Mixing device for particle suspension in bags

Abstract

A mixing technique and associated apparatus design that generates fluid flow within a fluid bag, reducing the accumulation of particles that may settle from a suspended state. The mixing system supports a flexible bag that holds the fluid to be mixed and engages with a paddle mechanism. The paddle mechanism is positioned so that the paddles are located near the bottom edge of the flexible bag, extending only partially across the bag and engaging with a portion of the bag. By activating the paddle mechanism to perform iterative displacement and release cycles, a recirculating flow of the fluid inside the bag is generated.

Description

Technical Field

[0001] The technical field of the present invention is to mix fluids and particles in a closed bag as a sterile process to produce a suspension. For example, this technology can be applied to mix living cells in a blood bag for transfusion for the production of biomedical products.

Background Art

[0002] Regenerative medicine and advanced cell therapy are emerging medical technologies that manipulate living human-derived cells to create constructs, induce immunogenic responses, or stimulate repair responses in patients. Some of these technologies can supply multiple doses to multiple patients from a single cell source (allogeneic products), but there is a growing recognition that it is safe and effective to process and supply cells from the patient themselves or a compatible donor. The production of specific cell products (autologous products) from patients or compatible donors usually requires small-scale batch processing.

[0003] To widely provide cell therapy to patients with regulatory approval, it is necessary not only to prove the safety and effectiveness of a specific therapy, but also to recognize that the devices and processes used in preparing cell products are safe and reliable. Product-specific closed systems have many advantages in cell product manufacturing. Such systems are designed for dedicated functions, that is, a single manufacturing process specialized for a specific cell product or a series of cell products obtained from a single manufacturing process. Such a dedicated functionally closed system is designed to provide a sterile processing environment for medical products through strict material traceability and an approved sterilization protocol.

[0004] There is often a need to mix cell suspensions. This is because cells settle unless stirred, and operations such as dispensing the final dose depend on a homogeneous cell suspension. This ensures a sufficient cell amount per dose per patient within a controlled liquid volume and guarantees consistency.

[0005] Traditionally, mixing techniques relied on humans handling bags containing cell suspensions during the "mixing procedure." Due to the non-uniformity of results from manual methods, automated mixing devices were developed. Automated mixing devices use mechanisms that shake or compress the bags to induce movement of the liquid within them.

[0006] A mixing device acts on a bag to rearrange the liquid in a systematic manner, with the aim of achieving a mixing function. Different mixing devices support the liquid in the bag in different positions and compress the liquid in different ways. Such devices can result in inconsistent mixing or insufficient liquid movement in certain areas of the bag, potentially leading to component sedimentation or separation. Non-uniformity of mixing is more likely to occur when the liquid in the bag is too much or too little compared to the optimal capacity range for the bag and mixing device combination. [Overview of the project] [Problems that the invention aims to solve]

[0007] Infusion bags for biomedical products are typically accessed through a tube port located at the bottom of the suspended bag. This allows for the draining of all the fluid inside the bag. A problem with insufficient mixing is that some particles may not remain suspended and may settle at the bottom of the bag. Settling can also occur when mixing stops (e.g., during setup or in case of malfunction). Resuspending these settled particles can be difficult. Settled particles can negatively affect the consistency of particle concentration in the fluid, at least initially, and later. Settled particles can also clog the tube port.

[0008] An alternative automated mixing device is needed. [Means for solving the problem]

[0009] According to one aspect of the present invention, a mixing system is provided, comprising: a support for a flexible bag for holding a fluid to be mixed; a paddle mechanism including at least two opposing paddles configured to engage with opposing sides of the bag supported by the support; a paddle drive mechanism; and a control system, wherein the paddle mechanism is positioned to extend only partially across the bag and engage with a portion of the bag near the bottom edge of the bag; the movement of the paddles by the operation of the paddle drive mechanism compresses the bag and displaces the fluid upward across the bag from the portion of the bag engaged by the paddles; and the control system controls the operation of the paddle drive mechanism.

[0010] In some embodiments, the control system controls the paddle drive mechanism to perform repetitive displacement and release cycles, thereby creating a recirculation flow of fluid inside the bag.

[0011] In some embodiments, a recirculating flow of fluid within the bag across the bottom of the bag acts to resuspend any settled particles.

[0012] In some embodiments, the paddle drive mechanism is configured to swing the paddle and includes paddle cycle speed control.

[0013] In some embodiments, the control system can change the paddle cycle speed through speed control.

[0014] In some embodiments, the control system varies the paddle cycle speed based on mixing requirements to perform one or more of the following: homogenization of a partially miscible fluid, generation of a homogeneous suspension, or maintenance of a suspension.

[0015] In one embodiment, if the required paddle cycle frequency is low, the control system intermittently operates the paddle drive mechanism by introducing a waiting period between each mixing cycle, so that the mixing operation is performed at a speed that supports active mixing.

[0016] In some embodiments, the mixer counter is further configured to count the paddle displacement and release cycles.

[0017] In some embodiments, the control system monitors a mixer counter and implements a mixer count trigger. This triggers a transition to the next stage of the mixing protocol based on the cycle count of the mixer counter.

[0018] In some embodiments, the paddle mechanism includes a force limiting mechanism.

[0019] In some embodiments, the control system includes a communication module.

