EA040896B1 - HOLLOW FIBER MEMBRANE WITH IMPROVED SEPARATING CAPABILITY AND OBTAINING OF HOLLOW FIBER MEMBRANE HAVING IMPROVED SEPARATING CAPABILITY - Google Patents

Description

Invention theme

The invention relates to hollow fiber membranes containing a material based on polysulfone and polyvinylpyrrolidone, which have improved separation characteristics, in particular an improved ability to separate substances in the range of medium molecular weights and take into account the selectivity in relation to the separation of substances in the range of high molecular weights

In addition, the invention relates to a method for producing hollow fiber membranes containing a material based on polysulfone and polyvinylpyrrolidone.

Further, the invention relates to a hollow fiber membrane filter comprising hollow fiber membranes with uniform permeability characteristics.

In particular, the invention relates to a method for sterilizing hollow fiber membranes made from a material based on polysulfone and polyvinylpyrrolidone.

State of the art

Hollow fiber membranes are widely used in liquid purification. In particular, hollow fiber membranes have applications in medical technology for water purification and blood purification in dialysis patients with kidney disease. The respective hollow fiber membranes are combined into bundles of hollow fiber membranes in filter modules. This type of filter modules for blood purification is produced on an industrial scale.

Hollow fiber membranes used in blood purification often consist of polysulfone (PSU) and polyvinylpyrrolidone (PVP) because these materials have been found to be preferentially hemocompatible and therefore medically preferred in blood purification, especially in hemodialysis. The basic principles for obtaining hollow fiber membranes, as well as their preparation, are described in documents of the prior art: Marcel Mulder; Principles of Membrane Technology; Kluwer Academic Publisher 1996; Chapter III, Preparation of synthetic membranes EP 0168783 WO2007/128440

According to the methods described in the prior art, a dope is prepared which contains a polysulfone-based hydrophobic material and a vinylpyrrolidone-based hydrophilic polymer, in particular polyvinylpyrrolidone, one or more solvents and, if necessary, additives. Suitable solvents are polar aprotic solvents, in particular dimethylacetamide, N-methylpyrrolidone, dimethylformamide or dimethylsulfoxide.

The dope may also contain small amounts of additives, such as polar protic solvents such as water.

The spinning mass is extruded through a circular die. In this case, the spinneret has an internal opening through which the precipitant is passed, which is co-extruded together with the spinning mass. The spinning mass is extruded through the annular gap surrounding the inner hole, with the formation of a hollow fiber, in the lumen of which is introduced a precipitator. Then, the spun fiber is introduced into a spinning bath containing an additional precipitant so that a membrane structure is formed by phase inversion and precipitation to form a hollow fiber membrane. Suitable precipitants are water or mixtures of protic and aprotic solvents, in particular water and dimethylacetamide, N-methylpyrrolidone, dimethylformamide or dimethylsulfoxide. The resulting hollow fiber membrane is then passed through washing baths, dried and wound on a drum. The hollow fiber membranes can be removed from the drum in the form of bundles of hollow fibers. For the manufacture of hollow fiber membrane filters, such bundles of hollow fibers are inserted into a housing, preferably a cylindrical housing. The ends of the bundle of hollow fiber membranes are embedded in the casting mass, and the open ends of the hollow fibers lie freely. The potting compound forms an insulating zone between the inside of the hollow fiber membranes, the housing and the area surrounding the hollow fiber membranes. As a result, a first chamber is formed in the finished hollow fiber membrane filter, which covers the inlet and outlet regions of the ends of the bundle of hollow fiber membranes, as well as the internal volume of the hollow fiber membranes. Accordingly, the second chamber is formed by a region in the intermediate space between the hollow fiber membranes and between the housing wall and the hollow fiber membranes. Fluid openings in the hollow fiber membrane filter housing allow liquids and gases to be introduced into and/or removed from the first and/or second chamber of the hollow fiber membrane filter.

At the same time, at least one fluid opening forms an inlet to the first chamber of the hollow fiber membrane filter. The at least one fluid port forms an inlet to the second chamber of the hollow fiber membrane filter. If necessary, depending on the purpose of the resulting hollow fiber membrane filter, it is possible to provide additional inlet and outlet openings in the first or second chamber. Hollow fiber membrane filters for extracorporeal blood purification typically have one first and one second fluid ports in the first chamber of the filter module and one first and one second port in the second chamber of the filter module. Thus, fluids, in particular liquids or gases, may be added to or removed from the chamber of the hollow fiber membrane filter through the first opening depending on the direction of flow, or may be supplied or discharged from the chamber.

- 1 040896 hollow fiber membrane filter through the second hole according to the direction of flow.

For hollow fiber membrane filters intended for medical purposes, in particular for purifying the blood of patients with diseased kidneys, after the manufacturing process of the hollow fiber membranes and filter formation, one or more washing and sterilization steps are usually carried out to clean and sterilize the hollow fiber membranes for medical use.

Appropriate methods are known in the prior art in which hollow fiber membranes in hollow fiber membrane filters are subjected to washing and sterilization steps. In particular, one known method for sterilizing hollow fiber membranes and hollow fiber membrane filters is heat sterilization with air, water or steam of hollow fiber membrane filters. Thermal sterilization refers to sterilization with fluids (eg water, air, steam or mixtures thereof) at temperatures above 100°C. Thermal sterilization with predominantly pure water vapor is also called steam sterilization. A suitable sterilization method for dialyzers is described in DE 3936785 C1. According to the method described in DE 3936785 C1, dialyzers are subjected to a washing process and then a sterilization process. During the sterilization process, dialyzers are washed with hot water or steam heated to a temperature above 121°C.

Other methods known in the art for sterilizing filter modules are vacuum steam sterilization, sterilization using sterilizing gases such as ethylene oxide, irradiation with ionizing or radical-forming radiation, such as electron radiation or gamma radiation.

Vacuum steam sterilization has been shown to adversely affect the stability of the hollow fiber membranes to be sterilized due to the variable heat load. In the process of steam sterilization in a vacuum, the technological stages of steam treatment and evacuation of the sterilization chamber alternate. At each stage of evacuation, the temperature of the sterilization chamber and the hollow fiber membrane filter inevitably drops much lower than during the steaming stage. Thus, the hollow fiber membrane filter is subjected to a continuously changing expansion of the material.

The disadvantage is that during the vacuum steam sterilization process, stresses can occur in the material. Accordingly, this greatly complicates the choice of material, and also places high demands on the processing and design of the hollow fiber membrane filter.

Sterilization with ionizing radiation, such as gamma radiation or electron radiation, is associated with high equipment costs and leads to a large additional processing time.

Ethylene oxide sterilization also requires huge process costs due to the toxicity of ethylene oxide. In addition, after sterilization, a long phase of complete removal of ethylene oxide is necessary.

Thermal sterilization carried out in accordance with DE 3936785 C1, which was carried out through the steps of washing and sterilization with water and/or steam, proved to be superior compared to the other sterilization methods mentioned in terms of equipment and process technology. In particular, heat sterilization with water and/or steam has been found to be superior to sterilization methods by irradiation or gassing with respect to the hemocompatibility of the sterilized hollow fiber membranes.

However, it has also turned out that for polysulfone membranes that contain polyvinylpyrrolidone, the steam sterilization method specified in DE 3936785 C1 can have a negative effect on the clearance of hollow fiber membranes. It is believed that the washing operation during the sterilization process increases the mobility of the PVP present on the hollow fiber membrane. Under the action of the capillary forces of the pores of the membrane, the PVP that has become mobile is drawn into the pores of the hollow fiber membrane and narrows or blocks the cross section of the pores. This results in a smaller pore cross section being available for filtration applications. Accordingly, deposits of PVP in the pores degrade the permeability characteristics of hollow fiber membranes.

