Membrane Package Cleaning and Usage Method

Abstract

The present application discloses a method for cleaning and using a membrane package. The method for cleaning the membrane package includes: an optional first rinsing step, which includes: (a) introducing a rinsing liquid into the inlet end, opening the reflux end and the permeate end, and the inlet flow rate is a first flow rate; or (b) introducing a rinsing liquid into the inlet end, opening the reflux end and closing the permeate end, the inlet flow rate is a second flow rate, and then opening the permeate end, and the inlet flow rate is a first flow rate; a disinfection step, which includes: (c) introducing a disinfectant liquid into the inlet end, closing the permeate end, and the inlet flow rate is a third flow rate; (d) circulating the disinfectant liquid; (e) opening the permeate end, and the inlet flow rate is a fourth flow rate; (f) circulating the disinfectant liquid; and a second rinsing step, which includes: (g) introducing a rinsing liquid into the inlet end, closing the permeate end, and the inlet flow rate is a fifth flow rate, and then opening the permeate end, and the inlet flow rate is a sixth flow rate.

Description

Technical Field

[0001] This application relates to the technical field of ultrafiltration concentration, and particularly to a method for cleaning and using a membrane package for ultrafiltration concentration. Background Art

[0002] In the field of biological protein products, ultrafiltration concentration and buffer exchange is a very important step in the downstream process. The main purpose of this step is to concentrate the protein solution to the target concentration and replace the product into the buffer solution where the stock solution is located. In ultrafiltration concentration and buffer exchange, by selecting an ultrafiltration membrane package with a suitable material, molecular cut-off pore size, and flow channel according to the molecular weight and the final product concentration, different process requirements can be achieved.

[0003] An ultrafiltration membrane package uses membranes of different materials as the filtration medium for sample concentration and buffer exchange. In the field of biological protein products, polyethersulfone (PES) and regenerated cellulose composite membrane ( PLC) materials are the most widely used; these membranes of different materials have various pore sizes and various screen flow channels (such as: A, D, C, V flow channels). Usually, in the purification process of biological products, the water flux (NWP) and integrity of the membrane package are important indicators for evaluating whether the membrane package can continue to be used. During the ultrafiltration concentration of protein drugs, the water flux of the membrane package usually decreases after use. For a given membrane package, the degree of decrease is mainly affected by protein properties and membrane package cleaning methods, etc., and the degree of decrease determines the number of times the membrane package can be used. Generally speaking, using the cleaning method recommended by the supplier cannot restore the NWP of the membrane package to a good state, resulting in problems such as limited use times and high costs.

[0004] Chinese Patent Application Publication No. CN112473390A discloses an ultrafiltration membrane cleaning agent and its cleaning method, which can remove contaminated retention substances, restore membrane flux, reduce operating resistance, and improve cleaning effect. However, this cleaning method involves using an aqueous solution of sodium hydroxide, sodium hypochlorite, and citric acid, and requires complex operations such as evacuation, backwashing, and forward flushing. It requires a variety of reagents and special equipment, with complex operations, high costs, and a risk of residual chlorine.

[0005] There is still a need in this field to find a new method for cleaning and using a membrane package, which can achieve the effect of restoring the water flux of the membrane package and increasing the number of times the membrane package can be used with lower reagent and equipment requirements and simple operations, thereby reducing the production cost of the pharmaceutical industry. Summary of the Invention

[0006] To solve the above technical problems, one aspect of this application provides a method for cleaning a membrane package, which includes:

[0007] An optional first rinsing step, which includes:

[0008] (a) Feed the rinsing solution into the inlet end of the membrane module, open the reflux end and the permeate end of the membrane module, and the inlet flow rate is the first flow rate until the first volume; or

[0009] (b) Feed the rinsing solution into the inlet end of the membrane module, open the reflux end of the membrane module and close the permeate end of the membrane module, the inlet flow rate is the second flow rate until the second volume, then open the permeate end of the membrane module, and the inlet flow rate is the first flow rate until the first volume;

[0010] The disinfection step, which includes:

[0011] (c) Feed the disinfectant solution into the inlet end of the membrane module, close the permeate end of the membrane module, and the inlet flow rate is the third flow rate until the third volume;

[0012] (d) Make the reflux end of the membrane module fluidly connected to the inlet end to circulate the disinfectant solution;

[0013] (e) Disconnect the fluid connection in (d), open the permeate end of the membrane module, and the inlet flow rate is the fourth flow rate until the fourth volume;

[0014] (f) Make the reflux end and the permeate end of the membrane module fluidly connected to the inlet end to circulate the disinfectant solution; and

[0015] The second rinsing step, which includes:

[0016] (g) Disconnect the fluid connection in (f), feed the rinsing solution into the inlet end of the membrane module, close the permeate end of the membrane module, the inlet flow rate is the fifth flow rate until the fifth volume, then open the permeate end of the membrane module, and the inlet flow rate is the sixth flow rate until the sixth volume.

