CN115155320A - Ultrafiltration membrane cleaning method and ultrafiltration method for protein solution - Google Patents
Ultrafiltration membrane cleaning method and ultrafiltration method for protein solution Download PDFInfo
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- CN115155320A CN115155320A CN202210929272.4A CN202210929272A CN115155320A CN 115155320 A CN115155320 A CN 115155320A CN 202210929272 A CN202210929272 A CN 202210929272A CN 115155320 A CN115155320 A CN 115155320A
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- 238000000108 ultra-filtration Methods 0.000 title claims abstract description 177
- 239000012528 membrane Substances 0.000 title claims abstract description 134
- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000004140 cleaning Methods 0.000 title claims abstract description 27
- 239000012460 protein solution Substances 0.000 title claims abstract description 25
- 238000005406 washing Methods 0.000 claims abstract description 154
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 115
- 239000000243 solution Substances 0.000 claims abstract description 72
- 239000003513 alkali Substances 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims abstract description 7
- 235000011130 ammonium sulphate Nutrition 0.000 claims abstract description 7
- 238000005554 pickling Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 57
- 239000007788 liquid Substances 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 230000008859 change Effects 0.000 claims description 8
- 238000011067 equilibration Methods 0.000 claims 1
- 230000004907 flux Effects 0.000 description 52
- 238000010992 reflux Methods 0.000 description 24
- 239000008213 purified water Substances 0.000 description 20
- 239000012466 permeate Substances 0.000 description 16
- 239000000523 sample Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 13
- 238000004659 sterilization and disinfection Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 6
- 239000011148 porous material Substances 0.000 description 5
- 239000012468 concentrated sample Substances 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 239000004627 regenerated cellulose Substances 0.000 description 4
- 239000007974 sodium acetate buffer Substances 0.000 description 4
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000002238 attenuated effect Effects 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000012487 rinsing solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
- B01D65/02—Membrane cleaning or sterilisation ; Membrane regeneration
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/145—Ultrafiltration
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2321/00—Details relating to membrane cleaning, regeneration, sterilization or to the prevention of fouling
- B01D2321/16—Use of chemical agents
- B01D2321/162—Use of acids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2321/00—Details relating to membrane cleaning, regeneration, sterilization or to the prevention of fouling
- B01D2321/16—Use of chemical agents
- B01D2321/164—Use of bases
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Water Supply & Treatment (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
The invention relates to an ultrafiltration membrane cleaning method and an ultrafiltration method of a protein solution. The ultrafiltration membrane cleaning method comprises the following steps: carrying out first water washing on the ultrafiltration membrane after the ultrafiltration is finished; performing alkali washing on the ultrafiltration membrane subjected to the first water washing; washing the ultrafiltration membrane subjected to alkali washing for the second time; pickling the ultrafiltration membrane subjected to the second washing; carrying out third water washing on the ultrafiltration membrane after acid washing; wherein the solution adopted by the acid cleaning comprises acetic acid with the concentration of 0.3M-0.7M and ammonium sulfate with the concentration of 15 mM-25 mM.
Description
Technical Field
The invention relates to the technical field of separation, in particular to an ultrafiltration membrane cleaning method and an ultrafiltration method of a protein solution.
Background
Ultrafiltration is one of membrane separation techniques using pressure as a driving force, and is generally used for separating and concentrating macromolecules and micromolecules, and the membrane aperture is generally between 20A DEG and 1000A deg. In the ultrafiltration process, the water solution flows through the membrane surface under the push of pressure, the solvent and the small molecular solute permeable membrane with the pore diameter smaller than that of the membrane become purified liquid, the solute with the pore diameter larger than that of the membrane is intercepted and is discharged along with the water flow to become concentrated liquid. The ultrafiltration process is dynamic filtration, separation is completed in a flowing state, solutes are deposited on the surface of the membrane, the ultrafiltration rate (flux) is attenuated, and the attenuation tends to be balanced to a certain degree, so the ultrafiltration membrane is usually cleaned after the ultrafiltration is completed to recover the flux.
Currently, most protein pharmaceutical preparations need to be administered by subcutaneous injection, so the concentration of the preparation is high, usually up to 100 or 200mg/mL. When ultrafiltration membranes are used to treat such protein solutions, both the purification ultrafiltration process and the subsequent washing and flux recovery are very difficult: on one hand, the flux is low in the ultrafiltration concentration process, and on the other hand, the flux is seriously attenuated and is difficult to effectively recover after the ultrafiltration membrane is used, for example, the flux can only be recovered to 50% usually by adopting a traditional alkali treatment mode, and the flux is difficult to recover to a specified standard water flux range (more than or equal to 70%).
