Method for improving human immune globulin nano-membrane filtration

Abstract

The invention relates to the technical field of biological pharmacy and separation and purification, and discloses a method for improving human immune globulin nano-membrane filtration, which comprises the following steps: S1, selecting a human immune globulin raw material solution which is a to-be-filtered solution containing immune globulin M macromolecular impurities after being treated by a preorder purification process; s2, a nanofiltration membrane with a specific aperture range is selected, a membrane material of the nanofiltration membrane is selected from one or a combination of more of regenerated cellulose, polyether sulfone, polyvinylidene fluoride or polysulfone, and the filtration flux is limited by the surface hydrophobicity in an initial state. According to the preparation method, a uniform physical hydrophilic adsorption layer is formed on the surface of the membrane through a multi-stage synergistic pretreatment process of'rinsing-surfactant adsorption-charge regulation ', and the charge characteristic of the surface of the membrane is regulated through a buffer solution, so that the inherent hydrophobicity of membrane materials such as regenerated cellulose and polyether sulfone is effectively improved, and the resistance of liquid passing through membrane pore channels is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biopharmaceuticals and separation and purification technology, in particular to an improved method for nanofiltration of human immunoglobulin. BACKGROUND

[0002] With the development of the biopharmaceutical industry, the purification technology of human immunoglobulin has become an important link to ensure product quality and production efficiency. However, the existing nanofiltration process has certain limitations in the separation and purification process of human immunoglobulin. The main problems include low flux, high cost, and long nanofiltration time leading to increased risk of microbial contamination. These problems pose challenges to the stability and economy of the process. In the prior art, although the nanofiltration membrane with a specific pore size range can achieve the retention of impurities to some extent, it still faces the following key problems: Firstly, the membrane surface hydrophobicity limits the filtration efficiency. Commonly used membrane materials such as regenerated cellulose and polyether sulfone exhibit strong hydrophobic properties in the initial state, which increases the resistance when the liquid passes through, thereby reducing the filtration flux. Secondly, long-time nanofiltration operation increases the process complexity. Due to the low flux, the filtration process needs longer time to complete, which not only increases the production cost, but also increases the possibility of microbial growth, posing a potential threat to product safety. In addition, the existing pretreatment process has limited effect on improving the performance of the membrane, and has not fully cooperated to improve the hydrophilicity and charge characteristics of the membrane surface, making it difficult to achieve the desired filtration efficiency. SUMMARY

[0003] (I) Technical problems solved In view of the deficiencies of the prior art, the present application provides an improved method for nanofiltration of human immunoglobulin, which solves the problem of low work efficiency in the background art.

[0004] (II) Technical solutions

[0005] To achieve the above purpose, the present application is implemented by the following technical solutions: an improved method for nanofiltration of human immunoglobulin, comprising the following steps: S1: selecting a human immunoglobulin raw material liquid, which is a to-be-filtered solution containing immunoglobulin M macromolecular impurities after being treated by a previous purification process; S2: selecting a nanofiltration membrane with a specific pore size range, the membrane material of the nanofiltration membrane is selected from one or more combinations of regenerated cellulose, polyether sulfone, polyvinylidene fluoride or polysulfone, and the initial state of the surface hydrophobicity limits the filtration flux; S3: implementing a systematic pretreatment process on the nanofiltration membrane provided in S2, which includes multiple stages and mainly cooperatively improves the hydrophilicity of the membrane surface; S4: The nanofiltration membrane treated by the S3 complete pretreatment process is directly used for nanofiltration operation of the human immunoglobulin raw material liquid provided in S1 under constant pressure or constant flow mode, so that macromolecular impurities are effectively intercepted, and a clear filtrate with higher filtration flux is obtained.