[0017] Another aspect of the present invention provides a method for using a membrane module, which includes:

[0018] (1) Obtain a membrane module device;

[0019] (2) Perform a membrane module cleaning method, which includes:

[0020] An optional first rinsing step, which includes:

[0021] (a) Feed the rinsing solution into the inlet end of the membrane module, open the reflux end and the permeate end of the membrane module, and the inlet flow rate is the first flow rate until the first volume; or

[0022] (b) Feed the rinsing solution into the inlet end of the membrane module, open the reflux end of the membrane module and close the permeate end of the membrane module, the inlet flow rate is the second flow rate until the second volume, then open the permeate end of the membrane module, and the inlet flow rate is the first flow rate until the first volume;

[0023] The disinfection step, which includes:

[0024] (c) Introduce the disinfectant solution into the inlet end of the membrane package, close the permeate end of the membrane package, and the inlet flow rate is the third flow rate until the third volume;

[0025] (d) Fluidly connect the return end of the membrane package to the inlet end to circulate the disinfectant solution;

[0026] (e) Disconnect the fluid connection in (d), open the permeate end of the membrane package, and the inlet flow rate is the fourth flow rate until the fourth volume;

[0027] (f) Fluidly connect the return end and the permeate end of the membrane package to the inlet end to circulate the disinfectant solution; and

[0028] The second rinsing step, which includes:

[0029] (g) Disconnect the fluid connection in (f), introduce the rinse solution into the inlet end of the membrane package, close the permeate end of the membrane package, and the inlet flow rate is the fifth flow rate until the fifth volume, and then open the permeate end of the membrane package, and the inlet flow rate is the sixth flow rate until the sixth volume;

[0030] (3) Use the membrane package for sample processing;

[0031] (4) Perform a membrane package cleaning method, which includes:

[0032] Optional first rinsing step, which includes:

[0033] (a) Introduce the rinse solution into the inlet end of the membrane package, open the return end and the permeate end of the membrane package, and the inlet flow rate is the first flow rate until the first volume; or

[0034] (b) Introduce the rinse solution into the inlet end of the membrane package, open the return end of the membrane package and close the permeate end of the membrane package, and the inlet flow rate is the second flow rate until the second volume, and then open the permeate end of the membrane package, and the inlet flow rate is the first flow rate until the first volume;

[0035] Disinfection step, which includes:

[0036] (c) Introduce the disinfectant solution into the inlet end of the membrane package, close the permeate end of the membrane package, and the inlet flow rate is the third flow rate until the third volume;

[0037] (d) Fluidly connect the return end of the membrane package to the inlet end to circulate the disinfectant solution;

[0038] (e) Disconnect the fluid connection in (d), open the permeate end of the membrane package, and the inlet flow rate is the fourth flow rate until the fourth volume;

[0039] (f) Fluidly connect the return end and the permeate end of the membrane package to the inlet end to circulate the disinfectant solution; and

[0040] The second rinsing step, which includes:

[0041] (g) Disconnect the fluid communication in (f), introduce the rinsing solution into the inlet end of the membrane package, close the permeate end of the membrane package, the inlet flow rate is the fifth flow rate until the fifth volume, then open the permeate end of the membrane package, and the inlet flow rate is the sixth flow rate until the sixth volume; and

[0042] (5) Store the membrane package. Description of the Drawings

[0043] The present application will be described in more detail below with reference to the drawings, in which:

[0044] Figure 1 is a schematic diagram of an ultrafiltration membrane package device used in the method of an embodiment of the present application;

[0045] Figure 2 is a comparison flowchart of the method of an embodiment of the present application (new method) and the cleaning method recommended by the supplier (control);

[0046] Figure 3 is a graph showing the change trend of NWP after treating the membrane package with different cleaning methods in an embodiment of the present application;

[0047] Figure 4 is a graph showing the change trend of NWP after treating with the cleaning method of the present invention in an embodiment of the present application;

[0048] Figure 5 is a schematic diagram showing the change of the water flux of the membrane package after using the membrane package cleaning method of the present invention 10 times in an embodiment of the present application. Detailed Embodiments

[0049] This application relates to a method for cleaning a membrane package. The method includes an optional first rinsing step, which includes (a) introducing a rinsing liquid into the inlet end of the membrane package, opening the reflux end and the permeate end of the membrane package, and the inlet flow rate being a first flow rate until a first volume; or (b) introducing the rinsing liquid into the inlet end of the membrane package, opening the reflux end of the membrane package and closing the permeate end of the membrane package, the inlet flow rate being a second flow rate until a second volume, and then opening the permeate end of the membrane package, and the inlet flow rate being the first flow rate until a first volume. In one embodiment of the present application, the membrane package cleaning method does not include the first rinsing step. In one embodiment of the present application, the membrane package cleaning method includes the first rinsing step, which includes (a) introducing a rinsing liquid into the inlet end of the membrane package, opening the reflux end and the permeate end of the membrane package, and the inlet flow rate being a first flow rate until a first volume. In one embodiment of the present application, the membrane package cleaning method includes the first rinsing step, which includes (b) introducing a rinsing liquid into the inlet end of the membrane package, opening the reflux end of the membrane package and closing the permeate end of the membrane package, the inlet flow rate being a second flow rate until a second volume, and then opening the permeate end of the membrane package, and the inlet flow rate being the first flow rate until a first volume. In the present application, the membrane package can be any membrane package suitable for ultrafiltration concentration of a liquid sample, which includes an inlet end, a permeate end, and a reflux end. In one embodiment of the present application, the membrane package includes an ultrafiltration membrane package. In one embodiment of the present application, the membrane package includes a polyethersulfone ultrafiltration membrane package. In one embodiment of the present application, the molecular weight cut-off of the membrane package is 2-100 kDa, preferably 10-50 kDa, more preferably about 30 kDa. In the present application, the rinsing liquid can be any suitable liquid for washing away the original liquid in the membrane package or wetting the membrane package. In one embodiment of the present application, the rinsing liquid includes water, preferably purified water. In one embodiment of the present application, the second flow rate is 0.5-10 times the first flow rate, preferably 1-5 times, more preferably 1.5-2.5 times, and even more preferably 2 times. In one embodiment of the present application, the first flow rate is 50-1600 LMH, preferably 100-800 LMH, more preferably 150-300 LMH, and even more preferably about 200 LMH. In one embodiment of the present application, the second flow rate is 100-1600 LMH, preferably 200-800 LMH, more preferably 300-500 LMH, and even more preferably about 400 LMH. In one embodiment of the present application, the first volume ≥ 5 L / m 2 , preferably ≥ 10 L / m 2 , more preferably ≥ 20 L / m 2 . In one embodiment of the present application, the second volume ≥ 5 L / m 2 , preferably ≥ 10 L / m 2 , more preferably ≥ 20 L / m 2。In one embodiment of the present application, in step (a), by controlling the flow rate at the reflux end of the membrane module, the membrane module is under transmembrane pressure (TMP), where TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, in step (b), when the inlet flow rate is the first flow rate, by controlling the pressure at the reflux end of the membrane module, the membrane module is under TMP, where TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, the duration of step (a) ≥ 30 s, preferably ≥ 2 min, more preferably ≥ 5 min. In one embodiment of the present application, the duration of step (b) ≥ 30 s, preferably ≥ 2 min, more preferably ≥ 5 min.