[0020] According to another aspect of the present invention, a mixing system is provided, comprising: a support for a flexible bag for holding a fluid to be mixed; a paddle mechanism including at least one paddle configured to engage with the bag supported by the support; a paddle drive mechanism; and a control system, wherein the paddle mechanism has at least one paddle positioned on a first side of the bag and configured to extend only partially across the bag and engage with a portion of the bag near the bottom edge of the bag, and a surface positioned on the opposite side of the bag, wherein the movement of at least one paddle by the operation of the paddle drive mechanism compresses the bag and displaces fluid upward across the bag from the portion of the bag engaged by at least one paddle, and the control system controls the operation of the paddle drive mechanism.

[0021] Some embodiments further include a temperature control plate, which is positioned to be in contact with the bag for heat exchange between the plate and the contents of the bag.

[0022] Embodiments of the mixing system described above can be integrated into a sterile (or non-sterile) processing system. For example, an embodiment of the mixing system is incorporated into a housing as a processing circuit component of a sterile system. In another embodiment, it is configured to be connectable to a sterile system, and a mixing system controller receives a mixing control command from a processing system controller to enable mixing control by the processing system.

[0023] According to another aspect of the present invention, there is provided a mixing method implemented using a mixing system having a paddle mechanism disposed to extend only partially across a bag near an edge at the bottom of the bag and engage a portion of a flexible bag that holds fluid. The method includes performing an iterative displacement and release cycle that generates a recirculating flow of fluid within the bag, each displacement and release cycle including the compression of the bag, the upward displacement of the fluid across the bag from the portion of the bag engaged by the paddle mechanism, and subsequent release, characterized by the operation of the paddle mechanism.

[0024] In some embodiments, the recirculating flow of fluid within the bag across the bottom of the bag acts to resuspend any settled particles.

[0025] One embodiment of the method includes varying the speed of the displacement and release cycles based on mixing requirements to perform one or more of homogenizing a partially immiscible fluid, generating a homogeneous suspension, or maintaining a suspension.

[0026] In one embodiment of the method, when the required paddle cycle frequency is low, a waiting time is provided between each cycle to intermittently perform the displacement and release cycles, thereby causing a mixing operation at a speed that supports active mixing.

[0027] Some embodiments of the method include counting the displacement and release cycles of the paddle, monitoring a mixer count trigger, and transitioning to the next stage of the mixing protocol based on the cycle count meeting the mixer count trigger.

[0028] One embodiment encompassing all aspects of the present invention will be exemplarily described below with reference to the accompanying drawings.

Brief Description of the Drawings

[0029] [Figure 1] FIG. 1 is a representative block diagram of the system. [Figure 2A] FIG. 2A is a representative view of a system embodiment. [Figure 2B] FIG. 2B is a side view of the system of FIG. 2A, showing the paddle mechanism in an open or released state without a bag attached. [Figure 2C] FIG. 2C is a side view of the system of FIG.​​​​​​​​​​​​​​​​​​ [Figure 2J] Figure 2J is another perspective view of the system in Figure 2A, showing the paddle mechanism in the open or released state with the bag installed. [Figure 3A] Figure 3A shows an example of applying the system to bags of different sizes. [Figure 3B] Figure 3B shows an example of applying the system to bags of different sizes. [Figure 4A] Figure 4A shows the fluid flow that occurs inside the bag when the paddle transitions to a compressed state. [Figure 4B] Figure 4B shows the fluid flow that occurs inside the bag when the paddle is released. [Figure 4C] Figure 4C shows the fluid flow that cleans the bottom of the bag. [Figure 5A] Figure 5A shows bag interference by a paddle according to an embodiment of the present invention. [Figure 5B] Figure 5B shows back interference with a conventional paddle configuration for comparison. [Figure 6A] Figure 6A is a representative block diagram showing a side view and a top view of an alternative example of a mixing apparatus. [Figure 6B] Figure 6B is a representative block diagram showing a side view and a top view of an alternative example of a mixing apparatus. [Figure 6C] Figure 6C is an example of a product concept of the embodiment shown in Figures 6A and 6B, and is indicated using the same reference numerals. [Figure 7A] Figure 7A is a typical block diagram showing an example of integrating a mixed system into a processing system. [Figure 7B] Figure 7B is a typical block diagram showing an example of integrating a mixed system into a processing system. [Figure 8] Figure 8 is a flowchart showing an example of how the mixed system according to the embodiment operates. [Modes for carrying out the invention]

[0030] This specification discloses a mixing technique and related apparatus design that generates fluid flow within a fluid bag, reducing the accumulation of particles that may settle from a suspended state. Figure 1 shows a block diagram of the main components of the mixing system 100, which includes a support 110 for a flexible bag 120 that holds the fluid to be mixed, a paddle mechanism 130, a paddle drive mechanism 140, and a control system 150.

[0031] The support section 110 has a bag support structure arranged to hold a sterile processing bag 120 containing fluid and particles and to engage with a paddle mechanism. Such a processing bag 120 is a known type, typically consisting of a flexible bag with associated tubing, sterilized, and designed for single use. The support section may include hooks, pegs, clamps, or other mechanisms for suspending or supporting the bag 120 and engaging it with the paddle mechanism 130.

[0032] The support section 110 supports the paddle mechanism 130 and can be mounted in a housing that accommodates the control system 150 and the paddle drive mechanism 130. Alternatively, the bag mechanism can be freestanding and positioned adjacent to the paddle device so that the supported bag 120 engages properly with the paddle (as described later). In some embodiments, the bag support structure is adjustable to accommodate bags of different sizes.

