Method for performing gas / liquid based integrity testing

Abstract

The invention relates to a method of performing a gas / liquid based integrity test, wherein air in a first membrane and a second membrane and air present there between is replaced by a water-soluble gas before the membranes are wetted. Furthermore, the invention relates to a method of producing an integrity tested object having a first membrane, a second membrane and at least one boundary member.

Description

[0001] This invention relates to a method for performing a gas / liquid-based integrity test, wherein air in a first and second membrane, and air present therebetween, is replaced by a water-soluble gas before the membranes are wetted. Furthermore, this invention relates to a method for producing an object having a first membrane, a second membrane, and at least one boundary member that has passed an integrity test.

[0002] Integrity testing is a critical quality assurance process when using microporous or ultraporous membrane filters in applications requiring bioburden control. The purpose of integrity testing is to provide assurance that the microporous or ultraporous filter will operate as needed, and to detect the presence of excessively large pores or defects that could affect the filter's retention capacity. In the biopharmaceutical industry, the so-called "Pre-use Sterilization Post-Integrity Testing" (PUPSIT) is a Good Manufacturing Practice (GMP) regulatory requirement for sterile pharmaceutical products. It re-validates the performance of liquid filters after exposure to filter manufacturing, sterilization, transportation, and installation, but before actual use of the filtration unit for drug manufacturing. The goal of PUPSIT is to reduce process risks and potential product sterility issues.

[0003] Microporous or ultraporous filters, typically used in sterile filtration or other filtration technologies, are characterized in that the peripheral region of the microporous or ultraporous filter membrane (referred to herein as the membrane) is connected to a member serving as its boundary (also referred to herein as the boundary member). By using a pre-filter, the lifespan of the filter element can be improved (i.e., extended). Alternatively, the first and second membranes can have the same pore size to enable redundant filtration processes. In some cases, the first and second membranes can even be identical.

[0004] Not limited to this, the boundary member can be an end cap, for example, in the case of a membrane with a tubular shape, or it can be a frame, for example, in the case of a membrane with a flat shape. Depending on the shape of the membrane, its peripheral area can be attached to the boundary member by various means, including embedding, overmolding, hydrophobic adhesive bonding, potting, laser welding, or ultrasonic welding. If necessary, more than one boundary member can be used to attach to the peripheral area of ​​the membrane. In each case, the peripheral area of ​​the membrane must be attached to the boundary member to ensure the sterility of the resulting filter.

[0005] Various integrity tests for such filters, including at least one membrane, are known for the purposes described above, such as particle challenge tests, or bacterial challenge tests for sterile filters, liquid-liquid porosity tests, gas / liquid-based tests such as bubble point tests, gas-liquid diffusion tests, and binary gas tests, and diffusion tests for measuring tracer components. Some of these tests are destructive and therefore unsuitable as pre-use tests, such as PUPSIT.

[0006] The non-destructive gas / liquid-based integrity test commonly used for membrane filters, particularly for virus filters, is the gas-liquid diffusion test. In this test, the filter membrane is first wetted. When wetted, the membrane provides a liquid layer across which diffuse gas flow occurs, as described by Fick's diffusion law. In the gas-liquid diffusion test, the gas pressure on the upstream side of the membrane increases, and the diffuse flow increases linearly until the liquid layer begins to thin, or until the bubble point is reached, at which point a stable, large volume of airflow begins to appear. Filters can be easily measured to pass or fail the gas-liquid diffusion test using automated testing equipment, where excessively large pores or defects in the filter are identified by an increase in flow rate exceeding the effective maximum value.

[0007] Another non-destructive gas-liquid integrity test used for membrane filters is the bubble point test. This test is particularly useful for small filter assemblies, such as filters housed in disc retainers, cartridge filter housings, or capsules. In the bubble point test, the membrane is first wetted, and air or nitrogen pressure is incrementally applied to the wetted membrane, measuring the gas flow across the membrane at each pressure stage. As the pressure increases, it reaches a point where it exceeds the capillary force of the largest pores in the membrane. Automated testing equipment measures the increase in air flow when the wetting liquid is expelled and a significant gas flow occurs. The measured value corresponds to the bubble point, which is defined as the pressure at which the flow changes from diffuse flow through the wetting liquid in the pores to convective flow through the pores. Based on the determined bubble point, the tested membrane or filter is evaluated as passing or failing when the measured value is compared with known literature values ​​for the membrane or filter.

[0008] Other non-destructive gas / liquid integrity tests used for microporous and ultraporous membranes include binary gas testing. This test uses a binary gas mixture and is based on the principle that the different permeabilities of gases passing through the liquid layer of a wetted membrane lead to an increased concentration of the faster-permeating gas. In intact membranes, the permeate composition can be predicted based on the transport characteristics of the gases permeating through the liquid layer and known operating conditions. Deviations from the expected composition ratio indicate the presence of defects or excessively large pores. Specifically, in intact membranes, slower-permeating gases are removed from the permeate stream. However, if defects, openings, or excessively large pores are present, leakage through the membrane will contaminate the permeate stream, leading to an increased concentration of the slower-permeating gas.

[0009] For gas / liquid-based integrity tests to perform correctly, complete wetting of filter elements, particularly all membranes, is a crucial prerequisite. This applies to the aforementioned gas-liquid diffusion tests, bubble point tests, and binary gas tests, as well as other known gas / liquid-based testing methods. Inadequate wetting can lead to ambiguous integrity test results or even false-negative results. False-negative results may cause operators to discard their filtered material after a "no post-use test" because they believe the filter is not intact. However, especially in the production of pharmaceutical biomolecules, discarding filtrate due to false-negative post-use tests can result in significant economic losses. On the other hand, "no pre-use test" can also lead to the rejection of suspected incomplete filter elements, potentially resulting in high rejection rates, particularly for filter element manufacturers. Furthermore, false-negative results in such pre-use tests cause additional work and delays in the production process, reducing productivity and potentially leading to further losses in time-sensitive operations such as bioreactor collection.

[0010] Before gas / liquid integrity testing, it is difficult to detect incomplete wetting of the filter or membrane under test. Two main sources of error that can lead to incomplete wetting are currently known. Firstly, macroscopic air inclusions in front of, between, or behind the filter or membrane material can hinder complete wetting. Specifically, during wetting, only the hydrodynamically accessible region of the filter or membrane can be traversed, while regions behind the air inclusions (i.e., less accessible regions) rely on capillary lateral fluid delivery through the material to wet these regions. However, incomplete wetting of the filter or membrane occurs when the capillary lateral fluid delivery to the hydrodynamically inaccessible regions is insufficient. Secondly, microscopic air inclusions trapped in the pores and / or voids of the filter or membrane material hinder complete wetting of the material surrounding the pores and / or voids.

[0011] To eliminate false negative results in integrity testing, operators will first seek repeatability of the gas / liquid-based integrity test, whether in pre-use or post-use testing. Therefore, operators typically apply a two-step gas / liquid-based integrity test following this workflow: 1. Arrange the filter / membrane in the space designated for wetting. 2. Wetting is performed under pressure using a wetting medium (preferably water) to displace air from the filter / membrane unit. 3. Apply gas pressure, such as air, for testing. 4. Perform gas / liquid-based integrity tests, such as bubble point tests, gas-liquid diffusion tests, or binary gas tests. 5. Repeat steps 1 through 4 if the result of the gas / liquid-based test is "fail". However, the described two-step gas / liquid-based integrity test has the disadvantages of increased water consumption and increased time required for the integrity test. Furthermore, even if the two-step integrity test is passed, false negative results cannot be ruled out, and filters may be evaluated as "failed" and discarded, even though they pass the integrity test using another method (e.g., the particle challenge test).

[0012] In the prior art, several methods for achieving improved wetting are known. For example, for hydrophilic membranes, it is known that these membranes become hydrophobic in their peripheral regions after being embedded in boundary members made of thermoplastic polymers, and therefore subsequent gas / liquid-based integrity tests are defective due to poor wetting in these hydrophobic peripheral regions. To overcome these difficulties caused by the hydrophobicity of the membrane's peripheral regions, EP 0 096 306 A3 teaches the application of heat-sealable non-porous polyester membranes. As alternative methods, WO 96 / 14913 A1 and DE 43 39 810 C1 teach the subsequent rehydration of the hydrophobic portions by a hydrophilizing agent.

[0013] In addition, the following techniques are known to be used to improve the wetting of filters and membranes: increasing the temperature of the wetting fluid, introducing back pressure, increasing the flow through the filter element, increasing the wetting time, using wetting agents such as glycerin and polyvinylpyrrolidone, and using alternative wetting fluids such as alcohols (isopropanol or ethanol-based alcohols).

[0014] However, known methods for improving the wetting of filters and membranes have the following drawbacks: the use of large flushing volumes; repeated integrity tests when test results are negative (i.e., when the filter or membrane is assessed as “incomplete” or “fail”); the use of organic solvents or additives, which may result in explosive atmospheres and potentially contaminate wastewater; mechanical damage to the membrane; undesirable changes in membrane properties due to the applied wetting agent or temperature treatment; and contamination of the filter material by the wetting agent.

[0015] Furthermore, additional problems may arise when performing integrity tests on multilayer (e.g., dual-layer) filters using the aforementioned gas / liquid-based integrity tests.

[0016] Specifically, when performing integrity tests, for example, on a dual-layer filter, such as during PUPSIT, as a result of a gas / liquid-based integrity test, gas may become trapped between the two wetted membranes because pressurized gas that has passed through the first membrane may not be able to pass through the second membrane. Specifically, during the test, the pressure increases on the upstream side of the filter elements, increasing the pressure between the main filter and the pre-filter, since the main filter typically has a smaller pore size and therefore resistance to higher pressures. After the test, when no external pressure is applied and the pressure decreases to atmospheric pressure, the pressurized gas between the membranes may expand, especially since the membranes are still wetted, causing gas to remain trapped. This can lead to defects in one or both membranes, at the junction of the membrane and boundary members, or in any other component of the filter. Furthermore, when gas is trapped between the membranes, the filter surface area is not fully exposed, and therefore, full filtration performance cannot be provided during subsequent use of the filter.

[0017] Therefore, there is a risk that a filter may be rated "pass" in the upstream (pre-use) integrity test but could be damaged due to pressure drop after the integrity test. Consequently, the filter could be mistakenly assumed to be defect-free, while actual filtration is performed using a defective filter. Therefore, in practice, PUPSIT is not used for multilayer filters, such as dual-layer filters.

[0018] Therefore, considering the above, the object of the present invention is to provide a method for performing gas / liquid-based integrity testing on an object having a first membrane and a second membrane, which will improve membrane wetting, reduce the occurrence of false negative test results in integrity tests that rely on providing liquid membranes in and on the membrane, and will avoid any damage to the object having the first membrane and the second membrane.

