US-12616940-B2 - Virus removal membrane and method for manufacturing virus removal membrane

US12616940B2US 12616940 B2US12616940 B2US 12616940B2US-12616940-B2

Abstract

A virus removal membrane includes cellulose, and a primary-side surface through which the protein-containing solution is to be applied and a secondary-side surface from which a permeate that has permeated the virus removal membrane is to be flowed, wherein a bubble point is 0.5 MPa or more and 1.0 MPa or less; and when a solution containing gold colloids having a diameter of 30 nm is applied through the primary-side surface to the virus removal membrane to allow the virus removal membrane to capture the gold colloids for measurement of brightness in a cross section of the virus removal membrane, a value obtained by dividing a standard deviation of a value of an area of a spectrum of variation in the brightness by an average of the value of the area of the spectrum of variation in the brightness is 0.01 or more and 0.30 or less.

Inventors

Akika FUTAMURA
Yusuke Kon
Tomoko Hongo

Assignees

ASAHI KASEI LIFE SCIENCE CORPORATION

Dates

Publication Date: 20260505
Application Date: 20221005
Priority Date: 20160331

Claims (18)

1 . A virus removal membrane for removing viruses from a protein-containing solution, the virus removal membrane comprising: cellulose; and a primary-side surface configured to have the protein-containing solution applied thereto, and a secondary-side surface configured to have a permeate that has permeated the virus removal membrane flow therefrom; wherein: a body of the virus removal membrane is configured such that: i) a bubble point is 0.5 MPa or more and 1.0 MPa or less; ii) an average pore size is 32.0 nm or more and 38.0 nm or less; iii) a value obtained by dividing a standard deviation of a value of an area of a spectrum of variation in brightness by an average of the value of the area of the spectrum of variation in the brightness is 0.01 or more and 0.30 or less, wherein the brightness is measured for a cross section of the virus removal membrane after 40 mL of solution containing gold colloids having a diameter of 30 nm is applied to a filtration area of 0.001 m 2 of the primary-side surface, filtered under a pressure of 78.4 kPa, and penetrates into the body of the virus removal membrane to allow the virus removal membrane to capture the gold colloids, and the brightness being measured by an optical microscope; and iv) a site where gold colloids having a diameter of 30 nm or more and 40 nm or less are captured in the cross section of the virus removal membrane in a wet state has a thickness (T) in a range of 17.0 μm or more and 20.0 μm or less, wherein the thickness is measured after 40 mL of solution containing gold colloids having a diameter of 30 nm or more and 40 nm or less is applied to the filtration area of 0.001 m 2 of the primary surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the virus removal membrane, and wherein the body of the virus removal membrane is further configured such that: a site where gold colloids having a diameter of 50 nm are captured is located at a place corresponding to 5% or more and 35% or less of the thickness of the virus removal membrane from the primary-side surface in the cross section of the virus removal membrane in a wet state after 40 mL of solution containing the gold colloids having a diameter of 50 nm is applied to the filtration area of 0.001 m 2 of the primary-side surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the virus removal membrane, the site where gold colloids having a diameter of 40 nm are captured is located at a place corresponding to 8% or more and 50% or less of the membrane thickness from the primary-side surface in the cross section of the virus removal membrane in a wet state after 40 mL of solution containing the gold colloids having a diameter of 40 nm is applied to the filtration area of 0.001 m 2 of the primary-side surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the virus removal membrane, the site where gold colloids having a diameter of 30 nm are captured is located at a place corresponding to 10% or more and 80% or less of the membrane thickness from the primary-side surface in the cross section of the virus removal membrane in a wet state after 40 mL of solution containing the gold colloids having a diameter of 30 nm is applied to the filtration area of 0.001 m 2 of the primary-side surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the virus removal membrane, and wherein each of the solutions containing gold colloids are diluted with distilled water, 1.59% by volume of polyoxyethylene-naphthyl ether, and 0.20% by volume of poly (sodium 4-styrenesulfonate) to obtain each respective 40 mL of solution so that the absorbance at the maximum absorption wavelength of the gold colloids of the solution is 0.25 measured by an ultraviolet-visible spectrophotometer.
2 . The virus removal membrane according to claim 1 , wherein a logarithmic removal rate of gold colloids having a diameter of 40 nm is 1.00 or more, a logarithmic removal rate of gold colloids having a diameter of 30 nm is 1.00 or more, and a logarithmic removal rate of gold colloids having a diameter of 20 nm is less than 0.10.
3 . The virus removal membrane according to claim 1 , wherein gold colloids having a diameter of 20 nm are not captured.
4 . The virus removal membrane according to claim 1 , wherein the average pore size is decreased and then increased from the primary-side surface towards the secondary-side surface in the cross section of the virus removal membrane.
