.g., same) unit in another line 106 (e.g., second line) until the malfunctioning unit is repaired or replaced.
  • the API feeder 122 can accurately feed the API powder into the manufacturing process.
  • the API feeder 122 can be operated in loss in weight control to maintain a desired flow rate.
  • the API feeder 122 can be made of a hopper, a conveying apparatus, and a bridge breaking system.
  • the conveying apparatus can be a screw, which can provide accuracy of the feeding process.
  • the unit including the API feeder 122 can include one or more in-situ sensors communicatively coupled to the controller 104. These one or more sensors can detect a rotational speed of the screw, a flow rate of the input to the API feeder 122, a flow rate of the output of the API feeder 122, and/or other suitable one or more parameters.
  • the processor, microcontroller 150 or controller 104 can provide instructions to modify, which in turn can modify, the input to the API feeder 122 and/or the speed of rotation of the screw (and thus the output of the API feeder 122) based on the detection by those one or more sensors.
  • each (or at least one, in another implementation) line 106 can include in-line or standalone sensors that can replace the functionality of the in-situ sensors described above.
  • the excipient feeder 124 can accurately feed the excipient powder into the manufacturing process. Like the API feeder 122, the excipient feeder 124 can be operated in loss in weight control to maintain a desired flow rate.
  • the excipient feeder 124 can be made of a hopper, a conveying apparatus, and a bridge breaking system.
  • the conveying apparatus can be a screw, which can provide accuracy of the feeding process.
  • the unit including the excipient feeder 124 can include one or more in-situ sensors communicatively coupled to the controller 104. These one or more sensors can detect a rotational speed of the screw, a flow rate of the input to the excipient feeder 124, a flow rate of the output of the excipient feeder 124, and/or other suitable parameters.
  • the processor, microcontroller 150 or controller 104 can provide instructions to modify, which in turn can modify, the input to the excipient feeder 124 and/or the speed of rotation of the screw (and thus the output of the excipient feeder 124) based on the detection by those one or more sensors.
  • each (or at least one, in another implementation) line 106 can include in-line or standalone sensors that can replace the functionality of the in-situ sensors described above.
  • the mill 126 can be a high shear mixer, which can have at least one rotating blade and a mesh screen.
  • the mill 126 can be used to break large lumps of material.
  • the mill 126 can have the shape of a cone, and thus can be referred to as a conical mill.
  • the mill 126 can have any other shape such as a cylinder, a cube, any other three dimensional shape, or the like.
  • the unit including the mill 126 can include one or more in-situ sensors communicatively coupled to the controller 104.
  • These one or more sensors can detect a rotational speed of the rotating blade, the flow rate of the feed output by the feeders 122 and 124 and input by the mill 126, distribution of the particle size, the flow rate of the output of the mill 126, and/or other suitable parameters.
  • the processor, microcontroller 150 or controller 104 can provide instructions to modify, which in turn can modify, the input to the mill 126 and/or the speed of rotation of the screw (and thus the particle size and the output flow rate from the mill 126) based on the detection by such one or more sensors.
  • each (or at least one, in another implementation) line 106 can include in-line or standalone sensors that can replace the functionality of the in- situ sensors described above.
  • the convective mixer 128 can be a mixer that can have a cylindrical shape, along the axis of which the material is convectively transported, which causes turbulence and thus the mixing.
  • the convective mixer 128 can have blades within the cylindrical body that can cause shearing of the material.
  • the unit including the convective mixer 128 can include one or more in-situ sensors communicatively coupled to the controller 104.
  • These one or more sensors can detect a rotational speed of the blades, the flow rate of the input received from the mill 126, level or quantity of mixture in the convective mixer 128, the flow rate of the output generated by the convective mixer 128, distribution or uniformity of the particle size in the output generated by the convective mixer 128, time for which the mixture remains within the convective mixer 128, and/or other suitable parameters.
  • the processor, microcontroller 150 or controller 104 can provide instructions to modify, which in turn can modify, the input to the convective mixer 128, the speed of the blade, and/or the time for which the mixture remains within the convective mixer 128 based on the detection by such one or more sensors.
