Method and system for testing integrity of a filter
By pressurizing and checking the flow rate upstream of the filter, combined with variable check duration and multi-stage stop criteria, the problems of low efficiency and insufficient reliability in filter integrity testing are solved, resulting in faster and more accurate test results.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SARTORIUS STEDIM BIOTECH GMBH
- Filing Date
- 2021-12-23
- Publication Date
- 2026-06-16
AI Technical Summary
Existing filter integrity testing methods are inefficient and unreliable, especially in non-destructive testing where it is difficult to obtain reliable test results in a short time.
By pressurizing the upstream side of the filter to the test pressure and performing a flow check after the stabilization phase, the flow measurement accuracy is ensured by dynamically adjusting the check steps based on the reliability of the flow rate using variable check duration and multi-stage stop criteria.
It improves the time efficiency and reliability of filter integrity testing, ensures the accuracy and speed of test results, and adapts to flow rate changes under different test conditions.
Smart Images
Figure CN116669784B_ABST
Abstract
Description
Technical Field
[0001] The following description relates to methods, media, and systems used in the pharmaceutical and / or biotechnology industries for testing the integrity of filters. Background Technology
[0002] Filter integrity is a fundamental element in ensuring sterility during the manufacture of pharmaceutical (e.g., biopharmaceutical) and / or biotechnology products. Different types of integrity tests can be performed, including destructive and non-destructive tests. Non-destructive tests are particularly advantageous because they can be performed before the filter is used. Examples of non-destructive tests include diffusion tests, bubble point tests, and water flow tests (also known as water intrusion tests).
[0003] The general concept for non-destructive integrity testing is as follows. An integrity tester pressurizes an external volume upstream of the filter to a set test pressure and maintains this pressure for a duration defined by a settling time. Subsequently, during a check phase (which lasts for a duration defined by a check phase), quantities indicating the filter's integrity are determined. If the measured quantities remain below predetermined limits, the integrity test is evaluated as passed. Therefore, the settling time and check phase affect the reliability and efficiency of the test. Optionally, direct flow measurement can also be performed, in which case a settling phase is not required. Summary of the Invention
[0004] The purpose of this invention is to improve the efficiency (especially time efficiency) of integrity testing, while also improving its reliability.
[0005] The achievement of this objective according to the invention is set forth in the independent claim. Further developments of the invention are the subject of the dependent claims.
[0006] In one respect, methods for testing the integrity of filters are provided. In other words, methods for performing integrity tests on filters are provided.
[0007] A filter can be any filter used in industrial processes in the biotechnology and / or biopharmaceutical fields. For example, a filter can be any of the following: depth filter, pre-filter, sterilization-grade filter, mycoplasma-preserving filter, cross-flow (or tangential flow) filter, ultrafiltration filter, membrane adsorption filter, virus-preserving filter. A filter can be hydrophilic or hydrophobic. A filter may also be referred to as a "filter assembly".
[0008] By way of example, the filter may be a sterile membrane filter, comprising a housing and a membrane within the housing, the membrane having a given pore size, which may be in the range of about 10 nm to about 5 μm, for example. The membrane may be made of, for example, polyethersulfone, polyvinylidene fluoride, polytetrafluoroethylene, cellulose acetate, regenerated cellulose, and nylon. The housing may be made of, for example, polypropylene, polyamide, or polytetrafluoroethylene.
[0009] Integrity testing can be used to inspect filters for cracks and other defects that could impair their function. Filter integrity can be tested using established non-destructive techniques such as diffusion testing (including multi-point diffusion testing) or flow testing. These tests rely on the correlation between physical quantities that can be readily determined through measurement and the filter's actual retention capacity. In diffusion testing, the physical quantity is the diffusion of gas through a wetting filter, while in flow testing, the physical quantity is the flow rate of water through a hydrophobic filter.
[0010] The method involves pressurizing the upstream side of the filter to a test pressure. In other words, the method involves increasing the pressure on the upstream side of the filter until the pressure reaches a predetermined value or a pre-defined value, i.e., the test pressure.
[0011] A filter has an upstream side and a downstream side. The upstream side is the feed side of the filter, i.e., the surface through which the feed material passes for filtration. The downstream side is the filtrate side of the filter, i.e., the surface through which the filtrate flows out after the feed material is retained by the filter. For example, if the filter includes a cylindrical membrane, the upstream side can be the outer surface of the cylinder, and the downstream side can be the inner surface of the cylinder.
[0012] The pressure at the upstream side of the filter corresponds to the pressure that can be measured in a closed volume, specifically defined by the upstream side of the filter, referred to as the upstream volume. The details of this volume depend on the type of filter and the configuration of the integrity tester. For example, for a filter including a housing, the upstream volume can be given based on the net volume of the housing, the volume of the connecting pipes, and the volume of components connected to the housing (such as the integrity tester).
