WO2024052678A1 - Système de biotraitement - Google Patents

Système de biotraitement Download PDF

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Publication number
WO2024052678A1
WO2024052678A1 PCT/GB2023/052310 GB2023052310W WO2024052678A1 WO 2024052678 A1 WO2024052678 A1 WO 2024052678A1 GB 2023052310 W GB2023052310 W GB 2023052310W WO 2024052678 A1 WO2024052678 A1 WO 2024052678A1
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WIPO (PCT)
Prior art keywords
vessels
cells
bioprocessing
cases
cell
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PCT/GB2023/052310
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English (en)
Inventor
James Davies
Antoine ESPINET
James Kusena
Original Assignee
Microfluidx Ltd
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Publication date
Application filed by Microfluidx Ltd filed Critical Microfluidx Ltd
Publication of WO2024052678A1 publication Critical patent/WO2024052678A1/fr

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    • 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
    • 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
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/58—Reaction vessels connected in series or in parallel
    • 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
    • C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
    • 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
    • C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
    • C12M41/36—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of biomass, e.g. colony counters or by turbidity measurements

Definitions

  • GMP Good Manufacturing Practices
  • reagent preparation i.e., thawing, mixing reagents together, aliquoting reagents from a batch
  • top-up and switching cell washing and cell transfers
  • manual sampling manual documentation entries.
  • the numerous manual operation steps contribute to a large need for highly skilled staff required for each batch, resulting in heightened costs for cell therapy treatment and fundamentally pose the question of scalability due to lack of highly skilled personnel.
  • Reagent preparation remains a time-consuming step.
  • Typical bioprocesses have a large footprint of expensive cleanroom space because they require multiple pieces of equipment and each piece of equipment must be validated through a series of time-consuming tests and documentation and take significant amount of space.
  • Due to lack of end-to-end automation cell therapy manufacturing use open processes, i.e., where cells are in contact with the ambient environment at some point during the process. This leads to regulatory limits on the number of batches that can be run at once in a given cleanroom to minimize the risk of cross-contamination.
  • most cleanrooms are grade B due to lack of closed processes, which is extremely expensive to build and operate (validation, filter grade, energy). Overall, cell therapy manufacturing is extremely space demanding of highly expensive facilities.
  • the present disclosure provides a bioprocessing system with end-to-end automation, that takes up a small footprint, uses a closed-end-to-end process, is equipped with integrated in-line analytics that can be shared across several batches, and has a flexible architecture where batches can be loaded into the system when required without disrupting other batches.
  • a bioprocessing system comprising: (a) one or more mixing tanks, wherein the one or more mixing tanks comprise reagents; (b) one or more vessels fluidly connected to the one or more mixing tanks; and (c) one or more waste tanks fluidically connected to the one or more vessels; wherein the one or more vessels are arranged in a vertical arrangement, and wherein the vertical arrangement comprises one or more physical barriers, wherein the one or more physical barriers separate a first portion of the one or more vessels from a second portion of the one or more vessels.
  • the one or more physical barriers are horizontal.
  • a first mixing tank of the one or more mixing tanks is kept at a different temperature than a second mixing tank of the one or more mixing tanks.
  • a mixing tank of the one or more mixing tanks is kept at ambient temperature.
  • a mixing tank of the one or more mixing tanks is kept at a temperature of about 20°C.
  • a mixing tank of the one or more mixing tanks is kept at a temperature of about 4°C.
  • a mixing tank of the one or more mixing tanks is kept at a temperature of about -20 °C
  • each of the one or more vessels is fluidically connected to the one or more mixing tanks through a connector system comprising one or more pumps, one or more valves, and tubing.
  • the system further comprises a steam sterilizer.
  • the steam sterilizer generates steam that flows through the one or more pumps, the one or more valves, or the tubing at a temperature at or above 121 °C at a pressure of 2 bars in absolute value.
  • the system further comprises one imaging system.
  • the one imaging system is configured to move among the one or more vessels, and wherein the imaging system is configured to capture images of cells in individual vessels of the one or more vessels.
  • the one or more vessels are configured to move to the imaging system, and wherein the imaging system is configured to capture images of cells in individual vessels of the one or more vessels.
  • a vessel of the one or more vessels comprises a pH sensor configured to measure pH of the vessel.
  • a vessel of the one or more vessels comprises a dissolved oxygen sensor configured to measure a level of dissolved oxygen in the vessel.
  • a vessel of the one or more vessels comprises a temperature sensor configured to measure a temperature in the vessel.
  • the one or more vessels each comprise one or more bioprocessing chambers.
  • the one or more bioprocessing chambers comprise a volume of less than 500 mL, 200 mL, 100 mL, 75 mL, or 25 mL.
  • the one or more bioprocessing chambers comprise a cell culturing surface of less than 1000cm 2 , 800cm 2 , 500cm 2 , 400cm 2 300 cm 2 , 200 cm 2 , 100 cm 2 , 90 cm 2 , 80 cm 2 , 70 cm 2 , 60 cm 2 , 50 cm 2 , 40 cm 2 , 30 cm 2 , 20 cm 2 , or 10 cm 2 .
  • the one or more bioprocessing chambers comprise a biocompatible material.
  • the biocompatible material is a U.S. Pharmacopeia Convention (USP) Class VI material.
  • the one or more bioprocessing chambers are sterile.
  • the one or more bioprocessing chambers comprise a plurality of cells.
  • each of the one or more bioprocessing chambers comprise at least 0.1, 0.25, 0.5, 1, 1.5, 2, 2.5, 5, 10, or 20 million cells/mL.
  • each of the one or more bioprocessing chambers comprises at least 0.25, 0.5, or 1 million cells.
  • each of the one or more bioprocessing chambers comprises at least 1 million, 5 million, 10 million, 50 million, 100 million, 250 million, 500 million, 750 million, 1 billion, or 3 billion cells.
  • the first portion of the one or more vessels comprises a biological sample of a first subject
  • the second portion of the one or more vessels comprises a biological sample of a second subject, wherein the first subject and second subject are different.
  • vessel of the first portion of the one or more vessels has a different function from another vessel of the first portion of the one or more vessels.
  • the biological sample comprises one or more cells of the first subject.
  • the first portion of the one or more vessels comprises vessels configured to perform different functions.
  • the different functions comprise cell selection, cell transduction, cell washing, cell expansion, or cell concentration.
  • the one or more physical barriers are configured to prevent leakage between the first portion of the one or more vessels and the second portion of the one or more vessels. In some cases, the one or more physical barriers are impermeable to liquids or gases. In some cases, the first portion of the one or more vessels are fluidically connected to each other.
  • the system further comprises an inline metabolite analyser fluidically connected to the one or more vessels.
  • the system has a total footprint of less than 2 square meter.