Disclosure of Invention
Based on the method, the invention provides an ultrafiltration membrane cleaning method capable of effectively recovering the flux of the ultrafiltration membrane and an ultrafiltration method of protein solution with high flux in the ultrafiltration concentration process.
In a first aspect of the present invention, there is provided a method for cleaning an ultrafiltration membrane, comprising the steps of:
carrying out first water washing on the ultrafiltration membrane after the ultrafiltration is finished;
performing alkali washing on the ultrafiltration membrane subjected to the first water washing;
washing the ultrafiltration membrane subjected to alkali washing for the second time;
pickling the ultrafiltration membrane subjected to the second washing;
carrying out third water washing on the ultrafiltration membrane after acid washing;
wherein the solution used for acid washing comprises acetic acid (HAC) with the concentration of 0.3-0.7M and ammonium sulfate ((NH) with the concentration of 15-25 mM) 4 ) 2 SO 4 )。
In one embodiment, the dosage of the solution used for acid washing is more than or equal to 20L/m 2 。
In one embodiment, the solution used for alkaline cleaning comprises sodium hydroxide (NaOH) with the concentration of 0.05M-0.15M, and the dosage of the solution is more than or equal to 20L/M 2 。
In one embodiment, the conditions of the first water washing, the second water washing or the third water washing include: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi;
and/or the amount of water used for the first water washing, the second water washing or the third water washing is more than or equal to 20L/m 2 。
In a second aspect of the present invention, there is provided a method for ultrafiltration of a protein solution, comprising the steps of:
carrying out ultrafiltration treatment on the protein solution by adopting an ultrafiltration membrane;
the ultrafiltration membrane is cleaned according to the ultrafiltration membrane cleaning method of the first aspect.
In one embodiment, the ultrafiltration treatment comprises the steps of:
carrying out primary ultrafiltration on the protein solution, and collecting a pre-concentrated solution;
carrying out second ultrafiltration on the pre-concentrated solution, and collecting a concentrated solution;
wherein the concentration of the pre-concentrated solution is 30-50 g/L, and the concentration of the concentrated solution is 180-200 g/L.
In one embodiment, the conditions of the first ultrafiltration or the second ultrafiltration comprise: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi.
In one embodiment, before the ultrafiltration membrane is cleaned, the method further comprises the step of rinsing the ultrafiltration membrane after the ultrafiltration treatment, wherein the rinsing solution comprises 15 mM-25 mM His solution or/and hydrochloric acid solution with pH of 5.5-6.
In one embodiment, the rinsing conditions include: the inlet flow rate is 200 LMH-400 LMH, the transmembrane pressure is controlled to be less than or equal to 15psi, and the cycle time is 3 min-7 min.
In one embodiment, the method further comprises a step of changing the solution between the first ultrafiltration and the first ultrafiltration, wherein the solution comprises a His solution with the concentration of 15 mM-25 mM or/and a hydrochloric acid solution of His, and the pH is 5.5-6.
In one embodiment, the liquid change conditions include: the inlet flow rate is 200 LMH-400 LMH, the transmembrane pressure is controlled to be less than or equal to 15psi, and the cycle time is 3 min-7 min; and/or stopping liquid change until the pH of the effluent is 5.7 +/-0.3 and the conductivity is 1.32 +/-0.13 mS/cm.
In one embodiment, the ultrafiltration membrane is pretreated before the first ultrafiltration, and the pretreatment sequentially comprises water washing, alkali washing, water washing and balancing.
According to the ultrafiltration membrane cleaning method, the ultrafiltration membrane after ultrafiltration is respectively subjected to water washing, alkali washing, water washing, acid washing and water washing, particularly, the solution with a specific composition is adopted for acid washing, so that the flux of the ultrafiltration membrane can be effectively recovered, and the flux reaches a specified standard flux range (more than or equal to 70%).
The ultrafiltration method of the protein solution can reduce the flux attenuation of the ultrafiltration membrane and is beneficial to the flux recovery.
Detailed Description
The method for washing an ultrafiltration membrane and the method for ultrafiltration of a protein solution according to the present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
As used herein, the term "and/or", "and/or" includes any one of two or more of the associated listed items, as well as any and all combinations of the associated listed items, including any two of the associated listed items, any more of the associated listed items, or all combinations of the associated listed items.
