Cell processing and subpackaging all-in-one machine

Abstract

The embodiment of the invention discloses a cell processing and subpackaging all-in-one machine. The all-in-one machine can comprise a centrifugal mechanism used for analyzing cells from a culture solution, preparing a cell preparation and the like, including mixing the cells and a preparation solution, and carrying out at least one of the following treatments: cell separation, cleaning or replacement; and the sub-packaging mechanism is used for sub-packaging the target preparation obtained after mixing treatment. According to the cell treatment and subpackaging all-in-one machine, a centrifugal system, a shaking table and a subpackaging system are effectively integrated, closed continuous treatment of links such as harvesting, dosing and subpackaging of cells can be achieved, and the cell treatment and subpackaging all-in-one machine is suitable for large-scale production and can meet the clean and sterile requirements of production operation.

Description

Technical Field

[0001] This application relates to the field of biological culture technology, and more specifically, to a cell processing and dispensing integrated machine. Background Technology

[0002] Cell culture technology, also known as cell cloning technology, involves obtaining large quantities of cells or their metabolites through cell culture. Cell culture technology is now widely used in various fields such as biology, medicine, and new drug development, and has become one of the most important basic sciences. Among these, the culture technology of universal immune cells is extremely important for research into cell therapy applications. Immune cells, when expanded and cultured in vitro, mostly grow in suspension.

[0003] Currently, in cell culture processes using suspension growth, multiple steps, such as cell separation, washing, and the preparation and packaging of cell preparations, are often performed using single machines and single steps. This single-step operation is a "manual" operation, which makes it impossible to achieve large-scale production. Furthermore, cell separation and washing are usually non-closed operations, thus failing to guarantee aseptic requirements and not conforming to the GMP (Good Manufacturing Practice of Medical Products) principles of the pharmaceutical industry.

[0004] In view of the above situation, those skilled in the art are dedicated to researching a device that can be used for large-scale production of cell culture and subsequent processing. Summary of the Invention

[0005] The technical solution provided in this application at least partially solves the above-mentioned technical problems.

[0006] According to an embodiment of this application, a cell processing and dispensing integrated machine is provided, comprising: a centrifugation mechanism for mixing cells and a formulation solution, and performing at least one of the following processes: cell separation, washing, or replacement; and a dispensing mechanism for dispensing the target formulation obtained after mixing.

[0007] In some embodiments, the aforementioned integrated machine also includes a liquid inlet mechanism for conveying one or more liquids to the centrifugation mechanism.

[0008] In some embodiments, the aforementioned integrated machine also includes a draining mechanism and a waste liquid collection container. The draining mechanism is used to discharge the waste liquid after cell separation, washing or replacement from the centrifugation mechanism to the waste liquid collection container.

[0009] In some embodiments, the inlet mechanism is used to deliver the culture medium to be treated to the centrifugation mechanism, the culture medium to be treated including cells and culture medium; the centrifugation mechanism is used to separate cells from the culture medium to be treated, and the waste liquid after cell separation is discharged to the liquid collection container through the outlet mechanism.

[0010] In some embodiments, the inlet mechanism is used to deliver the cleaning solution or replacement solution to the centrifugation mechanism; the centrifugation mechanism is used to clean cells with the cleaning solution or to replace the culture medium with the replacement solution.

[0011] In some embodiments, the aforementioned integrated machine further includes a liquid storage device, which includes a shaker and a liquid storage container located on the shaker; a liquid inlet mechanism for conveying the formulation solution to a centrifugation mechanism; a centrifugation mechanism for mixing the formulation solution with cells and discharging the mixed formulation solution after mixing to the liquid storage device through a liquid outlet mechanism; a shaker for adjusting the amplitude and frequency of the shaking of the liquid storage container to prevent cell precipitation or aggregation in the liquid storage container; and a dispensing mechanism for dispensing the target formulation from the liquid storage device into dispensing bags.

[0012] In some embodiments, the all-in-one machine also includes a control unit, which is connected to the liquid inlet mechanism, centrifugation mechanism, liquid outlet mechanism and dispensing mechanism respectively.

[0013] In some embodiments, the centrifugation mechanism includes a sealed housing and a centrifugation chamber located within the sealed housing; the liquid inlet mechanism and the liquid outlet mechanism are respectively in sealed communication with the centrifugation chamber; wherein the centrifugation chamber is made of 316L stainless steel or is a disposable plastic centrifugation chamber.

[0014] In some embodiments, the aforementioned integrated machine also includes a temperature control device for controlling the temperature of the liquid storage device, the temperature control device including at least one of a heating plate and an external refrigerant.

