WO2023110682A2 - Système de biotraitement et collecteur de capteur associé - Google Patents

Système de biotraitement et collecteur de capteur associé Download PDF

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Publication number
WO2023110682A2
WO2023110682A2 PCT/EP2022/085245 EP2022085245W WO2023110682A2 WO 2023110682 A2 WO2023110682 A2 WO 2023110682A2 EP 2022085245 W EP2022085245 W EP 2022085245W WO 2023110682 A2 WO2023110682 A2 WO 2023110682A2
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WO
WIPO (PCT)
Prior art keywords
sensor
manifold
fluid
sensors
syringe tube
Prior art date
Application number
PCT/EP2022/085245
Other languages
English (en)
Other versions
WO2023110682A3 (fr
Inventor
Blaik A. Musolf
Eric Favre
Romain LESAGE
Willem Frederik Tim JAARSMA
Original Assignee
Norgren LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Norgren LLC filed Critical Norgren LLC
Publication of WO2023110682A2 publication Critical patent/WO2023110682A2/fr
Publication of WO2023110682A3 publication Critical patent/WO2023110682A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C12M33/04—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by injection or suction, e.g. using pipettes, syringes, needles
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/48—Automatic or computerized control

Definitions

  • a bioreactor refers to a manufactured device or system that supports a biologically active environment.
  • a bioreactor can be a vessel in which a chemical process is carried out which involves organisms or biochemically active substances derived from such organisms.
  • Managing a bioprocessing system also involves measuring properties of fluids and mixtures.
  • Existing measuring methods in bioprocessing systems have limitations in the areas of reliability, resolution, and overall performance. For example, measuring devices are pieced together from different suppliers resulting in differences in performance ranges, outputs, and compatibility that hinder precise, efficient, and real-time control of a bioprocessing system. It may thus be desirable to provide a consolidated package of sensors, valves, manifolds, and system controller to alleviate such issues.
  • the present disclosure describes implementations that relate to a bioprocessing systems and associated sensor manifold.
  • the present disclosure describes a sensor manifold assembly of a bioprocessing system.
  • the sensor manifold assembly includes: a syringe pump comprising: (i) a syringe tube having a port configured to be fluidly-coupled to a bioreactor of the bioprocessing system, (ii) a piston slidably-accommodated in the syringe tube, and (iii) a piston driver configured to drive the piston within the syringe tube, wherein the piston driver moves the piston in a first direction to draw fluid through the port into the syringe tube and in a second direction to discharge the fluid from the syringe tube through the port; and a sensor manifold disposed about the syringe tube of the syringe pump, wherein the sensor manifold comprises one or more sensors configured to measure fluid properties of fluid in the syringe tube.
  • the present disclosure describes a sensor manifold of a bioprocessing system.
  • the sensor manifold includes: a manifold body have (i) a plurality of slots, (ii) an internal fluid passage, and (iii) an inlet port configured to receive fluid from a bioreactor of the bioprocessing system and provide the fluid to the internal fluid passage; and one or more sensors, each sensor being removably-disposed in a respective slot of the plurality of slots, wherein each sensor has a sensing element configured to measure a property of the fluid flowing through the internal fluid passage of the manifold body.
  • Figure 1 illustrates a bioprocessing system, in accordance with an example implementation.
  • Figure 2 illustrates a perspective view of a sensor manifold assembly having a sensor manifold mounted about a syringe pump, in accordance with an example implementation.
  • Figure 3 illustrates a partial cross-sectional elevational view of the sensor manifold assembly of Figure 2, in accordance with an example implementation.
  • Figure 4 illustrates a partial cross-sectional elevational view of a sensor manifold assembly, in accordance with an example implementation.
  • Figure 5 illustrates a partial perspective view of a sensor manifold having a manifold body and replaceable sensors, in accordance with an example implementation.
  • Figure 6 illustrates a partial perspective view of a sensor of the sensor manifold of Figure 5, in accordance with an example implementation.
  • Figure 7 illustrates a cross-sectional side view of the sensor manifold of Figure 5, in accordance with an example implementation.
  • Figure 8 illustrates a partial perspective front view of the sensor manifold of Figure 5, in accordance with an example implementation.
  • Figure 8A illustrates another cross-sectional view of the sensor of Figure 6, in accordance with an example implementation.
  • Figure 8B illustrates a cross-sectional view of a sensor having a probe, in accordance with an example implementation.
  • Figure 9 illustrates a partial perspective view of another sensor manifold having a manifold body and replaceable sensors, in accordance with an example implementation.
  • Figure 10 illustrates a partial cross-sectional view of the sensor manifold of Figure 9 with a sensor positioned within a cylindrical hole, in accordance with an example implementation.
  • Figure 11 illustrates a partial cross-sectional view of the sensor manifold of Figure 9 with a sensor being removed from the manifold body, in accordance with an example implementation.
  • FIG. 1 illustrates a bioprocessing system 100, in accordance with an example implementation.
  • the bioprocessing system 100 can include, or can be fluidly-coupled to, a plurality of storage containers 102 storing fluid that are to be used to form a desired biochemical composition in a bioreactor 104.
  • the term “fluid” is used throughout herein to indicate gases, nutrients, biological fluids, chemicals, etc.
  • the storage containers 102 are fluidly-coupled via feedlines 106 (e.g., tubes, hoses, pipes, or any type of fluid lines) to a flow control module 108.
  • the flow control module 108 can include several components or subsystems.
  • the flow control module 108 includes filters to filter any contaminants from fluids provided from the storage containers 102.