[0050] The membrane module cleaning method further includes a disinfection step, which includes: (c) allowing the disinfectant solution to enter the inlet end of the membrane module, closing the permeate end of the membrane module, with the inlet flow rate being the third flow rate until the third volume; (d) fluidly connecting the reflux end of the membrane module to the inlet end to circulate the disinfectant solution; (e) disconnecting the fluid connection in (d), opening the permeate end of the membrane module, with the inlet flow rate being the fourth flow rate until the fourth volume; (f) fluidly connecting the reflux end and the permeate end of the membrane module to the inlet end to circulate the disinfectant solution. In the present application, the disinfectant solution can be any suitable solution for removing deposited substances in the membrane module. In one embodiment of the present application, the disinfectant solution includes an alkaline solution, preferably a NaOH solution, more preferably a 1M NaOH solution. In one embodiment of the present application, the concentration of the alkaline solution is 0.1 - 3M, more preferably 0.5 - 2M, even more preferably about 1M. In one embodiment of the present application, the third flow rate is 0.5 - 10 times the fourth flow rate, preferably 1 - 5 times, more preferably 1.5 - 2.5 times, even more preferably 2 times. In one embodiment of the present application, the third flow rate is 100 - 1600 LMH, preferably 200 - 800 LMH, more preferably 300 - 500 LMH, even more preferably about 400 LMH. In one embodiment of the present application, the fourth flow rate is 50 - 1600 LMH, preferably 100 - 800 LMH, more preferably 150 - 300 LMH, even more preferably about 200 LMH. In one embodiment of the present application, the third volume ≥ 5 L / m 2 , preferably ≥ 10 L / m 2 , more preferably ≥ 20 L / m 2 . In one embodiment of the present application, the fourth volume ≥ 5 L / m 2 , preferably ≥ 10 L / m 2 , more preferably ≥ 20 L / m 2。In one embodiment of the present application, in step (e), by controlling the pressure at the reflux end of the membrane package, the membrane package is maintained under TMP, where TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, in step (f), by controlling the pressure at the reflux end of the membrane package, the membrane package is maintained under TMP, where TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, the duration of step (c) ≥ 30 s, preferably ≥ 2 min, more preferably ≥ 5 min. In one embodiment of the present application, the duration of step (d) ≥ 10 min, preferably ≥ 20 min, more preferably ≥ 30 min. In one embodiment of the present application, the duration of step (e) ≥ 30 s, preferably ≥ 2 min, more preferably ≥ 5 min. In one embodiment of the present application, the duration of step (f) ≥ 10 min, preferably ≥ 20 min, more preferably ≥ 30 min.

[0051] The membrane package cleaning method further includes a second rinsing step, which includes: (g) disconnecting the fluid communication in (f), allowing the rinsing liquid to enter the inlet end of the membrane package, closing the permeate end of the membrane package, with the inlet flow rate being the fifth flow rate until the fifth volume, and then opening the permeate end of the membrane package, with the inlet flow rate being the sixth flow rate until the sixth volume. In one embodiment of the present application, the fifth flow rate is 0.5 - 10 times the sixth flow rate, preferably 1 - 5 times, more preferably 1.5 - 2.5 times, even more preferably 2 times. In one embodiment of the present application, the fifth flow rate is 100 - 1600 LMH, preferably 200 - 800 LMH, more preferably 300 - 500 LMH, even more preferably approximately 400 LMH. In one embodiment of the present application, the sixth flow rate is 50 - 1600 LMH, preferably 100 - 800 LMH, more preferably 150 - 300 LMH, even more preferably approximately 200 LMH. In one embodiment of the present application, the fifth volume ≥ 5 L / m 2 ,preferably ≥ 10 L / m 2 ,more preferably ≥ 20 L / m 2 。In one embodiment of the present application, the sixth volume ≥ 5 L / m 2 ,preferably ≥ 10 L / m 2 ,more preferably ≥ 20 L / m 2 。In one embodiment of the present application, in step (g), when the inlet flow rate is the sixth flow rate, by controlling the flow rate at the reflux end of the membrane package, the membrane package is maintained under TMP, where TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, the duration of step (g) ≥ 30 s, preferably ≥ 2 mmin, more preferably ≥ 5 mmin.

