A method for removing viruses by filtration using an in-situ sterilized nanofilm

Abstract

The present invention relates to the technical field of the production of biological products and blood products, and particularly relates to a virus removal filtration system for in-situ sterilization of a nano-membrane and an operation method thereof. The virus removal filtration system includes a nano-membrane, with an A port and a B port respectively provided at both ends of the nano-membrane, and a C port and a D port provided on the side wall of the nano-membrane. It also includes a pre-membrane pipeline, a post-membrane pipeline and a first pipeline arranged in the virus contamination risk area. The feeding end of the pre-membrane pipeline is respectively connected to a buffer tank and a material tank, and the buffer tank is connected to the material tank. The nano-membrane is detachably installed on the pre-membrane pipeline and the post-membrane pipeline. When the nano-membrane is installed, the pre-membrane pipeline is connected to the A port and the B port of the nano-membrane, and the post-membrane pipeline is connected to the C port and the D port of the nano-membrane. The first pipeline is connected to the virus-free area and is connected in parallel with the post-membrane pipeline. The present invention does not involve the transfer of regional articles and completes all operations in the virus contamination risk area.

Description

Technical Field

[0001] The present invention relates to the technical field of biologic and blood product production, and particularly relates to a virus removal filtration system for in-situ sterilized nano-films and an operation method thereof. Background Art

[0002] In the production of biologic and blood products, viruses may be introduced into the product raw materials or the processing process, resulting in the risk of virus or potential virus contamination in the products. Therefore, methods for virus inactivation or removal must be introduced during the production process.

[0003] The nano-film filtration method is safe and effective, and can preserve the biological activity of the product while removing viruses. At present, mainstream manufacturers usually adopt this method to remove viruses from biologic and blood products. However, the current GMP (Good Manufacturing Practice) requires in Article 16 of Chapter 4, Buildings and Equipment: In the production of blood products, measures should be taken to prevent cross-contamination of products before and after virus removal and / or inactivation. The products after virus removal and / or inactivation should be produced in an isolated dedicated production area and with dedicated equipment, and an independent air purification system should be used.

[0004] Chinese Patent CN112933971A discloses a nano-film virus removal filtration system across clean areas and an operation method thereof. This method processes materials in a virus-free risk area and transfers them into the virus-contaminated area under positive pressure protection. For the parts that cannot be protected during the transfer process, the contamination risk is eliminated by SIP. This method is applicable to the situation where the filter does not support SIP and the total filtration volume (liquid volume or protein content) is not high, and usually one filter can match the production scale.

[0005] Therefore, it is necessary to provide a virus removal filtration system for in-situ sterilized nano-films and an operation method thereof. Summary of the Invention

[0006] Aiming at the technical problem of regional material transfer in the virus removal filtration system for biological or blood products, the present invention provides a virus removal filtration system for in-situ sterilized nano-films and an operation method thereof. For the situation where the filter supports SIP, there is no need to transfer materials across regions. Instead, direct SIP and positive pressure protection are carried out on all areas that may contaminate the products after virus removal in the virus-contaminated risk area.

[0007] In a first aspect, the present invention provides a virus removal filtration system for an in-situ sterilized nano-membrane, which includes a nano-membrane. An A port and a B port are respectively provided at both ends of the nano-membrane, and a C port and a D port are provided on the side wall of the nano-membrane. The virus removal filtration system further includes a pre-membrane pipeline, a post-membrane pipeline and a first pipeline arranged in the virus contamination risk area. The feeding end of the pre-membrane pipeline is respectively communicated with a buffer tank and a material tank, and the buffer tank is communicated with the material tank. The nano-membrane is detachably installed on the pre-membrane pipeline and the post-membrane pipeline. When the nano-membrane is installed, the pre-membrane pipeline is communicated with the A port and the B port of the nano-membrane, and the post-membrane pipeline is communicated with the C port and the D port of the nano-membrane. The first pipeline is communicated with the virus-free area and is connected in parallel with the post-membrane pipeline.

[0008] Further, the pre-membrane pipeline includes at least two pre-membrane sub-pipelines, and the multiple pre-membrane sub-pipelines are arranged in parallel with each other. A nano-membrane is detachably installed on each pre-membrane sub-pipeline;

[0009] The post-membrane pipeline includes at least two post-membrane sub-pipelines, and the multiple post-membrane sub-pipelines are arranged in parallel with each other. A nano-membrane is detachably installed on each post-membrane sub-pipeline.