[0013] The upstream volume is pressurized by introducing gas into the volume, for example, via a gas inlet line connecting the integrity tester and the filter. The gas can be, for example, compressed air, compressed carbon dioxide, or compressed nitrogen. The test pressure is the pressure that must be reached to perform the integrity test. In practice, for fluid to pass through the filter to "test" it, a pressure difference is required between the upstream and downstream sides of the filter. The fluid can be a liquid or a gas (pure gas or a gas mixture). The test pressure p1 can range from approximately 25 mbar to approximately 10 bar. The test pressure is a gauge pressure measured relative to ambient atmospheric pressure.
[0014] Pressurization is one phase of the integrity test. The next phase is the inspection phase, which optionally precedes the stabilization phase. The inspection phase is the actual integrity check part of the test, where it is determined whether the filter is intact.
[0015] In practice, the method also includes performing an inspection step. This inspection step includes determining the flow rate of the fluid from the upstream side of the filter to the downstream side. The flow rate is the amount (or volume) of fluid passing through the filter per unit time. The fluid can be a gas, and the flow rate can be a diffusion flow rate. This is the case, for example, when the integrity test is a diffusion test that can be performed on a hydrophilic filter. Alternatively, the fluid can be a liquid, such as water, and the flow rate can be a volumetric (or dimensional) flow rate. This is the case, for example, when the integrity test is a water flow test (or water intrusion test) that can be performed on a hydrophobic filter.
[0016] Depending on the specific integrity test, the filter may need to be prepared before the test begins. For example, a hydrophilic filter can be wetted with a wetting liquid (such as water or a mixture of water and alcohol), while a hydrophobic filter can be wetted with isopropanol.
[0017] Determining flow rate can include measuring one or more physical quantities and / or performing calculations, depending on the method used. For example, determining flow rate can include measuring pressure drop.
[0018] During the inspection phase, as fluid diffuses through the filter, the pressure on the upstream side of the filter decreases. If p2(t i ) is at a given time point t i The instantaneous pressure measured at time point t i The pressure drop can be defined as Δp = p1 - p2, separated from the start of the inspection phase (which may coincide substantially with the end of the pressurization phase) or, alternatively, the end of the stabilization phase as discussed below, by a time interval δt, where p1 is the pressure at the start of the inspection phase.
[0019] In the case of diffusion testing, at time point t i flow rate F(t) i )=D(t i This can be determined, for example, as follows:
[0020]
[0021] D = Diffusion flow rate (ml / min)
[0022] p1 = Test pressure (mbar) at the start of the inspection phase
[0023] Δp = p1 - p2 pressure drop (mbars)
[0024] V1 = Upstream volume (milliliters)
[0025] δt = Elapsed time (seconds)
[0026] p0 = 1000 mbar (or measured air pressure).
[0027] The upstream volume can be given a priori (e.g., retrieved from a storage medium or input by a user), or in a specific example, the method can further include measuring the upstream volume, i.e., the volume on the upstream side of the filter. Determining the upstream volume can be performed according to conventional techniques (e.g., using Boyle's law) or can be input by the user.
[0028] In the case of a water flow test, at time point t i the flow rate F(t i ) = B(t i ) can be determined exemplarily as follows:[[]]
[0029]
[0030] B = Volume / volumetric flow rate (milliliters / minute)
[0031] p1 = Test pressure (mbar)
[0032] Δp = p1 - p2 Pressure drop (mbar)
[0033] V1 = Upstream volume (milliliters)
[0034] δt = Elapsed time (seconds).
[0035] Other ways of determining the flow rate can be used.
[0036] The checking step further includes comparing the determined flow rate with a flow rate range including a flow rate threshold. The flow rate range is a range of values defined by a lower limit F1 and an upper limit F2, or in other words, a set of values including all values between the lower limit and the upper limit. The flow rate range can be an open interval or a closed interval. The flow rate threshold F th is a threshold and belongs to the flow rate range, i.e., F1 < F th < F2 with constants C1, C2 or F1 = F th - C1 and F2 = F th + C2. In some examples, the flow rate threshold can be the midpoint of the flow rate range, i.e., C1 = C2.
[0037] A flow threshold is an upper limit on the flow rate: a filter exhibiting a flow rate exceeding this limit can be declared incomplete. The value of the flow threshold can depend on several factors, including but not limited to the type of integrity test, the area of the filter, the thickness of the filter, and the test pressure. For example, for diffusion tests, the flow threshold can range from approximately 1 to 3 ml / min to approximately 200 to 300 ml / min, depending on the characteristics of the filter. Exemplarily, the value of the flow threshold can be evaluated by performing a bacterial attack test, and the value of the flow threshold can be provided in the filter's technical specifications.
[0038] Accordingly, lower and upper limits are determined to create an interval containing the traffic threshold, and their specific values can be set based on at least some of the factors listed above. For example, F1 could be F... th At least 85%, further exemplarily F th At least 90%, and further exemplarily, is F th 92%. For example, F2 could be F... th At most 115%, further exemplified by F th At most 110%, and further exemplarily F th 108%.
[0039] Traffic ranges can be stored, for example, in a storage medium, such that comparing determined traffic with a traffic range can include retrieving the traffic range from the storage medium.
[0040] The checking step also includes setting a stop criterion based on comparison and determining whether the stop criterion is met. If the stop criterion is not met, the method includes repeating the checking step until the stop criterion is met.
