Method for improved sensitivity of integrity tests of filters in assemblies

Abstract

The invention is directed toward new methods for improving sensitivity of integrity tests of filters in assemblies.

Description

METHOD FOR IMPROVED SENSITIVITY OF INTEGRITY TESTS OF FILTERS IN ASSEMBLIESRelated Applications

[0001] The present application claims the benefit of priority of U.S. provisional patent application no.: 63 / 662,007, filing date June 20, 2024, the entire content of which is incorporated herein by reference in its entirety.Background

[0002] The gas-liquid (often air-water) integrity test is commonly used to assess the integrity of filters. Gas pressurized to below the wetted filter bubble point is applied to the upstream volume of a wetted filter, forcing diffusive gas flow through the liquid layer of the integral filter. If a filter defect exists, the convective flow through the defect will elevate the measured flow rate, and the excess flow rate is a signal for a leak.

[0003] Automated integrity testers are typically used for this purpose and can be directly connected to the filters. The integrity testers work on the principle of pressure decay measurement of the upstream side of the filter to infer the diffusive flow rate across the filter. In single use assemblies (or housings), however, there is usually plumbing (in the form of flexible tubing) and other connections between the integrity tester and the filter. Upon pressurization, the tubing can expand, and some gas can also permeate across the walls of the tubing or the device housing. This added pressure decay interferes with the measurement of the diffusive flow rate across the filter, as any potential excess flow rate through the filter resulting from a defect is confounded by the added flow rate or pressure decay associated with the system during the measurement. In addition, the pressure decay measurement can be influenced by any temperature changes within the system during the testing. These noise elements result in reduced defect detection sensitivity as there is reduced ability to separate the test defect signal (excess flow rate) from the background flow rate, also referred to as background noise, associated with the test.

[0004] Thus, what is needed in the art are improved methods of integrity testing of filters by reducing background noise in a measured flow rate compared to methods of gas-liquid integrity tests presently used in in the art, thereby improving sensitivity of the test to detect smaller defects.Summary of the invention

[0005] Some embodiments of the method described herein comprise increasing the defect detection sensitivity of a gas-liquid diffusion integrity test for filters by reducing the background noise of the test and thereby improving the signal (excess diffusive flow rate) to noise (background flow rate not associated with the filter itself, but instead associated with rest of the assembly, e.g., plumbing, connections, permeation) ratio of the test. In some embodiments, the method is used for single use systems that utilize flexible tubing and other components connected to the filter, which are known in the art to add background noise to the measured flow rate. In some embodiments, the method is used for systems with relatively small filters with a small integral filter diffusive flow rate, relative to the added background noise of the single use system tubing and components. In some embodiments, a relatively small filter has an area less than or equal to (<) 1000 cm2.

[0006] In some embodiments, the method allows for the integrity test of the filter in place within the system, without the need to disconnect the filter from the system to test it separately. In some embodiments, the test for background noise needs be run only once for a given plumbing and connection configuration, to determine the plumbing / connection contribution, which can then be used to establish as system specific integrity test specification.

[0007] In some embodiments, the method of testing the integrity of a filter, the method comprising:(a) providing: i) a filter assembly for testing, ii) an integrity testing instrument, and iii) a pressure generating source;(b) fluidly connecting the integrity testing instrument and the pressure generating source to the inlet of the filter for testing;(c) wetting the filter and then applying pressure to the filter assembly from the pressure generating source with both an inlet and an outlet of the filter assembly open;(d) measuring the pressure decay of the upstream side of the filter with the integrity testing instrument to determine the total system flow rate across the wet filter;(e) comparing the total system flow rate across the wet filter to the background flow rate noise across at least one identical dry filter assembly determined by applying pressure to the at least one dry filter assembly with the inlet of the assembly open and the outlet of the assembly closed to determine the background flow rate; and,(f) subtracting the value of the background flow rate from the total system flow rate generated testing the wet filter assembly to determine excess flow rate and the integrity of the wet filter.

[0008] In some embodiments, the method further comprises measuring the background flow rate for more than one dry filter assembly. In some embodiment, the method further comprises averaging the individual measurements of background flow rate for the more than one dry filter assembly. In some embodiments, an average of the background flow rate for the more than one dry filter assembly is the value subtracted in step (f).