[0033] In the illustrated embodiment, the paddle mechanism 130 is configured to engage with opposing sides of the bag 120, which is supported by the support 110. The paddle mechanism 130 is driven by the paddle drive mechanism 140 to compress the bag 120. The operation of the drive mechanism is controlled by the control system 150. When the bag 120 is properly positioned, the paddle mechanism 130 extends partway across the bottom surface of the bag, contacting only a portion of the bottom surface of the bag 120. The paddle mechanism is designed to compress and release the portion of the bag 120 that it is in contact with. For example, the reciprocating motion of paddles on both sides of the bag compresses and releases the bag between the paddles. Compression causes fluid to move laterally and upward within the bag from the portion of the bag on which the paddle mechanism acts. When the compression is released, the fluid returns to this portion of the bag. The repeated cycles of compression and release, and the resulting repeated displacement and backflow, create a circulating flow within the bag 120. This circulating flow is effective in keeping the particles suspended. Furthermore, the circulating flow has the beneficial effect of cleaning the bottom of the bag and reducing particle sedimentation. This cleaning effect can also promote the resuspending of settled particles.

[0034] Experiments demonstrated that a combination of compressing only a portion of the bag's bottom and repeating the compression and release cycle was significantly more effective than existing designs. Experiments with the applicant's prototype confirmed that the fluid flow within the bag generated by the mixing action actively cleans the lower region of the suspended bag where settled particles accumulate. These settled particles can be difficult to resuspend. In some fluids, resuspending these particles is known to be particularly difficult. The experimental prototype also confirmed that the fluid flow within the bag generated by the mixing action induces large-scale circulation from top to bottom, forming a uniformly dispersed suspension.

[0035] In the experimental prototype, it was also confirmed that the mixing operation is independent of the amount of fluid in the bag. This is because the mixing operation physically replaces only a small portion of the bag's volume, meaning that a general-purpose mixing device design can accommodate a wide range of bag sizes and fluid volumes.

[0036] Furthermore, because each compression operation on the bag replaces only a small portion of the fluid inside, the force and power required for effective mixing can be significantly reduced compared to methods that attempt to lift and then release the majority of the fluid inside the bag. This reduction in force and power for the mixing function allows for an inherently safe mixing device with built-in safety features to be available to workers without the need for a barrier guard.

[0037] An embodiment of the paddle mechanism is described with reference to Figures 2A-2J. For convenience, the same reference numerals are used when referring to the same components between different drawings. In this embodiment, the mixing device housing 155 is mounted on a single pole 280. A pair of paddles 210 that vibrate between open and closed states extend from the housing 155. A bag 120 containing the fluid and particles to be mixed is suspended from a support consisting of an arm 285 and a hook 290, so that the bottom of the bag is positioned near the bottom of the closed paddle 210. In some embodiments, the height of the arm 285 and hook 290 can be adjusted to accommodate bags of different sizes. Figures 3A and 3B show examples of the mixing system 200 in use with bags 120, 320 of different sizes. As is clear from Figure 3B, the system is adjustable in the relative position of the arm 285 to the housing 155, thereby accommodating longer bags 320. In some embodiments, this adjustment is made by raising the arm 285 relative to the housing 155. In another embodiment, the position of the arm 285 relative to the paddle 210 can be adjusted by fixing the support and allowing the housing 155 to be repositioned on the pole 280. In some embodiments, the position of the bottom of the bag relative to the paddle can be set using a height-adjustable bag suspension hook.

[0038] The paddle mechanism consists of two paddles 210 positioned on either side of the bag 120 when it is properly positioned. In this embodiment, the paddles are substantially rectangular, but square, elliptical, or other shapes are also available, configured to engage with the portion near the bottom edge of the bag and one of its sides. Each paddle has two lower arms 220 and two upper arms 225 for connecting the paddle to two shafts 235 (upper and lower shafts), and these arms 220, 225 are mounted to allow relative rotation between the shafts 235 and the paddles. The shafts 235 are connected to a crank 230, which is driven by a motor (not shown) of the paddle drive mechanism 140. The motor is housed within a housing. The crank is operably connected to the motor and driven by a oscillating motion. Figure 2B shows the initial or stationary position of the paddles. The motor's operation drives the crank 230, which rotates partially in the direction shown in Figure 2B to the position shown in Figure 2C. This causes the paddle 210, supported by arms 220 and 225, to move in the direction shown in Figure 2B, reaching the compressed position shown in Figure 2C. Upon release, the paddle 210 and other components return to the stationary position shown in Figure 2B. This action has the effect of compressing a portion of the bag 120 between the paddles, as shown in Figures 2D-2J. Figures 2E, 2I, and 2J show the bag and paddles in the stationary position from different viewpoints, and Figures 2F-2H show the bag and paddles in the compressed position. Figure 2E is a cross-sectional view of the apparatus 200 and bag 120 along line AA in Figure 2D. As is evident from these figures, the paddles contact the lower quarter of the bag, and the bag is compressed (i.e., squeezed) between the paddles, causing the fluid inside the bag to be expelled from the area between the paddles.