[0041] A stopping criterion is a condition that allows determination of whether the determined flow rate is sufficiently reliable, i.e., whether it provides a sufficiently accurate estimate of the actual flow rate. In reality, for all physical quantities, the true value (actual flow rate) cannot be known, but only estimated. In particular, since flow rate is derived from the measured quantity, the determined flow rate is affected by errors inherent in the measurement process, such as uncertainties and / or artifacts.
[0042] Therefore, the flow rate determined at a given point in time may not accurately reflect the actual flow rate. However, the actual flow rate is related to the retention capacity of the filter being tested for integrity. Therefore, to properly assess the integrity of the filter, the determined flow rate should be ensured to be sufficiently reliable.
[0043] Therefore, the inspection steps (especially the determination of flow rate) are repeated over time until the determined flow rate is established to be sufficiently accurate, i.e., meeting the stopping criteria. Thus, the inspection phase may include one or more iterations of the inspection steps, and further, it includes determining whether the filter is complete.
[0044] Each repetition of the checking step can occur after a predetermined time interval or a pre-defined time interval since the previous execution of the checking step, such that the first checking step is executed at time t1, the second checking step is executed at time t2 = t1 + Δt1, the third checking step is executed at time t3 = t1 + Δt1 + Δt2, and so on. Exemplarily, the time intervals between iterations can have varying durations, such as decreasing durations as time passes (Δt1 > Δt2), or they can be constants (Δt1 = Δt2). The duration of the time intervals can be a fixed constant or can depend on the satisfaction of one or more conditions.
[0045] Once the stopping criteria are met, the repeated determination of the flow can be stopped. The time period between the start of the checking phase and the last iteration of the checking step, i.e., the duration of the checking phase, can be represented as the checking duration. The end time of the checking phase can be represented as the checking end time.
[0046] Therefore, the repetition of the inspection steps results in a time series, i.e., a sequence of data points corresponding to different times, where each data point is a determined flow rate F(t). i ), where i∈[1,n] and t n This is the check completion time. Each determined flow corresponds to different time points and different iterations of the check steps.
[0047] Typically, the check duration is a predetermined, fixed amount, set long enough to ensure a reliably determined flow rate. According to the present invention, the check duration is not a fixed amount, but depends on when the stopping criterion is met. In other words, the check duration is a variable dependent on the actual reliability of the determined flow rate specified by the stopping criterion.
[0048] This results in more time-efficient and accurate integrity testing compared to a fixed check duration. In fact, if the determined traffic is reliable before the fixed check end time, the variable check duration will be shorter than the fixed check duration. If the determined traffic becomes reliable after the fixed check end time, the test results will be more accurate with the variable check duration.
[0049] Optionally, the stopping criterion can be supplemented by a maximum check duration, which can be pre-programmed or user-defined. If the duration of the check phase reaches the maximum check duration, the repetition of the check step can be stopped even if the stopping criterion has not yet been met. In this case, the finally determined traffic can be compared with a traffic threshold, as discussed below.
[0050] Furthermore, different stopping criteria are set based on the comparison between the determined flow rate and the flow range. Specifically, if the determined flow rate is within the flow range, the stopping criterion is set as the first stopping criterion; and if the determined flow rate is outside the flow range, the stopping criterion is set as the second stopping criterion.
[0051] The second stopping criterion differs from the first stopping criterion. In particular, the second stopping criterion is less stringent than the first stopping criterion. This means that a flow rate determined by the second stopping criterion does not necessarily meet the first stopping criterion, while a flow rate determined by the first stopping criterion always meets the second stopping criterion.
[0052] Therefore, the flow rate determined at a given point in time may only meet the second stopping criterion, but not the first stopping criterion. Consequently, the check duration varies depending on how the stopping criterion has been set; specifically, if the stopping criterion is the second stopping criterion, the check duration can be shorter, making the test faster without being less accurate.
[0053] The selection of the stopping criterion and, consequently, the selection of the inspection duration, is based on a comparison between the determined flow rate and the flow range. In other words, the value of the determined flow rate F(t) is checked against the flow range to verify the determined flow rate F(t). i Whether it is within or outside the flow range, i.e., whether it satisfies F(t) i )∈[F1,F2].
[0054] Since the flow range is an interval around the flow threshold, if the determined flow is within the flow range, it is closer to the flow threshold, and if the determined flow is outside the flow range, it is farther from the flow threshold. As will be discussed below, to assess the integrity of the filter, it is necessary to check whether the determined flow exceeds the flow threshold.
[0055] Because the relationship between the determined flow rate and the flow rate threshold is decisive, the accuracy of the determined flow rate is particularly important when the determined flow rate is close to the flow rate threshold. In fact, in this case, even a relatively small inaccuracy in the determined flow rate can lead to an incorrect assessment of the filter's integrity. Conversely, if the determined flow rate is far enough away from the flow rate threshold (i.e., outside the flow rate range), even a relatively large inaccuracy will not change the assessment result.