[0006] Preferably, the systematic pretreatment process comprises: S301: Membrane system rinse stage: using water for injection or purified water, under the conditions of preset flow rate and pressure, the filtration system installed with the nanofiltration membrane is fully circulated and rinsed to remove the particulate impurities and soluble protective agents possibly existing in the membrane pores, until the water quality parameters of the circulating discharge reach the stable baseline; S302: Surfactant balance stage: a pretreatment solution containing a predetermined concentration of nonionic surfactant is configured, the pretreatment solution is pumped into the filtration system after S301 rinsing, and is in continuous contact and circulation balance with the effective filtration surface of the nanofiltration membrane, so that the nonionic surfactant molecules can be fully adsorbed on the membrane surface and the inner wall of the pores to form a physical hydrophilic modification layer; S303: Surface charge adjustment stage: a buffer solution with a specific pH value is configured, the pH value of the buffer solution is controlled within a range that can change the dissociation state of the inherent functional groups on the surface of the nanofiltration membrane, the buffer solution is pumped into the filtration system after S302 balance, and the nanofiltration membrane is treated, so that the type or density of the charges on the membrane surface is adjusted to realize the chemical enhancement of the hydrophilic performance of the membrane surface, and the synergistic effect with the physical hydrophilic modification layer formed in S302 is generated.

[0007] Preferably, in the step S302, the nonionic surfactant in the pretreatment solution is a polysorbate compound, and the chemical composition is polyoxyethylene sorbitan fatty acid ester.

[0008] Preferably, the polysorbate compound is polysorbate 80, and the mass-volume concentration in the pretreatment solution is accurately controlled within the concentration range of 0.01% to 0.5%, so as to ensure the formation of a stable and uniform hydrophilic adsorption layer on the surface of the nanofiltration membrane, while avoiding potential residual pollution to the subsequent protein product due to too high concentration.

[0009] Preferably, in the S303, the buffer solution for adjusting the surface charge of the nanofiltration membrane is an acidic buffer system, and the pH value of the acidic buffer system is set within the range of 3.5 to 5.5, which mainly reduces the protonation degree of the acidic functional groups of the carboxyl groups on the surface of the nanofiltration membrane or increases the protonation degree of the basic functional groups of the amino groups, so as to change the net charge of the membrane surface and enhance the interaction force between the membrane surface and water molecules.

[0010] Preferably, the acid buffer system is selected from one of acetic acid-sodium acetate buffer system, citric acid-sodium citrate buffer system or phosphate buffer system, and the ionic strength of the buffer system is controlled in the range of 10-100 mmol / L to maintain the osmotic pressure environment of the filtration system stable while effectively adjusting the surface charge.

[0011] Preferably, the nanofiltration operation in S4 is performed under a constant transmembrane pressure difference controlled in the range of 0.1-0.3 MPa, and the temperature during the whole nanofiltration operation is strictly maintained in a low temperature environment of 2-15℃ to guarantee the bioactivity and structural stability of human immunoglobulin.

[0012] Preferably, the nanofiltration membrane provided in S2 is a flat membrane package or hollow fiber membrane column specially designed for virus removal or large molecular protein separation, and the molecular weight cut-off or nominal pore size is selected to effectively cut off particles with a diameter greater than 20 nm, especially immunoglobulin M pentamer, while ensuring that the target product immunoglobulin G monomer can pass through efficiently.

[0013] Preferably, before performing the systematic pretreatment process in S3, a preliminary step is included to detect and confirm the physicochemical parameters of the human immunoglobulin raw material liquid, including but not limited to adjusting its pH value to the range of 6.0-7.5 and detecting and confirming that its turbidity value is lower than a preset threshold value, to ensure that the state of the raw material liquid is most suitable for subsequent nanofiltration operation and prevent irreversible contamination or clogging of the pretreated membrane.

