SE510792C2 - Polyvinylidenflouridmembran - Google Patents

Abstract

The present invention provides an isotropic, skinless, porous, polyvinylidene fluoride membrane having a KUF of at least about 15 psi (103 kPa), and preferably below about 50 psi (345 kPa), when tested using liquid pairs having an interfacial tension of about 4 dynes/cm (4 mN/m). The present inventive membrane preferably has a titer reduction of at least about 108 against T1 bacteriophage, more preferably also against PR772 coliphage, and even more preferably also against PP7 bacteriophage. The present inventive membrane can have a thickness of about 20 mil (500 .mu.m) or less and even as low as about 5 mil (125 .mu.m) or less. The present invention also provides a method of preparing such a membrane by providing a casting solution comprising polyvinylidene fluoride and a solvent therefor, heating the casting solution to a uniform temperature of about 57 .degree.C to about 60 .degree.C, spreading the casting solution onto a substrate to form a film, quenching the film in a quench bath so as to form a porous membrane, and washing and drying the porous membrane.

Description

510 792 2 includes viruses that are about 0.025 - 0.028 μm in effective diameter, eg hepatitis virus, poliovirus and parvovirus.

The effective screening of viruses is currently limited by available filtration membranes. Although both micro- porous and ultrafiltration membranes have been proposed for screening viruses, each of these membranes is unsuitable in different seenden.

Microporous membranes are characterized by being isotropic and skin free. In other words, they have a uniform pore structure and their ability to remove particles, measured by, for example, titer reduction tion depends on the pore size and thickness of the membrane. The smallest average pore size that is available today in this type of however, the membrane is only about 0.04 μm, eg Ultipor N66-NDP (Pall Corporation, Glen Cove, New York). Although such membranes can remove the relatively large viruses using membranes with reasonable thickness, they can not generally remove those that fall into the smaller size category. Try to make a microporous one membranes with smaller pores have been unsuccessful to date.

Ultrafiltration membranes are characterized by being asymptomatic metric, i.e. they have a non-uniform pore size over their thickness. Specifically, such membranes normally consist of an integral bilayer, where a layer is a thin film that exhibits what called slit-like fissures, while the second layer is a thick substructure containing a high concentration of finger-like indentations or macro cavities. The thin membrane has a relatively small pore size while the thick substructure has one relatively larger pore size. It is the membrane that is trained in a piece with the rest of the membrane imparting the membrane to it filtering capability. Ultrafiltration membranes are widely available in a pore diameter range of from 0.001 to 0.02 μm.

Ideally, the integral membrane completely covers the macro cavities on the thick substrate. In practice contains however, the membrane over the macro cavities is practically always significant defects, such as cracks, small holes and other defects and imperfections, which either break the film layer or leads to rupture during use. Thus, no security can regarding the integrity of the membrane and its removal ability available. 510 792 3 Although ultrafiltration membranes were practically used the membranes were thus used on a statistical basis depending on the integrity defects. This means that because only a small part of the liquid that is filtered will pass through some defect and since only a portion of all filtered liquid contains the unwanted material that one strives to remove is it likely that only a small amount of such material will pass through the membrane. Although this may be acceptable for certain applications, it is unacceptable for many other applications, especially in those situations in which it is filtered the liquid is intended to be administered to humans or animals and any viruses or the like that have passed through the membrane can create a serious health problem for the recipient.

Furthermore, the manufacture of acceptable ultrafiltration membranes difficult due to their structure and the defects that inevitably comes with this structure. To date, no ultra- filtration membrane manufactured that is completely free of defects.

Furthermore, depending on the extremely thin membrane (of the order of a few pm in thickness), which is responsible for all filtration properties of an ultrafiltration membrane, it is relatively difficult to make replicas in a uniform manner of ultra- filtration membranes that show the same degree of defects, pore size and pore size distribution. In addition, integrity and others properties of such membranes are not even but further tested after manufacturing and before actual use depending on normal test procedures, such as "bubble point" and KL tests would require so extremely high test pressures that the membranes should be crushed or damaged in other ways.

Thus, a great need remains for a filtration membranes that can achieve effective and predictable removal of small particles, such as viruses, from a fluid. One such membranes should preferably have minimal adsorption properties to prevent clogging and other unwanted filtration effects. Furthermore, the filtration membrane should be easily reproducible and that it is undamaged should be able to be tested before actual use.

A commercially adaptable method for manufacturing one such a membrane is also desirable. The present invention provides such a filtration membrane as well as associated methods for manufacture and use of such a membrane. These and others 0510 792 4 objects and advantages of the present invention as well as additional more characteristic features will become apparent from the description of the finding given herein.

Brief summary of the invention The present invention provides an isotropic, film-free, porous polyvinylidene fluoride membrane having a KUF of at least about 103 kPa (15 psi) and preferably below about 345 kPa (50 psi), when tested using liquid pairs having a interfacial tension of approx. 4 mN / m (4 dynes / cm). The membrane according to the present invention preferably has a titer reduction of at least about 108 against Tl bacteriophage, more preferably also against PR772 coliphage and even more preferably also against PP7 bacterio- fag. The membrane of the present invention may have a thickness of about 500 μm (20 miles) or less and even as small as about 125 um (5 mil) or less.

The present invention also provides a method of manufacture such a membrane by providing a casting solution comprising polyvinylidene fluoride and a solvent therefore, heating the casting solution to a uniform temperature of about 57 ° C to about 60 ° C, spreading the casting solution on a substrate to form a film, cooling the film in a cooling bath to formation of a porous membrane and washing and drying thereof porous membrane.

Brief description of the drawings Figures 1A and 1B are scanning electron micrographs of a poly vinylidene fluoride membranes of the present invention taken up 500 times magnification (Fig. 1A) and 5,000 times magnification (fig is).

Figures 2A and 2B are scanning electron micrographs of the top (Fig. 2A) and the bottom (Fig. 2B) of a polyvinylidene fluoride membrane according to the present invention taken at 100 times failure.

Fig. 3 is a graph depicting a curve showing the ratio of the casting temperature (° C) to that of the membrane resulting KUF (psi and kPa).