  • the system is located at a manufacturing site and configured to be monitored or controlled in a control room.
  • the manufacturing site and control room are located more than 1 miles apart.
  • the manufacturing site and control room are located more than 100 miles apart.
  • the manufacturing site and control room are located more than 1000 miles apart.
  • FIG. 1 schematically illustrates a process flow diagram of a bioprocessing system, in accordance with some embodiments.
  • FIG. 2A illustrates a rendering of two bioprocessing devices, in accordance with some embodiments.
  • FIG. 2B illustrates a rendering of a multifluidic tray of a bioprocessing device, in accordance with some embodiments.
  • FIG. 3 schematically illustrates a single chip design, in accordance with some embodiments.
  • FIGs. 4 and 5 schematically illustrate a 64-chip array based on four 16-chip units.
  • FIGs. 6 and 7 schematically illustrates a 64-chip array based on two 32-chip units.
  • FIG. 8 schematically illustrates a computer system that is programmed or otherwise configured to implement methods provided herein.
  • T-cells used mostly in immuno-oncology
  • mesenchymal stem cells mostly used for immune-modulation
  • induced pluripotent stem cells used in regenerative medicine or as a source of other cell types.
  • Each technology has a wide variety of process sequences and within each process, a wide range of process parameters. However, ultimately, most processes involve mixing the cells with a reagent or a combination of reagents, provide the cells with an environment that promotes their viability (e.g., temperature, CO2 concentration). In some cases, processes involve cells moving, e.g., for cell separation, where cells, attached to magnetic beads via an antibody bound, move towards a magnet, or cell passage or cell transfer, where cells are harvested from a cell culture vessel to another cell culture vessel or system.
  • a reagent or a combination of reagents provide the cells with an environment that promotes their viability (e.g., temperature, CO2 concentration).
  • processes involve cells moving, e.g., for cell separation, where cells, attached to magnetic beads via an antibody bound, move towards a magnet, or cell passage or cell transfer, where cells are harvested from a cell culture vessel to another cell culture vessel or system.
  • Analytics can also play an important role in processing cells for subjects or patients.
  • Cell therapy makers have to show that their processes, input materials, and cells have met certain criteria, called Critical Process Parameters, Critical Material Attributes, Critical Quality Attributes respectively.
  • operators will have to: 1) before the process starts, ensure that all reagents are correct, that all plasticware are correctly loaded, and ensure that the correct cells are loaded; 2) during the process, take samples (e.g., once a day) of the fluid and cells and carry out QC operations on these, e.g., sterility analysis, cell count, flow cytometry, etc.; and 3) after the process, take samples of the final cell product and carry testing to ensure identity, potency and purity and safety.
  • These consist of multiple analytical panels, including outsourced analyses.
  • GMP Good Manufacturing Practices
  • facilities must be of high standard, typically grade A, B, C, or D depending on the level of exposure of the cells to the environment, strict documentation protocols should be followed (e.g., non-alterable records, identifiable person for each action), and numerous validations should be carried out for each piece of equipment used.
  • the present disclosure provides a microfluidic-based bioprocessing system that can permit streamlined ex-vivo bioprocessing for cells.
  • the bioprocessing system can include a vertical arrangement of cell culture vessels.
  • the bioprocessing system includes a vertical arrangement of 10 vessels, 25 vessels, 50 vessels, 75 vessels, 90 vessels, or 100 vessels.
  • the bioprocessing system includes a vertical arrangement of over 100 cell culture vessels.
  • FIG. 2A shows an example of two bioprocessing systems described herein with a vertical arrangement of cell culture vessels.
  • FIG. 2B shows a microfluid tray of the bioprocess system, which can be vertically stacked with other microfluidic trays.
  • the bioprocessing system described herein can comprise one or more reagent or mixing tanks.
  • the one or more reagent or mixing tanks can be kept at different temperatures.
  • the system can comprise at least one reagent loading bay, which can be called a main reagent stock.
  • stock reagents can be connected sterilely to the system, via a sterile connector system.
  • the system can comprise three reagent (or mixing) tanks.
  • Reagent tank 100 can be kept at a temperature of 20°C (ambient temperature).
  • Reagent tank 105 can be kept at a temperature of 4°C.
  • Reagent tank 110 can be kept at a temperature of -20°C. Any particular reagent in the -20°C bay can be reheated to ambient temperature when needed and brought back to -20°C. Any reagent loaded onto the system can be mixed together with another, in a ratio of the user’s choice.
  • a cell culture vessel (or cassette) 165 can have its own mixing or buffer tank, both for small volumes 145 and large volumes 150.
  • Each cell culture vessel’s mixing or buffer tank can be connected to the main reagent stock (one or more reagent or mixing tanks 100, 105, or 110) via a sterile barrier.
  • Reagents can be fed through a connector box 120 and through a selector valve 125 and another connector box 140.
  • One or more pumps 130 and 155 can be used to facilitate flow of reagents.
  • the pump 130 or 155 can be a peristaltic pump, a syringe pump, a pressure pump, and canbe combined with a selector valve.
  • the goal of this system is to send the correct reagent or reagent mix from a particular stock reagent or stock reagent mix (100, 105, or 110) to the correct cell culture vessel reagent tank.
  • a selector valve 125 can be able to direct fluid from the reagent stock to any cell culture vessel buffer or mixing tank (145 or 150).
  • the valve system can take the form of a manifold fitted with pinch valves, or one or several rotary valves, e.g., n-to-1 valves and 1-to-n valves combinations.
  • the selector valve 125 can be fully automated.
  • the selector valve 125 can be connected to a steam sterilizer.
  • Each cell culture vessel can come pre-connected with at least one reagent tank, such that the output of the reagent tank is the input of the cell culture vessels.
  • the input of the reagent tank can be fitted with tubing connected to a naturally closed connector, which can be a sterile connector.
  • the fluid output of each cell culture vessel can be fitted with tubing and naturally closed connector, which can be a sterile connector.
  • a sampling output can also be fitted on each cell culture vessel, so that an operator can connect via a sterile connector and take a sample of cells and fluid within the cell culture vessel.
  • the bioprocessing system described herein can comprise a gas input 115.
  • a cell culture vessel 165 can fited with a gas input, and optionally a gas output, each fited with tubing and connector, which can be a sterile connector.
  • a gas mixture can be flowed into each cell culture vessel through a valve 135 and via a gas line 160.
  • the selector valve 135 can be connected to a steam sterilizer.
  • a cell culture vessel can contain a vent fited with a filter. In some cases, the filter can comprise 0.2pm pores.
  • a gas mixture can be flowed into each cell culture vessel via a gas permeable membrane in contact with the fluid in the cell culture vessel. In some cases, the system can accommodate up to 3 compressed gases.