[0014] Preferably, in S302, the non-ionic surfactant is polysorbate 80 with a concentration of 0.1%, and the duration of the equilibrium stage is not less than 30 minutes, and in S303, the buffer is acetic acid-sodium acetate buffer with a pH value of 4.5, and the treatment time is not less than 20 minutes, and after S303 and before S4, an additional final rinse step is included, using injection water without surfactant and pH adjuster to rinse the nanofiltration membrane after surface charge adjustment to remove residual buffer salt ions and unabsorbed surfactant molecules in the system, until the conductivity and pH value of the effluent return to the level consistent with the injection water used.

[0015] (Three) beneficial effects

[0016] The present application provides an improved method for nanofiltration of human immunoglobulin. It has the following beneficial effects: (1) The improved human immunoglobulin nanometer membrane filtration method, when used, through the multi-stage synergistic pretreatment process of "rinsing-surfactant adsorption-charge adjustment", forms a uniform physical hydrophilic adsorption layer on the membrane surface and adjusts the charge characteristics of the membrane surface through the buffer, effectively improves the inherent hydrophobicity of the membrane material such as regenerated cellulose and polyether sulfone, reduces the resistance of the liquid passing through the membrane pore, improves the filtration flux, shortens the single batch nanofiltration operation time, reduces the equipment occupation cost and energy consumption caused by long time filtration, and at the same time reduces the economic loss caused by the extension of the production cycle.

[0017] (2) The improved human immunoglobulin nanometer membrane filtration method, when used, shortens the operation time by improving the filtration flux, and strictly controls the temperature in the whole filtration process in a low-temperature environment of 2-15℃. The low-temperature condition not only can guarantee the biological activity and structural stability of human immunoglobulin, but also can significantly inhibit the growth and reproduction of microorganisms; combined with the higher filtration efficiency after pretreatment, the time window of the raw material liquid in the system is reduced, and the potential risk of microbial contamination is reduced from two dimensions, which provides more reliable guarantee for product safety.

[0018] (3) The improved human immunoglobulin nanometer membrane filtration method, when used, effectively removes the particulate impurities and soluble protective agents in the membrane pore through the rinsing stage, avoids the initial pollution; the surfactant adsorption and charge adjustment stage optimizes the membrane surface characteristics through physical and chemical synergistic effect, reduces the non-specific adsorption of macromolecular impurities on the membrane surface and the pore blockage in the filtration process. Reducing the membrane pollution rate, prolonging the effective service life of the membrane, reducing the membrane replacement frequency, further reducing the consumable cost in the production process, improving the economic efficiency and stability of the process. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 The flowchart of the present application is shown in the figure. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0021] Please refer to Figure 1 The present application provides an improved human immunoglobulin nanometer membrane filtration method, which comprises the following steps: S1: Select the human immunoglobulin raw material liquid to be treated, the raw material liquid is a solution still containing macromolecular impurities after being treated by the previous purification process. First, the pH value of the raw material liquid is detected and adjusted to ensure that it is within the range of 6.0 to 7.5. This range is chosen to avoid the impact of excessively high or low pH values on the performance of the membrane in the subsequent filtration process. At the same time, the turbidity value of the raw material liquid needs to be detected to confirm that it is below the preset threshold to prevent irreversible contamination or clogging of the pretreated membrane. After the preparation stage of the raw material liquid is completed, the selection and pretreatment of the nanofiltration membrane are entered.

[0022] S2: Select the nanofiltration membrane, the material selection of the nanofiltration membrane includes one or more combinations of regenerated cellulose, polyether sulfone, polyvinylidene fluoride, or polysulfone. These materials have different pore size ranges and surface properties, which can be flexibly matched according to actual needs. In this embodiment, a flat membrane package with a molecular weight cut-off or nominal pore size capable of effectively retaining particles with a diameter greater than 20 nanometers is selected as the filtration medium. The goal is to ensure that immunoglobulin M (IgM) pentamers are retained, while the target product, immunoglobulin G (IgG) monomers, can pass through efficiently. After the membrane package is installed, a systematic pretreatment process is performed, which is a key step to improve filtration efficiency and ensure product quality.

