An online dynamic continuous flow mixer with detection feedback function

Abstract

This invention discloses an online dynamic continuous flow mixer with detection feedback function, relating to the biopharmaceutical field. It includes a distributor at the bottom, a mixer positioned above the distributor, and a motor fixed above the mixer. The distributor housing has two liquid inlets, which are connected to two internal guide pipes via distributor pipes. The mixer includes a cylindrical housing and an internal threaded rod, with a cavity between the internal threaded rod and the cylindrical housing for solution flow and mixing. A solution outlet is located at the top of the cylindrical housing. Multiple solution parameter sensors measure the results to adjust the solution flow direction and reflux, ensuring uniform solution mixing. A PID controller controls the motor and pump to keep the solution pressure and flow rate within a preset range. This invention solves the problems of existing mixers, such as large size, high leakage risk, complex operation, high shear force, and inability to accurately control the mixing degree and rate.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceuticals, and more specifically, to an online dynamic continuous flow mixer with detection feedback function. Background Technology

[0002] In biopharmaceutical manufacturing, solution preparation typically involves adding various types and concentrations of solutions (including biopharmaceutical intermediates, buffer solutions, and high-concentration solutions produced in the previous process step) into a disposable 3D stirring bag or stainless steel container for mixing. Once the mixing reaches a fixed standard (e.g., time, stirring speed, pH value, concentration, conductivity, etc.), stirring is stopped, and the process proceeds to the next step.

[0003] Reactions used for solution preparation typically require volumes ranging from tens to hundreds of liters. This method occupies a large area, has a long reaction time, and is complex and cumbersome to operate. Furthermore, due to the large volume of solution, high requirements are placed on rotational speed and system pressure resistance. The shear force generated by the agitator can adversely affect biopharmaceutical products, such as increasing the risk of protein aggregation and inactivation. Large agitators are also more prone to leakage risks. Moreover, after the reaction, a large amount of plastic waste (such as disposable mixing bags and pipes) or cleaning work (such as online cleaning and sterilization of stainless steel containers) needs to be handled, requiring significant energy consumption and generating substantial amounts of chemical waste.

[0004] Disposable mixing bag systems typically include 3D disposable mixing bags, protective cases, and control software. These systems are expensive, have complex operating procedures, and are prone to human error. Furthermore, the large contact area and long contact time between the mixing bag and the biopharmaceutical process solution increase the risk of leachates / extracts affecting the biopharmaceutical product.

[0005] In addition, it is difficult to achieve intelligent and precise control of parameters such as solution homogeneity, pressure, and output flow rate in the current biopharmaceutical production process. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide an online dynamic continuous stream mixer with detection feedback function to solve the problems mentioned in the background art.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] An online dynamic continuous flow mixer with detection feedback function includes a splitter located at the bottom, a mixer disposed above the splitter and communicating with the splitter, and a motor fixed above the mixer;

[0009] The distributor is a container structure with an open top. The distributor has two internal guide pipes, one of which surrounds the other. Multiple diversion holes are opened on the sides of both internal guide pipes. The distributor shell has two liquid inlets, which are connected to the two internal guide pipes through the distributor pipes.

[0010] The mixer is a cylindrical shell with an internal threaded rod inside. A cavity for solution flow and mixing is provided between the internal threaded rod and the cylindrical shell. A solution outlet is provided at the top of the cylindrical shell.

[0011] The drive shaft of the motor passes downward through the top surface of the mixer and connects to the internal threaded rod to drive the internal threaded rod to rotate;

[0012] The solution outlet is connected to one end of the reflux pipe and the outlet pipe via a three-way valve;

[0013] The two liquid inlets are connected to two ports of the five-way valve, and the other three ports of the five-way valve are respectively connected to the other end of the two inlet pipes and the return pipe;

[0014] Multiple solution parameter sensors are evenly arranged around the inner wall of the top of the mixer; the solution parameter sensors measure the solution parameters at the corresponding positions in real time.