  • the compressed gases can include carbon dioxide (CO2), air or nitrogen. Gases can be mixed together with another, in a ratio of the user’s choice. For example, if CO2 and air are connected, the device can flow the following gas mixtures (all units in volume proportions): 1) 0% CO2, 100% air; 2) 5% CO2, 95% air; 3) 10% CO2, 90% air.
  • the one or more cell culture vessels can be arranged in a vertical arrangement.
  • the vertical arrangement can include one or more physical barriers 170 and 175.
  • the one or more physical barriers can separate a first portion of the one or more vessels from a second portion of the one or more vessels.
  • a portion of vessels isolated from other vessels by one or more physical barriers can be referred to as a stack 172.
  • Each cell culture vessel can within a stack have the same form factor but optionally different functionalities, corresponding to steps of the bioprocess, e.g., cell selection, cell transduction and washing, cell expansion and washing, cell concentration, etc.
  • Each stack can be segregated from other stacks by a horizontal physical barrier 170 and 175, so that any leakage from one stack cannot contaminate other stacks.
  • each stack 172 contains samples from a first subject or patient.
  • a second stack can contain samples from a second subject or patient.
  • the physical barrier can prevent cross-contamination between the first patient and second patient samples.
  • the one or more physical barriers 170 and 175 can be impermeable to liquids or gases.
  • a cell culture vessel can be fluidically connected to another cell culture vessel. Cells can be flowed from one cell culture vessel to another cell culture vessel.
  • cells can be flowed from a first cell culture vessel with a first functionality and a first combination of reagents to a second cell culture vessel with a second functionality and a second combination of reagents.
  • the first and second cell culture vessels can be configured to perform different functionalities.
  • a cell culture vessel can be connected to its own pH sensor configured to measure pH of the vessel.
  • a cell culture vessel can be connected to its own a dissolved oxygen sensor configured to measure a level of dissolved oxygen in the vessel.
  • a cell culture vessel can be connected to its own temperature sensor configured to measure temperature of the vessel.
  • cells and fluids in each cell culture vessel are agitated by a mechanical agitation device, in contact with each cell culture vessel.
  • a series of analytical and bioprocessing tools can be located adjacent to the stacks of cell culture vessels.
  • the analytical and bioprocessing tools are able to move to (optionally over, underneath or to the side of) any cell culture vessels.
  • Analytical tools can include at least one imaging system 180, which can be a brightfield or holographic microscope, at least one pH sensor reader, at least one dissolved oxygen sensor reader, or at least one temperature sensor.
  • Bioprocessing tools can at least one magnetic plate 185, optionally an electromagnetic plate.
  • the system can contain one or more waste tanks 196.
  • the one or more waste tanks can be fluidically connected to the one or more vessels via a connector box 190 and a selector valve 197.
  • the one or more waste tanks can be connected and disconnected from the system via a sterile connector.
  • Each cell culture vessels fluid output line can lead to the one or more waste tanks via a sterile barrier 195, e.g., an autosampler.
  • the system is fitted with an inline metabolite analyzer 198.
  • the metabolite analyser 198 can be connected to each cell culture vessel fluid output via a selector valve 197.
  • the selector valve 197 can be able to direct fluid from a cell culture vessel buffer to the metabolite analyser 198.
  • the valve system can take the form of a manifold fitted with pinch valves, or one or several rotary valves, e.g., n-to-1 valves and 1-to-n valves combinations.
  • the selector valve 197 can be fully automated.
  • the selector valve 197 can be connected to a steam sterilizer.
  • the system can be able to self-sterilize.
  • the sterilization concerns any internal tubing and surfaces with which fluid or cells can be in contact with.
  • the system can use steam sterilization.
  • the system can generate steam which flows through the system at a temperature at or above 121 °C which has a corresponding pressure of 2 bars in absolute value.
  • the system can first create a vacuum to optimize steam distribution and reduce the probability of a trapped air pocket within all tubes and surfaces.
  • the system can generate hydrogen peroxide vapor instead of steam.
  • the ports for the reagents, the cell culture vessels, and the waste can be naturally closed so that contaminants cannot penetrate the system when the ports are unused. These consumable parts of the system would be initially supplied in a sterile state.
  • the system can contain a reusable connector system, where each connector port can be sterilized by the system before a fluidic connection is established between the reagent and the system, or the cell culture vessels and the system or the waste tank and the system.
  • Cell therapy can be a treatment approach in which engineered cells are administered into or to a subject (e.g., a patient)
  • the present disclosure provides a vessel comprising a bioprocessing chamber that is capable of performing bioprocessing operations involved in cell culture.
  • the vessel can utilize microfluidics, which can involve manipulating fluids inside channel dimensions of the micrometer range.
  • the channels described herein can have one or more channel dimensions.
  • the one or more channel dimensions can correspond to one or more of a channel width, a channel length, a channel height, or a channel diameter.
  • the channel dimensions can range from about 1 micrometer to about 10 centimeters. In some cases, the channel dimensions can be less than 1 micrometer.
  • the channel dimensions can be greater than 10 centimeters.
  • the channels described herein can have a channel volume.
  • the channel volume can range from 10% of the total vessel volume to 90% of the total vessel volume. In some cases, the channel volume can be less than 10% of the total vessel volume. In some cases, the channel volume can be greater than 90% of the total vessel volume.
  • Microfluidic cell culture can provide several advantages, including, for instance: (1) better control of process parameters: cells can have equal access to molecules present in the surrounding fluid due to homogenous cell distribution and fluid circulation in microenvironments, which can result in a more homogeneous end product and less process failure (e.g. cell death); (2) better overall cell health: e.g., paracrine effects can be amplified in a small environment (i.e.
  • a reduction in reactant volume can be 10-20 fold reduction, due to smaller volumes of fluid used in microfluidic vessels as well as the ability to recirculate unspent reactant (e.g., growth media (fluid) can be re-enriched and recirculated at defined intervals, e.g., due to rapid oxygen or glucose depletion inside the vessel).
  • unspent reactant e.g., growth media (fluid)
  • unspent reactant e.g., growth media (fluid) can be re-enriched and recirculated at defined intervals, e.g., due to rapid oxygen or glucose depletion inside the vessel.
  • the cell culture vessel can comprise a cassette.
  • a plurality of chips can be parallelized in a cassette.
  • the chip can comprise a microfluidic chip.
  • the chip or microfluidic chip can comprise a bioprocessing chamber.
  • the bioprocessing capabilities of the chip can be scaled up via parallelization to achieve high throughput bioprocessing.
  • a plurality of cassettes can be placed in a machine for parallelized bioprocessing.
  • the plurality of cassettes can be stackable.
  • the cell culture vessels or plurality of cassettes are stacked in a vertical arrangement.
  • FIG. 3 schematically illustrates an exemplary chip.
  • a chip can be a support or a solid support comprising a bioprocessing chamber, e.g., one bioprocessing chamber.