In the present invention, "first aspect", "second aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor are they to be construed as implicitly indicating the importance or quantity of the technical features indicated. Also, "first," "second," "third," etc. are for non-exhaustive enumeration description purposes only and should not be construed as constituting a closed limitation to the number.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, the numerical intervals are regarded as continuous, and include the minimum and maximum values of the range and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
The percentage contents referred to in the present invention mean, unless otherwise specified, mass percentages for solid-liquid mixing and solid-solid phase mixing, and volume percentages for liquid-liquid phase mixing. The solvent of the solution of the present invention is water unless otherwise specified.
The percentage concentrations referred to in the present invention are, unless otherwise specified, the final concentrations. The final concentration refers to the ratio of the additive component in the system to which the component is added.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a certain temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The room temperature in the present invention is generally 4 ℃ to 30 ℃, preferably 20. + -. 5 ℃.
The invention provides a method for cleaning an ultrafiltration membrane, which comprises the following steps:
s1-1, carrying out first water washing on the ultrafiltration membrane after ultrafiltration is finished;
s1-2, performing alkaline washing on the ultrafiltration membrane subjected to the first water washing;
s1-3, carrying out secondary water washing on the ultrafiltration membrane subjected to alkali washing;
s1-4, carrying out acid washing on the ultrafiltration membrane subjected to the second washing;
and S1-5, carrying out third water washing on the ultrafiltration membrane after acid washing.
In one example, the ultrafiltration membrane is a regenerated cellulose ultrafiltration membrane.
In one example, the pore size of the ultrafiltration membrane is 20-100 KDa.
Specifically, in step S1-1:
in one example, the conditions of the first water washing include: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi. Further, the transmembrane pressure is controlled to be 5 psi-15 psi.
In one example, the amount of water used in the first water washing is 20L/m or more 2 。
Specifically, in step S1-2:
in one example, the solution used for the alkaline wash comprises sodium hydroxide (NaOH) at a concentration of 0.05M to 0.15M.
Specifically, the concentration of sodium hydroxide in the solution used for the caustic wash includes, but is not limited to: 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.11M, 0.12M, 0.13M, 0.14M, 0.15M.
In one example, the amount of the solution used for the alkaline washing is 20L/m or more 2 。
In one example, after the alkaline cleaning is finished, the method further comprises a circulating disinfection step, wherein the time is more than or equal to 60min. The recycle sterilization can be carried out using a sterilizing liquid known in the art, such as 0.1M aqueous NaOH solution.
Specifically, in step S1-3:
in one example, the conditions of the second water washing include: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi. Further, the transmembrane pressure is controlled to be 5psi to 15psi.
In one example, the amount of water used in the second water washing is more than or equal to 20L/m 2 。
Specifically, in step S1-4:
in one example, the solution used for acid washing includes acetic acid (HAC) at a concentration of 0.3M to 0.7M and ammonium sulfate ((NH) at a concentration of 15mM to 25 mM) 4 ) 2 SO 4 )。
Specifically, the concentration of acetic acid in the solution used for the acid wash includes, but is not limited to: 0.3M, 0.4M, 0.5M, 0.6M, 0.7M. The concentration of ammonium sulfate in the solution used for the acid wash includes, but is not limited to: 15mM, 16mM, 17mM, 18mM, 19mM, 20mM, 21mM, 22mM, 23mM, 24mM, 25mM.
In one example, the amount of the solution used for pickling is 20L/m or more 2 。
Specifically, in step S1-5:
in one example, the conditions of the third water washing include: the inlet flow rate is 200-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi. Further, the transmembrane pressure is controlled to be 5psi to 15psi.
In one example, the amount of water used in the third water washing is more than or equal to 20L/m 2 。
The invention also provides an ultrafiltration method of the protein solution, which comprises the following steps:
s2-1, carrying out ultrafiltration treatment on the protein solution by using an ultrafiltration membrane;
s2-1, cleaning the ultrafiltration membrane according to the ultrafiltration membrane cleaning method of the steps S1-1 to S1-5.
In one example, the molecular weight of the protein molecules in the protein solution is 140 KD-150 KD.
In one example, the ultrafiltration membrane is a regenerated cellulose ultrafiltration membrane.
In one example, the pore size of the ultrafiltration membrane is 20-100 KDa.