  • the flow control module 108 includes a plurality of pumps such as peristaltic pumps. Such pumps can be configured to draw fluid via the feedlines 106 from a respective storage container of the storage containers 102 and discharge the fluid through an output fluid line 110 to the bioreactor 104.
  • the flow control module 108 can further include a plurality of valves (e.g., flow control valves or pinch valves that are electrically- actuated) to control fluid flow rate and/or pressure level of fluids flowing through the flow control module 108 to the bioreactor 104.
  • the bioprocessing system 100 can include a controller 112.
  • the controller 112 can include one or more processors mounted to a controller board (e.g., a printed circuit board).
  • a processor can comprise one or more microprocessors.
  • a processor can include a general purpose processor (e.g., an INTEL® single core microprocessor or an INTEL® multicore microprocessor), or a special purpose processor (e.g., a digital signal processor, a graphics processor, or an application specific integrated circuit (ASIC) processor).
  • a processor can be configured to execute computer-readable program instructions (CRPI) to perform operations described throughout herein.
  • CRPI computer-readable program instructions
  • a processor can be configured to execute hard-coded functionality in addition to or as an alternative to software-coded functionality (e.g., via CRPI).
  • the controller 112 can be configured to send command signals (e.g., send electric signals via wires or via a bus such as a Communication Area Network (CAN) bus) to the pumps and valves of the flow control module 108.
  • command signals e.g., send electric signals via wires or via a bus such as a Communication Area Network (CAN) bus
  • the controller 112 is configured to control which valves to actuate, and thus which input fluid (e.g., gas, liquid, or nutrient) to provide to the bioreactor 104.
  • the controller 112 can also control the valves proportionally to control the fluid flow rate through the valves and the pressure level of the fluid. This way, the controller 112 can achieve desired characteristics of the mixture in the bioreactor 104.
  • the output fluid line 110 provide fluid discharged from the flow control module 108 to the bioreactor 104.
  • the bioreactor 104 has a container or vessel 114 in which a chemical process is carried out, which involves mixing and chemically reacting fluids (e.g., gases, liquids, nutrients, etc.) received from the flow control module 108 to produce cells, organisms or biochemically active substances derived from such organisms.
  • the bioprocessing system 100 can include an alternative type of bioreactor 116, which can include a disposable bag or liner bioreactor housed within a shell 118.
  • the bioreactor 104 is used for describing operations of the bioprocessing system 100; however, it should be understood that the description is applicable to the bioreactor 116 or any other type of bioreactors.
  • the bioprocessing system 100 further includes a sensor manifold 120.
  • the sensor manifold 120 can be directly or indirectly fluidly-coupled to the bioreactor 104.
  • the bioprocessing system 100 can have a sampling fluid line 122 that returns a sample of the mixture in the bioreactor 104 to the flow control module 108, and the sensor manifold 120 can then receive the sample from the flow control module 108.
  • the sensor manifold 120 can be directly fluidly-coupled to the bioreactor 104 to receive the sample directly therefrom.
  • the sensor manifold 120 has one or more pumps (e.g., syringe pump 204 described below with respect to Figure 2) configured to draw a sample from the mixture in the vessel 114 of the bioreactor 104 via the sampling fluid line 122.
  • the sensor manifold 120 has one or more sensors such as sensor 124 configured to measure various properties and characteristics of the mixture such as pH (i.e., a measure of how acidic/basic the mixture is), temperature, CO2, cell density, conductivity, dissolved oxygen, concentration of metabolites, turbidity (e.g., a measure of relative clarity of a liquid), etc.
  • one or more of the sensors are fluid contact sensors where a sensing element of the sensor is subjected to fluid flowing through the sensor manifold 120, while other sensors are non-contact fluid sensor (measure fluid properties without contacting the fluid).
  • Integration of sensors in the sensor manifold 120 and having the controller 112 receiving sensor information and taking action accordingly provides a system that is simple to configure. Such a system may facilitate testing and verification and may ensure consistency and compatibility between various components.
  • the sensor manifold 120 can have an exhaust or waste port through which such sample of fluid is provided to the flow control module 108, when then provides the returned sample via a return fluid line 125 to a waste tank 126.
  • the sensor manifold 120 can be directly fluidly-coupled to the waste tank 126 via a return line as opposed to providing the sample to the flow control module 108 and then to the waste tank 126. If the fluid lines (e.g., the output fluid line 110, the sampling fluid line 122, and the return fluid line 125 are made of multiple tube or hose connections, sanitary fitting such as sanitary fitting 128 can be used to couple the tubes to each other.
  • the senor manifold 120 can have a printed circuit board (PCB) 130.
  • PCB printed circuit board
  • PCB 130 has electronic components (e.g., chips, wires traces, resistors, capacitors, etc.) associated with the sensors of the sensor manifold 120 (e.g., the sensor 124) and configured to provide the sensor signals to pins of an electric connector to the controller 112.
  • a manifold cable or bus 132 is configured to plug into the electric connector of the sensor manifold 120 to provide the sensors signals to the controller 112 and receive electric power for the sensors.
  • Components of the bioprocessing system 100 may be configured to work in an interconnected fashion with each other and/or with other components coupled to respective systems.
  • One or more of the described operations or components of the bioprocessing system 100 may be divided up into additional operational or physical components, or combined into fewer operational or physical components.
  • the sensor manifold 120 can be integrated with the flow control module 108 into a single block or manifold.
  • Components of the flow control module 108 can be divided into separate components.
  • bioprocessing system 100 may be included within other systems.
