PROCESS FOR TESTING FILTERS

Abstract

The present disclosure relates to a process for testing the integrity of membranes in a filter module. Specifically, the process is applied to filters for extracorporeal blood treatment, in particular, filters comprising both filter membranes and particulate material.

Claims

1. A process for testing a filter comprising two compartments separated by a porous membrane, said process comprising the steps of: i) providing a filter having both compartments filled with a testing liquid; ii) introducing a testing gas into one of the compartments, displacing the testing liquid from the compartment, and establishing a pressure gradient between the compartments; iii) monitoring the pressure gradient between the compartments or measuring flow of the testing gas through the membrane; wherein the testing liquid is selected from the group consisting of i) water; ii) aqueous solutions comprising at least one physiologically acceptable salt selected from the group consisting of chlorides, carbonates, hydrogen carbonates, sulfates, hydrogen sulfates, and carboxylates of ammonium, alkali metals and alkaline earth metals, and having a salt concentration in the range of from about 10 wt. % to about 30 wt. %; and iii) aqueous solutions of polysorbates comprising about 0.5 wt. % to about 3 wt. % of polysorbate; and the testing gas is selected from the group consisting of nitrogen; air; noble gases; SF.sub.6; and per-fluorinated (cyclo) alkanes; with the proviso that the combination of water as testing liquid and nitrogen, air, helium, neon, argon or krypton as testing gas is excluded.

2. The process of claim 1, wherein one compartment of the filter comprises particulate matter selected from polymer heads and particles comprising activated carbon.

3. The process of claim 2, wherein one compartment of the filter comprises polymer beads.

4. The process of claim 1, wherein the porous membrane is a bundle of hollow fiber membranes.

5. The process of claim 1, wherein the testing liquid is an aqueous solution of sodium chloride or an aqueous solution of ammonium sulfate.

6. The process of claim 5, wherein the testing liquid has a salt concentration in the range of from about 10 wt. % to about 20 wt. %.

7. The process of claim 1, wherein the testing liquid is an aqueous solution of from about 1 wt. % to about 2 wt. % of at least one polysorbate.

8. The process of claim 1, wherein the testing gas is sulfur hexafluoride.

9. The process of claim 1, wherein the testing gas is a perfluorinated alkane or a perfluorinated cycloalkane.

10. The process of claim 9, wherein the perfluorinated alkane or perfluorinated cycloalkane is selected from the group consisting of hexafluoroethane, octafluoropropane and octafluorocyclobutane.

11. The process of claim 2, wherein the porous membrane is a bundle of hollow fiber membranes.

12. The process of claim 3, wherein the porous membrane is a bundle of hollow fiber membranes.

13. The process of claim 2, wherein the testing liquid is an aqueous solution of sodium chloride or an aqueous solution of ammonium sulfate.

14. The process of claim 3, wherein the testing liquid is an aqueous solution of sodium chloride or an aqueous solution of ammonium sulfate.

15. The process of claim 4, wherein the testing liquid is an aqueous solution of sodium chloride or an aqueous solution of ammonium sulfate.

16. The process of claim 2, wherein the testing gas is sulfur hexafluoride.

17. The process of claim 3, wherein the testing gas is sulfur hexafluoride.

18. The process of claim 2, wherein the testing gas is a perfluorinated alkane or a perfluorinated cycloalkane.

19. The process of claim 3, wherein the testing gas is a perfluorinated alkane or a perfluorinated cycloalkane.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows an apparatus for testing the integrity of membranes in a filter device;

[0015] FIG. 2 shows a plot of pressure vs. time for 1: intact membrane; 2: slightly damaged membrane; 3: heavily damaged membrane;

[0016] FIG. 3 shows a plot of pressure vs. time for a filter device comprising polymer beads tested with different testing gases;

[0017] FIG. 4 shows a plot of pressure vs. time for different filter devices comprising polymer beads tested with octafluoropropane as testing gas

[0018] FIG. 5 shows a plot of pressure vs. time for a filter device comprising polymer beads tested with different testing liquids;

[0019] FIG. 6 shows a plot of pressure vs. time for intact filter devices comprising polymer beads and filter devices comprising polymer beads, wherein the membranes have pinholes with a diameter of 50 m.