Specifically, in step S2-1:
in one example, the ultrafiltration process comprises the steps of:
s2-1-1: carrying out primary ultrafiltration on the protein solution, and collecting a pre-concentrated solution;
s2-1-2: and carrying out secondary ultrafiltration on the pre-concentrated solution, and collecting the concentrated solution.
Specifically, in step S2-1-1:
in one example, the conditions of the first ultrafiltration include: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi. Further, the transmembrane pressure is controlled to be 5psi to 15psi.
In one example, the pre-concentrated solution has a concentration of 30 to 50g/L.
Specifically, in step S2-1-2:
in one example, the conditions of the second ultrafiltration include: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi. Further, the transmembrane pressure is controlled to be 5psi to 15psi.
In one example, the concentration of the concentrated solution is 180-200 g/L.
In one example, before washing the ultrafiltration membrane, the method further includes rinsing the ultrafiltration membrane after completion of the ultrafiltration treatment.
In one example, the solution used for rinsing comprises a His solution or/and a hydrochloric acid solution with a concentration of 15mM to 25mM, and a pH of 5.5 to 6.
In one example, the rinsing conditions include: the inlet flow rate is 200 LMH-400 LMH, the transmembrane pressure is controlled to be less than or equal to 15psi, and the cycle time is 3 min-7 min. Further, the transmembrane pressure is controlled to be 5psi to 15psi.
In one example, the rinsing solution is used in an amount of 30L/m or more 2 。
In one example, the harvest from the rinse is combined into the concentrate.
In addition, in one example, a liquid changing step is further included between the first ultrafiltration and the first ultrafiltration, and the adopted solution comprises a His solution with the concentration of 15 mM-25 mM or/and a hydrochloric acid solution of His, and the pH value is 5.5-6.
In one example, the liquid change condition comprises: the inlet flow rate is 200 LMH-400 LMH, the transmembrane pressure is controlled to be less than or equal to 15psi, and the cycle time is 3 min-7 min. Further, the transmembrane pressure is controlled to be 5 psi-15 psi.
In one example, the exchange of effluent is stopped during the exchange step until the effluent has a pH of 5.7. + -. 0.3 and a conductivity of 1.32. + -. 0.13 mS/cm.
In addition, in one example, before the first ultrafiltration, pretreatment of the ultrafiltration membrane is further included, and the pretreatment sequentially includes water washing, alkali washing, water washing and balancing.
The following examples are given as specific examples, and all reagents used in the examples are commercially available products unless otherwise specified.
Ultrafiltration membrane package used in the examples, cat No.: UFLCA0030001P; the manufacturer: cobetter; the material of the film is as follows: regenerated Cellulose (RC); membrane area: 100cm 2 (ii) a The membrane pore diameter: 30KDa;
the samples used in the examples are monoclonal antibody molecule solutions, which are purified from CHO cell culture supernatants by conventional affinity chromatography, wherein the molecular weight of the monoclonal antibody molecule is 146KD.
Abbreviations referred to in the examples:
TMP: trans-membrane pressure;
NWP (NWP): normal water treatment, standard water flux.
Example 1
This example is a method for ultrafiltration of a monoclonal antibody molecule solution, comprising the following steps:
(1) Pretreatment:
1.1 water washing: washing the ultrafiltration membrane package with purified water, controlling inlet flow 300LMH, transmembrane pressure at 10 psi), and washing volume at 20L/m 2 ；
1.2 alkali washing: the membrane package was rinsed with 0.1M NaOH in a volume of 20L/M 2 Fully opening a permeation valve; after the washing is finished, the circulating disinfection time is 60min;
1.3 water washing: washing the ultrafiltration membrane package with purified water, controlling the inlet flow rate to 300LMH and the transmembrane pressure to 10psi, and washing until the pH of the effluent at the permeation end is neutral;
after this step, the ultrafiltration membrane package was subjected to a first water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
1.4 flushing with an equilibrium solution: the membrane package was washed with 20mM acetic acid-sodium acetate buffer at a volume of 20L/m 2 ；
(2) And (3) ultrafiltration:
2.1 sample concentration: sample concentration was started, the inlet flow rate was controlled to be within 300LMH, the transmembrane pressure was controlled to be 10psi, and the product concentration was controlled to be within 40g/L as required. When the concentration of the sample reaches the target value, closing the permeation valve, and circulating the system for 5min;
2.2 liquid change: performing ultrafiltration liquid exchange by using a 20mM His solution with the pH value of 5.7, controlling the flux of an inlet in the range of 300LMH, controlling the transmembrane pressure to be 10psi, keeping the volume in a circulating container basically unchanged, after the permeation volume of a permeation end is 7 times of the volume of a concentrated product, taking the effluent of the ultrafiltration permeation end to detect the pH value and the conductivity until the pH value is 5.7 +/-0.3 and the conductivity is in the range of 1.32 +/-0.13 mS/cm, and stopping liquid exchange;
2.3 sample concentration twice: the pump was started, flux was controlled within 300LMH, transmembrane pressure was controlled at 10psi, and product was concentrated to 200g/L as required. The permeation valve was closed and the system cycled for 5min. Closing the permeation valve, and emptying the concentrated sample in the system;