Fig. 4 is a graph depicting a curve the ratio of the pressure drop across the diaphragm (AP) divided by membrane thickness (inches Hg / mil and cm Hg / μm; logarithmic scale) and membrane KUF (psi and kPa). 510 792 5 Description of the Preferred Embodiments The present invention provides a novel isotropic, membrane-free, porous membrane having a pore amount lower than what has previously been achieved with such membranes. Pore size characteristics statistics for the membrane of the present invention can be expressed in terms of KUF as well as titer reduction. specifically provided in accordance with the present invention an isotropic, skinless, porous polyvinylidene fluoride membrane having a KUF of at least about 103 kPa (15 psi), preferably at least about 117 kPa (17 psi) and most preferably at least about 138 kPa (20 psi) psi), when tested using pairs of liquids having a interfacial tension of approx. 4 mN / m (4 dynes / cm). The membrane according to The present invention normally exhibits a KUF below about 345 kPa (50) psi), for example about 103 kPa (15 psi) to about 345 kPa (50 psi), and will more generally have a KUF below about 276 kPa (40 psi), eg about 117 kPa (17 psi) to about 276 kPa (40 psi), when tested using liquid pairs having an interface voltage of approx 4 mN / m (4 dynes / cm). Even more generally, the membrane will, according to the present invention to have a KUF below about 207 kPa (30 psi), eg 124 kPa (18 psi) to about 207 kPa (30 psi), when tested with use of liquid pairs having an interface voltage of about 4 mN / m (4 dynes / cm).

The membrane of the present invention can also characterized by its titer reduction relative to different phages.

The membrane of the present invention preferably has one titer reduction of at least about 108 relative to T1 bacteriophage, more also towards the smaller PR772 coliphage and most drawn against the even smaller PP7 bacteriophage as well. Titer- the reduction for a particular membrane according to the present invention. finning is completely predictable based on the KUF value and the membrane thickness. Furthermore, the titer reduction can be tailored to lie within relatively narrow limits, which is proof of a narrow pore size distribution. For example, the membrane of the present invention present invention have a titer reduction of at least about 108 relative to T1 bacteriophage or even versus PR772 coliphage, at the same time shows a titer reduction of about 102 or less compared to PP7.

The membrane of the present invention can also be prepared so that it has any suitable thickness and can be layered to achieve a desired thickness. In general, the membrane has according to 510 792 6 the present invention has a thickness of about 500 microns (20 mils) or less, preferably about 250 microns (10 mils) or less and most preferably about 125 μm (5 mils) or less. For most applications ions, the membrane of the present invention may have a thickness of about 75 μm (3 mils) to about 125 μm (5 mils). The membrane according to the present invention can have these different thicknesses and can still characterized by the above-mentioned KUF and / or titration reduction values. Thus, at the same time as the membrane according to the present invention can be manufactured so that it is very thin, eg about 25 - 125 pm (1 - 5 miles) in thickness or even as thin as 25 - 75 μm (1 - 3 mils) in thickness, the membrane according to the present invention still exhibit excellent titer reduction against virus.

Since the membrane of the present invention is isotropically, it has a substantially uniform and symmetrical pore structure. lucky. Representative membranes of the present invention are shown in the scanning electron micrographs of Figs. 1A (500X) and 1B (5.00KX), which depict the fine and uniform pore structure of the membrane and in the scanning electron micrographs of Fig. 2A and 2B (both 10.1KX), which depict top and bottom views of the same membrane. In addition, the isotropic nature of the present is illustrated medium according to the invention by the rectilinear curve in the diagram Fig. 4. This figure depicts a membrane pressure curve. case (AP) independent of membrane thickness (inches Hg / mil and cm Hg / μm) on a logarithmic scale against the membrane KUF (psi and kPa). The the resulting rectilinear curve indicates an isotropic membrane.

KUFZÉÉÉÉÄEQÄQQ Test methods known as "bubble point" (ASTM F316-86) and The KL (US-A-4,340,479) test methods have previously been used to evaluate the pore size properties of microporous membranes. Although these test methods, especially the KL test method, can be used to Evaluating the membrane of the present invention requires such tests high pressures in conjunction with membranes with very small pores, which can cause reliability issues. Thus characteristic the membrane of the present invention is preferably formed by using the KUF test method developed by Pall Corporation to designate an agent that more reliably evaluates pore size and membrane integrity for membranes with very small pore attitudes.

Pans. 9404249-6 510 7 The KW test method is described in US-A-5,480,554. According with the KW test method, the membrane to be tested is wetted first carefully with a hydrogen fluid that has the ability to completely wet the membrane. An expulsion liquid, which is immiscible with it wetting fluid used to wet the membrane but having a low, stable interfacial tension, was placed in contact with the wet membrane nets upstream side. Pressure is then applied stepwise to the displacement the liquid and the flow of displacement liquid through the membrane are measured as a function of the applied pressure. The displacement fluid should be stable but immiscible with the wetting liquid and interfacial tension the gap between the two liquids should be about 10 mN / m (10 dynes / cm) or lower. Control of the interfacial voltage to less than 10 mN / m (10 dynes / cm) allows fluid displacement to be achieved at high lower pressure than in similar testing normally performed with a water / air interface (ie in Ky or bubble point - the test methods). In addition, it is important that the interface voltage between the two liquids remains constant during the test procedure. One curve over the flow rate of the displacement liquid per unit area of the membrane through the membrane as a function of applied pressure can be made and a straight line can be drawn through the steep part of the resulting curve using regression analysis, which will cross the horizontal axis at a given pressure value.

This intersection indicates the KW value and is directly related to membrane pore size. Because there is nothing diffuse flow through a membrane that has no defects is the flow rate of the displacement liquid through the diaphragm before the KW value zero, i.e. a flat line in the normal curve flow rate vs pressure.

The KW values given herein were determined using fluid pairs having an interfacial tension of about 4 mN / m (4 dynes / cm).

More specifically, the KW values set forth herein were determined using n-pentanol, saturated with water, as wetting liquid, and water saturated with n-pentanol as the displacing liquid. They do not The miscible phases are saturated to ensure that the interfacial tension between the liquids, which is about 4.4 mN / m (4.4 dyn / cm) at ambient temperature, does not change depending on dissolution of one phase in the other. Other factors such as temperature shall also remain relatively constant during the test procedure to: avoid significant changes in the interface voltage between them 510 792 8 immiscible liquids during the test. While other liquid pairs can be used to determine KUF, such as n-butanol and aqueous n-pentanol and water are used herein because they are thus the KUF values obtained were within a comfortable range for measurement and due to the high relative solubilities of n-pentanol and water which ensured that if there was selective adsorption of one of the components of the membrane such adsorption would have small or no effect on the obtained KUF value. Other alcohols hol / water systems include, for example, n-octanol / water and n-hexa- zero / water and other non-alcoholic liquid pairs can of course similarly used in determining KUF.