[0019] The above objective has been achieved by providing the embodiments characterized in the claims.

[0020] In a first aspect of the invention, a method for performing a gas / liquid-based integrity test is provided, the method comprising the steps (a) through (f) in sequence: (a) Providing an object having a first membrane and a second membrane; (b) Arrange the object in a space for wetting; (c) The air in the first membrane and the second membrane is replaced by a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide; (d) Wet the first and second membranes of the object with water or an aqueous solution; (e) Applying the gas pressure of the water-soluble gas to the first membrane; and (f) The integrity of the object is tested by performing a bubble point test.

[0021] As the inventors have discovered, membrane wetting can be improved by replacing the air in the membrane with a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide before wetting the membrane. This is because the water-soluble gas is more water-soluble than nitrogen (a major component of air), and therefore more water-soluble than air.

[0022] When air is replaced with this water-soluble gas before wetting the membrane, it is impossible for macroscopic and microscopic air inclusions to form within the membrane because the air is replaced by the water-soluble gas. Instead, only water-soluble gas inclusions can form when the membrane is wetted. Due to its higher solubility in water, this initially formed inclusion of the water-soluble gas dissolves more effectively in the water or aqueous solution applied during the wetting step compared to air. Furthermore, by dissolving the water-soluble gas in water or an aqueous solution, the volume of the gas inclusions decreases, and the inclusions themselves also decrease (if not completely removed). This effect is more pronounced for gases with higher solubility in water, and therefore even more significant when air is replaced with water-soluble gas before wetting the membrane. Therefore, the method for gas / liquid integrity testing according to the present invention (which includes the step of replacing air with a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide) reduces macroscopic gas inclusions that prevent complete membrane wetting compared to wetting in ambient air, and these inclusions can even be removed, thereby increasing the surface area of ​​the membrane's hydrodynamically accessible region. Similarly, microscopic gas inclusions trapped in the pores and / or voids of the membrane are reduced or even removed by dissolving the water-soluble gas in water or an aqueous solution. Therefore, the wetting of the membrane by water or an aqueous solution can be improved.

[0023] Advantageously, due to improved membrane wetting, false negative test results for gas / liquid-based integrity tests of the membrane can be reduced. Therefore, operators do not need to retest filters or membranes assessed as incomplete through the aforementioned two-step gas / liquid-based integrity test, thus reducing the total number of gas / liquid-based integrity tests required.

[0024] Furthermore, because a gas pressure containing at least 15 vol.% water-soluble gases of carbon dioxide and / or nitrous oxide is applied during the preparation for the bubble point test, the gas that expands between the membranes when the pressure is reduced after the bubble point test is completed is not trapped. Instead, it can dissolve in water or an aqueous solution that still wets both membranes. Therefore, defects in one or both membranes, at the junction of the membrane and boundary members, or in any other component of the filter can be prevented, and the filter surface area is fully exposed.

[0025] The following describes in detail a method for performing a gas / liquid-based integrity test according to the present invention, the method comprising the steps of replacing air in a membrane with a water-soluble gas and applying a gas pressure of the water-soluble gas to a first membrane, wherein the water-soluble gas contains at least 15 vol.% carbon dioxide and / or nitrous oxide.

[0026] In this document, gas / liquid-based integrity testing refers to a test used to evaluate the integrity of an object having a first membrane and a second membrane, based on a liquid membrane provided within the membrane and a gas prevented from freely passing through the membrane by the liquid membrane. Integrity means that the tested object functions perfectly for its intended use. For objects with membranes, integrity means that they do not allow unwanted components to pass through. The integrity of an object with a membrane is not given in the case of defects or excessively large pores in the object or membrane. Gas / liquid-based integrity testing is a bubble point test. The principles and procedures of the gas / liquid-based integrity test are readily known to those skilled in the art and can be easily modified by those skilled in the art using additional steps of the gas / liquid-based integrity test according to the present invention.

[0027] In step (a) of the method for performing a gas / liquid-based integrity test, an object having a first membrane and a second membrane is provided.

[0028] Objects having a first membrane and a second membrane are not particularly limited, provided that the object includes both a first membrane and a second membrane and its integrity can be assessed by a gas / liquid-based integrity test.

[0029] In a preferred embodiment of the invention, the object having a first membrane and a second membrane is a filter, preferably a filter for sterile filtration.

[0030] An object having a first membrane and a second membrane (e.g., a filter) may include a first membrane, a second membrane, and at least one boundary member, wherein a peripheral region of the membrane is fluid-tightly connected to the at least one boundary member. Typically, the at least one boundary member comprises a thermoplastic polymer material in the region to which the membrane is connected. Preferably, the boundary member is composed of at least one thermoplastic polymer material. Thus, a particularly stable and fluid-tight connection between the boundary element and the membrane is possible by melting the thermoplastic polymer material in the intended connection region and then placing the boundary element on the membrane. Thermoplastic polymer materials may include low-melting-point thermoplastics, such as polyolefins, including, but not limited to, polyethylene, polypropylene, and poly(ethylene propylene). In a preferred embodiment, the polyolefin is polypropylene. In addition to the membrane and at least one boundary member, an object having a first membrane and a second membrane (e.g., a filter) may include a backflow protector and / or a core. Furthermore, one or more drainage elements or supporting nonwovens may be provided as additional components in the object having a first membrane and a second membrane. These additional components, if present, are suitably arranged in or on the membrane.

[0031] In this document, a membrane refers to a porous layer, such as a continuous solid matrix containing pores therein. Each membrane has a first primary surface and a second primary surface opposite to the first primary surface.

[0032] Within an object, the first membrane and the second membrane are arranged in order from the upstream side to the downstream side of the object (e.g., a filter). That is, the first membrane is closer to the upstream side of the object than the second membrane, and the second membrane is closer to the downstream side of the object than the first membrane.

[0033] Independently, the first and second membranes can be monolayer membranes or combinations of two or more (individual) membranes. That is, the membrane can consist of only a single membrane or two or more different membranes, each of which can have different membrane properties (e.g., pore size, material, thickness).

[0034] The type of connection between each of the first and second membranes and the object is not particularly limited. For example, the layers may be loosely in contact with each other, loosely connected within the boundary member, or the layers may be sealed by clamping (at their edges), heat-sealing overmolding (plastic silicone), etc. According to a preferred embodiment, the membranes are loosely connected (e.g., within the boundary member, i.e., the connection between layers is driven by the connection with the boundary member) without lamination between them.

[0035] The first and second membranes may contain the same or different materials. Independently, the first and second membranes may contain at least one of hydrophobic and hydrophilic materials. According to a preferred embodiment of the invention, the first and second membranes contain or are composed of a hydrophobic material. Since hydrophobic materials are inherently waterproof, the surface of the membrane containing at least one hydrophobic material is generally not sufficiently wettable, leading to a large number of false negative results in gas / liquid-based integrity tests. Therefore, due to the improved wetting of the membrane by the method according to the invention, the number of false negative test results is particularly reduced when integrity tests are performed on membranes containing at least one hydrophobic material. A material is hydrophobic when it has a contact angle greater than 90° with a water droplet (as determined according to EN ISO 19403-2:2020-04). When the contact angle between the material and the water droplet is 90° or less, the material is considered hydrophilic.

[0036] Depending on the intended application of the object having the first and second membranes (e.g., a filter), hydrophilic or hydrophobic membranes can be used independently of each other.

[0037] Preferably, the first and second membranes are hydrophobic membranes. Similar to membranes containing at least one hydrophobic material, the method according to the invention particularly reduces the number of false negative test results when performing integrity tests on hydrophobic membranes. A membrane is considered hydrophilic when its water contact angle is 90° or less, while a hydrophobic membrane has a water contact angle greater than 90°. The water contact angle of the membrane can be determined according to EN ISO 19403-2: 2020-04.

[0038] Alternatively, the first and second membranes can be hydrophilic membranes. When performing integrity testing on hydrophilic membranes, the number of false negative test results can be reduced by the method according to the invention.

[0039] The hydrophobic material of the membrane can be inherently hydrophobic and / or hydrophobically modified. Hydrophobic modification of the material can be achieved using fluorinated reagents, for example, in monomeric, oligomeric, or polymeric forms. Suitable modification methods are known to those skilled in the art. The hydrophobic material of the membrane may include at least one polymer selected from: cellulose esters such as nitrocellulose, cellulose acetate, and mixtures thereof; polyamides; polyethersulfones; polysulfones; polyetherketones; polyolefins; polyacrylonitrile; polyvinylidene fluoride; and polytetrafluoroethylene. Suitable polyolefins are polyethylene, polypropylene, poly(ethylene propylene), and mixtures thereof. Preferably, the polymer is selected from cellulose acetate, polyethersulfones, polysulfones, polyamides, polyacrylonitrile, polyvinylidene fluoride, and polytetrafluoroethylene.

[0040] The hydrophilic material of the membrane can be inherently hydrophilic and / or hydrophilically modified. Suitable modification methods, such as saponification of the ester side chains of polymers (e.g., cellulose acetate), are known to those skilled in the art. The hydrophilic material of the membrane may include at least one cellulose derivative. Examples of cellulose derivatives are nitrocellulose, mixed cellulose esters, and regenerated cellulose. At least one cellulose derivative may be crosslinked. If crosslinked, 0.05% to 20% of the hydroxyl groups in the cellulose derivative may be crosslinked.

[0041] Regardless of their hydrophilicity / hydrophobicity, the first and second membranes preferably contain polymers selected from cellulose acetate, polyethersulfone, polysulfone, polyamide, polyacrylonitrile, polyvinylidene fluoride and polytetrafluoroethylene independently of each other.

[0042] Depending on the intended use of the object being tested, i.e., the size of the particles to be separated, each of the first and second membranes has a suitable pore size. Typical pore sizes are from 0.005 μm to 10 μm, for example, from 0.01 μm to 1.2 μm or from 0.02 μm to 0.45 μm. Preferably, the first and second membranes have different pore sizes. In a preferred embodiment, the first membrane has a larger pore size than the second membrane. In this case, the first membrane may also be referred to as a pre-filtration membrane, and the second membrane may be referred to as a main filtration membrane, preferably a sterile-grade filter. Alternatively, the first and second membranes may have the same pore size, i.e., substantially the same pore size, to enable redundant filtration processes. In some cases, the first and second membranes may be identical.

[0043] Membranes can also be classified based on their pore size. Typically, they are distinguished as microporous membranes (pore size from 0.1 μm to 10 μm), ultraporous membranes (pore size from 0.01 μm to less than 0.1 μm), and nanoporous membranes (pore size from 0.001 μm to less than 0.01 μm). According to a preferred embodiment of the invention, the first and second membranes are independently microporous, ultraporous, or nanoporous membranes, preferably independently microporous or ultraporous membranes.