[0015] If the difference between the maximum and minimum values ​​of solution parameters measured at multiple locations simultaneously is less than a preset threshold, then:

[0016] The solution outlet is connected to the output pipe by controlling the three-way valve, and the connection between the return pipe and the solution outlet is cut off by controlling the five-way valve; the two liquid inlets are connected to the two input pipes by controlling the five-way valve, and the connection between the liquid inlets and the return pipe is cut off.

[0017] If the difference between the maximum and minimum values ​​of solution parameters measured at multiple locations simultaneously exceeds a preset threshold, then:

[0018] The solution outlet is connected to the return pipe by controlling the three-way valve, and the connection between the output pipe and the solution outlet is cut off by controlling the five-way valve; the return pipe is connected to the liquid inlet by controlling the five-way valve, and the connection between the two input pipes and the liquid inlet is cut off.

[0019] A pump for providing power to the solution is installed at the input pipe. A first PID controller is installed at the pump. The first PID controller is connected to a pressure sensor inside the mixer for measuring the pressure at one point or the average pressure at multiple points in the solution. The first PID controller controls the rotational speed of the pump so that the pressure at one point or the average pressure at multiple points measured by the pressure sensor is within a preset range.

[0020] The pump is also equipped with a second PID controller, which is connected to flow rate sensors installed at the two input pipes for measuring the solution flow rate. The second PID controller controls the pump speed so that the solution flow rate and ratio measured by the two flow rate sensors are within a preset range.

[0021] In some embodiments, the online dynamic continuous flow mixer further includes a controller connected to the solution parameter sensor, the three-way valve, and the five-way valve.

[0022] In some embodiments, the three-way valve and the five-way valve are electric three-way valves, pneumatic three-way valves, or hydraulic three-way valves; the controller is a PLC controller, a microcontroller, or an industrial PC.

[0023] In some embodiments, the probe of the solution parameter sensor extends horizontally into the interior of the mixer after passing through the top sidewall of the mixer.

[0024] In some embodiments, the probes of the plurality of solution parameter sensors extend vertically downward into the interior of the mixer after passing through the top surface of the mixer around the edge of the top surface of the mixer.

[0025] In some embodiments, the solution parameter sensor is any one or more of the following: pH sensor, concentration sensor, conductivity sensor, osmotic pressure sensor; the pH sensor is a glass electrode pH sensor or an ion-sensitive field-effect transistor sensor.

[0026] In some embodiments, both internal flow channels are annular, with one annular internal flow channel surrounding the other. The central axes of both annular internal flow channels coincide with the central axis of the mixer.

[0027] In some embodiments, the diversion holes are disposed on the sidewalls of the internal guide pipes and are evenly distributed around the central axis.

[0028] In some embodiments, the outer wall of the internally threaded rod includes two discontinuous upper and lower threads with different inclination angles.

[0029] In some embodiments, the mixer has a top opening at its center, the drive shaft of the motor passes downward through the top opening, and a seal is provided between the inner wall of the top surface and the drive shaft of the motor.

[0030] Furthermore, the size of the online dynamic continuous flow mixer can be adjusted according to production needs, and its volume can be adjusted by adjusting the diameter and height of the equipment. Compared with existing large mixers, it is small in size and occupies a very small area.

[0031] The advantages of this invention compared to existing technologies lie in the fact that, since the speeds of both the pump and motor are adjustable, the feed rate and the rotation speed of the internal threaded rod can be adjusted by controlling the pump and motor speeds, thereby regulating the liquid inlet speed and the rate of liquid mixing and transfer. Furthermore, by adjusting the input volumes of the two solutions, the online dynamic continuous flow mixer can precisely control the proportions of different components, which is crucial for production processes requiring specific ratios of mixtures (e.g., the mixing of antibody and drug linker solutions in antibody-drug conjugate (ADC) production, or the mixing of antibody linkers and small molecule drug solutions). Therefore, this invention employs an internal rotation combined with a diversion mechanism, enabling the thorough mixing of key process solutions of different components in a short time, resulting in higher mixing efficiency compared to existing large-scale mixers.