The interfacial stresses of several different organic liquids such as forms a phase boundary with water, as reported in the book Interfacial Phenomena, 2nd Edition, by J.T. Davies and E.K.

Rideal (1963) is listed below along with the solubilities for those various compounds in water as reported in Chemical Rubber Handbook (CRC), edition 1970.

Compound Interface voltage Temp ° C Solubility (g / 100 g (dyn / cm or H 2 O) mN / m) ethyl ether 10.7 20 7.5 n-octanol 8.5 0.054 n-hexanol 6.8 25 0.6 aniline 5.85 20 n-pentanol 4.4 25 22 2.7 ethyl acetate 2.9 30 15 8.5 isobutanol 2.1 20 10.0 n-butanol 1.8 25 1.6 20 15 9.0 Although only organic liquids and water are listed in table immediately above, the KUF test method can be as specified previously performed using any pair of non miscible liquids.

According to the KUF test method, the wetting liquid can be a single liquid compound, such as n-octanol, and the the penetrating liquid can also be a single compound, such as water, which is substantially insoluble in the n-octanol. Alternatively, it can 510 7 * i32 9 the wetting liquid being an equilibrium mixture comprising a first liquid compound such as n-pentanol, which is saturated with a second liquid compound such as water. The second liquid the unit, saturated with the first, was then used as the displacer liquid. No matter which of the embodiments it is it is important that the interfacial tension between the two liquids remains relatively constant during the performance of the test. It is so it is recommended that the phases be stable in composition, d V s when the phases are in contact no net flow of either the fluid appears across the interface. Thus, there is none significant variation in the solubility of the displacing liquid in the wetting liquid which, where applicable, could affect the results.

In practice, the KUF test is usually run with each of them immiscible phases saturated with the fluid in which it stands in intimate plug. For example, the solubility of n-pentanol in water is 2.7 g per 100 g of water at 22 ° C. Because some n-pentanol dissolves in water it is preferred that the aqueous phase be saturated with n-pentanol. On same with the n-pentanol phase, it is preferred that it be saturated with water. Mutually saturated phases are easily achieved through shaking a mixture containing sufficient quantities of each of the fluids together in a container or separator rat funnel. In the tests and examples described herein, it was used the organic phase in each of the cases to wet the membrane.

An obvious extension of the method is to reverse the fluids, i.e. wetting the membrane with the aqueous phase and pressurizing the membrane upstream side of the plant with the organic phase.

The absolute KUF values will of course vary depending on the particular alcohol / water system even if the values obtained using other alcohol / water systems can generally be correlated to the KUF values of the n-pentanol / water system by using the ratio of their respective interfacial nings. For example, a KUF value of about 310 kPa (45 psi) in n- pentanol / water system equivalent to a KUF value of about 124 kPa (18 psi) in the n-butanol / water system (i.e. 310 kPa (or 45 psi) x 1.8 / 4.4).

Titer reduction Titer reduction refers to the ability of a particular membrane to remove a given particle from a fluid. As 510 792 10 thus, titer reduction is a standard measure of a membrane's ability to remove biological organisms such as bacteria and viruses. Sam- early as any suitable particle can be used in determining titer reduction, the titer reduction of the membrane was determined according to present invention by subjecting the membrane to T1 and PP7 bacteriophages (essentially a 50:50 mixture of the two bacteriophages phages at a level of 109-1010 bacteriophages / ml) in a gel phosphate buffer. For the values reported herein, E. coli ATCC # 11303 The source of the Tl phage and P. aeruginosa ATCC # 15612 the source of the PP7 phage. In addition to the T1 and PP7 bacteriophages were tested also the membrane of the present invention against the PR772 the coliphage. The source for the PR772 subject in and for the values as reported here was prof. H.W. Ackerman, Department of Microbiology, Faculty of Medicine, Laval University, Quebec, Canada.

The titer reduction of a membrane is defined as the ratio that of the subject included in the influencer to the one obtained in effluents. Since the size of the T1 phage is about 0.078 μm, the size the play of the PR772 phage is about 0.053 μm and the size of the PP7 phage is about 0.027 μm, these phages are excellent models for tuning the removability of a membrane with respect to larger, medium-sized and smaller viruses. A membrane is considered generally have an "absolute" removal ability with respect to a special particle, eg the T1 phage as a representative of larger virus, when it has at least one 108 and preferably at least one 1010 titer reduction relative to this particle. Of course one should absolute removability of a membrane with respect to PR772 or the PP7 phages confirm the absolute removal ability of this membrane with respect to larger viruses.

Because these biological organisms have an ability to Rapid replication allows the easy detection of the absolute the minimum quantities in the filtrate of a test solution. The inability to detect a quantity of a particular such biological model organism in the filtrate of a test solution is thus an excellent confirmation of the fact that the particular membrane really prevents all of the biological organism in the test fluid from to pass through the membrane. Furthermore, because the quantity of virus which are found as contaminants in most commercial processes rarely exceeds about 104 / ml, the capacity of the membrane according to 792 ll 510 present invention to have a titer reduction of 108 or higher give almost absolute assurance of removal of everything viruses from a large number of different fluids, especially those included in commercial handling, eg pharmaceutical production.

Titer reduction is a function of the KUF value of a membrane and the thickness of the membrane. Because the pressure drop over one membrane is affected exponentially by a membrane KUF, while the pressure drop across the diaphragm is only linearly affected by the diaphragm thickness can be small improvements in the titer reduction of a particular membranes are generally achieved in a more economical way by increasing of the thickness of the membrane, for example by arranging multiple layers of same membrane.

Pressure drop The pressure drop across a diaphragm is very important at use of such membranes for filtration purposes. Membrane according to the present invention advantageously provides the desired the titer reduction with respect to a certain particulate matter with a satisfactory pressure drop (Ap) across the membrane. The pressure drops referred to herein were calculated using conventional techniques, as described in U.S. Patent No. 4,340,479 and all printing fall values reported herein (inches Hg (cm Hg) or psi (kPa)) was determined at a constant air flow rate of 61 cm / min (2 feet / min).

Production method The membranes of the present invention are made of polyvinylidene fluoride (PVDF) using the wet casting process procedure described in US-A-4,340,479 in connection with the particular temperature limitations discussed herein. Any suitable poly- vinylidene fluoride can be used, such as Kynar (® 761 and 761 PVDF) resins. The polyvinylidene fluoride normally has a molecular weight of at least about 5,000 daltons, preferably a molecular weight of at least about 10,000 daltons.