The deterioration of the permeability of the hollow fiber membranes caused by the sterilization operation has been attempted to be counteracted by appropriate adaptation of the production of the hollow fiber membranes. As a result, it turned out that the pore size distribution of the hollow fiber membrane was expanded, which is a disadvantage. The pore size distribution of hollow fiber membranes has a direct effect on the selectivity of hollow fiber membranes.

In addition, from the method according to DE 3936785 C1 it follows that in the previous methods during sterilization with water or steam, due to the presence of PVP in the hollow fiber membrane filter, the hollow fiber membranes could stick together in the dialyzer. This is not a disadvantage in terms of the required sterility. However, such adherent hollow fiber membranes have been found to lead, due to the sterilization process, to non-uniform performance of the hollow fiber membranes in the hollow fiber membrane filter. In particular, it has been found that zones of a hollow fiber membrane filter in which the hollow fiber membranes are clumped during the sterilization process have a lower permeability compared to zones without clumping of the hollow fiber membranes.

Considering this aspect, there is reason to improve the washing and sterilization operations in the method of steam sterilization of the hollow fiber membrane filter in such a way as to prevent the crowding of the hollow fiber membranes in the hollow fiber membrane module and, in addition, avoid constriction or blockage of the pores by the mobile precipitated PVP and at the same time maintain high sterility and hemocompatibility. hollow fiber membranes and hollow fiber membrane filter.

In this regard, an important characteristic feature of hollow fiber membranes is the clearance. Clearance is a measure of the separation power of a hollow fiber membrane and indicates the efficiency with which harmful metabolites can be removed during blood purification by processing on hollow fiber membranes. Methods for determining the clearance of hollow fiber membranes are known in the art. Reference can be made in this respect to DIN/EN/ISO 8637:2014. Meanwhile, the clearance of the hollow fiber membrane is determined according to the standard after the membranes are formed into a test filter suitable for the respective conditions.

In developing hollow fiber membranes for extracorporeal blood purification, the goal is to provide hollow fiber membranes having the highest possible separating power in order to provide effective forms of therapy for extracorporeal blood treatment.

The separating power of a substance depends, in particular, on the porosity and the average pore size of the membrane. Porosity indicates the proportion of volume occupied by pores in the membrane. If, in this case, the membrane has a larger pore volume than the reference membrane, a more intense mass transfer through the membrane wall is observed depending on the average pore size.

In particular, for therapy in chronic extracorporeal blood purification, a high efficiency of separation of plasma proteins in the range of average molecular weights is desirable. However, high retention of plasma proteins in the high molecular weight range is simultaneously required, eg retention of albumin. At the same time, a high hemocompatibility of hollow fiber membranes during extracorporeal blood processing is also desirable.

The task of the invention

It has been shown that a disadvantage of the prior methods for preparing steam-sterilized hollow fiber membranes based on polysulfone and polyvinylpyrrolidone, due to the sterilization procedure, is the limited separation power and selectivity, in particular, the limited ability to separate plasma proteins in the range of average molecular weights for a given retention of albumin.

Thus, in the first aspect, the object of the invention is to provide a hollow fiber membrane having a high separating power (clearance) in the medium molecular weight range and a high retention in the high molecular weight range, while the hollow fiber membrane must simultaneously have high blood compatibility, which is ensured by heat sterilization water or steam.

In a second aspect, it is an object of the invention to provide a hollow fiber membrane filter having uniform performance with hollow fiber membranes within the hollow fiber membrane filter.

In a third aspect, it is an object of the invention to provide an improved method for producing hollow fiber membranes that includes washing and/or sterilization steps based on water or steam, without reducing the separating power of the hollow fiber membranes in the washing and/or sterilization steps.

Furthermore, in a fourth aspect, it is also an object of the invention to provide a method for washing and/or sterilizing hollow fiber membrane filters with water or steam, which does not adversely affect the performance of the hollow fiber membranes.

The essence of the invention

Unexpectedly, it turned out that the problem indicated above for the first aspect of the invention is solved by means of a hollow fiber membrane with features according to claim 15 of the claims. Claims 16-24 present preferred embodiments of the invention relating to the first aspect.

Surprisingly, the problem mentioned above for the second aspect of the invention is solved by means of a hollow fiber membrane filter with the features according to claim 26.

It has been shown that the problem indicated above for the third aspect of the invention is solved by a new method for producing hollow fiber membranes with the features according to claims 1 to 7.

It has been shown that the problem indicated above for the fourth aspect of the invention is solved by the cleaning method of a hollow fiber membrane filter with the features according to claims 8 to 14.

Detailed description of the invention

In accordance with the first aspect of the invention, it has surprisingly turned out that a hollow fiber membrane having improved separating power in the average molecular weight range can be obtained when the hollow fiber membrane contains at least one material based on

- 3 040896 polysulfone and at least one polymer based on vinylpyrrolidone, and the hollow fiber membrane has a porosity of 77.5 to 82% and a sieving factor for dextran with a molecular weight of 10,000 g/mol from 0.42 to 0.75.

The hollow fiber membrane according to the first aspect of the invention is characterized by high permeability in the average molecular weight range. In particular, such hollow fiber membranes have also been shown to be hemocompatible since they can be made from polymers based on polysulfone and polyvinylpyrrolidone and can be cleaned in a washing process and sterilized in a sterilization process.

According to a first aspect of the invention, the hollow fiber membrane material is based on a polysulfone. According to the terminology of the present description, a polysulfone-based polymer is understood to mean a polymer containing a sulfo group in the main or side polymer chain. The term polysulfone (PSU) in the context of this application should be understood as a generic term for all polymers containing sulfo groups. Representative materials based on polysulfone are polysulfone (PSU), polyether sulfone (PES), polyphenylsulfone and copolymers containing sulfonic groups. In the prior art, other, not specifically listed here, representatives of polysulfone polymers are known, suitable in the context of the invention for obtaining membranes for blood purification. Polysulfone materials have shown to be superior to other materials in the production of membranes for blood purification since they can be steam sterilized and have good hemocompatibility.

Polysulfone (PSU)

Polyethersulfone (PES)

By vinylpyrrolidone-based polymer is meant a polymer obtained using the vinylpyrrolidone monomer or its derivatives. In particular, polyvinylpyrrolidone (PVP) is well suited in the context of the present invention for the preparation of hollow fiber membranes according to the invention. PVP is a water-soluble polymer that is used as an aid in the preparation of polysulfone-based hollow fiber membranes. In addition, PVP improves the hemocompatibility of polysulfone hollow fiber membranes, as it imparts hydrophilicity to the hydrophobic polysulfone material and thereby improves blood wettability.

Polyvinylpyrrolidone (PVP)

In this case, hemocompatibility should be understood as being compatible with human blood, in particular, it is understood that blood in contact with polysulfone materials does not enter into any negative reactions that could be harmful to the health of patients during blood purification. Under such reactions can be understood, for example, the phenomena of blood clotting or the tendency to damage blood cells (cytotoxicity). The use of PSU/PVP polymers has proven to be superior in terms of hemocompatibility compared to other blood contact materials in hollow fiber membranes.

In particular, hollow fiber membrane materials based on polysulfone and polyvinylpyrrolidone differ in their zeta potential. Zeta potential is a measure of the electrical charge that can be induced on substrate surfaces. Particularly in blood purification membranes, their surface charge is associated with harmful reactions. Membranes based on polysulfone and polyvinylpyrrolidone show different zeta potential values depending on the method used to obtain the hollow fiber membrane.

