Mixing system

Abstract

This invention relates to a mixing system for a bioreactor, comprising: - a plurality of supply units (10), each capable of holding a medium for use in the bioreactor; - a mixing unit (30) for forming a homogeneous mixture of the medium; - a first supply mechanism (20) arranged to supply the medium from the supply units (10) to the mixing unit (30); - a control unit (40) operatively connected to the first supply mechanism (20) and the mixing unit (30), the control unit (40) being configured to control the first supply mechanism (20) to supply a predetermined amount of medium from the plurality of supply units (10) to the mixing unit (30), and further configured to control the mixing unit (30) to form a homogeneous mixture of the medium. The invention also relates to a method for mixing a medium used in a bioreactor.

Description

Technical Field

[0001] This invention relates to a mixing system for a bioreactor, and to a method for mixing media used in a bioreactor. Background Technology

[0002] The use of bioreactors for culturing cell samples is well known in the art. Generally, media are introduced into cell bags and conditions are closely monitored to optimize the culture process. Media are typically formed by mixing several media types to achieve a mixture with suitable properties before being supplied to the cell bags.

[0003] Currently, media are typically prepared through time-consuming and cumbersome multi-step processes. For example, some improvements have been proposed through US 5350080 A, US 5069370 A, US 5686304 A, US 5941635 A, US 6923567 B2, US 6908223 B2, and US8272255 B2.

[0004] However, there is still a need for improvements to achieve efficient and reliable media mixing without the drawbacks of existing methods and systems. Summary of the Invention

[0005] The object of this invention is to eliminate or at least minimize the problems mentioned above. This is achieved through a mixing system according to the appended independent claims. Due to this invention, media for use in bioreactors can be mixed and prepared without the need for input or action from operators or users, and the media preparation process is significantly improved with a reduced risk of media contamination. The mixing system of this invention can operate independently as desired or be controlled by an external unit or operator, and feedback within the system can be used to check the quality of the prepared media and to further improve the media mixture in response to such feedback.

[0006] According to one aspect of the invention, the mixing system is integrated with the bioreactor. Thus, the operation of the bioreactor and the preparation of the medium can be performed together, allowing for fewer controls and components, and forming a separate system for cell culture in which media with suitable properties are automatically prepared and supplied as needed.

[0007] According to another aspect of the invention, the first supply mechanism includes a peristaltic pump for pumping the medium from each supply unit to the mixing unit. Preferably, the peristaltic pump is controlled by at least one stepper motor. Thus, the first supply mechanism can be controlled in a simple and efficient manner, providing the desired portion of medium as determined by the control unit.

[0008] According to another aspect of the invention, the first supply mechanism includes valves for controlling the flow of medium from each supply unit to the mixing unit. This allows for the partial supply of medium to the mixing unit in a simple and efficient manner, requiring fewer components and thus making the mixing system more cost-effective.

[0009] According to another aspect of the invention, the bioreactor is operatively connected to and capable of controlling the operation of the control unit. Thus, the mixing system can be used as a subordinate device to the bioreactor and performs its operation according to the direct instructions of the bioreactor, but has a separate control unit relative to the bioreactor's control unit, so that processes can be executed in parallel without requiring a higher-level control unit. This also allows the mixing system to be a separate system connected to any suitable bioreactor, without requiring the bioreactor's control unit to control the specific components of the mixing system.

[0010] According to another aspect of the invention, the mixing system further includes a pH sensor operatively connected to the control unit and arranged to measure the pH value in the mixing unit, and the control unit further includes an input device for receiving pH data from the bioreactor. Thus, pH feedback from the media mixture within the mixing unit can be used to determine the supply amount of additional media portions, and the pH of the media mixture can be adapted to meet the specific needs of the bioreactor at any given time due to the pH input given by the bioreactor. Preferably, the control unit is capable of receiving pH data from the pH sensor and from the input device, and the control unit is arranged to control the operation of the first supply mechanism in response to the pH data.