[0009] In some embodiments, the background flow rate of the dry filter assembly is from historic data.

[0010] In some embodiments, the background flow rate of the dry filter assembly is determined by using a non-porous membrane in an otherwise identical filter assembly.

[0011] In some embodiments, the background flow rate of the dry filter assembly is determined by using an identical wetted filter membrane and wherein the outlet is closed in an otherwise identical filter assembly.

[0012] In some embodiments, the integrity testing instrument is an automatic integrity testing (AIT) device.

[0013] In some embodiments, the pressure generating source is integral with the integrity testing instrument.

[0014] In some embodiments, at least a part of the connection to fluidly connect the integrity testing instrument to the filter comprises tubing. In some embodiments, at least a part of the connection to fluidly connect the integrity testing instrument to the filter comprises tubing and the tubing may be resiliently flexible. In some embodiments, tubing may be made of any one or more of plastic, synthetic rubber, or natural rubber.

[0015] In some embodiments, where the method further comprises when testing the integrity of the wet filter, a flow meter is fluidly connected to an outlet of the filter assembly.

[0016] In some embodiments, the pressure used to test the filter assembly is applied at approximately 20 to approximately 100 psi, at approximately 30 to approximately 50 psi, or at approximately 35 to approximately 45 psi. In some embodiments, the pressure is applied at approximately 40 psi.

[0017] In some embodiments, the method is conducted at a temperature within the range of approximately 4 °C to approximately 40 °C. In some embodiments, the method is conducted at ambient temperature.

[0018] In some embodiments, the filter assembly further comprises an upstream vent wherein the inlet is one or both of a filter inlet or a vent inlet and wherein if only one of the filter inlet or vent inlet is open, and the other is closed.

[0019] In some embodiments, the wetting fluid is selected from an aqueous solution, alcohol and an alcohol / water mixture.

[0020] In some embodiments, the pressure generating force is a gas. In some embodiments, the gas is nitrogen or air.Description of the Figures

[0021] Figure 1A and Figure 1 B) illustrate the principle of the gas / diffusion integrity test. Figure 1 A illustrates some embodiments of a wetted membrane that provides a liquid layer across which diffusionflow occurs. Figure 1 B illustrates that an excess measured gas flow rate is a signal for a defect.

[0022] Figure 2 shows some embodiments of a filter within a single-use assembly connected to an automated integrity tester. Arrows indicate potential sources of flow as interpreted by the automated integrity tester due to pressure changes in the system associated with permeation across system components, component expansion, or temperature changes.

[0023] Figure 3A and Figure 3B show: Figure 3A - an illustration of some embodiments of an automated integrity test (AIT) system (e.g. MilliporeSigma Integritest® 5) connected to a filter assembly with the inlet and outlet of a dry filter assembly and the assembly ports closed by port caps. For example, some embodiments of the configuration used to measure the background noise; and Figure 3B - an illustration of some embodiments of the same system as (A) with a wetted filter assembly connected to a mass flow meter. For example, some embodiments of the configuration used to establish the total system flow rate.

[0024] Figure 4 shows MilliporeSigma Integritest® 5 flow rate measurements at 40 psi of the background (State 1 , Figure 3A configuration) and total system flow rate (State 2, Figure 3B configuration) using a Millipak®-200 filter assembly at multiple integrity testing stabilization time points. Figure 4 further shows the corresponding diffusive flow measurements using a mass flowmeter.

[0025] Figure 5 shows a graph of air flow rate vs. time for a wetted Millipak®-200 device pressurized at 40 psi with air illustrating the air / water diffusion integrity test stabilization time required for this filter device format ( / .e., 20 minutes).Detailed Description of the Invention

[0026] Before describing the embodiments in further detail, a number of terms will be defined.