Membrane porosity indicates the proportion of pore volume in the membrane material. In this case, in the case of hollow fiber membranes, only the fraction of the pore volume on the membrane wall is taken into account. The lumen of the hollow fiber membrane is not included in the porosity calculation. Porosity characterizes a measure of the permeability of a hollow fiber membrane to liquids and thus is also a measure of the separating ability of the membrane in relation to molecules of a certain size. In particular, in combination with the sieving ratio of a molecule of a particular molecular weight, porosity is considered as a measure of the separation capacity of the membrane for said molecule. In the present case, it was found that a hollow fiber membrane having a sieving ratio of 0.42 to 0.75 with respect to dextran molecules with a molecular weight of 10,000 g/mol belonging to the average molecular weight range of plasma proteins, in combination with a porosity of 77.5- 82% hollow fiber membrane, is characterized by high permeability or clearance in the medium molecular weight range and high separation selectivity for high molecular weight plasma proteins, in particular albumin. A hollow fiber membrane is preferred, characterized in that it is substantially free of macrovoids or dendritic cavities. Dendritic cavities are macrovoids having elongated finger-like elongations. Macrovoids are described in the cited literature (Mulder). In addition, examples of the formation of dendritic cavities can be found in WO 2004/056460 A1 (Fig. 1), WO 2013/034611 A1 (Fig. 1, 2 and 3) or WO 2015/056460 A1 (Fig. 5). Membranes without dendritic cavities or macrovoids have higher mechanical stability. More preferred is a membrane having a wall thickness of 35 µm or less and substantially free of macrovoids or dendritic cavities. With such small wall thicknesses, it is especially important to ensure good mechanical stability.

The sieving factor indicates how much of the substance in question is able to penetrate the membrane wall during the filtration process. In particular, for a hollow fiber membrane with a low sieving ratio of high molecular weight molecules, it is true that during filtration they are mostly retained by the membrane walls, and only a small proportion is able to penetrate through the pores of the hollow fiber membrane. In the production of hollow fiber membranes for blood purification, the aim is to create a porous structure of the hollow fiber membrane which will achieve a high retention of high molecular weight plasma proteins, such as albumin, and which is characterized by a correspondingly low albumin sieving coefficient, 0.01, preferably 0.005, particularly preferably 0.001 . In contrast, the high screening ratio of low molecular weight molecules suggests that almost all of these molecules are able to pass through the wall of the hollow fiber membrane through its pore structure.

Meanwhile, the pore size distribution of the membrane according to the invention is configured to obtain, as described above, a sieving factor for dextran with a molecular weight of 10,000 g/mol in the range of 0.42 to 0.75 and a sieving factor for albumin as described higher, less than 0.1.

In another embodiment of the first aspect of the invention, the hollow fiber membrane of the invention has a zeta potential value of -3 mV to -10 mV. It turned out, in particular, that harmful reactions with blood cells in this range of values occur only to a small extent.

In a further embodiment of the first aspect of the invention, it has been found that the selectivity of the hollow fiber membrane can be improved if the hollow fiber membrane has a porosity of 78 to 81%, in particular a porosity of 79 to 80.5%.

In yet another embodiment of the first aspect of the invention, it has turned out that the selectivity of the hollow fiber membrane can be further improved if the hollow fiber membrane has a sieving factor for a dextran molecule with a molecular weight of 10,000 g/mol from 0.45 to 0.75, preferably from 0.55 to 0 .7, in particular, has a screening factor of 0.6 to 0.7.

In a further embodiment of the first aspect of the invention, it has turned out that the selectivity of the hollow fiber membrane can be improved if the hollow fiber membrane has an albumin sieving factor of less than 0.005, in particular less than 0.001.

In a further embodiment of the first aspect of the invention, it appears that the hemocompatibility of the hollow fiber membrane can be improved if the hollow fiber membrane has a zeta potential of -4 to -8 mV, in particular -6 to -8 mV.

In a further embodiment of the first aspect of the invention, it has been found that the hemocompatibility of the hollow fiber membrane can be improved if the hollow fiber membrane has a PVP content of 2.5 to 5%.

In a further embodiment of the first aspect of the invention, it turned out that the membrane according to the invention has a maximum nominal pore size distribution in the range of 22 to 26A (A=angstrom=100 ppm). In particular, it has been found that by maximizing the nominal pore size distribution in this molecular weight range, the desired high separation of medium molecular weight plasma proteins can be achieved. In this case, the distribution of pores by size indicates what is the probability of meeting a pore of a certain size among all the pores present in the hollow fiber membrane. Thus, the maximum nominal pore size distribution indicates which particular pore size is most common among all pores. In addition, in the present case, it was shown that if you set the nominal pore size distribution in the production of a hollow fiber membrane so that the maximum nominal pore size distribution lies in the range from 22 to 26A, preferably from 23 to 26A, and the sieving ratio of albumin in range was less than 0.01, a membrane with improved selectivity can be obtained.

In a second aspect, the invention relates to a hollow fiber membrane filter. The hollow fiber membrane filter consists of a cylindrical body containing a plurality of hollow fiber membranes. In particular, hollow fiber membranes can be obtained in accordance with one of the embodiments of the first aspect of the invention. Hollow fiber membranes are embedded

- 5 040896 the cavity of the hollow fiber membrane filter with the casting mass in such a way that the first chamber encloses the interior of the hollow fiber membranes, and the second chamber encloses the space between the hollow fiber membranes. Further, the hollow fiber membrane filter comprises a first inlet for supplying fluids, in particular liquids or gases, into the inside of the hollow fiber membranes, and a second inlet for withdrawing liquids or gases from the internal volume of the hollow fiber membranes. The hollow fiber membrane filter is characterized in that the hollow fiber membranes have a uniformly distributed permeability characteristic, in particular a uniform ultrafiltration coefficient, in different areas, in particular over the cross section of the hollow fiber membrane filter. The uniformity of the permeability characteristics of hollow fiber membranes in different areas of a hollow fiber membrane filter is said to be when the hollow fiber membranes have ultrafiltration coefficients in different areas that differ from each other by no more than 20%.

The uniform ultrafiltration coefficient of the hollow fiber membranes in the hollow fiber membrane filter is due to the fact that in the production process a process step is applied in which a transmembrane transition of a fluid occurs, in particular water vapor or water. Water vapor in the context of this application refers to water in a gaseous state of aggregation. In the context of the present application, water vapor is also understood to mean the form of gaseous water, which is accompanied by so-called visible puffs of steam; those. water droplets dispersed in the air in the form of mist. Thus, the term steam, as used in this application, covers other additional designations of steam, such as hot steam, wet steam, saturated steam, superheated steam, and supercritical steam.

The transmembrane transition of the medium can occur from the first chamber, which encloses the internal volume of the hollow fiber membranes, through the membrane wall to the second chamber, which encloses the space between the hollow fiber membranes. In an alternative embodiment, the transmembrane junction may be from a second chamber that spans the space between the hollow fiber membranes, through the membrane wall, to a first chamber that spans the internal volume of the hollow fiber membranes. It is contemplated that the transmembrane junction may cause the PVP to be washed out of the pores so that possible constriction or blockage of the pores of the hollow fiber membrane that could occur during preparation due to PVP precipitation can be eliminated. It is also believed that the transmembrane passage of water and/or water vapor also prevents the hollow fiber membranes from clumping together. As a result of the transmembrane transfer of a fluid, in particular water vapor or water, from the inside of the hollow fiber membranes to the outside of the hollow fiber membranes, such agglomeration is destroyed by the medium flowing from the inside of the fibers. As a result, loosening of the hollow fiber membranes in the bundle of hollow fiber membranes is observed. The flow of the medium along the hollow fiber membranes from the outside and passing through the membrane wall into the membrane also causes disaggregation of the adhered hollow fiber membranes. In addition, it has been observed that the ultrafiltration coefficient of the hollow fiber membrane filter as a whole increases.