[0011] According to another aspect of the invention, the mixing system further includes a refrigeration mechanism arranged to maintain the contents of at least one of the supply units at a first predetermined temperature. This allows media optimally stored at a specific temperature to be maintained in optimal condition. Preferably, the refrigeration mechanism is further arranged to maintain the contents of at least one of the supply units at a second predetermined temperature different from the first predetermined temperature. This allows media suitable for storage at different temperatures to be maintained at their respective optimal storage temperatures within the same system.

[0012] According to another aspect of the invention, the mixing system further includes a temperature sensor operatively connected to a control unit and arranged to measure the temperature in the mixing unit, wherein the control unit is also arranged to control the first supply mechanism in response to input from the temperature sensor. Preferably, a heating mechanism is also provided, arranged to heat the medium in at least one of the mixing unit or the supply unit. This allows the temperature of the medium mixture to be controlled and adapted such that the resulting medium mixture for supply to the bioreactor is at any desired value, while simultaneously allowing for cryogenic storage of the medium in the supply unit.

[0013] According to another aspect of the invention, the mixing system further includes a second supply mechanism arranged to supply media from the mixing unit to the bioreactor. Thus, the media mixture in the mixing unit can be supplied to the bioreactor as desired.

[0014] According to another aspect of the invention, the control unit is arranged to control the mixing system in response to a predetermined program. Thus, a series of media mixtures having the same or different properties can be prepared at predetermined intervals to allow for insertion into a bioreactor at a suitable time for cell culture to be carried out there.

[0015] According to another aspect of the invention, the control unit is arranged to control the mixing system in response to input from a user. This achieves dynamic control, whereby the user can provide specific inputs and allow the preparation of a media mixture corresponding to those inputs.

[0016] Many additional benefits and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. Attached Figure Description

[0017] The invention will now be described in more detail with reference to the accompanying drawings, in which: Figure 1 A schematic diagram of a hybrid system according to a preferred embodiment of the present invention is disclosed; Figure 2 It was made public. Figure 1 A more detailed schematic diagram of the hybrid system; Figure 3a shows a perspective view of a hybrid system according to an embodiment of the present invention; Figure 3b shows a perspective view of an alternative embodiment of the present invention; Figure 3c shows a perspective view of another alternative embodiment of the present invention; Figure 4a shows a perspective view of an embodiment of the present invention, in which a mixing system is integrated with a bioreactor; Figure 4b discloses a perspective view of an embodiment of the present invention, wherein the hybrid system is a standalone system; and Figure 5 This is a schematic diagram of an embodiment of the present invention, which discloses the interaction between various components and the control unit of a hybrid system. Detailed Implementation

[0018] Figure 1 A mixing system 100 according to a preferred embodiment of the invention is disclosed, wherein a supply unit 10 is connected to a mixing unit 30 via a first supply mechanism 20, the first supply mechanism 20 being capable of supplying media stored in the supply unit 10 to the mixing unit 30. A control unit 40 is also provided, operatively connected to the mixing unit 30 and the first supply mechanism 20, and capable of controlling their operation to achieve a desired supply of media to the mixing unit 30 and to achieve mixing to achieve a desired media mixture suitable for supply to a bioreactor, as will be described in further detail below. A bioreactor is an ideally sterile, substantially enclosed volume for culturing cells or microorganisms, such as a flexible bag-type bioreactor commonly referred to as a cell bag.

[0019] Sensors, such as a pH sensor 31 and a temperature sensor 32, may also be provided at the mixing unit 30, arranged to measure the pH value and temperature in the mixing unit 30 and transmit them to the control unit 40. The control unit 40 may also be provided with an input device 41 for receiving input from the bioreactor, which will also be described further below, and may also have a user interface 42 connected to the control unit 40, capable of supplying input from the user to the control unit 40 and presenting output from the control unit 40 to the user.