[0027] When introducing elements of the present disclosure or the preferred embodiments(s) thereof, the articles "a," "an," "the" and"said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0028] Furthermore, the transitional phrases “comprising,” “consisting essentially of” and “consisting of” have the meanings as given in MPEP 2111.03 (Manual of Patent Examining Procedure; United States Patent and Trademark Office, 9th Ed., Revision Feb 2023 [R-07.2022]). Any claims using the transitional phrase “consisting essentially of” will be understood as reciting only essential elements ( / .e., the basic and novel characteristics) of the invention and any other elements recited in dependent claims are understood to be non-essential to the invention recited in the claim from which they depend. Likewise, any additional elements over those claimed that are described in a prior art reference(s) are excluded from the claims by use of the transitional phrase “consisting essentially of” as being non-essential to the claimed invention.

[0029] The expression “integral” as used herein when referring to porous materials such as a porous single layer or porous membrane, porous multilayers, or a plurality of porous membranes, means a nondefective porous material.

[0030] The expression “non-integral” or as used herein when referring to porous materials such as a porous single layer or porous membrane, porous multilayers, and a plurality of porous membranes means a defective porous material. Non-limiting examples of defects in a porous layer or membrane include, but are not limited to, oversized pores, improper bonding (e.g., delamination or separation) between a plurality of porous layers or membranes that are bonded together to form a multilayer element, and defects on the porous layer or porous membrane.

[0031] The expression “porous material,” as used herein, may include, but is not limited to, one or more porous membranes, sheets, rods, discs, tubes, layers, filters, filter elements, filtration media, containers, cylinders, cassettes, cartridges, columns, chips, beads, plates,monoliths, hollow fibers, and combinations thereof. The porous materials may be pleated, flat, spirally wound, and combinations thereof. It may be a single layered or multilayered membrane device. The membrane may be symmetric or asymmetric. The porous material may be contained in a assembly or housing, which may have an inlet and an outlet. It may be used for filtration of unwanted materials including contaminants such as infectious organisms and viruses, as well as environmental toxins and pollutants. The porous material may be comprised of any suitable material, including, but not limited to polyether sulfone, polyamide, e.g., nylon, cellulose, polytetrafluoroethylene, polysulfone, polyester, polyvinylidene fluoride, polypropylene, a fluorocarbon, e.g., poly (tetrafluoroethylene-co- perfluoro(alkyl vinyl ether)), poly carbonate, polyethylene, glass fiber, polycarbonate, ceramic, and metals.

[0032] Embodiments disclosed herein include a method for integrity testing porous materials, including porous single layer materials, porous materials having a multi-layered configuration, porous membranes and filters. The porous material(s) of this invention may interchangeably be referred to as a “filter,” or “filter material.” The porous material may be in an assembly or housing providing a feed or inlet side or inlet port and a permeate or outlet side or outlet port. The filter assembly may also comprise a vent on the upstream and / or downstream side of the filter. In one embodiment, the gas used to test the filter assembly is air or nitrogen. In certain embodiments, the porous material is “wetted” or “wet” ( / .e., the pores in the material are filled) with a liquid, such as water, alcohol or an alcohol / water mixture and a first surface of the wetted porous material to be tested is contacted, under pressure, with the test gas. In certain embodiments, the test gas may be humidified and the liquid used to humidify the test gas is the same as the liquid used to wet the porous material.

[0033] In some embodiments, the porous material is wetted with a liquid (a “wetting liquid”) by saturating the porous material with the liquid. Suitable liquids include water, isopropyl alcohol and mixtures ofisopropyl alcohol and water. Other liquids also could be used depending on desired cost or convenience of using the liquid.

[0034] In some embodiments, the suitable temperatures for carrying out the integrity test is within a range from about 4° C. to about 40° C. In some embodiments, the temperature for carrying out the integrity test is within a range between about 22 - 24° C or at ambient temperature.

[0035] In some embodiments, a suitable feed pressures range from about 15 psig to about 100 psig. In some embodiments, a suitable feed pressure is selected from a range of about 30 - 70 psig. In some embodiments, a suitable feed pressure is about 40 psig. The selection of a suitable temperatures may be dependent upon the filter material or other physical parameters and can be determined by one of ordinary skill in the art.