A hollow fiber membrane filter in the context of the second aspect of the invention may comprise from 50 to 20,000 hollow fiber membranes, which are located in a hollow fiber membrane filter housing with a packing density of 50 to 70%. In this case, the placement density is understood as the filling of the space with hollow fiber membranes in a bundle of hollow fiber membranes located in the housing. The density of the hollow fiber membranes is equal to the sum of the cross-sectional areas of the individual hollow fiber membranes divided by the total cross-sectional area that bounds all the sections of the hollow fiber membranes in the system. Usually this is the cross section of the body. For hollow fiber membranes and housing geometry with a round cross section, the packing density is calculated using the following formula:

D ² _? ^and (fiber)

O (placement density) ^- 2 ^ (body) where d (fiber) - the average outer diameter of the unloaded hollow fiber membrane, d (body) - the inner diameter of the body, n - the number of hollow fiber membranes in the body.

The expression unloaded hollow fiber membrane refers to a single free hollow fiber membrane. In the housing, under the action of compression, the hollow fiber membranes can be deformed, i.e. have a deformed section under load. However, when calculating the packing density, the diameter of the unloaded hollow fiber membrane should always be taken into account.

The loosening of the hollow fiber membrane filter due to transmembrane fluid transfer during the manufacturing process of the hollow fiber membrane filter is more effective in the case of denser packing, i.e., for hollow fiber membrane filters with a high packing density, than for hollow fiber membrane filters having a low packing density. In particular, the opening of the hollow fiber membranes in the hollow fiber membrane filter is considered to be particularly effective when the packing density of the hollow fiber membranes is 50-70%, preferably 55-65%, more preferably 55-65%.

- 6 040896

In particular, the transmembrane transition of a fluid, in particular water vapor or water, may be carried out as part of a heat sterilization process or even be part of a heat sterilization step. In the latter case, it is envisaged to use steam with a temperature of 121-140°C, so that bactericidal sterilization also occurs as a result of the transmembrane transition of water vapor.

In a third aspect, the invention relates to a method for producing a bundle of hollow fiber membranes for use in a hollow fiber membrane filter comprising a plurality of hollow fiber membranes. In particular, the hollow fiber membrane filter may be a hollow fiber membrane filter according to one embodiment of the second aspect of the invention; in addition, in particular, hollow fiber membranes can be made in accordance with one embodiment of the first aspect of the invention. The production method includes the process of molding hollow fiber membranes based on polysulfone and polyvinylpyrrolidone; in particular, the molding process is carried out in a dry-wet molding process. The production method includes technological steps: preparation of a spinning solution containing a polysulfone-based material, in particular polysulfone, a vinylpyrrolidone-based polymer, in particular polyvinylpyrrolidone, an aprotic solvent, in particular dimethylacetamide, preparation of a coagulant solution containing water and an aprotic solvent, in particular , dimethylacetamide, coextruding the spinning solution and the coagulant solution through a concentric annular die to obtain a hollow filament, wherein the filament lumen is filled with the coagulant solution, passing the filament through the precipitation gap, introducing the filament into a spin bath containing mainly water to obtain a hollow fiber membrane passing the hollow fiber membranes through at least one washing bath and drying the obtained hollow fiber membranes, arranging the obtained hollow fiber membranes into a bundle of hollow fiber membranes, processing the bundle of hollow fiber membranes during steamy steam. Furthermore, the method is characterized in that the steam treatment includes at least one step in which water vapor is conducted into the fibers and penetrates through the membrane wall to the outside of the fibers when pressure is applied.

After the hollow fiber membranes are placed in the hollow fiber membrane bundle, but before the hollow fiber membrane bundle is treated with water vapor, the hollow fiber membrane bundle can be placed in the hollow fiber membrane filter housing and cast with curable resin at the ends of the hollow fiber membrane bundle according to known prior art methods.

The bundle of hollow fiber membranes embedded in the housing can be further processed to form a hollow fiber membrane filter so as to form two fluid flow chambers, the first chamber enclosing the internal volume of the hollow fiber membranes and the second chamber enclosing the spaces between the fibers, and wherein the hollow fiber membrane filter comprises at least at least one inlet for inlet of medium into the first chamber of the hollow fiber membrane filter; and at least one inlet for inlet of medium into the second chamber of the hollow fiber membrane filter. Then, inside the hollow fiber membrane filter, the step of steaming the bundle of hollow fiber membranes can be carried out by introducing water vapor into the first chamber of the hollow fiber membrane filter, covering the internal volume of the hollow fiber membranes, through the first inlet, and passing the steam through the membrane wall into the second chamber of the hollow fiber membrane filter, covering the gaps between hollow fiber membranes, when pressure is applied, and the removal of steam to the outside from the second chamber through the second hole on the hollow fiber membrane filter.

The steaming step can be implemented as part of a washing operation or as part of a heat sterilization; specifically, the steaming step itself constitutes a washing step when the hollow fiber membranes are introduced into the hollow fiber membrane filter as a bundle of hollow fiber membranes.

The production of a hollow fiber membrane filter according to the above method makes it possible to obtain a hollow fiber membrane filter in which the pores of the hollow fiber membranes do not suffer from blockage or narrowing due to polyvinylpyrrolidone and in which the individual hollow fiber membranes do not stick together. As a result, the clearance of the hollow fiber membranes in the hollow fiber membrane filter obtained by the method of the invention is increased, since a large membrane surface for transmembrane mass transfer is effectively provided due to the absence of fiber agglomeration and freeing the pores of precipitated PVP.

Further, the production method ensures excellent biocompatibility of the hollow fiber membranes when the steaming step is carried out as part of heat sterilization. In this case, fragments of destroyed cells and endotoxins arising under sterilization conditions are washed off the membrane surface. Therefore, in one preferred embodiment, prior to the steaming step, the bundle of hollow fiber membranes is further processed to form a filter and steamed on the hollow fiber membrane filter as part of the sterilization step.

In a further embodiment of the third aspect of the invention, a dope solution is used for the process of forming hollow fiber membranes, which contains 14-18% polysulfone-based polymer, preferably polysulfone, and 3-6% vinylpyrrolidone-based polymer, preferably polyvinylpyrrolidone. The other part of the spinning solution is a polar aprotic solvent, preferably dimethylacetamide (DMAC).

In a further embodiment of the third aspect of the invention, the process according to the invention for producing a bundle of hollow fiber membranes is characterized in that the coagulant solution contains 25-40% of a polar aprotic solvent, in particular dimethylacetamide, in particular 25-40% DMAC and 60-75% water.

In another embodiment of the third aspect of the invention, the process according to the invention for producing a bundle of hollow fiber membranes is characterized in that the temperature of the spinning bath during the spinning process is controlled at 70 to 90°C, in particular from 75 to 90°C. This spinning bath temperature promotes a high ultrafiltration ratio and a high sieving ratio of molecules in the average molecular weight range.

In yet another embodiment of the third aspect of the invention, the method according to the invention for producing a bundle of hollow fiber membranes is characterized in that the hollow fiber membranes are washed at a temperature of from 75 to 90°C. For the washing process, a washing liquid, preferably water, is passed into a hollow fiber membrane filter and the filter in the first chamber and the second chamber is rinsed with water. This process flushes out residual particles and eluted components of the hollow fiber membrane and filter housing from the hollow fiber membrane filter.

In a further embodiment of the third aspect of the invention, the process according to the invention for producing a bundle of hollow fiber membranes is characterized in that the hollow fiber membranes are dried at a temperature of 100 to 150°C.

In a further embodiment of the third aspect of the invention, the method according to the invention is characterized in that the steam treatment of the bundle of hollow fiber membranes is carried out at a temperature of more than 60 to 140°C.