[0056] Therefore, the stopping criteria are more stringent when the determined flow is within the flow range, and less stringent when the determined flow is outside the flow range. Consequently, the inspection duration is adaptively determined: a longer inspection duration when a more thorough inspection is required, and a shorter inspection duration when the determined flow is robust enough for comparison with a flow threshold. Thus, this method improves the time efficiency of integrity testing while maintaining its accuracy, in other words, its quality.
[0057] In a specific example, if, in addition to the determined flow range being outside the first flow range, the determined flow range is further within the second flow range (where the first flow range is included within the second flow range), then the flow range can be the first flow range, and the stop criterion can be set as the second stop criterion; and the method may further include: if the determined flow is outside the second flow range, then setting the stop criterion as the third stop criterion.
[0058] More generally, there can be more than two different stopping criteria, where the stopping criteria become less stringent as the determined flow moves further away from the flow threshold. In this case, multiple flow ranges can be defined, where the number of different stopping criteria corresponds to the number of flow ranges plus one.
[0059] Each flow range can be near a flow threshold (e.g., centered on the flow threshold): the first flow range [F1, F2] can be F th Minimum surrounding range, second flow range [F1] 2 F2 2 This can include the first flow range. The third flow range may include the second flow range. Therefore, for n flow ranges,
[0060] Therefore, the stopping criteria can be set as follows:
[0061] If the determined flow rate is within the first flow rate range F(t) i If )∈[F1,F2], then the stopping criterion is set as the first stopping criterion;
[0062] If the determined flow rate is outside the first flow rate range and within the second flow rate range (Or, equivalently, if F(t) i )∈[F1 2 F2 2 If [F1,F2] is selected, then the stop criterion will be set as the second stop criterion. [...]
[0064] If the determined flow rate is outside the (n-1)th flow rate range and within the nth flow rate range Then the stop criterion is set to the nth stop criterion; and if the determined flow rate is outside the nth flow rate range... Then the stopping criterion will be set to the (n+1)th stopping criterion.
[0065] In this case, the first stopping criterion is the most stringent, and the (n+1)th stopping criterion is the least stringent.
[0066] The stopping criteria include at least one quantitative constraint indicating the reliability of the determined flow rate. One or more quantitative constraints may constrain any one or any combination of the following: the determined flow rate itself, quantities derived from it, and other quantities related to the filter and / or the test environment. One or more constrained quantities are related to the reliability of the determined flow rate. For example, some constraint quantities may be related to the measurement error of the determined flow rate.
[0067] Constraints can be exemplified as numerical ranges, such as X must be in [X1, X2], or X must be greater than X1 or less than X2. Optionally or additionally, constraints can be in the form of distributions, such as values Y1, Y2, Y3 must follow a normal distribution.
[0068] The first and second stop criteria can be exemplarily stored in a storage medium, such that setting the stop criteria may include retrieving the first and second stop criteria from the storage medium. Optionally or additionally, the stop criteria may be dynamically determined during the inspection phase, for example, based on user input.
[0069] Determining whether a stopping criterion is met means verifying whether one or more constraints are satisfied. Therefore, it can include first measuring and / or calculating one or more constraint quantities. If multiple constraints exist, the stopping criterion is met only if all constraints are satisfied.
[0070] As described above, if the stopping criterion is not met, the checking steps are repeated until the stopping criterion is met. If the stopping criterion is met, the method includes setting the determined flow rate F(t) to... n The filter is compared with a flow threshold. If the determined flow is greater than or equal to the flow threshold, the filter is determined to be incomplete; if the determined flow is less than the flow threshold, the filter is determined to be complete.
[0071] In other words, the flow rate is determined as the final flow rate during a check phase considered reliable, based on the flow threshold check. If the determined flow rate is greater than or equal to the flow threshold, this means that more fluid passes through the filter per unit time than would pass through if the filter were intact. In fact, if, for example, a crack exists in the filter, more fluid will pass through it.
[0072] In addition to determining whether the filter is complete, i.e., the result of the integrity test, the method may, by way of example, further include providing the result to the user, such as displaying the result.
[0073] Traffic thresholds may be stored, for example, in a storage medium, such that comparing determined traffic with a traffic threshold may include retrieving the traffic threshold from the storage medium. Optionally or alternatively, the value of the traffic threshold may be provided by the user.
[0074] Based on the methods described above, filter integrity testing is performed in a manner that always provides reliable results related to the integrity of the filter, and where possible, the testing is made faster.
[0075] In a specific example, stopping criteria may include a stable range and a voltage drop threshold. The stable range is a numerical range, and the voltage drop threshold is a numerical value. Stopping criteria may include constraints indicating that the stability metric must be within the stable range and constraints indicating that the voltage drop must be greater than or equal to the voltage drop threshold.
[0076] As mentioned above, the measured pressure drop is the difference between the pressure at the start of the inspection phase and the instantaneous pressure measured upstream of the filter. The measured pressure drop is related to the error (or uncertainty) in the determined flow rate; specifically, the higher the pressure drop, the lower the error. Therefore, the pressure drop is a physical quantity significant for determining the reliability of the determined flow rate.
