A positive pressure transfer nanomembrane cross clean room viral removal filtration system and method of operation thereof
By monitoring the external space pressure through a positive pressure transfer nanomembrane system, the problem of insufficient nanomembrane leakage monitoring in existing technologies is solved, achieving efficient virus removal and cross-contamination-free filtration, which is suitable for virus filtration of large-scale, high-concentration protein products.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG TAIBANG BIOLOGICAL PROD CO LTD
- Filing Date
- 2023-08-21
- Publication Date
- 2026-08-04
AI Technical Summary
Existing virus removal filtration systems cannot effectively monitor whether leakage occurs in the space outside the nanomembrane, posing a risk of virus contamination, and cannot meet the cross-contamination prevention measures required by GMP.
The cross-clean zone virus removal filtration system using positive pressure transfer nanomembranes monitors the positive pressure status of the space outside the nanomembrane by installing pressure gauges and flow meters in the positive pressure transfer components, and controls the pressure difference during the filtration process to ensure no virus contamination.
It enables effective monitoring of the leak-free state of the external space of the nanomembrane during the filtration of large-scale, high-concentration protein products, ensuring product safety and GMP-compliant cross-contamination protection.
Smart Images
Figure CN117000044B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biological products and blood products manufacturing technology, specifically to a positive pressure transfer nanomembrane cross-clean zone virus removal filtration system and its operation method. Background Technology
[0002] In the production of biological products and blood products, viruses may be introduced into the raw materials or processing, resulting in the risk of viral or potential viral contamination in the products. Therefore, methods for virus inactivation or removal must be introduced during the production process.
[0003] Nanofiltration is a safe and effective method that can remove viruses while preserving the bioactivity of products. Currently, mainstream manufacturers typically use this method to remove viruses from biological products and blood products. However, the current GMP (Good Manufacturing Practice) requires in Chapter 4, Plant and Equipment, Article 16, that in the production of blood products, measures should be taken to prevent cross-contamination between products before and after virus removal and / or inactivation. Products after virus removal and / or inactivation should be produced in isolated, dedicated production areas and with independent air purification systems.
[0004] Patent application CN 116251476 A discloses an in-situ sterilization nanomembrane virus removal filtration system and its operation method. The virus removal filtration system includes a nanomembrane with ports A and B at both ends and ports C and D on its sidewalls. It also includes a pre-membrane pipeline, a post-membrane pipeline, and a first pipeline located within a virus contamination risk area. The feed end of the pre-membrane pipeline is connected to a buffer tank and a material tank, respectively. The buffer tank is connected to the material tank. The nanomembrane is detachably installed on the pre-membrane and post-membrane pipelines. When the nanomembrane is installed, the pre-membrane pipeline is connected to ports A and B of the nanomembrane, and the post-membrane pipeline is connected to ports C and D of the nanomembrane. The first pipeline connects to a virus-free area and is connected in parallel with the post-membrane pipeline. This method lacks an effective means to monitor whether leakage occurs in the space outside the nanomembrane, posing a risk of virus contamination in the filtered product. Summary of the Invention
[0005] To address the technical problem that existing virus removal filtration systems cannot monitor for leaks in the space outside the nanomembrane, posing a risk of viral contamination in the filtered product, this invention provides a positive pressure transfer nanomembrane cross-cleanroom virus removal filtration system and its operating method. This system employs a clean transfer positive pressure protection method to ensure the space after nanomembrane filtration remains free from viral contamination. The positive pressure transfer nanomembrane cross-cleanroom virus removal filtration system and its operating method provided by this invention are suitable for high-protein-concentration biological products and large-scale (kilogram-level protein filtration) virus removal filtration, particularly meeting the requirements of large-scale industrial production.