In a fourth aspect, the invention relates to a sterilization procedure for sterilizing a hollow fiber membrane filter. Accordingly, a hollow fiber membrane filter is sterilized, which includes a plurality of hollow fiber membranes end-embedded in the hollow fiber membrane filter body so that a first chamber is formed that encloses the inner volume of the hollow fiber membranes and a second chamber that encloses the space between the hollow fiber membranes. In addition, the hollow fiber membrane filter comprises at least fluid inlets connected to the first chamber and at least two fluid inlets connected to the second chamber, the holes being suitable for connection to a sterilizer, and the method comprising at least the following steps: washing the hollow fiber membrane filter with a fluid medium, in particular water, wherein the washing liquid is passed through the first and second chambers of the hollow fiber membrane filter by selecting medium inlet holes, sterilizing the hollow fiber membrane filter with a sterilizing medium, in particular water or water steam, wherein the sterilizing medium is conducted through the first and second chambers of the hollow fiber membrane filter by selecting the medium inlets, the supply of the medium, in particular water or steam, to the first or second chamber of the hollow fiber membrane filter by selecting the medium inlets, and the transmembrane passage of a medium, in particular water or water vapor, through the membrane wall into the corresponding second or first chamber of the hollow fiber membrane filter.

One embodiment of the process according to the invention according to the fourth aspect of the invention involves carrying out the washing step on the hollow fiber membranes embedded in the hollow fiber membrane filter using sterile water or steam, respectively sterilizing water or steam. Sterilization in this case means that the washing steps are carried out under heat and pressure conditions. Sterilizing conditions within the thermal sterilization of hollow fiber membrane filters correspond to temperatures from more than 105 to 150°C, preferably from 121 to 140°C, and an absolute pressure from 1.1 bar to 10 bar, preferably from 2 bar to 4 bar.

In a further embodiment of the fourth aspect of the invention, the method according to the invention includes the step in which a fluid, in particular water or water vapor, is introduced into the first chamber of the filter module, is transferred by means of the created pressure difference across the membrane wall into the second chamber and is discharged from there. Alternatively, a fluid, in particular water or water vapor, can also be supplied to the second chamber of the hollow fiber membrane filter by selecting a medium opening, and by means of a pressure drop created, be conducted from the second chamber through the membrane wall into the first chamber of the hollow fiber membrane filter. At the same time, the inlets of the hollow fiber membrane filter are connected to a sterilizer capable of supplying a sterilizing medium, in particular heated water and/or steam, to the hollow fiber membrane filter. Preferably, a fluid, in particular water or water vapor, is led into the first chamber through the first opening, and the second opening for the inlet of the medium into the first chamber of the hollow fiber membrane filter, if any, is closed. However, a fluid, in particular water or water vapor, can also be fed into the hollow fiber membrane filter at the same time through both openings. In both cases, the increase in pressure due to the supply of a medium, in particular water or steam, causes the medium, in particular water or steam, to pass through the membrane wall and pass into the second chamber. The medium that has passed into the second chamber, in particular water or water vapor, can be discharged through an additional opening.

In a further embodiment of the fourth aspect of the invention, it has turned out that the transmembrane transition of the fluid, in particular water or steam, is preferably carried out prior to the sterilization process.

In yet another embodiment of the fourth aspect of the invention, the hollow fiber membrane filter is sterilized by supplying a sterilizing liquid through two orifices that are provided to supply fluid to the first chamber and the second chamber of the hollow fiber membrane filter. The media are discharged from the first chamber and the second chamber of the hollow fiber membrane filter through the respective other two media outlets, so that the sterilizing liquid is flushed out of both chambers and the filter. Preferably, water is used as the sterilizing liquid, the temperature of which is maintained at 105-140°C.

In a further embodiment of the fourth aspect of the invention, a rinsing operation with a liquid, in particular sterile water, can be provided. Alternatively, aqueous mixtures can be used as the washing liquid. Washing preferably takes place at an elevated temperature. In this case, the washing liquid may have a temperature of from 50 to 120°C. In particular, the washing operation at an elevated temperature allows better removal of particles and other eluting substances. If the membrane material also contains hydrophilic components, too high a temperature during the washing process is undesirable, since excessive sticking of the membrane material may occur. A washing temperature of 60-98°C is preferred, and a temperature of 70-98°C is particularly preferred.

Steam sterilization is carried out at temperatures of 124°C±5°C. Technological equipment does not always allow to accurately maintain a pre-selected temperature. Therefore, it turned out to be technically expedient to choose temperatures in the range from 105 to 140°C. In this case, pressures up to 4 bar should be provided. At a sterilization temperature of 124°C, the required sterility can be achieved within 12 minutes. Alternatively, sterilization can also be carried out at lower temperatures with longer sterilization times, for example at 121° C. for 15 minutes.

The transmembrane transition of a fluid, such as water or steam, preferably occurs at elevated temperatures. In this case, it is preferable to use water vapor in a sterile form. In particular, as a result of the transmembrane transfer of water vapor at temperatures from 50 to 98 ° C, it is also possible to wash particles and eluted substances from the membrane wall and from the inner surfaces of pores that are not directly on the membrane surface.

For the sterilization and rinsing process as a whole, it has proven advantageous if, between the first rinsing step with the rinsing medium, in particular water or steam, a rinsing step with compressed air or an alternative compressed gas is carried out. In this case, both chambers of the filter module are blown with sterile compressed air, without the formation of a pressure gradient through the membrane material between the first and second chambers. In this case, the liquid from the previous washing process remains in the pores. This intermediate step facilitates the subsequent transmembrane washing process. Thus, this further embodiment of the fourth aspect of the invention is characterized in that an additional rinsing step is carried out with compressed gas, in particular sterile compressed air.

Description of the invention by means of measurement methods, figures and examples

Measurement method 1. Determination of porosity.

Weigh the bundle of hollow fiber membranes, which has previously been dried for 2 hours at 105 °C in an oven and which consists of identical hollow fiber membranes. Determine the average length of the fibers, the average inner diameter, the average outer diameter and the number of fibers. Average dimensions are determined on at least 10 different fibers of the hollow fiber membrane bundle. Sizing is carried out at a constant temperature of 20°C. From the dimensions, the volume contained between the walls of the hollow fiber membranes of the bundle of hollow fiber membranes is determined, assuming that the geometry of the hollow fiber membranes corresponds to a hollow cylinder. From the calculated volume and the measured weight, the average density of the membrane structure in hollow fiber membranes can be determined. The porosity, expressed as a percentage, is obtained as the ratio of the calculated and theoretical densities of the hollow fiber membrane at full densification of the polysulfone material, according to the following formula:

_π measured fiber density _L

Porosity =------- ^Ξ --100 Density of densified polysulfone

- 9 040896

Measurement method 2. Determination of the zeta potential.