The method of the present invention for manufacturing of the membranes described herein include the provision of a casting solution containing polyvinylidene fluoride and a solution means, heating the casting solution to a uniform temperature. turn from about 57 ° C to about 60 ° C, spreading the casting solution on one substrate for forming a film, cooling the film in a cooling bath to form a porous membrane and wash and dry 510 792 12 the porous membrane. The temperature of the casting solution is directly related to row to KUF for the resulting membrane, as illustrated in the diagram in Fig. 3 which contains a plotted curve of casting solution temperature (° C) versus resulting membrane KUF (psi and kPa). For example, a casting temperature of about 58 ° C results in the formation of a membrane having a KUF of about 214 kPa (31 psi), while a casting temperature of about 60 ° C is coming to result in the formation of a membrane having a KUF of approx 117 kPa (17 psi).

It has surprisingly been found that the temperature at which polyvinylidene fluoride casting solution is kept is very critical for the manufacture of the membrane according to the present invention.

Great care must be taken to ensure that casting the solution temperature is uniform, i.e. at a special temperature at 0.01 ° C to ensure the essential uniformity of the pore structure inside the membrane. Furthermore, it seems, without the intention is to be bound by some particular theory that lies behind the present invention, as if the casting solution has at least a short-term memory, in such a way that it is difficult to produce the membrane of the present invention with a desired KUF value if the temperature of the casting solution significantly exceeds about 60 ° C at at any time during the treatment of this casting solution, even if the temperature is then lowered to below about 60 ° C. A possible clearance to this prominent effect is that, while a single temperature can be reported for the casting solution, the reported the temperature is in fact an average of a range (or distribution) of temperatures inside the casting solution so that a significant part of the casting solution may in fact be over the reported temperature. This may explain the special success in the manufacture of suitable membranes through use of the preferred techniques of the method of the present invention invention, which comprises approaching the desired temperature of the casting solution with heating devices with ever higher precision (which not only effectively provides a uniform temperature for the casting solution but also significantly reduces the possibility of some part of the casting solution would significantly exceed about 60 ° C, and more preferably the desired final temperature of the casting solution, at each given step of the heating process). 510 792 13 While the method of the present invention may carried out in a number of different suitable ways begins a preferred embodiment of the method according to the present invention with imaging the solution of a solution consisting of polyvinylidene fluoride in powder form, a solvent for the resin, preferably dimethylacetamide, and a non-solvent, preferably isopropanol. Solution comprises about 10 to about 20% by weight and preferably from about 15 to 17 % by weight of polyvinylidene fluoride. The remaining part of the solution includes the solvent and the non-solvent in a weight ratio such as is from about 90:10 to about 70:30, preferably about 80:20.

The temperature of the polymer solution is then raised to the desired one the casting temperature. Small quantities of polymer can be effective handled at uniform temperatures in a one-step process, e.g. a few hundred grams of polymer in a liter of solution can be heated in a jacketed kettle with impeller agitation at high speed. In the case of larger quantities, in particular commercial production quantities, it is not practical to use a single stage heating process such as a jacketed kettle depending on the significant temperature changes in the casting solution, which must is avoided in order to satisfactorily produce the membrane according to the present invention.

For larger quantities, the casting solution is therefore increased temperature preferably in steps so that the temperature unit is carefully controlled while minimizing the time required to raise the temperature. At each successive step, the temperature and brought closer to the casting temperature necessary to produce set a membrane with the desired KUF, but in a way that sets greater uniformity (ie a narrower temperature distribution) to ensure that the casting solution does not exceed the desired one casting temperature.

More specifically, a larger quantity of polyvinylidene fluoride placed in a thermostatically controlled tank and dispersed in a suitable mixture of solvents and non-solvents. During mixed the pouring solution maintains the temperature in the tank of a temperature which allows its contents to reach a temperature of approx 47 ° C to about 51 ° C, which is well below the desired casting solution the temperature. This average temperature is chosen so that one ensures that no significant part of the solution exceeds it desired casting solution temperature between about 57 ° C and about 60 ° C. 510 792 14 The components should remain in the tank until the polyvinylidene fluoride dissolved and the resulting solution is uniformly heated with this equipment, for example for about 16 hours or so.

The casting solution is then preferably transported through a heat exchanger to increase its temperature to about 52 ° C and run then through an in-line mixer (or other suitable high-speed precision heating device) which increases the temperature of the casting solution to the desired uniform casting solution between about 57 ° C and about 60 ° C to 0.0l ° C. The uniformity of the temperature is very important for the uniformity of the pore structure inside the resulting membrane.

After heating the casting solution in the in-line mixer and before the casting solution is spread (i.e. cast) on a substrate the viscosity of the casting solution is normally increased by feeding the casting solution through a viscosity leveler, eg another heat exchanger that lowers the temperature of the casting solution to about 35 ° C or so. The casting solution is then spread on a suitable substrate, eg mylar, is cooled by exposure to a suitable cooling bath, e.g. an aqueous solution of dimethylacetamide and isopropanol, and washed, for example with deionized water, by conventional techniques to form the membrane of the present invention.

After washing, the wet is collected membrane and dried. Although drying can be carried out with each suitable means, for example with heat in an oven, it has been found that drying by direct heat application, such as in an oven, results in an undesired increase in pore size of the resulting membrane.

However, this has been overcome by the addition of microwave energy to the membrane to effect the drying of the membrane.

Microwaves having a frequency of about 25 MHz were used for stepwise, although any other frequency may be used for as long as the pore size or KUF value of the membrane is not affected in the negative direction.

Heat treatment The resulting polyvinylidene fluoride membrane can heat treated or expired, if desired, to improve its characteristics. In particular, the membrane of the present invention heated under conditions such that the strength is improved and subsequent hydrophilization of the membrane.

Preferably, the membrane according to the present is heated invention to a temperature of at least about 80 ° C for a period of time 510 792 15 sufficient to obtain a permit such that, in the event of subsequent hydrophilization, the resulting hydrophilized membrane the plant has substantially uniform hydrophilic properties. Of course the membrane of the present invention should not be heated to such high temperature that the membrane becomes soft and deformed, either under its own weight or depending on the voltage from any technical means by which the membrane is supported during the heating process cessen. Normally the upper temperature limit is about 160 ° C. Heat The duration of the heating varies with the heating temperature and the type of membranes that are heated. For example, small membrane pieces in planar require sheet form, which are in direct contact with a high temperature surface only a short exposure, eg less than one minute, for heating, while a rolled membrane of several hundred linear feet can require many hours of heating at low temperature in order to the mixture must reach an appropriate equilibrium temperature. Most preferred the membrane of the present invention is heated to a temperature of about 120 ° C for about 24-72 hours, especially for about 48 hours.