  • the sensor manifold 120 can be a separate manifold or can be mounted to the bioreactor 104 or other parts of the bioprocessing system 100.
  • the configuration of the sensor manifold 120 depicted in Figure 1 is an example for illustration only.
  • the sensor manifold can have different shapes and configuration.
  • Figures 2-11 describe various example implementations of the sensor manifold.
  • Figure 2 illustrates a perspective view of a sensor manifold assembly 200 having a sensor manifold 202 mounted about a syringe pump 204, in accordance with an example implementation.
  • the syringe pump 204 includes a plunger or piston 206 slidably-accommodated in a syringe tube 208.
  • the syringe tube 208 has a port 210 that is fluidly-coupled to a bioreactor such as the bioreactor 104, for example.
  • the port 210 can be fluidly-coupled directly to the bioreactor 104 (e.g., mounted to a side or top cover of the bioreactor 104) and is thus in directly fluid communication with the bioreactor 104.
  • the sensor manifold assembly 200 can be mounted to the flow control module 108 or other fluid lines connected to the bioreactor 104.
  • the piston 206 fits tightly against the interior surface of the syringe tube 208 so as to form a fluid seal therewith.
  • the piston 206 is retracted (e.g., moves upward in Figure 2), the volume within the syringe tube 208 is increased and fluid is drawn via the port 210 into the syringe tube 208.
  • the piston 206 extends (e.g., moves downward in Figure 2), fluid is discharged from the port 210 and the volume contained in the syringe tube 208 between the piston 206 and the port 210 decreases. This way, the piston 206 provides a positive displacement pumping action, which displaces the fluid from the syringe tube 208 back into the fluid line to which the sensor manifold assembly 200 is fluidly-coupled.
  • the syringe pump 204 includes a piston driver, which drives the piston 206 with respect to the syringe tube 208.
  • the piston driver can be an electric motor 212 mounted to the syringe tube 208 and coupled to the piston 206 via a rod, rail, or screw 214.
  • the electric motor 212 can be stepper motor and the screw 214 can be a power screw that is coupled to the piston 206 such that rotation of the screw 214 via the electric motor 212 causes the piston 206 to move linearly.
  • linear rails or slide rails can be used to guide, or provide linear movement to, the piston 206.
  • the sensor manifold assembly 200 is configured such that rotary motion of the electric motor 212 is transformed into liner motion of the piston 206.
  • other mechanisms could be used to provide linear motion of the piston 206.
  • a linear motor can be used instead of a rotary motor, wherein a linear motor is an electric motor that has had its stator and rotor “unrolled,” and thus instead of producing a torque (rotation) it produces a linear force along its length.
  • the electric motor 212 can provide precise and slow movement of the piston to draw precise amounts of the fluid into the syringe tube 208 and discharge that amount back via the port 210.
  • the flow rate or displacement of the fluid can be controlled by knowing the geometry of the syringe tube 208 and accurately controlling the movement of the piston 206.
  • the sensor manifold 202 is disposed about a circumference of the syringe tube 208.
  • the sensor manifold 202 can be ring-shaped or disk-shaped with a central hole through which the syringe tube 208 is disposed.
  • a disk- shaped is used herein an example. Other shapes (e.g., rectangular prism) can be used.
  • the sensor manifold 202 can have an array of sensors, such as sensor 216 and sensor 218, disposed radially within the sensor manifold 202 such that the sensors can measure properties of the fluid in the syringe tube 208.
  • the sensors can be threaded in respective radial holes formed in the sensor manifold 202.
  • a plurality of sensors can be used and can be disposed in a circular array about the sensor manifold 202 to measure various properties of the fluid in the syringe tube 208.
  • Figure 3 illustrates a partial cross-sectional elevational view of the sensor manifold assembly 200, in accordance with an example implementation.
  • the sensor 216 can have a sensor probe 300 and the sensor 218 can have a sensor probe 302 pointing radially inward toward the syringe tube 208 to measure respective fluid properties of fluid within the syringe tube 208.
  • the sensors 216, 218 can be non-contact fluid sensors (i.e., sensors that can measure fluid properties without contacting the fluid).
  • the sensor 216 can be an optical sensor probe having an optical disc that operates as a window overseeing fluid disposed within the syringe tube 208.
  • Such optical sensor can have a source of light that emits light through the optical disc.
  • the optical sensor can also have a sensing element (e.g., the sensor probes 300, 302) that receives the light reflected from the fluid and converts light rays into electronic signals.
  • the sensing element measures the physical quantity of light and then coverts it into an electric signal indicative of a property of the fluid.
  • the optical sensor can measure the changes from one or several light beams. When a change occurs, the optical sensor can operate as a photoelectric trigger, and therefore either increases or decreases the electrical output.
  • the controller 112 can determine a property of the fluid through the electrical output received from such optical sensor.
  • the optical sensor may be a turbidity sensor configured to measure relative clarity of a liquid in the syringe tube 208. Turbidity is an optical characteristic of the liquid and can be measured by an optical sensor as the amount of light that is scattered by material in the fluid when a light is projected through the fluid.
  • one of the sensors can be a pH non-contact optical sensor.
  • the sensor can have a sensor patch or sensor spot 304 disposed or mounted within the syringe tube 208 and attached (e.g., via an adhesive) to the interior surface of the syringe tube 208.
  • the sensor spot 304 can have an acid-based pH indicator to mark the hydrogen ions in the fluid in the syringe tube 208.
  • the interaction between the sensor spot 304 and the hydrogen ions changes the structure of the indicator molecule, varying the optical characteristics of the sensors spot 304 (absorption rate, reflectance, fluorescence, refractive index, color, etc.).