[0039] The motor of the paddle drive mechanism can be operated by the control system to repeatedly move between a rest position and a compression position according to a mixed protocol. The reciprocating motion of the paddle can be controlled to be one or more of the following: periodic oscillating motion, variable motion, or pulsed motion with pauses between paddle movements.

[0040] Each crank 230 has a shaft extending into the housing to engage with a gear system connected to a drive motor for driving. In some embodiments, the gear system is configured to convert the rotational motion of the motor into the oscillating motion of the crank. In other embodiments, the motor can be driven in forward and reverse directions to drive the oscillating motion of the crank, which can then be converted into the oscillating motion of the paddle 210. In one embodiment, the motor is driven intermittently to cause rotational motion to a compressed or displaced position (see Figure 2C), and to relax back to the initial or released position (see Figure 2B) when there is no motor driving force. In other alternative embodiments, the motor is driven in forward and reverse directions to drive the reciprocating motion of the paddle.

[0041] Figures 4A–4C illustrate the fluid movement within the bag caused by the paddle's moving mixing action. Figure 4A highlights the fluid flow within the bag 120 as it moves away from the area compressed by the closing paddle 210. During the compression phase of the paddle cycle, the fluid at the bottom of the bag moves outward 410 along the bottom of the bag and is pushed upward by the sides of the bag, and the fluid also flows upward 415 away from between the paddles 210. Figure 4B highlights the fluid flow within the bag when the paddles are open. As the paddles 210 return to their initial positions, the fluid flows downward 420 along the bottom of the bag and into the space created by the retracting paddles. It also flows downward 425 to refill the space between the paddles 210. The different flow paths resulting from the paddles 210 only partially covering the bottom surface of the bag 120 can create turbulence within the fluid, which is beneficial for mixing. The repeated action of the paddles can also create a recirculating flow of the fluid.

[0042] Figure 4C shows how the fluid flow washes (detaches) particles from the bottom of the bag because the bottom of the bag is partially covered. Because the bottom of the bag is only partially covered, some of the fluid returning to the space between the paddles flows along the bottom of the bag. This reduces particle settling (also called sedimentation) at the bottom of the bag. The movement of fluid along the bottom of the bag also has the effect of agitating settled particles (which occur during storage, setup, processing interruptions, etc.) and resuspending them through the mixing process. In addition, the different directions of fluid flow create turbulence in the bag, which has the advantage of contributing to mixing efficiency and maintaining the suspension of particles.

[0043] The control system 150 controls the paddle drive mechanism to perform iterative displacement and release cycles, thereby generating a recirculating flow of fluid within the bag. The control system includes a processor and memory configured to control the paddle drive mechanism. For example, the processor may be a microprocessor, programmable hardware (such as a programmable logic controller (PLC) or field-programmable gate array (FPGA)). The memory may include volatile and non-volatile memory. For example, solid memory within the processor circuitry, or a conventional processor and memory board may be used.

[0044] The control system is programmable to issue commands to operate the paddle drive mechanism for executing one or more mixing protocols. Each mixing protocol may define a series of mixing stages, for example, by defining the time intervals and frequency of paddle operations in each stage, or by specifying the number of operations to be performed and the pause time between each operation. For example, mixing protocols executable in this system are designed to homogenize partially miscible fluids, create a homogeneous suspension, or maintain a suspension. As an example, a homogenization state can be used as an initial stage, performing high-speed continuous mixing cycles with a controlled number of cycles (one cycle being compression and release of the bag by the paddle) to mix particles in the suspension medium and form a homogeneous suspension. Following the homogenization state, a maintenance state is used, employing relatively slow or pulsed mixing cycles to maintain the particles in suspension. For example, the homogenization state may use a cycle rate of one or more cycles per second, while the maintenance state may use pulsed cycles with one-second mixing cycles occurring every 3-5 seconds. In the maintenance state, it is also possible to use a slower continuous cycle rate, for example, one cycle every 2 seconds. The cycle rate in various mixing states, or the choice between pulsed and continuous modes, differs between embodiments based on the variable values ​​of the mixing parameters. Mixing parameters include measurements of any physical properties that may affect mixing, such as volume, particle size, particle density, carrier fluid viscosity, and temperature. Some chemical properties may also be considered. It should be noted that mixing protocols vary significantly depending on the mixing parameters and the purpose of mixing. For example, forming a homogeneous mixture may require different mixing requirements (i.e., higher cycle frequency and longer duration) than simply maintaining the particles in suspension (i.e., preventing particle sedimentation).

[0045] In some embodiments, the paddle drive mechanism is configured to oscillate the paddle. This oscillation is a reciprocating motion of the paddle between a compressed and uncompressed state, causing the paddle to move at a constant speed at a specific cycle frequency. The paddle drive mechanism may include one or more of the following: paddle speed control, paddle cycle speed control (frequency control), or variable speed control. Embodiments allow a controller to control the system to change the paddle cycle speed. In some embodiments, the control system changes the paddle cycle speed based on mixing requirements and executes one or more mixing protocols.

[0046] In some embodiments where the required paddle cycle frequency is low, the control system intermittently operates the paddle drive mechanism with a waiting period between each mixing cycle. This ensures that the mixing operation occurs at a speed that supports active mixing.

[0047] In some embodiments, the controller includes a mixer counter configured to count the displacement and release cycles of the paddles. Such embodiments may also implement counter triggers that can trigger actions based on the cycle count. For example, a stage in the mixing protocol may specify the number of mixing (compression and release) cycles, and the completion of this specified number of mixing cycles triggers a change in the system's operation. As an example, the control system monitors the mixer counter, and the transition to the next stage of the mixing protocol is triggered based on the cycle count of the mixer counter.