The heat treatment of the membrane according to the present invention can be carried out without locking the membrane; the membrane is however, dimensionally limited during the heat treatment to minimize or avoid dimensional changes in the membrane, e.g. shrinkage. Any suitable means can be used to dimensionally restrict the membrane. For example, the membrane can be placed in a frame or it can be wound on a core or roll, preferably with an intermediate material such as a fibrous non-woven material to prevent layer-to-layer contact of the membrane. Most preferably the membrane of the present invention is heat treated in roll form with a liner with a polyester fibrous non-woven fabric material.

The heat treatment of polyvinylidene fluoride membranes is are fully disclosed in U.S. Patent Nos. 5,196,508 and 5,198,505 also describes improvements in surface modifications which can be obtained by heat treatment of polyvinylidene fluoride membranes.

Surface modification The resulting polyvinylidene fluoride membrane is hydro- fobt and shows a marked tendency to adsorb proteins and similar, which may be present in the liquid being filtered. These properties are undesirable to the extent that they contribute to one higher pressure drop across the diaphragm and may eventually result in 510 792 16 premature clogging of the membrane and / or, in some cases, imaging of a secondary screen layer on the surface of the membrane. As a consequence of which the membrane according to the present invention is surface modified preferably to make it hydrophilic (i.e. having one critical wetting surface tension (CWST) of at least about 72 mN / m (72 dynes / cm) determined by the CWST test described in US-A-4,880,548) and less prone to protein adsorption and clogging.

Such surface modification of the membrane according to the present invention can be practiced in any suitable manner and achieved preferably by graft polymerization of a suitable monomer on membrane surface. Preferred examples of such monomers include acrylic or methacrylic monomers having functional alcoholic groups such as hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate and combinations thereof, in particular hydroxypropyl acrylate and / or hydroxyethyl methyl acrylate. These monomers may be combined with small amounts acrylic monomers which do not exhibit any functional alcohol groups such as methyl methacrylate as described in US-A-5,019,260.

Any suitable agent can be used to polymerize them suitable monomers on the membrane of the present invention.

Radiation grafting is the preferred technique to achieve one such a result. The radiation source may be radioactive isotopes such as carbon bolts 60, strontium 90 and cesium 137 or from machines such as X-ray equipment, electron accelerators and ultraviolet armor. Preferably, however, the radiation is in form of electron beam radiation. It has been shown that by using of this type of radiation a very uniform distribution of the radiation can be produced. This in turn results in a end product that is grafted more uniformly compared to the membranes which have been inoculated using other radiation sources, e.g. cobalt 60.

Inoculation is normally achieved either by irradiation of membrane and then exposure thereof to a suitable monomer solution or irradiation of the membrane at the same time as it is exposed for a suitable solution of the monomer. No matter what the procedure used, the inoculation should be carried out in the absence of oxygen, eg during a nitrogen atmosphere, because oxygen will react with them reactive sites created by exposure to radiation, and thereby reducing the number of available sites for the desired one 92 17 510 7 the polymer bond. If the membrane is irradiated before immersion in monomer solution, the membrane should come into contact with the monomer solution. as quickly as possible to avoid unwanted reactions resulting in loss of reactive sites for bonding of the polymer to the surface of the membrane. The monomer solution may comprise any suitable concentration of the monomer to be graft polymerized, typically 1 - 10% by volume of monomer in a solvent system, usually water alone or with a suitable alcohol such as t-butyl alcohol. The preferred monomer solution in connection with the present invention is 4% by volume of hydroxypropyl acrylate, 25% by volume of t-butyl alcohol and 71% by volume of deionized water. The details and parameters of the polymer grafting of the membrane is well known in the art.

While the graft polymerization can be carried out in absence of crosslinking agents, it is preferred that such crosslinking agents are used, especially when the above-mentioned acrylate monomers are graft polymerized on the surface of the membrane. Any appropriate crosslinking agents may be used in connection with the present invention. finding. Suitable crosslinking agents include di- or poly- acrylates and methacrylates of diols and polyols, in particular linear or branched aliphatic diols such as ethylene glycol, 1,2- propylene glycol, diethylene glycol, dipropylene glycol, dipentylene glycol glycol, polyethylene glycol, polytetramethylene oxide glycol and polyethylene (ethylene oxide-copropylene oxide) glycol as well as triolacrylates such as trimethylolpropane triacrylate. Examples of other crosslinking mono- more that can be used in the present invention include allyls, maleimides, unsaturated dicarboxylic acids, aromatic vinyls compounds, polybutadienes and trimellitic acid esters. Other suitable crosslinking agents are described in U.S. Patent 4,440,896, 4,753,988; 4,788,055 and 4,801,766.

Polyethylene glycol dimethacrylates where the molecular weight for polyethylene glycol is about 200 to about 600 are preferred cross-sections. binding agents in connection with the present invention. Polyethylene glycol 600 dimethacrylate, especially in combination with graft hydroxypropyl acrylate on the surface of the membrane is the most preferred crosslinking agent.

The crosslinking agent can be used in any suitable amount. Normally, the crosslinking agent is added to the inoculum. the solution in an amount of about 0.025% by volume to about 5% by volume, and preferably in an amount of about 0.05% by volume to about 2% by volume. Thus 510 792 18 contains, for example, a monomer solution containing 4% by volume of hydroxy- propyl acrylate in water and t-butyl alcohol preferably about 0.5 volume% polyethylene glycol 600 dimethacrylate as the crosslinking medlet.

Illustrative uses The membrane of the present invention can be used in any suitable application, including many applications there ultrafiltration membranes are currently used. Due to the excellent titer reduction of the membrane against virus and particles of corresponding size, the membrane according to of the present invention particular utility in filtering pharmacological liquids and the like, although the membrane according to the present invention can be used to filter each suitable fluid.

Thus, the present invention provides a method of filtering a fluid comprising passing a fluid through the membrane of the present invention, more particularly one isotropic, skinless, porous polyvinylidene fluoride membrane having a KUF of at least about 103 kPa (15 psi) when tested for use of liquid pairs having an interfacial tension of about 4 mN / m (4 dynes / cm) and / or exhibiting a titer reduction of at least about 108 relative to T1 bacteriophage. The fluid to be passed through the membrane according to the present invention may contain viruses, for example more than 102 / ml or up to 104 / ml, before passing through the membrane, which viruses can removed from the fluid so that the fluid contains less than 102 / ml or no virus at all after being passed through the membrane. Thus the membrane of the present invention can be used to treat fluids to reduce or remove viruses therein and can also be used to recover and concentrate viruses from fluids for viral identification, testing and the like.