[0006] In a first aspect, the present invention provides a positive pressure transfer nanomembrane cross-cleanroom virus removal filtration system, comprising a pre-membrane conduit and a post-membrane conduit; and further comprising a positive pressure transfer component, the positive pressure transfer component comprising a positive pressure transfer conduit and at least two nanomembranes, one end of the positive pressure transfer conduit being a C' port and the other end being a D' port, each nanomembrane having an A port and a B port at its two ends, and each nanomembrane having a C port and a D port on its sidewall, the C ports and D ports of each nanomembrane being connected to the positive pressure transfer conduit via flexible tubing, and the C port being connected to the positive pressure transfer conduit... A pressure gauge is installed on the hose connecting the pipeline; the pre-membrane pipeline is located in the virus contamination risk area, and the feed end of the pre-membrane pipeline is connected to the buffer tank and the material tank respectively. The pre-membrane pipeline is equipped with pre-membrane sub-pipelines, the number of which is the same as the number of nanomembranes. The pre-membrane sub-pipelines are connected in parallel. The A port and B port of each nanomembrane are detachably connected to the corresponding pre-membrane sub-pipeline; the C' port and D' port of the positive pressure transfer pipeline are detachably connected to the post-membrane pipeline. The post-membrane pipeline comes from the virus-free area and goes to the virus-free area.
[0007] Furthermore, a flow meter is installed on the pre-membrane pipeline. The flow meter can be a mass flow meter or an electromagnetic flow meter, which is used to measure the amount of material flowing into the nanomembrane.
[0008] Furthermore, a filter and a pressure gauge are installed on the pre-membrane tubing between the buffer tank and the pre-membrane sub-tubing. The pressure gauge is used to test the pre-membrane pressure.
[0009] Furthermore, valves are installed on the flexible tubes connecting the C port of each nanomembrane to the positive pressure transfer pipeline, valves are installed on the flexible tubes connecting the D port of each nanomembrane to the positive pressure transfer pipeline, and valves are installed on the positive pressure transfer pipeline. Individual control of each nanomembrane can be achieved through valve control.
[0010] Furthermore, a pressure gauge is installed on the post-membrane pipeline near the D' port of the positive pressure transfer pipeline. The pressure gauge is used to detect the post-membrane pressure.
[0011] Secondly, the present invention provides an operating method for a positive pressure transfer nanomembrane cross-clean zone virus removal filtration system, comprising the following steps:
[0012] S1. Preparations for a virus-free zone:
[0013] S11. Clean all parts of the positive pressure transfer component;
[0014] S12. Perform pre-use water washing and pre-use integrity testing on the nanofilm;
[0015] S13. Assemble the positive pressure transfer components;
[0016] S14. Pour clean compressed air into the positive pressure transfer component until the pressure gauge shows ≥0.1 Bar, close the corresponding valve, and carry out positive pressure transfer to enter the virus contamination risk area;
[0017] S2. Preparations for areas at risk of virus contamination:
[0018] S21. Before the positive pressure transfer component is transferred in, the pre-membrane sub-pipeline is cleaned by CIP and the post-membrane pipeline is cleaned by CIP.
[0019] S22. Connect the C' and D' ports of the positive pressure transfer line to the post-membrane line, and perform SIP on the post-membrane line connected to the positive pressure transfer line;
[0020] S23. After the membrane post-pipeline to be connected to the positive pressure transfer component is cooled down, the positive pressure protective membrane post-pipeline and the positive pressure transfer component are connected from the virus-free contamination area.
[0021] S3, Nanofiltration operation:
[0022] S31. Connect port A and port B of the nanofilm to the pre-membrane sub-tube respectively;
[0023] S32. Use the buffer solution in the buffer tank to wash and / or balance the pre-membrane tubing connected to the positive pressure transfer component, balancing one by one according to the tank weight reduction or according to the flow meter.
[0024] S33. Filter the contents of the nanofiltration tank and use a flow meter to detect the total amount of filtered protein.
[0025] Furthermore, in S23, the cooling method for the post-membrane tubing connected to the positive pressure transfer tubing is either natural cooling or cooling and purging by introducing buffer solution into the tubing. The buffer solution is prepared and provided from a virus-free contamination area, and the clean compressed air used for purging is from a virus-free contamination area.