  • the pH value of the fluid can be determined.
  • a polymer optical fiber cable can be coupled to the sensor 216 to transfer excitation light to the sensor 216 and the sensor response back to the controller 112.
  • the senor 218 can also be a non-contact sensor having a respective sensor spot 306 to measure another properties such as pCCh.
  • one or more of the sensors of the sensor manifold 202 can be fluid contact sensors (i.e., the sensor probe is subjected or exposed to the fluid).
  • Figure 4 illustrates a partial cross-sectional elevational view of a sensor manifold assembly 400, in accordance with an example implementation.
  • the sensor manifold assembly 400 is similar to the sensor manifold assembly 200, and thus similar components are designated with the same reference numbers.
  • the sensor manifold assembly 400 has fluid contact sensors such as sensor 402 and sensor 404.
  • the sensors 402, 404 can be molded or threaded into the sensor manifold 202.
  • the sensor 400 has a sensing element 406 that extends radially to within, or to the interior surface of, the syringe tube 208 such that the sensing element 406 is subjected or exposed to fluid in the syringe tube 208.
  • the syringe tube 208 can further have a sealing grommet 408.
  • the sealing grommet 408 can be configured as a ring-shaped or annular bushing that is disposed about the sensing element 406 through the syringe tube 208 to hold the sensor 402 in position.
  • the sealing grommet 408 can be a molded rubber bushing that is inserted into the syringe tube 208 about the sensing element 406.
  • the sealing grommet 408 can be made of metal or plastic.
  • the sealing grommet 408 operates as a seal that precludes leakage from within the syringe tube 208 around the sensing element 406 to an external environment of the sensor manifold assembly 400. Further, the sealing grommet 408 may also prevent any contaminants in the external environment of the sensor manifold assembly 400 from entering the syringe tube 208 and contaminating the fluid therein. This may be desirable particularly if the sample of fluid drawn from the bioreactor 104 is be returned thereto as opposed to being discarded to a waste tank.
  • the piston 206 can be at a first position (shown in solid lines at the bottom of the syringe tube 208 in Figure 4) and then the electric motor 212 can retract the piston 206 a second position (shown in dashed lines at the top of the syringe tube 208 in Figure 4).
  • vacuum or low pressure is created within the syringe tube 208 as the piston 206 moves upward and fluid is drawn from the bioreactor 104 via the port 210 into the syringe tube 208.
  • the piston 206 may form a tight seal with the interior surface of the syringe tube 208.
  • the piston 206 wipes any fluid on the interior surface of the syringe tube 208 to allow the sensing element 406 to be exposed to fluid in the fresh sample being drawn.
  • the electric motor 212 can move the piston 206 back to its first position while again wiping fluid off the interior surface of the syringe tube 208 to return substantially the entire sample that has been drawn to the bioreactor 104 with minimal loss.
  • the shape of the piston 206 and the syringe tube 208 can be configured to reduce the dead volume to ensure that substantially the entire sample is returned to the bioreactor 104.
  • the sealing grommet 408 may preclude such contamination.
  • the piston 206 moves past the sealing grommet 408 (e.g., below the sealing grommet 408), the area of the syringe tube 208 above the piston 206 is sealed and remains sterile.
  • the sensor 404 can be configured similar to the sensor 402 and can have a respective sensing element 410 and a respective sealing grommet 412.
  • the sensor manifold assembly 200, 400 can have a mix of non-contact sensors and fluid contact sensors.
  • Figure 5 illustrates a partial perspective view of a sensor manifold 500 having a manifold body 501 and replaceable sensors such as sensor 502, and Figure 6 illustrates a partial perspective view of the sensor 502, in accordance with an example implementation.
  • the sensor manifold 500 is configured to be modular such that its sensors are removably-disposed within slots in the manifold body 501 and can be readily removed and replaced.
  • the sensor manifold 500 is depicted as including multiple sensors, it is contemplated that a sensor manifold can include a single sensor.
  • the manifold body 501 can be configured generally as a rectangular prism with rectangular slots such as slot 504, which operate as receptacles for sensors such as sensor 502.
  • the manifold body 501 can be made with additive manufacturing techniques (e.g., 3D printing) and can be formed from layers deposited on each other. However, other manufacturing techniques can be used (casting, machining, molding, etc.).
  • additive manufacturing techniques e.g., 3D printing
  • other manufacturing techniques can be used (casting, machining, molding, etc.).
  • Other materials may be used, however.
  • the manifold body 501 can be made from polypropylene layers. Polypropylene is lightweight and suitable for applications involving chemicals as polypropylene might not react with chemicals and might not cause leaching.
  • the manifold body 501 can have an inlet port 506 that can be fluidly-coupled to the bioreactor 104 via a sampling fluid line (e.g., the sampling fluid line 122) and is configured to receive fluid therefrom.
  • the manifold body 501 has an internal fluid passage 508 formed therein through which fluid received from the bioreactor 104 flows.
  • the manifold body 501 is depicted with one internal fluid passage, in other examples, more than one fluid passage can be formed in the manifold body 501, and the fluid passages can be disposed in series or in parallel to reduced dead volume and contamination.
  • the sensor manifold 500 can have a pump (e.g., a peristaltic pump or any positive displacement pump, not shown) that, when actuated by the controller 112, for example, draws fluid from the bioreactor 104 through the inlet port 506 and the internal fluid passage 508, then provides the fluid to an outlet port 510, which discharges the fluid back to the bioreactor 104 via a return fluid line.