2.4 rinsing: adding 30mL of 20mM His, pH 5.7, controlling the inlet flux within the range of 300LMH, adjusting the transmembrane pressure to 10psi, circulating for 5min, and combining the circulated ultrafiltration displacement liquid into the concentrated collection liquid;
(3) Cleaning an ultrafiltration membrane:
3.1 water washing: washing the ultrafiltration membrane with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10psi and washing volume of 20L/m 2 ；
3.2 alkali washing: the membrane was rinsed with 0.1M NaOH in a volume of 20L/m 2 Fully opening the permeation valve; the circular disinfection time is 60min after the washing is finished;
3.3 Water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
3.4 acid washing: the membrane package was washed with 0.5M HAC,20mM ammonium sulfate in a washing volume of 20L/m 2 ；
3.5 water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) at a volume of 20L/m 2 ；
After this step, the ultrafiltration membrane package was subjected to a second water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
(4) And (3) storage: the membrane package was rinsed with 0.05M NaOH in a volume of 20L/M 2 。
The results of the two water flux tests are shown in table 1 below, with the standard water flux after use being 87% before use:
TABLE 1
| Step (ii) of | Permeability per minute (mL) | NWP(LMH/bar) |
| First water flux test | 31 | 186 |
| Second Water flux test | 27 | 162 |
Comparative example 1
The comparative example is an ultrafiltration method of a monoclonal antibody molecule solution, and the steps are the same as those of the example 1, and the main differences are that: no acid washing was performed.
The method comprises the following specific steps:
(1) Pretreatment:
1.1 water washing: washing the ultrafiltration membrane package with purified water under inlet flow control of 300LMH and transmembrane pressure control of 10 psi) at a volume of 20L/m 2 ；
1.2 alkali washing: the membrane package was rinsed with 0.1M NaOH in a volume of 20L/M 2 Fully opening the permeation valve; after the washing is finished, the circulating disinfection time is 60min;
1.3 water washing: washing the ultrafiltration membrane package with purified water, controlling the inlet flow rate to 300LMH and the transmembrane pressure to 10psi, and washing until the pH of the effluent at the permeation end is neutral;
after this step, the ultrafiltration membrane package was subjected to a first water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
1.4 flushing with an equilibrium solution: the membrane package was washed with 20mM acetic acid-sodium acetate buffer at a volume of 20L/m 2 ；
(2) And (3) ultrafiltration:
2.1 sample concentration: sample concentration was started by controlling the inlet flow rate to within 300LMH, the transmembrane pressure to 10psi and the product concentration to within 40g/L as required. When the concentration of the sample reaches the target value, closing the permeation valve, and circulating the system for 5min;
2.2 liquid change: performing ultrafiltration liquid exchange by using a 20mM His solution with the pH value of 5.7, controlling the flux of an inlet in the range of 300LMH, controlling the transmembrane pressure to be 10psi, keeping the volume in a circulating container basically unchanged, after the permeation volume of a permeation end is 7 times of the volume of a concentrated product, taking the effluent of the ultrafiltration permeation end to detect the pH value and the conductivity until the pH value is 5.7 +/-0.3 and the conductivity is in the range of 1.32 +/-0.13 mS/cm, and stopping liquid exchange;
2.3 sample concentration twice: the pump was started, flux was controlled in the range of 300LMH, transmembrane pressure was controlled at 10psi, and the product was concentrated to a concentration of 200g/L as required. The permeation valve was closed and the system cycled for 5min. Closing the permeation valve, and emptying the concentrated sample in the system;
2.4 rinsing: adding 30mL of 20mM His, pH 5.7, controlling the inlet flux within the range of 300LMH, adjusting the transmembrane pressure to 10psi, circulating for 5min, and combining the circulated ultrafiltration displacement liquid into the concentrated collection liquid;
(3) Cleaning an ultrafiltration membrane:
3.1 Water washing: washing the ultrafiltration membrane package with purified water, controlling inlet flow rate at 300LMH, transmembrane pressure at 10psi, and washing volume at 20L/m 2 ；
3.2 alkali washing: rinsing the membrane package with 0.1M NaOHThe volume is 20L/m 2 Fully opening the permeation valve; after the washing is finished, the circulating disinfection time is 60min;
3.3 Water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
3.4 Water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
After this step, the ultrafiltration membrane package was subjected to a second water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
(4) And (3) storage: the membrane package was rinsed with 0.05M NaOH in a volume of 20L/M 2 。
The results of the two water flux tests are shown in table 2 below, with the standard water flux after use being 50% before use:
TABLE 2
| Step (ii) of | Permeability per minute (mL) | NWP(LMH/bar) |
| First water flux test | 30 | 180 |
| Second Water flux test | 15 | 90 |
Comparative example 2
The comparative example is an ultrafiltration method of a monoclonal antibody molecule solution, and the steps are the same as those of the example 1, and the main differences are that: ammonium sulfate is not used in the acid washing process.