[0048] The mixer count trigger can also be used to trigger operations outside of another system or the mixing system. For example, it can be used to start or stop a processing phase in a connected system, trigger input from another system, or initiate fluid output from a bag. In such embodiments, the mixer count trigger can send a signal to the other system, and the connected system operates in response to the trigger signal. In another embodiment, the control system of the mixing system is integrated with the control system of the connected processing system, and the mixer count trigger is used to directly influence the processing protocol. As an example, a dispensing system connected in series with the mixing system and dependent on the precise mixing of products is paused by the control system while the paddle mixing system completes a predetermined number of mixing cycles. Once the predetermined number of mixing cycles is complete, the mixer count trigger sends a signal to the dispensing system to proceed.

[0049] In some embodiments, the controller includes a communication module that can receive commands from other devices or systems to control mixed operation via the communication module. The communication module can use wired or wireless data transfer technology in various embodiments. In one embodiment, conventional transceiver hardware, software, and protocols can be used. Alternatively, embodiments compatible with proprietary communication protocols can be developed. The communication system can be used to integrate the mixed system with a processing system that utilizes mixed operation at some stage of processing, enabling integrated process control. The communication system can also be used to download or upload data logs in a controller programmed to record data during processing.

[0050] In the embodiment shown in Figures 2A-2H, the paddle mechanism configuration and the crank-shaft drive system cause the paddle to swing upward. This motion pushes the bag slightly up to the hook rather than pulling it down during compression. However, other embodiments are also applicable to this disclosure. For example, the paddle mechanism may be configured to perform only horizontal reciprocating or oscillating motion.

[0051] One embodiment may include only a single paddle that acts on one side of the bag to compress the bag against a fixed surface. For example, a single paddle may be mounted in the housing, with a fixed plate (rather than another paddle) on the opposite side, providing a gap between the plate and the paddle to receive the bag when the paddle is resting or uncompressed. Such a mechanism may utilize a paddle and paddle drive mechanism similar to that shown in Figure 2A, but one paddle may be replaced with a fixed plate, and the drive mechanism may be modified to increase the horizontal linear travel distance of the paddle, compensating for having only one paddle.

[0052] Alternatively, in an embodiment with only one movable paddle, the paddle may be mounted parallel to the housing, with a fixed plate mounted on the opposite side. The fixed plate is connected only along the vertical edge of the housing, at a distance that ensures a clearance between the fixed plate and the paddle to receive a bag in the resting position. In this embodiment, the paddle drive mechanism may be configured to achieve direct horizontal linear motion of the plate, for example, using a piston mechanism or other linear actuator. This moves the paddle away from the housing and toward the fixed plate during the compression phase of the cycle, and returns it toward the housing during the release phase.

[0053] In the embodiment shown in Figure 2A, the paddle mechanism extends perpendicular to the housing. However, this relative orientation is not mandatory, and other orientations are possible. For example, the paddle mechanism may be configured to extend parallel to the housing. Different orientations may require modifications to the paddle mechanism and drive unit from the examples disclosed herein.

[0054] An example of an alternative embodiment is shown in the representative block diagrams of Figures 6A and 6B. These represent side and top views of an alternative arrangement of the mixing apparatus 600. An example of this configuration being implemented in a commercial embodiment is shown in Figure 6C. This embodiment of the mixing apparatus 600 includes a fixing plate 630 that supports a fluid bag 620 at an inclined angle. The fixing plate is inclined at a sufficient angle to the horizontal plane so that the bag is held in a supported position on the plate, while gravity causes the liquid to flow to the bottom of the bag 620. This angle also allows for the discharge of the fluid through one or more tubes 625 at the bottom of the bag 620. In another embodiment, the bag can also be supported upright relative to a vertical plane. A paddle 610 is positioned to cover a portion of the bottom surface of the bag 620 and is driven toward the fixing plate by a paddle drive mechanism. This compresses the bottom surface of the bag, pushing the liquid upward and outward from beneath the paddle. When the paddle is released, the liquid returns to this portion. This repeated compression and release creates a circulating flow inside the bag, as mentioned earlier.

[0055] In some embodiments, the plate 630 is temperature-controllable to facilitate temperature control of the liquid in the bag. For example, the temperature control is for cooling or heating the contents of the bag 620. In some embodiments, the plate may have a temperature-controlled region 660. For example, this is a region in which a heating coil or heat exchange fluid path is embedded in or held by the fixed plate. Any suitable temperature control mechanism can be used to control the temperature of the plate in order to regulate the temperature of the contents of the bag by heat exchange between the plate and the bag. For example, to maintain the liquid in the bag within a target temperature range during mixing.

[0056] In one embodiment, a pressure plate 640 is provided to press most of the liquid in the bag 620 against a temperature control plate 630. In the example shown in Figure 6A, the pressure plate 640 is positioned above the bag 620, which is attached to a fixing plate (or housing 630) by a clamp 645. This arrangement is set at a predetermined distance from the plate 630 to apply a slight compressive force to the bag, preventing liquid from accumulating at the bottom of the bag due to gravity, while allowing the liquid to move due to the operation of the paddle 610.