5 . The virus removal membrane according to claim 4 , wherein the site where gold colloids having a diameter of 30 nm are captured encompasses a site where the pore size is a minimum value.
6 . The virus removal membrane according to claim 1 , wherein a thickness of the virus removal membrane in a dry state is 25.0 μm or more and 45.0 μm or less.
7 . The virus removal membrane according to claim 1 , wherein the bubble point is 0.7 MPa or more and 1.0 MPa or less.
8 . The virus removal membrane according to claim 1 , wherein a pure water permeation rate is 100 L/m 2 /hrs/0.1 MPa or more and 500 L/m 2 /hrs/0.1 MPa or less.
9 . The virus removal membrane according to claim 1 , which is a flat membrane.
10 . The virus removal membrane according to claim 1 , which is a hollow fiber membrane.
11 . The virus removal membrane according to claim 10 , wherein an inner diameter in a dry state is from 250 μm to 400 μm.
12 . The virus removal membrane according to claim 11 , wherein a standard deviation of the inner diameter is 15.0 μm or less.
13 . The virus removal membrane according to claim 1 , wherein a logarithmic removal rate (LRV) of viruses of 40 nm or more is 4.0 or more.
14 . The virus removal membrane according to claim 1 , wherein a logarithmic removal rate (LRV) of bovine viral diarrhea viruses (BVDV) is 4.0 or more.
15 . The virus removal membrane according to claim 1 , wherein the virus removal membrane is manufactured by a method comprising: an aging process of maintaining a raw spinning solution at 30° C. or higher and 40° C. or lower; and a membrane formation process of forming a membrane by use of the raw spinning solution.
16 . The virus removal membrane according to claim 15 , wherein the aging process is performed for 45 hours or more and 100 hours or less.
17 . The virus removal membrane according to claim 15 , wherein the raw spinning solution comprises a cuprammonium solution in which cellulose and a silicate are dissolved, and wherein the cellulose is selected from the group consisting of regenerated cellulose and native cellulose.
18 . A hollow fiber virus removal membrane for removing viruses from a protein-containing solution, wherein the hollow fiber virus removal membrane is made from an aging process of maintaining a raw spinning solution at 30° C. or higher and 40° C. or lower for 45 hours or more and 100 hours or less, wherein the raw spinning solution comprises a cuprammonium solution in which cellulose and a silicate are dissolved, and wherein the cellulose is selected from the group consisting of regenerated cellulose and native cellulose the hollow fiber virus removal membrane comprising: the cellulose; and a primary-side surface configured to have the protein-containing solution applied thereto, and a secondary-side surface configured to have a permeate that has permeated the hollow fiber virus removal membrane flow therefrom; wherein: a body of the hollow fiber virus removal membrane is configured such that: i) a bubble point is 0.5 MPa or more and 1.0 MPa or less; ii) an average pore size is 32.0 nm or more and 38.0 nm or less; iii) a value obtained by dividing a standard deviation of a value of an area of a spectrum of variation in brightness by an average of the value of the area of the spectrum of variation in the brightness is 0.01 or more and 0.30 or less, wherein the brightness is measured for a cross section of the hollow fiber virus removal membrane after 40 mL of solution containing gold colloids having a diameter of 30 nm is applied to a filtration area of 0.001 m 2 of the primary-side surface, filtered under a pressure of 78.4 kPa, and penetrates into the body of the hollow fiber virus removal membrane to allow the hollow fiber virus removal membrane to capture the gold colloids, and the brightness being measured by an optical microscope; and iv) a site where gold colloids having a diameter of 30 nm or more and 40 nm or less are captured in the cross section of the hollow fiber virus removal membrane in a wet state has a thickness (T) in a range of 17.0 μm or more and 20.0 μm or less, wherein the thickness is measured after 40 mL of solution containing gold colloids having a diameter of 30 nm or more and 40 nm or less is applied to the filtration area of 0.001 m 2 of the primary surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the hollow fiber virus removal membrane, and wherein the body of the hollow fiber virus removal membrane is further configured such that: a site where gold colloids having a diameter of 50 nm are captured is located at a place corresponding to 5% or more and 35% or less of the thickness of the hollow fiber virus removal membrane from the primary-side surface in the cross section of the hollow fiber virus removal membrane in a wet state after 40 mL of solution containing the gold colloids having a diameter of 50 nm is applied to the filtration area of 0.001 m 2 of the primary-side surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the hollow fiber virus removal membrane, the site where gold colloids having a diameter of 40 nm are captured is located at a place corresponding to 8% or more and 50% or less of the membrane thickness from the primary-side surface in the cross section of the hollow fiber virus removal membrane in a wet state after 40 mL of solution containing the gold colloids having a diameter of 40 nm is applied to the filtration area of 0.001 m 2 of the primary-side surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the hollow fiber virus removal membrane, the site where gold colloids having a diameter of 30 nm are captured is located at a place corresponding to 10% or more and 80% or less of the membrane thickness from the primary-side surface in the cross section of the hollow