[0010] A plurality of pre-membrane sub-pipelines and post-membrane sub-pipelines are provided to match the production scale and meet the use under the condition of a large total filtration volume (a large liquid volume and / or a high protein content).

[0011] Further, the number of pre-membrane sub-pipelines is the same as the number of post-membrane sub-pipelines.

[0012] Further, a flowmeter is installed on the pre-membrane pipeline and / or the post-membrane pipeline. The type of the flowmeter is a mass flowmeter or an electromagnetic flowmeter, which is used to measure the amount of the material flowing into and / or out of the nano-membrane.

[0013] In a second aspect, the present invention provides an operation method for a virus removal filtration system of an in-situ sterilized nano-membrane, including the following steps:

[0014] S1. Preparation work:

[0015] (11) Perform CIP on the post-membrane pipeline;

[0016] (12) Install the nano-membrane on the post-membrane pipeline, and seal the A port and the B port of the nano-membrane with a blind plate, and perform SIP on the post-membrane pipeline;

[0017] (13) After the SIP is completed, perform positive pressure protection on the first pipeline and the post-membrane pipeline;

[0018] S2. Nanofiltration work:

[0019] (21) Perform CIP on the pre-membrane pipeline;

[0020] (22) Connect the A port and the B port of the nano-membrane to the pre-membrane pipeline respectively;

[0021] (23) Detect the airtightness of the nano - membrane before use;

[0022] (24) Wash and / or balance the pipeline in front of the membrane with the buffer solution in the buffer tank;

[0023] (25) Filter the materials in the material tank.

[0024] Further, before performing CIP on the pipeline behind the membrane in step (11), first perform CIP on the first pipeline;

[0025] Before performing SIP on the pipeline behind the membrane in step (12), first perform SIP on the first pipeline.

[0026] Further, in step (12), after SIP is completed, immediately introduce clean compressed air with a pressure ≥ 0.1 Bar. The air source is from the virus - free pollution area;

[0027] In step (13), the positive - pressure protection is to continuously introduce clean compressed air with a pressure ≥ 0.1 Bar. The air source is from the virus - free pollution area.

[0028] Further, S2, the nanofiltration operation also includes step (26) using the buffer solution to rinse the products in the material tank or back - wash the nano - membrane to maximize the recovery of products; The specific method is that when the products in the material tank are reduced to 10 kg or the liquid - level sensor in the material tank reaches the bottom of the tank, switch to the buffer tank to back - wash the nano - membrane, and at the same time use the buffer solution in the buffer tank to rinse the material tank, then switch to the material tank to continue nanofiltration, and repeat until the residual products in the material tank after rinsing reach the acceptable level and the products on the back - washed nano - membrane reach the acceptable level.

[0029] Further, it also includes S3, the work after nanofiltration:

[0030] (31) Perform integrity testing on the nano - membrane after use;

[0031] (32) Remove the nano - membrane and perform CIP on the pipeline in front of the membrane, the pipeline behind the membrane and the first pipeline.

[0032] Further, the access site of the integrity tester is set on the side of the discharge end of the pipeline in front of the membrane.

[0033] The beneficial effects of the present invention are as follows:

[0034] The virus - removing filtration system for in - situ sterilization nano - membrane and its operation method provided by the present invention are applicable to the virus - removing filtration of biological products with high protein concentration and large - scale (kilogram - level protein filtration), and are particularly suitable for large - scale industrial production; The present invention does not involve the transfer of regional articles, and all operations are completed in the virus - contaminated risk area (potential virus - contaminated area or virus - contaminated area). Description of the Drawings

[0035] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, for those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0036] Figure 1 It is a schematic structural diagram when the nano - membrane is not installed in the post - membrane pipeline in Embodiment 2.

[0037] Figure 2 It is a schematic structural diagram when the nano - membrane is installed in the post - membrane pipeline in Embodiment 2.

[0038] Figure 3 It is a schematic structural diagram when the nano - membrane is installed in the pre - membrane pipeline in Embodiment 2.