[0015] In some embodiments, the liquid inlet mechanism includes at least one liquid inlet line, at least one valve, and at least one pump.

[0016] In some embodiments, the drainage mechanism includes at least one drainage pipe and at least one switching valve, which is connected to the waste liquid collection container and the liquid storage device respectively, and is used to switch the liquid flow direction in the drainage pipe.

[0017] In some embodiments, the dispensing mechanism includes a dispensing peristaltic pump and a weighing assembly, with one end of the dispensing peristaltic pump connected to a liquid storage device and the other end connected to at least one dispensing bag.

[0018] The cell processing and dispensing integrated machine provided according to the embodiments of this application can realize closed continuous processing of subsequent processing steps after cell culture, including cell (and culture medium) separation, elution of culture medium, preparation and dispensing of cell preparations, etc. It is suitable for large-scale production and can meet the aseptic requirements of production operation. Attached Figure Description

[0019] Other features, objects, and advantages of this application will become more apparent from the following detailed description of non-limiting embodiments, with reference to the accompanying drawings:

[0020] Figure 1 This is a schematic diagram of the structure of the cell processing and dispensing integrated machine according to an embodiment of this application;

[0021] Figure 2 This is a schematic diagram of the control section of a cell processing and dispensing machine according to an embodiment of this application. Detailed Implementation

[0022] To better understand this application, various aspects of this application will be described in more detail with reference to the accompanying drawings. It should be understood that these detailed descriptions are merely illustrative of exemplary embodiments of this application and are not intended to limit the scope of this application in any way. Throughout the specification, the same reference numerals refer to the same elements. The expression "and / or" includes any and all combinations of one or more of the associated listed items.

[0023] It should also be understood that expressions such as "comprising," "including," "having," "containing," and / or "comprising" are open-ended rather than closed-ended expressions in this specification, indicating the presence of the stated features, elements, and / or components, but not excluding the presence of one or more other features, elements, components, and / or combinations thereof. Furthermore, when expressions such as "at least one of..." appear after a list of listed features, they modify the entire list of features, not just individual elements in the list. Additionally, when describing embodiments of this application, the word "may" is used to mean "one or more embodiments of this application." And the term "exemplary" is intended to refer to examples or illustrations.

[0024] Unless otherwise specified, all terms used herein (including engineering and technical terms) shall have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. It should also be understood that, unless expressly stated herein, terms defined in common dictionaries shall be interpreted as having the meaning consistent with their meaning in the context of the relevant art, and not as having an idealized or overly formalized meaning.

[0025] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. Any one or more embodiments or elements thereof described herein, or arrangements or combinations of some or all embodiments or elements thereof, are merely exemplary and are not intended to limit the scope of this application.

[0026] After the cell culture stage, various cell types need to be harvested, separated, formulated, and packaged. For laboratory or small-scale trials, individual equipment such as centrifuges and peristaltic pumps are often used to separate and harvest cells. In a Class A clean environment, the prepared formulation solution is added to the cells manually using a device. After mixing the cells with the formulation solution, the target formulation is obtained and then packaged into multiple small bags for storage.

[0027] In existing technologies, cell harvesting and separation, as well as formulation and dispensing, are often carried out by stand-alone operations. Such stand-alone operations are not conducive to the large-scale production of cell preparations. Furthermore, this operation method also increases the risk of cross-contamination during the transfer of separated cells to dispensing equipment.

[0028] In view of the above situation, this application provides a multifunctional cell processing and dispensing integrated machine 100, which can be used for the post-culture processing of various types of cells, such as general immune cells, such as cell harvesting, separation, washing and replacement, reagent preparation and dispensing, etc., and can at least solve or partially solve at least one of the problems or other problems existing in the above-mentioned prior art.

[0029] The features, principles and other aspects of this application will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0030] Figure 1 This application illustrates a multifunctional cell processing and dispensing machine according to one embodiment of the present application. This machine can be used, for example, for cell separation, washing or replacement after cell culture, as well as for the preparation and dispensing of formulations.

[0031] Combination Figure 1As shown, the cell processing and dispensing integrated machine 100 (hereinafter also referred to as the "integrated machine") mainly includes a liquid inlet mechanism 10, a centrifugation mechanism 20, a liquid outlet mechanism 30, and a dispensing mechanism 50. The liquid inlet mechanism 10 may include one or more liquid inlet pipes (branches) for simultaneously or sequentially supplying one or more liquids, such as cell fluid, buffer solution, or one or more formulation solutions, to the centrifugation mechanism 20 at different stages. Further implementation details of the liquid inlet mechanism 10 will be described in detail below. The centrifugation mechanism 20 is used for separating cells from the culture medium and preparing cell preparations, specifically for mixing cells and formulation solutions, and also for cell separation, washing, or replacement. The liquid outlet mechanism 30 is used to discharge waste liquid after cell separation and waste liquid after washing or replacement from the centrifugation mechanism 20. The dispensing mechanism 50 is used to dispense the target formulation obtained after mixing. The integrated machine according to the embodiments of this application can be used as an integrated device for cell separation, washing / replacement, formulation mixing, and dispensing of various types of cells.