[0026] Furthermore, S3, nanofiltration also includes S34, using buffer solution to rinse the product in the material tank or top-wash the nanomembrane to maximize product recovery; the specific method is to wait until the product in the material tank is reduced to 10kg or the liquid level sensor in the material tank reaches the bottom of the tank, switch the buffer solution tank to top-wash the nanomembrane, and at the same time use the buffer solution in the buffer tank to rinse the material tank, then switch the material tank to continue nanofiltration, repeating until the residual product in the material tank is rinsed to an acceptable level, and the nanomembrane product is top-washed to an acceptable level.
[0027] Furthermore, this also includes S4 and post-nanofiltration processes:
[0028] S41. The nanofilm undergoes an integrity test after use.
[0029] S42. Remove the nanomembrane and perform CIP on the pre-membrane and post-membrane pipelines.
[0030] Furthermore, the access point for the integrity tester is located on the discharge end side of the pre-membrane pipeline.
[0031] The beneficial effects of this invention are as follows:
[0032] This invention pressurizes the membrane to ≥0.1 bar before positive pressure transfer and uses pressure gauges within the positive pressure transfer component to monitor and ensure that the external space of each nanomembrane maintains positive pressure throughout the transfer process, thus demonstrating safety. After the positive pressure transfer is completed and connected to the post-membrane pipeline, pressurizing the pipeline to ≥0.1 bar further confirms that the external space of the nanomembrane remains under positive pressure after the transfer, thereby proving that there is no risk of leakage in the external space of the membrane fibers throughout the entire process.
[0033] This invention addresses the filtration of viruses from large-scale, high-concentration protein products. It involves setting multiple parallel nanomembranes in a positive pressure transfer component and using a flow meter installed on the pre-membrane sub-pipeline to detect the total filtration volume and control the total filtration volume of the nanomembranes to ensure it does not exceed the specified limit. Attached Figure Description
[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0035] Figure 1 This is a structural schematic diagram of the positive pressure transfer component in a specific implementation.
[0036] Figure 2 This is a schematic diagram of the post-membrane pipeline in a specific implementation method.
[0037] Figure 3 This is a schematic diagram of the structure in which the C' and D' ports of the positive pressure transfer pipeline are connected to the post-membrane pipeline in a specific implementation.
[0038] Figure 4 This is a schematic diagram of the pre-membrane piping in a specific implementation method.
[0039] Figure 5 This is a schematic diagram of the structure in a specific embodiment where port A and port B of the nanomembrane are connected to the pre-membrane conduit.
[0040] In the diagram, 1-pre-membrane tubing, 2-post-membrane tubing, 3-positive pressure transfer component, 4-positive pressure transfer tubing, 5-C' port, 6-D' port, 7-nano-membrane, 8-A port, 9-B port, 10-C port, 11-D port, 12-buffer water tank, 13-material tank, 14-pre-membrane sub-tubing, 15-filter. Detailed Implementation
[0041] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.
[0042] Example 1
[0043] A positive pressure transfer nanomembrane cross-cleanroom virus removal filtration system includes a pre-membrane pipeline 1, a post-membrane pipeline 2, and a positive pressure transfer component 3. The positive pressure transfer component 3 includes a positive pressure transfer pipeline 4 and four nanomembranes 7. One end of the positive pressure transfer pipeline 4 is a C' port 5, and the other end is a D' port 6. Each nanomembrane 7 has an A port 8 and a B port 9 at its two ends, respectively. The sidewall of each nanomembrane 7 has a C port 10 and a D port 11. The C port 10 of each nanomembrane 7 is connected to the side of the positive pressure transfer pipeline 4 near the C' port 5 through a flexible tube. A pressure gauge is installed on the flexible tube connecting the C port 10 to the positive pressure transfer pipeline 4. The pressure gauge is used to detect positive pressure transfer. The D port 11 of each nanomembrane 7 is connected to the side of the positive pressure transfer pipeline 4 near the D' port 6 through a flexible tube.
[0044] Each nanomembrane 7 has a valve on the flexible tube connecting its C port 10 to the positive pressure transfer pipeline 4, and each nanomembrane 7 has a valve on the flexible tube connecting its D port 11 to the positive pressure transfer pipeline 4. The positive pressure transfer pipeline 4 also has a valve. Individual control of each nanomembrane can be achieved through valve control.