[0023] S3: The systematic pretreatment process is divided into: S301: Wetting stage, using water for injection or purified water, the filtration system installed with nanofiltration membrane is circulated and wetted under the condition of set flow rate and pressure. The flow rate is usually controlled at 10 to 30 liters per minute, and the pressure is maintained at 0.05 to 0.1 megapascals to ensure that the water can fully penetrate the membrane pores and remove the possible particulate impurities and soluble protective agents in the membrane. The wetting process continues until the water quality parameters of the circulating discharge reach the stable baseline, which usually takes 30 to 60 minutes, and the specific time is determined according to the initial state of the membrane and the wetting effect.

[0024] S302: Surfactant adsorption stage, after the wetting is completed, a pretreatment solution containing a predetermined concentration of non-ionic surfactant is prepared. The non-ionic surfactant selected is polysorbate 80, with a mass-volume concentration strictly controlled within the range of 0.01% to 0.5% (w / v). In this embodiment, the concentration is selected as 0.1% (w / v) to form a uniform adsorption layer on the surface of the nanofiltration membrane, while avoiding potential residual effects on the subsequent protein product due to excessively high concentration. The pretreatment solution is pumped into the filtration system after wetting and continuously contacts and balances with the effective filtration surface of the nanofiltration membrane. The duration of the adsorption stage is not less than 30 minutes to ensure that the non-ionic surfactant molecules can be fully adsorbed on the membrane surface and the inner wall of the pores to form a physical hydrophilic modification layer S303: After the surfactant adsorption stage, a buffer solution with a specific pH value is prepared. The pH value of the buffer solution is controlled in the range of 3.5 to 5.5. In this embodiment, an acetic acid-sodium acetate buffer solution with a pH value of 4.5 is selected, and the ionic strength thereof is controlled in the range of 10 mmol / L to 100 mmol / L. The preparation of the buffer solution needs to accurately control the pH value and the ionic strength, so as to maintain the stability of the osmotic pressure environment of the filtration system while adjusting the surface charge of the membrane. The buffer solution is pumped into the filtration system after the surfactant adsorption stage, so as to realize the chemical hydrophilic enhancement by adjusting the type or density of the charge on the membrane surface. The processing time of the charge adjustment stage is not less than 20 minutes, so as to ensure that the buffer solution can fully act on the membrane surface.

[0025] After the completion of the charge adjustment stage, a rinsing step is performed. Purified water without surfactants and pH adjusters is used to rinse the nanofiltration membrane, so as to remove the residual buffer salt ions and unadsorbed surfactant molecules in the system. The rinsing process continues until the conductivity and pH value of the effluent recover to the level consistent with the purified water used. The time of the final rinsing step is usually 15 to 30 minutes, and the specific time is determined according to the rinsing effect.

[0026] S4: After the completion of the pretreatment process, the nanofiltration membrane subjected to the complete pretreatment process is used for filtration operation in a constant pressure or constant flow mode. The filtration operation is performed under a constant transmembrane pressure difference, and the transmembrane pressure difference is controlled in the range of 0.1 MPa to 0.3 MPa. At the same time, the temperature during the entire filtration operation is strictly maintained in a low-temperature environment of 2°C to 15°C, so as to guarantee the biological activity and structural stability of the human immunoglobulin. During the filtration operation, the raw material liquid enters the filtration system from the feed port, and the macromolecular impurities are effectively removed by the retention effect of the nanofiltration membrane, and the clarified filtrate flows out from the discharge port. The time of the filtration operation is determined according to the volume of the raw material liquid and the flux performance of the membrane, and is usually 2 to 4 hours.