[0044] In this paper, capillary flow porometry was applied to determine pore sizes equal to or greater than 0.1 μm. Capillary flow porometry is a gas-liquid porosimetry technique in which differential gas pressure and flow rate through a membrane sample are measured first in a wetted state and then in a dry state. Before measurement, the membrane sample is brought into contact with a wetting liquid such that all existing pores are filled with the wetting liquid. Once the pores are filled, the membrane sample is introduced into the measurement unit. After the measurement unit is closed and measurement begins, the gas pressure is increased automatically and gradually, and with the applied pressure, the pore diameter is cleared due to the gas pressure. This is completed until all relevant pore sizes have been captured (i.e., until even the smallest pores present in the measurement range have been cleared from the liquid). Afterward, the pressure is reduced back, and the measurement is automatically repeated on the now-dry membrane sample. The pore size distribution is calculated from the difference between the two pressure / flow rate curves using the Young-Laplace equation (see also...). A. Shrestha, "Characterization of porous membranes via porometry”, 2012, Mechanical Engineering Graduate Theses & Dissertations, Paper 38, University of Colorado at Boulder ).

[0045] On the other hand, in this paper, a liquid-liquid displacement porosity determination method is applied to determine pore sizes smaller than 0.1 μm. As is known to those skilled in the art, the liquid-liquid displacement porosity determination method is similar to the capillary flow pore size determination method. However, it measures not the gas flow rate, but the flow rate of the displaced liquid as a function of the increase in differential pressure (see also...). R. Davila, "Characterization of ultra and nanofiltration commercial filters by liquid-liquid displacement porosimetry", 2013 ).

[0046] The porosity of the first and second membranes is not particularly limited, and can be readily selected by those skilled in the art based on the intended use of the membranes and their desired specifications. For example, independently of each other, the porosity of the first and second membranes can be from 5% to 90%, preferably from 40% to 85%. Generally, porosity represents the ratio of pore volume to the total volume of the membrane. Herein, the total volume of the membrane refers to the volume defined by the first and second principal surfaces of the membrane. Methods for determining the porosity of membranes are known to those skilled in the art, such as those described in ISO 15901-1:2016. For example, the porosity of the membrane can be determined based on the thickness, the area of ​​the first and second principal surfaces, the weight of the membrane, and the density of the materials constituting the membrane.

[0047] The present invention is not subject to any particular limitation regarding the thickness of the first and second membranes. For example, independently of each other, the first and second membranes can have thicknesses ranging from 20 μm to 400 μm, preferably from 80 μm to 300 μm. The membrane thickness is measured using a commercially available membrane thickness gauge (HAHN+KOLB Werkzeuge GmbH, Ludwigsburg, Germany) with a scale of 1 μm.

[0048] Similarly, the geometry of the first and second membranes is not further restricted. Preferably, the first and second membranes are identical.

[0049] The membrane of an object (e.g., a filter) can have a tubular shape. For this purpose, a rectangular membrane can be closed by ultrasonic welding. This results in a cylindrical arrangement with two open end faces. Each of these two open end faces can be considered as a peripheral region to be connected to a corresponding boundary member, for example, by embedding the peripheral regions of the first and / or second membranes into the boundary member after softening it. If necessary, the rectangular membrane can be pleated before being closed to form a tube. Therefore, the membrane area can be increased while the overall dimensions of the membrane geometry remain the same. In the case where the object having the first and second membranes is a filter, it includes a membrane with a tubular shape, optionally pleated, which can also be referred to as a filter cartridge. In this case, the at least one boundary member is typically an end cap.

[0050] Instead of a tubular shape, the first and / or second membranes may also have a flat shape. Preferably, each of the first and second membranes is a flat membrane. Here, the term "flat" means that the respective membrane material is substantially located in a single plane with a specific thickness. Preferably, all membranes are located in planes that are substantially parallel to each other. The outer edge of the membrane can be considered as being wholly or partially connected to the peripheral area of ​​the respective boundary member, for example, by overmolding, hydrophobic adhesive, or ultrasonic welding the boundary member to the peripheral area of ​​the membrane. In the case where the object having the first and second membranes is a filter, it includes membranes with a flat shape, which may also be referred to as a flat panel filter or flat panel module. In this case, the at least one boundary member is typically a frame.

[0051] In embedded applications, for example, to connect to the peripheral region of the membrane, the boundary member, or at least a portion thereof, must be able to be softened. For this reason, low-melting-point thermoplastics are typically used as the material for the boundary member. Low-melting-point thermoplastics are compatible with the materials constituting the membrane, enabling a fluid-tight connection. For example, the at least one boundary member is formed of a polyolefin, including, but not limited to, polyethylene, polypropylene, and poly(ethylene propylene). In a preferred embodiment, the polyolefin is polypropylene.

[0052] The geometry of the at least one boundary member is not further limited, as long as the peripheral region of the membrane can be connected to it. Those skilled in the art will select a suitable geometry for the at least one boundary member based on the intended use of the object having the first and second membranes (e.g., a filter). Naturally, the geometry of the at least one boundary member needs to be compatible with the geometry of the membrane. In the case of two or more boundary members, each boundary member may have its own geometry if desired.

[0053] As needed, in addition to the first membrane, the second membrane, and the at least one boundary member, an object having a first membrane and a second membrane (e.g., a filter) may include additional components, such as, for example, a backflow protector and / or a core. Depending on the intended use of the object having the first membrane and the second membrane (e.g., a filter), those skilled in the art will select suitable backflow protectors and / or suitable cores for the object having the first membrane and the second membrane (e.g., a filter). Furthermore, an object having a first membrane and a second membrane may include one or more drainage elements or supporting nonwovens as additional components, which may be arranged on one or both sides of the first membrane and / or the second membrane. Like the membrane, these one or more drainage elements or supporting nonwovens may be pleated.

[0054] In step (b) of the method for performing a gas / liquid-based integrity test according to the present invention, the object is arranged in a space for wetting.

[0055] Here, "arranging an object" means positioning the object within the space. The object is positioned in such a manner that subsequent steps of the method according to the invention can be performed. For example, the object may be arranged or positioned in a mounting device located in the space.

[0056] The space is not further limited, provided that the object having the first and second membranes arranged therein can be wetted and the air can be replaced by a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide. Therefore, the space is suitable for carrying out subsequent steps (c) and (d) of the method according to the invention, preferably all subsequent steps of the method according to the invention, so that the entire method can be carried out in the same space.

[0057] For this purpose, the space can be located within a fluid-tight, sealable chamber. For subsequent steps of the method according to the invention, the chamber may include at least one gas inlet and at least one gas outlet, at least one liquid inlet and at least one liquid outlet, a mounting device for holding an object, and at least one pressure measuring device. The mounting device may be positioned in the chamber in such a way that, when holding an object having a first membrane and a second membrane, any bypassing or flow of gas or liquid is prevented. For example, the outer circumferential surface of the mounting device may be fluid-tightly connected to the chamber, and the inner surface of the mounting device may be configured to hold the object and provide a fluid-tight connection with the object.

[0058] As needed, the chamber may include at least one mechanism for measuring and controlling the temperature of the space or the gas and liquid contained therein. The at least one gas and liquid inlet and the gas and liquid outlet may be connected to means necessary for subsequent steps of the method according to the invention. For example, each of the at least one gas inlet may be independently connected to at least one of a water-soluble gas source or a component thereof, a pressurized test gas source and a reference gas source, optionally connected to a binary gas source for binary gas testing, or an air source, while each of the at least one liquid inlet may be independently connected to a water source or an aqueous solution source.

[0059] Each of the at least one gas outlet may be independently connected to at least one vacuum pump, exhaust outlet, or container for gaseous waste, while each of the at least one liquid outlet may be connected to a device for disposing of water or aqueous solutions or to a liquid pump.

[0060] The specific arrangement of at least one gas inlet, at least one gas outlet, at least one liquid inlet, at least one liquid outlet, mounting device for holding the object, at least one pressure measuring device, and at least one mechanism for measuring and controlling temperature is not limited, as long as the subsequent steps of the method according to the invention can be performed. The specific arrangement of the gas and liquid inlets and outlets in the chamber for independently wetting the object and testing its integrity, or the use of the same chamber, is known to those skilled in the art.

[0061] In order to replace the air in the first and second membranes in step (c) of the method according to the invention, at least one source gas inlet connected to a water-soluble gas source or a component thereof may be arranged on one side of the chamber relative to the mounting device, while at least one of the gas outlet connected to a vacuum pump and the gas outlet connected to an exhaust outlet or a container for gaseous waste may be arranged on the other side relative to the mounting device.

[0062] In step (c) of the method for performing a gas / liquid-based integrity test according to the invention, the air in the first and second membranes is replaced by a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide. Therefore, the air possibly located between the two membranes is also replaced by the water-soluble gas. Here, air is understood to be atmospheric air. Water-soluble gases have significantly higher solubility in water than air. That is, the solubility of water-soluble gases in water is higher than that of air in water.

[0063] As a result of step (c) (i.e., replacing air with a water-soluble gas), in the subsequent step (d) of wetting the first and second membranes according to the method of the invention, air with low solubility in water is (substantially) absent in the first membrane, the second membrane, and the space between them. Instead, only water-soluble gases with higher solubility in water than air are present in the first and second membranes. When the first and second membranes are wetted with water or an aqueous solution in the subsequent step (d), initially only macroscopic and / or microscopic inclusions of the water-soluble gas can be formed. Since the inclusions are formed by water-soluble gases with higher solubility in water than air, the solubility of the gas in the water or aqueous solution applied in step (d) is increased compared to conventional air inclusions. Based on the increased solubility of the water-soluble gas, the volume of the inclusions initially formed during membrane wetting is significantly reduced compared to air inclusions. Therefore, the inclusions of water-soluble gas are at least reduced or even removed compared to air inclusions. Therefore, by replacing air with a water-soluble gas in step (c), the wetting of the membrane in step (d) can be improved because the high solubility of the water-soluble gas in the applied water or aqueous solution reduces or even eliminates macroscopic gas inclusions (which prevent complete wetting of the membrane) and microscopic gas inclusions trapped in the pores and / or voids of the membrane material and in the space between the two membranes (which prevent complete wetting of the material surrounding the pores and / or voids). Thus, the wetting of the membrane by water or aqueous solution can be improved. Based on the improved wetting of the membrane, the occurrence of false negative test results in gas / liquid-based integrity tests can be reduced. Therefore, the total number of gas / liquid-based integrity tests to be performed is reduced because membranes that have been (erroneously) tested negative do not need to be re-evaluated.

[0064] In principle, the above effect can be achieved by replacing air with any gas that has high solubility in water. However, the effect is particularly significant when using a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide, making the improved wettability of the membrane have a significant impact on the number of false negative test results.