  • the chip can comprise a feeding input that connects to one or more feeding input channels 301.
  • the feeding input can comprise a single hole or a plurality of holes.
  • the plurality of holes can provide separate inputs for both seeding and perfusion.
  • These feeding input channels can be used for seeding and perfusion.
  • the input channels 301 can take several forms. It can be a single channel or a plurality of channels in the form of a standard or modified binary tree network.
  • a bioprocessing chamber 304 can comprise a recess in fluid communication with the one or more feeding input channels 301.
  • the recess can comprise a vertical depth perpendicular to the flow direction where cells can settle.
  • the recess can be protected from damaging shear stress because of minimal fluid velocity acting on the recess.
  • the bioprocessing chamber 304 can be elongated in the primary direction of seeding and perfusion flow, such that length » width.
  • the microfluidic chip can have a length that is about, at least, or at most 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, or 60 times its width.
  • the edges of the bioprocessing chamber 304 e.g., at the ends
  • the bioprocessing chamber can comprise a recess with one or more walls that are angled relative to the feeding input channels and/or the feeding output channels. In some non- limiting embodiments, the angle can range from about 45 degrees to about 90 degrees.
  • the bioprocessing chamber can have one or more dimensions.
  • the one or more dimensions can comprise, for example, a length, a width, a height, or a depth.
  • the one or more dimensions of the bioprocessing chamber can range from about 1 millimeter to about 60 centimeters. In some cases, the dimensions of the bioprocessing chamber can be less than 1 millimeter. In some cases, the dimensions of the bioprocessing chamber can be greater than 60 centimeters.
  • the bioprocessing chamber can comprise a volume of less than 400mL, 200mL, lOOmL, 75mL, 50mL, 20mL, 10 mL, 7 mL, 5 mL, 4 mL, 3 mL, 2 mL, 1 mL, or 0.5 mL.
  • the bioprocessing chamber can have a bottom surface, as described elsewhere herein.
  • the bottom surface can be used for cell culturing.
  • the bottom surface can have a surface area ranging from about 1 mm 2 to about 300 cm 2 . In some cases, the surface area can be less than 1 mm 2 . In some cases, the surface area can be greater than 300 cm 2 .
  • the bottom surface can have a surface area of less than 300 cm 2 , 200 cm 2 , 100 cm 2 , 90 cm 2 , 80 cm 2 , 70 cm 2 , 60 cm 2 , 50 cm 2 , 40 cm 2 , 30 cm 2 , 20 cm 2 , 10 cm 2 , 6 cm 2 , 5 cm 2 , or 1 cm 2 .
  • a length dimension of the bioprocessing chamber can be at least 2x, 3x, 4x, 5x, lOx, 15x, or 20x a width dimension of the bioprocessing chamber.
  • the bioprocessing chamber has a height of at least 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5 mm.
  • the bioprocessing chamber can comprise a cross-sectional shape.
  • the cross-sectional shape can be a circle, an oval, an ellipse, a triangle, a square, a rectangle, or any other polygon having three or more sides.
  • the cross-sectional shape can correspond to a horizontal cross-section and/or a vertical cross-section of the bioprocessing chamber.
  • the upper outlet can connect to a filter
  • the filter 308 can serve as a barrier to prevent cells from exiting the chamber prematurely, hence increasing seeding efficiency.
  • growth medium can be replenished, e.g., gradually replenished, by a fresh batch of fluid
  • the cells can still be retained in the bioprocessing chamber 304 while the fluid exits through the feeding output channel 306.
  • the filter 308 can comprise a filter membrane, and the filter membrane can comprise polyethersulfone (PES), e.g., with a pore size structure of about 5 micrometers.
  • PES polyethersulfone
  • the filter 308 comprises a pore size of less than 10 pm, less than 7.5 pm, less than 5 pm, or less than 2.5 pm.
  • the shape of the filter can be rectangular or circular.
  • the lower outlet of the chip can be fluidically connected to a drain 307 for harvesting or collection purposes. When this outlet is open, fluid containing cells can be drawn out of the bioprocessing chamber 304. To improve harvest efficiency, fluid can be pulled via the lower outlet, e.g., via a syringe pump or a suction generated by a negative pressure source. Alternatively, fluid can be introduced via the feeding input and/or feeding output to help “push” the fluid out.
  • collecting can also be done via a combination of push and pull, where fluid is simultaneously pulled from the lower outlet and pushed via the feeding input and/or output.
  • the collection drain 307 can be positioned directly below the filter 308 or at a position away from the filter 308.
  • an inclined/sloped structure can be provided to facilitate the fluid’s exit.
  • the inclined/sloped structure can be integrated with the bottom surface of the bioprocessing chamber 304 and can connect the bioprocessing chamber 304 to the drain 307.
  • the inclined/sloped structure can be formed as part of the drain 307.
  • the filter can comprise a pore size.
  • the pore size can range from about 1 nanometer to about 1 millimeter.
  • the filter can comprise a plurality of different pore sizes ranging from about 1 nanometer to about 1 millimeter.
  • the filter can comprise a membrane.
  • the membrane can be permeable or semi-permeable.
  • the membrane can comprise, for example, Polytetrafluoroethylene (PTFE) or expanded polytetrafluoroethylene (ePTFE), poly ethersulfone (PES), modified poly ethersulfone (mPES), polysulfone (PS), modified polysulfone (mPS), ceramics, polypropylene (PP), cellulose, regenerated cellulose or a cellulose derivative (e.g. cellulose acetate or combinations thereof), polyolefin, polypropylene, polytetrafluoroethylene, polyvinyl chloride, polyester, or any other type of polymer.
  • PTFE Polytetrafluoroethylene
  • ePTFE expanded polytetrafluoroethylene
  • PES poly ethersulfone
  • mPES modified poly ethersulfone
  • PS polysulfone
  • ceramics ceramics
  • polypropylene (PP)
  • the membrane can comprise a biomedical polymer, e.g., polyurethane, polyethylene, polypropylene, polyester, poly tetra fluoro-ethylene, polyamides, polycarbonate, or polyethylene-terephthalate.
  • a biomedical polymer e.g., polyurethane, polyethylene, polypropylene, polyester, poly tetra fluoro-ethylene, polyamides, polycarbonate, or polyethylene-terephthalate.
  • the cells described herein can comprise a range of sizes.
  • the cells can have a size of at least about 1 micrometer, 5 micrometers, 10 micrometers, 20 micrometers, 30 micrometers, 40 micrometers, 50 micrometers, 60 micrometers, 70 micrometers, 80 micrometers, 90 micrometers, 100 micrometers, or any size that is between any of the preceding values.
  • the cells can have a size that is less than about 1 micrometer.