[0052] In one embodiment of the present application, in one or more of steps (a)-(g), when the permeate end of the membrane package is opened, the pressure at the retentate end of the membrane package is controlled such that the membrane package is under a TMP, where each of the TMPs is independently ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi.

[0053] The present application also relates to a method for using a membrane package, which method comprises (1) obtaining a membrane package device. In one embodiment of the present application, the membrane package device comprises an unused membrane package. In one embodiment of the present application, the membrane package device comprises a used membrane package.

[0054] The method for using the membrane package further comprises (2) performing a membrane package cleaning method according to any embodiment of the present application. In one embodiment of the present application, the membrane package cleaning method in step (2) comprises a first rinsing step, and the first rinsing step comprises (a). In one embodiment of the present application, the membrane package device comprises a used membrane package, and the membrane package cleaning method in step (2) does not comprise the first rinsing step. In one embodiment of the present application, the membrane package device comprises a used membrane package, and the membrane package cleaning method in step (2) comprises the first rinsing step, and the first rinsing step comprises (b).

[0055] The method for using the membrane package further comprises (3) using the membrane package for sample treatment. In one embodiment of the present application, step (3) comprises equilibration, ultrafiltration concentration, optional buffer exchange, and recovery. In one embodiment of the present application, equilibration comprises using an equilibration solution. In the present application, the equilibration solution can be any solution suitable for preparing the membrane package for subsequent ultrafiltration concentration treatment, such as a buffer solution. In one embodiment of the present application, during equilibration, the inlet flow rate is 50 - 1600 LMH, preferably 100 - 800 LMH, more preferably 150 - 300 LMH, even more preferably about 200 LMH. In one embodiment of the present application, during equilibration, the retentate end and the permeate end of the membrane package are opened and both are connected to a discharge container. In one embodiment of the present application, during equilibration, the flow rate at the retentate end of the membrane package is controlled such that the membrane package is under a TMP, where the TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, the equilibration volume ≥ 5 L / m 2 preferably ≥ 10 L / m 2 more preferably ≥ 20 L / m 2. In one embodiment of the present application, the duration of equilibrium is ≥30s, preferably ≥2min, more preferably ≥5min. In one embodiment of the present application, the sample in ultrafiltration concentration can be a solution to be replaced and / or concentrated. In one embodiment of the present application, the sample can be a protein solution, such as an antibody solution, or a monoclonal antibody solution. In one embodiment of the present application, in ultrafiltration concentration, the inlet flow rate is 50-1600LMH, preferably 100-800LMH, more preferably 150-300LMH, even more preferably about 200LMH. In one embodiment of the present application, in ultrafiltration concentration, the permeate end of the membrane package is opened and connected to a discharge container, the reflux end of the membrane package is opened and connected to the inlet end of the membrane package or the inlet container. In one embodiment of the present application, in ultrafiltration concentration, the pressure at the reflux end of the membrane package is controlled so that the membrane package is under TMP, and the TMP is ≤43.5psi, preferably ≤29psi, more preferably ≤24psi. In one embodiment of the present application, the liquid exchange may include adding a solution different from the sample to the sample that has been concentrated by ultrafiltration, for example, a buffer solution different from the sample. In one embodiment of the present application, in the liquid exchange, the inlet flow rate is 50-1600LMH, preferably 100-800LMH, more preferably 150-300LMH, even more preferably about 200LMH. In one embodiment of the present application, in the liquid exchange, the permeate end of the membrane package is opened and connected to the discharge container, the reflux end of the membrane package is opened and connected to the inlet end or the inlet container. In one embodiment of the present application, in the liquid exchange, the pressure at the reflux end of the membrane package is controlled so that the membrane package is under TMP, and the TMP is ≤43.5psi, preferably ≤29psi, more preferably ≤24psi. In one embodiment of the present application, in the liquid exchange, different solutions are added once or intermittently or continuously. In one embodiment of the application, in recovery, the inlet flow rate is 50-1600LMH, preferably 100-800LMH, more preferably 150-300LMH, even more preferably about 200LMH. In one embodiment of the application, in recovery, the permeate end of the membrane bag is closed, the reflux end of the membrane bag is opened and connected to the inlet end or the inlet container of the membrane bag. In one embodiment of the application, recovery includes using a recovery solution, such as a recovery buffer. In one embodiment of the application, in recovery, the membrane bag is circulated and flushed using a recovery solution.

[0056] The membrane package use method further includes (4) performing a membrane package cleaning method as described in any embodiment of the present application. In one embodiment of the present application, the membrane package cleaning method in step (4) does not include a first rinsing step. In one embodiment of the present application, the membrane package cleaning method in step (4) includes a first rinsing step, and the first rinsing step includes (b).