[0027] During the entire implementation process, the operation conditions and parameter settings of each link are strictly optimized, so as to maximize the filtration efficiency and product quality. For example, the flow rate and pressure setting of the wetting stage are to ensure that water can fully penetrate the membrane pores, and the concentration and time control of the surfactant adsorption stage are to form a uniform adsorption layer on the membrane surface. The pH value and ionic strength setting of the charge adjustment stage is to adjust the charge characteristics of the membrane surface and enhance the interaction force between the membrane surface and water molecules. The execution of the final rinsing step is to remove the residual buffer salt ions and unadsorbed surfactant molecules in the system, so as to ensure the purity of the filtration operation.

[0028] In addition, the setting of low-temperature environment not only can guarantee the biological activity and structural stability of human immunoglobulin, but also can reduce the risk of microbial contamination. Through the systematic pretreatment process of multi-stage synergistic modification, the hydrophilic performance and filtration flux of the nanofiltration membrane are significantly improved. The physical hydrophilic modification layer formed in the surfactant adsorption stage is combined with the chemical hydrophilic enhancement achieved in the charge adjustment stage, effectively overcoming the limitation of membrane surface hydrophobicity on filtration efficiency. The setting of constant transmembrane pressure difference and low-temperature environment further guarantees the stability of the filtration process and the biological activity of the target product.

[0029] In order to better enable those skilled in the art to fully understand and implement the present application, the specific implementation principles of the present application are further supplemented below in combination with specific application scenarios.

[0030] In actual operation, first, the physicochemical parameters of the human immunoglobulin raw material liquid to be treated need to be detected and adjusted. The pH meter is used to measure the acidity and alkalinity of the raw material liquid, and the buffer solution is used to adjust it to the target range of 6.0 to 7.5. Within this range, the functional groups such as carboxyl and amino on the surface of the nanofiltration membrane can maintain appropriate dissociation state, thereby avoiding the decline of membrane performance caused by too high or too low pH value. At the same time, the turbidity of the raw material liquid is detected by using the turbidity meter to ensure that it is lower than the preset threshold, so as to prevent particulate matter from blocking the membrane pore channel, thereby providing a stable raw material basis for the subsequent filtration process.

[0031] Then, a flat membrane package with a specific molecular weight cut-off is selected as the filtration medium. The target of the membrane package is to effectively retain macromolecular impurities with a diameter greater than 20 nanometers, while allowing the target product immunoglobulin G (IgG) monomer to pass through efficiently. After the membrane package is installed, the rinse stage is entered. In this stage, water for injection or purified water is used to circulate and rinse the membrane system under the condition that the flow rate is controlled at 10 to 30 liters per minute and the pressure is maintained at 0.05 to 0.1 megapascal. During the rinse process, the shear force generated by the water flow through the membrane pore channel can remove the particulate impurities and soluble protective agents that may exist on the membrane surface and in the pore channel. The rinse time usually lasts for 30 to 60 minutes, until the water quality parameters reach a stable baseline, indicating that the membrane pore channel has been thoroughly cleaned.

[0032] After the rinse is completed, a polysorbate 80 solution with a mass volume concentration of 0.1% (w / v) is prepared as a pretreatment liquid. Polysorbate 80 is a non-ionic surfactant, and the hydrophilic groups in its molecule can form a uniform adsorption layer on the membrane surface, thereby reducing the hydrophobicity of the membrane surface. When the pretreatment liquid is pumped into the filtration system, through continuous contact and circulation balance, non-ionic surfactant molecules gradually adsorb on the membrane surface and the inner wall of the pore channel, forming a layer of physical hydrophilic modification layer. The adsorption time is not less than 30 minutes to ensure that the surfactant molecules fully cover the membrane surface and reduce the resistance when the liquid passes through.

[0033] Subsequently, an acetic acid-sodium acetate buffer solution with a pH value of 4.5 is prepared, and the ionic strength is controlled in the range of 10-100 mmol / L. After the buffer solution is pumped into the filtration system, it reacts with the membrane surface, changing the dissociation state of the inherent functional groups on the membrane surface. For example, the degree of protonation of the carboxyl group increases under acidic conditions, making the membrane surface exhibit positive charge characteristics, while the degree of protonation of the amino group decreases, making the membrane surface exhibit negative charge characteristics. This change in charge characteristics enhances the interaction between the membrane surface and water molecules, further improving the hydrophilic properties of the membrane. The treatment time of the charge adjustment stage is not less than 20 minutes to ensure that the buffer solution can fully act on the membrane surface.

