Material mixing detection method

Abstract

The material mixing detection method comprises the following steps: stirring: adding materials to be mixed into a flexible preparation container, and stirring and mixing through a stirring mechanism; detecting: enabling the mixture in the preparation container to flow in from a bottom sampling port of the preparation container and a top sample inlet of the preparation container by adopting a sampling device to form dynamic circulation with set flow, and detecting physical and chemical parameter values of the mixture flowing in the sampling device through a detection mechanism; and verification: when the physical and chemical parameter values of the mixture detected by the detection mechanism are kept in a set range after set duration fluctuation, extracting the mixture in the preparation container to the outside by adopting the sampling device, and detecting the physical and chemical parameter values of the mixture flowing in the sampling device through the detection mechanism in the extraction process. The material mixing detection method has the advantages that a test result is used for evaluating the mixing uniformity condition, whether a dead angle without uniform mixing exists in the preparation container or not is judged, and distortion of the test result is avoided.

Description

Technical Field

[0001] The invention relates to the technical field of food and medicine production, and in particular to a material mixing detection method. Background Art

[0002] In recent years, biopharmaceutical technology has developed rapidly. Antibodies, nucleic acids and cells have been applied to the treatment of diseases in many fields. At the same time, the supporting requirements for drug production have become more stringent and standardized with the rapid development of the biopharmaceutical industry. The preparation of solutions is one of the key process steps in the production of various drugs. The preparation operation in the production process must strictly comply with GMP standards. In the traditional preparation process, stirring equipment is widely used for mixing liquids or intermediate process samples. Traditional equipment is mostly stainless steel stirring tanks, which have a large overall footprint and many problems. For example, when preparing liquids and feeding, powders are easily scattered to various pipelines. On the one hand, it is easy to nourish microorganisms and cause pollution, and the number of equipment and pipelines that need to be cleaned is large; on the other hand, cleaning during the preparation process requires a lot of time and water. In addition, for the preparation of intermediate drugs, toxic or organic solutions, cleaning residues need to be strictly verified for cleaning, otherwise cross contamination is likely to occur.

[0003] In response to the above problems, disposable product technology came into being. Disposable liquid preparation equipment is small, does not take up space, and is relatively easy to clean. The liquid preparation process comes into contact with disposable bags, avoiding problems such as cleaning, residue and cross-contamination. This type of liquid preparation equipment is called a disposable Mixer, which has significant advantages in biopharmaceutical processes, such as reducing operation time, reducing contamination risks, and meeting GMP requirements. The Mixer uses disposable blades, and different blades are changed according to process requirements. For example, low shear is used for mixing preparations or intermediates, high shear large blades are used for mixing high viscosities, and other culture media or buffer preparations use paddle protruding mixing devices. In general, the goal of all Mixers is to achieve fast and uniform mixing effects.

[0004] Conventional existing mixing devices evaluate the mixing effect only by conductivity, which can only represent the mixing situation in a small local area where the detection device is located, and cannot represent the real mixing situation where there may be a stirring dead corner.

[0005] The existing Chinese patent document with application number 201120139874.7 discloses an online conductivity monitoring device for tank liquid with electric field, and specifically discloses the working principle and process of the online conductivity monitoring device for tank liquid with electric field: the time controller in the control cabinet is used to set the front electromagnetic valve to open for 5 seconds and close for 5 seconds. When the front electromagnetic valve is opened, the electrode probe and the rear electromagnetic valve are closed. When the front electromagnetic valve is closed, the electrode probe and the rear electromagnetic valve are opened. The online conductivity monitoring of the electronic aluminum foil forming tank is performed 6 times per minute, each time for 5 seconds. The online conductivity monitoring device for tank liquid with electric field performs online conductivity monitoring by alternately switching the front electromagnetic valve and the rear electromagnetic valve. The whole cycle is not a continuous process, and it is actually static conductivity online monitoring. If it is used for the evaluation of the mixing uniformity effect, the static conductivity online monitoring cannot truly reflect the mixing situation in the reaction tank, resulting in monitoring distortion and evaluation distortion.