  • each (or at least one, in another implementation) line 106 can include in-line or standalone sensors that can replace the functionality of the in-situ sensors described above.
  • the tablet press 130 can take the powder mixture from the convective mixer 128, and compress it into compact tablets.
  • the tablet press 130 can include holes, which can receive the powder to be pressed. Two vertically opposite punches within the tablet press 130 can compress the material.
  • the unit including the tablet press 130 can include one or more in-situ sensors communicatively coupled to the controller 104. These one or more sensors can detect a flow rate of the input to the tablet press 130, compression force used by the tablet press 130 to press the powder into the tablet, concentration of the particles within the tablet, and/or other suitable parameters.
  • the processor, microcontroller 150 or controller 104 can provide, based on the detection by such one or more sensors, instructions to modify, which in turn can modify, the input to the tablet press 130, compression force used by the tablet press 130 to press the powder into the tablet, concentration of the particles within the tablet, and/or other suitable parameters.
  • instructions to modify which in turn can modify, the input to the tablet press 130, compression force used by the tablet press 130 to press the powder into the tablet, concentration of the particles within the tablet, and/or other suitable parameters.
  • each (or at least one, in another implementation) line 106 can include in-line or standalone sensors that can replace the functionality of the in-situ sensors described above.
  • the coater 132 can coat the tablet with thin organic and inorganic films.
  • the unit including the coater 132 can include one or more in-situ sensors communicatively coupled to the controller 104. These one or more sensors can detect a strength (e.g., hardness) of the coated tablet, API composition of the coated tablet, weight of the coated tablet, composition uniformity of the coated tablet, dissolution time of the coated tablet, ratio of the coating to the API, and/or other suitable parameters.
  • the processor, microcontroller 150 or controller 104 can provide, based on the detection by such one or more sensors, instructions to modify, which in turn can modify, the strength (e.g., hardness) of the coated tablet, the API composition of the coated tablet, the weight of the coated tablet, the composition uniformity of the coated tablet, the dissolution time of the coated tablet, the ratio of the coating to the API, the inputs and outputs of a component for any of the processes 108, and/or other suitable parameters.
  • the strength e.g., hardness
  • the API composition of the coated tablet the weight of the coated tablet
  • the composition uniformity of the coated tablet the dissolution time of the coated tablet
  • the ratio of the coating to the API the inputs and outputs of a component for any of the processes 108, and/or other suitable parameters.
  • the specific processes 108 shown in FIG. 2 are some non-limiting examples of processes used in manufacturing of drugs.
  • the processes within each line 106 can be different, as discussed below. Further variations of the processes 108 are also possible.
  • any process that is used in the manufacturing of a drug can be added as a new process to a line 106 or replace an existing process 108. In some instances at least some of the processes 108 may be removed as unnecessary.
  • some designs can have additional processes 108 of compressing multi-component mixtures, and reducing particle size. Each of these two processes can be performed by corresponding units such as a roller compactor and a mill, respectively, that can be connected between the convective mixer 128 and the tablet press 130.
  • Another design can, for example, have additional processes 108 of wet granulation and drying, which can be performed by a wet granulator and a dryer, respectively that can be connected between the convective mixer 128 and the tablet press 130.
  • a feeder could deliver API into a liquid binder material
  • a dispenser can deliver a mixture of the API into a mold where the liquid binder material is cured, e.g., by photopolymerization or heat, to form particles or molecules of the API in a matrix of solidified binder material.
  • FIG. 3 illustrates pipes 152 and 154 connecting units 156 of different lines (e.g., N-lth line and Nth line) 106 of the multi-line parallel processing platform 102, in accordance with some implementations of the current subject matter.
  • Each of the units 156 can be one of the units 122-132.
  • the units 156 and connections between them are shown just for simplicity, and each line 106 can have additional units 156 as described above by FIG. 2.
  • N can be any integer value, ranging from 2 to a threshold integer value.
  • the threshold integer value can be 2 in one implementation, 5 in another implementation, 10 in yet another implementation, 15 in a further implementation, 50 in another implementation, and 100 in a further implementation.