DETAILED DESCRIPTION

[0020] The present invention provides a process for testing a filter comprising two compartments separated by a porous membrane, comprising [0021] i) providing a filter having both compartments filled with a testing liquid; [0022] ii) introducing a testing gas into one of the compartments, displacing the testing liquid from the compartment, and establishing a pressure gradient between the compartments; [0023] iii) monitoring the pressure gradient between the compartments or measuring flow of the testing gas through the membrane,

[0024] wherein the testing liquid is selected from the group consisting of water; aqueous solutions of physiologically acceptable salts; and aqueous solutions of polysorbates; and the testing gas is selected from the group consisting of nitrogen; air; noble gases like helium, neon, argon, krypton, and xenon; SF.sub.6; and perfluorinated (cyclo)alkanes like C.sub.2F.sub.6, C.sub.3F.sub.8, and C.sub.4F.sub.8;

[0025] with the proviso that the combination of water as testing liquid and nitrogen, air, helium, neon, argon or krypton as testing gas is excluded.

[0026] The process of the present disclosure is suitable for testing the integrity of filters comprising two compartments separated by a porous membrane. Examples of such filters are membrane filters used in extracorporeal blood treatment, e.g. dialyzers; filters used in the preparation of medical fluids, e.g., pyrogen-free and germ-free fluids like dialysis fluid or substitution fluid; virus filters; blood oxygenators; and reverse osmosis filters. The process of the present disclosure is particularly useful for testing the integrity of filters wherein one compartment additionally comprises particulate matter, e.g., polymer beads or particles comprising activated carbon. Examples of filters additionally comprising particulate material have been described in EP 2 735 326 B1 and EP 2 735 360 B1, respectively.

[0027] Each one of the two compartments of the filter generally has at least one fluid inlet or outlet, respectively. In one embodiment, each of the two compartments has one fluid inlet and one fluid outlet. In another embodiment, only one of the compartments has both a fluid inlet and a fluid outlet, while the other compartment only has a fluid inlet. In still another embodiment, only one of the compartments has both a fluid inlet and a fluid outlet, while the other compartment only has a fluid outlet. In still another embodiment, only one of the compartments only has a fluid inlet, while the other compartment only has a fluid outlet. In a particular embodiment, one compartment has a fluid inlet and a fluid outlet, and the other compartment either has neither fluid inlet nor fluid outlet, or a fluid inlet and a fluid outlet of the compartment have been sealed permanently.

[0028] The porous membrane of the filter may take different forms. In one embodiment, the membrane is a flat sheet membrane or a stack of flat sheet membranes. In another embodiment, the porous membrane is a hollow fiber membrane or a bundle of hollow fiber membranes.

[0029] The porous membrane may be hydrophilic or hydrophobic, and are comprised of synthetic polymers. Examples of suitable membrane materials comprise hydrophobic polymers like polysulfones, polyethersulfones, polyacrylonitrile (PAN) and its copolymers, polytetrafluoroethylene, polyWO vinylidene fluoride, and hydrophilic polymers like polyvinylpyrrolidone (PVP), polyetherimine (PEI) or EVA.

[0030] The testing liquid is a liquid which is able to wet the membrane surface and fill the pores of the membrane. Suitable testing liquids are chosen according to the properties of the membrane. For hydrophilic membranes, the testing liquid is selected from the group consisting of water; and aqueous solutions of physiologically acceptable salts, or aqueous solutions of polysorbates.

[0031] Suitable aqueous solutions of polysorbates comprise 0.5 to 3 wt. % polysorbate, for instance 0.5 to 2 wt. %, e.g., 1 wt. %. Polysorbates are derived from ethoxylated sorbitan esterified with fatty acids. Common brand names for polysorbates include Scattics, Alkest, Canarcel, and Tween. Examples include Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and Polysorbate (polyoxyethylene (20) sorbitan monooleate). The number 20 following the polyoxyethylene part refers to the total number of oxyethylene (CH.sub.2CH.sub.2O) groups found in the molecule. The number following the polysorbate part is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule. Monolaurate is indicated by 20, monopalmitate is indicated by 40, monostearate by 60, and monooleate by 80. In one embodiment, an aqueous solution of Polysorbate 20 is used as testing liquid. In a further embodiment, the concentration of Polysorbate 20 in the testing liquid is 1 wt. %.