[0045] The pre-membrane pipeline 1 is located in the virus contamination risk area. The inlet end of the pre-membrane pipeline 1 is connected to the buffer tank 12 and the material tank 13 respectively. The pre-membrane pipeline 1 is equipped with four parallel pre-membrane sub-pipelines 14. The A port 8 and B port 9 of each nanomembrane 7 are detachably connected to the corresponding pre-membrane sub-pipeline 14. The pre-membrane pipeline 1 between the buffer tank 12 and the pre-membrane sub-pipeline 14 is equipped with a filter 15 and a pressure gauge for testing the pre-membrane pressure. A flow meter (mass flow meter or electromagnetic flow meter) is installed on the pre-membrane sub-pipeline 14. The flow meter can measure the amount of material flowing into each nanomembrane 7. The C' port 5 and D' port 6 of the positive pressure transfer pipeline 4 are detachably connected to the post-membrane pipeline 2. The post-membrane pipeline 2 comes from the virus-free area and goes to the virus-free area. A pressure gauge for detecting the post-membrane pressure is installed on the post-membrane pipeline near the D' port 6 side of the positive pressure transfer pipeline 4.
[0046] In other embodiments, the number of nanofilms in the positive pressure transfer component can be designed and adjusted, for example, two, six, or seven, to better match production needs.
[0047] Example 2
[0048] The positive pressure transfer nanomembrane cross-clean zone virus removal filtration system of Example 1 was used to remove viruses from products in material tanks. The specific operation method is as follows:
[0049] S1. Preparations:
[0050] S11. Clean the valves, hoses, pressure gauges and other parts of the positive pressure transfer components;
[0051] S12. Perform pre-use water washing and pre-use integrity testing on the four nanofilms;
[0052] S13. Assemble the positive pressure transfer components;
[0053] S14. Pour clean compressed air into the positive pressure transfer component until the four pressure gauges show ≥0.1 Bar, close the corresponding valves, and carry out positive pressure transfer to enter the virus contamination risk area;
[0054] S2. Preparations for areas at risk of virus contamination:
[0055] S21. Before the positive pressure transfer component is transferred in, the pre-membrane sub-pipeline is cleaned by CIP and the post-membrane pipeline is cleaned by CIP.
[0056] S22. Connect the C' and D' ports of the positive pressure transfer line to the post-membrane line, and perform SIP on the post-membrane line connected to the positive pressure transfer line;
[0057] S23. After the post-membrane tubing to be connected to the positive pressure transfer component is cooled naturally or cooled using buffer solution and clean compressed air from a virus-free area, the positive pressure protective membrane tubing and positive pressure transfer component are connected from the virus-free area.
[0058] S3, Nanofiltration operation:
[0059] S31. Connect the A and B ports of the four nanofilms to their respective in-membrane sub-tubes. Figure 5 The structure of one of the nanofilms connected to the corresponding pre-membrane sub-channel is shown;
[0060] S32. Use the buffer solution in the buffer tank to wash and / or balance the pre-membrane tubing connected to the positive pressure transfer component, balancing one by one according to the tank weight reduction or according to the flow meter.
[0061] S33. For the filter products inside the nanofiltration tank, use a flow meter to detect the total amount of filtered protein and control the pressure difference between the membrane pre-pressure and the membrane post-pressure to be between 2 and 3.5 Bar.
[0062] S34. When the product in the material tank is reduced to 10kg or the liquid level sensor in the material tank reaches the bottom of the tank, switch to the buffer tank to rinse the nanomembrane from the top; at the same time, use the buffer in the buffer tank to rinse the material tank; then switch to the material tank to continue nanofiltration; repeat this process until the material tank rinses the residual product to an acceptable level and the nanomembrane product from the top is rinsed to an acceptable level, so as to maximize the recovery of the product. Throughout the process, the pressure difference between the pressure before and after the membrane is controlled at 2~3.5 Bar.
[0063] S4. Post-nanofiltration operation:
[0064] S41. After use, the nanomembrane undergoes an integrity test. The access point of the integrity tester is set on the discharge end side of the pre-membrane pipeline.