  • Each unit 156 in a line 106 can be connected to a preceding and/or a subsequent unit in the same line 106 via pipes 152, and to a preceding and/or a subsequent unit in an adjacent line 106 (e.g., Nth line) via bypass pipes 154.
  • the material can move between the units 154 of a line 106 (e.g., N-lth line) via the pipes 152.
  • the ends of the pipes 152 and 154 can include, or alternately be connected to, control valves 158, which can be controlled by the microcontroller of that line 106.
  • the microcontroller of that line 106 can control the valves 158 to reroute material to the corresponding (e.g., same) unit 158 in another line 106 (e.g., Nth line) until the malfunctioning unit 156 is repaired or replaced. For example, if the “second unit”
  • the microcontroller controls the valves 158 — and coordinates with the microcontroller of the Nth line 106 to control the valves 160 — to route the material for processing to the “second unit” in the Nth line 106 until the “second unit” 156 in the N-lth line is repaired or replaced.
  • the valves 158 and 160 can also be referred to as control valves.
  • the valves 158 and/or 160 can include electrical, hydraulic and/or pneumatic actuators — which are controlled by the microcontroller of the corresponding line 106 — to open and close those valves.
  • the valves 158 and/or 160 can be modulating valves, which can be set to any position between fully open and fully closed. Valve positioners can be used to ensure the valve 158 or 160 attains the desired degree of opening.
  • pipes 152 and 154, and valves 158 and 160 are described as means (e.g., way) for controllably moving material between the units 122-132, in other implementations, the material can controllably be moved between units via other means such as by at least one robot (e.g., one or more robotic arms), at least one conveyer belt, pipes with gravity, any other such means, and/or any combination thereof.
  • at least one robot e.g., one or more robotic arms
  • at least one conveyer belt e.g., pipes with gravity, any other such means, and/or any combination thereof.
  • FIG. 4 illustrates one non-limiting schematic of the multi-line parallel processing platform 102 that includes M parallel systems, such as a first system 401, a second system 402, and so on until the M th system, in accordance with some implementations of the current subject matter.
  • the term system, as used in FIG. 4 can correspond to the term line, as used in FIG. 1.
  • each system can be referred to as a line
  • the system 401 can be a line 106.
  • Each system is at least partially provided by a single unit 400 having multiple stations or chambers 402.
  • the unit 400 can be a cluster tool, with stations or chambers 402 positioned around a central transfer chamber 410.
  • Each station or chamber 402 can provide a different process provided by one of the units noted above, or some stations or chambers can provide the same process.
  • Material to be processed e.g., particulates or tablet
  • a robot 406 can be positioned in the transfer chamber 410. The robot 406 can transfer the container with the material from the fab interface unit 412 to one of the chambers or stations 402 for processing, from one chamber or station to another chamber or station 402, or from a chamber or station 402 back to the fab interface unit 412.
  • This configuration may be useful where large-molecule biologies are being fabricated in containers, e.g., bioreactors or petri dishes.
  • Each system 401 can have units 402, as noted above.
  • Each system 401 can have a microcontroller 404, which can control parameters of the stations or chamber 402 within the unit 400.
  • the controller 104 can be communicatively coupled to the microcontroller 404 of each system 401 via a wired connection or a wireless connection.
  • Such wireless connection can be over a communication network, such as a local area network, a wide area network, internet, intranet, Bluetooth network, infrared network, any other one or more networks, and/or any combination thereof.
  • the microcontrollers 404 of the systems 401 can enable rerouting of the material between the units (e.g., units 122-132 in FIG. 2).
  • the microcontrollers 404 can also enable rerouting of the material between any of the units 402.
  • Such rerouting can advantageously avoid delays when a unit 402 — for example, one of the units 122-132 within the corresponding unit 402 — within a particular system 401 (e.g., first system 401, which is the top system in FIG. 4) malfunctions, as in such case the process performed by that unit 402 can be rerouted to a corresponding unit 402 in another system 401 (e.g., second system 401, which is the system below the top system in FIG. 4), as described in further detail below by FIG. 6.