[0032] Suitable aqueous salt solutions are solutions of physiologically acceptable salts. In one embodiment, the testing liquid is an aqueous salt solution having a salt concentration in the range of from 5 wt. % to 30 wt. %, for instance, 10 to 20 wt. %. Examples of physiologically acceptable salts include chlorides, carbonates, hydrogen carbonates, sulfates, hydrogen sulfates, and carboxylates like lactates, acetates, or citrates of ammonium; alkali metals like sodium; or alkaline earth metals like magnesium or calcium. In one embodiment, the salt is sodium chloride. In another embodiment, the salt is ammonium sulfate.

[0033] The testing gas is selected from the group consisting of nitrogen; air; noble gases like helium, neon, argon, krypton, and xenon; SF.sub.6; and perfluorinated (cyclo)alkanes, e.g., C.sub.2F.sub.6, C.sub.3F.sub.8, and C.sub.4F.sub.8. If water is used as the testing liquid, the testing gas is not nitrogen, air, helium, neon, argon nor krypton. In this case, the testing gas is selected from the group consisting of sulfur hexafluoride (SF.sub.6) and perfluorinated (cyclo)alkanes, e.g., hexafluoroethane (C.sub.2F.sub.6), octafluoropropane (C.sub.3F.sub.8), or octafluorocyclobutane (C.sub.4F.sub.8).

[0034] At the beginning of the process of the present disclosure, a filter having both compartments filled with a testing liquid is provided.

[0035] In one embodiment starting from a dry filter, the filter is first filled with the testing liquid. In a particular embodiment, the dry filter is evacuated and connected to a reservoir of the testing liquid. The testing liquid is sucked into the filter, filling both compartments and wetting the porous membrane. In one embodiment of the process, the pressure in the filter is reduced by connecting one compartment of the filter to a vacuum line or a vacuum pump, and, subsequently or simultaneously, connecting the other compartment to a reservoir containing the testing liquid, so that the testing liquid is sucked into the filter. In another embodiment of the process, the entire filter is evacuated, all inlets/outlets of the filter are closed and one of the inlets is subsequently connected to a reservoir containing the testing liquid. In still another embodiment of the process, one compartment of the filter is connected to a pressurized reservoir containing a testing liquid, so that the pressure forces the testing liquid into the filter.

[0036] In another embodiment starting from a filter comprising a liquid which is not the desired testing liquid, for instance, a water-filled or liquid-filled filter, the filter is emptied and subsequently filled with the testing liquid. In an alternative embodiment starting from a filter comprising a liquid which is not the desired testing liquid, for instance, a water-filled or liquid-filled filter, the liquid in the filter is replaced with the testing liquid, for instance, by flushing the filter with the testing liquid, thereby displacing the liquid initially present in the filter.

[0037] In one embodiment, the filter having both compartments filled with a testing liquid is degassed before a testing gas is introduced. Residual air is removed from the filter to make sure that the pores of the membrane are completely filled with the testing liquid, that the testing liquid does not contain any dissolved gas that could impair the measurements, and that air is removed even from spaces within the device which are difficult to access, i.e., dead zones.

[0038] The pores of the membrane are filled with the testing liquid. As a result, gas permeability of the membrane is substantially reduced and the membrane becomes largely impermeable to gas, if the membrane is intact.

[0039] A testing gas is introduced into one of the compartments filled with the testing liquid. The testing gas displaces the testing liquid from the compartment. By filling the compartment with testing gas and generating a positive pressure of the testing gas, a pressure gradient is established between the compartments.

[0040] The magnitude of the pressure gradient is not critical for the process. It will be chosen to be large enough to be within the measuring range of the equipment used for monitoring the pressure gradient between the compartments of the filter or for measuring testing gas flow through the membrane, respectively. On the other hand, it will be chosen small enough not to compromise mechanical stability of the membrane or the filter.

[0041] The pressure gradient between the compartments can then be monitored or the testing gas flow through the membrane can be measured using methods known in the art, for instance with commercially available leak detectors, to verify the integrity of the filter membrane. In comparison to filters having intact membranes, filters having defective membranes show a faster decrease of the pressure gradient over time between the compartments of the filter, or an increased leak rate.

[0042] In one embodiment of the process, an overpressure is applied to one compartment of the filter after the membrane has been wetted, and the increase of pressure in the other compartment over time is monitored. As an alternative, gas flow through the membrane may be measured. In another embodiment of the process, an overpressure is applied to one compartment of the filter through an inlet of the respective compartment after the membrane has been wetted, the inlet is closed and the decrease of pressure in the compartment over time is monitored.