[0057] By using this pressure plate, temperature control characteristics can be improved by reducing liquid accumulation at the bottom of the bag and increasing the surface area of ​​the plate covered by the liquid. Additionally, the pressure plate may also provide thermal insulation against ambient temperature.

[0058] The pressure plate 640 may have a notch in the paddle area to accommodate the paddle. Alternatively, embodiments may be provided in which the paddle operates from below the pressure plate. The pressure plate may have a thin-walled area near the paddle to reduce the risk of interference with the paddle. In another embodiment, the paddle operates from below the bag and is configured to press the bag against the pressure plate. Embodiments also exist in which the pressure plate is held at a predetermined distance from a fixed plate (e.g., using clamps, clips or other fasteners). In the embodiment shown in Figure 6A, the pressure plate 640 is supported by an arm (not shown) attached to a clip 645.

[0059] The arm is adjustable, allowing the plate to compensate for the volume within the bag 620. In this embodiment, the mixer paddle 610 acts through the clearance gap of the pressure plate 640.

[0060] In another embodiment, the pressure plate may be supported in a manner that allows for limited movement, for example, by using an elastic or elastic spring mount. Such embodiments are useful when mixing is performed simultaneously with the discharge of liquid from or filling of the bag, and the volume inside the bag may change significantly during mixing. Similarly, this embodiment is also advantageous in applications where the contents of a frozen liquid need to be thawed from a frozen state, because the shape of the bag may change as the liquid inside the bag thaws. Mixing during thawing can improve thawing efficiency. Furthermore, since the components of a mixture thaw at different rates and tend to separate during thawing, mixing can recombine the separated components to reform the original mixture composition.

[0061] In the example block diagram in Figure 6A, the fixed plate 630 is supported by a housing 630, which may also house a controller with a paddle drive mechanism 650 and a user interface 660. However, this is not mandatory. For example, the fixed plate may be mounted on a stand, and the angle of the plate may be adjustable.

[0062] In the embodiment shown in Figure 6C, the paddle drive mechanism 650 is a piston-type drive mechanism. The paddle moves linearly toward the fixed plate 630 and also moves linearly away from the fixed plate 630 to perform mixing.

[0063] To avoid the safety protection limitations of the mixing system, the exposed mixing paddle must meet the Australian standard, UL61010-1, Section 7.3.4, "Limitations of force and pressure," so as not to pose a danger to the operator. The main advantage of the embodiments of the present invention is that, compared to the prior art known as of the relevant priority date, the volume change due to the mixing operation is small, thus reducing the force required to mix the products in the bag.

[0064] Embodiments of paddle drive mechanisms may include force limiting mechanisms for operator safety. For example, incorporating a pre-pressurized force limiting device into the paddle drive mechanism can protect the operator from injury if their fingers become trapped between the paddles. For example, a force limiting device controlled by a mechanical spring or gas spring may provide this primary safety function.

[0065] The force limiting mechanism is designed to suppress further movement of the paddle when a predetermined threshold force is applied to it.

[0066] In some embodiments, the control system may be configured to reverse the paddle's movement if the paddle force exceeds a threshold. In addition to primary safety systems, the electronic control system may be configured to detect such events and respond to minimize user risk. For example, one or more pressure sensors within the paddle or support surface can be used to monitor the applied force and detect when the threshold is exceeded. Alternatively, a method for monitoring the drive motor's fault condition can be used. For example, fluctuations in load torque can be used as an indicator of paddle force, with fluctuations outside the predicted range being considered as suggesting interference with paddle movement by an obstacle. The drive motor's power consumption, operation, or operating resistance can also be monitored and used as an indicator of paddle fault condition or as an indicator to trigger a safe shutdown of the motor.

[0067] If the configuration of the paddle drive mechanism is different, the force limiting device may also be different.

[0068] As mentioned above, the system of this disclosure can be used with liquid bags of different sizes. The relative size of the paddle and the bag is not important as long as the paddle mechanism only partially covers the width of the bag.

[0069] Figures 5A and 5B illustrate the difference in bag and fluid displacement between the present invention (Figure 5A) and an example showing bag covering with paddles equivalent to existing bag mixer technology (Figure 5B). As is evident from the example in Figure 5B, current known compression-type mixing devices with paddles extending across the entire width of the bag require the entire contents of the bag to be lifted (displaced upward), and this displacement can reach about one-third of the bag height. This limits the amount of liquid that can be contained in the bag and requires considerable force and power for active mixing.

[0070] In contrast, the mixing device of the present invention (Figure 5A) only requires lifting about 25% of the liquid in each cycle. This offers the advantage of dramatically reducing the force and power required for mixing compared to conventional mixing systems for equivalent bag size and liquid volume. It also offers the advantage of relaxing constraints regarding the bag filling level.

[0071] A further advantage of the embodiments of the present invention is that, since the bottom of the bag is only partially covered, the bag can be positioned so that at least one discharge line located at the bottom of the bag is not blocked even when the paddle is closed. This allows fluid to be drawn from the bag even during the mixing process. For example, it is possible to maintain a homogeneous suspension during a drug administration operation.