[0065] Those skilled in the art are familiar with the water solubility of various gases and the methods for determining the water solubility of gases from bibliographies, such as the CRC Handbook of Chemistry and Physics, 95th edition. Based on this, those skilled in the art can determine the water solubility of any gas or mixture of gases using suitable equations, such as Dalton's law combined with Henry's law, using the partial pressure and water solubility of each individual gas.

[0066] The improved wetting effect of the membrane can be further enhanced by increasing the water solubility of the water-soluble gas.

[0067] Water-soluble gases are not further restricted, provided they are compatible with objects having a first membrane and a second membrane. That is, the water-soluble gas does not react with any component of the object, and in particular, does not react with the material of the membrane. Similarly, when dissolved in water or an aqueous solution, the water-soluble gas does not form compounds that react with the membrane.

[0068] To ensure proper membrane functionality after integrity testing, the water-soluble gas is preferably a gas that evaporates from the membrane after the integrity test, without requiring specific measures typically applied in or after gas / liquid-based integrity testing. For example, the water-soluble gas is completely evaporated from the object by exposure to air or a vacuum, optionally combined with heating. Therefore, when dissolved in the water or aqueous solution applied in step (d), the water-soluble gas preferably does not contain any compounds that form salts.

[0069] From an environmental perspective, water-soluble gases are preferably neither toxic, corrosive, nor environmentally harmful. From a safety perspective, water-soluble gases are preferably non-flammable.

[0070] To avoid damaging the membrane, the water-soluble gas is preferably substantially free of compounds that form strong acids or bases when dissolved in water. Criteria for evaluating whether an acid or base represents a strong acid or base are known to those skilled in the art. For example, any acid or base that effectively and completely dissociates in solution represents a strong acid or base. In this document, an acid having a pK of 3.75 or less is considered a strong acid or base. s In the case of a value, it can be considered to represent a strong acid, and in the case of a base having a pK of 4.75 or less. bIn the case of a value, it can be considered to represent a strong base. For example, the water-soluble gas is substantially free of nitrogen dioxide, hydrogen iodide, hydrogen bromide, hydrogen chloride, hydrogen fluoride, chlorine, sulfur dioxide, sulfur trioxide, and / or ammonia. Generally, according to the invention, the water-soluble gas is substantially free of a component when the content of the component in the water-soluble gas is less than 100 ppm (preferably the component has a content of less than 10 ppm). When rinsing the object having the first and second membranes after the integrity test in step (f), the content of the component in the water-soluble gas can also be limited to the value so as not to exceed a reasonable rinsing volume of water (e.g., water for injection or sterile water for injection).

[0071] For similar reasons, water-soluble gases may not be suitable for reducing the pH of the water or aqueous solution used in step (d) of the method according to the invention to a value less than 1.0, preferably less than 5.0, and more preferably less than 6.0, and are not suitable for increasing the pH of the water or aqueous solution used in step (d) to a value greater than 13, preferably greater than 9.0, and more preferably greater than 8.0.

[0072] Water-soluble gases may contain only one gaseous component or a mixture containing at least two gaseous components.

[0073] According to the present invention, the water-soluble gas comprises carbon dioxide and / or nitrous oxide. These gaseous components have a higher solubility in water than nitrogen and oxygen, which constitute air (approximately 99 vol.%). Therefore, the presence of carbon dioxide and / or nitrous oxide increases the solubility of the water-soluble gas, thereby improving membrane wetting. To obtain a water-soluble gas with high solubility in water, the water-soluble gas preferably comprises carbon dioxide. In this case, the water-soluble gas preferably comprises at least 15 vol.% carbon dioxide. In addition to carbon dioxide and / or nitrous oxide, the water-soluble gas may comprise at least one of nitrogen, oxygen, argon, xenon, and krypton.

[0074] The purity of the water-soluble gases is not particularly limited, provided that the membrane is not contaminated during step (c) and their properties are not negatively affected. Preferably, the impurity content in the water-soluble gases is 10 ppm or less. In this document, the term "impurity" refers to any component in the water-soluble gases that is not carbon dioxide, nitrous oxide, xenon, krypton, nitrogen, oxygen, or argon. In a preferred embodiment of the invention, the water-soluble gases and / or the gaseous components contained therein comply with Commission Regulation (EU) No 231 / 2012 of 9 March 2012, which sets out the specifications for food additives listed in Annex II and Annex III of Regulation (EC) No 1333 / 2008 of the European Parliament and the Council, applicable to the EEA.

[0075] According to the present invention, the total content of carbon dioxide and / or nitrous oxide in the water-soluble gas is at least 15 vol.%.

[0076] The minimum 15 vol.% content refers to the total content of water-soluble gases carbon dioxide and nitrous oxide. Other components contained in the water-soluble gases may be gases that are not particularly water-soluble, such as nitrogen, oxygen, and argon. Water-soluble gases containing at least 15 vol.% of total carbon dioxide and / or nitrous oxide have sufficient solubility in water to improve membrane wetting and reduce the number of false negative tests.

[0077] When the solubility of water-soluble gases should be further increased, the total content of carbon dioxide and / or nitrous oxide is preferably at least 25 vol.%, more preferably at least 50 vol.%, even more preferably at least 75 vol.%, even more preferably at least 90 vol.%, highly preferably at least 95 vol.%, particularly preferably at least 98 vol.%, and most preferably at least 99 vol.%. This can improve the solubility of water-soluble gases.

[0078] When the water-soluble gas contains more than one of carbon dioxide, nitrous oxide, xenon, and krypton, the content of the more expensive gaseous component can be lower than the content of the cheapest gaseous component. Therefore, the cost of carrying out the method of the present invention can be reduced. For example, the content of each of xenon and krypton in the water-soluble gas (if included) can be 1 vol. % or less.

[0079] The principles and workflow of providing the water-soluble gas described herein in step (c) of the method according to the invention are known to those skilled in the art and can be readily modified by those skilled in the art as needed. For example, the composition of the water-soluble gas, particularly the content of carbon dioxide and / or nitrous oxide, can be controlled by a flow meter installed at the corresponding gas inlet or at a pipe connecting the gas inlet to a water-soluble gas source or its components.

[0080] For economic reasons, reducing the amount of expensive gaseous components in water-soluble gases and avoiding the use of high-purity gases can be considered. For example, the total content of each of carbon dioxide, nitrous oxide, xenon, and krypton in water-soluble gases can be less than 99.9 vol.%, less than 99.8 vol.%, less than 99.6 vol.%, less than 99.5 vol.%, less than 95 vol.%, or less than 90 vol.%.

[0081] Several methods for replacing air in the membrane with a water-soluble gas are known to those skilled in the art, and the method applied in step (c) is not particularly limited. Here, replacing air with a water-soluble gas means exchanging air with a water-soluble gas. Air or any gas in the first and second membranes refers to gas located on the surface of the membrane material and between the membrane materials, as well as in the pores and / or voids of the membrane. Since the membrane is arranged in a space for wetting in step (b), the step of replacing air in the membrane with a water-soluble gas is achieved by replacing air in the space where the object is arranged with a water-soluble gas.

[0082] When the air is not completely replaced by water-soluble gas, a mixture of air and water-soluble gas will remain in the membrane and the space. That is, the degree to which the air is replaced by water-soluble gas is not 100%. In this case, the gas mixture in the membrane and the space is considered to be the same. Although not complete, in the method according to the invention, replacing the air in the membrane with water-soluble gas to a certain extent is generally sufficient to improve the wetting of the membrane. Since complete replacement of air in the membrane is technically complex and time-consuming, the air is only replaced to a certain extent.

[0083] For example, in step (c), air can be replaced by water-soluble gas by at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, particularly preferably at least 90%, and most preferably at least 95%. The degree to which air is replaced by water-soluble gas can be measured and controlled by determining the composition of the gas mixture present in the space in which the object is arranged and calculating the degree of replacement based on the composition of air and water-soluble gas.

[0084] Alternatively, in step (c), air can be replaced in the membrane with a water-soluble gas to such an extent that the resulting mixture of water-soluble gas and air in the first and second membranes has sufficient solubility in water to improve the wetting of the membrane by water or an aqueous solution in step (d). That is, if the mixture of water-soluble gas and air in the membrane obtained in step (c) has a certain solubility in water, the effect of the method for performing gas / liquid integrity testing according to the invention is independent of the degree of air replacement in the first and second membranes in step (c) and the solubility of the water-soluble gas. In principle, the above effect can be achieved by using a mixture of water-soluble gas and air in the membrane that has a higher solubility in water than air.

[0085] To further improve membrane wetting, the water solubility of the gas mixture obtained in step (c) can be increased. The values, ranges, and limits of solubility as described herein, as well as the specifications and composition of the water-soluble gas itself, are similarly applied to the water-soluble gas and air-water-soluble gas mixture in the membrane obtained in step (c).

[0086] In another preferred embodiment, the gas mixture obtained in step (c) comprises at least 15 vol.% of a total content of carbon dioxide and / or nitrous oxide. This gas mixture has a higher solubility in water than in air. Where the solubility of the gas mixture obtained in step (c) should be further increased, the total content of carbon dioxide and / or nitrous oxide is preferably at least 25 vol.%, more preferably at least 50 vol.%, even more preferably at least 75 vol.%, even more preferably at least 90 vol.%, highly preferably at least 95 vol.%, particularly preferably at least 98 vol.%, and most preferably at least 99 vol.%.

[0087] Clearly, when the air replacement rate in step (c) is 100%, the water solubility of the gas mixture of water-soluble gas and air obtained in step (c) is only the same as the water solubility of the water-soluble gas itself. In all other cases, the water solubility of the gas mixture obtained in step (c) is lower than the water solubility of the applied water-soluble gas. The water solubility of the gas mixture of water-soluble gas and air obtained in step (c) can be improved by increasing the air replacement rate and / or the water solubility of the water-soluble gas.

[0088] The water solubility of the gas mixture of water-soluble gas and air obtained in step (c) can be determined or calculated using methods similar to those described in the context of the water solubility of water-soluble gases. For example, the water solubility of the gas mixture obtained in step (c) can be calculated based on the partial pressures of the individual gases using Dalton's law in combination with Henry's law and known gas solubility, as well as methods for determining gas solubility from reference books (e.g., CRC Handbook of Chemistry and Physics, 95th edition).

[0089] Air is replaced in the first and second membranes by removing air with a vacuum and adding a water-soluble gas, or by replacing the air with a water-soluble gas.

[0090] In a preferred embodiment of the method according to the invention, step (c) comprises at least one cycle of steps (c1) and (c2); step (c1): removing air from the space by applying a vacuum; step (c2): subsequently filling the evacuated space with a water-soluble gas.

[0091] Through the at least one cycle, air can be sufficiently replaced in the first and second membranes by applying a vacuum to remove air and subsequently adding a water-soluble gas. Here, the term vacuum does not refer to a perfect vacuum, but rather to a reduced pressure.