  • a pump e.g., a peristaltic pump or any positive displacement pump, not shown
  • fluid is provided from the outlet port 510 to the waste tank 126 via a return fluid line (e.g., the return fluid line 125).
  • the manifold body 501 has a plurality of slots similar to the slot 504 that are configured to respectively receive sensors therein.
  • the sensor manifold 500 is depicted with four sensors, the sensor 502, sensor 512, sensor 514, and sensor 516. However, more or fewer sensors can be used.
  • the sensors 502 and 512-516 are configured to properties of fluid flowing through the internal fluid passage 508.
  • the sensors can be snap-in sensors that can be inserted into their respective slots and then retained by a snap configuration.
  • the sensor 502 can have a protrusion or tab 518 and a tab 520 on one side of the sensor 502, and may have respective tabs on the other side of the sensor 502.
  • the surfaces of the manifold body 501 that bound the slot 504 can have corresponding recesses, such as recess 522 and recess 524.
  • the sensor 502 When the sensor 502 is inserted (in a top to bottom direction, for example) into the slot 504, the sensor 502 is inserted until its tabs snap into or are received within the corresponding recess of the manifold body 501, thereby retaining or securing the sensor 502 within the slot 504. Pulling the sensor 502 outward (e.g., upward in Figure 5), can disengage the tabs of the sensor 502 from their respective recesses to remove the sensor 502.
  • the sensor manifold 500 can have electric contacts, such as electric contact 526, electric contact 528, and electric contact 530, exposed in the respective slot of the sensor.
  • the sensors also have respective electric contacts, such as electric contact 600, electric contact 602, and electric contact 604 shown in Figure 6.
  • the electric contacts 600-604 interface with the electric contacts 526-530 of the sensor manifold 500.
  • the electric contacts 526-530 of the sensor manifold 500 can be electrically-coupled to respective conductive points on the PCB (e.g., the PCB 130) of the sensor manifold 500.
  • the sensor manifold 500 can provide power and earth ground connections to the sensor 502 via two of the electric contacts 526-530, and receive the sensor signal (e.g., signal measurement) via the third contact.
  • Three contacts are shown here as an example. More (e.g., five electric contacts) of fewer electric contacts could be used.
  • the manifold body 501 is configured to provide access to fluid within the internal fluid passage 508 to the sensors 502, 512-516.
  • the sensor manifold 500 can have a breakthrough window that aligns with a sensing element of the sensor to allow the sensor to have access to the fluid flowing in the internal fluid passage 508 and measure properties of the fluid.
  • Figure 7 illustrates a cross-sectional side view of the sensor manifold 500
  • Figure 8 illustrates a partial perspective front view of the sensor manifold 500, in accordance with an example implementation.
  • the manifold body 501 can have a respective counterbore in each slot, such as counterbore 700 in the slot 504.
  • the counterbore 700 is sufficiently deep to reach the internal fluid passage 508 such that a slit 800 shown in Figure 8 is formed to provide access to fluid flowing through the internal fluid passage 508.
  • the counterbore 700 and the slit 800 operate as a breakthrough window that allows a sensing element 702 of the sensor 502 to have access to the fluid in the internal fluid passage 508.
  • the sensor 502 can be a conductivity sensor, and in this example, the sensing element 702 can comprise a first electrode 606 and a second electrode 608.
  • the electrodes 606, 608 are in contact with the fluid in the internal fluid passage 508.
  • An alternating electric current is applied to the electrodes 606, 608 in contact with the fluid and the resulting voltage is measured.
  • the fluid acts as an electrical conductor between the electrodes 606, 608, and thus the resulting voltage is indicative of the level of conductivity of the fluid.
  • a conductivity sensor is used herein as an example for illustration only, and other types of the sensors, contact and non-contact sensors, can be used (e.g., pH, temperature, CO2, cell density, conductivity, dissolved oxygen, concentration of metabolites, turbidity, etc.).
  • the senor 502 further includes a sealing ring 610 disposed about the sensing element 702 (e.g., the electrodes 606, 608) of the sensor 502 as shown in Figure 6.
  • the sealing ring 610 is configured to mate or rest against the interior surface of the manifold body 501, such that the sealing ring 610 surrounds and covers the counterbore 700.
  • the sealing ring 610 can be configured as an elastomeric (e.g., rubber) seal that precludes leakage from the slit 800 to an external environment, and precludes contaminating the fluid flow through the internal fluid passage 508.
  • the counterbore 700 can have another sealing mechanism (similar to the sealing flaps 1006 described below with respect to Figures 10-11) to enhance sealing of the slit 800 and preclude contaminating fluid within the internal fluid passage 508 when the sensor 502 is removed to be replaced with another sensor, for example.
  • another sealing mechanism similar to the sealing flaps 1006 described below with respect to Figures 10-11
  • the manifold body 501 can have a bypass channel and/or a shut-off features that allows removal of sensors without contaminating fluid.
  • the internal fluid passage 508 can be bypassed or shut off while a sensor is being remove, and after another sensor is placed in the respective slot, flow can be restored to the internal fluid passage 508.
  • FIG 8A illustrates another cross-sectional view of the sensor 502, in accordance with an example implementation.
  • the sensor 502 can have a channel or conduit 802 through which a cable or wires can be extended from the electric contacts 600-604 to an electronic board or PCB 804 embedded in the sensor 502.
  • the electrodes 606, 608 also extend to, and are connected to, the PCB 804.
  • the PCB 804 includes traces and connections that allow for communication between the electrodes 606, 608 and the electric contacts 600-604, which in turn are electrically-coupled to the PCB 130 when the sensor 502 is mounted in the sensor manifold 500 (e.g., via the electric contacts 526-530).