[0006] The existing Chinese patent document with application number 201420333721.X discloses a dynamic oil-water mixed liquid conductivity test device, which specifically discloses that it adopts a closed circulation method of test liquid to realize dynamic measurement of the oil-water mixed liquid conductivity. During the test process, the test liquid does not contact the external environment that affects the test result, thereby realizing a fully closed circulation operation of the test liquid; the existing static conductivity test method overcomes the problems of liquid stratification, test conditions not matching actual working conditions, and poor reproducibility of measurement results when testing the oil-water mixed liquid conductivity, avoids the oil-water mixed liquid static stratification phenomenon, and makes the test conditions closer to the actual working conditions; the test conditions are stable, the test conditions are closer to the actual working conditions, and the dynamic measurement of the conductivity of the test liquid can be realized. The purpose of the dynamic oil-water mixture conductivity test device is to more realistically test the conductivity of the oil-water mixture. If it is used to evaluate the mixing uniformity effect, the following problems will exist: 1) It is not known how to apply the test results to evaluate the mixing uniformity; 2) During the overall dynamic cycle test, there may be dead corners in the test liquid storage tank where the mixture is not mixed evenly, and it is not known how to detect whether there are such dead corners to avoid distortion of the test results. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a material mixing detection method that uses test results to evaluate the uniformity of mixing, determine whether there are dead corners in the preparation container where the mixing is not uniform, and avoid distortion of the test results.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] A material mixing detection method comprises the following steps:

[0010] Stirring: Add the materials to be mixed into a flexible preparation container and stir and mix them through a stirring mechanism;

[0011] Detection: A sampling device is used to make the mixture in the preparation container flow out of the sampling port at the bottom of the preparation container and into the sampling port at the top, forming a dynamic cycle of a set flow rate, and the physical and chemical parameter values ​​of the mixture flowing in the sampling device are detected by a detection mechanism;

[0012] Verification: When the detection mechanism detects that the physical and chemical parameter values ​​of the mixture remain within the set range after a set period of fluctuation, a sampling device is used to extract the mixture in the preparation container to the outside. During the extraction process, the detection mechanism detects the physical and chemical parameter values ​​of the mixture flowing in the sampling device.

[0013] As a further improvement of the above technical solution:

[0014] Also includes the steps:

[0015] Judgment: Determine whether the test results of the verification step detection agency are stable. If the physical and chemical parameter values ​​of the mixture remain within the set range after the set time, it is stable and there is no dead angle in the stirring. Otherwise, it is unstable and there is a dead angle in the stirring.

[0016] Before stirring, the material to be stirred is divided into N equal parts according to the same specifications, where N is an integer greater than 1;

[0017] Each equal portion of the material to be mixed is stirred, tested and verified according to different stirring conditions;

[0018] Compare the test results of each aliquot of the material to be mixed and select the stirring conditions that will allow the test results to reach the stable stage the fastest.

[0019] The test results are the physical and chemical parameter values ​​and time trend diagrams of each portion of the material to be mixed generated during the stirring process, and the time taken to reach the stable stage is determined by the test results.

[0020] Before adding the material to be mixed into the preparation container, clean water is added to the preparation container for cleaning, and the cleaning water in the preparation container is extracted to the outside using a sampling device. During the extraction process, the physical and chemical parameter values ​​of the cleaning water flowing in the sampling device are tested by a detection mechanism until the test results are stable.

[0021] The preparation container is square and has a plurality of sampling ports, each of which is connected to an independent sampling device.

[0022] In the verification, the time length is set to 5s and the setting range is -5% to 5%.

[0023] The sampling device comprises a sampling tube and a sampling pump. The sampling tube is connected with the bottom and the top of the preparation container, and the sampling pump is arranged on the sampling tube.

[0024] The detection mechanism comprises a conductivity sensor and a control interface. The conductivity sensor extends into the sampling tube and is electrically connected to the control interface.

[0025] The preparation container is arranged on a rigid supporting mechanism corresponding to the preparation container, the stirring mechanism is arranged in the preparation container, and the stirring mechanism is driven by an external magnetic driving member.

[0026] Compared with the prior art, the advantages of the present invention are:

[0027] The material mixing detection method of the present invention, on the one hand, first obtains the dynamic test results of the physical and chemical parameter values ​​of the mixture flowing in the sampling device through a verification step, and when the dynamic test results fluctuate and remain within a set range after a set time, it is evaluated whether the mixture in the preparation container is mixed evenly, that is, the test results are well used to evaluate the uniformity of the mixing; on the other hand, in order to improve the accuracy of the evaluation, a sampling device is used to extract the mixture in the preparation container to the outside, and during the extraction process, the physical and chemical parameter values ​​of the mixture flowing in the sampling device are detected by a detection mechanism, and then the detection evaluation can be verified by the detection results to determine whether there are dead corners in the preparation container where the mixture is not mixed evenly, thereby avoiding distortion of the test results. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a structural schematic diagram of material mixing detection of the material mixing detection method of the present invention.

[0029] Figure 2 It is a comparison diagram of the detection results of different stirring speeds and the mixing time trend of the material mixing detection method of the present invention.