[0032] Because this invention allows for the simultaneous transfer of the production solution during the mixing process—meaning the solution can be rapidly and continuously transferred to the next process step after mixing—the actual amount of solution mixed is not limited by the mixer volume. This allows the invention to be manufactured in a smaller volume and with a smaller footprint than existing mixers, thus saving production and material costs. Furthermore, its small size reduces the contact area with the process solution, minimizing the risk of leachates / leaching affecting the product. It also reduces the use of expensive stainless steel containers, disposable bags, and equipment, as well as the resulting process waste and chemical waste, making it a more environmentally friendly method. Due to its small size, simple structure, and ease of operation, cleaning and maintenance are also relatively convenient. By selecting appropriate manufacturing materials, this invention can also be made into a disposable mixer product using polymer materials, further reducing the requirements for cleaning validation and aseptic equipment handling.

[0033] In addition, this invention uniformly arranges multiple solution parameter sensors on the inner wall of the top of the mixer to monitor solution homogeneity. For example, a conductivity sensor can measure the conductivity value at a corresponding location. For electrolyte solution mixing, ideally, if the conductivity values ​​at all locations are the same, it means that the solution has been mixed very uniformly by the time it reaches the top, and can be directly output. Conversely, if the difference between the maximum and minimum conductivity values ​​at multiple locations is very large, it means that the solution is not mixed uniformly enough, and it needs to be refluxed for mixing. When the refluxing solution continues to mix through the mixer until the maximum and minimum conductivity values ​​at the top are within a preset threshold, it indicates that the solution homogeneity meets the requirements. The refluxing pipe can then be cut off by controlling a three-way valve to output the solution, thus greatly ensuring the uniformity of the output solution. Other solution parameter sensors have similar advantages.

[0034] By setting two PID controllers, this invention can further intelligently control the speed of the pump and motor, thereby keeping the internal pressure of the mixer within a preset range and the solution flow rate and ratio within a preset range. This can avoid the risk of bursting caused by excessive pressure and effectively control the mixing rate. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of the overall invention;

[0036] Figure 2 This is a schematic diagram of the discontinuous thread of the internal threaded rod of the present invention;

[0037] Figure 3 This is an external schematic diagram of the current splitter of the present invention;

[0038] Figure 4 This is a top view of the shunt of the present invention.

[0039] In the diagram, 1 is the distributor, 2 is the cylindrical outer shell, 3 is the internal threaded rod, 4 is the solution outlet, 5 is the motor, 6 is the thread, 7 is the liquid inlet, 8 is the distributor pipe, 9 is the distributor hole, and 10 is the internal guide pipe. Detailed Implementation

[0040] The specific embodiments of the present invention will now be described with reference to the accompanying drawings.

[0041] like Figure 1 The diagram shown is a general schematic of the present invention. The present invention provides an online dynamic continuous flow mixer with detection feedback function, comprising a splitter 1 located at the bottom, a mixer disposed above and connected to the splitter 1, and a motor 5 fixed above the mixer;

[0042] The distributor 1 is a container structure with an open top. Two internal guide pipes 10 are provided inside the distributor 1, with one internal guide pipe 10 surrounding the other. Multiple diversion holes 9 are formed on the side walls of both internal guide pipes 10. Two liquid inlets 7 are provided on the outer shell of the distributor 1, and these two liquid inlets 7 are connected to the interiors of the two internal guide pipes 10 respectively via distributor pipes 8. The diversion holes 9 and the internal guide pipes 10 are as follows: Figure 4 As shown;

[0043] The mixer is a cylindrical shell 2, with an internal threaded rod 3 inside the cylindrical shell 2. A cavity for solution flow and mixing is left between the internal threaded rod 3 and the cylindrical shell 2; a solution outlet 4 is opened at the top of the cylindrical shell 2.

[0044] The drive shaft of motor 5 passes downward through the top surface of the mixer and connects to the internal threaded rod 3 to drive the internal threaded rod 3 to rotate. The rotation direction of the internal threaded rod 3 causes the solution, after being dispersed and initially mixed by the distributor, to first move and mix upward along the thread 6. Then, the change in the shape and inclination angle of the upper thread of the threaded rod promotes the final uniform mixing of the solution. That is, through the different inclination angles and protrusion designs of the lower and upper threads of the threaded rod, the motor provides a driving force to the solution in the mixer cavity to form a non-unidirectional flow, thereby driving the final uniform mixing of the solution. Of course, the pump also provides the power for the upward flow of the solution and controls the flow rate. Figure 2 As shown.