  • such rerouting can beneficially allow in-situ cleaning without delays in the manufacturing, as described in greater detail below by FIG. 7.
  • Each system 401 is described as having six stations or chambers 402, which in some non-limiting examples can correspond to six units 122-132 in FIG. 2.
  • each line 106 can have a number of stations or chambers equaling the number of units used in the process for manufacturing the drug.
  • FIG. 5 illustrates one non-limiting example 500 of a unit 156 within a line 106 of the multi -line parallel processing platform 102, in accordance with some implementations of the current subject matter.
  • the unit has a chamber 501 that can have multiple sub-chambers 502.
  • each sub-chamber 502 can include a component (e.g., a mechanical component of the API feeder 122, excipient feeder 124, mill 126, convective mixer 128, tablet press 130, coater 132, roller compactor, mill, wet granulator, or dryer, as discussed above) that is positioned in or extends into the sub chamber.
  • the robotic system 406 can bring the input material to the sub-chambers 502, and take the output material from those sub-chambers 502.
  • the sub-chambers 502 can be used for separate types of drugs (e.g., same drug with customized quantities of various constituents per the requirement of that type of patient), thereby offering personalized medication features while manufacturing different types of drugs at the same time.
  • the sub-chambers 502 can house same types of contents but in different proportions so as to manufacture different medications for different types of patients within a single multi-line parallel processing platform 102.
  • Different sub-chambers 502 can have the same capacity, i.e., be able to process the same volume of material.
  • each sub-chamber 502 has the same component (e.g., a component of the API feeder 122, excipient feeder 124, mill 126, convective mixer 128, tablet press 130, coater 132, roller compactor, mill, wet granulator, and dryer, as discussed above in the discussion for FIG. 2) that can perform the process 108 on the material stored in that sub-chamber 502, different sub chambers 502 can have the same throughput (i.e., rate at which the component within the sub-chamber 502 processes the material within that chamber 502).
  • different sub-chambers can perform different recipes, e.g., have different control parameters, e.g., different motor speeds for the mill, different gas composition inlet into the coater, etc.
  • Each of the separate sub-chambers 502 can have an array of sensors 504.
  • the sensors 504 can detect the parameters noted above, including in the discussion for FIGS. 1 and 2. Additionally, the sensors 504 within each sub-chamber 502 can detect the quantity of the content within that sub-chamber 502 to determine whether the sub-chamber 502 may be cleaned, as noted below by FIG. 7.
  • Each sub chamber 502 can be physically connected to a corresponding input valve 506, and a corresponding output valve 508.
  • the microcontroller of the line 106 in which the chamber 501 and corresponding unit is located, controls the opening and closing of the input valve 506 and the output valve 508.
  • the material to be processed by that malfunctioning sub chamber 502 can be routed, via pipes (flow through which is controlled by valves), to another functional sub-chamber 502 for processing.
  • That functional sub-chamber 502 can process the material for the malfunctioning sub-chambers 502 (i.e., the material that the malfunctioning sub-chamber 502 would have processed had there been no malfunctioning) at a time period separate from that of processing the material by the functional sub-chamber 502, thereby preventing mixing of the materials.
  • the upstream processing may be slowed temporarily until the malfunctioning sub-chamber 502 is repaired or replaced.
  • the material that is ready to be processed but is not currently being processed may be stored in a container connected to the functional sub-chamber 502.
  • FIG. 6 illustrates a method performed by the controller 104 for avoiding delays in manufacturing due to malfunctioning of one or more units within the lines 106, in accordance with some implementations of the current subject matter.
  • the controller 104 can identify, at 602 and by using one or more sensors 504, a location of malfunctioning of a unit, and/or station or chamber (which can include, for example, any sub-chamber) within a first line 106.
  • the controller 104 can reroute, the material flow immediately before the chamber 402 to a corresponding chamber in another line 106 (e.g., second line), and reroute output through that unit in another line (e.g., second line) to the subsequent unit in the original line 106 (e.g., first line in which there was a malfunctioning).