  • the sensors such as the sensor 502 may be disposable.
  • the PCB 130 e.g., a microprocessor of the PCB 130
  • the sensor 502 is depicted as a conductivity sensor as an example for illustration.
  • Sensors of the sensor manifold 500 can be configured to measure various properties of fluid passing through the sensor manifold 500.
  • the sensor can have a probe that extends to the fluid to measure a particular property.
  • Figure 8B illustrates a cross-sectional view of a sensor 806 having a probe 808, in accordance with an example implementation.
  • the sensor 806 can have a channel or conduit 810 through which a cable or wires can be extended from the electric contacts (e.g., similar to the electric contacts 600-604) to an electronic board or PCB 812 embedded in the sensor 806.
  • the probe 808 is configured to contact the fluid flow through the internal fluid passage 508 to measure a particular property of the fluid.
  • the probe 808 also extends to, and is connected or coupled to, the PCB 812.
  • the PCB 812 includes traces and connections that allow for communication between the probe 808 and the electric contacts, which in turn are electrically-coupled to the PCB 130 when the sensor 806 is mounted in the sensor manifold 500.
  • the sensor 502 is configured as a fluid contact sensor, in other examples, the sensor manifold 500 can have non-contact fluid sensors (e.g., optical sensors) that may measure fluid properties without contacting fluid in the internal fluid passage 508.
  • non-contact fluid sensors e.g., optical sensors
  • Figure 9 illustrates a partial perspective view of a sensor manifold 900 having a manifold body 901 and replaceable sensors such as sensor 902, in accordance with an example implementation.
  • the sensor manifold 900 is configured to be modular such that its sensors are removably-disposed within slots in the manifold body 501 and can be readily removed and replaced.
  • the manifold body 901 can be configured generally as a rectangular prism with a plurality of slots configured as cylindrical holes such as cylindrical hole 904, which operate as receptacles for sensors such as the sensor 902.
  • the manifold body 901 has an inlet port 906 that can be fluidly-coupled to the bioreactor 104 via a sampling fluid line (e.g., the sampling fluid line 122) and is configured to receive fluid therefrom.
  • the sensor manifold 900 has an internal fluid passage 908 formed therein through which fluid received from the bioreactor 104 flows.
  • the sensor manifold 900 can have a pump (e.g., a peristaltic pump or any positive displacement pump, not shown) that, when actuated by the controller 112, for example, draws fluid from the bioreactor 104 through the inlet port 906 and the internal fluid passage 908, then provides the fluid to an outlet port 910, which discharges the fluid back to the bioreactor 104 via a return fluid line.
  • a pump e.g., a peristaltic pump or any positive displacement pump, not shown
  • fluid is provided from the outlet port 910 to the waste tank 126 via a return fluid line (e.g., the return fluid line 125).
  • the manifold body 901 has a plurality of cylindrical holes similar to the cylindrical hole 904 that are configured to respectively receive sensors therein.
  • the sensor manifold 900 is depicted with four sensors, the sensor 902, sensor 912, sensor 914, and sensor 916. However, more or fewer sensors can be used.
  • the sensors 902 and 912-916 are configured to properties of fluid flowing through the internal fluid passage 908.
  • the sensors can have an orientation feature such as a notch 918 of the sensor 902 that facilitates orienting the sensor 902 in a particular direction to be inserted within the manifold body 901 at a particular orientation.
  • the manifold body 901 has a corresponding orientation feature such as an opening or groove 920 that correspond in shape to the notch 918 of the sensor 902.
  • the sensor 902 can be rotated until the notch 918 is aligned with the groove 920, thereby allowing the sensor 902 to be inserted in the cylindrical hole 904 at the particular orientation.
  • electric contacts of the sensor 902 can be aligned with the respective electric contacts of the sensor manifold 900.
  • both the sensor 902 and the manifold body 901 can be marked to facilitate aligning the marks and inserting the sensor 902 in a particular orientation.
  • a spline or ridge can be used, and the manifold body 901 can have a corresponding spline groove.
  • the sensor 902 can have a key and the manifold body 901 can have a key way to receive the key.
  • the sensor manifold 900 can have pivotable retainer arms such as pivotable retainer arm 922 that is pivotably-mounted to the manifold body 901. Particularly, pivotable retainer arm 922 can rotate about a pivot 924 in the manifold body 901. The pivotable retainer arm 922 can be rotated counter-clockwise to a first position shown in Figure 9, for example, to expose the cylindrical hole 904 and allow the sensor 902 to be inserted and positioned therein as.
  • pivotable retainer arms such as pivotable retainer arm 922 that is pivotably-mounted to the manifold body 901.
  • pivotable retainer arm 922 can rotate about a pivot 924 in the manifold body 901.
  • the pivotable retainer arm 922 can be rotated counter-clockwise to a first position shown in Figure 9, for example, to expose the cylindrical hole 904 and allow the sensor 902 to be inserted and positioned therein as.
  • the pivotable retainer arm 922 can be rotated clockwise to a second position in which the pivotable retainer arm 922 is positioned on top of the sensor 902 (see respective pivotable retainer arms of the sensors 912-916 in Figure 9), thereby retaining and securing the sensor 902 within the manifold body 901 (e.g., preclude the sensor 902 from moving upward in Figure 9). Rotating the pivotable retainer arm 922 back in the counter-clockwise direction releases the sensor 902 and facilitates its removal and replacement.