[0077] Specifically, if the pressure drop is greater than or equal to a pressure drop threshold, the determined flow rate can be considered sufficiently accurate. The value of the pressure drop threshold can be determined tentatively and can be, for example, between about 10 mbar and about 100 mbar, depending on the volume. For example, for a volume between about 3 liters and about 8 liters, and for a stop criterion set as a first stop criterion, the pressure drop threshold can be between about 10 mbar and about 20 mbar, for example, about 15 mbar, and for a stop criterion set as a second stop criterion, the pressure drop threshold can be between about 30 mbar and about 50 mbar, for example, about 40 mbar.
[0078] Pressure drop increases over time, or in other words, instantaneous pressure decreases over time. Therefore, the measurement error of the determined flow rate also decreases over time. Pressure drop is chosen as a representative factor of measurement error, rather than simply the amount of time elapsed, for the following reasons: Pressure drop is a physical quantity of a system affected by multiple physical parameters (such as volume, temperature, or the number of air molecules). Elapsed time is independent of such physical parameters. Therefore, pressure drop is a better representative of the physical characteristics of the measured system than elapsed time.
[0079] A stability metric is a parameter that quantifies how stable a determined flow rate is. In reality, a determined flow rate may experience an unstable phase, possibly due to measurement artifacts, and then reach a substantially stable phase. A determined flow rate can be considered stable, and therefore reliable once it has reached a stable phase. The stability metric indicates whether a stable phase has been reached.
[0080] For example, the stability metric could be the arithmetic mean of a subset of the last determined flows preceding (i.e., excluding) the currently considered determined flows. Therefore, the method could also include, for example, storing each determined flow in a storage medium.
[0081] Since the subset of the last l determined flows changes each time a new flow is determined, it can also be said that the stability metric is the moving average A of the determined flows with filter length l. l That is, the moving average over two values:
[0082]
[0083] Among them, t c It is the time point in time for the determined flow currently under consideration, and t c -1 represents the time point of the last determined traffic before the currently determined traffic.
[0084] The stable range can be defined by the currently determined flow rate F(t). c The range centered at F(t). In other words, the upper limit of this range can be F(t). c )+R and the lower bound of this range can be F(t) c )-R, where R is F(t) c The given percentage of ), for example, for the first stopping criterion, R ≤ 0.004F(t). c Or, for the second stopping criterion, R ≤ 0.015F(t) c ).
[0085] In other examples, the stable range can include the currently determined flow A. l (t cThe moving average of t is used as the center. More generally, when performing comparisons with flow ranges, the arithmetic mean Al(t) can also be used. c To replace the instantaneously determined flow rate F(t) c In these cases, the inspection step can be performed c-1 times to determine only the flow, and then from the (c+1)th time onwards, the remaining operations are also included.
[0086] In summary, in one example, the stability range is a numerical interval centered on the determined traffic corresponding to the c-th executed check step, and the stability index is the average of the l subsets of determined traffic corresponding to the (c1)th to (c-1)th executed check steps. Exemplarily, l can be at least 5, for example, 10.
[0087] For example, for such a stability metric, the stopping criterion can only be considered met if the stability metric can be calculated, i.e., if the check step has been performed at least l+1 times. Therefore, if the stability metric cannot be determined (e.g., an error message is received due to insufficient date points), the stopping criterion can be considered not met, and the check step must be repeated.
[0088] In the examples discussed above, the stability metric is a moving average of the determined flow rate. Other statistical and / or mathematical methods can also be used to calculate the stability metric based on the determined flow rate. For example, the amount of variation in the determined flow rate can be calculated, and the stability range can be provided by stored variance values, such as variance values obtained from theoretical considerations and / or from data saved from previous tests. In other examples, the stability metric may not be derived from the determined flow rate. For example, the stability metric could be temperature measured by, for example, a sensor located inside or near the filter housing (upstream).
[0089] In the above example of the stop criteria, determining whether the stop criteria are met may include: determining a stability index for the determined flow rate; measuring the instantaneous pressure upstream of the filter to obtain a measured pressure drop as the difference between the test pressure and the instantaneous pressure; and comparing the stability index with a stability range and comparing the measured pressure drop with a pressure drop threshold. If the pressure drop has already been measured when the flow rate is determined, it is not necessary to measure the pressure drop again.
[0090] The stop criterion is not met when the stability index is outside the stability range and / or the measured voltage drop is less than the voltage drop threshold. The stop criterion is met when the stability index is within the stability range and the measured voltage drop is greater than or equal to the voltage drop threshold.
[0091] In the example above, the stopping criteria are based on pressure drop and stability indicators as parameters upon which constraints are imposed. Additional or optional parameters can be used. For example, the measurement error itself can be determined based on empirical data and / or, such as the amount of time elapsed and the amount of pressure drop. It can then be ensured that the checking phase does not stop until the measured value (determined flow rate) considering the error is strictly less than or greater than the flow rate threshold. In other words, the checking steps can be repeated until the flow rate threshold is ruled out as a possible value for the determined flow rate, even if it falls within the error bar.