The ability of the membrane of the present invention to be able to be tested for integrity with relative ease and consistently on a commercial scale enables the membrane according to the present invention to provide a predictable removal degree for given substances. Furthermore, the outstanding ones are obtained removal characteristics of the membrane of the present invention finning at a reasonable pressure drop across the diaphragm. Thus, in it the extent to which the membrane of the present invention can be used in applications where ultrafiltration membranes are used for 510 792 19 present, the membrane of the present invention will show be more desirable than and outshine ultrafiltration membranes in the same applications.

The membrane of the present invention can be used alone or it may be composed of an appropriate support structure. On similarly, the membrane of the present invention can be used in suitable filters, filter cartridges and the like. Of course can with taking into account the very uniform nature of the pore structure inside the membrane according to the invention as well as the low tendency to protein adsorption of the inoculated embodiment of the membrane, the solution of the present invention can be used in the bottom filtration applications, as well as in tangential or cross-flow filters applications.

The membrane of the present invention is expected to be particularly useful in filter elements such as filter cartridges which is generally described in US-A-4,340,479. Preferred filter elements utilizing the membrane of the present invention the membrane according to the invention in sheet form, where the sides of the membrane overlapped and sealed to form a tubular con- figuration having an outer surface, an inner surface and two ends and end caps sealed to the ends of the tube, wherein at least one of the end caps have a central opening that allows access to the tube inner and where all the seals are fluid tight. The membrane according to the present invention is preferably corrugated in one filter elements to provide a large membrane area for the volume of the filter element. At least one of the sides of the membrane normally adheres to a porous backing layer and in such a situation is generally both the membrane and the porous backing layer both corrugated. The filter element may contain a single membrane according to present invention or more preferably include multiples such membranes adhered to each other. When available multiple membranes in the filter element, the membranes are preferably separated by a porous support layer to which each membrane attached. Other aspects of the filter element can have each suitable construction and made of any suitable material.

For example, the end caps may be made of suitable polymeric materials such as polyester, especially polybutylene glycol terephthalate or polyethylene glycol terephthalate. The filter element can be designed with techniques well known in the art. 510 792 20 The following examples further illustrate present invention and should of course not be construed in any way confirm its scope.

Example 1 This example illustrates the representation of a plurality filtration membrane in accordance with the present invention. The different filtration membranes were prepared using different castings solution temperatures to demonstrate the effect of casting temperature of the KUF for the resulting filtration membrane.

A casting solution was prepared from 17.0% by weight of polyvinylidene. fluoride resin, 66.4% by weight of dimethylacetamide (solvent) and 16.6 % by weight of isopropanol (non-solvent). The casting solution was stirred in a closed vessel for dissolving polyvinylidene fluoride resin therein 80:20 w / w solvent / non-solvent mixture and the temperature of the casting solution was increased to 50.9 ° C and maintained this temperature.

Four casting solution samples were then passed through an in-line mixers and each of the casting solution samples was raised to different temperatures. Each of the solutions was then cooled to increase the viscosity, was cast as a film on a substrate and exposed a cooling bath containing 42% by weight of water, 51% by weight of dimethylacetate amide and 7% by weight of isopropanol. The cooling bath was maintained at 30 ° C. The cast the film generally remained in contact with the cooling bath for less than one minute. The resulting membrane was then washed with water to remove solvent and the membrane was microwave dried underneath holding to prevent shrinkage. Membranes were made thus with each of the four casting solution samples.

The temperatures of each of the casting solution samples and The KUF values for each of the resulting membranes are given below.

Sample Temperature KUF (° C 1 0.01 ° C) (psi) [kPa] 1A 58.22 30 [207] 1B 58.97 23 [159] 1C 59.77 18 [124] 1D 60.17 17 [1l7] 0 792 21 51 The resulting data have been entered in the form of casting solution temperature (° C) versus KUF (psi and kPa) as the curve in Fig. 3. As data shows an increase in casting temperature in the range of about 57 ° C to about 60 ° C in a corresponding decrease of KUF for the filtration membrane prepared from the casting solution.

Example 2 This example illustrates the preparation of poly- vinylidene fluoride membranes of the present invention which provided with a graft polymerized coating to make the membrane hydrophilic and less prone to protein binding. The properties for such membranes both before and after inoculation were evaluated for to demonstrate that the grafting process does not adversely affect membrane pore distribution and only contributes to a modest increase in pressure drop across the filtration membrane.

A number of membranes with different KUF values were produced with the procedure described in Example 1. A portion of each membrane were inoculated using an electron beam inoculation procedure. More determined, the membranes were passed under an electron beam generator (with settings 175 kV and 3 mAmp) at a speed of 20 ft / min to achieve a total radiation dose of 2.4 Mrad. The membranes were moved then into an inoculum of 4% by volume of hydroxypropyl acrylate, 25 vol% t-butyl alcohol and 71 vol% deionized water, were rolled up under a nitrogen atmosphere (i.e. V s were protected from oxygen), and were stored for several hours before freewashing from non grafted monomer. The inoculated membranes were frame dried at 100 ° C for 10 h minutes.

KUF, thickness and pressure drop (AP) across each membrane, i uninoculated and inoculated form, was determined and the results are given below. 510 792 22 Sample Oympat Membrane Inoculum membrane thickness KUF AP KUF AP water- (spleen 0.2 (P51) (inches Hg) (P51) (inches Hg) wettable mil) [kPa] [cm Hg] [kPa] [cm Hg] [ymtâpm] 2A 1.6 17 5.5 18 5.7 yes

[41] [117] [14.0] [124] [14.5] 28 1.6 24 10.2 25 13.8 yes

[41] [165] [25.9] [172] [35.1] 2C 1.9 21 16.7 24 28.7 yes

[48] (1451 [42.4] [165] [72.9] 2D 2.0 24 16.6 25 28.7 yes

[51] [165] [42.2] [172] [72.9] 2E 1.9 17 8.0 16 6.8 yes

[48] [l17] [20.3] [110] [l7,3] As is apparent from the resulting data, the inoculation does of the membranes of the present invention these membranes on desired way hydrophilic, i.e. water-wettable, which is negative affects the KUF and pressure drop properties of the diaphragm only on a limited way.