  • the sensor manifold 900 can have electric contacts, such as electric contact 926, electric contact 928, and electric contact 930, exposed in the respective cylindrical hole of the sensor.
  • the sensors also have respective electric contacts (such as electric contact
  • the electric contacts 926-930 of the sensor manifold 900 are electrically-coupled to respective conductive points on the PCB (e.g., the PCB 130) of the sensor manifold 900.
  • the sensor manifold 900 can provide power and earth ground connections to the sensor 902 via two of the electric contacts 926-930, and receive the sensor signal (e.g., signal measurement) via the third contact.
  • the sensor manifold 900 is configured to provide access to fluid within the internal fluid passage 908 to the sensors 902, 912-916 in a sealed manner.
  • Figure 10 illustrates a partial cross-sectional view of the sensor manifold 900 with the sensor 902 positioned within the cylindrical hole 904, in accordance with an example implementation.
  • the sensor manifold 900 can have sealing flaps 1006 covering a hole or channel 1008 that is in fluid communication with the internal fluid passage 908.
  • the sealing flaps 1006 can be made from an elastomeric, flexible material for example. When the sensor 902 is not inserted in the cylindrical hole 904, the sealing flaps 1006 seal the channel 1008, and thus prevents fluid flowing through the internal fluid passage 908 from getting inside the cylindrical hole 904.
  • the sensor 902 has a sensing element or sensing probe 1010 that, when the sensor 902 is inserted and placed in position, breaks through the sealing flaps 1006, passes through the channel 1008 and reaches the internal fluid passage 908.
  • the sensing probe 1010 can reach the channel 1008 without extending to the internal fluid passage 908.
  • the sensing probe 1010 is subjected to fluid from the internal fluid passage 908 communicated to the channel 1008.
  • the sealing flaps 1006 flex to allow the sensing probe 1010 to pass, and then lips such as lip 1012 and lip 1014 of the sealing flaps 1006 form a sealing contact about the circumference of the sensing probe 1010 to seal fluid within the channel 1008 and preclude fluid flow to the cylindrical hole 904.
  • the sealing flaps 1006 return to their original, un-flexed position to reseal the channel 1008.
  • Figure 11 illustrates a partial cross-sectional view of the sensor manifold 900 with the sensor 902 being removed from the manifold body 901, in accordance with an example implementation.
  • the sensor 902 is configured as a fluid contact sensor
  • the sensor manifold 900 can have non-contact fluid sensors (e.g., optical sensors) that may measure fluid properties without contacting fluid in the internal fluid passage 908.
  • the sealing flaps 1006 may be replaced with a transparent disk, for example.
  • any enumeration of elements, blocks, or steps in this specification or the claims is for purposes of clarity. Thus, such enumeration should not be interpreted to require or imply that these elements, blocks, or steps adhere to a particular arrangement or are carried out in a particular order.
  • devices or systems may be used or configured to perform functions presented in the figures.
  • components of the devices and/or systems may be configured to perform the functions such that the components are actually configured and structured (with hardware and/or software) to enable such performance.
  • components of the devices and/or systems may be arranged to be adapted to, capable of, or suited for performing the functions, such as when operated in a specific manner.
  • Implementations of the present disclosure can thus relate to one of the enumerated example implementations (EEEs) listed below.
  • EEE 1 is a sensor manifold assembly of a bioprocessing system, the sensor manifold assembly comprising: a syringe pump comprising: (i) a syringe tube having a port configured to be fluidly-coupled to a bioreactor of the bioprocessing system, (ii) a piston slidably- accommodated in the syringe tube, and (iii) a piston driver configured to drive the piston within the syringe tube, wherein the piston driver moves the piston in a first direction to draw fluid through the port into the syringe tube and in a second direction to discharge the fluid from the syringe tube through the port; and a sensor manifold disposed about the syringe tube of the syringe pump, wherein the sensor manifold comprises one or more sensors configured to measure fluid properties of fluid in the syringe tube.
  • a syringe pump comprising: (i) a syringe tube having a port configured
  • EEE 2 is the sensor manifold assembly of EEE 1 , wherein the sensor manifold is diskshaped and has a central hole through which the syringe tube is disposed.
  • EEE 3 is the sensor manifold assembly of EEE 2, wherein the one or more sensors are disposed in a circular array, and respective sensors of the one or more sensors are disposed radially within the sensor manifold.
  • EEE 4 is the sensor manifold assembly of any of EEEs 1-3, wherein a sensor of the one or more sensors has a sensing element that is exposed to fluid in the syringe tube.
  • EEE 5 is the sensor manifold assembly of EEE 4, wherein the sensor manifold further comprises a sealing grommet configured as an annular bushing disposed about the sensing element of the sensor.
  • EEE 6 is the sensor manifold assembly of any of EEEs 1-5, wherein a sensor of the one or more sensors has a sensing probe configured to measure a property of the fluid in the syringe tube without contacting fluid.
  • EEE 7 is the sensor manifold assembly of EEE 6, wherein the sensor is an optical sensor, and wherein the sensor manifold assembly further comprises: a sensor spot mounted within the syringe tube, such that the sensor spot is subjected to the fluid in the syringe tube and faces the sensing probe, and wherein the sensor measures the property of the fluid by the sensing probe detecting variation in optical characteristics of the sensor spot when subjected to the fluid.
  • EEE 8 is a sensor manifold of a bioprocessing system, the sensor manifold comprising: a manifold body have (i) a plurality of slots, (ii) an internal fluid passage, and (iii) an inlet port configured to receive fluid from a bioreactor of the bioprocessing system and provide the fluid to the internal fluid passage; and one or more sensors, each sensor being removably-disposed in a respective slot of the plurality of slots, wherein each sensor has a sensing element configured to measure a property of the fluid flowing through the internal fluid passage of the manifold body.