[0092] In step (c1), the pressure within the space is reduced by applying a vacuum. By reducing the pressure within the space, at least partially removing the air or air / water-soluble gas mixture from the space, and improving air replacement by subsequently filling the evacuated space with water-soluble gas in step (c2), the evacuated space is referred to here as the space after which a vacuum has been applied. This evacuated space has a reduced pressure compared to atmospheric pressure. The final pressure reduction achieved by applying a vacuum is not particularly limited. For example, after applying a vacuum, the pressure within the space can be less than 200 mbar, preferably less than 20 mbar, more preferably less than 2 mbar.

[0093] For step (c2), filling the evacuated space with water-soluble gas means adding water-soluble gas to increase the pressure within the space. Preferably, water-soluble gas is added until atmospheric pressure is reached within the space, where atmospheric pressure refers to the sea-level standard pressure of 1.013 bar (101.3 kPa). Here, the pressure within the space and the pressure of the space refer to the pressure of the gas located within the space.

[0094] In the context of this invention, pressure means the pressure of a gas (e.g., air, a water-soluble gas, or a mixture thereof) or a liquid (e.g., water or an aqueous solution), which is a measure of the average linear momentum of the moving molecules of the gas or liquid. Gas or liquid pressure can be applied to the upstream side of the first membrane or the downstream side of the second membrane. Here, applying gas or liquid pressure to one side of the membrane means bringing one side of the membrane into contact with a gas or liquid having a pressure higher than atmospheric pressure. One side of the membrane refers to the main surface of the membrane.

[0095] The cycle of steps (c1) and (c2) can be repeated several times until the desired level of replacement is achieved. For example, the cycle can be repeated two, three, or four times, preferably three times.

[0096] If the air in the membrane is removed by at least one cycle of steps (c1) and (c2), the space can be located within a fluid-tight sealable chamber, which includes a mounting device, at least one gas inlet connected to at least one source of a water-soluble gas or a component thereof, and at least one gas outlet connected to at least one vacuum pump. The at least one gas inlet and at least one gas outlet can be located on the same side of the chamber or on different sides relative to the mounting device.

[0097] In a preferred embodiment of the method according to the invention, step (c) includes displacing air by the flow of water-soluble gas through the first and second membranes. Here, displacement refers to the process by which the water-soluble gas removes air from its position and removes air from the membranes by the flow. Or in other words, when air is displaced by the flow of water-soluble gas through the first and second membranes, air is pushed out of each membrane by the flow of water-soluble gas through the membranes. The flow of water-soluble gas is a fluid flow, preferably a laminar fluid flow. The flow can be quantified by its volumetric flow rate, which represents the volume of water-soluble gas passing through per unit time. The volumetric flow rate is not particularly limited when air is displaced by the flow of water-soluble gas. An increased volumetric flow rate increases the degree of displacement. For example, a sufficient volumetric flow rate for proper displacement can be achieved when a volume of water-soluble gas corresponding to 2 times, preferably 3 times, and more preferably 5 times the volume of the space in which the object is arranged is passed through within 5 minutes, preferably 2 minutes.

[0098] The volume of water-soluble gas flowing through the membrane can be provided by adding water-soluble gas into the space in the region facing the membrane and creating a pressure difference in the space.

[0099] In this application, the pressure difference of gases in space means that the gas in contact with one side of the membrane (e.g., a water-soluble gas, air, or a mixture thereof) has a different pressure than the gas in contact with the opposite side of the membrane.

[0100] The pressure difference can be generated by adding a water-soluble gas under pressure to the space in the region facing the membrane and releasing or reducing the pressure in the space region facing the membrane. Alternatively, the pressure difference can be generated by adding a water-soluble gas to the space in the region facing the membrane and reducing the pressure in the space region facing the membrane by a vacuum pump. In this document, releasing the pressure in the space region facing the membrane means reducing the pressure in that region by allowing air, a water-soluble gas, or a mixture thereof to flow out of the space in which the object is arranged, for example, into a space having a lower pressure than the space in which the object is arranged (e.g., an environment with atmospheric pressure). Reducing the pressure in the space region facing the membrane means actively reducing the pressure in that region, for example, by a (vacuum) pump.

[0101] The pressure difference is not particularly limited, provided that the object having the first and second membranes (e.g., a filter) is not damaged. Therefore, the pressure difference can be adjusted based on the maximum permissible operating pressure of the object having the first and second membranes (e.g., a filter). For example, the pressure difference can be 20% of the maximum permissible operating pressure, and preferably 40%. The upper limit of the pressure difference is the maximum permissible operating pressure, preferably 90%.

[0102] In this document, the maximum permissible operating pressure refers to the maximum pressure that the weakest component of an object having a first membrane and a second membrane can withstand. When the object having a first membrane and a second membrane is a filter, the maximum permissible operating pressure corresponds to its highest operating pressure, which depends on its geometry and materials and is typically given by the manufacturer. Furthermore, when the object is a filter, the upstream side of the membrane generally refers to the side of the membrane facing the unfiltered medium (i.e., the feed), while the downstream side of the membrane refers to the side of the membrane facing the filtered material.

[0103] In cases where air in the membrane is removed by displacement of a water-soluble gas through the membrane, the space can be arranged within a fluid-tight sealable chamber. This fluid-tight sealable chamber includes a mounting device, at least one gas inlet connected to at least one source of the water-soluble gas or a component thereof, and at least one gas outlet connected to a vacuum pump, an exhaust outlet, or a gaseous waste container. The at least one gas inlet and the at least one gas outlet can be positioned on different sides of the chamber relative to the mounting device. This arrangement of the at least one gas inlet and the at least one gas outlet on different sides relative to the mounting device results in the flow of the water-soluble gas through the membrane, thereby effectively displacing the air. The mounting device can be positioned in the chamber in such a way that flow bypass is prevented when holding an object having a first membrane and a second membrane. For example, the outer circumferential surface of the mounting device can be fluid-tightly connected to the chamber, and the inner surface of the mounting device can be configured to hold the object and provide a fluid-tight connection with the object. When air is displaced by the flow of the water-soluble gas, at least a portion of a main surface of the membrane can be arranged perpendicular to the flow.

[0104] After the air in the membrane is replaced with a water-soluble gas and before the membrane is wetted with water or an aqueous solution in step (d), preferably, the object having the first and second membranes does not come into contact with air or another gas with lower water solubility than the water-soluble gas. Otherwise, the water-soluble gas located in the membrane, particularly in the voids and grooves of the membrane, will be diluted or completely removed, and the wetting of the first and second membranes in step (d) will not be improved to the same extent. Therefore, it is preferable that there are no additional steps between steps (c) and (d), and that steps (c) and (d) are carried out in the same space. That is, after step (c), the object is not removed from the space, and before step (d), a gas other than the water-soluble gas is not added to the space in which the object is arranged.

[0105] In step (d) of the method for performing a gas / liquid-based integrity test according to the present invention, the first and second membranes of the object are wetted with water or an aqueous solution.

[0106] Wetting the membrane with water or an aqueous solution corresponds to the step of wetting the membrane surface with water or an aqueous solution. This wetting step provides a liquid layer across each membrane. Additionally, by wetting the membrane, any gas within the membrane, particularly in the membrane's voids and grooves, is preferably displaced by water or an aqueous solution. Since modern filters (which represent specific objects having a first membrane and a second membrane) typically have complex geometries of stacked or folded membranes and support layers, it is also important to displace gas from the folds, bends, and stacks of the membrane material.

[0107] There is no particular limitation on the wetting time of the membrane with water or an aqueous solution, as long as the membrane is sufficiently wetted, in order to reduce the occurrence of false negative test results in integrity testing by relying on the liquid membrane provided in and on the membrane. For economic reasons, it may be considered to limit the wetting time to less than 30 minutes, and preferably less than 5 minutes, to increase the number of objects wetted.

[0108] The aqueous solution is water-based and may contain at least one additive. Such additives can improve the wettability of the membrane. For example, membrane wettability can be improved by additives that reduce the surface tension of water. Compositions of various additives that improve membrane wettability and aqueous solutions containing at least one of these additives are known to those skilled in the art. For example, at least one additive selected from glycerol and alcohols (e.g., isopropanol or ethanol) may be added. Some additives may potentially cause an explosive atmosphere and / or may contaminate the water, therefore the aqueous solution containing these additives must be treated separately. To avoid any potentially explosive atmosphere and / or costly disposal of contaminated water, the aqueous solution preferably does not contain glycerol, polyvinylpyrrolidone, or alcohols (e.g., isopropanol and ethanol). The aqueous solution is water-based and has a water content of at least 90% by mass, preferably at least 95% by mass, more preferably at least 98% by mass, and particularly preferably at least 99% by mass.

[0109] Any solids or salts contained in the water or aqueous solution used in step (d) may remain in the membrane after integrity testing and may degrade membrane performance, for example, by blocking the membrane's pores. Such degradation of membrane performance should be especially avoided when testing the integrity of an object prior to its intended use, i.e., in pre-use testing. Therefore, the content of solids and salts in the water or aqueous solution should be low. For example, the content of solids and salts can be evaluated by the total dry residue of the water or aqueous solution. A low total dry residue of water or aqueous solution can be less than 10 mg / L, preferably less than 7 mg / L, more preferably less than 5 mg / L, particularly preferably less than 3 mg / L, and most preferably less than 2 mg / L. The total dry residue of water and aqueous solution is determined according to DIN 38409 H1-1.

[0110] To avoid the formation of any solids or salts in the water or aqueous solution during membrane wetting, the water or aqueous solution preferably does not contain any other compounds that react with the gaseous components of the water-soluble gas or with another compound formed from the dissolved components of the water-soluble gas. Here, water itself is not considered an additional compound that reacts with the gaseous components of the water-soluble gas or with another compound formed from the dissolved components of the water-soluble gas. For example, the water or aqueous solution preferably does not contain components that react with carbonic acid formed from carbon dioxide dissolved in water. That is, the water or aqueous solution preferably does not contain any hydroxides or amines.

[0111] In a preferred embodiment of the method for performing a gas / liquid-based integrity test according to the present invention, (pure) water is used in step (d).

[0112] When (pure) water is used in step (d), an object having a first membrane and a second membrane, such as a filter, can be tested for integrity using the method according to the invention and can subsequently be applied in processes requiring specific water purity standards. That is, the method of the invention can be performed as a pre-use test, and the tested object having a first membrane and a second membrane (e.g., a filter) can be used without any additional steps (e.g., purification). For this purpose, it is preferable to use pure water in step (d).