[0032] It should be noted that, Figure 1 The orientations (e.g., left, right) or relative positional relationships (e.g., above, below, inside, outside) of the various mechanisms or components shown in the accompanying drawings are for the purpose of description and understanding of this application only, and are not intended to indicate or imply that these mechanisms or components necessarily have specific orientations, structures and relative positional relationships, and therefore should not be construed as limitations on this application.

[0033] In an exemplary embodiment, the liquid inlet mechanism 10 may include at least one switching valve 101 and at least one pump 102. The liquid inlet mechanism 10 may add one or more solutions, such as culture medium, buffer solution, and preparation solution, to the centrifugation unit 20 through the liquid inlet line 110 (or branch line) according to different stages.

[0034] In an exemplary embodiment, the all-in-one machine 100 also includes a waste liquid collection container, which can be used to collect and store waste liquid generated during cell separation or cleaning and replacement processes.

[0035] In an exemplary embodiment, the all-in-one machine 100 further includes a liquid storage device 40. The liquid storage device 40 may include a shaker 401 and a liquid storage container 402 located on the shaker 401. As an exemplary embodiment, the shaker 401 may be equipped with a swing mechanism, which is driven by a drive motor to swing back and forth within a certain angle range, thereby adjusting the swing amplitude and frequency of the liquid storage container 402 to prevent cell precipitation or aggregation in the liquid storage container 402 and to ensure uniform cell distribution in the liquid storage container 402. The liquid storage container 402 may be a disposable liquid storage bag or a repeatedly washed and sterilized glass or stainless steel container.

[0036] In an exemplary embodiment, the drainage mechanism 30 may include a drainage pipeline, which may include multiple drainage branches. Exemplarily, at least one drainage branch is connected to a waste liquid collection container, and at least one drainage branch is connected to a liquid storage device 40. Exemplarily, the drainage pipeline may include at least one switching valve 305, which is connected to both the waste liquid collection container and the liquid storage device 40, for switching the flow direction of liquid in the drainage pipeline, so that the discharged waste liquid flows to the waste liquid collection container (not shown) through one of the drainage branches and the waste liquid outlet 306, or that the prepared cell preparation solution flows to the liquid storage device 40 through another drainage branch.

[0037] In an exemplary embodiment, the centrifugation mechanism 20 may include a sealed housing 201 and a centrifugation chamber 202 located within the sealed housing 201. The sealed housing 201 has an inlet 203 and an outlet 205. The inlet mechanism 10 and the outlet mechanism 30 can be in sealed communication with the centrifugation chamber 202 within the sealed housing 201 through the inlet 203 and outlet 205, respectively. For example, a sterile interface or sterile tubing can be used to achieve sealed communication with the centrifugation chamber 202. The centrifugation chamber 202 can be made of 316L stainless steel, facilitating disassembly, cleaning, and offline sterilization, meeting industry requirements for cleanliness and sterility. Alternatively, the centrifugation chamber 202 can be replaced by an irradiated disposable plastic centrifuge bucket, eliminating the need for sterilization and offering greater convenience and efficiency.

[0038] In an exemplary embodiment, the centrifugation mechanism 20 can be used for at least one of the following processes:

[0039] Cells are separated from the culture medium to be treated, and the waste liquid after cell separation is discharged into the waste liquid collection container through the drainage mechanism;

[0040] The cells in the centrifuge are cleaned with a cleaning solution, or the culture medium in the centrifuge is replaced with a replacement solution, and the waste liquid obtained after cleaning or replacement is discharged into a waste liquid collection container through a draining mechanism.

[0041] The formulation solution delivered by the liquid inlet mechanism is mixed with the cells in the centrifugation mechanism to obtain a formulation solution containing suspended cells, which is then discharged into the storage device through the liquid outlet mechanism.