  • the cells can have a size that is at most about 1 micrometer, 900 nanometers, 800 nanometers, 700 nanometers, 600 nanometers, 500 nanometers, 400 nanometers, 300 nanometers, 200 nanometers, 100 nanometers, 90 nanometers, 80 nanometers, 70 nanometers, 60 nanometers, 50 nanometers, 40 nanometers, 30 nanometers, 20 nanometers, 10 nanometers, or less.
  • the vessels described herein can be a microfluidic tray, like the tray shown in FIG. 5 or FIG. 7.
  • the tray comprises a suspension, micro-carrier, or mono-layer adherent cell culture.
  • the trays can be single use.
  • the trays can be GMP -grade click and connect.
  • the tray can be able to hold 200 mL of fluid for every 400 cm 2 or tray area.
  • Each tray can be associated with a unique identifier, allowing batches to be traced from start to finish.
  • FIG. 4 illustrates a 64- chip array based on four 16-chip units.
  • Panel A shows a perfusion inlet and filter outlet layer connecting the perfusion inlets and filter outlets of four 16-chip units. This is at the top of the 16- chip units.
  • Panel B shows a 64-chip unit layer comprising the four 16-chip units.
  • Panel C shows a harvest layer connecting the four harvest lines of the 16-chip units. This is at the bottom of the 16- chip units.
  • Panel D shows an overlay of the layers shown in Panels A, B, and C.
  • FIG. 5 illustrates an exploded view of a 64-chip array based on two 16-chip units.
  • the chip array can comprise a layer (A) comprising feeding input channels for all four 16-chip units and feeding output channels for all four 16-chip units.
  • the 64-chip array can comprise a layer (B) comprising the four 16-chip units.
  • the 64-chip array can comprise a layer (C) comprising collection output channels for all four 16-chip units.
  • FIG. 6 illustrates a 64-chip array based on two 32-chip units.
  • Panel A shows a perfusion inlet and a filter outlet layer connecting the perfusion inlets and filter outlets of the two 32-chip units. This is at the top of the 32-chip units.
  • Panel B shows a 64-chip unit layer comprising two 32- chip units.
  • Panel C shows a harvest layer connecting the two harvest lines in the 32-chip units. This is at the bottom of the 32-chip units.
  • Panel D shows an overlay of the layers illustrated in Panels A, B, and C.
  • FIG. 7 illustrates an exploded view of a 64-chip array based on two 32-chip units.
  • the chip array can comprise a layer (A) comprising feeding input channels for two 32-chip units and feeding output channels for two 32-chip units.
  • the 64-chip array can comprise a layer (B) comprising the two 32-chip units.
  • the 64-chip array can comprise a layer (C) comprising collection output channels for both of the two 32-chip units.
  • COC cyclic olefin copolymer
  • the cells can settle on or come in contact with thermoplastic substitutes such as polycarbonate.
  • COC can be sterilized using standard methods (e.g., steam, ethylene oxide, gamma irradiation, and hydrogen peroxide) without altering its properties. It can also permit UV transmission, which can be best suited for diagnostic analysis. COC can also have low leachables and extractables, making it best suited for direct drug contact. It can be classified USP Class VI and is ISO 10993 compliant including biocompatibility, USP 661.1 and FDA drug and device master files.
  • the vessels can comprise a polydimethylsiloxane (PDMS) component, which can form the wall of the bioprocessing chambers, as well as the top layer, which can form part of its ceiling.
  • PDMS can have gas permeability, which can be advantageous for cell growth.
  • PDMS can permit gas equilibration between the bioprocessing chamber and that of the surrounding controlled environment (e.g. incubator), and can withstand autoclave conditions.
  • the PDMS component can be replaced with another gas permeable polymer. Cells can settle on the COC portion of the bioprocessing chamber.
  • the vessels can comprise a plurality of components or layer comprising a plurality of materials.
  • the plurality of materials can comprise different materials.
  • the plurality of materials can comprise a cyclic olefin polymer (COP), a cyclic olefin copolymer (COC), or a polydimethylsiloxane (PDMS) material.
  • the plurality of materials can comprise a USP Class VI material.
  • the plurality of materials can comprise any type of material that is biocompatible and/or biostable.
  • the materials for the various components or layers of the vessel can have a high permeability (e.g., liquid or gas permeability) to permit a flow of fluid and/or cells into, out of, or through the vessel (and any components or layers thereof).
  • a high permeability e.g., liquid or gas permeability
  • the presently disclosed vessels can also contain a filter, e.g., filter membrane made of polyethersulfone (PES). Contrary to other types of membranes (e.g. PTFE), PES can retain its rigid structure over longer periods of time.
  • the filter can have one or more pores. The pore size can be about 5 pm or less, which can be used to retain cells of 10- m diameter in the bioprocessing chamber.
  • the microfluidic device can be fabricated in optically transparent material or a combination of different types of materials.
  • the bioprocessing chamber that can be used for cell culture can be made of a USP (United States Pharmacopoeia) Class VI Material. Such materials can be transparent so that imaging technology can be coupled.
  • the device can also possess tolerances on the design requirements (e.g. channels) not lower than 5 micrometers in absolute value for the smallest feature and 5% for larger dimensions. This can ensure that fabrication of these devices can be suitable with standard manufacturing processes (e.g. sheet or roll processing).
  • the device can also comprise usable surface culture space (for the individual vessel) that is potentially capable of handling up to at least about 100 thousand, 500 thousand, 1 million, 5 million, 10 million cells, 20 million cells, , 50 million cells, , 100 million, 500 million, 1 billion, or 3 billion cells.
  • the harvested cells from the presently disclosed bioprocessing system can be used for various applications.
  • the applications can include, for example, regenerative medicine, treatment of diabetes, cancer, and/or treatment of cardiac-related diseases or neurogenerative diseases.
  • the application can include autologous cell transplantation, allogenic cell transplantation, or reinfusion of cells in a patient.
  • the bioprocessing system disclosed herein can yield a large number of cells after cell expansion occurs. In some cases, at least about 1 million, 10 million, 100 million, 1 billion, 5 billion, 10 billion, 50 billion, 100 billion, 300 billion cells or morecells can be harvested from the vessels disclosed herein.
  • the cells can comprise, for example, human cells (e.g., stem cells, bone cells, blood cells, muscle cells, fat cells, skin cells, nerve cells, immune cells (e.g., T-cells) etc.) or non-human cells (including, for instance, animal cells, plant cells, bacterial cells, fungal cells, etc.).
  • the systems of the present disclosure can provide a multi-functional design with numerous advantages over other systems.
  • the systems referred to herein can comprise any of the mixing tanks, vessels, pumps, valves, waste tanks, and other devices, hardware, or apparatuses described herein.
  • End-to-end automation can include automated reagent preparation to final formulation.