The method comprises the following specific steps:
(1) Pretreatment:
1.1 water washing: washing the ultrafiltration membrane package with purified water, controlling inlet flow 300LMH, transmembrane pressure at 10 psi), and washing volume at 20L/m 2 ；
1.2 alkali washing: the membrane package was rinsed with 0.1M NaOH in a volume of 20L/M 2 Fully opening a permeation valve; the circular disinfection time is 60min after the washing is finished;
1.3 Water washing: washing the ultrafiltration membrane package with purified water, controlling the inlet flow rate to 300LMH and the transmembrane pressure to 10psi, and washing until the pH of the effluent at the permeation end is neutral;
after this step, the ultrafiltration membrane package was subjected to a first water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
1.4 flushing with an equilibrium solution: the membrane package was washed with 20mM acetic acid-sodium acetate buffer at a volume of 20L/m 2 ；
(2) And (3) ultrafiltration:
2.1 sample concentration: sample concentration was started, the inlet flow rate was controlled to be within 300LMH, the transmembrane pressure was controlled to be 10psi, and the product concentration was controlled to be within 40g/L as required. When the concentration of the sample reaches the target value, closing the permeation valve, and circulating the system for 5min;
2.2 liquid change: performing ultrafiltration liquid exchange by using a 20mM His solution with the pH value of 5.7, controlling the flux of an inlet in the range of 300LMH, controlling the transmembrane pressure to be 10psi, keeping the volume in a circulating container basically unchanged, after the permeation volume of a permeation end is 7 times of the volume of a concentrated product, taking the effluent of the ultrafiltration permeation end to detect the pH value and the conductivity until the pH value is 5.7 +/-0.3 and the conductivity is in the range of 1.32 +/-0.13 mS/cm, and stopping liquid exchange;
2.3 sample concentration twice: the pump was started, flux was controlled in the range of 300LMH, transmembrane pressure was controlled at 10psi, and the product was concentrated to a concentration of 200g/L as required. The permeation valve was closed and the system cycled for 5min. Closing the permeation valve, and emptying the concentrated sample in the system;
2.4 rinsing: adding 30mL of 20mM His into a container, controlling the pH value to be 5.7, controlling the inlet flux to be within the range of 300LMH, adjusting the transmembrane pressure to be 10psi, circulating for 5min, and combining the circulated ultrafiltration displacement liquid into the concentrated collection liquid;
(3) And (3) cleaning the ultrafiltration membrane:
3.1 water washing: washing the ultrafiltration membrane package with purified water, controlling inlet flow rate at 300LMH, transmembrane pressure at 10psi, and washing volume at 20L/m 2 ；
3.2 alkali washing: the membrane was rinsed with 0.1M NaOH in a volume of 20L/m 2 Fully opening the permeation valve; the circular disinfection time is 60min after the washing is finished;
3.3 Water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
3.4 acid washing: the membranes were washed with 0.5M HAC in a volume of 20L/M 2 ；
3.5 Water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
After this step, the ultrafiltration membrane package was subjected to a second water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
(4) And (3) storage: the membrane package was rinsed with 0.05M NaOH in a volume of 20L/M 2 。
The results of the two water flux tests are shown in table 3 below, with the standard water flux after use being 57% before use:
TABLE 3
| Step (ii) of | Permeability per minute (mL) | NWP(LMH/bar) |
| First water flux test | 30 | 180 |
| Second Water flux test | 17 | 103 |
Comparative example 3
The comparative example is an ultrafiltration method of a monoclonal antibody molecule solution, and the steps are the same as those of the example 1, and the main differences are that: the acid wash was replaced with a caustic wash.