  • another line 106 e.g., second line
  • FIG. 7 illustrates a method performed by the controller 104 for performing in-situ cleaning of any chamber (e.g., the chamber discussed with respect to FIGS. 1 and 2, the chamber 402 discussed with respect to FIG. 4, or the chamber 501 discussed with respect to FIG. 5) that houses a unit during the manufacturing of the drug, in accordance with some implementations of the current subject matter.
  • the controller 104 can determine, at 702 and using one or more sensors (e.g., sensors 504 within the chamber 501), quantity of content within the chamber that is to be processed.
  • the controller 104 can determine, at 704, whether the quantity is below a corresponding threshold value for the content within the chamber.
  • the controller 104 can reroute, at 706 and in response to the quantity being below the corresponding threshold value, the material flow immediately before the chamber and immediately after the chamber to a corresponding chamber of another line 106.
  • the controller 104 can initiate, at 708, a cleaning system connected to the controller 104 to clean the chamber — where the quantity has been determined to be below a corresponding threshold value — while the process 108 configured to be performed by that chamber is being performed by a similar (which can be same in some implementations) chamber in another line 106.
  • the cleaning system can perform the cleaning by, for example, injecting water, or other cleaning liquid, directly into the chamber, followed by injecting air to dry the wet chamber.
  • the controller 104 can route, at 710, the material flow back to the disconnected chamber 402, thereby putting that chamber back in the line 106 from which it was disconnected so that the now-connected chamber 402 can continue to perform the corresponding process 108.
  • chambers in processing systems adapted for large-scale drug manufacturing e.g., at 10 kg/hour
  • a chamber adapted as discussed above e.g., for 1 ⁇ 2 to 3 kg/hour
  • such chamber can advantageously provide, as compared to larger chambers, a better accessibility for spraying of a cleaning fluid to reach all surfaces within the chamber.
  • the smaller chamber is easier to maintain at uniform temperature when heating the chamber to perform dry to remove the cleaning fluid.
  • the term “drug,” as described herein can include, in its broadest sense, all small molecule (e.g., non-biologic) APIs.
  • the drug could be selected from the group consisting of an analgesic, an anesthetic, an anti-inflammatory agent, an anthelmintic, an anti-arrhythmic agent, an antiasthma agent, an antibiotic, an anticancer agent, an anticoagulant, an antidepressant, an antidiabetic agent, an antiepileptic, an antihistamine, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antineoplastic agent, an antioxidant agent, an antipyretic, an immunosuppressant, an immunostimulant, an antithyroid agent, an antiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent
  • Exemplary types of small molecule drugs include, but are not limited to, acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib HC1, palbociclib, and amoxicillin potassium clavulanate.
  • a drug can also be referred to as a tablet in some implementations.
  • compositions include, but are not limited to: (1) surfactants and polymers including: polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, poly vinylalcohol, crospovidone, polyvinylpyrrolidone- polyvinylacrylate copolymer, cellulose derivatives, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl cellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, carbomer and their polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl pyrrolidone and vinyl acetate;
  • surfactants and polymers including: polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, poly vinylalcohol, crospovidone, polyvinylpyrrolidone- poly
  • binding agents such as cellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose
  • filling agents such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches
  • lubricating agents such as agents that act on the flowability of a powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel
  • sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K
  • flavoring agents (7) preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quartemary compounds
  • Various implementations of the subject matter described herein can be realized/implemented in digital electronic circuitry, integrated circuitry, specially designed application specific integrated circuits (ASICs), computer hardware, firmware, software, and/or combinations thereof. These various implementations can be implemented in one or more computer programs. These computer programs can be executable and/or interpreted on a programmable system.
  • the programmable system can include at least one programmable processor, which can have a special purpose or a general purpose.
  • the at least one programmable processor can be coupled to a storage system, at least one input device, and at least one output device.
  • the at least one programmable processor can receive data and instructions from, and can transmit data and instructions to, the storage system, the at least one input device, and the at least one output device.