[0039] In the figure, 1 - post - membrane pipeline, 2 - pre - membrane pipeline, 3 - flowmeter, 4 - nano - membrane, 5 - buffer tank, 6 - material tank, 7 - No.1 pipeline. Specific embodiments

[0040] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0041] Embodiment 1

[0042] A virus - removing filtration system for in - situ sterilization of a nano - membrane includes a nano - membrane. At both ends of the nano - membrane, there are respectively an A port and a B port, and on the side wall of the nano - membrane, there are a C port and a D port. It also includes a post - membrane pipeline 1, a pre - membrane pipeline 2, and a No.1 pipeline 7 arranged in the virus - contaminated risk area. The feeding end of the pre - membrane pipeline 2 is respectively connected to a buffer tank 5 and a material tank 6, and the buffer tank 5 is connected to the material tank 6; the No.1 pipeline 7 is connected to the virus - free area and is connected in parallel with the post - membrane pipeline 1, providing CIP, SIP, clean compressed air, and buffer solution from the virus - free area for the post - membrane pipeline 1. The product after virus removal by filtration through the nano - membrane goes to the virus - free area through the No.1 pipeline 7;

[0043] The nano - membrane 4 is detachably installed on the post - membrane pipeline 1 and the pre - membrane pipeline 2. When the nano - membrane 4 is installed, the post - membrane pipeline 1 is connected to the C port and D port of the nano - membrane 4, and the pre - membrane pipeline 2 is connected to the A port and B port of the nano - membrane 4.

[0044] Embodiment 2

[0045] On the basis of Embodiment 1, to adapt to the scale of process filtration, the post-membrane pipeline 1 includes n (n≥2) post-membrane sub-pipelines arranged in parallel with each other and connected by a multi-channel valve, and a flow meter 3 is installed on each post-membrane sub-pipeline; the pre-membrane pipeline 2 includes m (m = n) pre-membrane sub-pipelines arranged in parallel with each other and connected by a multi-channel valve, and a flow meter 3 (not shown) is installed on each pre-membrane sub-pipeline; correspondingly, the number of nano-membranes is r (r = m = n), the C port and D port of each nano-membrane 4 are connected to the corresponding post-membrane sub-pipeline to form a passage, and the A port and B port of each nano-membrane 4 are connected to the corresponding pre-membrane sub-pipeline to form a passage.

[0046] Embodiment 3

[0047] Use the virus removal filtration system (n = m = r = 4) of the in-situ sterilization nano-membrane of Embodiment 2 to perform virus removal treatment on the product in the material tank. The specific operation method is as follows:

[0048] S1. Preparation work:

[0049] (11) Perform CIP on the No. 1 pipeline and each post-membrane sub-pipeline in sequence;

[0050] (12) Install the C port and D port of each nano-membrane onto the corresponding post-membrane sub-pipeline respectively, and seal the A port and B port of each nano-membrane with a blind plate. Perform SIP on the No. 1 pipeline and each post-membrane sub-pipeline in sequence. After completion, immediately introduce clean compressed air with a pressure ≥0.1 Bar. The air source is from the virus-free pollution area;

[0051] (13) After all SIP is completed, uniformly perform continuous positive pressure protection with clean compressed air with a pressure ≥0.1 Bar. The air source is from the virus-free pollution area;

[0052] S2. Nanofiltration work:

[0053] (21) Perform CIP on each pre-membrane sub-pipeline;

[0054] (22) Install the A port and B port of each nano-membrane onto the corresponding pre-membrane sub-pipeline respectively;

[0055] (23) Detect the airtightness of the nano-membrane and wash it with water before use;

[0056] (24) Wash each pre-membrane sub-pipeline with the buffer solution in the buffer tank in sequence, and balance them one by one according to the weight reduction of the tank;

[0057] (25) Filter the material in the material tank, use a flow meter to detect the total amount of filtered protein, and control the pressure difference between the pre-membrane pressure and the post-membrane pressure at 2 - 3.5 Bar;

[0058] When the product in the material tank is reduced to 10 kg or the liquid level sensor in the material tank reaches the bottom of the tank, switch to wash the nano-film at the top of the buffer tank; at the same time, use the buffer liquid in the buffer tank to wash the material tank; then switch the material tank to continue nanofiltration; repeat repeatedly until the residual product in the material tank is washed to an acceptable level and the product washed at the top of the nano-film is at an acceptable level to maximize the recovery of the product. During the whole process, control the pressure difference between the pre-membrane pressure and the post-membrane pressure within 2 - 3.5 Bar;

[0059] S3. Work after nanofiltration:

[0060] (31)After use, conduct an integrity test on the nano-film. The access point of the integrity tester is set on the outlet end side of the pre-membrane pipeline;

[0061] (32)Remove the nano-film from the post-membrane sub-pipeline and the pre-membrane sub-pipeline, and conduct CIP on the pre-membrane pipeline, the post-membrane pipeline, and the first pipeline.