[0030] Figure 3 It is the detection result and mixing time trend diagram of the material mixing detection method of the present invention when the stirring speed is 100 rpm.

[0031] Figure 4 It is the detection result and mixing time trend diagram of the material mixing detection method of the present invention when the stirring speed is 200 rpm.

[0032] Figure 5 It is the detection result and mixing time trend diagram of the material mixing detection method of the present invention when the stirring speed is 300 rpm.

[0033] Figure 6 It is the test result and mixing time trend diagram of the mixture with a stirring speed of 100 rpm in the verification of the material mixing detection method of the present invention.

[0034] Figure 7 It is the test result and mixing time trend diagram of the mixture with a stirring speed of 200 rpm in the verification of the material mixing detection method of the present invention.

[0035] Figure 8 It is the test result and mixing time trend diagram of the mixture with a stirring speed of 300 rpm in the verification of the material mixing detection method of the present invention.

[0036] The symbols in the figure represent:

[0037] 1. Preparation container; 2. Stirring mechanism; 3. Sampling device; 31. Sampling tube; 32. Sampling pump; 4. Detection mechanism; 41. Conductivity sensor; 42. Control interface. DETAILED DESCRIPTION

[0038] The present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0039] In the description of the present invention, it should be understood that the terms "length", "width", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" etc., indicating orientations or positional relationships, are based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present invention.

[0040] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0041] In the present invention, unless otherwise clearly specified and limited, the terms "assemble", "connect", "connect", "fix" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0042] Figures 1 to 8 An embodiment of the material mixing detection method of the present invention is shown. The material mixing detection method of this embodiment includes the following steps:

[0043] Stirring: Add the materials to be mixed into the flexible preparation container 1 and stir and mix them through the stirring mechanism 2;

[0044] Detection: The sampling device 3 is used to make the mixture in the preparation container 1 flow out of the bottom sampling port of the preparation container 1 and into the top sampling port, forming a dynamic cycle of a set flow rate, and the physical and chemical parameter values ​​of the mixture flowing in the sampling device 3 are detected by the detection mechanism 4;

[0045] Verification: When the detection mechanism 4 detects that the physical and chemical parameter values ​​of the mixture remain within the set range after a set period of time, the sampling device 3 is used to extract the mixture in the preparation container 1 to the outside. During the extraction process, the physical and chemical parameter values ​​of the mixture flowing in the sampling device 3 are detected by the detection mechanism 4.

[0046] The material mixing detection method, on the one hand, first obtains the dynamic test result of the physical and chemical parameter value of the mixture flowing in the sampling device 3 through a verification step, and when the dynamic test result fluctuates and remains within a set range after a set time, it is evaluated whether the mixture in the preparation container 1 is mixed uniformly, that is, the test result is well used to evaluate the uniformity of the mixing; on the other hand, in order to improve the accuracy of the evaluation, the sampling device 3 is used to extract the mixture in the preparation container 1 to the outside, and during the extraction process, the physical and chemical parameter value of the mixture flowing in the sampling device 3 is detected by the detection mechanism 4, and then, the detection evaluation can be verified by the detection result to determine whether there is a dead corner in the preparation container 1 where the mixture is not mixed uniformly, thereby avoiding distortion of the test result.

[0047] Furthermore, in this embodiment, the following steps are also included: judging: judging and verifying whether the detection result of the detection mechanism 4 is stable. If the fluctuation of the physical and chemical parameter values ​​of the mixture remains within the set range after the set time, it is stable and there is no dead angle in stirring. Otherwise, it is unstable and there is a dead angle in stirring. The mixture in the preparation container 1 is extracted to an external process, and the physical and chemical parameter values ​​of the mixture passing through the detection mechanism 4 are detected. If the fluctuation of the physical and chemical parameter values ​​of the mixture remains within the set range after the set time, such as when the mixture in the preparation container 1 is exhausted, it proves that the test result is stable and there is no dead angle in the preparation container 1 where the mixture is not mixed evenly. Otherwise, it proves that the test result is unstable and there is a dead angle in the preparation container 1 where the mixture is not mixed evenly. This material mixing detection method can detect the uniformity of the mixture in the preparation container 1 and verify the detection (test) result through a detection mechanism 4, thereby avoiding distortion of the test result. On the one hand, it saves costs, and on the other hand, it improves the accuracy of the test structure.