[0043] In one embodiment of the process, the orientation of the filter during the test is such that the membrane is in a horizontal position. In another embodiment of the process, the orientation of the filter during the test is such that the membrane is in a vertical position. Although the filter can be tested regardless of its orientation, for filters comprising a bundle of hollow fiber membranes, it is preferred that the bundle of hollow fiber membranes is in vertical position during the test.

[0044] The testing liquid may be introduced into either compartment of the filter. For filters comprising membranes having a homogeneous structure, e.g., a sponge structure, choice of the compartment is not expected to have substantial impact on the test. If the filter comprises an asymmetric membrane, it is generally preferred to introduce the predefined amount of testing liquid into the compartment bordering the selective side of the membrane, i.e. the membrane surface having the smallest pores. For example, for filters comprising a bundle of asymmetric hollow fiber membranes which have the smallest pores on the inside of the fiber, it is preferred that the predefined amount of testing liquid is introduced into the compartment encompassing the lumen of the hollow fiber membranes.

[0045] The process of the present disclosure shows improved selectivity in distinguishing damaged filters from intact filters. The process thus allows for the reliable identification of defective filters, even filters which additionally comprise particulate matter in one of the compartments. For filters comprising particulate matter, the prior art integrity tests often cannot distinguish between intact and defective filters. In particular, known processes often produce false positives. The process of the present disclosure can advantageously be used for quality management in the context of filter production processes.

[0046] It will be understood that the features mentioned above and those described hereinafter can be used not only in the combination specified but also in other combinations or on their own, without departing from the scope of the present invention.

[0047] The present invention will now be described in more detail in the examples below. It is to be understood that the examples are not intended to limit the scope of the present invention and are merely an illustration of a preferred embodiment of the invention.

EXAMPLES

[0048] FIG. 1 shows a setup 10 for testing the integrity of a filter 11. As shown in FIG. 1, the filter 11 features two fluid ports 12, 13 connected to a first compartment within the filter 11 (the blood ports) and two fluid ports 14, 15 connected to a second compartment within the filter 11 (the dialysis fluid ports). A testing liquid 16 can be introduced into the first compartment of the filter 11 via the lower blood port 13. The flow F of testing fluid 16 is monitored by flowmeter 20. A testing gas 17 can be introduced into the first compartment of the filter 11 via the upper blood port 12. The pressure P1 in the first compartment is monitored by manometer 18 and the pressure P2 in the second compartment is monitored by manometer 19 which is connected to dialysis fluid port 14. Dialysis fluid port 15 is closed during the measurement. Valves 21 are present to control the fluid flow within the setup 10. Fluids are removed from the setup via drain 22.

[0049] In an exemplary procedure, both compartments of filter 11 are filled with a testing liquid 16 through port 13. A testing gas 17 is subsequently introduced into the first compartment of filter 11 through port 12 until a predetermined overpressure P1 has been reached. Ports 12 and 13 are shut off using valves 21 and the pressure P2 within the second compartment of the filter 11 is monitored by manometer 19. In an alternative embodiment, only port 12 is shut off using valve 21 and the pressure P2 within the second compartment of the filter 11 is monitored by manometer 19.

[0050] Verification of the integrity of the membrane in the filter 11 includes monitoring the pressures P1 and P2. These can be used in several alternative ways:

[0051] For instance, the pressure P1 is measured after a predetermined period of time T. If the pressure has dropped by a quantity P1<P1.sub.max where P1.sub.max is a predetermined threshold value, it is considered that the membrane is intact. If P1>P1.sub.max it is considered that the membrane is not intact, or that the closed system has leaks. Alternatively it is possible to check the time the pressure P1 takes to drop beyond a predetermined limit, or to check the speed of drop of pressure P1.

[0052] Alternatively, if after a predetermined time T the pressure P2 has risen by a quantity P2<P2.sub.max where P2.sub.max is a predetermined threshold value, it is considered that the membrane is intact. If P2>P2.sub.max it is presumed that the membrane is not intact, or that the closed system is subject to leakage. It is also possible to verify the time required for the pressure P2 to rise beyond a predetermined limit, or to check the speed of increase of pressure P2.

[0053] If after a time T, both P1>P1.sub.max and P2>P2.sub.max, it is considered that the membrane is not intact, while if only one of the measured pressure variations P1 and P2 is greater than the respective threshold value, it is considered that the membrane is intact and that there is a leak in the circuit.