To determine the zeta potential of the studied hollow fiber membranes, a hollow fiber membrane filter (dialyzer) containing 10752 hollow fiber membranes with an inner diameter of 185 µm and a wall thickness of 35 µm is used. The length of the hollow fiber membranes relevant for the measurement of the zeta potential is 279 mm. The hollow fiber membranes are cast at the ends in the hollow fiber membrane filter so that a first chamber is formed that encloses the inner volume of the hollow fiber membranes and a second chamber encloses the space between the hollow fiber membranes. Polyurethane from Elastogran (polyol C6947 and isocyanate 136-20) is used as the potting material. The casting height at each end of the beam is 22 mm. The device shown in Fig. 1. The hollow fiber membrane filter (1) comprises fluid inlets (2, 2a, 3, 3a) leading respectively to the first and second chambers of the hollow fiber membrane filter (1). Each opening in the first chamber of the hollow fiber membrane filter (1) is provided with an Ag/AgCl electrode (4, 4a) and a pressure measurement access (5, 5a). The inlets (3, 3a) into the second chamber of the hollow fiber membrane filter (1) are sealed so that the second chamber of the hollow fiber membrane filter remains unfilled. Thus, between the two electrodes, the potential difference AE _z (mB) is recorded using a voltmeter (6), and between accesses for measuring pressure (5, 5a), the pressure drop AP (in N/m ² ) is recorded using a pressure gauge (7). The test liquid consists of a solution of KCl 1 mmol in water with a pH of 7.4 and is located in a tank (8) placed approximately 1000 mm above the filter. The pH value is set in accordance with the following instructions: In 100 l of KCl solution add 50 mg of K ₂ CO ₃ . The mixture is stirred in an open tank until a pH of 7.4 is reached. The reservoir is then hermetically sealed. The measurement is carried out at a temperature of 23°C±2°C.

To measure the zeta potential, the test liquid is injected through the first inlet (2) into the first chamber of the hollow fiber membrane, which covers the inner volume of the hollow fiber membranes, and through the second hole (2a) on the hollow fiber membrane filter, which is connected to the inner volume of the hollow fiber membranes, is again withdrawn from the dialyzer. In this configuration, the hollow fiber membrane filter is first flushed with the test liquid for 10 minutes until a stable value is reached, and if necessary, for another 5 minutes. The pressure drop and potential difference are read simultaneously from the manometer and multimeter, respectively, and the zeta potential is calculated from the obtained values. To increase the measurement accuracy, it is provided that, after recording the measured values, both 4-way valves are switched so that a reverse flow of the test liquid occurs through the interior of the hollow fiber membranes. The measured value of the zeta potential is then calculated as the average of the measurements in both directions of flow.

The zeta potential is calculated from the following equation

I L _about dEz ε ₀ ε _Γ dAP where ζ = zeta potential (mV), P = solution viscosity (0.001 NSt / m ² ), L0 = solution conductivity (A / (V * m)), εo = dielectric vacuum constant (8.85 * 10 ^-12 A * s / (V * m)), εr = relative permittivity of the solution (80), E _Z = flow potential (mV), A _P = pressure drop (N / m ² ).

Measurement method 3. Determination of the dextran screening factor.

The sieving ratio of dextran with a hollow fiber membrane is measured according to DIN EN ISO 8637:2014 on a finished hollow fiber membrane filter. For this, a filter containing 10752 hollow fiber membranes with an inner diameter of 185 µm and a wall thickness of 35 µm is used. The active length of the hollow fiber membrane is 235 mm. The active length of the hollow fiber membrane is to be understood as the length of the hollow fiber membrane without potting compound, which can be used to determine permeability characteristics such as screening ratio, clearance and ultrafiltration ratio. The inner diameter of the hollow fiber membrane filter is 34mm at the center. Otherwise, the hollow fiber membrane filter has the same design as the filter described in Measurement Method 2. Unlike the standard, an aqueous solution of dextran with a wide 1000 to 100,000 Da molecular weight distribution of dissolved dextran is used as the test liquid, or a mixture of several dextrans in this range of molecular weights to obtain the specified molecular weight distribution. The dextran solution is passed through the fluid ports through the first chamber of the hollow fiber membrane filter enclosing the internal volume of the hollow fiber membranes at a flow rate of 446.6 ml/min. In the second chamber of the hollow fiber membrane filter, clean water is set to flow through the holes at a flow rate of 89.9 ml/min. After 12 minutes, the concentration of dextran is determined by gel permeation chromatography as a function of the respective molecular weight at the first and second openings of the first chamber of the hollow fiber membrane filter for the entire molecular weight range, and from this the sieving coefficient curve is determined over the entire molecular weight range . The sieving ratio of a particular molecular weight dextran molecule can then be determined from the sieving ratio curve.

Measurement method 4. Determination of the sieving coefficient of albumin.

Determination of the sieving ratio of albumin at the hollow fiber membrane is carried out on the filter as in measurement method 3. The measurements use human plasma according to DIN EN ISO 8637:2014 to determine the sieving ratio. Thus, the plasma screening ratio of albumin is determined. The analyzer used is a Cobas Integra 400 plus model from Roche Diagnostics GmbH, Mannheim. The measurement is carried out using the ALBT2 test when applied to urine. Set the plasma flow at 446.6 ml/min and the dialysate (deionized water) flow at 89.9 ml/min.

Measurement method 5. Determination of the clearance of sodium, phosphate and vitamin B12.

The hollow fiber membrane clearance is determined, according to DIN EN ISO 8637:2014, on a hollow fiber membrane filter configured as in measurement method 2. membranes) in accordance with standard 5.6.1.2, aqueous solutions of sodium at a concentration of 5 g/l NaCl and 0.05 g/l vitamin B12 are used. Vitamin B12 is used for the dialysis solution area (the dialysis solution area corresponds to the second chamber of the hollow fiber membrane filter, covering the space between the fibers), and distilled water is used. Phosphate is used at a concentration of 3 mmol/l in the dialysis solution, the measurement is also made against the dialysis solution on the side of the dialysate. For phosphate, the following dialysis solution is prepared: 34.63 liters of water, 102.9 g NaHCO ₃ , 210.68 g NaCl, 2.61 g KCl, 5.15 g CaCl ₂ *2H ₂ O, 3.56 g MgCl ₂ * 6H ₂ O, 6.31 g CH3COOH, 38.5 g glucose monohydrate. Phosphate is determined photometrically by reaction with ammonium molybdate in sulfuric acid solution using a Cobas integra 400 plus from Roche Diagnostics GmbH, Mannheim, Germany, and a PHOS2 test (Roche). The sodium concentration is determined through a conductivity measurement. The concentration of vitamin B12 is determined photometrically. The clearance test uses a hollow fiber membrane filter of the same design as that used in the measurements of measurement method 2. In the first chamber of the hollow fiber membrane filter, enclosing the internal volume of the hollow fiber membranes, the hollow fiber membrane filter manufactured in accordance with the present application is set to a flow rate of 300 ml/min, and the second chamber of the hollow fiber membrane filter was set to a flow rate of 500 ml/min.

Measurement method 6. Determination of the local ultrafiltration coefficient.

To determine the local UF, a hollow fiber membrane filter with 10752 hollow fiber membranes 185 µm in inner diameter and 35 µm wall thickness is used as described in Measurement Method 3. The active length of the hollow fiber membrane is 235 mm. The active length of the hollow fiber membrane is to be understood as the length of the hollow fiber membrane without potting compound, which can be used to determine permeability characteristics such as screening ratio, clearance and ultrafiltration ratio. The inner diameter of the hollow fiber membrane filter is 34mm at the center. The inlet cap of the filter on the blood side is removed from the hollow fiber membrane module and replaced with an inlet containing a device that deflects the flow of the test fluid only into the round part of the hollow fiber bundle having a diameter of 1 cm. Unlike DIN ISO 8637:2014, here as the test liquid, water is used, thus the water ultrafiltration coefficient known to those skilled in the art is determined. This device is designed such that the end of the device penetrates approximately 3 mm into the upper end of the hollow fiber membrane bundle, thus insulating the device from the hollow fiber membrane bundle. This ensures that only a local circular area of 1 cm diameter is measured. To measure elsewhere, either use a modified device or move the device to a new desired location. A schematic representation of the cross-sectional regions of a hollow fiber membrane filter is shown in FIG. 2. When setting the flow rate of the test liquid, it must be ensured that the same transmembrane pressures (TMP) are set as when measuring water ultrafiltration coefficients in accordance with DIN ISO 8637: 2014. The maximum TMP value set is 600 mm Nd.