  • EEE 9 is the sensor manifold of EEE 8, wherein a sensor of the one or more sensors has one or more tabs, and wherein the manifold body has one or more corresponding recesses formed on an interior surface of the manifold body bounding a respective slot of the plurality of slots, and wherein when the sensor is inserted in the respective slot, the one or more tabs engage with the one or more corresponding recesses to retain the sensor within the respective slot.
  • EEE 10 is the sensor manifold of any of EEEs 8-9, further comprises: electric contacts disposed on an interior surface of the manifold body bounding a slot of the plurality of slots, wherein a respective sensor of the one or more sensors has respective electric contacts that, when the respective sensor is inserted in the slot, interface with the electric contacts of the manifold body.
  • EEE 11 is the sensor manifold of any of EEEs 8-10, wherein the sensing element of a sensor of the one or more sensors has access to fluid flowing through the internal fluid passage of the manifold body, thereby allowing the sensor to measure properties of the fluid, wherein the manifold body further comprises: a breakthrough window formed therein to provide access to the internal fluid passage formed within the manifold body to the sensor mounted in a respective slot of the plurality of slots.
  • EEE 12 is the sensor manifold of EEE 11, wherein the breakthrough window comprises a counterbore formed in the manifold body, such that the counterbore is sufficiently deep to reach the internal fluid passage, thereby forming a slit through which the sensing element accesses fluid flowing the internal fluid passage.
  • EEE 13 is the sensor manifold of EEE 12, wherein the sensor comprises a sealing ring disposed about the sensing element and configured rest against an interior surface of the manifold body, such that the sealing ring surrounds and covers the counterbore.
  • EEE 14 is the sensor manifold of any of EEEs 8-13, wherein the plurality of slots are configured as cylindrical holes configured to respectively receive the one or more sensors therein.
  • EEE 15 is the sensor manifold of any of EEEs 8-14, wherein a sensor of the one or more sensors has an orientation feature, and wherein the manifold body has a corresponding orientation feature, and wherein the orientation feature of the sensor is aligned with the corresponding orientation feature of the manifold body to insert the sensor in a particular orientation.
  • EEE 16 is the sensor manifold of EEE 15, wherein the orientation feature of the sensor comprises a notch, and wherein the corresponding orientation feature of the manifold body comprises a groove configured to receive the notch of the sensor therein.
  • EEE 17 is the sensor manifold of any of EEEs 8-16, further comprising: a pivotable retainer arm that is pivotably-mounted to the manifold body, wherein the pivotable retainer arm is configured to rotate to a first position, thereby allowing a sensor of the one or more sensors to be inserted into a respective slot of the plurality of slots, and configured to rotate to a second position at which the pivotable retainer arm retains the sensor within the respective slot.
  • EEE 18 is the sensor manifold of any of EEEs 8-17, further comprising: sealing flaps disposed within a slot of the plurality of slots, wherein a sensor disposed in the slot has a sensing element that passes through the sealing flaps to have access to the fluid flowing in the internal fluid passage of the manifold body, and wherein the sealing flaps have lips that form a sealing contact about the sensing element of the sensor.
  • EEE 19 is the sensor manifold of EEE 18, wherein as the sensor is removed from the slot and the sensing element is withdrawn through the sealing flaps, the lips of the sealing flaps make a respective sealing contact with each other to preclude contaminating the fluid flowing in the internal fluid passage and leakage of the fluid into the slot.
  • EEE 20 is the sensor manifold of any of EEEs 18-19, wherein the manifold body further comprises: a channel that fluidly couples the internal fluid passage to the slot, wherein the sensing element is disposed through the sealing flaps to reach the channel.

Abstract

Un exemple de collecteur de capteur d'un système de biotraitement comprend un corps de collecteur ayant une pluralité de fentes, un passage de fluide interne, et un orifice d'entrée conçu pour recevoir un fluide provenant d'un bioréacteur du système de biotraitement et fournir le fluide au passage de fluide interne ; et un ou plusieurs capteurs, chaque capteur étant disposé de manière amovible dans une fente respective de la pluralité de fentes, chaque capteur ayant un élément de détection conçu pour mesurer une propriété du fluide s'écoulant à travers le passage de fluide interne du corps de collecteur.
PCT/EP2022/085245 2021-12-15 2022-12-09 Système de biotraitement et collecteur de capteur associé WO2023110682A2 (fr)

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US6688184B2 (en) * 2002-02-01 2004-02-10 Hamilton Sunstrand Sensor manifold for a flow sensing venturi
US9283521B2 (en) * 2002-06-14 2016-03-15 Parker-Hannifin Corporation Single-use manifold and sensors for automated, aseptic transfer of solutions in bioprocessing applications
US9575087B2 (en) * 2012-09-06 2017-02-21 Parker-Hannifin Corporation Risk-managed, single-use, pre-calibrated, pre-sterilized sensors for use in bio-processing applications
US20080253911A1 (en) * 2007-02-27 2008-10-16 Deka Products Limited Partnership Pumping Cassette
US7509855B2 (en) * 2007-07-25 2009-03-31 The Lubrizol Corporation Sensor manifolds
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US9410626B2 (en) * 2013-07-24 2016-08-09 Pall Corporation Sensor probe seal
SG11202004646TA (en) * 2017-12-01 2020-06-29 Global Life Sciences Solutions Usa Llc Methods for cell enrichment and isolation

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