[0057] The method for using the membrane package further includes (5) storing the membrane package. In the present application, any suitable method can be used to store the membrane package treated by the membrane package cleaning method of any embodiment of the present application. In one embodiment of the present application, step (5) includes using a storage solution. In the present application, the storage solution can be any solution suitable for storing the membrane package. In one embodiment of the present application, the storage solution includes an alkaline solution, preferably an NaOH solution, more preferably a 0.1M NaOH solution. In one embodiment of the present application, the concentration of the alkaline solution is 0.01 - 1M, preferably 0.05 - 0.2M, more preferably about 0.1M. In one embodiment of the present application, the inlet flow rate in step (5) is 50 - 1600 LMH, preferably 100 - 800 LMH, more preferably 150 - 300 LMH, even more preferably about 200 LMH. In one embodiment of the present application, in step (5), the reflux end and the permeate end of the membrane package are opened and both are connected to a discharge container. In one embodiment of the present application, in step (5), by controlling the flow rate of the reflux end of the membrane package, the membrane package is under TMP, where TMP ≤ 43.5 psi, preferably ≤ 29 psi, more preferably ≤ 24 psi. In one embodiment of the present application, the storage volume in step (5) ≥ 5 L / m 2 , preferably ≥ 10 L / m 2 , more preferably ≥ 20 L / m 2 . In one embodiment of the present application, the duration of step (5) ≥ 30 s, preferably ≥ 2 min, more preferably ≥ 5 min.

[0058] In the present application, unless otherwise stated, the volume refers to the volume of the liquid entering the membrane package through the inlet end.

[0059] The technical solutions of the present application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without creative efforts fall within the scope of protection of the present application.

[0060] Example

[0061] Experimental materials

[0062] In the following examples, unless otherwise specified, the reagents used in the examples are all commercially available products.

[0063] Reagent list:

[0064] Reagent name Supplier Catalog number NaCl Merck or J.T.baker 1.16224.9029 or 3627.01 NaOH Merck 1.06482 or equivalent Tris-base Merck or Angus 1.08386 or 288737 HAc J.T.baker 9526-07 L-Histidine J.T.Baker 2080-06 / 07 or equivalent L-Histidine monohydrochloride J.T.Baker 2081-06 / 07 or equivalent

[0065] Buffer formulation

[0066]

[0067] The following examples all use the following instruments:

[0068] Peristaltic pump, model BT100, from Baoding Longer;

[0069] Electronic balance, model ME4002E, from Mettler;

[0070] Pressure probe and pressure sensor, model PMAT3P, from PendoTECH;

[0071] Ultrafiltration membrane module, made of polyethersulfone, 30 kDa, A-channel, membrane area 50 cm 2 , from Millipore, model: PelliconXL, part number: PXB030A50.

[0072] The sample used in the following examples is a monoclonal antibody solution, which is the supernatant of the culture medium of the CHO-K1 cell line expressing recombinant IgG1 monoclonal antibody after downstream purification to the nanofiltration step, with a concentration of 14 g / L.

[0073] The membrane module device (UF / DF system) used in the following examples is as Figure 1 shown and is assembled as follows: The outlet end of the buffer container is fluidly connected to the inlet end of the inlet container through a pipeline equipped with a peristaltic pump. The outlet end of the inlet container is fluidly connected to the inlet end of the ultrafiltration membrane module through a pipeline equipped with a peristaltic pump and a pressure sensor. The reflux end of the ultrafiltration membrane module is fluidly connected to the reflux port of the inlet container and the discharge container respectively through a pipeline equipped with a pressure sensor and a clamp. And the permeate end of the ultrafiltration membrane module is fluidly connected to the discharge container through a pipeline equipped with a pressure sensor and a clamp.

[0074] The buffer container (part number 430518) and the inlet container (part number 430518) are both Corning bottles, and the discharge container is a waste liquid tank, and any suitable form of waste liquid tank can be used.

[0075] The specific process implemented in the following examples mainly includes three parts: pretreatment of the membrane module; sample treatment of the membrane module; and post-treatment after using the membrane module. The process comparison between the method (new method) of one embodiment of the present application and the cleaning method recommended by the supplier (control) is as Figure 2 shown, and the specific implementation process is as follows:

[0076] I. Pretreatment of the membrane module

[0077] a) Rinsing 1 before using the membrane module:

[0078] Flush the ultrafiltration membrane module with purified water at the inlet end. The inlet flow rate is 200 LMH, the permeate end is opened and connected to the discharge container, the reflux end is connected to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤24.0 psi for cleaning, and the rinsing volume is 20 L / m 2 。

[0079] b) Disinfection of the membrane module before use:

[0080] The cleaning process recommended by the supplier: Flush the ultrafiltration membrane module with 1M NaOH solution at the inlet end. The inlet flow rate is 200 LMH, the permeate end is opened and connected to the discharge container, the reflux end is connected to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤24.0 psi, and the disinfection volume reaches 20 L / m 2 After that, both the permeate end and the reflux end are switched to the inlet container, and the UF / DF system is circulated for disinfection for 60 minutes.

[0081] The membrane module cleaning method of this application: First, use a 1M NaOH solution to rinse the surface of the ultrafiltration membrane module from the inlet end to the reflux end: the inlet flow rate is controlled at 400 LMH, the permeate end is closed, the reflux end is fully opened and connected to the discharge container, and the rinsing volume reaches 20 L / m 2 After that, switch the reflux end to the inlet container and perform a circulating membrane surface rinse for 30 minutes. Then, adjust the inlet flow rate to 200 LMH, open the permeate end and connect it to the discharge container, switch the reflux end to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤24.0 psi, and the disinfection volume reaches 20 L / m 2 After that, switch the reflux end and the inlet end to the inlet container and circulate for disinfection for 30 minutes.