[0065] S42. Remove the nanomembrane, install a detachable short pipe at the corresponding position in the post-membrane pipeline, and perform CIP on the pre-membrane pipeline and post-membrane pipeline.
[0066] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.
Claims
1. A method of operating a positive pressure transfer nanomembrane cross clean zone viral removal filtration system, comprising: Includes the following steps: S1. Preparations for a virus-free zone: S11. Clean all parts of the positive pressure transfer component; S12. Perform pre-use water washing and pre-use integrity testing on the nanofilm; S13. Assemble the positive pressure transfer components; S14. Pour clean compressed air into the positive pressure transfer component until the pressure gauge shows ≥0.1 Bar, close the corresponding valve, and carry out positive pressure transfer to enter the virus contamination risk area; S2. Preparations for areas at risk of virus contamination: S21. Before the positive pressure transfer component is transferred in, the pre-membrane sub-pipeline is cleaned by CIP and the post-membrane pipeline is cleaned by CIP. S22. Connect the C' and D' ports of the positive pressure transfer line to the post-membrane line, and perform SIP on the post-membrane line connected to the positive pressure transfer line; S23. After the membrane post-pipeline to be connected to the positive pressure transfer component is cooled down, the positive pressure protective membrane post-pipeline and the positive pressure transfer component are connected from the virus-free contamination area. S3, Nanofiltration operation: S31. Connect port A and port B of the nanofilm to the pre-membrane sub-tube respectively; S32. Use the buffer solution in the buffer tank to wash and / or balance the pre-membrane tubing connected to the positive pressure transfer component, balancing one by one according to the tank weight reduction or according to the flow meter. S33. For products in the filter material tank, use a flow meter to detect the total amount of filtered protein. The positive pressure transfer nanomembrane cross-cleanroom virus removal filtration system used in the described operation method includes a pre-membrane pipeline and a post-membrane pipeline, as well as a positive pressure transfer component. The positive pressure transfer component includes a positive pressure transfer pipeline and at least two nanomembranes. One end of the positive pressure transfer pipeline is a C' port, and the other end is a D' port. Each nanomembrane has an A port and a B port at both ends, and a C port and a D port on its sidewall. The C and D ports of each nanomembrane are connected to the positive pressure transfer pipeline via flexible tubing, and the C port is connected to the positive pressure transfer pipeline... A pressure gauge is installed on the connecting hose; the pre-membrane pipeline is located in the virus contamination risk area, and the feed end of the pre-membrane pipeline is connected to the buffer tank and the material tank respectively. The pre-membrane pipeline is equipped with pre-membrane sub-pipelines, the number of which is the same as the number of nanomembranes. The pre-membrane sub-pipelines are connected in parallel. The A port and B port of each nanomembrane are detachably connected to the corresponding pre-membrane sub-pipeline; the C' port and D' port of the positive pressure transfer pipeline are detachably connected to the post-membrane pipeline. The post-membrane pipeline comes from the virus-free area and goes to the virus-free area. A pressure gauge is installed on the post-membrane pipeline on the side of port D' near the positive pressure transfer pipeline.
2. The operating method of claim 1, wherein, A flow meter is installed on the pre-membrane pipeline.
3. The operating method of claim 2, wherein, A filter and a pressure gauge are installed on the pre-membrane tubing between the buffer tank and the pre-membrane tubing.
4. The operating method of claim 1, wherein, The cooling method for the post-membrane tubing connected to the positive pressure transfer tubing in S23 is either natural cooling or cooling by introducing buffer solution into the tubing and then purging.
5. The operating method of claim 1, wherein, S3, Nanofiltration also includes S34, using buffer solution to rinse the contents of the tank or top rinse the nanomembrane.
6. The operating method of claim 1, wherein, It also includes S4 and post-nanofiltration processes: S41. The nanofilm undergoes an integrity test after use. S42. Remove the nanomembrane and perform CIP on the pre-membrane and post-membrane pipelines.
7. The operating method of claim 1, wherein, The access point for the integrity tester is located on the discharge end side of the pre-membrane pipeline.