[0020] Figure 2 The mixing system 100 is disclosed in more detail, and a bioreactor 50 capable of receiving media from the mixing unit 30 is also shown. Therefore, the supply unit 10 includes media containers 11, 12, 13, and 14, each holding a supply of a type of media suitable for use in the bioreactor. In this embodiment, the media containers 11, 12, 13, and 14 are held by two supply holders 10' and 10'', which provide freezing and protection to protect the media containers 11, 12, 13, and 14 from light and other factors that could affect the media. The temperature in one of the supply holders 10' may differ from the temperature in the other supply holder 10'' if the temperature in one of the supply holders 10' is suitable for the type of media stored therein. The number of supply holders 10' and 10'' in the supply unit 10 may also vary depending on the type of media stored in the mixing system 100. Therefore, the supply holders 10' and 10'' also serve as freezing mechanisms 10' and 10''.

[0021] In this embodiment, the first supply mechanism 20 includes a plurality of pumps 21, 22, 23, and 24, each connected via a conduit to one of the media containers 11, 12, 13, and 14, allowing the media to be delivered through the conduit and pumped by the pumps 21, 22, 23, and 24, which are further connected via conduits to the mixing unit 30. The pumps 21, 22, 23, and 24 are preferably peristaltic pumps and can be driven by stepper motors to pump the desired amount of media to the mixing unit 30. Depending on the desired media mixture at a specific time, the flow of various types of media can be controlled by the pumps 21, 22, 23, and 24. This can be dynamically controlled by the control unit 40.

[0022] When the media arrive at the mixing unit 30, they are mixed so that the different types of media supplied form a homogeneous mixture. The temperature and pH of the mixture can also be controlled, and a heating mechanism is provided in the mixing unit 30 to heat the media to a desired temperature measured by the temperature sensor 32. The heating mechanism 34 is preferably integrated with the tank 34 of the mixing unit 30. The pH sensor 31 detects the pH of the mixture, and the control unit 40 can then control the pH by operating the first supply mechanism 20 to supply media of the desired type and quantity to the mixing unit 30 and to bring the media mixture to the desired pH value.

[0023] In one embodiment, mixing unit 30 may include a mixer at an inlet leading to mixing unit 30, the mixer being connected to a tank for holding the mixture. Sensors 31, 32 are then disposed inside the tank so that they are in contact with the mixture. An outlet connected to a second supply mechanism 60 is also provided for supplying the mixture to bioreactor 50.

[0024] The second supply mechanism 60 may be controlled by the control unit 40, or alternatively by the bioreactor 50.

[0025] Figure 3a is shown in perspective. Figure 1-2The mixing system 100 includes a supply unit 10 comprising two supply holders 10', 10'', each holding two disposable bags forming media containers 11, 12, 13, 14. Media is pumped from each disposable bag via conduits from the respective media containers 11, 12, 13, 14 to a first supply mechanism 20 via peristaltic pumps 21, 22, 23, 24, and guided to the mixing unit 30 via a common conduit 25 in the form of a tube. The mixing unit 30 includes a mixer 33 through which the media is mixed and heated before entering a tank 34, which also includes a heater or warmer for controlling the temperature of the media mixture. In this embodiment, the mixing system 100 is mounted to form a compact unit and can be connected to a bioreactor via an outlet conduit (not shown) from the tank 34. A control unit may also be directly mounted in the mixing system 100 or may be remotely placed and connected via a wired or wireless connection to control the operation of the mixing system 100. Alternatively, the control unit may be integrated with or formed part of the bioreactor, thereby providing the advantage of using data from the bioreactor (such as the properties of the contents of the cell bags) as input for controlling the mixing system 100.