[0082] c) Second rinsing of the membrane module before use:

[0083] The cleaning process recommended by the supplier: Flush the ultrafiltration membrane module with purified water at the inlet end. The inlet flow rate is 200 LMH, the permeate end is opened and connected to the discharge container, the reflux end is connected to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤24.0 psi for cleaning, and the rinsing volume is 20 L / m 2 。

[0084] The membrane module cleaning method of this application: First, use purified water to perform a surface rinse on the surface of the ultrafiltration membrane module: the inlet flow rate is controlled at 400 LMH, the permeate end is closed, the reflux end is fully opened and switched to the discharge container, and the rinsing volume is 20 L / m 2; Then adjust the inlet flow rate to 200 LMH, open the permeate end and connect it to the discharge container. By controlling the pressure at the reflux end, maintain the TMP of the membrane module at ≤ 24.0 psi, and the rinsing volume is 20 L / m 2 .

[0085] d) Testing of NWP before use

[0086] By adjusting the inlet flow rate and the pressure at the reflux end, make the inlet pressure 10 psi and the reflux end pressure 5 psi, and operate stably for 5 - 10 minutes to ensure the stability of pressure and water temperature. Record data such as the permeate rate, inlet and reflux pressures, and water temperature. Calculate NWP according to the following formula and repeat 3 times, then take the average value.

[0087]

[0088] Where R = permeate rate mL / min, F = temperature correction factor, A = total area of the filter membrane (m 2 )

[0089] Pin = inlet pressure psi (bar), Pout = outlet pressure psi (bar), Pp = permeate port pressure psi (bar)

[0090] Temperature correction factor comparison table:

[0091]

[0092] e) Sample treatment of the membrane module

[0093] Equilibration

[0094] Equilibrate the ultrafiltration membrane module with the equilibration buffer at the inlet end. The inlet flow rate is 200 LMH, and both the permeate end and the reflux end are connected to the discharge container. By controlling the pressure at the reflux end, maintain the TMP of the membrane module at ≤ 24.0 psi, and the equilibration volume is 20 L / m 2 .

[0095] Ultrafiltration concentration

[0096] The inlet flow rate is 200 LMH, the permeate end is connected to the discharge container, and the reflux end is connected to the inlet container. By controlling the pressure at the reflux end, maintain the TMP of the membrane module at ≤ 24.0 psi, and perform ultrafiltration concentration on the sample to be concentrated. After concentrating to the target concentration, prepare for buffer exchange.

[0097] Buffer exchange

[0098] At an inlet flow rate of 200 LMH, maintain the TMP of the ultrafiltration membrane module at ≤ 24.0 psi, and perform buffer exchange on the concentrated sample. After buffer exchange to the target volume, perform sample recovery.

[0099] Sample Recovery

[0100] At an inlet flow rate of 200 LMH, with the permeate end closed and the reflux end fully open and connected to the inlet container, the ultrafiltration membrane module is rinsed in a loop with the sample recovery buffer to recover the sample remaining in the membrane module.

[0101] II. Post - treatment of the Membrane Module after Use

[0102] f) Rinsing 3 of the Membrane Module after Use:

[0103] Cleaning process recommended by the supplier: Rinse the ultrafiltration membrane module with purified water at the inlet. The inlet flow rate is 200 LMH, the permeate end is open and connected to the discharge container, the reflux end is connected to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤ 24.0 psi for cleaning, and the rinsing volume is 20 L / m 2 .

[0104] Membrane module cleaning method of this application: First, perform surface rinsing on the surface of the ultrafiltration membrane module with purified water: Control the inlet flow rate at 400 LMH, close the permeate end, fully open the reflux end and switch it to the discharge container, and the rinsing volume is 20 L / m 2 ; Then adjust the inlet flow rate to 200 LMH, open the permeate end and connect it to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤ 24.0 psi, and the rinsing volume is 20 L / m 2 .

[0105] g) Disinfection of the Membrane Module after Use:

[0106] Cleaning process recommended by the supplier: Rinse the ultrafiltration membrane module with 1M NaOH solution at the inlet. The inlet flow rate is 200 LMH, open the permeate end and connect it to the discharge container, connect the reflux to the discharge container, and by controlling the pressure at the reflux end, the TMP of the membrane module is maintained at ≤ 24.0 psi, and the disinfection volume reaches 20 L / m 2 After that, both the permeate end and the reflux end are switched to the inlet container, and the UF / DF system is circulated for disinfection for 60 minutes.

[0107] Membrane module cleaning method of this application: First, perform membrane surface rinsing from the inlet end to the reflux end on the surface of the ultrafiltration membrane module with 1M NaOH solution: Control the inlet flow rate at 400 LMH, close the permeate end, fully open the reflux end, and connect it to the discharge container, and the rinsing volume reaches 20 L / m 2After that, switch the reflux end to the inlet container and perform a 30-minute circulatory membrane surface flush. Then, adjust the inlet flow rate to 200LMH, open the permeate end and connect the discharge container, switch the reflux end to the discharge container, and control the pressure at the reflux end to maintain the TMP of the membrane package at ≤24.0psi, and the disinfection volume reaches 20L / m 2 Finally, the reflux end and the permeate end are switched to the inlet container and circulated for disinfection for 30 minutes.