[0048] Furthermore, in this embodiment, before stirring, the material to be stirred is divided into N equal parts according to the same specifications, where N is an integer greater than 1;

[0049] Each equal portion of the material to be mixed is stirred, tested and verified according to different stirring conditions;

[0050] Compare the test results of each equal portion of the material to be mixed, and select the stirring condition that is the fastest from the test result to the stable stage. In this way, the stirring condition that is the fastest from the test result to the stable stage can be selected, and the optimal preparation scheme can be selected by comparing the shortest mixing time, which can save production time or improve the evaluation effect of the stirring design; and for large-scale liquid preparation such as 2000L Mixer design, a fast mixing time test scheme can be provided to debug excellent equipment.

[0051] Furthermore, in this embodiment, the detection result is the physical and chemical parameter value and time trend diagram of each portion of the material to be mixed generated during the stirring process during the detection, and the time taken to reach the stable stage is determined by the detection result.

[0052] Further, in this embodiment, before the material to be mixed is added to the preparation container 1, clean water is added to the preparation container 1 for cleaning, and the cleaning water in the preparation container 1 is extracted to the outside by the sampling device 3. During the extraction process, the physical and chemical parameter values ​​of the cleaning water flowing in the sampling device 3 are detected by the detection mechanism 4 until the detection result is stable. Before the material to be mixed is added to the preparation container 1, clean water is added to the preparation container 1 for cleaning to prevent the presence of impurities in the preparation container 1 from affecting the accuracy of the test structure. The cleaning water in the preparation container 1 is extracted to the outside by the sampling device 3. During the extraction process, the physical and chemical parameter values ​​of the cleaning water flowing in the sampling device 3 are detected by the detection mechanism 4 until the detection result is stable, thereby ensuring that the inside of the preparation container 1 is clean.

[0053] Furthermore, in this embodiment, the preparation container 1 is square and has one sampling port. Of course, in other embodiments, the preparation container 1 may have multiple sampling ports, each of which is connected to an independent sampling device 3, so that sampling ports at different positions on the preparation container 1 can be selected for detection, further improving the accuracy of the detection result.

[0054] Furthermore, in this embodiment, during verification, the time length is set to 5s and the setting range is -5% to 5%.

[0055] Furthermore, in this embodiment, the sampling device 3 includes a sampling tube 31 and a sampling pump 32 . The sampling tube 31 communicates with the bottom and the top of the preparation container 1 , and the sampling pump 32 is disposed on the sampling tube 31 .

[0056] Furthermore, in this embodiment, the detection mechanism 4 includes a conductivity sensor 41 and a control interface 42 . The conductivity sensor 41 extends into the sampling tube 31 and is electrically connected to the control interface 42 .

[0057] Furthermore, in this embodiment, the preparation container 1 is disposed on a rigid support mechanism corresponding to the preparation container 1 , the stirring mechanism 2 is disposed in the preparation container 1 , and the stirring mechanism 2 is driven by an external magnetic driving member.

[0058] This material mixing detection method can be applied to different types of material tests. The following is a detailed description taking sodium chloride NaCl as an example. Table 1 is a mixing time test scheme. The NaCl concentration is 20 g / L, the preparation volume is 50 L, and three stirring speeds of 100 rpm, 200 rpm, and 300 rpm are tested. The mixing index is evaluated by the conductivity value.

[0059] Table 1 Mixing time test scheme

[0060]

[0061] Add 50L or 50kg of purified water into the preparation container 1, weigh three portions of material (1kg), set the stirring speed to 100rpm, set the flow rate of the sampling pump 32 to 1-2L / min, start the self-circulation of the sampling pump 32, and start recording the initial time and data of the conductivity after feeding. The material enters the preparation container 1 for stirring and mixing. The conductivity changes continuously during the self-circulation process, and the final area is stable. 5-10 minutes after the conductivity stabilizes, record the end time, and complete the first batch of mixing time tests.

[0062] Mixing effect test, start preparing the discharge solution of container 1, record the initial time, set the sampling pump 32 to 1-2L / min, collect the solution into the collection container, monitor the process conductivity and weighing data, and when the weighing drops to 0, end the sampling pump 32 and the test.

[0063] Clean the preparation container 1 with purified water until the conductivity value of the discharged material stabilizes to the conductivity of pure water, indicating that it is clean, and then repeat the test of 200rpm and 300rpm effects in the above manner.

[0064] Take the average conductivity value from 1 minute to 5 minutes of the preparation process, and take the average value ± 5.0% as the acceptance range. The time that first reaches the average value ± 5.0% is the mixing time, that is, the time that first reaches 95% or 105% of the average value, such as Figure 2 As shown in the figure, the mixing time of the three speeds of low, medium and high is 21s, 18s and 9s respectively, and the conductivity is within the acceptable range. The medium can be mixed quickly within 1 minute. Figure 3 , Figure 4 and Figure 5 The continuous mixing effect at 100rpm, 200rpm and 300rpm respectively, the conductivity is within the acceptable range.