[0026] Figure 3b shows an alternative embodiment that differs from the embodiment shown in Figure 3a in that the mixing unit 30 is raised (as indicated by the vertical arrow below tank 34). This allows for the supply of media to the bioreactor without the use of pumps in the second supply mechanism. In a similar alternative embodiment disclosed in Figure 3c, the mixing unit 30 is lowered relative to the supply unit 10 to allow the use of valves 21', 22', 23', 24' instead of pumps 21, 22, 23, 24 to use gravity to deliver media from the supply unit 10 to the mixing unit 30.

[0027] In the embodiment shown in FIG. 4a, the mixing system 100 is integrated with the bioreactor 50 and controlled by the bioreactor control unit 55. The components of the mixing system 100 are substantially the same as those in FIG. 3a, and the tank 34 of the mixing unit 30 is connected to the cell bag 51 of the bioreactor 50 to supply a media mixture suitable for the cell bag 51. The CBCU is also connected to multiple sensors for measuring the properties of the culture process in the cell bag 51, wherein a pH sensor 53 determines the pH value inside the cell bag. Depending on the properties of the contents of the cell bag 51, the components of the media mixture from the mixing system 100 are designed to be suitable and are prepared and mixed by the mixing system 100 for insertion into the cell bag 51, as controlled by the bioreactor control unit 55. A pump unit 54 is also provided in the bioreactor 50 for pumping nutrients into the cell bag 51 and pumping waste products from the cell bag 51, and the pump unit 54 can also be used as a second supply mechanism 60 for supplying the media mixture from the mixing unit 30 to the cell bag 51.

[0028] Figure 4b discloses another embodiment in which the mixing system 100 is a standalone unit that can be connected to the bioreactor 1 via a second supply mechanism 60 in the form of a pump unit 54. The mixing system 100 is also operatively connected to a bioreactor control unit 55, which controls both the bioreactor 50 and the mixing system 100, and thus serves as a control unit 40 for the mixing system 100.

[0029] Figure 5 An independent embodiment of Figure 4b is disclosed, and a feedback system for controlling the pH of the cell bag 51 by means of a control unit 40 is shown more clearly in that it receives pH measurements (pH-1) from the cell bag 51 itself and pH measurements (pH-2) from the container 34 of the mixing unit 30, as well as the pH values ​​of the individual media in each of the media containers 11, 12, 13, 14 (pH-3, pH-4, pH-5, and pH-6, respectively). The control unit 40 may be in the form of a microcontroller. Based on the pH values ​​measured inside the cell bag 51, the mixing unit 30, and the media containers 11, 12, 13, 14, the control unit 40 determines the appropriate amount of each media type from the media containers 11, 12, 13, 14 to be inserted into the mixing unit 30, such that the resulting media mixture inserted into the cell bag 51 can affect the pH of the contents of the cell bag 51 in a desired manner. Then, the control unit 40 controls the operation of pumps 21, 22, 23, and 24 (F1, F2, F3, and F4, respectively) to achieve the medium mixture in the mixing unit 30.

[0030] The operation of the hybrid system 100 according to the present invention will now be described in more detail below.

[0031] When a medium needs to be supplied to the bioreactor, the desired medium mixture is determined by the bioreactor control unit 55 or by the control unit 40 of the mixing system 100 itself. In some cases, the desired medium mixture may also be predetermined and given as an input to the mixing system 100 by the user (dynamic input) or by a separate unit or protocol.

[0032] The control unit 40 then determines suitable media portions of different types for forming the desired media mixture and allows these media portions to be guided from the supply unit 10 to the mixing unit 30 by operating the first supply mechanism 20 to deliver media from the respective media containers 11, 12, 13, 14 of the supply unit 10 according to the selected media portions of each type. In the mixing unit 30, the media are thoroughly mixed by means of a mixer and are also substantially heated to the desired temperature. The media mixture is then ready to be supplied to the bioreactor 50 and inserted into the cell bag 51.