[0042] In an exemplary embodiment, the dispensing mechanism 50 may include a dispensing peristaltic pump 502 and a weighing assembly 501. One end of the dispensing peristaltic pump 502 may be connected to the liquid storage device 40, and the other end may be connected to at least one dispensing bag 509. Figure 1As shown, the dispensing mechanism 50 can be pre-connected with dispensing bags 509, such as cell storage bags, and equipped with a dispensing peristaltic pump 502. The cell preparation is dispensed according to the set dispensing dosage via the weighing component 501, thereby achieving precise control of the dispensing dosage. The dispensing mechanism 502 is connected to the storage bag 402 of the storage device 40, dispensing the mixed target preparation into the dispensing bag 509, and the dispensing dosage can be precisely controlled via the weighing component 501.

[0043] The multifunctional cell processing and dispensing integrated machine according to the embodiments of this application provides a more efficient production solution suitable for the post-processing of large-scale cell culture. It can realize continuous production of cell culture in a closed manner, avoiding contamination by the external environment during cell harvesting, separation, preparation and dispensing.

[0044] Figure 2 A schematic diagram of the control section of the multifunctional cell processing and dispensing integrated machine provided according to an embodiment of this application (e.g.) Figure 2 (The dotted line in the image). This integrated machine provides a large-scale production solution for post-cell culture processing, and also enables precise control of each production stage, avoiding the quality inconsistencies caused by manual operation.

[0045] As mentioned above, the integrated machine may include a liquid inlet mechanism 10, a centrifugation mechanism 20, a liquid outlet mechanism 30, a liquid storage device 40, and a dispensing mechanism 50. For the sake of brevity, some structural descriptions similar to those in the aforementioned embodiments will be omitted in this embodiment.

[0046] Combination Figure 1 and Figure 2 As shown, the integrated machine may also include a control unit 60, wherein the liquid inlet mechanism 10, the centrifugation mechanism 20, the liquid outlet mechanism 30, the liquid storage device 40 and the dispensing mechanism 50 are all connected to the control unit 60, and the control unit 60 can realize precise control of each of the above devices or mechanisms.

[0047] In an exemplary embodiment, the control unit 60 can control the type and volume of liquid added to the centrifugation unit 20 via the pump 102 of the liquid inlet mechanism 10.

[0048] In an exemplary embodiment, the control unit 60 can set the rotational speed of the centrifuge mechanism 20 to meet the needs of different stages such as cell separation, washing and replacement, and preparation mixing.

[0049] In an exemplary embodiment, the control unit 60 can control the flow direction of the liquid discharged from the centrifuge chamber by controlling the switching angle valve 305, for example, directing the waste liquid generated after separation or washing to the waste liquid collection container, and directing the prepared cell preparation solution to the liquid storage device 40, etc.

[0050] In an exemplary embodiment, the all-in-one machine may further include a temperature control device to regulate the temperature of the liquid storage container (more specifically, a cell storage bag) of the liquid storage device 40. The temperature control device may include, for example, a heating plate, an external refrigerant, etc. This temperature-controlled shaker design ensures that the quality of temperature-sensitive and / or easily sedimented products is guaranteed during the dispensing process.

[0051] In an exemplary embodiment, the centrifuge chamber of the centrifuge mechanism may include a centrifuge bucket, which may be made of 316L stainless steel. Compared with disposable plastic centrifuge buckets, it is more economical and environmentally friendly, and more suitable for large-scale mass production in multiple batches.

[0052] The integrated machine according to the embodiments of this application creatively and effectively integrates the centrifugation system, shaker, and dispensing system, and realizes precise and automated control of liquid inlet, liquid exchange, liquid discharge, centrifugation mechanism, and shaker through the control unit, thereby enabling large-scale continuous production; at the same time, the closed centrifugation system and sterile disposable consumables (such as tubing, bags, connectors, etc.) realize closed-loop automated operation of the entire process from cell culture post-processing to formulation dispensing, ensuring that the product is not contaminated by the external environment and meets the industry standard requirements for clean and sterile production.

[0053] In a specific application example, the method for achieving cell separation, washing or replacement, and formulation and dispensing in post-cell culture processing using the aforementioned multifunctional cell processing and dispensing machine may include the following steps:

[0054] Step 1: Connect the cell culture medium, replacement medium or washing solution, preparation solution, etc. to the inlet through the inlet pipe of the inlet mechanism.

[0055] Step 2: Set the speed of the centrifuge tank and the speed of the peristaltic pump, and open the waste liquid valve. Under the control of the control unit, the culture medium containing cells is pumped into the centrifuge tank to separate the cells from the culture medium.

[0056] Step 3: After cell separation, under the control of the control unit, the replacement solution or washing solution is pumped into the centrifuge tank to clean the cells or replace the residual culture medium in the tank.