[0092] In a specific example, the method may further include: waiting for a settling time after pressurizing the upstream side of the filter before performing the inspection step, wherein the settling time is retrieved from a table based on the test pressure and the volume of the upstream side of the filter.
[0093] In other words, the method can include a stabilization phase in addition to the pressurization and inspection phases. A stabilization phase may be necessary to ensure the test pressure is maintained for a period of time to counteract temperature variations and their effects, and to provide a stable environment for performing the inspection phase. A stable temperature environment improves the accuracy of the determined flow rate calculated based on the formulas described above.
[0094] As mentioned above, the volume on the upstream side of the filter is known, for example, by measurement during a volume measurement phase that occurs before the pressurization phase or by manual input by the user. The settling time (i.e., the duration of the settling phase) can be set based on the volume and the test pressure. The relationship between these parameters can be represented in a lookup table, making it easy to select an appropriate settling time, thereby making the process more efficient.
[0095] In another example, the duration of the stabilization phase can also be adaptively adjusted by allowing the integrity tester to determine when the phase should end. The temperature sensor can be placed near the filter assembly, for example, as close as possible to the actual filter membrane. Once a stable temperature is reached, the stabilization phase can end.
[0096] The methods described above are, in particular, computer-implemented methods. Computer-implemented methods can be automatically executed by at least one processor, such as one that controls valves and measuring devices, performs calculations, stores values, retrieves values, etc.
[0097] In some examples, user input may be required before, during, or after the execution of an action, such as for one or more test parameters (e.g., test pressure or flow threshold). Test parameters are quantities that affect test performance (i.e., the ability to perform a test based on test parameters) and its results. Any test parameter, and in particular flow threshold, flow range, first stop criterion, and second stop criterion, can be input by the user or pre-programmed. In both cases, the values of some test parameters can be stored in storage media and then retrieved when needed.
[0098] The principles described above have been discussed with particular reference to diffusion and flow tests as integrity tests. Of course, the same principles can be applied to multi-point diffusion tests, which are a series of diffusion tests performed sequentially on the same filter at different test pressures. Similarly, they can be applied to the "diffusion portion" of combined diffusion and bubble point tests.
[0099] Conversely, for independent bubble point tests, the automatic stabilization time from the lookup table can be used.
[0100] Another aspect of the invention relates to a computer program product comprising computer-readable instructions that, when executed on a computer system, cause the computer system to perform operations as previously described.
[0101] Another aspect of the invention relates to a system (also known as an "integrity tester") for testing the integrity of a filter. The system includes: at least one processor; memory; and a communication channel configured to be connected to the filter. The at least one processor is configured to:
[0102] Apply pressure to the upstream side of the filter to the test pressure;
[0103] Perform the inspection steps, including:
[0104] - Determine the flow rate of the fluid from the upstream side of the filter to the downstream side of the filter;
[0105] - Compare the determined flow rate with a flow rate range that includes the flow rate threshold;
[0106] - A stopping criterion is set based on comparison, wherein the stopping criterion includes at least one quantitative constraint indicating the reliability of the determined flow rate, and wherein:
[0107] If the determined flow rate is within the flow range, then the stop criterion is set as the first stop criterion; and
[0108] If the determined flow rate is outside the flow rate range, the stop criterion will be set as the second stop criterion.
[0109] - Determine if the stopping criteria are met;
[0110] If the stopping criteria are not met, repeat the check steps until the stopping criteria are met.
[0111] If the stopping criteria are met, the determined flow rate is compared with the flow rate threshold:
[0112] If the determined flow rate is greater than or equal to the flow rate threshold, the filter is determined to be incomplete; and
[0113] If the determined flow rate is less than the flow rate threshold, then the filter is considered complete.
[0114] The connection channel may be, for example, a gas inlet line connected to the upstream or inlet side of the filter, and exemplaryly, it may be a pipe. The system may also include output units (e.g., a display), input units (e.g., a keyboard or touchscreen), and one or more additional connectors and / or ports. Attached Figure Description
[0115] Details of exemplary embodiments are now set forth with reference to the exemplary accompanying drawings. Other features will become apparent from the description, drawings, and claims. However, it should be understood that even though embodiments are described separately, individual features of different embodiments may be combined with other embodiments.
[0116] Figure 1 A schematic diagram of an integrity tester connected to a filter is shown.
[0117] Figure 2 A flowchart of an exemplary integrity test is shown.
[0118] Figure 3 A graph showing pressure versus time at different stages of the integrity test is presented.
[0119] Figure 4 An exemplary table is shown, showing the settling time values as a function of test pressure and upstream volume.
[0120] Figure 5 A flowchart of an exemplary inspection phase of an integrity test is shown.
[0121] Figure 6 An exemplary flowchart of an adaptive assessment of the duration of the inspection phase is shown.
[0122] Figure 7 The representation of flow thresholds and flow ranges is shown.
[0123] Figure 8 The diagram shows the pressure drop and diffusion (or "diffusion-based") flow rate versus time during the inspection phase.
[0124] Figure 9 An exemplary table is shown, which has a voltage drop threshold as a function of the upstream volume.
