Liquid purification or separation – Filter – Material
Reexamination Certificate
2002-05-01
2004-09-28
Fortuna, Ana (Department: 1723)
Liquid purification or separation
Filter
Material
C210S500400, C210S500410, C210S500290, C210S500230
Reexamination Certificate
active
06797169
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a filter membrane used to effectively remove pathogens such as viruses from solutions of medicinal products or physiologically active products used as the raw materials thereof.
BACKGROUND ART
In the purification process of plasma derivatives or biopharmaceutical products, technology for preventing virus infection, which may be caused by administration of products, has been used. A method of inactivating or removing viruses is employed as this type of technology. As examples of the method of inactivating viruses, a heat treatment method and a chemical treatment method (Solvent/Detergent (S/D) treatment, for example) can be given. As examples of the method of removing viruses, a membrane filtration method can be given. In the membrane filtration method, particles are separated by size exclusion based on a sieving principle. Therefore, viruses can be removed only by size irrespective of chemical or thermal characteristics thereof. Because of this, the membrane filtration method using a virus removal membrane has been widely put into practical use on an industrial scale.
The heat treatment method exerts little effect on heat-resistant human parvovirus B19, hepatitis A virus, and the like. The S/D treatment method has essentially no effect on human parvovirus B19, poliovirus, reovirus, and SV-40 having no lipid envelope. In particular, since human parvovirus B19 is heat resistant and has no lipid envelope, the virus removal membrane is effective for inactivating or removing human parvovirus B19.
In the purification process of plasma derivatives or biopharmaceutical products, it is necessary to increase removability or inactivation capability of viruses and permeability for physiologically active products at the same time.
Virus removal membranes available at present are either a membrane which allows high-molecular-weight physiologically active products such as human immunoglobulin and Factor VIII to pass therethrough, but exhibits inferior small virus removal performance, or a membrane which can remove small viruses, but cannot allow high-molecular-weight physiologically active products such as human immunoglobulin or Factor VIII to pass therethrough at a practical level.
Specifically, conventional virus removal membranes are either a membrane which allows high-molecular-weight physiologically active products such as human immunoglobulin or Factor VIII to pass therethrough, but cannot remove small viruses such as human parvovirus B19, or a membrane which can remove small viruses such as human parvovirus B19, but cannot allow high-molecular-weight physiologically active products such as human immunoglobulin or Factor VIII to pass therethrough at a practical level.
Japanese Patent Application Laid-open No. 7-265674 discloses a polyvinylidene fluoride membrane capable of effectively removing small particles from liquid and exhibiting minimum adsorption, for which an integrity test before actual use can be employed. Although the inventors clam that this membrane is useful for removing viruses from a solution, its capability of allowing high-molecular-weight physiologically active products to pass therethrough with high permeability is still unconcern.
Japanese Patent No. 1873816 and U.S. Pat. No. 4,808,315 disclose polymer porous hollow fiber membranes. These hollow fiber membranes have a specific micropore structure effective for removing viruses from a solution of physiologically active products. These hollow fiber membranes are characterized by the specific micropore structure exhibiting superior virus removability and high permeability for physiologically active products at the same time. However, these patents neither describe nor suggest whether or not the membranes are effective in the case of sieving high-molecular-weight physiologically active products such as human immunoglobulin or Factor VIII from small viruses such as human parvovirus B19 or poliovirus.
Japanese Patent Application Laid-open No. 4-505579 discloses a membrane for separating viruses from a solution. This membrane is a composite asymmetric membrane which selectively separates viruses from a solution which includes viruses. This membrane exhibits≧3 log reduction value for bacteriophage &PHgr;×174 (28 nm) and ≧3 log reduction value for small viruses such as human parvovirus B19 or poliovirus. However, the membrane exhibits an extremely low human immunoglobulin permeability of 10-20% and, therefore, cannot be used in practice.
Conventional filter membranes which selectively separate physiologically active products from small viruses such as human parvovirus B19 have a problem whereby virus removability decreases as the volume of filtration is increased during continuous filtration. In particular, filter membranes excelling in initial virus removability have a problem whereby virus removability suddenly decreases accompanied by an increase in the volume of filtration.
DISCLOSURE OF THE INVENTION
The present invention has been achieved to solve the above problems in the prior art. Specifically, an object of the present invention is to provide a filter membrane for solutions of medicinal products or physiologically active products used as the raw materials of medicinal products which may be contaminated with viruses, which can allow the physiologically active products to pass therethrough at a practical level and remove small viruses such as human parvovirus B19 or poliovirus, of which the characteristics can be maintained without substantial change depending on the volume of filtration. As a result, another object of the present invention is to provide technology for providing safer products.
The present inventors have conducted extensive studies in order to achieve the above object to attain the present invention.
Specifically, according to one aspect, the present invention provides a filter membrane for solutions of physiologically active products, of which the ratio (BP/&ggr;) of a bubble point BP (MPa) to surface tension &ggr; (N/m) is 110 or more and permeability for bovine immunoglobulin with a monomer content of 80% or more is 70% or more.
According to another aspect, the present invention provides a filter membrane for solutions of physiologically active products, of which the log reduction value for porcine parvovirus are 3 or more at both 0-5 l/m
2
filtration and 50-55 l/m
2
filtration, and permeability for bovine immunoglobulin with a monomer content of 80% or more is 70% or more.
According to still another aspect, the present invention provides a filter membrane for solutions of physiologically active products, of which the BP/&ggr; ratio is 110 or more, the log reduction value for porcine parvovirus are 3 or more at both 0-5 l/m
2
filtration and 50-55 l/m
2
filtration, and permeability for bovine immunoglobulin with a monomer content of 80% or more is 70% or more. In the pore structure of the filter membrane, the thickness of a region with a pore size logarithmic standard deviation &sgr;
g
of 2.0 or less is preferably 3-90 &mgr;m. The purified water permeation rate of the filter membrane is preferably 70-200 l/h/0.1 MPa per m
2
of the membrane area. The filter membrane preferably has no skin layer on the surface. The thickness of the filter membrane is preferably 5-100 &mgr;m.
The pore size characteristics of the membrane of the present invention may be represented by the BP/&ggr; ratio and/or the log reduction value for porcine parvovirus, and permeability for bovine immunoglobulin with a monomer content of 80% or more.
The BP/&ggr; ratio and the log reduction value for porcine parvovirus are indexes regarding to the pore structure of the filter membrane. The BP/&ggr; ratio relates to the pore structure at early stage of filtration. The log reduction value for porcine parvovirus is an index relating not only to performance at early stage of filtration, but also to the durability of filtration performance over time.
The virus concentration in the filtrate may vary depending on the volume of filtration. In the case of a membrane havin
Ide Shoichi
Noda Toshiaki
Asahi Kasei Pharma Corporation
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Fortuna Ana
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