  • the subject matter described herein can be implemented on a computer that can display data to one or more users on a display device, such as a cathode ray tube (CRT) device, a liquid crystal display (LCD) monitor, a light emitting diode (LED) monitor, or any other display device.
  • a display device such as a cathode ray tube (CRT) device, a liquid crystal display (LCD) monitor, a light emitting diode (LED) monitor, or any other display device.
  • CTR cathode ray tube
  • LCD liquid crystal display
  • LED light emitting diode
  • the computer can receive data from the one or more users via a keyboard, a mouse, a trackball, a joystick, or any other input device.
  • other devices can also be provided, such as devices operating based on user feedback, which can include sensory feedback, such as visual feedback, auditory feedback, tactile feedback, and any other feedback.
  • the input from the user can be received in any form, such as acoustic input, speech input, tactile input, or any other input.
  • the subject matter described herein can be implemented in a computing system that can include at least one of a back-end component, a middleware component, a front-end component, and one or more combinations thereof.
  • the back-end component can be a data server.
  • the middleware component can be an application server.
  • the front-end component can be a client computer having a graphical user interface or a web browser, through which a user can interact with an implementation of the subject matter described herein.
  • the components of the system can be interconnected by any form or medium of digital data communication, such as a communication network. Examples of communication networks can include a local area network, a wide area network, internet, intranet, Bluetooth network, infrared network, or other networks.
  • the computing system can include clients and servers.
  • a client and server can be generally remote from each other and can interact through a communication network.
  • the relationship of client and server can arise by virtue of computer programs running on the respective computers and having a client-server relationship with each other.

Abstract

Une plate-forme de traitement parallèle à lignes multiples destinée à la fabrication de médicaments comprend une pluralité de lignes parallèles, chaque ligne de la pluralité de lignes parallèles comprenant une pluralité d'unités de traitement qui réalisent une pluralité de procédés de fabrication d'un médicament. Un système de commande reçoit des données de la pluralité des capteurs et est configuré pour déconnecter une unité de traitement d'une première ligne correspondante en réponse à la détection d'un état d'erreur et pour connecter une unité de traitement correspondante dans une deuxième ligne avec au moins l'une d'une unité de traitement précédente dans la première ligne et d'une unité de traitement suivante dans la première ligne.
PCT/US2020/064528 2019-12-11 2020-12-11 Plate-forme de traitement parallèle à lignes multiples destinée à la fabrication de médicaments WO2021119438A1 (fr)

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US5166874A (en) * 1989-04-27 1992-11-24 Nissan Motor Co. Ltd. Method and apparatus for production line fault management
US20060167659A1 (en) * 2002-08-30 2006-07-27 Nsk Ltd. Method and device for monitoring status of mechanical equipment and abnormality diagnosing device
US20100100234A1 (en) * 2006-10-20 2010-04-22 Forhealth Technologies, Inc. Automated drug preparation apparatus including syringe loading, preparation and filling
EP2213274A1 (fr) * 2007-10-23 2010-08-04 Yuyama Mfg. Co., Ltd. Système d'administration de médicament, et dispositif d'administration de médicament
WO2016049542A2 (fr) * 2014-09-25 2016-03-31 Nxstage Medical, Inc. Préparation médicamenteuse et dispositifs, méthodes et systèmes de traitement

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5166874A (en) * 1989-04-27 1992-11-24 Nissan Motor Co. Ltd. Method and apparatus for production line fault management
US20060167659A1 (en) * 2002-08-30 2006-07-27 Nsk Ltd. Method and device for monitoring status of mechanical equipment and abnormality diagnosing device
US20100100234A1 (en) * 2006-10-20 2010-04-22 Forhealth Technologies, Inc. Automated drug preparation apparatus including syringe loading, preparation and filling
EP2213274A1 (fr) * 2007-10-23 2010-08-04 Yuyama Mfg. Co., Ltd. Système d'administration de médicament, et dispositif d'administration de médicament
WO2016049542A2 (fr) * 2014-09-25 2016-03-31 Nxstage Medical, Inc. Préparation médicamenteuse et dispositifs, méthodes et systèmes de traitement

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