[0113] In this document, the term "pure water" refers to any water that meets the specifications for water for injection or sterile water for injection. For example, the pure water used in step (d) is water for injection or sterile water for injection as described in European Pharmacopoeia 11.4, 04 / 2024: 0169. Water for injection has a maximum total organic carbon content of 0.5 mg / L and a carbon dioxide emission rate of 2.1 μS·cm at 25 ± 1 °C. -1 Maximum electrical conductivity, bacterial endotoxin content less than 0.25 IU / mL, and optional maximum aluminum content of 10 ppb. Sterile water for injection has a conductivity of 5 μS·cm at 25±1℃. -1 Maximum electrical conductivity, maximum evaporation residue of 0.003%, bacterial endotoxin content of 0.25 IU / mL, and optional maximum aluminum content of 10 ppb, and passed the potassium permanganate test for oxidizable substances and the test for subvisible particles.

[0114] The various measures for wetting the first and second membranes in step (d) of the method for performing a gas / liquid-based integrity test according to the present invention are known to those skilled in the art, and the method is not particularly limited. These measures are based on wetting the membranes by surrounding them with water or an aqueous solution in a space. For example, the step of wetting the membranes may include at least one step of filling the space in which the object is arranged with water or an aqueous solution, and preferably providing water or an aqueous solution flowing through the membranes.

[0115] For the steps of wetting the first and second membranes, the space in which the object is arranged can be located within a fluid-tight sealable chamber. This fluid-tight sealable chamber includes a mounting device, at least one gas outlet connected to a vacuum pump, an exhaust outlet, or a container for gaseous waste, at least one liquid inlet connected to a source of water or an aqueous solution, and at least one liquid outlet connected to a device or liquid pump for treating the water or aqueous solution. When the wetting step involves filling the space in which the object is arranged with water or an aqueous solution, the arrangement of the mounting device, at least one gas outlet, at least one liquid inlet, and at least one liquid outlet is not particularly limited, provided that any component is suitably arranged to perform its function. For example, at least one gas outlet can be located at the highest point of the chamber.

[0116] Step (d) of the method according to the invention preferably includes providing a flow of water or an aqueous solution through the membrane. By providing a flow of water or an aqueous solution through the membrane, the wetting of the membrane is improved compared to simply filling the space with water or an aqueous solution. The flow of water or an aqueous solution is a fluid flow, preferably a laminar fluid flow.

[0117] By adding water or an aqueous solution into a space in the region facing the membrane and creating a pressure difference in that space, the flow of water or an aqueous solution through the membrane can be provided.

[0118] In this application, the pressure difference of water or an aqueous solution in space means that the water or aqueous solution in contact with one side of the membrane has a different pressure than the water or aqueous solution in contact with the opposite side of the membrane, and that the pressure difference is the difference between these two pressures. The pressure difference is not particularly limited, as long as the object having the first and second membranes (e.g., a filter) is not damaged. Therefore, the pressure difference can be adjusted according to the maximum permissible operating pressure of the object having the first and second membranes (e.g., a filter). For example, the pressure difference can be 20% of the maximum permissible operating pressure, and preferably 40% of the maximum permissible operating pressure. The upper limit of the pressure difference is the maximum permissible operating pressure, preferably 90% of the maximum permissible operating pressure.

[0119] The pressure difference can be generated by adding water or an aqueous solution under pressure to a space in the region facing the membrane and discharging the water or aqueous solution from a space in the region facing the membrane. Alternatively, the pressure difference can be generated by adding water or an aqueous solution to a space in the region facing the membrane and pumping the water or aqueous solution out of a space in the region facing the membrane. Furthermore, the pressure difference can be increased by adding water or an aqueous solution under pressure to a space in the region facing the membrane and pumping the water or aqueous solution out of a space in the region facing the membrane.

[0120] At least one gas outlet can be located at the highest point of the chamber. Therefore, water-soluble gases can be easily displaced by water or an aqueous solution within the space. At least one gas outlet can also serve as a liquid outlet. At least one liquid inlet and said at least one liquid outlet can be located on different sides of the chamber relative to the mounting device. The arrangement of said at least one liquid inlet and said at least one liquid outlet on different sides of the chamber relative to the mounting device causes water or an aqueous solution to flow through the membrane, thereby effectively wetting the membrane. The mounting device can be arranged in the chamber in such a way that bypassing of the water or aqueous solution flow is prevented when holding an object having the first and second membranes. For example, the outer circumferential surface of the mounting device can be fluid-tightly connected to the chamber, and the inner surface of the mounting device is configured to hold the object and provide a fluid-tight connection to the object. Therefore, flow through the membrane can be improved. When the membrane is wetted by the flow of water or an aqueous solution, at least a portion of a main surface of the membrane can be arranged in a position perpendicular to the flow.

[0121] In step (d), the wetting of the first and second membranes can be further improved by several measures. For example, wetting can be improved by introducing back pressure or by increasing the flow of water or an aqueous solution through the membranes. Additionally, membrane wetting can be further improved by increasing the wetting time, using wetting agents such as glycerol and polyvinylpyrrolidone, or adding a wetting fluid such as an alcohol (isopropanol or an ethanol-based alcohol). These measures can be performed by those skilled in the art without specific guidance.

[0122] Membrane wetting can be further improved by lowering the water temperature in step (d) and / or by performing step (d) at a pressure higher than atmospheric pressure. Lowering the temperature and performing step (d) at a pressure higher than atmospheric pressure can be done alone or in combination.

[0123] In a preferred embodiment of the method for performing a gas / liquid-based integrity test according to the present invention, step (d) is performed at a temperature below 20°C. This temperature refers to the temperature of the water or aqueous solution in the space where the objects having the first and second membranes are arranged, i.e., the temperature of the water or aqueous solution surrounding the objects having the first and second membranes. Since the solubility of a gas increases as the temperature of the water or aqueous solution decreases, the solubility of water-soluble gases can be improved by performing step (d) at a temperature below 20°C. Improving the solubility of water-soluble gases further improves membrane wetting. Specifically, the more macroscopic and microscopic inclusions of water-soluble gases in the membrane dissolve in the water or aqueous solution applied in step (d), the more the inclusions are reduced. Furthermore, performing step (d) at a temperature below 20°C also accelerates wetting.

[0124] Since the solubility of water-soluble gases is further improved and the wetting of the membrane is accelerated at lower temperatures, the temperature in step (d) can be further reduced. For example, step (d) can be carried out at temperatures below 15°C, preferably below 10°C, and particularly preferably below 5°C.

[0125] The lower limit of the temperature of the water or aqueous solution is limited to above 0°C to avoid freezing of the water or aqueous solution during step (d). Therefore, in step (d), the temperature can be above 0°C and below 20°C, preferably above 0°C and below 15°C, more preferably above 0°C and below 10°C, and particularly preferably above 0°C and below 5°C.

[0126] In a preferred embodiment of the method for gas / liquid-based integrity testing according to the present invention, the temperature is reduced to below 20°C during step (d) while the membrane is being wetted. Here, temperature refers to the final temperature of the water or aqueous solution in step (d). The initial temperature of the water or aqueous solution when starting step (d) is not particularly limited. For example, the initial temperature can be ambient temperature, which is understood herein as 25°C.

[0127] In step (d), the final temperature can be further reduced to further improve the solubility of the water-soluble gas and further accelerate wetting. For example, in step (d), the temperature can be reduced to less than 15°C, preferably to less than 10°C, and particularly preferably to less than 5°C.

[0128] The temperature cannot be lowered to 0°C or lower because water begins to freeze at that temperature. Therefore, in step (d), the temperature may not be lowered to 0°C or lower. That is, in step (d), the temperature may be lowered to above 0°C and below 20°C, preferably above 0°C and below 15°C, more preferably above 0°C and below 10°C, and particularly preferably above 0°C and below 5°C.

[0129] When performing the gas / liquid-based integrity test according to the invention at temperatures below 20°C, or in step (d) where the temperature is lowered to below 20°C while wetting the membrane, the space in which the object is arranged may be provided within a fluid-tight sealable chamber, the fluid-tight sealable chamber comprising at least one mechanism for measuring the temperature of water or an aqueous solution and / or at least one mechanism for controlling the temperature of water or an aqueous solution. Various mechanisms for these purposes are known to those skilled in the art and are not particularly limited thereto.

[0130] In a preferred embodiment of the method for performing a gas / liquid-based integrity test according to the invention, step (d) is performed at a pressure higher than atmospheric pressure. Here, pressure refers to the highest pressure of the water or aqueous solution within the space used to wet the membrane (i.e., the water or aqueous solution surrounding the object having the first and second membranes).

[0131] The solubility of a gas in a liquid generally depends on the applied pressure. Typically, the solubility of a gas increases with increasing pressure. Therefore, increasing the pressure of the water or aqueous solution within the space used for wetting can further improve the solubility of the water-soluble gas applied in step (d) in the water or aqueous solution. Furthermore, applying pressure above atmospheric pressure also accelerates wetting.

[0132] For example, step (d) can be performed at a pressure 0.2 bar or higher than atmospheric pressure, preferably at a pressure 0.5 bar or higher than atmospheric pressure, more preferably at a pressure 1 bar or higher than atmospheric pressure, even more preferably at a pressure 2 bar or higher than atmospheric pressure, and particularly preferably at a pressure 3 bar or higher than atmospheric pressure. Here, pressure refers to the pressure of water or an aqueous solution, and atmospheric pressure refers to the sea-level standard pressure of 1.013 bar (101.3 kPa). That is, step (d) can be performed at a pressure of 1.213 bar (121.3 kPa) or higher, preferably at a pressure of 1.513 bar (151.3 kPa) or higher, preferably at a pressure of 2.013 bar (201.3 kPa) or higher, more preferably at a pressure of 3.013 bar (301.3 kPa) or higher, and particularly preferably at a pressure of 4.013 bar (401.3 kPa) or higher.

[0133] The upper limit of the pressure of water or aqueous solution in the space used for wetting is not particularly limited, and may be limited only by the pressure of the chamber and the object having a first membrane and a second membrane.

[0134] Therefore, the pressure of the water or aqueous solution within the wetting space can be adjusted based on the maximum permissible operating pressure of the object having the first and second membranes (e.g., a filter). For example, the upper limit of the pressure can be the maximum permissible operating pressure or less, preferably 90% or less of the maximum permissible operating pressure, and more preferably 80% or less of the maximum permissible operating pressure. Specific examples of the upper limit of the pressure of the water or aqueous solution within the wetting space are 20 bar or less, preferably 15 bar or less, more preferably 10 bar or less, and particularly preferably 5 bar or less.

[0135] The upper and lower limits of the pressure of the water or aqueous solution in step (d) can be combined as needed. For example, the pressure of the water or aqueous solution can be 1.213 bar or higher and 20 bar or lower, preferably 2.013 bar or higher and 10 bar or lower, more preferably 3.013 bar or higher and 10 bar or lower, and particularly preferably 4.013 bar or higher and 5 bar or lower.

[0136] In a preferred embodiment of the method for performing a gas / liquid-based integrity test according to the present invention, in step (d), pressure is increased while wetting the first and second membranes.