[0036] A commonly applied nondestructive integrity test for membrane filters, especially sterilizing and virus filters, is the gas-liquid diffusion test. As illustrated in Figure 1A, a wetted membrane provides a liquid layer across which diffusive flow occurs in accordance with Fick's law of diffusion (eq 1 ), expressed below:(eq 1 )

[0037] where Q is the permeation flow rate, A is the membrane area, s is the membrane porosity, D is the diffusivity of the gas in the liquid, S is the solubility coefficient of the gas, Pf and Ppare the feed and permeate side pressures, T is the pore tortuosity, and L the thickness of liquid in the membrane. The test pressure for a gas-liquid diffusion test must be below the membrane bubble point, that is, the minimum pressure at which the pores will be evacuated of liquid. As shown in Figure 1 B, a measured gas flow rate in excess of that predicted by eq 1or higher than a flow rate empirically established for an integral membrane is a signal for a defect.

[0038] The sensitivity of this test is limited by the minimum detectable excess flow rate. There can be device-to-device variability in gas diffusion flow rates of integral membrane filter devices due to differences in membrane area, membrane thickness, membrane porosity, and pore tortuosity. Other factors such as thinning of the liquid due to evaporation, liquid retention in membrane support layers (porous nonwovens, for example), and membrane movement or compression can also affect measured gas diffusion rate. This variability in gas flow rate acts as background flow rate, also referred to as background noise, that can diminish the sensitivity of the gas-liquid diffusion test

[0039] In addition to the background noise factors inherent to the filter, there can be background noise associated with components external to the filter membrane. Automated integrity testers are often employed for running filter gas-liquid integrity tests, with the diffusion rate typically determined by pressurizing the upstream volume of the filter, isolating that upstream volume, and measuring the rate of pressure decay of the upstream volume as gas flows from the upstream side to the downstream side of the filter which is typically open to atmosphere. The upstream volume between the integrity tester and the filter can, as is often the case in single-use assemblies, include flexible tubing connecting the filter to the integrity tester. This tubing can expand upon pressurization and can also be permeable to the test gas. The tubing expansion will impact the pressure decay and permeation of gas through the tubing will also increase the rate of pressure decay, in effect adding background noise to the determination of flow rate and thereby further diminishing the sensitivity of the integrity test.

[0040] In some embodiments, the method of this invention quantifies the background noise associated with components external to the filter and between the filter and the integrity tester, thereby reducing the impact of these noise factors on the sensitivity of the integrity test to detect defects. The background noise effects external to the filter (e.g.,tubing expansion, permeation through tubing, permeation through filter assembly or housing materials, temperature changes) are measured first, and then subtracted out from the total flow rate determined for the filter assembly during the gas / liquid diffusion test.

[0041] A schematic of a filter within a single-use assembly connected to an automated integrity tester is shown in Figure 2. Between the filter 2 and the integrity tester 1 are various tubing and connection components such that there is fluid communication between that filter and integrity tester. As part of the integrity test, the volume between the wetted filter and the integrity tester if filled with pressurized test gas. Any expansion of this volume or leaks of gas through any of the components or any transient temperature changes will contribute to the flow rate as determined by the integrity tester. This is in addition to the flow through the wetted filter and in the prior art method acts as background noise that reduces the sensitivity of the test.

[0042] In some embodiments, the background noise is based on historic data for a given filter or filter assembly. One way in which historic data can be provided is as follows. Multiple measurements of identical dry assemblies (e.g., 5 or more) can be used to establish the background noise for an assembly design. Then, the air diffusion specification for a given filter size is added to establish the specific air diffusion specification for an assembly. The wetted filter assembly integrity test is then conducted and compared to this assembly specification. If the value is below it, the assembly passes, if the value is above it, the assembly fails.

[0043] In some embodiments of the method, the apparent flow rate through all the components between the integrity tester and filter outlet as determined by the integrity tester is measured as a separate step. This can be done by closing the outlet of the dry filter assembly / housing (position 3 in Figure 2) and proceeding with the integrity test protocol. Since the system is closed, any measured flow rate can be attributed to the components of the assembly, including the filter itself. This procedure is repeated with the outlet of the filter open and with a wetted filter, such that the diffusive flow through the filter isincluded in the flow rate measurement. The diffusive flow rate through the filter can be determined by subtracting the measured flow rate of a dry filter assembly with a closed outlet from that with a wetted filter assembly with an open outlet.