  • End-to-end automation can include electronic batch records. This can ensure that cell therapy treatments can be manufactured by moderately skilled personnel and that one person has the capacity to produce several dozens of batches at one time by elimination numerous manual operations. Manual operations translate into heightened costs for cell therapy treatment and fundamentally pose the question of scalability due to lack of highly skilled personnel.
  • the systems described herein can automatically prepare reagent mixtures, without the manual intervention by a skilled operator. This can result in minimal reagent preparation hands-on time.
  • the bioprocessing system described herein can utilize a centralized remote control that monitors real-time cell imaging, cell count, pH, and dissolved oxygen of up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 analytes.
  • the automated GMP platform described herein can be used to instantly scale-up a process from process development to manufacturing.
  • the automated GMP platform described herein can be used to replicate or copy and paste an existing process, resulting in the same cell yields.
  • the automated GMP platform can use walk-away automation to control cell seeding, washing, selection, expansion, media, exchange, activation, transduction, transfection, differentiation, or formulation, or a combination thereof.
  • the systems described herein can utilized decentralized control.
  • a centralized control room is used to monitor or control bioprocessing systems located in one or more manufacturing sites.
  • Manufacturing sites can be located in a geographically distinct location from a centralized control room.
  • a control room and manufacturing site can be separated by about 1 mile to about 2,000 miles.
  • a control room and manufacturing site can be separated by about 1 mile to about 10 miles, about 1 mile to about 50 miles, about 1 mile to about 100 miles, about 1 mile to about 500 miles, about 1 mile to about 1,000 miles, about 1 mile to about 2,000 miles, about 10 miles to about 50 miles, about 10 miles to about 100 miles, about 10 miles to about 500 miles, about 10 miles to about 1,000 miles, about 10 miles to about 2,000 miles, about 50 miles to about 100 miles, about 50 miles to about 500 miles, about 50 miles to about 1,000 miles, about 50 miles to about 2,000 miles, about 100 miles to about 500 miles, about 100 miles to about 1,000 miles, about 100 miles to about 2,000 miles, about 500 miles to about 1,000 miles, about 500 miles to about 2,000 miles, or about 1,000 miles to about 2,000 miles.
  • a control room and manufacturing site can be separated by about 1 mile, about 10 miles, about 50 miles, about 100 miles, about 500 miles, about 1,000 miles, or about 2,000 miles.
  • a control room and manufacturing site can be separated by at least about 1 mile, about 10 miles, about 50 miles, about 100 miles, about 500 miles, or about 1,000 miles.
  • a control room and manufacturing site can be separated by at most about 10 miles, about 50 miles, about 100 miles, about 500 miles, about 1,000 miles, or about 2,000 miles.
  • a device or system described herein can have a small footprint as compared to other bioprocessing systems.
  • the bioprocessing system described herein (including all necessary equipment) is less than one square meter for 20 end-to-end batches.
  • FIG. 2A shows an example of the bioprocessing system described herein, which has a compact footprint and utilizes a vertical arrangement of cell culture vessels.
  • FIG. 2B shows a microfluidic tray that can be used in the bioprocessing system.
  • the bioprocessing system may contain stacks of multiple microfluidic trays.
  • the bioprocessing system described herein can perform 20 end-to-end batches and take up about 0.3 square meters to about 1 square meter.
  • the bioprocessing system described herein can perform 20 end-to-end batches and take up about 0.3 square meters to about 0.5 square meters, about 0.3 square meters to about 0.75 square meters, about 0.3 square meters to about 1 square meter, about 0.5 square meters to about 0.75 square meters, about 0.5 square meters to about 1 square meter, or about 0.75 square meters to about 1 square meter. In some cases, the bioprocessing system described herein can perform 20 end-to-end batches and take up about 0.3 square meters, about 0.5 square meters, about 0.75 square meters, or about 1 square meter. In some cases, the bioprocessing system described herein can perform 20 end-to-end batches and take up at least about 0.3 square meters, about 0.5 square meters, or about 0.75 square meters.
  • the bioprocessing system described herein can perform 20 end-to-end batches and take up at most about 0.5 square meters, about 0.75 square meters, or about 1 square meter. In some cases, the bioprocessing system described herein can perform up to 100 end-to-end batches per square meter.
  • a bioprocessing system provided herein can be closed at all times, i.e., operations can be carried out in a closed environment (no opening of the system at any time).
  • a bioprocessing system described herein can be a low grade facility, e.g., grade D, meaning a closed end-to-end process, where reagents and cells never come into contact with the environment, even when sampling.
  • grade D relaxed standards
  • a bioprocessing system described herein can comprise integrated in-line analytics.
  • Analytics can be shared across several batches to reduce the cost per batch and maximize analytical equipment utilization, such that processes can be monitored and pre-approved adjustments to the process can be made in real time and automatically.
  • Analytical in-line capabilities can include cell imaging, cell counting, pH measurements, dissolved gas concentration measurements, metabolites measurements, etc.
  • In-line analytics can allow deviations in the process to be detected that would not be detected otherwise or that would be detected at a later time. For example, many processes require only one sample a day to be taken and analyzed (with results sometimes taking several hours), which is too infrequent to allow correcting deviation efficiently.
  • In-line analytics can alert operators to a deviation before the sample has been taken and analyzed. This can reduce the need for sampling cells to the strict minimum, i.e., where required analytical processes cannot be integrated or where it would be too onerous to do so.
  • a bioprocessing system described herein can have a flexible architecture that allows batches to be loaded onto the system without disrupting other ongoing batches. This added flexibility can eliminate system down-time and increase efficiency of a bioprocessing system. In some cases, a single vessel can be removed and/or replaced without any disruption to the surrounding vessels.
  • systems provided herein can be primed with fluid, e.g., in order to facilitate injection of the growth media.
  • the height of the bioprocessing area can be, e.g., around 3-5mm, which can permit natural "separation" of the cells and occurring bubbles. While the cells settle at the bottom surface, bubbles can be naturally buoyant and thus float towards the top part of the bioprocessing chamber, away from the cells.
  • the environment can be controlled to minimize evaporation and mitigate impacts on the cell growth.
  • the vessels provided herein can permit high efficiency cell seeding, minimizing loss.
  • the cells can be spread homogeneously throughout the bioprocessing chamber to enable optimal growth. In some cases, confluent growth can be prematurely reached in some areas and therefore decrease cell culture efficiency.
  • a filter e.g., filter membrane
  • Mass transport or advection can be a phenomenon due in large part that cells can be relatively large (> 10pm). Their large size can help them sediment into the recess.
  • the vessels can be attached to a mechanical agitation device, which can facilitate re-distribution of the seeded cells all throughout the bioprocessing chambers.
  • the mechanical agitation device can be used with a single vessel, a plurality of vessels, a portion of the plurality of vessels, or compartments of such vessels.