[0108] h) Rinse the membrane package after use 4:

[0109] The cleaning process recommended by the supplier is to rinse the ultrafiltration membrane cassette with purified water at the inlet end. The inlet flow rate is 200LMH, the permeate end is open and connected to the discharge container, and the reflux end is connected to the discharge container. By controlling the pressure at the reflux end, the TMP of the membrane cassette is maintained at ≤24.0psi for cleaning. The rinse volume is 20L / m 2 .

[0110] The membrane cleaning method of this application is: first use purified water to rinse the surface of the ultrafiltration membrane package: the inlet flow rate is controlled at 400LMH, the permeate end is closed, the reflux end is fully opened and switched to the discharge container, and the flushing volume is 20L / m 2 Then adjust the inlet flow rate to 200LMH, open the permeate end and connect it to the discharge container, and control the pressure at the reflux end so that the TMP of the membrane package is maintained at ≤24.0psi. The rinse volume is 20L / m 2 .

[0111] i) NWP test after use

[0112] Same as step d).

[0113] j) Storage

[0114] The ultrafiltration membrane package was preserved using 0.1M NaOH solution at the inlet. The inlet flow rate was 200LMH, and the reflux and permeate ends were connected to the discharge container. By controlling the pressure at the reflux end, the TMP of the membrane package was maintained at ≤24.0psi, and the preservation volume was 20L / m 2 .

[0115] Example 1

[0116] Experimental design: Two different cleaning methods (the cleaning method recommended by the supplier and the membrane cleaning method of this application) were used to conduct three complete ultrafiltration concentration experiments, respectively, and the changes in NWP after treatment with the two different cleaning methods were compared.

[0117] Experimental results

[0118] like Figure 3As shown, when using the cleaning method recommended by the supplier, the water flux of the membrane package is significantly lower than that of the membrane package cleaning method of the present application after use; moreover, for the membrane package using the cleaning method recommended by the supplier, its NWP has a tendency to gradually decrease as the number of uses increases. When using the membrane package cleaning method of the present application, the water flux basically remains stable after use and shows no downward trend.

[0119] Example 2

[0120] Experimental design: For the ultrafiltration membrane package with a relatively large decrease in water flux, after cleaning the membrane package using the membrane package cleaning method of the present application, continue to conduct 3 complete ultrafiltration concentration liquid change experiments to investigate the change in the water flux of the membrane package after use.

[0121] Experimental results:

[0122] As Figure 4 shown, when using the cleaning method recommended by the supplier, the water flux gradually decreases to 41.6% of the initial flux after 3 uses. For this ultrafiltration membrane package, clean it using the cleaning method of the present application, continue to use it 3 times, the water flux of the membrane package significantly increases, and after using it three times, the NWP basically remains stable without showing a downward trend.

[0123] Example 3

[0124] Experimental design: Clean the new ultrafiltration membrane package using the cleaning method of the present application, use it 10 times using the complete process, measure the water flux after use, and observe the influence of the cleaning method of the present application on the NWP as the number of uses of the membrane package increases.

[0125] Experimental results:

[0126] When cleaning the membrane package using the cleaning method of the present application, after the ultrafiltration membrane package is used 10 times, the water flux after use remains stable, indicating that this cleaning method can effectively maintain the NWP of the ultrafiltration membrane package.

[0127] In summary, compared with the prior art, the present invention has the following advantages:

[0128] 1) For a new ultrafiltration membrane package, when cleaning it using the new method / improved method and comparing it with the method recommended by the supplier, the number of uses can be increased. According to the obtained data, the number of uses can be increased by more than one time.

[0129] 2) For a used ultrafiltration membrane package, when cleaning it using the cleaning method of the supplier, before and after the next use, using the new method / improved method can increase the water flux and increase the number of uses of the used ultrafiltration membrane package.

[0130] 3) Using the ultrafiltration membrane module cleaning method recommended by the supplier, after one use, the water flux decays to 54.2% of the initial flux. After 2 and 3 uses, the water fluxes decay to 48.0% and 41.6% of the initial flux respectively, indicating that using the method recommended by the supplier, the water flux decays rapidly after use, and the water flux has been showing a downward trend with the increase in the number of uses; using the cleaning method for the ultrafiltration membrane module developed in the present invention, after 1, 2, and 3 uses, the water fluxes decay to 62.4%, 57.9%, and 59.8% of the initial flux respectively. This result shows that using the new cleaning method can effectively maintain the stability of NWP and alleviate the continuous decline trend of NWP of the ultrafiltration membrane module.

[0131] 4) Using the ultrafiltration membrane module cleaning method recommended by the supplier, after the ultrafiltration membrane module is used 3 times, the water flux decays to 41.6% of the initial flux. On this basis, using the new cleaning method can significantly improve the NWP of the membrane module, and the NWP can be maintained stable during subsequent use.

[0132] 5) Using the ultrafiltration membrane module cleaning method recommended by the supplier, after the membrane module is used about 3 times, the water flux after use decays to about 40% of the initial flux; while using the cleaning method for the ultrafiltration membrane module developed in the present invention, after the membrane module is used 10 times, the NWP has been maintained constant. This data further confirms that the membrane module cleaning method of the present invention can more effectively alleviate the decay of NWP, extend the number of uses of the membrane module, and thus reduce the production cost.