[0033] Thanks to sensors 31 and 32 for measuring pH and temperature, and other possible sensors arranged in conjunction with the mixing unit 30, the condition of the media mixture can be continuously monitored by the control unit. Therefore, if the media mixture does not have the desired properties (e.g., regarding pH), the control unit 40 can control the first supply mechanism 20 to supply an additional portion of any available media type in the media containers 11, 12, 13, and 14, thereby changing the pH of the resulting media mixture. Temperature monitoring also allows control of the heater located in the mixing unit 30 to change the temperature of the media mixture as desired.

[0034] In some embodiments, input is provided to the control unit 40 via a user interface 42, and the control unit 40 performs mixing of the media portion according to predetermined parameters, thereby potentially using pH feedback from the pH sensor 31 and temperature feedback from the temperature sensor 32 to determine that the resulting media mixture has the desired properties given by the input from the user interface 42. In such embodiments, the operation of the mixing system 100 is independent of the bioreactor 50.

[0035] However, in other embodiments, the operation of the mixing system 100 may be controlled by the bioreactor 50 itself via input to the input device 41 of the control unit. In one embodiment, the mixing system 100 is a subordinate device to the bioreactor, and in another embodiment, the mixing system 100 may be integrated with the bioreactor control unit 55 of the bioreactor 50 itself.

[0036] In some embodiments, the mixing system 100 may also operate independently of the bioreactor, but receives input via input device 41, such as parameters giving the temperature, pH, and amount of the medium present in cell bag 51. These parameters are used to determine the desired medium mixture and allow control unit 40 to determine the portion of the medium of each type to be inserted into mixing unit 30. In such embodiments, feedback from mixing unit 30 (such as pH and temperature feedback) may also be used to further refine the medium mixture.

[0037] Of particular advantage is that the mixing system 100 can operate independently of the user or operator, thereby providing the desired media mixture at predetermined times and in response to the needs of the bioreactor 50. The system is also a closed system, thus preventing media contamination and providing the bioreactor with high-quality media.

[0038] In some embodiments, the mixing system 100 may operate according to a predetermined program, wherein media mixtures with specific properties are prepared at given time intervals. This may also be combined with the opportunity for a user to dynamically interrupt or modify the program by providing additional input (via user interface 42), such that the prepared media mixture corresponds to a combination of the predetermined program and newer input.

[0039] In some embodiments, monitoring and controlling the pH of the media mixture includes: detecting the current pH value of the media mixture in the mixing unit; determining a pH correction amount to achieve a desired pH value for the media mixture; and identifying a media portion corresponding to the pH correction amount and supplying that media portion to the media mixture in the mixing unit. Thus, the pH of the media mixture can be controlled and regulated by selecting a suitable media portion having a pH value that will generally affect the pH of the media mixture. The desired pH value may be determined based on pre-programmed information in the control unit 40 or based on dynamic input by the user, but it may also be based on input received from the bioreactor 50. Preferably, the temperature of the media mixture is monitored as described above, and the media mixture is heated to reach the desired temperature.

[0040] As is known in the art, the method according to the invention can be executed as a computer-implemented method and can be stored on a computer-readable storage medium. The control unit 40 and other components of the invention can form a data processing system including means for executing the method. As is also known in the art, software including instructions for performing the method steps can also be stored as a computer program product.

[0041] It should be noted that the features of the various embodiments of the invention described herein can be freely combined unless explicitly stated that such a combination is unsuitable.

Claims

1. A mixing system (100) for a bioreactor, comprising: - Multiple supply units (10), each capable of holding the medium for use in the bioreactor, - A mixing unit (30) for forming a uniform mixture of media. - A first supply mechanism (20) is arranged to supply the medium from the supply unit (10) to the mixing unit (30). - A control unit (40) operatively connected to the first supply mechanism (20) and the mixing unit (30), the control unit (40) being configured to control the first supply mechanism (20) to supply a predetermined amount of medium from the plurality of supply units (10) to the mixing unit (30), and further configured to control the mixing unit (30) to form a uniform mixture of the medium, wherein the mixing unit (30) is raised or lowered relative to the supply unit (10).