[0065] After the mixing is completed, stirring is stopped, and the preparation container 1 is drained using a pump speed of 1.6L / min. During the drainage process, the conductivity shows that there is no dead zone in the system, and the mixing result is good. During the mixing process, bubbles generated by stirring enter the detection flow path of the conductivity sensor 41, resulting in a small fluctuation in conductivity, which is a normal phenomenon. After the stirring is stopped, the conductivity will increase to a certain extent, but the process remains stable. Figure 6 , Figure 7 and Figure 8 These are the preparation and drainage results of the solutions prepared at 100rpm, 200rpm and 300rpm respectively. The green line is the equipment weighing line. During the drainage process from 50kg to 0kg, the conductivity is relatively stable, indicating that all the solutions in the preparation container 1 have been prepared evenly without any local dead corners.

[0066] Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the technical content disclosed above without departing from the scope of the technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention should fall within the scope of protection of the technical solution of the present invention.

Claims

1. A material mixing detection method, characterized in that: The steps include: Stirring: adding the materials to be mixed into the flexible preparation container (1) and stirring and mixing them by means of the stirring mechanism (2); Detection: a sampling device (3) is used to allow the mixture in the preparation container (1) to flow out of the bottom sampling port of the preparation container (1) and into the top sampling port, thereby forming a dynamic cycle with a set flow rate, and the physical and chemical parameter values ​​of the mixture flowing in the sampling device (3) are detected by a detection mechanism (4); Verification: When the detection mechanism (4) detects that the value of the physical and chemical parameter of the mixture remains within the set range after a set period of fluctuation, the sampling device (3) is used to extract the mixture in the preparation container (1) to the outside. During the extraction process, the detection mechanism (4) detects the value of the physical and chemical parameter of the mixture flowing in the sampling device (3).

2. The material mixing detection method according to claim 1, characterized in that: Also includes the steps: Judgment: Judgment verification step detection mechanism (4) whether the test results are stable, if the physical and chemical parameter values ​​of the mixture after a set time, the fluctuations remain within the set range, then the mixture is stable, stirring without dead angles, otherwise it is unstable, stirring with dead angles.

3. The material mixing detection method according to claim 1, characterized in that: Before stirring, the material to be stirred is divided into N equal parts according to the same specifications, where N is an integer greater than 1; Each equal portion of the material to be mixed is stirred, tested and verified according to different stirring conditions; Compare the test results of each aliquot of the material to be mixed and select the stirring conditions that will allow the test results to reach the stable stage the fastest.

4. The material mixing detection method according to claim 3, characterized in that: The test results are the physical and chemical parameter values ​​and time trend diagrams of each portion of the material to be mixed generated during the stirring process, and the time taken to reach the stable stage is determined by the test results.

5. The material mixing detection method according to any one of claims 1 to 4, characterized in that: Before adding the material to be mixed into the preparation container (1), clean water is added into the preparation container (1) for cleaning, and the cleaning water in the preparation container (1) is extracted to the outside by using a sampling device (3). During the extraction process, the physical and chemical parameter values ​​of the cleaning water flowing in the sampling device (3) are detected by a detection mechanism (4) until the detection result is stable.

6. The material mixing detection method according to any one of claims 1 to 4, characterized in that: The preparation container (1) is square and has a plurality of sampling ports, each of which is connected to an independent sampling device (3).

7. The material mixing detection method according to any one of claims 1 to 4, characterized in that: In the verification, the time length is set to 5s and the setting range is -5% to 5%.

8. The material mixing detection method according to any one of claims 1 to 4, characterized in that: The sampling device (3) comprises a sampling tube (31) and a sampling pump (32); the sampling tube (31) is connected to the bottom and the top of the preparation container (1); and the sampling pump (32) is arranged on the sampling tube (31).

9. The material mixing detection method according to claim 8, characterized in that: The detection mechanism (4) comprises a conductivity sensor (41) and a control interface (42); the conductivity sensor (41) extends into the sampling tube (31) and is electrically connected to the control interface (42).

10. The material mixing detection method according to any one of claims 1 to 4, characterized in that: The preparation container (1) is arranged on a rigid support mechanism corresponding to the preparation container (1), the stirring mechanism (2) is arranged in the preparation container (1), and the stirring mechanism (2) is driven by an external magnetic driving member.

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