[0137] Here, pressure refers to the highest pressure of the water or aqueous solution (i.e., the water or aqueous solution surrounding the object having the first and second membranes) within a given time period used for wetting the membrane. The pressure can be increased gradually and / or continuously. If the pressure is increased gradually, it can be increased by 1 kPa (10 mbar) or less per step, or by 0.2 kPa (2 mbar) or more per step and 5 kPa (50 mbar) or less per step. The initial pressure of the water or aqueous solution used for wetting in step (d) is not particularly limited. For example, the initial pressure can be atmospheric pressure, i.e., 1.013 bar (101.3 kPa).

[0138] By increasing the pressure of the water or aqueous solution, the solubility of water-soluble gases therein increases. Therefore, the wetting of the membrane is further improved and accelerated. When the pressure of the water or aqueous solution is increased in step (d), the pressure can be increased to 0.2 bar or higher than atmospheric pressure, preferably 0.5 bar or higher, more preferably 1 bar or higher, even more preferably 2 bar or higher, and particularly preferably 3 bar or higher. Here, pressure refers to the pressure of the water or aqueous solution, and atmospheric pressure refers to the sea-level standard pressure of 1.013 bar (101.3 kPa). That is, when the pressure of water or aqueous solution is increased in step (d), the pressure can be increased to 1.213 bar (121.3 kPa) or higher, preferably 1.513 bar (151.3 kPa) or higher, more preferably 2.013 bar (201.3 kPa) or higher, even more preferably 3.013 bar (301.3 kPa) or higher, and particularly preferably 4.013 bar (401.3 kPa) or higher. Here, this value refers to the final pressure reached in step (d).

[0139] When pressure is increased in step (d), the upper limit of the pressure of the water or aqueous solution in the space used for wetting is not particularly limited, and can be limited only by the pressure of the chamber and the object having the first and second membranes. For example, the pressure can be adjusted according to the maximum permissible operating pressure of the object having the first and second membranes (e.g., a filter). For example, the upper limit of pressure can be the maximum permissible operating pressure or less, preferably 90% or less of the maximum permissible operating pressure, and more preferably 80% or less of the maximum permissible operating pressure. Specific examples of the final pressure upper limit are 20 bar or less, preferably 15 bar or less, more preferably 10 bar or less, and particularly preferably 5 bar or less.

[0140] The upper and lower limits of the increased pressure (i.e., the final pressure) of the water or aqueous solution in step (d) can be combined as needed. For example, the pressure of the water or aqueous solution can be increased to 1.213 bar or higher and 20 bar or lower, preferably 2.013 bar or higher and 15 bar or lower, more preferably 3.013 bar or higher and 10 bar or lower, and particularly preferably 4.013 bar or higher and 5 bar or lower.

[0141] In the case where the gas / liquid-based integrity test method according to the invention is performed at a pressure higher than atmospheric pressure or when the pressure is increased while wetting the membrane, the pressure can be measured and adjusted by those skilled in the art using known means. For example, the pressure can be controlled by adding water or an aqueous solution at the desired pressure. Furthermore, the fluid-sealed, sealable chamber arranged in the space of the object having the first and second membranes can be equipped with at least one pressure measuring device.

[0142] In step (e) of the method for performing a gas / liquid-based integrity test according to the invention, a gas pressure of a water-soluble gas is applied to the first membrane.

[0143] In the context of this invention, gas pressure refers to the pressure of a gas, which is a measure of the average linear momentum of the moving molecules of the gas. Applying gas pressure to one side of the first membrane, preferably the upstream side of the first membrane, means that one side of the first membrane is in contact with a gas having a pressure higher than atmospheric pressure. One side of the first membrane refers to the main surface of the first membrane.

[0144] The side of the first membrane to which the applied gas pressure is applied can also be called the test side, and the gas in contact with it can also be called the test gas. The side opposite to the test side is called the reference side, and the gas in contact with it is called the reference gas. The pressure of the reference gas can be atmospheric pressure or lower than atmospheric pressure. The reference gas can be the same as the test gas and can be selected as needed.

[0145] The applied pressure and pressure difference are not particularly limited and depend on the stability of the first and second membranes. Suitable values ​​for the pressure applied to the membranes and the pressure difference are known to those skilled in the art. For example, the gas pressure / pressure difference applied to one side of the first membrane can be from 10 kPa to 500 kPa, preferably from 100 kPa to 500 kPa.

[0146] The test gas is the aforementioned water-soluble gas. Therefore, the above statement regarding the water-soluble gas used to replace air in step (c) of the method according to the invention also applies to the water-soluble gas (test gas) used in step (e). That is, in step (e), a pressure of a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide is applied to the first membrane. In steps (c) and (e), the water-soluble gas can be selected independently, or the same gas can be used.

[0147] Because a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide is used, in step (e), no air or another poorly water-soluble gas is trapped between the first and second membranes. Unlike air (or another poorly water-soluble gas), the water-soluble gas is not trapped between the membranes because it dissolves in the water or aqueous solution of the wetted membrane. Therefore, when the applied pressure is reduced after step (f), the water-soluble gas does not expand between the two membranes because it dissolves in the liquid layer of the still-wet membrane. Thus, in the method of the present invention, defects in the object can be prevented, whereas in conventional methods, the object, particularly its membrane, is damaged due to the expansion of the gas trapped between the membranes. Furthermore, since the water-soluble gas cannot be trapped between the wetted membranes, the membrane surface is fully exposed during subsequent use of the object as a filter, and full filter performance can be achieved.

[0148] When gas pressure is applied to the first membrane, the mounting device is disposed in the chamber, the space being disposed in such a way that flow bypass is prevented when holding an object having the first and second membranes. For example, the outer circumferential surface of the mounting device can be fluid-tightly connected to the chamber, and the inner surface of the mounting device can be configured to hold the object and provide a fluid-tight connection with the object. To apply gas pressure to the first membrane in step (e), it is preferable to use the same space, i.e., the same chamber, as in the preceding steps (a) to (d). Or in other words, between steps (d) and (e), the object having the first and second membranes is not transferred to another space or chamber. Therefore, the chamber described for steps (a) to (d) may, as needed, include at least one additional gas inlet connected to a test gas source, at least one additional gas inlet connected to a reference gas source, and at least one gas outlet. In this case, at least one gas inlet connected to the test gas source and at least one additional gas inlet connected to the reference gas source are disposed on different sides of the chamber relative to the mounting device, while at least one gas outlet is disposed on one or both sides of the chamber relative to the mounting device. Once gas pressure is applied to the first membrane in step (e), the subsequent step (f) is performed in the same space.

[0149] In step (f) of the method for performing a gas / liquid-based integrity test according to the present invention, the integrity of an object having a first membrane and a second membrane is tested by performing a bubble point test.

[0150] Here, testing the integrity of an object means evaluating whether an object with a first membrane and a second membrane, in particular whether its membranes function as required, or detecting the presence of excessively large pores or defects. In the case of a filter, testing integrity also includes assessing whether the filter's retention capacity is affected.

[0151] When performing a bubble point test, no steps already performed in steps (a) through (e) are repeated. That is, performing a bubble point test should be understood as completing the corresponding tests based on steps (a) through (e) that have already been performed. Or in other words, performing a bubble point test means performing at least one test necessary for data collection, evaluating the integrity of the object based on the data, and evaluating the integrity of the object and / or the filter.

[0152] The bubble point test can be performed by someone skilled in the art without further guidance. Nevertheless, the principle of the test is briefly described below, based on which someone skilled in the art can implement any measures necessary to perform the test.

[0153] A wetted membrane provides a liquid layer across which diffuse gas flow occurs, as described by Fick's diffusion law. The gas diffusion flow rate of the membrane is proportional to the pressure difference and the total surface area of ​​the membrane. In a gas-liquid diffusion test, the gas pressure on one side of the membrane increases and the diffusion flow increases linearly until the liquid layer begins to thin or until the bubble point is reached (at which point a steady, large flow of air begins to appear). Automated testing equipment measures whether a filter passes or fails a gas-liquid diffusion test, where excessively large pores or defects in the filter are identified by an increase in flow rate exceeding the effective maximum value.

[0154] In bubble point testing, the pressure of a water-soluble gas is incrementally applied to a wetted membrane, and the gas flow across the membrane is measured at each pressure stage. As the pressure increases, it reaches a point where it exceeds the capillary force of the largest pore in each membrane. The increase in airflow is measured using automated testing equipment as the wetting liquid is expelled and a large volume of gas flow occurs. The measured value corresponds to the bubble point, which is defined as the pressure at which the flow transitions from diffuse flow of wetting liquid through the pores to a large volume flow through the pores. Based on the determined bubble point, the tested membrane is evaluated for pass or fail by comparing the determined value with known literature values ​​for the membrane or filter.

[0155] As needed, the chamber may include additional mechanisms for measuring and controlling parameters related to bubble point testing of the water-soluble gas. Such mechanisms are known to those skilled in the art and may be connected to a space provided by an object having a first membrane and a second membrane, or arranged within the chamber by those skilled in the art without further guidance. For example, the chamber may be provided with at least one pressure measuring device, a mechanism for measuring flow across the membrane, and / or at least one mechanism for analyzing the gas composition. If said at least one mechanism for analyzing the gas composition is provided, it is arranged relative to the mounting device on at least one side of the chamber, preferably the side in contact with the reference gas.

[0156] In addition to steps (a) to (f) described above, the method for performing gas / liquid-based integrity testing according to the present invention may include additional steps. These additional steps are not particularly limited and may be selected by those skilled in the art as needed, depending on the object and membrane to be tested.

[0157] For example, between step (d) and step (e), the method for performing a gas / liquid-based integrity test according to the invention may include an additional step of removing excess water or aqueous solution from the space in which the object is arranged. Here, excess water or aqueous solution refers to water or aqueous solution that is not adhered to the object having a first membrane and a second membrane. In this step, water or aqueous solution adhered to the object is not removed, particularly water or aqueous solution located within the membrane and providing a liquid layer across the membrane. The principles and workflow for removing excess water or aqueous solution are readily known from known gas / liquid-based integrity tests and can be readily modified by those skilled in the art as needed. For example, excess water or aqueous solution can be removed by draining it from the space without removing water or aqueous solution adhered to the object. The excess water or aqueous solution can be drained via the at least one liquid outlet described with respect to step (d).

[0158] In the aforementioned step, excess water or aqueous solution in the space where the object is arranged can be replaced by test gas and / or reference gas as described with respect to step (e). The test gas and reference gas can be provided through at least one gas inlet, as described in step (e). That is, in the step of draining water or aqueous solution, the object having the first membrane and the second membrane is brought into contact with the test gas and / or reference gas. Preferably, the two main surfaces of the membrane are each independently brought into contact with the test gas and / or reference gas.