[0034] After the charge adjustment is completed, the nanofiltration membrane is rinsed with water for injection without surfactants and pH adjusters to remove residual buffer salt ions and unabsorbed surfactant molecules in the system. During the rinsing process, the conductivity and pH of the effluent are monitored in real time until they return to the same level as the water for injection used. The time of the final rinsing step is usually 15-30 minutes, and the specific duration is determined according to the rinsing effect.

[0035] After completing the above pretreatment process, the nanofiltration membrane is used for filtration operation in constant pressure mode. Under the condition that the transmembrane pressure difference is controlled at 0.1-0.3 MPa, the raw material liquid enters the filtration system from the feed port, and the macromolecular impurities are effectively removed by the retention action of the nanofiltration membrane, and the clear filtrate flows out from the discharge port. The temperature during the entire filtration operation process is strictly maintained in a low-temperature environment of 2-15°C to ensure the biological activity and structural stability of human immunoglobulin. The low-temperature environment not only inhibits the growth and reproduction of microorganisms, but also slows down the denaturation rate of protein molecules, thereby improving the safety and reliability of the filtration process.

[0036] Although embodiments of the present application have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and alterations can be made thereto without departing from the principles and spirit of the present application, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for improving human immunoglobulin nanomembrane filtration, characterized in that: The following steps are involved: S1: selecting a human immunoglobulin raw material solution, wherein the human immunoglobulin raw material solution is a solution to be filtered containing immunoglobulin M macromolecular impurities after being treated by a previous purification process; S2: Selecting a nanofiltration membrane with a specific pore size range, wherein the membrane material of the nanofiltration membrane is selected from one or more combinations of regenerated cellulose, polyethersulfone, polyvinylidene fluoride, or polysulfone, and the surface hydrophobicity in the initial state limits the filtration flux; S3: performing a multi-stage systematic pretreatment process on the nanofiltration membrane provided in S2, mainly for synergistically improving the hydrophilicity of the membrane surface; S4: The nanofiltration membrane that has undergone the complete pretreatment process in S3 is directly used to perform nanofiltration operation on the human immunoglobulin raw material solution provided in S1 under constant pressure or constant flow mode, thereby effectively retaining large molecular impurities while obtaining a clarified filtrate with a higher filtration flux.

2. The method for improving human immunoglobulin nanomembrane filtration according to claim 1, characterized in that: The systematic pretreatment process includes: S301: Membrane system rinsing stage: using injection water or purified water, under preset flow rate and pressure conditions, the filtration system equipped with the nanofiltration membrane is fully circulated and rinsed to remove possible particulate impurities and soluble protective agents in the membrane pores until the water quality parameters of the circulating discharge reach a stable baseline; S302: Surfactant equilibration stage: A pretreatment solution containing a nonionic surfactant at a predetermined concentration is prepared and pumped into the filtration system after rinsing in S301. The pretreatment solution is continuously contacted and circulated with the effective filtration surface of the nanofiltration membrane to allow the nonionic surfactant molecules to be fully adsorbed on the membrane surface and pore inner wall to form a physically hydrophilic modified layer. S303: Surface charge adjustment stage: A buffer solution with a specific pH value is prepared, and the pH value of the buffer solution is controlled within a range that can change the dissociation state of the inherent functional groups on the surface of the nanofiltration membrane. The buffer solution is pumped into the filtration system after being balanced in S302 to treat the nanofiltration membrane. By adjusting the type or density of the charge on the membrane surface, the hydrophilic properties of the membrane surface are chemically enhanced, and a synergistic effect is produced with the physical hydrophilic modification layer formed in S302.