[0125] Figure 10 A graph showing the stable range versus time during the inspection phase is shown. Detailed Implementation
[0126] In the following detailed description of the examples, reference will be made to the accompanying drawings. It should be understood that various modifications can be made to the examples. Unless otherwise expressly stated, elements of one example can be combined and used in other examples to form new examples.
[0127] Figure 1 A schematic diagram of an integrity tester 10 connected to a filter 30 via a conduit 15 is shown. The integrity tester 10 is a system including at least one processor and memory (not shown), two output units (a printer and a display), and an input unit (a keyboard and / or a barcode scanner). Optionally, the integrity tester 10 may include a touchscreen serving as both the output and input units.
[0128] The filter (or filter assembly) 30 includes a housing 32 and a membrane 34. The filter 30 is connected to a drainage device via an upstream pipe 36 and to the downstream filtrate side via a downstream pipe 38.
[0129] The function of the communication channel (pipeline 15) between the integrity tester 10 and the filter 30 is to supply gas to the filter 30 during the pressurization phase.
[0130] The device can also have additional external valves or external sensors connected to the filter 30 under test. These external valves can be used for additional safety and to prevent backflow. External sensors can be used to supplement or replace the internal sensors of the integrity tester 10.
[0131] Figure 2 A flowchart of an exemplary integrity test 100 performed by an integrity tester 10 is shown. Prior to test 100, filters may be prepared; for example, a hydrophilic filter may be wetted with a wetting liquid, while a hydrophobic filter may be blocked with water.
[0132] During (optional) sensor verification 110, the tester 10 ensures that the internal sensor is correctly calibrated and operated. Then, in response to user input, it is set whether to perform a volume measurement 120 of the upstream volume of filter 30. The volume measurement 120 can be performed, for example, using Boyle's law. If no volume measurement is performed, the volume value can be input by the user.
[0133] Pressurization 130 is performed directly after sensor verification 110 or after volume measurement 120. During the pressurization phase, the pressure at the upstream side of filter 30 reaches the test pressure, the value of which can be input by the user or pre-programmed in the integrity tester 10 (e.g., for a specific filter model).
[0134] After pressurizing the upstream volume to the test pressure, the tester 10 ensures that the pressure is maintained for a specific amount of time. This is the stabilization phase, and its duration (or stabilization time) is set based on the test pressure and the upstream volume. Figure 4 The table shows exemplary settling time values related to different ranges of test pressure and upstream volume. Therefore, using a similar... Figure 4 The lookup table in the system automatically sets an appropriate settling time.
[0135] After stabilizing at 140, test 100 includes check 150, during which actual integrity checks are performed. See below for reference. Figure 5 The inspection at 150 is described in more detail. At the end of test 100, the filter is vented at 160.
[0136] Figure 3 A graph showing the pressure versus time for different phases of the integrity test 100 is presented. It can be seen that the pressure increases to eventually reach the test pressure during the pressurization phase, then remains at the test pressure during the stabilization phase, begins to decrease during the inspection phase, and finally drops to zero after venting.
[0137] Figure 5 A flowchart illustrating an exemplary inspection phase of an integrity test is shown. Inspection phase 150 of the integrity test 100 includes determining the flow rate of fluid 240 from the upstream side to the downstream side of the filter 30. The flow rate is determined as an indicator of the filter's actual retention capacity.
[0138] To determine the flow rate, it may be necessary to measure the pressure drop upstream of the filter, for example. Therefore, the inspection phase may optionally include first measuring the effective test pressure at 210, i.e., measuring the initial pressure at the start of the inspection phase, which may be slightly different from the nominal test pressure. Measuring the effective test pressure at 210 is performed only once at the start of inspection phase 150 and is not part of the inspection steps, which may be repeated multiple times.
[0139] Then, at 220, the inspection procedure begins, and the instantaneous pressure on the upstream side of the filter is measured to obtain the pressure drop at 230. Using the pressure drop, at 240, for example for a diffusion test, the flow rate can be determined as a diffusion flow rate that depends logarithmically on the pressure drop. Alternatively, for a flow test, the volumetric / volume flow rate depends linearly on the pressure drop.
[0140] As mentioned above, the determined flow rate is a quantity used to evaluate the integrity of the filter, and therefore, it is important that the determined flow rate is accurate. Conventionally, the flow rate is determined at each of a series of time points, and after a fixed, relatively long period, it is assumed that the determined flow rate is sufficiently accurate for the purpose of integrity assessment. In other words, the last data point in the time series of the determined flow rate is considered reliable.
[0141] While waiting long enough to ensure the determined flow rate is sufficiently accurate, the time efficiency of test 100 is negatively impacted by this. Instead, according to the invention, the duration of the inspection phase is adaptively determined at 250. Reference will be made below. Figure 6 Describe this adaptive assessment in detail.
[0142] The adaptability assessment determines whether the determined flow rate at a given time point is sufficiently reliable for the testing purpose. If not, the checking phase continues by repeating the checking steps and redetermining the flow rate at subsequent time points; if yes, the checking phase terminates and the (final) determined flow rate is compared with the flow rate threshold.