[0062] Although the present invention has been described in detail by referring to the accompanying drawings and in combination with the preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, those of ordinary skill in the art can make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions should all be within the scope of the present invention. / Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should all be covered by the protection scope of the present invention.

Claims

1. A virus removal filtration system for in-situ sterilization of a nanofilm, comprising a nanofilm, with an A port and a B port respectively provided at both ends of the nanofilm, and a C port and a D port provided on the side wall of the nanofilm, characterized in that, The virus removal filtration system further includes a pre-membrane pipeline, a post-membrane pipeline, and a first pipeline disposed in the virus contamination risk area. The feed end of the pre-membrane pipeline is respectively connected to a buffer tank and a material tank, the buffer tank is connected to the material tank, and the nano-membrane is detachably installed on the pre-membrane pipeline and the post-membrane pipeline. When the nano-membrane is installed, the pre-membrane pipeline is connected to ports A and B of the nano-membrane, and the post-membrane pipeline is connected to ports C and D of the nano-membrane. The first pipeline is connected to the virus-free area and is connected in parallel with the post-membrane pipeline; The pre-membrane pipeline includes at least two pre-membrane sub-pipelines, and the multiple pre-membrane sub-pipelines are arranged in parallel with each other. A nano-membrane is detachably installed on each pre-membrane sub-pipeline; The post-membrane pipeline includes at least two post-membrane sub-pipelines, and the multiple post-membrane sub-pipelines are arranged in parallel with each other. A nano-membrane is detachably installed on each post-membrane sub-pipeline.

2. The virus removal filtration system according to claim 1, wherein The number of pre-membrane sub-pipelines is the same as the number of post-membrane sub-pipelines.

3. The virus removal filtration system according to claim 1, wherein, A flow meter is installed on the pre-membrane pipeline and / or the post-membrane pipeline.

4. An operating method of a virus removal filtration system as claimed in claim 1, characterized in that, It includes the following steps: S1. Preparation work: (11) Perform CIP on the post-membrane pipeline; (12) Install the nano-membrane on the post-membrane pipeline, and seal ports A and B of the nano-membrane with a blind plate, and perform SIP on the post-membrane pipeline; (13) After SIP is completed, perform positive pressure protection on the first pipeline and the post-membrane pipeline; S2. Nanofiltration work: (21) Perform CIP on the pre-membrane pipeline; (22) Connect ports A and B of the nano-membrane to the pre-membrane pipeline respectively; (23) Detect the airtightness of the nano-membrane before use; (24) Use the buffer solution in the buffer tank to wash and / or balance the pre-membrane pipeline; (25) Filter the material in the material tank.

5. The operating method according to claim 4, wherein Before performing CIP on the post-membrane pipeline in step (11), first perform CIP on the first pipeline; Before performing SIP on the post-membrane pipeline in step (12), first perform SIP on the first pipeline.

6. The operating method according to claim 4, wherein In step (12), after SIP is completed, immediately introduce clean compressed air with a pressure of ≥0.1 Bar, and the air source is from the virus-free contamination area; In step (13), the positive pressure protection is to continuously introduce clean compressed air with a pressure of ≥0.1 Bar, and the air source is from the virus-free contamination area.

7. The operating method according to claim 4, wherein S2. The nanofiltration work further includes step (26) using the buffer solution to rinse the product in the material tank or backwash the nano-membrane to maximize the recovery of the product.

8. The operating method according to claim 4, wherein It further includes S3. Post-nanofiltration work: (31) Perform an integrity test on the nano-membrane after use; (32) Remove the nano-membrane, and perform CIP on the pre-membrane pipeline, the post-membrane pipeline, and the first pipeline.

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