3. The method for improving human immunoglobulin nanomembrane filtration according to claim 2, characterized in that: In the step S302, the nonionic surfactant in the pretreatment solution is a polysorbate compound, and its specific chemical composition is polyoxyethylene sorbitan fatty acid ester.

4. The method for improving human immunoglobulin nanomembrane filtration according to claim 3, characterized in that: The polysorbate compound is polysorbate 80, and its mass volume concentration in the pretreatment solution is precisely controlled within a concentration range of 0.01% to 0.5% to ensure the formation of a stable and uniform hydrophilic adsorption layer on the surface of the nanofiltration membrane, while avoiding potential residual contamination of subsequent protein products due to excessively high concentration.

5. The method for improving human immunoglobulin nanomembrane filtration according to claim 2, characterized in that: In S303, the buffer used to adjust the surface charge of the nanofiltration membrane is an acidic buffer system, and the pH value of the acidic buffer system is set in the range of 3.5 to 5.

5. This pH range mainly reduces the protonation degree of the acidic functional groups of the carboxyl groups on the surface of the nanofiltration membrane or increases the protonation degree of the basic functional groups of the amino groups, thereby changing the net charge of the membrane surface and enhancing the interaction between it and water molecules.

6. The method for improving human immunoglobulin nanomembrane filtration according to claim 5, characterized in that: The acidic buffer system is selected from one of an acetic acid-sodium acetate buffer system, a citric acid-sodium citrate buffer system or a phosphate buffer system, and the ionic strength of the buffer system is controlled within the range of 10 mmol / L to 100 mmol / L to maintain the osmotic pressure environment of the filtration system stable while effectively regulating the surface charge.

7. The method for improving human immunoglobulin nanomembrane filtration according to claim 1, characterized in that: The nanofiltration operation in S4 is carried out under the condition of a constant transmembrane pressure difference, which is controlled in the range of 0.1 MPa to 0.3 MPa. At the same time, the temperature during the entire nanofiltration operation is strictly maintained in a low temperature environment of 2 degrees Celsius to 15 degrees Celsius to ensure the biological activity and structural stability of human immunoglobulin.

8. The method for improving human immunoglobulin nanomembrane filtration according to claim 1, characterized in that: The nanofiltration membrane provided in S2 is a planar membrane package or hollow fiber membrane column designed specifically for virus removal or large molecular protein separation. The molecular weight cutoff or nominal pore size is selected to effectively retain particles with a diameter greater than 20 nanometers, especially immunoglobulin M pentamers, while ensuring that the target product immunoglobulin G monomer can pass through efficiently.

9. The method for improving human immunoglobulin nanomembrane filtration according to claim 1, characterized in that: Before executing the systematic pretreatment process of S3, a preliminary step is also included to detect and confirm the physicochemical parameters of the human immunoglobulin raw material liquid, including but not limited to adjusting its pH value to the range of 6.0-7.5, and detecting and confirming that its turbidity value is lower than a preset threshold value to ensure that the state of the raw material liquid is most suitable for subsequent nanofiltration operations and to prevent irreversible contamination or clogging of the pretreated membrane.

10. The method for improving human immunoglobulin nanomembrane filtration according to claim 2, characterized in that: In S302, the nonionic surfactant is polysorbate 80 with a concentration of 0.1%, and the duration of the equilibrium stage is not less than 30 minutes. In S303, the buffer is an acetic acid-sodium acetate buffer with a pH value of 4.5, and the treatment time is not less than 20 minutes. After S303 and before S4, an additional final flushing step is included, in which the nanofiltration membrane after surface charge adjustment is flushed with injection water without surfactant and pH regulator to remove residual buffer salt ions and unadsorbed surfactant molecules in the system until the conductivity and pH value of the discharge liquid are restored to a level consistent with the injection water used.

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