[0072] As described above, embodiments of the mixing system may be used in conjunction with or integrated into a processing system. Figures 7A and 7B are block diagrams showing several examples of integrating the mixing system into a processing system. In the example of Figure 7A, the mixing system is integrated into the same housing or cabinet as the processing system 710. In this example, the housing of the processing system 710 is configured to support one or more input fluid bags 740 and mixed fluid bags 760 that engage with one or more paddles 770 driven by a motor-driven system (not shown) within the housing under the control of a controller (not shown) of the processing system 710. The processing system flow path 720 connects the input fluid bags 740, the mixed fluid bags 760, and one or more output flow paths 750 to form a processed fluid circuit. Within this circuit, fluid can be moved by the operation of a pump 730 (e.g., a peristaltic pump) under the control of the system controller. The system controller can also control valves (e.g., pinch valves) in the fluid processing system flow path to adjust the flow rate of fluid flowing through the system. The output flow path 750 is connected to a container or bag for collecting the output product, or to another independent processing system. In this embodiment, the processing system controller is configured to control all components of the processing system (including the paddle drive motor of the mixing system) and to execute one or more processing processes or protocols. Note that the processing system is a sterile processing system and enables fully autonomous execution of the processing processes.

[0073] In the example shown in Figure 7B, the mixing system 780 is separate from the processing system 710' and is configured, for example, to be installed near the processing system cabinet, so that the mixing system 780 can support the mixed fluid bag 760 connected to the processing circuit of the processing system. This embodiment is suitable for processing systems capable of performing various processing processes. It is useful when not all of these processing processes require mixing, or when mixing is an optional step in the processing. The mixing system 780 is installed on a bench or stand adjacent to the cabinet of the processing system 710'. In some embodiments, the stand for the mixing system is physically attached to or can be attached to the processing system cabinet. Any suitable arrangement in which the mixed fluid bag 760 connected to the processing circuit is made operable by the mixing system 780 is envisioned within the scope of the present invention.

[0074] The controller 790 of the mixing system 780 is independent of the controller of the processing system 710'. In some embodiments, the mixing system may be manually started or controlled by a human operator, suitable, for example, for processes requiring constant mixing. In some embodiments, the operator can set a timer or mixing program and execute a mixing process controlled independently by the mixing system, while coordinating the processing system's processes and timing. In another embodiment, the controller 790 of the mixing system is configured to receive commands from the controller of the processing system and control the mixing process. For example, the controller of the mixing system may be provided with a data communication module that connects to the processing system controller via a wired (e.g., data cable, USB, Ethernet, optical fiber) or wireless (e.g., WiFi, infrared, Bluetooth) data connection. The controller of the mixing system can receive "start" and "stop" trigger signals for pre-programmed automatic mixing operations or mixing sequences. Alternatively, a controller of an external system may provide signals to control the mixing process, such as signals to control paddle oscillation speed, pulse control, speed change, or temperature control (in embodiments where the mixing system includes such functions) during the execution of the processing process.

[0075] It should be noted that the circuit, consisting of fluid bags 740, 760 and a processing system channel 720 for a sterile process, is typically provided as a kit configured for the process and processing system, providing a pre-connected and closed sterile environment for the fluid processing circuit. The kit may also include an output container. Therefore, the kit can be configured to include a fluid mixing bag channel of sufficient length to accommodate a mixing system 780 located near the processing system 710'. For example, the mixing system 780 may be located on a bench or stand adjacent to the cabinet of the processing system 710'. In some embodiments, a stand for the mixing system is physically mounted or mountable to the cabinet of the processing system. A processing fluid circuit is provided that allows the mixing bag to be connected to the channel of the fluid processing system, and the fluid moves within the system by the operation of a system pump 730. All such kits are included within the scope of this disclosure.

[0076] It should be noted that the mixing systems described herein can be used in combination with various different processing systems or as standalone mixing operations. Examples of processing systems that can be integrated with or used in conjunction with the disclosed mixing systems are described in the applicant's own prior patent application publications WO2018 / 204992, WO2019 / 140491, and WO2023 / 272360.

[0077] Figure 8 is a flowchart illustrating an example of a mixing process that can be carried out using the mixing system described herein. In the setup phase (810), a flexible mixing bag connected to the fluid circuit is mounted on a support of the mixing system. This support is positioned to engage with the paddle mechanism. The bag is positioned so as to partially extend across the bag and engage with a portion of the bag, near the bottom of the flexible bag in which the paddle holds the fluid. If the fluid bag does not already hold fluid, fluid may be pumped into the bag (820). Repeated cycles of displacement 830 and release 840 are performed to generate a recirculating flow of fluid within the bag. Each displacement and release cycle involves activating the paddle mechanism to compress the bag (830), thereby moving the fluid from the portion of the bag in contact with the paddle mechanism across the bag and upward. Then, by releasing the compression (840), the fluid flows back into the previously compressed portion of the fluid bag. Repeating these cycles creates a recirculating flow of fluid within the bag across the entire bottom surface of the bag, which serves to resuspend settled particles.

[0078] The processing of the mixing system may include counting displacement and release cycles. Once the count is reached, the mixing process terminates or proceeds to the next processing step 850 (e.g., changing the mixing rate or pulse operation). The mixing process includes counting the paddle displacement and release cycles, monitoring the mixer count trigger, and proceeding to the next stage of the mixing protocol based on whether the cycle count satisfies the mixer count trigger.

[0079] The mixing process involves varying the displacement and release cycle rates based on mixing requirements. For example, different rates may be required for homogenizing partially miscible fluids, creating a homogeneous suspension, or maintaining a suspension. If the required paddle cycle frequency is low, the mixing process can be configured to perform displacement and release cycles intermittently with waiting periods between each cycle, so that the mixing action occurs at a rate that supports active mixing.