The method comprises the following specific steps:
(1) Pretreatment:
1.1 water washing: washing the ultrafiltration membrane package with purified water, controlling inlet flow 300LMH, transmembrane pressure at 10 psi), and washing volume at 20L/m 2 ；
1.2 alkali washing: the membrane package was rinsed with 0.1M NaOH in a volume of 20L/M 2 Fully opening the permeation valve; the circular disinfection time is 60min after the washing is finished;
1.3 Water washing: washing the ultrafiltration membrane package with purified water, controlling the inlet flow rate to 300LMH and the transmembrane pressure to 10psi, and washing until the pH of the effluent at the permeation end is neutral;
after this step, the ultrafiltration membrane package was subjected to a first water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
1.4 flushing with an equilibrium solution: the membrane package was washed with 20mM acetic acid-sodium acetate buffer at a volume of 20L/m 2 ；
(2) And (3) ultrafiltration:
2.1 sample concentration: sample concentration was started, the inlet flow rate was controlled to be within 300LMH, the transmembrane pressure was controlled to be 10psi, and the product concentration was controlled to be within 40g/L as required. When the concentration of the sample reaches the target value, closing the permeation valve, and circulating the system for 5min;
2.2 liquid change: performing ultrafiltration liquid exchange by using a 20mM His solution with the pH value of 5.7, controlling the flux of an inlet in the range of 300LMH, controlling the transmembrane pressure to be 10psi, keeping the volume in a circulating container basically unchanged, after the permeation volume of a permeation end is 7 times of the volume of a concentrated product, taking the effluent of the ultrafiltration permeation end to detect the pH value and the conductivity until the pH value is 5.7 +/-0.3 and the conductivity is in the range of 1.32 +/-0.13 mS/cm, and stopping liquid exchange;
2.3 sample concentration twice: the pump was started, flux was controlled in the range of 300LMH, transmembrane pressure was controlled at 10psi, and the product was concentrated to a concentration of 200g/L as required. The permeation valve was closed and the system cycled for 5min. Closing the permeation valve, and emptying the concentrated sample in the system;
2.4 rinsing: adding 30mL of 20mM His, pH 5.7, controlling the inlet flux within the range of 300LMH, adjusting the transmembrane pressure to 10psi, circulating for 5min, and combining the circulated ultrafiltration displacement liquid into the concentrated collection liquid;
(3) And (3) cleaning the ultrafiltration membrane:
3.1 water washing: washing the ultrafiltration membrane with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10psi and washing volume of 20L/m 2 ；
3.2 alkali washing: the membrane package was rinsed with 0.1M NaOH in a volume of 20L/m 2 Fully opening the permeation valve; the circular disinfection time is 60min after the washing is finished;
3.3 Water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
3.4 alkali washing: the membrane package was rinsed with 0.1M NaOH in a volume of 20L/m 2 Fully opening the permeation valve; the circular disinfection time is 60min after the washing is finished;
3.5 water washing: washing the ultrafiltration membrane package with purified water at inlet flow rate of 300LMH and transmembrane pressure of 10 psi) and washing volume of 20L/m 2 ；
After this step, the ultrafiltration membrane package was subjected to a second water flux test:
setting inlet flow rate to be 35mL/min, fully opening a permeation valve, adjusting a reflux valve, controlling transmembrane pressure to be less than or equal to 1bar, and recording inlet pump speed, permeation end flow rate, inlet pressure, reflux pressure and permeation end pressure after system pressure is stable. NWP, NWP = permeate end flow rate/(total membrane area × TMP), unit LMH/bar, TMP = (inlet pressure + reflux pressure-permeate end pressure)/2 was calculated according to the following formula.
(4) And (3) storage: the membrane package was rinsed with 0.05M NaOH in a volume of 20L/M 2 。
The results of the two water flux tests are shown in table 4 below, with the standard water flux after use being 53% before use:
TABLE 4
| Step (ii) of | Permeability per minute (mL) | NWP(LMH/bar) |
| First water flux test | 30 | 180 |
| Second Water flux test | 16 | 96 |
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, which is convenient for specific and detailed understanding of the technical solutions of the present invention, but the present invention should not be construed as being limited to the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the present patent should be subject to the content of the appended claims, and the description can be used to interpret the content of the claims.