fiber virus removal membrane in a wet state after 40 mL of solution containing the gold colloids having a diameter of 30 nm is applied to the filtration area of 0.001 m 2 of the primary-side surface, filtered under the pressure of 78.4 kPa, and penetrates into the body of the hollow fiber virus removal membrane, and wherein each of the solutions containing gold colloids are diluted with distilled water, 1.59% by volume of polyoxyethylene-naphthyl ether, and 0.20% by volume of poly (sodium 4-styrenesulfonate) to obtain each respective 40 mL of solution so that the absorbance at the maximum absorption wavelength of the gold colloids of the solution is 0.25 measured by an ultraviolet-visible spectrophotometer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Divisional of U.S. patent application Ser. No. 16/088,347, filed Sep. 25, 2018, which is a National Stage Entry of International Patent Application No. PCT/JP2017/013277, filed Mar. 30, 2017, which claims the benefit of Japanese Patent Application No. 2016-072468, filed Mar. 31, 2016. The disclosure of each of the applications listed above is incorporated by reference herein in its entirety. TECHNICAL FIELD The present invention relates to a virus removal membrane for removing viruses from a solution, and a method for manufacturing a virus removal membrane. BACKGROUND ART In recent years, a measure to enhance virus safety has been necessary for not only plasma derivatives derived from human blood, but also bio-pharmaceuticals. Therefore, pharmaceutical manufacturers have studied to introduce a virus removal/inactivation step in a manufacturing process. In particular, a virus removal method by filtration with a virus removal membrane is an effective method that can provide virus reduction without denaturing useful proteins. For example, Patent Literature 1 discloses a polymeric porous hollow fiber membrane having a pore structure where the in-plane porosity is initially decreased from the inner wall surface of the membrane towards the inner wall portion of the membrane, passes through at least one local minimum and thereafter is again increased on the outer wall portion of the membrane (hereinafter, also referred to as “gradient structure”), and a virus removal method including filtering an aqueous protein solution with the membrane. A virus removal membrane having such a gradient structure and having a specified average pore size, when used for removal of viruses from an aqueous protein solution, is considered to be suitable for removal of such viruses at a high removal rate and for recovery of a protein at a high permeation efficiency without denaturing any protein. Patent Literature 2 discloses a method for manufacturing a hollow fiber membrane, in which a cuprammonium cellulose solution can be solidified in a U-shaped tube to thereby suppress structure breakage due to stretching during structure formation in microphase separation as much as possible, thereby allowing high virus removal properties to be achieved. Patent Literature 4 discloses a virus removal membrane suitable for removal of parvoviruses, the membrane having an average pore size of 13 nm or more and 21 nm or less. Patent Literature 3 discloses characteristic evaluation of a virus removal membrane by use of viruses and proteins. CITATION LIST Patent Literatures Patent Literature 1: Japanese Patent Laid-Open No. H01-148305Patent Literature 2: Japanese Patent Laid-Open No. H04-371221Patent Literature 3: International Publication No. WO 2015/156401 Patent Literature 4: Japanese Patent Laid-Open No. 2010-14564 SUMMARY OF INVENTION Technical Problem A virus removal membrane is demanded to be high in virus removal capability, high in filtration capability with clogging of the membrane in filtration being suppressed, and small in the differences in virus removal capability and filtration time between products. An object of the present invention is then to provide a virus removal membrane small in the difference in filtration capability between products and thus high in safety, and a method for manufacturing a virus removal membrane. Solution to Problem An aspect of the present invention provides a virus removal membrane for removing viruses from a protein-containing solution. The virus removal membrane includes cellulose, and a primary-side surface through which the protein-containing solution is to be applied and a secondary-side surface from which a permeate that has permeated the virus removal membrane is to be flowed, in which a bubble point is 0.5 MPa or more and 1.0 MPa or less; when a solution containing gold colloids having a diameter of 30 nm are applied through the primary-side surface to the virus removal membrane to allow the virus removal membrane to capture the gold colloids for measurement of brightness in a cross section of the virus removal membrane, a value obtained by dividing a standard deviation of a value of an area of a spectrum of variation in the brightness by an average of the value of the area of the spectrum of variation in the brightness is 0.01 or more and 0.30 or less; and a thickness of a site where gold colloids having a diameter of 30 nm or more and 40 nm or less are captured in the cross section of the virus removal membrane in a wet state is 17.0 or more and 20.0 μm or less. In the virus removal membrane, a site where gold colloids having a diameter of 50 nm are captured may be located at a place corresponding to 5% or more and 35% or less of a thickness of the virus removal membrane from the primary-side surface, a site where gold colloids having a diameter of 40 nm are captured may be located at a place corresponding to 8% or more and 50% or less of