Example 3 This example illustrates the excellent titer reductions against different viruses that are characteristic of the membrane according to the present invention.

Different membranes (142 mm discs approx. 38 - 50 μm (1.5 - 2.0) mil) in thickness) was prepared according to the procedure described in Example 1 and inoculated according to the procedure as described in Example 2. The inoculated membranes were tested with a 50:50 mixture of T1 and PP7 bacteriophages (with a content of about 1010 bacteriophages / ml) in a gel phosphate buffer. As discussed earlier- re, the size of the T1 phage is about 0.078 pm while the size of The PP7 phage is about 0.027 μm. Thus, these bacteriophages are abundant representative of large and small viruses, respectively. The titer reductions for each membrane, single or multilayered, was determined as the ratio that of the particular subject included in the influencer to the one who is present in the effluent. KUF for the ungrafted membrane, the number tested membrane layers and the titer reduction (TR) for each phage are indicated below. 510 792 23 Sample KUF Number of layers TR (Tl fag) TR (psi) [kPa] (PP7 phage) 3A 23 [1s9] 3> 1.3x1o1 °> 4.4x1o9 33 21 (1451 3> 1.3x1o1 ° s, ox1o6 ac 24 [165] 1> 9.1x1o9 s, ox1o1 3D 24 [165] 2> 9.1x1o9 4, ox1o2 3E 24 [165] 3> 1, ox1o9 s, ox1o4 3F 24 [16s] 3 1, ox1o1 ° 1, ox1o5 3G 23 [159] 3> 1, ox1o1 ° 9, ox1o5 3H 17 [117] 3> 1, ox1o1 ° 5.7 The resulting data demonstrate that filtration the membrane of the present invention can have a very high titer reduction and may be capable of the "absolute" removal virus, which is particularly clear with sample 3A.

Furthermore, this high titer reduction capability can be achieved with extremely thin membranes, as exemplified by Sample 3C.

In addition, the resulting data demonstrate that the filtration membrane according to the present invention has a very uniform pore structure.

For example, sample 3H is capable of removing all T1 bacteriophage while allowing substantially all PP7 bacteriophages to pass through. Thus, the sample 3H membrane has a pore size as is between about 0.078 μm and about 0.027 μm, which is a lot narrow pore size distribution.

Example 4 This example further illustrates the extraordinary the virus titer reduction which is characteristic of the membrane according to present invention.

The grafted filtration membrane of Example 3 as designated as sample 3F was tested with a mixture of PR777-coliphage (at a level of 5.2x108 phage / ml) and PP7 bacteriophage (at a level of 1.7x109 phage / ml) in a gel phosphate buffer. As previously stated written, the size of the PR777 phage is about 0.053 μm, while the size of the PP7 phage is about 0.027 μm. Thus, these phages are complete representative of medium and small viruses. Titer reduction 510 792 24 for each membrane, single or multilayer, was determined as the relationship of the particular subject included in the influencer to it which is present in the effluent. KUF for the ungrafted membrane, the number of membrane layers tested and the titer reduction (TR) for each subjects are listed below.

Sample KUF Number of layers TR TR (psi) [kPa] (PR772 phage) (PP7 phage) 3G 23 [159] 3> 5.2x1o8 2.2x1o5 The established results confirm the outstanding the titer reduction of the membrane of the present invention against medium-sized viruses. Furthermore, with regard to the moderate the removal ability of this particular membrane sample relative to it much smaller PP7 phage turns out the pore size for this particular membrane samples be relatively small, i.e. below about 0.053 μm, below that the pore size distribution for the sample was also shown to be very narrow, i.e. from slightly below about 0.027 pm to below approx 0.053 cm.

Example 5 This example illustrates the estimated lower functioning the limit expressed as the pore size of the membrane of the present invention invention regarding a satisfactory titer reduction against larger viruses.

A membrane with a thickness of 46 μm (1.8 mils) was prepared in in accordance with the procedure described in Example 1 and regarding KUF, pressure drop (AP) and titer reduction (TR) against T1 and PP7 bacteriophages as described in Example 3. data are given below.

Sample KUF AP Number TR TR (psi) [kPa] (inch Hg) layer (T1-phage) (PP7-phage) [Cm HQ] 5A 17 [117] 6.8 [17.3] 1 7x1o6 <1o ss 17 [117] 6,8 [17,3] 2> 9x1o8 <1o The resulting data show that the membrane according to the present invention has a KUF value of about 117 kPa (17 psi) and a thickness of at least about 92 μm (3.6 mils) will be 25 510 792 show a titer reduction of over 108 compared to larger viruses. The the fact that the membrane of the present invention according to this example had an "absolute" removal ability with respect to it the larger T1 phage while it essentially had none removal ability with respect to the smaller PP7 phage shows that the medium of the present invention not only has a pore size of between about 0.078 μm and about 0.027 μm, without the pore size the division is very narrow, i.e. below about 0.078 pm to above approx 0.027 pm.

Example 6 This example illustrates the low protein adsorption the properties of the grafted filtration membrane according to the present invention.

An immersion load binding test was performed on samples of inoculated filtration membranes prepared in according to the procedure of Example 2 (Samples 6A - 6D) as well as on inoculated control samples (samples 6E and 6F). Each membrane was immersed in IgG solution containing 125 I goat IgG and 200 pg / ml unlabeled goat IgG for 60 minutes. Each membrane was washed with phosphate buffered saline. solution (PBS) and evaluated for adsorbed IgG. Membranes was then washed with an aqueous solution of 1% SDS in 2 M urea and was again evaluated for adsorbed IgG. The results of these assessments are set out below.

Sample Substrate Inoculation Thickness Post-PBS Post-SDS (mil) [pm] adsorption adsorption wq / cmz) (uq / cmz) 6A PVDF 12% HEMA 1.9 [48] 25.9 19.5 6B PVDF 9% HEMA 1.8 [46] 28.8 23.9 6C PVDF 9% HEMA 1.7 [43] 22.4 19.6 6D PVDF 4% HPA 1.7 [43] 12.4 8.8 6E PVDF no 1.6 [41] - 86.6 6F PVDF none 1.5 [38] - 82.6 The resulting data show that a filtration membrane according to the present invention which has been graft polymerized on suitably will have a low degree of protein absorption. Member the compound of the present invention grafted with hydroxyethyl acrylate (HEMA) showed a very reduced degree of protein adsorption compared to the inoculated control samples. Further adsorbent the membrane of the present invention grafted with hydroxy propyl acrylate (HPA) only about half as much protein as they 510 792 26 HEMA-grafted membranes of the present invention.