[0045] In some embodiments, one of the two internal guide pipes 10 surrounds the other internal guide pipe 10; both internal guide pipes 10 have multiple diversion holes 9 on their sidewalls; wherein the central axes of the two internal guide pipes coincide, and the central axes of both internal guide pipes also coincide with the central axis of the mixer. The diversion holes 9 are disposed on the sidewall of each internal guide pipe and are evenly distributed around the central axis.

[0046] The solution outlets are connected to one end of the reflux pipe and the outlet pipe via three-way valves at four points.

[0047] Two liquid inlet ports 7 are connected to two ports of the five-way valve, and the other three ports of the five-way valve are connected to the other ends of the two inlet pipes and the return pipe, respectively; liquid inlet ports 7 are as follows: Figure 3 As shown;

[0048] The following example considers setting the solution parameter sensor as a conductivity sensor; the operation is exactly the same for other sensors:

[0049] Multiple conductivity sensors are evenly arranged around the inner wall of the top of the mixer; the conductivity sensors measure the conductivity value at the corresponding position in real time.

[0050] If the difference between the maximum and minimum conductivity values ​​measured at multiple locations at the same time is less than a preset threshold, then:

[0051] By controlling the three-way valve, the solution outlet 4 is connected to the output pipe, and the connection between the return pipe and the solution outlet 4 is cut off; by controlling the five-way valve, the two liquid inlets 7 are connected to the two input pipes, and the connection between the liquid inlets 7 and the return pipe is cut off.

[0052] If the difference between the maximum and minimum conductivity values ​​measured at multiple locations at the same time is greater than a preset threshold, then:

[0053] By controlling the three-way valve, the solution outlet 4 is connected to the return pipe, and the connection between the output pipe and the solution outlet 4 is cut off; by controlling the five-way valve, the return pipe is connected to the liquid inlet, and the connection between the two input pipes and the liquid inlet is cut off.

[0054] A pump for powering the solution is installed at the input pipeline. A first PID controller is installed at the pump. The first PID controller is connected to a pressure sensor inside the mixer to measure the pressure at one point (when there is only one point, the pressure sensor can be placed at a designated location inside, such as the bottom or the top, so that a preset pressure range is set accordingly) or the average pressure at multiple points (for example, pressure sensors are set at the top, middle and bottom, and the average of the measured values ​​is taken). The first PID controller controls the speed of the pump so that the pressure at one point or the average pressure at multiple points measured by the pressure sensor is within the preset range.

[0055] A second PID controller is also installed at the pump. The second PID controller is connected to the flow rate sensors installed at the two input pipes for measuring the solution flow rate. The second PID controller controls the pump speed so that the solution flow rate and ratio measured by the two flow rate sensors are within a preset range.

[0056] In some embodiments, the online dynamic continuous flow mixer further includes a controller connected to a solution parameter sensor, a three-way valve, and a five-way valve.

[0057] In some embodiments, the three-way valve and the five-way valve are electric three-way valves, pneumatic three-way valves, or hydraulic three-way valves; the controller is a PLC controller, a microcontroller, or an industrial PC.

[0058] In some embodiments, the probe of the solution parameter sensor extends horizontally into the interior of the mixer after passing through the top sidewall of the mixer.

[0059] In some embodiments, the probes of a plurality of solution parameter sensors extend vertically downward into the interior of the mixer after passing through the top surface of the mixer around the edge of the top surface of the mixer.

[0060] In some embodiments, the pH sensor is a glass electrode pH sensor or an ion-sensitive field-effect transistor sensor.

[0061] In some embodiments, a top opening is provided at the center of the top surface of the mixer, the drive shaft of the motor 5 passes downward through the top opening, and a seal is provided between the inner wall of the top surface and the drive shaft of the motor 5.