Measurement method 7. Determination of the PVP content in the hollow fiber membrane.

The content of PVP in the hollow fiber membrane is determined by IR spectroscopy. To do this, the sample is first dried for 2 hours in an oven at 105°C. Then 1 g of the fibers are dissolved in dichloromethane. Additionally prepare a calibration standard using dry PVP, which is also dissolved in dichloromethane. This covers the range of concentrations of HP in the hollow fiber from about 1% to 10%. Each solution is placed in a liquid cuvette to a layer thickness of 0.2 mm. The absorption band of the carbonyl group is used for evaluation.

Measurement method 8. Graphical representation of nominal pore size distribution and nominal average pore size.

A measure for the pore size distribution in the membrane of the invention can be derived from the sieving ratio curve as shown in FIG. 7. To do this, obtain a sieving coefficient curve as described in Measurement Method 3 for a dextran sample with a broad molecular weight distribution or a mixture of several dextran samples. The sieving coefficient curve gives, for each molecular weight, the probability that the corresponding dextran molecule will pass through the membrane wall. At a given temperature and a given solvent, molecular weight correlates with the size of a particular molecule, which can be described in terms of the Stokes radius. The relationship between Stokes radius and molecular weight is given by the following equation (J. Bandrup, EH Immergut (Polymer Handbook (1989) VII pp. 112-113, John Wiley): Stokes radius [A] = 0.4456M ^0.4 where M means molecular dextran weight For each point measured on the sieving coefficient curve of Fig. 7, the molecular weight is converted to a Stokes radius using a computer program such as Excel.

The corresponding figure, similar to the sieving coefficient curve, shows the passage probability with which a dextran molecule with a certain Stokes radius, i.e. with a certain molecular size, can pass through the membrane wall. At the same time, this figure provides information on the structure of the pore size distribution, thereby indicating how high the probability is to find a pore of a certain size in the membrane, which is able to pass a dextran molecule with a given molecular size, i.e. Stokes radius.

Further, by recalculation using the Excel computer program, the first derivative is determined at each point of the curve. The curve configuration thus obtained gives a distribution curve which is a measure of the nominal pore size distribution for the membrane under study. The corresponding curve is shown in Fig. 8 for the membrane according to the invention and for the comparative membrane. The maximum of the distribution curve corresponds to the nominal average pore size of the membranes.

Example 1. Method for cleaning a hollow fiber membrane filter.

In FIG. 3 schematically shows the first step of the hollow fiber membrane filter cleaning procedure, including the washing and sterilization steps used in the manufacture of the hollow fiber membranes of the present invention or the hollow fiber membrane filters in accordance with the first, second and third aspects of the invention. In FIG. 3 shows a fluid inlet 118 leading to a first chamber 119 of the hollow fiber membrane filter 113, enclosing the inner volume of the hollow fiber membranes, which is in hydraulic communication with the connection 101 via a line 109 with a valve 105. connection 102 and forms access to the second chamber 120 of the hollow fiber membrane filter 113, covering the space between the hollow fiber membranes. The next hole 114 through the line 111 with the valve 107 hydraulically communicates with the connection 103 and forms access to the second chamber 120 of the hollow fiber membrane filter. Port 115 is in fluid communication with valve 108 via line 112 to connection 104. In addition, connections 101 and 103 are in fluid communication with each other via adapter 101a.

In one embodiment of the flushing operation in the first step shown, flushing fluid is supplied through connection 104 through line 112 to hollow fiber membrane filter 113. Preferably, flushing fluid is sterile water at a controlled temperature maintained in the range of 50-98°C. In this case, the valve 108 is turned on for passing the flow. The washing liquid flows into the first chamber 119 of the hollow fiber membrane filter through the second opening 115 and exits said first chamber through the first opening 118. This configuration allows the internal volume of all of the hollow fiber membranes in the bundle to be flushed.

Next, the washing liquid passes through the bubble detector 114, which does not perform any function in this washing operation, and through the line 109 and is directed through the connection 101 and the adapter 101a to the line 111. Through the inlet 114, the washing liquid flows into the second chamber 120 of the filter module 113 and flushes the second chamber formed between the hollow fiber membranes. Through the opening 117 and the line 110 is the return of the washing liquid, which is then either discarded or processed to become available again for the washing operation.

In FIG. 4 schematically shows the second step of the washing and sterilization procedure which is used in the production of hollow fiber membranes according to the invention, respectively hollow fiber membrane filters according to the invention, in accordance with the first, second and third aspects of the invention. Fig. 4 is used to illustrate compressed air flushing. Connections 201, 202, supplied from a compressed air source, are supplied with sterile air. Compressed air is supplied to the hollow fiber membrane module 213 via lines 209 and 201 through open valves 205 and 206 and through a pumping means (not shown). As a result of the previous washing step in accordance with the washing operation,

- 12 040896 shown in FIG. 3, the first chamber 219 and the second chamber 220 are initially still filled with water. Valves 207 and 208 are open and ready to drain flushing fluid. Compressed air is passed through the filter module at a pressure of 1.5-2 bar. Thus, the compressed air through the corresponding opening 218, 217 displaces the residual water from the first and second chambers of the hollow fiber membrane filter further through the openings 215 and 214 into the return part of the flow loop. Residual water and compressed air are discharged through lines 212, 211. The flushing process lasts for 2-5 minutes. Because both chambers 219 and 220 are set to the same pressure, there is no flushing through the membrane wall. As a result, the pores of the membrane wall remain filled with water from the washing operation.

In FIG. 5 schematically shows the third step of the washing and sterilization process used in the production of hollow fiber membranes of the invention or hollow fiber membrane filters of the invention, in accordance with the first, second and third aspects of the invention. In FIG. 5 shows connections 302 and 304 that block flushing fluids from flowing through valves 306 and 308 when in the closed position. Water vapor is supplied to the sterilization system through connection 301 and to the filter module 313 via line 309. The water vapor is expanded in the first chamber 319 of the hollow fiber membrane filter; withdrawal through opening 315 is not possible because connection 304 is closed. The expansion of the water vapor in line 312 can only occur by compressing the pressurized pure vapor or by diffusion.

Since the pressure in the first chamber is higher than in the second chamber, a transmembrane transition of pure vapor occurs. Residual water remaining in the pores from the washing process according to the first washing and sterilization step according to FIG. 3 is withdrawn and fed through the second chamber 320 to line 311. Since connection 302 is closed, line 310 does not serve the movement of fluids. Neighboring hollow fiber membranes are far apart due to the transmembrane washing process. In this case, water vapor is supplied to the filter module at a pressure of 1.3 to 2 bar. In addition, flushing the pores further prevents the hollow fibers from sticking together. This flushing process can be completed in a few minutes. In particular, the washing operation is carried out for 2-5 minutes. The temperatures are maintained at 50-98° C., in particular, in order to carry out also thermal conditioning of the filter module for the next sterilization process.

In FIG. 6 schematically shows the fourth step of the washing and sterilization process used in the preparation of the hollow fiber membranes of the invention, respectively of the hollow fiber membrane filters of the invention, in accordance with the first, second and third aspects of the invention. In the fourth step, a sterilizing medium, such as water vapor, at a temperature of 124° C. and a pressure of 2 bar, is fed into the hollow fiber membrane filter. At the same time, thanks to the open valves 405-408, flow through connections 401, 402, 403, 404 is possible. Pure steam enters the hollow fiber membrane filter through lines 409 and 410 and flushes the first chamber 419 and the second chamber 420 of the filter module 413. Pure vapor returns through lines 412 and 411 and through holes 415 and 414 and are either discarded or reused after additional processing. The duration of the sterilization process can be from 5 to 30 minutes, depending on the selected sterilization temperature. At a preferred temperature of 124°C, sterilization can be considered complete after 12 minutes. Additional washing steps may be performed to bring the hollow fiber membrane filter into a clean and sterile form for use.