  • the fluid can comprise at least 20,000, 200,000, 350,000, 500,000, 1,000,000, 3,500,000, 10,000,00, 25,000,000, or 50,000,000 cells/mL.
  • the cells can comprise microorganisms, mammalian cells, HEK293 cells, T-cells, Jurkat cells, CHO cells, mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, or hematopoietic stem cells.
  • the bioprocessing chambers can comprise at least 0.35, 0.5, 1, 3.5, 5, 10, 15, 50, 100, or 200 million cells/mL.
  • Cells can deplete surrounding media from nutrients in static conditions. The rate of media flow in the vessels can be carefully regulated. In the microscale, numerous parameters can be involved in ensuring cell growth, including temperature gradients, oxygen levels, chemical gradients, cell-to-cell interactions, cell-to-molecule interactions, CO2 level, shear stress, and cellsubstrate interactions.
  • Nutrient and gas diffusion as well as cell consumption can also be optimized.
  • a consumption rate that follows a Poisson distribution can be expected where there is a higher consumption rate near the position of the feeding input channels (since it can be in first contact with the nutrients).
  • Mechanical agitation can be employed during seeding can be beneficial for perfusion to ensure that nutrients are distributed all throughout the bioprocessing chamber.
  • the methods described herein can further comprise expanding the distributed cells to generate expanded cells.
  • the expanding comprises expanding the distributed cells about, or at least 2-fold, 3 -fold, 4-fold, 5 -fold, 6-fold, 6.5 -fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 25-fold, 50-fold, 100-fold, 150-fold, or 200-fold.
  • the expanding occurs over about, or at least 24 hr, 48 h, 72 hr, 96 hr, 120 hr, 144 hr, 168 hr, 192 hr, 216 hr, 240 hr, 264 hr, 288 hr, 312 hr, 336 hr, 360 hr, 720 hr, 1080 hrs, or 1200 hrs.
  • Appropriate surface treatment can also be performed inside the bioprocessing chamber of the vessel depending on the experimental conditions. Such surface treatments can allow adherent particles or cells to stick unto the surface such that particle-wall adhesion takes place. Additional coating methods can be used to facilitate cell attachment or detachment on the COC substrate. In some cases, the coating can comprise one or more polymeric surfactants. In some cases, the coating can comprise any type of biocompatible or biostable material that facilitates cell adhesion or growth. [0092] In some cases, harvesting can comprise harvesting at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the cells to provide harvested cells.
  • the harvesting occurs in 5 min or less, 1 min or less, 50 seconds or less, 40 seconds or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less. In some cases, at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, or 94% of the harvested cells can be viable. In some cases, the harvesting of cells from the presently disclosed vessels can result in about, or least, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% cell recovery with about or at least 95%, 94%, 93%, 92%, 91%, or 90% viability.
  • Sampling can involve taking representative samples of cells from inside the bioprocessing chamber without interfering with cell growth and without opening the vessel. Varying the drawing flow rate at the harvest or collection drain can control the amount of fluid (and cells) collected. Because the system can be a closed end-to-end process, reagents and cells can never come into contact with the environment, even when sampling.
  • the method can further comprise washing the distributed cells.
  • the method can further comprise expanding the distributed cells to generate expanded cells.
  • the expanding comprises expanding the distributed cells about, or at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 6.5-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 25-fold, 50-fold, 100-fold, 150-fold, or 200-fold.
  • the expanding occurs over about, or at least 24 hr, 48 h, 72 hr, 96 hr, 120 hr, 144 hr, 168 hr, 192 hr, 216 hr, 240 hr, 264 hr, 288 hr, 312 hr, 336 hr, 360 hr, 720 hr, 1080 hrs, or 1200 hrs.
  • the method can further comprise imaging the distributed cells. In some embodiments, the method can further comprise imaging the expanded cells.
  • the system comprises only one imaging system. The imaging system can operate as a brightfield microscope or a holographic microscope. In some cases, the one imaging system is configured to move among the vessels, and the imaging system is configured to capture images of individual vessels. In some cases, the one or more vessels are configured to move to the imaging system, and the imaging system is configured to capture images of individual vessels.
  • the system comprises at least one magnetic plate.
  • the magnetic plate can be an electromagnetic plate.
  • the one magnetic plate is configured to move among the vessels.
  • the one or more vessels are configured to move to the magnetic plate.
  • the method can further comprise using a computer system to predict time to confluence of the expanded cells.
  • the method can further comprise contacting the distributed cells with a reagent after the washing. In some embodiments, the method can further comprise, after the contacting, performing a second wash of the distributed cells. In some embodiments, the method can further comprise, after the second wash of the distributed cells, harvesting the distributed cells.
  • the reagents can comprise, for example, balanced salt solutions, buffers, detergents, chelators, or any materials or substances that promote or facilitate cell adhesion.
  • the cells can be seeded at a flow rate ranging from 0.1 microliters per second (pL/s) to 1 mL/s or more.
  • the cells can be harvested at a flow rate ranging from about 1 milliliter per second (mL/s) to about 10 mL/s or more.
  • the cells can be harvest at a flow rate ranging from about 1 mL/s to about 10 mL/s.
  • FIG. 8 shows a computer system 2001 that is programmed or otherwise configured to implement a method for bioprocessing.
  • the computer system 2001 can be configured to, for example, control a flow of fluid comprising one or more cells into a bioprocessing system.
  • the computer system 2001 can be configured to adjust a flow rate or an amount of fluid flow into or through the one or more vessels, based on one or more sensor readings.
  • the computer system can have several functionalities: 1) guiding a user through the setup of a batch (cell culture vessel connections) and reagent connections; 2) automated system checks, e.g., testing of valve and pump functionalities, commencing a sterilizing cycle, steam flow rate, pressure, temperature, confirmation of fluidic connection with reagents and cell culture vessels, calibration of sensors; 3) providing information to the user about each batch while the batch is run, such as past, current and future sequence steps and timings, sensor measurement values, alerts based on preset parameter values measured by the system, alerts about operational issues (such as reagent shortage or valve failure); 4) guiding the user through the unloading of cell culture vessels at the end of a batch (disconnection of cell culture vessels) and system cleaning steps.
  • automated system checks e.g., testing of valve and pump functionalities, commencing a sterilizing cycle, steam flow rate, pressure, temperature, confirmation of fluidic connection with reagents and cell culture vessels, calibration of sensors
  • the system sends data about each batch to the cloud or to a central database, so that decisions about non-planned deviations can be actioned by a group of centrally located cell manufacturing experts.
  • the computer system 2001 can be an electronic device of a user or a computer system that is remotely located with respect to the electronic device.
  • the electronic device can be a mobile electronic device.
  • the computer system 2001 can include a central processing unit (CPU, also "processor” and “computer processor” herein) 2005, which can be a single core or multi core processor, or a plurality of processors for parallel processing.