[0044] Some embodiments of the methods can be used to eliminate the contribution of the diffusive flow through the filter from the apparent flow rate in the components between the integrity tester and the filter. In one embodiment, a filter device with an impermeable filter 2 (no diffusive flow through the filter) is used as shown in Figure 2. In some embodiments, a filter in which the pathway between the filter inlet and outlet is blocked can be used. In another embodiment, the integrity test is first run with a wet filter and the outlet of the filter closed, so that the pressure in the system quickly reaches equilibrium.

[0045] For a given system configuration, the flow rate associated with the filter assembly only needs to be determined once, and this value can be used to subtract from the flow rate determined with the wetted filter in place. In some embodiments, a system or single use assembly design specific integrity test specification can be established by adding the filter-only integrity test specification to the background flow rate measured for the plumbing between the filter and the integrity tester. In some embodiments, the method will not only identify leaks through the filter, but through any part of the assembly between the integrity tester and the filter.ExemplificationExample 1

[0046] A Millipak®-200 (0.22 pm filter with 1000 cm2filtration area in a single use assembly) using a MilliporeSigma (Burlington, MA) Integritest® 5 filter integrity test instrument or equivalent (the terms “instrument,” “device” and “tester” are used interchangeably herein when referring to an integrity testing instrument) was used to demonstrate the feasibility of the described method. The system was set up as in Figure 2 with a simplified depiction as shown in Figure 3A. The outlet of the filter and any assembly ports were capped to preventair flow through the filter or assembly ports during this background noise measurement. Using a standard integrity test protocol at 40 psig (pounds per square inch gauge) inlet pressure, the apparent diffusive flow rate (background noise) was measured over several integrity test stabilization times (2, 10 and 20 minutes) to quantify any timedependent noise factors (e.g., transient temperature changes). The background noise associated with the dry assembly decreased with time as can be seen by the state 1 group of bars in Figure 4. Next, the air / water diffusion value of the wetted filter in the assembly was measured at 40 psig using the same integrity testing times as the dry testing (Figure 3B and Figure 4 State 2). During this testing, a mass flow meter on the downstream side of the filter was used to independently quantify the diffusive flow rate through the device. A downstream flow measurement is considered to be the gold standard for diffusive flow measurements as it measures only the flow across the membrane and is independent of any upstream noise factors. It was observed that, independent of the background noise factors, a certain amount of equilibration time was needed (approximately 20 minutes) to achieve a stable diffusive flow rate, as measured by the independent mass flow meter measurement (Figure 5). By subtracting the 20- minute assembly + dry filter noise from the 20 minute assembly + wetted device air / water diffusion measurement, the air / water diffusion value as measured by the automated integrity tester, matched the independent mass flow meter measurement.Example 2

[0047] Millipak®-20, Millipak®-40, Millipak®-60, Millipak®-100, Millipak®-200 (0.22 pm filter with 100 to 1000 cm2filtration area in a single use assembly) using a MilliporeSigma (Burlington, MA) Integritest® 5 filter integrity test instrument or equivalent (the terms “instrument,” “device,” and “tester” are used interchangeably herein when referring to an integrity testing instrument) was used to demonstrate the feasibility of some embodiments of the described method. Five (5) identical assemblies were constructed for each filtersize tested. State 1 (Figure 3A) was measured for each assembly. Next, State 2 (Figure 3B) was measured for each assembly.

[0048] Prior art methods would compare State 2 to the Filter Specification which defines the maximum air diffusion test flow rate acceptable for an integral filter. Based on the prior art methods, integral Millipak®-20, Millipak®-40, and Millipak®-60 assemblies would have failed the test, highlighting the negative impacts of background noise associated with components external to the filter membrane on the sensitivity of the integrity test.

[0049] The test described herein uses the Assembly specification (Filter spec. + State 1) when using State 2 to determine if the system is integral. If State 2 is less than the Assembly specification, the system passes the test. To confirm the contribution of the filter diffusive flow alone, a mass flow meter was used to compare to State 2 minus State 1.