Example 7 This example illustrates that microwave drying of the membrane of the present invention had no significant edge negative effect on the filtration properties of the membrane.

Two membrane samples were prepared according to the procedure as described in Example 1. One of the membranes was dried in a micro wave dryer (designated 7A) while the other of the membranes was dried with a steam drum dryer (designated 7B). The KUF values for the two the membranes were determined both before and after drying and the results listed below.

Sample KUF (as cast) KUF (dried) (PS1) [kPa] (PS1) [kPa] 7A 22 [l52] 21 [l45] 7B 22 [152] 17 [117] These results show that microwave drying of the membranes, in contrast to conventional drying, does not significantly affect the pore size of the membrane according to the invention.

Example 8 This example illustrates the isotropic nature, i.e. it symmetrical pore structure, of the membrane of the present invention invention.

Several membranes with different KUF values were prepared according to using the procedure described in Example 1. KUF and pressure case (AP) divided by the thickness (inches Hg / mil and cm Hg / pm) for each membrane was determined and the results are given below. 27 510 792 Sample KUF AP / mil I (psi) [kPa] (inches Hg / mil) [cmHg / pm] 8A 12 [83] 1.50 [o, 1s] ss 12 [83] 1.32 [0.13] ac 13 [90] 1.50 [0.1s] L sn 16 [110] 3.27 [0.33] 8E 17 [117] 2.84 [0.2a] 8F 17 [117] 2.93 [0.29] se 17 [117] 2.63 [0.26] an 17 [117] 4,27 [o, 43] 8I 18 [124] 2.65 [0.27] 8J 18 [124] 4.06 [0.41] ax 19 [131] 3.90 [0.39] sL 21 [145] 11.20 [1.12] 8M 21 [145] 5.33 [0.53] 8N 22 [152] 20.75 [2.08] Sat 22 (1521 7.85 [0.79] sp 23 [159] 8.00 [0, so] 8Q 23 [159] 14.40 [1.44] sR 23 [159] 11.00 [1.10] 8S 24 [165] 12.08 [1.21] 8T 24 [165] 14.96 [1.50] su 24 [165] 14.07 [1.41] 8V 24 [165] 11.93 [1.19] 8W 24 [l65] 14.52 [1.45] sx 24 [165] 9.70 [o, 97] 8Y 25 [172] 22.27 [2.23] 510 792 28 The resulting data has been entered in the form of pressure drops across the membrane (AP) divided by the thickness of the membrane (inches Hg / mil and cm Hg / pm) on a logarithmic scale against membrane KUF (psi and kPa) as the curve in Fig. 4. The plotted curve is the result of a smallest square fit and has a correlation factor of 0.87.

As can be seen from these data, an increase in KUF results in a log rhythmic increase in pressure drop as a function of filtration membrane thickness. This relationship is characteristic of one isotropic filtration membrane and confirms that the filtration medium according to the present invention is isotropic to nature.

All references cited herein are hereby incorporated by reference in: in its entirety by reference. Although this invention has been described with emphasis on preferred embodiments, it will be apparent to those skilled in the art area that variations of the preferred products and methods can be used and the intention is that the invention should be able to practice in a manner other than as specifically described herein. Thus the invention includes all modifications that fall within the scope of the invention as defined in the following patent claims.

Claims (20)

29 51Ûdn792v i P.ans. No. 9404249-6 P a t e n t k r a v An isotropic, skinless, porous polyvinylidene fluoride membrane, characterized in that it comprises a coating of a polymer which renders the membrane hydrophilic and less prone to adsorb proteins and has (a) a K "of at least about 103 kPa when tested liquid vessels exhibiting an interfacial tension of about 4 mN / m and / or (b) a titer reduction of at least about 108 relative to T1 bacteriophage. Membrane according to claim 1, characterized in that it has a K ”of about 103 kPa to about 345 kPa. Membrane according to Claim 1 or 2, characterized in that it has a titer reduction of at least about 108 relative to T1-bacteriophage. Membrane according to claim 3, characterized in that it has a titer reduction of at least about 108 relative to PR772-coliphage and / or PP7-bacteriophage. Membrane according to one of Claims 1 to 4, characterized in that it has a titer reduction of about 102 or less relative to PP7 bacteriophage. Membrane according to one of Claims 1 to 5, characterized in that it has a thickness of about 500 μm or less. Membrane according to Claims 1 to 6, characterized in that the polymer comprises one or more acrylic or methacrylic monomers having hydroxyl functional groups. Membrane according to Claim 7, characterized in that the polymer has been radiation-grafted onto the membrane. Membrane according to Claim 8, characterized in that the radiation is electron beam radiation. 510 792 30 10. A method of producing a membrane having (a) a K 'of at least about 103 kPa when tested using liquid vessels having an interfacial tension of about 4 mN / m and / or (b) a titer reduction of at least about 108 relative to T1 bacteriophage, characterized in that it comprises preparing a casting solution containing polyvinylidene fluoride and a solvent therefor, heating the casting solution to a uniform temperature of about 57 ° C to about 60 ° C, spreading the casting solution on a substrate to form a film, cooling of the film in a cooling bath to form a porous membrane and wash and dry the porous membrane. Method according to Claim 10, characterized in that the membrane is dried at least in part by exposing the membrane to microwave radiation. A method according to claim 10 or 11, characterized in that the membrane is treated to provide the membrane with a coating of a polymer which makes the membrane hydrophilic and less prone to adsorption of proteins. A method according to claim 12, characterized in that said treatment comprises bonding a polymer comprising one or more acrylic or methacrylic monomers having functional hydroxyl groups to the surface of the membrane. A method according to claim 12 or 13, characterized in that the polymer is radiation grafted onto the membrane. A method according to claim 14, characterized in that said radiation is electron beam radiation. A filter element comprising the membrane according to any one of claims 1 to 9, having sides overlapped and sealed to form a tubular structure having an outer surface, an inner surface and two ends and end caps sealed to the ends of the tube, wherein at least one of said end caps has a central 31 510 792 opening which allows access to the interior of the pipe and where all seals are fluid tight. Filter element according to claim 16, characterized in that said membrane is corrugated. Filter element according to Claim 16 or 17, characterized in that at least one of the sides of the membrane adheres to a porous support layer. Filter element according to claim 18, characterized in that said filter element comprises multiple membranes adhering to each other. Filter element according to claim 19, characterized in that said membrane is separated by a porous support layer to which each membrane adheres.