Claims (12)
1. The method for cleaning the ultrafiltration membrane is characterized by comprising the following steps of:
carrying out primary water washing on the ultrafiltration membrane after the ultrafiltration is finished;
performing alkali washing on the ultrafiltration membrane subjected to the first water washing;
washing the ultrafiltration membrane subjected to alkali washing for the second time;
pickling the ultrafiltration membrane subjected to the second washing;
carrying out third water washing on the ultrafiltration membrane after acid washing;
wherein the solution adopted by the acid cleaning comprises acetic acid with the concentration of 0.3M-0.7M and ammonium sulfate with the concentration of 15 mM-25 mM.
2. The ultrafiltration membrane cleaning method according to claim 1, wherein the amount of the solution used for acid cleaning is not less than 20L/m 2 。
3. The ultrafiltration membrane cleaning method according to claim 1, wherein the solution used for alkali cleaning comprises sodium hydroxide with the concentration of 0.05M-0.15M, and the using amount of the solution is more than or equal to 20L/M 2 。
4. The method for cleaning an ultrafiltration membrane according to any one of claims 1 to 3, wherein the conditions of the first water washing, the second water washing or the third water washing include: the inlet flow rate is 200 LMH-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi;
and/or the dosage of the water for the first water washing, the second water washing or the third water washing is more than or equal to 20L/m 2 。
5. An ultrafiltration method of a protein solution, comprising the steps of:
carrying out ultrafiltration treatment on the protein solution by adopting an ultrafiltration membrane;
the ultrafiltration membrane cleaning method according to any one of claims 1 to 4.
6. The method for ultrafiltration of a protein solution according to claim 5, wherein the ultrafiltration treatment comprises the steps of:
carrying out primary ultrafiltration on the protein solution, and collecting a pre-concentrated solution;
carrying out second ultrafiltration on the pre-concentrated solution, and collecting a concentrated solution;
wherein the concentration of the pre-concentrated solution is 30-50 g/L, and the concentration of the concentrated solution is 180-200 g/L.
7. The method for ultrafiltration of a protein solution according to claim 6, wherein the conditions of the first ultrafiltration or the second ultrafiltration comprise: the inlet flow rate is 200-400 LMH, and the transmembrane pressure is controlled to be less than or equal to 15psi.
8. The method for ultrafiltration of a protein solution according to any one of claims 5 to 7, further comprising a step of rinsing the ultrafiltration membrane after completion of the ultrafiltration treatment before the ultrafiltration membrane is washed, wherein the solution to be used for rinsing comprises a His solution having a concentration of 15mM to 25mM or/and a hydrochloric acid solution of His and has a pH of 5.5 to 6.
9. The method for ultrafiltration of a protein solution according to claim 8, wherein the rinsing conditions comprise: the inlet flow rate is 200 LMH-400 LMH, the transmembrane pressure is controlled to be less than or equal to 15psi, and the cycle time is 3 min-7 min.
10. The method for ultrafiltration of a protein solution according to any one of claims 5 to 7, wherein between the first ultrafiltration and the first ultrafiltration, a step of changing the solution is further included, and the solution to be used comprises a His solution or/and a hydrochloric acid solution having a concentration of 15mM to 25mM and a pH of 5.5 to 6.
11. The method for ultrafiltration of a protein solution according to claim 10, wherein the conditions for changing the solution comprise: the inlet flow rate is 200 LMH-400 LMH, the transmembrane pressure is controlled to be less than or equal to 15psi, and the cycle time is 3 min-7 min; and/or stopping liquid change until the pH of the effluent is 5.7 +/-0.3 and the conductivity is 1.32 +/-0.13 mS/cm.
12. The method for ultrafiltration of a protein solution according to any one of claims 5 to 7, further comprising a pretreatment of the ultrafiltration membrane prior to the first ultrafiltration, the pretreatment comprising water washing, alkali washing, water washing and equilibration in this order.
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| CN103189130A (en) * | 2010-10-29 | 2013-07-03 | 东丽株式会社 | Fresh water generation method and fresh water generation device |
| US20150045276A1 (en) * | 2012-05-30 | 2015-02-12 | Kurita Water Industries Ltd | Agent and method for cleaning permeable membranes |
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