For an additional quality check, the bubble point test known from the prior art is carried out. This test is a pressure maintenance test in which one side of the membrane is under the action of a gas at a higher pressure than the opposite side of the membrane, over which the liquid flows. To do this, the second chamber 120, 220, 320, 420 of the hollow fiber membrane filter shown in FIG. 3-6 is flushed with sterile compressed air, leaving the first chamber filled with the liquid left over from the flushing process. The sterilization system applies a higher pressure in the second chamber than in the first chamber 119, 219, 319, 419. Since the pores are filled with water from the previous washing step, the transfer of compressed gas from the first chamber to the second chamber will only begin when the applied pressure exceeds the surface tension water in the pores. The bubble detectors 114, 214, 314, 414 shown can analyze the amount of gas passed into the first chamber and evaluate the results accordingly. From the number of gas bubbles correlated with the pressure applied in the second chamber of the filter modules 120-420, the quality of the membrane material can be inferred and it can be decided whether the filter module meets the technical standards.

Finally, it can be provided that the first chamber is also flushed with sterile compressed air. In certain cases, an additional clean steam washing step can remove water left over from previous washing processes. A drying operation can then be carried out in which the filter module is blown with sterile compressed air until the desired degree of dryness is achieved.

Example 2 An embodiment of a hollow fiber membrane according to the invention.

Spinning solution, consisting of 16 wt.h. polysulfone (P3500 from Solvay), 4.4 parts by weight 13 040896 livinylpyrrolidone (K82-86 from Ashland) and 79.6 parts by weight. DMAC, mixed, heated to 60°C and degassed, obtaining a homogeneous spinning mass. The spinning mass is extruded through an annular die with a centrally conducted precipitant consisting of 35% DMAC and 65% water to form a filament. The precipitant is introduced into the hollow filament. The temperature of the annular die is 70°C.

The extruded filament is passed through a settling chamber whose atmosphere has a relative humidity of 100%. The height of the settling gap is 200 mm; the residence time in the settling gap is set to 0.4 s. The filament is introduced into a spinning bath of water maintained at 80° C. and deposited to form a hollow fiber membrane. Then the hollow fiber membrane is passed through washing baths with a temperature set in the range from 75 to 90°C. Thereafter, the hollow fiber membrane is dried at a temperature of 100 to 150°C. Then, the obtained hollow fiber membrane is wound on a drum and converted into a tow. A bundle of hollow fiber membranes is obtained from a wound bundle. The porosity of the hollow fiber membranes is then determined.

Next, the bundle of hollow fiber membranes is processed into hollow fiber membrane filters using known methods as described in measurement method 3. The obtained hollow fiber membrane filter is combined in the next step with a sterilizer following Example 1, and the hollow fiber membrane filter is sterilized in the same way as described in Example 1. On 10,000 g/mol molecular weight dextran sieving factor, zeta potential, albumin sieving factor, fiber PVP content, and local water UF of the sterilized hollow fiber membrane filter were determined at 5 different positions in the hollow fiber membrane filter. The results are shown in table. 1.

Example 3. Comparative example.

The same materials are used as in example 2. Spinning solution, consisting of 16 wt.h. polysulfone, 4 wt.h. polyvinylpyrrolidone and 80 wt.h. DMAC, mixed, heated to 50°C and degassed, obtaining a homogeneous spinning mass. The spinning mass is extruded through an annular die along with a centrally conducted precipitator consisting of 54% DMAC and 46% water to form a filament. The precipitant is injected into the hollow filament. The temperature of the annular die is 40°C. The extruded filament is passed through a settling chamber whose atmosphere has a relative humidity of 30%. The height of the settling gap is 600 mm; the residence time in the settling gap is set to 1.35 s. The filament is introduced into a spinning bath of water maintained at 68° C. and deposited to form a hollow fiber membrane. Then the hollow fiber membrane is passed through washing baths with a temperature set in the range from 75 to 90°C. Thereafter, the hollow fiber membrane is dried at a temperature of 100 to 150°C. Then, the obtained hollow fiber membrane is wound on a drum and converted into a tow. A bundle of hollow fiber membranes is obtained from a wound bundle. The porosity of the hollow fiber membranes is then determined.

Next, the bundle of hollow fiber membranes is processed by known methods to obtain a hollow fiber membrane filter. In the next step, the obtained hollow fiber membrane filter is sterilized in the manner described in the prior art (DE 3936785 C1). On a sterilized hollow fiber membrane filter, the sieving factor for dextran with a molecular weight of 10,000 g/mol, zeta potential, sieving factor for albumin, the PVP content in the fiber and the local water ultrafiltration coefficient of the sterilized hollow fiber membrane filter are determined at 5 different positions. The results are shown in table. 1.

- 14 040896

Table 1

UF coefficient determined in local positions [ml/b*mmNd] Example 2: according to the invention Example 3: comparative pos. 1 137 119 pos. 2 142 152 pos. 3 148 154 pos. 4 142 160 pos. 5 144 150 Difference min./max. eleven 35 Deviation from the maximum value 7.7% 21.8% Zeta potential -7 mV -10 mV Porosity 79.7% 77% Albumin screening ratio 0.06 0.07 Sieving ratio of dextran (10000 g/mol) 0.63 0.40 clearance, sodium 268 260 clearance, phosphate 237 200 Clearance, vitamin B12 169 146

CLAIM

Claims (6)

1. A method for sterilizing a hollow fiber membrane filter comprising a plurality of polysulfone- and PVP-based hollow fiber membranes that are sealed at their ends in a hollow fiber membrane filter housing so as to form a first chamber enclosing the internal volume of the hollow fiber membranes and a second chamber enclosing the space between the hollow fiber membranes. membranes, wherein the hollow fiber membrane filter comprises at least two fluid inlets connected to the first chamber and at least two inlets connected to the second chamber, and the holes are configured to be connected to a sterilizer, the method comprising at least at least the following steps: flushing the hollow fiber membrane filter with a fluid, while the flushing medium is conducted through the first and second chambers of the hollow fiber membrane filter by selecting inlets, sterilizing the hollow fiber membrane filter with a sterilizing medium food, and the sterilizing medium is conducted through the first and second chambers of the hollow fiber membrane filter by selecting the inlets, supplying water vapor to the first or second chamber of the hollow fiber membrane filter by selecting the inlets, and flushing the hollow fiber membrane by transmembrane passage of water vapor through the membrane wall to the corresponding second or the first chamber of the hollow fiber membrane filter, while water vapor is supplied to the filter module at a pressure of 1.3 to 2 bar, where the fluid is supplied to the first or second chamber of the hollow fiber membrane filter and the transmembrane transition of water vapor to the second or first chamber of the hollow fiber membrane module occurs between flushing and sterilization operations. 2. The method according to claim 1, characterized in that the sterilization is heat sterilization. 3. The method according to claim 1 or 2, characterized in that the washing operation is carried out at temperatures from 50 to 120°C. 4. The method according to one of claims 1 to 3, characterized in that the heat sterilization is carried out at temperatures from 105 to 140°C, preferably from 121 to 140°C. 5. The method according to one of paragraphs. 1-4, characterized in that the supply of fluid to the first or second chamber of the hollow fiber membrane filter and the transmembrane transition of the medium to the corresponding second or first chamber of the hollow fiber membrane module is carried out at temperatures from 70 to 98°C. 6. Method according to one or more of claims 1 to 5, characterized in that an additional operation of purging with compressed gas is carried out.