[0080] Those skilled in the art will understand that many modifications are possible without departing from the spirit and aspects of the present invention.

[0081] Where prior art documents are referenced in this specification, it should be understood that such references do not constitute an admission that such documents constitute part of the publicly known art in Australia or any other country.

[0082] In the following claims and description of the prior art, unless otherwise required by the contextual language or implicit meaning, the words “comprise,” “comprises,” and “comprising” are used in a comprehensive sense; that is, they identify the presence of the described features but do not preclude the presence or addition of further features in various embodiments of the invention. [Prior art documents] [Patent Documents]

[0083] [Patent Document 1] International Publication No. WO2018 / 204992 [Patent Document 2] International Publication No. WO2019 / 140491 [Patent Document 3] International Publication No. WO2023 / 272360

Claims

1. A support for a flexible bag that holds the fluid for mixing, A paddle mechanism including at least two opposing paddles configured to engage with opposing sides of the bag supported by the support portion, Paddle drive mechanism, Control system and Equipped with, The paddle mechanism is positioned to extend across the bag only partially at the edge of the bottom of the bag and engage with a portion of the bag, and the movement of the paddle drive mechanism causes the paddle to compress the bag and displace the fluid upward across the bag from the portion of the bag engaged by the paddle. The mixing system is characterized in that the control system controls the operation of the paddle drive mechanism.

2. The mixing system according to claim 1, characterized in that the control system controls the paddle drive mechanism to perform repetitive displacement and release cycles, thereby generating a recirculating flow of fluid within the bag.

3. The mixing system according to claim 2, characterized in that the recirculation flow of the fluid inside the bag, which crosses the bottom of the bag, acts to resuspend any settled particles.

4. The mixing system according to any one of claims 1 to 3, characterized in that the paddle drive mechanism is configured to swing the paddle, and the paddle drive mechanism includes paddle cycle speed control.

5. The mixing system according to claim 4, characterized in that the control system can change the paddle cycle speed by the speed control.

6. The control system changes the paddle cycle speed based on the mixing requirements. Homogenization of fluids that are difficult to mix in parts, Formation of a homogeneous suspension, or Maintaining the suspension The mixed system according to claim 5, characterized in that it performs one or more of the following:

7. The mixing system according to claim 5 or 6, characterized in that, when the required paddle cycle frequency is low, the control system intermittently operates the paddle drive mechanism by providing a waiting time between each mixing cycle so that the mixing operation is performed at a speed that supports active mixing.

8. The mixing system according to any one of claims 1 to 7, further comprising a mixer counter configured to count the displacement and release cycles of the paddle.

9. The mixing system according to claim 8, characterized in that the control system monitors the mixer counter and implements a mixer counter trigger, thereby triggering a transition to the next stage of the mixing protocol based on the cycle count of the mixer counter.

10. The mixing system according to any one of claims 1 to 9, characterized in that the paddle mechanism includes a force limiting mechanism.

11. The mixed system according to any one of claims 1 to 9, characterized in that the control system includes a communication module.

12. A support for a flexible bag that holds the fluid for mixing, A paddle mechanism including at least one paddle configured to engage with the bag supported by the support portion, Paddle drive mechanism, Control system and Equipped with, The paddle mechanism has at least one paddle positioned on the first side of the bag and configured to extend only partially across the bag and engage with a portion of the bag near the bottom edge of the bag, and a surface positioned on the opposite side of the bag, wherein the movement of the at least one paddle by the operation of the paddle drive mechanism compresses the bag and displaces the fluid upward across the bag from the portion of the bag engaged by the at least one paddle. The mixing system is characterized in that the control system controls the operation of the paddle drive mechanism.

13. The mixing system according to claim 12, further comprising a temperature control plate, the temperature control plate being positioned in contact with the bag to exchange heat between the plate and the contents of the bag.

14. A mixing method carried out using a mixing system having a paddle mechanism positioned to extend only partially across the bag near the bottom edge of the bag and engage with a flexible part of the bag that holds the fluid, the method being: The process includes performing iterative displacement and release cycles to generate a recirculating fluid flow within the bag, A mixing method characterized in that each displacement and release cycle includes the operation of the paddle mechanism causing compression of the bag, displacement of the fluid upward across the bag from the portion of the bag engaged by the paddle mechanism, and subsequent release.

15. The mixing method according to claim 14, characterized in that the recirculation flow of the fluid inside the bag, which crosses the bottom of the bag, acts to resuspend any settled particles.

16. The process includes changing the displacement and release cycle rates based on mixing requirements, Homogenizing fluids that are partially difficult to mix, To produce a homogeneous suspension, or Maintain the suspension. The mixing method according to claim 15, which involves performing one or more of the following.

17. The mixing method according to any one of claims 14 to 16, characterized in that, when the required paddle cycle frequency is low, a waiting time is provided between each cycle to intermittently perform displacement and release cycles, so that the mixing operation occurs at a rate that supports active mixing.

18. A mixing method according to any one of claims 14 to 17, comprising the steps of counting the displacement and release cycles of the paddle, monitoring a mixer count trigger, and moving to the next stage of the mixing protocol based on the cycle count satisfying the mixer count trigger.

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