[0057] Step 4: After cleaning or replacement, one or more formulation solutions are pumped into the centrifuge tank under the control of the control unit to mix with the cells in the tank to obtain a cell formulation solution. The waste liquid discharge passage is closed by controlling the switching valve to discharge the cell formulation solution in the tank into the cell storage bag of the storage device.

[0058] Step 5: Control the swing amplitude of the shaker holding the cell storage bag through the control unit to prevent cell precipitation or aggregation.

[0059] In some implementations, the temperature of the cell storage bag can be controlled by a heating plate or an external refrigerant under the control of a control unit, depending on the preparation requirements of different types of cell products.

[0060] Step 6: Connect the liquid storage device to the dispensing bag, set the dispensing peristaltic pump through the control unit, and dispense the formulation solution according to the set dispensing dosage through the weighing component to achieve precise control of the dispensing dosage.

[0061] The above description is merely an illustration of the embodiments of this application and the technical principles employed. Those skilled in the art should understand that the scope of protection involved in this application is not limited to technical solutions formed by specific combinations of the above-described technical features, but should also cover other technical solutions formed by arbitrary combinations of the above-described technical features or their equivalents without departing from the technical concept. For example, technical solutions formed by substituting the above features with (but not limited to) technical features with similar functions disclosed in this application.

Claims

1. A cell processing and dispensing integrated machine, comprising: A centrifuge mechanism for mixing cells and formulation solutions, and for performing at least one of the following processes: cell separation, washing, or replacement; The dispensing mechanism is used to dispense the target formulation obtained after the mixing process.

2. The all-in-one machine according to claim 1, wherein, The integrated machine also includes a liquid inlet mechanism for conveying one or more liquids to the centrifugation mechanism.

3. The all-in-one machine according to claim 2, wherein, The integrated machine also includes a draining mechanism and a waste liquid collection container. The drainage mechanism is used to discharge the waste liquid after cell separation, washing or replacement from the centrifugation mechanism to the waste liquid collection container.

4. The all-in-one machine according to claim 3, wherein, The liquid inlet mechanism is used to deliver the culture medium to be processed to the centrifugation mechanism, wherein the culture medium to be processed includes cells and culture medium; The centrifugation mechanism is used to separate cells from the culture medium to be processed, and the waste liquid after cell separation is discharged to the waste liquid collection container through the drainage mechanism.

5. The all-in-one machine according to claim 3, wherein, The liquid inlet mechanism is used to deliver the cleaning solution or replacement solution to the centrifugation mechanism; The centrifugation mechanism is used to clean cells with the cleaning solution or to replace the culture medium with the replacement solution.

6. The all-in-one machine according to any one of claims 3-5, wherein, The all-in-one machine also includes a liquid storage device, which includes a shaker and a liquid storage container located on the shaker; The liquid inlet mechanism is used to deliver the formulation solution to the centrifugation mechanism; The centrifugation mechanism is used to mix the preparation solution with the cells, and the mixed preparation solution after mixing is discharged to the storage device through the drainage mechanism; The shaker is used to adjust the amplitude and frequency of the shaking of the liquid storage container to prevent cells in the liquid storage container from settling or aggregating. The dispensing mechanism is used to dispense the target formulation from the storage device into dispensing bags.

7. The all-in-one machine according to any one of claims 3-5, wherein, The integrated machine also includes a control unit, which is connected to the liquid inlet mechanism, the centrifugation mechanism, the liquid outlet mechanism and the dispensing mechanism respectively.

8. The all-in-one machine according to claim 6, wherein, The centrifuge mechanism includes a sealed housing and a centrifuge chamber located within the sealed housing; The liquid inlet mechanism and the liquid outlet mechanism are respectively in sealed communication with the centrifuge chamber; The centrifuge chamber is made of 316L stainless steel or is a disposable plastic centrifuge chamber.

9. The all-in-one machine according to claim 6, wherein, The integrated machine also includes a temperature control device for controlling the temperature of the liquid storage device, the temperature control device including at least one of a heating plate and an external refrigerant.

10. The all-in-one machine according to claim 2, wherein, The liquid inlet mechanism includes at least one liquid inlet pipe, at least one valve, and at least one pump.

11. The all-in-one machine according to claim 6, wherein, The drainage mechanism includes at least one drainage pipe and at least one switching valve. The switching valve is connected to the waste liquid collection container and the liquid storage device, respectively. The switching valve is used to switch the liquid flow direction in the drainage pipe.

12. The all-in-one machine according to claim 6, wherein, The dispensing mechanism includes a dispensing peristaltic pump and a weighing assembly. One end of the dispensing peristaltic pump is connected to the liquid storage device, and the other end is connected to at least one of the dispensing bags.

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