[0062] First, considering the reflux pipe being cut off and all other pipes being open, the method of using this invention is described. When using this invention, a pump connected to the input pipe is activated. The pump propels two different solutions through two liquid inlets 7 into two nested internal guide pipes 10 (the solution ratio can be adjusted by regulating the pump speed). In some embodiments, these internal guide pipes 10 are annular cylindrical containers with their central axes completely overlapping, resulting in more uniform flow and distribution of the solution. After the solutions enter the two internal guide pipes 10, they are ejected from the diversion holes 9, which are evenly arranged around the central axis. The ejected solutions undergo initial mixing.

[0063] After the initial mixing is complete, the solution flows upwards to the mixing area due to the rising liquid level. The mixer comprises an internal threaded rod 3 and a cylindrical outer shell 2, with a cavity between them for solution flow and mixing. The internal threaded rod 3 is driven by a motor 5 located above the mixer. The drive shaft of the motor 5 passes through the top surface of the mixer and connects to the internal threaded rod 3, enabling it to rotate. The outer wall of this internal threaded rod 3 contains two discontinuous threads 6 (multiple protrusions can also be provided) to improve mixing efficiency and effectiveness. The rotation and stirring of the threads 6 promotes solution mixing. The design of the threads 6 in the threaded rod 3 creates a non-unidirectional flow of the solution within the mixing cavity, thereby driving uniform mixing of the solution and improving solution transfer efficiency. Finally, after mixing and transfer by the mixer, the solution is output through the solution outlet 4 located at the top of the mixer.

[0064] In addition, this invention includes a reflux pipe for refluxing and remixing the solution in cases of uneven mixing. Specifically, this invention uniformly arranges multiple solution parameter sensors on the inner wall of the top of the mixer. For example, a conductivity sensor can be placed at regular intervals, such as 90 degrees, to measure the conductivity value at the corresponding location. Ideally, for electrolyte solution mixing, if the conductivity values ​​at all locations are the same, it means that the solution has been mixed very evenly by the time it reaches the top, and can be directly output. Conversely, if the difference between the maximum and minimum conductivity values ​​at multiple locations is very large, it means that the solution is not mixed evenly enough. Therefore, the solution is refluxing by controlling a five-way valve until the maximum and minimum conductivity values ​​of the refluxing solution reach the top and are within a preset threshold, indicating that the uniformity of the solution has met the requirements. Then, the reflux pipe can be cut off by controlling a three-way valve to output the solution, thus greatly ensuring the uniformity of the output solution. Of course, the conductivity sensor can also be replaced with a pH sensor, concentration sensor, osmotic pressure sensor, etc., to measure other parameter values ​​of the solution, thereby obtaining more accurate and comprehensive information about the homogeneity of the solution. The implementation method is the same.

[0065] By setting two PID controllers, the speed of the pump and motor 5 can be controlled, so that the internal pressure of the mixer is within the preset range and the flow rate is also within the preset range. This can avoid the risk of bursting caused by excessive pressure, and can effectively control the mixing rate and the processing rate of the subsequent solution.