[0050] Table 1 shows the results for the range of filter sizes (100-1000 cm2) tested within assemblies designed for each filter size. Flow rate measurements at 40 psi of the background (State 1 , Figure 3A configuration) and total system flow rate (State 2, Figure 3B configuration) are shown compared to the filter integrity test specification (historic methodology: if State 2 < filter specification = integral filter) and the assembly specific specification (novel methodology: if State 2 < assembly specification = integral filter) where the assembly specific specification adds state 1 to the filter specification. The filter assembly specification flow rate (State 2 - State 1) was confirmed by a mass flow meter measurement.Table 1

[0051] Therefore, each of the tested filter passed the integrity test using an embodiment of the method described herein.

Claims

ClaimsWe claim :1 . A method of testing the integrity of a filter, the method comprising: a. providing: i) a filter assembly for testing, ii) an integrity testing instrument, and iii) a pressure generating source; b. fluidly connecting the integrity testing instrument and the pressure generating source to the inlet of the filter for testing; c. wetting the filter and then applying pressure to the filter assembly from the pressure generating source with both an inlet and outlet of the filter assembly open; d. measuring the pressure decay of the upstream side of the filter with the integrity testing instrument to determine the total system flow rate across the wet filter; e. comparing the total system flow rate across the wet filter to the background flow rate noise across at least one identical dry filter assembly determined by applying pressure to the at least one dry filter assembly with the inlet of the assembly open and the outlet of the assembly closed to determine the background flow rate; and, f. subtracting the value of the background flow rate from the total system flow rate generated testing the wet filter assembly to determine excess flow rate and the integrity of the wet filter.

2. The method of claim 1 , wherein the background flow rate of the dry filter assembly is historic data.

3. The method of any one of claims 1 and 2, wherein the background flow rate of the dry filter assembly is determined by using a non-porous membrane in an otherwise identical filter assembly.

4. The method of any one of claims 1-3, wherein the background flow rate of the dry filter assembly is determined by using an identical wetted filter membrane and wherein the outlet is closed in an otherwise identical filter assembly.

5. The method of any one of claims 1-4, wherein the integrity testing instrument is an automatic integrity testing (AIT) device.

6. The method of any one of claims 1-5, wherein said pressure generating source is integral with the integrity testing instrument.

7. The method of any one of claims 1 -6, wherein at least a part of the connection to fluidly connect the integrity testing instrument to the filter comprises tubing.

8. The method of claim 7, wherein said tubing is resil iently flexible.

9. The method of claim 8, wherein said resiliently flexible tubing is made of plastic, synthetic rubber or natural rubber.

10. The method of any one of claims 1 -9 further comprising, wherein, when testing the integrity of the wet filter, a flow meter is fluidly connected to an outlet of the filter.11 . The method of any one of claims 1-10, wherein said pressure is applied at approximately 20 to approximately 100 psig.

12. The method of any one of claims 1-10, wherein said pressure is applied at approximately 30 to approximately 50 psig.

13. The method of any one of claims 1-10, wherein said pressure is applied at approximately 35 to approximately 45 psig.

14. The method of any one of claims 1-10, wherein said pressure is applied at approximately 40 psi.

15. The method of any one of claims 1-14, wherein said method is conducted at approximately 4 °C to approximately 40 °C.

16. The method of any one of claims 1-14, wherein said method is conducted at ambient temperature.

17. The method of any one of claims 1-16, wherein said filter assembly further comprises an upstream vent where in the inlet is one or both of a filter inlet or a vent inlet and wherein, if only one of the filter inlet or vent is used as the inlet, the other is closed.

18. The method of any one of claims 1-17, wherein said wetting fluid is selected from alcohol and an alcohol / water mixture.

19. The method of any one of claims 1-18, wherein said pressure generating force is a gas.

20. The method of claim 19, wherein said gas is nitrogen or air.21 . The method of any one of claims 1-20, further comprising measuring the background flow rate for more than one dry filter assembly.

22. The method of claim 21 , further comprising averaging the individual measurements of background flow rate for the more than one dry filter assembly.

23. The method of claim 22, wherein an average of the background flow rate for the more than one dry filter assembly is the value subtracted in step (f).

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