[0054] It is possible to verify the time the pressure P1 takes to fall below a predetermined limit, and to verify the time pressure P2 takes to rise beyond a predetermined limit, and it can be decided that the membrane is intact if both times exceed a predetermined minimum time. It is also possible to verify whether the speeds of change of the pressures P1 and P2 both exceed a predetermined threshold speed.

[0055] FIG. 2 shows how the pressure P2 evolves over time for 1: a filter 11 comprising an intact membrane; 2: a filter 11 comprising a slightly damaged membrane (e.g., a membrane comprising one or more pinholes); and 3: a filter 11 comprising a severely damaged membrane (e.g., a ruptured membrane). If the membrane in the filter 11 is intact, permeation of the testing gas 17 through the membrane is controlled by diffusion. The pressure P2 in the second compartment rises slowly (curve 1). If the membrane in the filter 11 is damaged, convective transport intensifies permeation of the testing gas 17 through the membrane, accelerating the increase of pressure P2 (curve 2). In case of membrane rupture, the rise of pressure P2 is almost instantaneous (curve 3).

[0056] For filters comprising particulate matter, the prior art integrity tests often cannot distinguish between intact and defective filters. In particular, known processes often produce false positives.

[0057] FIG. 3 shows the results of integrity tests conducted on a filter device as described in EP 2 735 326 B1, Example 2. The filter device comprises a bundle of hollow fiber membranes and contains adsorbent material in the closed filtrate compartment in form of a packed beads bed surrounding the hollow fibers.

[0058] An intact filter device was used in the tests. The tests were conducted using water as testing liquid; and a different testing gas was employed in each integrity test. As can be seen in FIG. 3, only with sulfur hexafluoride (SF.sub.6) as testing gas, the correct result is achieved. Nitrogen, compressed air, helium and argon yield false positive results, i.e., indicate a defective filter although the device is intact.

[0059] FIG. 4 shows the results of a series of integrity tests conducted on different filter devices comprising polymer beads (as described in EP 2 735 326 B1, Example 2). The tests were conducted using water as testing liquid; and octafluoropropane as testing gas. As can be seen from FIG. 4, the curves for the intact filter devices all fall inside a narrow window. The two defective devices are clearly distinguishable by the steeper pressure increase.

[0060] FIG. 5 shows the results of a series of integrity tests conducted on a filter device comprising polymer beads (as described in EP 2 735 326 B1, Example 2). The tests were conducted using air as testing gas; and a different testing liquid was employed in each integrity test. Aqueous solutions of sodium chloride having different salt concentrations were employed as testing liquids. Solutions containing 0.9 wt % NaCl, 5 wt % NaCl, 10 wt % NaCl, 20 wt % NaCl, and 30 wt % NaCl, respectively, as well as a saturated sodium chloride solution were used as the testing liquids.

[0061] As can be seen from FIG. 5, satisfactory results were obtained in a concentration range of from about 10 wt % to about 30 wt % NaCl. With 0.9 wt % and 5 wt % NaCl, respectively, the pressure curve is too steep to reliably distinguish between intact and defective filters. Surprisingly, saturated sodium chloride solution produced the steepest pressure curve in the test, falsely indicating a defective device.

[0062] In order to test the reliability of the integrity test, well defined holes having a diameter of 50 m were generated in the hollow fiber membranes of a number of filter devices using a laser beam. 30 filters comprising polymer beads (22 intact filters and 8 filters comprising membranes with 50 m holes) were tested using water as testing liquid and sulfur hexafluoride as testing gas. The results are shown in FIG. 6.

[0063] The solid lines in FIG. 6 represent the upper and lower limit, respectively, of the pressure curves of the intact filter devices. The curves of all 22 intact devices are within the window spanned by these solid lines. The dotted lines represent the pressure curves of the 8 filter devices comprising hollow fiber membranes having 50 m holes. As is evident from FIG. 6, the pressure curves of the defective devices are clearly distinguished from those of the intact devices. The defective devices are reliably identified, as their pressure curves are outside the window for intact devices.

LIST OF REFERENCE SIGNS

[0064] 10 Testing setup [0065] 11 filter [0066] 12 blood port [0067] 13 blood port [0068] 14 dialysate port [0069] 15 dialysate port [0070] 16 testing liquid [0071] 17 testing gas [0072] 18 manometer [0073] 19 manometer [0074] 20 flowmeter [0075] 21 valve [0076] 22 drain [0077] F flow rate [0078] P1 pressure [0079] P2 pressure