[0066] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An online dynamic continuous flow mixer with detection feedback function, characterized in that, It includes a splitter (1) located at the bottom, a mixer disposed above the splitter (1) and communicating with the splitter (1), and a motor (5) fixed above the mixer; The diverter (1) is a container structure with an open top. The diverter (1) has two internal guide pipes (10), one of which surrounds the other. Multiple diverting holes (9) are provided on the side walls of both internal guide pipes (10). The outer shell of the diverter (1) has two liquid inlets (7), which are connected to the two internal guide pipes (10) through the diverter pipes (8). The mixer includes a cylindrical shell (2), an internal threaded rod (3) is provided inside the cylindrical shell (2), and a cavity for solution flow and mixing is provided between the internal threaded rod (3) and the cylindrical shell (2); a solution outlet (4) is provided at the top of the cylindrical shell (2); The drive shaft of the motor (5) passes downward through the top surface of the cylindrical outer shell (2) and connects to the internal threaded rod (3) to drive the internal threaded rod (3) to rotate; The solution outlet (4) is connected to one end of the return pipe and the output pipe via a three-way valve; The two liquid inlets (7) are connected to the two ports of the five-way valve, and the other three ports of the five-way valve are respectively connected to the two input pipes and the other end of the return pipe; Multiple solution parameter sensors are evenly arranged around the inner wall of the top of the mixer; the solution parameter sensors measure the solution parameters at the corresponding positions in real time. If the difference between the maximum and minimum values ​​of the solution parameters measured at multiple locations at the same time is less than a preset threshold, then: By controlling the three-way valve, the solution outlet (4) is connected to the output pipe, and the connection between the return pipe and the solution outlet (4) is cut off; by controlling the five-way valve, the two liquid inlets (7) are connected to the two input pipes, and the connection between the liquid inlets (7) and the return pipe is cut off. If the difference between the maximum and minimum values ​​of solution parameters measured at multiple locations simultaneously exceeds a preset threshold, then: By controlling the three-way valve, the solution outlet (4) is connected to the return pipe, and the connection between the output pipe and the solution outlet (4) is cut off; by controlling the five-way valve, the return pipe is connected to the liquid inlet (7), and the connection between the two input pipes and the liquid inlet (7) is cut off. A pump for providing power to the solution is installed at the input pipe. A first PID controller is installed at the pump. The first PID controller is connected to a pressure sensor inside the mixer for measuring the pressure at one point or the average pressure at multiple points in the solution. The first PID controller controls the rotational speed of the pump so that the pressure at one point or the average pressure at multiple points measured by the pressure sensor is within a preset range. The pump is also equipped with a second PID controller, which is connected to flow rate sensors installed at the two input pipes for measuring the solution flow rate. The second PID controller controls the pump speed so that the solution flow rate and ratio measured by the two flow rate sensors are both within their respective preset ranges. Both of the internal flow guide pipes (10) are annular, with one annular internal flow guide pipe (10) of larger diameter surrounding the other annular internal flow guide pipe (10) of smaller diameter; the central axis of both annular internal flow guide pipes (10) coincides with the central axis of the mixer; the flow divider holes (9) are provided on the sidewall of each internal flow guide pipe (10) and are evenly arranged around the central axis; The rotation direction of the internal threaded rod (3) causes the solution, which has been dispersed and initially mixed by the distributor (1), to first move and mix upward along the thread (6), and then the change in the thread shape and inclination angle at the upper end of the internal threaded rod (3) facilitates the final uniform mixing of the solution.

2. The online dynamic continuous flow mixer with detection feedback function according to claim 1, characterized in that, The online dynamic continuous flow mixer also includes a controller connected to the solution parameter sensor, the three-way valve, and the five-way valve.

3. The online dynamic continuous flow mixer with detection feedback function according to claim 1 or 2, characterized in that, The three-way valve and the five-way valve are electric valves, pneumatic valves, or hydraulic valves; the controller is a PLC controller, microcontroller, or industrial PC.

4. The online dynamic continuous flow mixer with detection feedback function according to claim 1, characterized in that, The probe of the solution parameter sensor extends horizontally into the interior of the mixer after passing through the top sidewall of the mixer.

5. The online dynamic continuous flow mixer with detection feedback function according to claim 1, characterized in that, The probes of the multiple solution parameter sensors extend vertically downwards into the interior of the mixer after passing through the top surface of the mixer around the edge of the top surface.

6. The online dynamic continuous flow mixer with detection feedback function according to claim 1, characterized in that, The solution parameter sensor can be any one or more of the following: pH sensor, concentration sensor, conductivity sensor, osmotic pressure sensor; the pH sensor can be a glass electrode pH sensor or an ion-sensitive field-effect transistor sensor.

7. The online dynamic continuous flow mixer with detection feedback function according to claim 1, characterized in that, The outer wall of the internal threaded rod (3) includes two discontinuous upper and lower threads with different inclination angles.

8. The online dynamic continuous flow mixer with detection feedback function according to claim 1, characterized in that, The mixer has a top opening at the center of its top surface, and the drive shaft of the motor (5) passes downward through the top opening. A seal is provided between the inner wall of the top surface and the drive shaft of the motor (5).

Images