  • the computer system 2001 also includes memory or memory location 2010 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 2015 (e.g., hard disk), a user interface, communication interface 2020 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 2025, such as cache, other memory, data storage and/or electronic display adapters.
  • the memory 2010, storage unit 2015, interface 2020 and peripheral devices 2025 are in communication with the CPU 2005 through a communication bus (solid lines), such as a motherboard.
  • the storage unit 2015 can be a data storage unit (or data repository) for storing data.
  • the computer system 2001 can be operatively coupled to a computer network (“network") 2030 with the aid of the communication interface 2020.
  • the network 2030 can be the Internet, an internet and/or extranet, or an intranet and/or extranet that is in communication with the Internet.
  • the network 2030 in some cases is a telecommunication and/or data network.
  • the network 2030 can include one or more computer servers, which can enable distributed computing, such as cloud computing.
  • the network 2030 in some cases with the aid of the computer system 2001, can implement a peer-to-peer network, which can enable devices coupled to the computer system 2001 to behave as a client or a server.
  • the CPU 2005 can execute a sequence of machine-readable instructions, which can be embodied in a program or software.
  • the instructions can be stored in a memory location, such as the memory 2010.
  • the instructions can be directed to the CPU 2005, which can subsequently program or otherwise configure the CPU 2005 to implement methods of the present disclosure. Examples of operations performed by the CPU 2005 can include fetch, decode, execute, and writeback.
  • the CPU 2005 can be part of a circuit, such as an integrated circuit.
  • a circuit such as an integrated circuit.
  • One or more other components of the system 2001 can be included in the circuit.
  • the circuit is an application specific integrated circuit (ASIC).
  • ASIC application specific integrated circuit
  • the storage unit 2015 can store files, such as drivers, libraries and saved programs.
  • the storage unit 2015 can store user data, e.g., user preferences and user programs.
  • the computer system 2001 in some cases can include one or more additional data storage units that are located external to the computer system 2001 (e.g., on a remote server that is in communication with the computer system 2001 through an intranet or the Internet).
  • the computer system 2001 can communicate with one or more remote computer systems through the network 2030.
  • the computer system 2001 can communicate with a remote computer system of a user (e.g., an operator managing or monitoring the bioprocessing).
  • remote computer systems include personal computers (e.g., portable PC), slate or tablet PC's (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android- enabled device, Blackberry®), or personal digital assistants.
  • the user can access the computer system 2001 via the network 2030.
  • Methods as described herein can be implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 2001, such as, for example, on the memory 2010 or electronic storage unit 2015.
  • the machine executable or machine readable code can be provided in the form of software.
  • the code can be executed by the processor 2005.
  • the code can be retrieved from the storage unit 2015 and stored on the memory 2010 for ready access by the processor 2005.
  • the electronic storage unit 2015 can be precluded, and machine-executable instructions are stored on memory 2010.
  • the code can be pre-compiled and configured for use with a machine having a processor adapted to execute the code, or can be compiled during runtime.
  • the code can be supplied in a programming language that can be selected to enable the code to execute in a pre-compiled or as- compiled fashion.
  • aspects of the systems and methods provided herein, such as the computer system 2001, can be embodied in programming.
  • Various aspects of the technology can be thought of as "products” or “articles of manufacture” typically in the form of machine (or processor) executable code and/or associated data that is carried on or embodied in a type of machine readable medium.
  • Machineexecutable code can be stored on an electronic storage unit, such as memory (e.g., read-only memory, random-access memory, flash memory) or a hard disk.
  • Storage type media can include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which can provide non-transitory storage at any time for the software programming. All or portions of the software can at times be communicated through the Internet or various other telecommunication networks. Such communications, for example, can enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server.
  • another type of media that can bear the software elements includes optical, electrical and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various airlinks.
  • a machine readable medium such as computer-executable code
  • a machine readable medium can take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium.
  • Non-volatile storage media including, for example, optical or magnetic disks, or any storage devices in any computer(s) or the like, can be used to implement the databases, etc. shown in the drawings.
  • Volatile storage media include dynamic memory, such as main memory of such a computer platform.
  • Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system.
  • Carrier-wave transmission media can take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications.
  • Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer can read programming code and/or data.
  • Many of these forms of computer readable media can be involved in carrying one or more sequences of one or more instructions to a processor for execution.
  • the computer system 2001 can include or be in communication with an electronic display 2035 that comprises a user interface (UI) 2040 for providing, for example, a portal for an operator to monitor or track one or more steps or operations of the bioprocessing methods and systems described herein.
  • UI user interface
  • the portal can be provided through an application programming interface (API).
  • API application programming interface
  • a user or entity can also interact with various elements in the portal via the UI.
  • Examples of UI's include, without limitation, a graphical user interface (GUI) and web-based user interface.
  • Methods and systems of the present disclosure can be implemented by way of one or more algorithms.
  • An algorithm can be implemented by way of software upon execution by the central processing unit 2005.
  • the algorithm can be configured to adjust a flow rate or an amount of fluid flow into the bioprocessing system, based on one or more sensor readings.
  • the system’s software can follow Good Manufacturing Practice (GMP) guidelines, which can require following the ALCOA+ guidelines (Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, Available) for records
  • GMP Good Manufacturing Practice

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Abstract

La présente divulgation concerne des systèmes et des procédés de biotraitement. Le système peut comprendre : (a) une ou plusieurs cuves de mélange, la ou les cuves de mélange comprenant des réactifs ; (b) une ou plusieurs cuves reliées fluidiquement à la ou aux cuves de mélange ; et (c) une ou plusieurs cuves de déchets reliées fluidiquement à la ou aux cuves ; la ou les cuves sont agencées verticalement, et l'agencement vertical comprend une ou plusieurs barrières physiques, la ou les barrières physiques séparant une première partie de la ou des cuves d'une deuxième partie de la ou des cuves.
PCT/GB2023/052310 2022-09-07 2023-09-07 Système de biotraitement WO2024052678A1 (fr)

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WO2018015561A1 (fr) * 2016-07-21 2018-01-25 Celyad Procédé et appareil de traitement de cellules par lots parallèle, indépendant et automatisé
US20210238523A1 (en) * 2018-07-19 2021-08-05 Platelet Biogenesis, Inc. Stacked Recirculating Bioreactor
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WO2018015561A1 (fr) * 2016-07-21 2018-01-25 Celyad Procédé et appareil de traitement de cellules par lots parallèle, indépendant et automatisé
US20210238523A1 (en) * 2018-07-19 2021-08-05 Platelet Biogenesis, Inc. Stacked Recirculating Bioreactor
US20210403847A1 (en) * 2019-03-19 2021-12-30 Fujifilm Corporation Cell culture system and cell culture method

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