[0133] 6) The cleaning and use method for the ultrafiltration membrane module developed in the present invention does not require complex additional devices, excessive types of disinfectants, or cumbersome cleaning operations. The method is simple and practical, with stable and lasting effects, and can adapt to various membrane cleaning applications, significantly reducing the experimental and production costs.

[0134] The above are only specific application examples of this application and do not constitute any limitation to the protection scope of this application. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all implementation manners here. All technical solutions formed by equivalent transformation or equivalent substitution that are similar to this kind fall within the scope of the rights protection of this application.

Claims

1. A method for cleaning a membrane package, characterized in that, The method includes: An optional first rinsing step, which includes: (a) introducing a rinsing solution into the inlet end of the membrane module, opening the reflux end and the permeate end of the membrane module, with the inlet flow rate being a first flow rate until a first volume; or (b) introducing a rinsing solution into the inlet end of the membrane module, opening the reflux end of the membrane module and closing the permeate end of the membrane module, with the inlet flow rate being a second flow rate until a second volume, and then opening the permeate end of the membrane module, with the inlet flow rate being the first flow rate until a first volume; A disinfection step, which includes: (c) introducing a disinfecting solution into the inlet end of the membrane module, closing the permeate end of the membrane module, with the inlet flow rate being a third flow rate until a third volume; (d) fluidly connecting the reflux end of the membrane module to the inlet end to circulate the disinfecting solution; (e) disconnecting the fluid connection in (d), opening the permeate end of the membrane module, with the inlet flow rate being a fourth flow rate until a fourth volume; (f) fluidly connecting the reflux end and the permeate end of the membrane module to the inlet end to circulate the disinfecting solution; and A second rinsing step, which includes: (g) disconnecting the fluid connection in (f), introducing a rinsing solution into the inlet end of the membrane module, closing the permeate end of the membrane module, with the inlet flow rate being a fifth flow rate until a fifth volume, and then opening the permeate end of the membrane module, with the inlet flow rate being a sixth flow rate until a sixth volume.

2. The method according to claim 1, wherein The rinsing solution includes water; and / or the disinfecting solution includes an alkali solution, and the concentration of the alkali solution is 0.1 - 3 M.

3. The method according to claim 2, wherein The rinsing solution includes purified water.

4. The method according to claim 2, wherein The disinfecting solution includes a NaOH solution.

5. The method according to claim 2, characterized in that, The concentration of the alkali solution is 0.5 - 2 M.

6. The method according to claim 2, characterized in that The concentration of the alkali solution is 1 M.

7. The method according to claim 1, wherein The first flow rate, the fourth flow rate, and the sixth flow rate are each independently 50 - 1600 LMH.

8. The method according to claim 7, wherein The first flow rate, the fourth flow rate, and the sixth flow rate are each independently 100 - 800 LMH.

9. The method according to claim 7, wherein The first flow rate, the fourth flow rate, and the sixth flow rate are each independently 150 - 300 LMH.

10. The method according to claim 7, characterized in that The first flow rate, the fourth flow rate, and the sixth flow rate are each independently 200 LMH.

11. The method according to claim 1, wherein The second flow rate, the third flow rate, and the fifth flow rate are each independently 100 - 1600 LMH.

12. The method according to claim 11, wherein The second flow rate, the third flow rate, and the fifth flow rate are each independently 200 - 800 LMH.

13. The method according to claim 11, characterized in that, The second flow rate, the third flow rate, and the fifth flow rate are each independently 300 - 500 LMH.

14. The method according to claim 11, wherein The second flow rate, the third flow rate, and the fifth flow rate are each independently 400 LMH.

15. The method according to claim 1, wherein One or more of the first volume, the second volume, the third volume, the fourth volume, the fifth volume, and the sixth volume ≥ 5 L / m 2 .

16. The method according to claim 15, wherein One or more of the first volume, the second volume, the third volume, the fourth volume, the fifth volume, and the sixth volume ≥ 10 L / m 2 .

17. The method according to claim 15, wherein One or more of the first volume, the second volume, the third volume, the fourth volume, the fifth volume, and the sixth volume ≥ 20 L / m 2 .

18. The method according to claim 1, wherein, In one or more of steps (a) - (g), when the permeate end of the membrane module is opened, the membrane module is maintained at TMP by controlling the pressure at the reflux end of the membrane module, and the TMP is each independently ≤ 43.5 psi.

19. The method according to claim 18, wherein The TMP is each independently ≤ 29 psi.

20. The method according to claim 18, wherein The TMP is each independently ≤ 24 psi.

21. The method according to claim 1, wherein The duration of step (d) and / or the duration of step (f) ≥ 10 min.

22. The method according to claim 21, wherein The duration of step (d) and / or the duration of step (f) ≥ 20 min.

23. The method according to claim 21, characterized in that, The duration of step (d) and / or the duration of step (f) ≥ 30 min.

24. A method for using a membrane package, characterized in that, The method includes: (1) Obtain a membrane package device; (2) Perform the membrane package cleaning method according to any one of claims 1-23; (3) Use the membrane package for sample processing; (4) Perform the membrane package cleaning method according to any one of claims 1-23; and (5) Store the membrane package.

25. The method according to claim 24, wherein The membrane package cleaning method in step (2) includes a first rinsing step, and the first rinsing step includes (a).

26. The method according to claim 24, wherein The membrane package cleaning method in step (4) does not include the first rinsing step; or the membrane package cleaning method in step (4) includes the first rinsing step, and the first rinsing step includes (b).

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