[0159] The time between steps (d) and (e) is not particularly restricted, as long as the membrane is sufficiently wetted at the start of step (e). That is, step (e) can be performed at any time, as long as the liquid layer across the membrane still exists. When step (e) is performed no later than 1 hour after step (d) is completed, the membrane is sufficiently wetted.

[0160] Following steps (a) to (f), the object having the first and second membranes can be rinsed with water and / or dried. That is, the method for performing a gas / liquid-based integrity test according to the present invention may include at least one of a rinsing step, a drying step, and a water-soluble gas replacement step. For example, the method for performing a gas / liquid-based integrity test may further include a rinsing step, a drying step, and a water-soluble gas replacement step in a given order, or a rinsing step and a drying step, or a rinsing step and a water-soluble gas replacement step, or a drying step and a water-soluble gas replacement step.

[0161] When a rinsing step is performed, the rinsing step is performed after step (f), preferably directly after step (f).

[0162] During the rinsing step, potential residues of water-soluble gases present on or within an object having a first and a second membrane, particularly in or on the membrane, can be partially or completely removed. Residues of water-soluble gases can be any gaseous component of the water-soluble gas or components formed by the reaction of any gaseous component with water or an aqueous solution. For example, carbonic acid, bicarbonate, and carbonate formed by the reaction of carbon dioxide with water or an aqueous solution represent potential residues. Here, rinsing means surrounding the object and / or membranes having a first and a second membrane with water.

[0163] Several methods for rinsing an object having a first membrane and a second membrane are known to those skilled in the art. These measures are based on surrounding the membrane with water, for example, in a space used for wetting. For example, the step of rinsing the membrane with water may include at least one step of filling the space surrounding the object with water, and preferably providing a flow of water through the membrane.

[0164] In this invention, the method of rinsing with water is not particularly limited. For example, the rinsing step can be performed similarly to step (d) of wetting the first and second membranes as described above. For example, the rinsing step may include at least one step of filling the space in which the object is arranged with water and providing a flow of water through the membrane. The water used in the rinsing step may be water for injection or sterile water for injection as described in European Pharmacopoeia 11.4, 04 / 2024: 0169.

[0165] When a drying step is performed, the drying step is performed after step (f), preferably directly after step (f) or directly after the rinsing step.

[0166] During the drying step, potential residues of water and water-soluble gases present on or in an object having a first and a second membrane, particularly in or on the membranes, can be partially or completely removed. Residues of water-soluble gases can be any gaseous component of the water-soluble gas or components formed by the reaction of any gaseous component with water or an aqueous solution. For example, carbonic acid, bicarbonate, and carbonate formed by the reaction of carbon dioxide with water or an aqueous solution represent potential residues. Several methods for drying objects having a first and a second membrane are known to those skilled in the art.

[0167] In this invention, the drying method is not particularly limited. For example, the drying step may include at least one of air drying, dry air treatment and temperature increase, and a combination of applying vacuum and microwave radiation. Preferably, the object having a first membrane and a second membrane is dried by a combination of applying vacuum and microwave radiation. With this combined treatment, the object is effectively dried, and if the water-soluble gas applied in step (c) contains carbon dioxide, carbon dioxide and / or carbonic acid that may remain in the membrane are effectively removed from the membrane.

[0168] When a water-soluble gas replacement step is performed, the water-soluble gas replacement step is performed after step (f), preferably directly after step (f) or directly after the drying step.

[0169] In the water-soluble gas replacement step, any residual water-soluble gas or its gaseous components can be replaced in the membrane by air, preferably sterile air. The water-soluble gas replacement step can be performed similarly to step (c), wherein any potential residues of the water-soluble gas or its gaseous components are replaced by air. For example, replacing residual water-soluble gas in the membrane can be done by removing it through a vacuum and introducing air, or by displacing it with a stream of air. In this document, the above-provided definitions of step (c) of the method for gas / liquid-based integrity testing according to the present invention are equally applicable to the water-soluble gas replacement step.

[0170] The method for performing gas / liquid-based integrity testing according to the present invention can be used as a pre-use test and / or a post-use test. That is, the integrity of an object having a first membrane and a second membrane can be tested before and / or after use using the method of the present invention. In the case where the object having the first membrane and the second membrane is a filter, the integrity of the filter can be tested before and / or after it is used for filtration using the method of the present invention.

[0171] In another aspect of the invention, a method is provided for preparing an object having a first membrane, a second membrane, and at least one boundary member, having undergone an integrity test, the method comprising the steps (I) to (III) in sequence:

[0172] (i) providing a first membrane, a second membrane, and at least one boundary member; (ii) Connecting the peripheral regions of the first membrane and the peripheral regions of the second membrane to the at least one boundary member to prepare an object having the first membrane and the second membrane; and (iii) The integrity test is performed on the object having the first membrane and the second membrane by performing any of the methods described above.

[0173] In this document, the definitions provided above for the method of performing gas / liquid-based integrity testing according to the present invention are equally applicable to the method of preparing an object having undergone integrity testing according to the present invention, having a first membrane and a second membrane. This is particularly true for components of objects having a first membrane and a second membrane (e.g., filters) and for performing gas / liquid-based integrity testing. By performing the preparation method according to the present invention, an object having undergone integrity testing, having a first membrane and a second membrane, can be obtained without unnecessary repetition of integrity testing, without the risk of damaging the object when reducing pressure after completing the integrity test, and without degrading filter performance due to gas trapped between the membranes.

[0174] The following describes in detail the method and specific process steps for preparing an object having a first membrane and a second membrane that has undergone integrity testing according to the present invention.

[0175] In step (I) of the preparation method according to the invention, a first membrane, a second membrane, and at least one boundary member are provided. In addition to these basic components, a backflow protector and / or core may be provided as additional components in step (I). Furthermore, one or more discharge members or supporting nonwoven fabrics may be provided as additional components in step (I). These additional components, if present, are suitably arranged in or on the membrane.

[0176] In step (II) of the preparation method according to the invention, the peripheral regions of the first membrane and the second membrane are connected to the at least one boundary member to prepare an object having the first membrane and the second membrane. By performing step (II), an object having the first membrane and the second membrane, such as a filter, is obtained. Various different means can be applied for this, including embedding, overmolding, hydrophobic adhesive bonding, or ultrasonic welding, depending on the shape of the membrane and the shape of the at least one boundary member. As needed, for example, in the case of embedding, the at least one boundary member is at least partially softened to allow connection. Softening can be achieved by point heat input at those locations of the at least one boundary member where it will be connected to the membrane. Suitable means for ensuring point heat input are described in the art. In this respect, the heat input is conventionally adjusted by those skilled in the art according to the material of the at least one boundary member.

[0177] For example, in the case where the membrane has a tubular shape and the at least one boundary member is an end cap, after softening, the at least one boundary member can be placed on the peripheral region of the membrane and any additional components (if present) for embedding. As described above, in the case where there are two open end faces, each of the two open end faces of the membrane can be embedded in the corresponding boundary member. After embedding, the at least one boundary member having the peripheral region of each membrane embedded therein is cooled to ambient temperature, which is understood herein as a temperature of 25°C.

[0178] For example, in the case where the membrane has a flat shape and the at least one boundary member is a frame, the at least one boundary member can be attached to the peripheral area of ​​each membrane and any additional components (if present) by overmolding, hydrophobic adhesive or ultrasonic welding, but is not limited to such means.

[0179] In step (III) of the preparation method according to the present invention, the integrity of the object having the first membrane and the second membrane is tested by performing the gas / liquid-based integrity test method of the present invention.

[0180] By using the gas / liquid-based integrity testing method according to the present invention, the number of false negative integrity tests can be reduced, the risk of damage to the object when the pressure is reduced after the integrity test is completed can be reduced, and the filter performance can be prevented from being reduced due to gas trapped between membranes.

[0181] Therefore, the number of membrane-containing objects (e.g., filters) that are incorrectly assessed as lacking integrity in conventional manufacturing methods is reduced, and fewer membrane-containing objects must be tested according to a two-step procedure (i.e., by repeating integrity tests). Thus, the number of integrity tests performed is reduced by the manufacturing method according to the invention, resulting in cost savings and increased production capacity. Furthermore, the risk of presuming a filter to be defect-free while filtering with a defective filter can be avoided. Therefore, PUPSIT can be used for multilayer filters, such as dual-layer filters.

Claims

1. A method for performing gas / liquid-based integrity testing, the method comprising the following steps (a) to (f): (a) Providing an object having a first membrane and a second membrane; (b) Arrange the object in a space for wetting; (c) The air in the first membrane and the second membrane is replaced by a water-soluble gas containing at least 15 vol.% carbon dioxide and / or nitrous oxide; (d) Wet the first and second membranes of the object with water or an aqueous solution; (e) Applying the gas pressure of the water-soluble gas to the first membrane; as well as (f) The integrity of the object is tested by performing a bubble point test.

2. The method for performing a gas / liquid-based integrity test according to claim 1, wherein water is used in step (d).

3. The method for performing a gas / liquid-based integrity test according to claim 2, wherein the water is water for injection or sterile water for injection.

4. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 3, wherein the water-soluble gas comprises carbon dioxide.

5. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 4, wherein the water-soluble gas is carbon dioxide.

6. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 5, wherein the membrane comprises a hydrophobic material, wherein the hydrophobic material is a material having a contact angle with a water droplet greater than 90° as determined according to DIN 55660-2.

7. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 6, wherein step (c) comprises at least one of the following cycles: Step (c1) involves removing air from the space by applying a vacuum, and Step (c2) involves filling the evacuated space with the water-soluble gas.

8. A method for performing a gas / liquid-based integrity test according to any one of claims 1 to 6, wherein step (c) comprises displacing air by the flow of the water-soluble gas through the membrane.

9. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 8, wherein step (d) is performed at a temperature below 20°C.

10. A method for performing a gas / liquid-based integrity test according to any one of claims 1 to 8, wherein in step (d), the temperature is reduced to below 20°C while the membrane is being wetted, wherein optionally, the temperature is reduced gradually and / or continuously.

11. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 10, wherein step (d) is performed at a pressure of 0.2 bar or higher than atmospheric pressure.

12. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 10, wherein in step (d), the pressure is increased to 0.2 bar or higher above atmospheric pressure while wetting the membrane, wherein optionally, the pressure is increased gradually and / or continuously.

13. The method for performing a gas / liquid-based integrity test according to any one of claims 1 to 12, wherein the object is a filter.

14. A method for producing an object having undergone an integrity test, comprising steps (I) through (III): (I) Providing a first membrane, a second membrane, and at least one boundary member; (II) Connecting the peripheral regions of the first membrane and the peripheral regions of the second membrane to the at least one boundary member to produce the object having the first membrane and the second membrane; as well as (III) The object having the first membrane and the second membrane is subjected to an integrity test by performing the method according to any one of claims 1 to 13.