2. The hybrid system according to claim 1, wherein, The mixing system (100) is integrated with the bioreactor (50).

3. The hybrid system according to claim 1 or claim 2, wherein, The first supply mechanism (20) includes pumps (21, 22, 23, 24) for pumping media from the various pumps in the supply unit (10) to the mixing unit (30), and wherein the pumps are preferably peristaltic pumps.

4. The hybrid system according to claim 1 or claim 2, wherein, The first supply mechanism (20) includes valves for controlling the flow of media from each of the supply units (10) to the mixing unit (30).

5. The hybrid system according to any one of claims 2 to 4, wherein, The bioreactor (50) is operatively connected to the control unit (40) and is able to control the operation of the control unit (40).

6. The hybrid system according to claim 3, wherein, The peristaltic pump is controlled by at least one stepper motor.

7. The mixing system according to any of the preceding claims further includes a pH sensor (31) operatively connected to the control unit (40) and arranged to measure the pH value in the mixing unit (30), and wherein the control unit (40) further includes an input device (41) for receiving pH data from the bioreactor (50).

8. The hybrid system according to claim 7, wherein, The control unit (40) is capable of receiving pH data from the pH sensor (31) and from the input device (41), and wherein the control unit (40) is arranged to control the operation of the first supply mechanism (20) in response to the pH data.

9. The mixing system according to any of the preceding claims, further comprising a freezing mechanism (10', 10'') arranged to maintain the contents of at least one of the supply units (10) at a first predetermined temperature.

10. The hybrid system according to claim 9, wherein, The refrigeration mechanism (10', 10'') is further arranged to maintain the contents of at least one of the supply units (10) at a second predetermined temperature, different from the first predetermined temperature.

11. The mixing system according to any of the preceding claims further includes a temperature sensor (32) operatively connected to the control unit (40) and arranged to measure the temperature in the mixing unit (30), wherein the control unit (40) is also arranged to control the first supply mechanism (20) in response to input from the temperature sensor (32).

12. The mixing system according to any of the preceding claims further includes a heating mechanism (34) arranged to heat the medium in at least one of the mixing unit (30) or the supply unit.

13. The mixing system according to any of the preceding claims further includes a second supply mechanism arranged to supply media from the mixing unit (30) to the bioreactor (50), preferably for supplying to the cell bag of the bioreactor.

14. The hybrid system according to any of the preceding claims, wherein, The control unit (40) is arranged to control the hybrid system (100) in response to a predetermined program.

15. The hybrid system according to any of the preceding claims, wherein, The control unit (30) is arranged to control the hybrid system (100) in response to input from the user.

16. A method for mixing a medium used in a bioreactor, the method comprising: - Determine the desired media mixture to be supplied to the bioreactor (50). - A media portion is supplied from multiple supply units (10) to a mixing unit (30) by means of a first supply mechanism (20), the first supply mechanism (20) and the mixing unit (30) being controlled by a control unit (40), wherein the media portion is selected to form the media mixture, and - Mix the media portions to form the desired media mixture in the mixing unit (30).

17. The method for mixing media according to claim 16, further comprising: - Detect the current pH value of the media mixture in the mixing unit. - Determine the amount of pH correction used to achieve the desired pH value of the medium mixture, and - Identify the medium portion corresponding to the pH correction amount and supply the medium portion to the medium mixture in the mixing unit (30).

18. The method for mixing media according to claim 17, further comprising receiving the desired pH value as input from the bioreactor (50).

19. The method for mixing media according to any one of claims 16 to 18, further comprising monitoring the temperature of the media mixture and heating the media mixture to reach a desired temperature.

20. A data processing system comprising means for performing the method according to any one of claims 16 to 19.

21. A computer program product comprising instructions that, when executed by a computer, cause the computer to perform the method according to any one of claims 16 to 19.

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