[0143] The flow threshold is a test parameter whose value can be input by the user or pre-programmed in the integrity tester 10 (e.g., for a specific filter model). If the determined flow is greater than or equal to the flow threshold, filter 30 fails test 100, indicating that its integrity has been compromised. If the determined flow is less than the flow threshold, filter 30 passes test 100, indicating that its integrity has been confirmed.
[0144] Figure 6 A flowchart illustrating an exemplary adaptive assessment 250 of the duration of the inspection phase is shown. The decision to terminate the inspection phase depends on a stopping criterion, which in turn depends on the determined flow rate F(t). c The degree of closeness to the critical value of the flow threshold.
[0145] The flow range can be limited to (1-x)F near the flow threshold. th and (1+x)F th The numerical range between x and 0.15, where x < 1. For example, x < 0.15, such as x = 0.08. In other words, the flow range is, for example, the interval around the flow threshold by 8%. Figure 7 The representation of flow thresholds and flow ranges is shown.
[0146] At point 310, the determined flow rate is compared to the flow range. If the determined flow rate is within the flow range (see...), then... Figure 7If the cross in the code is used, then at 320 the stop criterion is set to either strict or first stop criterion. If the determined flow rate is outside the flow range (see [link to relevant documentation]), the stop criterion is set to strict or first stop criterion. Figure 7 If the circle in the diagram is used, then the stop criterion at 330 will be set to either a lenient criterion or a second stop criterion.
[0147] Then, at 340, check if the stopping criteria are met. The stopping criteria include constraints on the pressure drop value when determining the flow rate. This is because the pressure drop is related to the error in the determined flow rate, such as... Figure 8 As shown in the graph: the higher the pressure drop, the lower the error bar. It should be noted that... Figure 8 A specific example of diffuse flow as flow is shown.
[0148] Therefore, to ensure the determined flow rate is sufficiently reliable, the constraint is that the pressure drop must be at least equal to the pressure drop threshold. The pressure drop threshold is a test parameter whose value can be input by the user or pre-programmed in the integrity tester 10 (e.g., for a specific filter model). The pressure drop threshold can vary based on the upstream volume.
[0149] Figure 9 An exemplary table is shown with strict pressure drop thresholds as a function of upstream volume. For example, for a 5-liter volume, if a first stop criterion has been selected, the pressure drop must be at least 40 millibars. For a second stop criterion, the pressure drop threshold for a 5-liter volume could be, for example, 15 millibars.
[0150] Therefore, at 340, the measured voltage drop is compared to the voltage drop threshold. Furthermore, another check is performed to verify that the stopping criteria are met, using a stability index. In practice, the stopping criteria include further constraints on this stability index.
[0151] By calculating the value F(t) under consideration c The stability index is obtained by averaging (arithmetic mean) the subset of previously determined flow values. Specifically, for F(t) c The average of the previous 10 values is F(t). c-10 )...F(t c-1 The constraint is the average value A. 10 (t c-1 ) must be in F(t) c Within the range (stable range) near ).
[0152] For example, for the first stopping criterion 0.998F(t) c )≤A 10 (t c-1 )≤1.002F(t c ), and for the second stopping criterion 0.989F(t) c )≤A10 (t c-1 )≤1.011F(t c The stability range is a test parameter whose value can be input by the user or pre-programmed in the integrity tester 10 (e.g., for a specific filter model). Figure 10 A graph showing the stable range versus time during the check phase of the diffusion flow is shown.
[0153] Therefore, at 340, the measured pressure drop is compared to the pressure drop threshold, and the stability index is compared to the stability range. If both constraints of the stop criteria are met—that is, the pressure drop is equal to or higher than the pressure drop threshold and the stability index is within the stability range—then at 260, it is determined that the inspection phase can be terminated. As discussed above, in this case, the determined flow rate is compared to the flow rate threshold.
[0154] If one or both constraints are not met, the inspection phase at point 350 should continue, and the inspection steps should be repeated. Therefore, new traffic is identified, and then the newly identified traffic is reassessed to ensure it is reliable enough to be compared with the traffic threshold, thus providing the test results. The inspection steps are repeated until the stopping criteria are met.
[0155] Therefore, the duration of the inspection phase is adaptively determined so that the inspection phase is as fast as possible while maintaining the desired accuracy.
Claims
1. A method for testing the integrity of a filter, the method comprising: Apply pressure (130) to the upstream side of the filter to the test pressure; Perform the inspection steps, including: - Determine (240) the flow rate of the fluid from the upstream side of the filter to the downstream side of the filter; - Compare the determined flow rate with the flow rate range that includes the flow rate threshold (310). - A stopping criterion is set based on the comparison, wherein the stopping criterion includes at least one quantitative constraint indicating the reliability of the determined flow rate, and wherein: If the determined flow rate is within the specified flow rate range, then the stop criterion is set (320) as the first stop criterion; and If the determined flow rate is outside the flow rate range, then the stop criterion is set (330) as the second stop criterion; - Determine whether (340) meets the stopping criteria; If the stopping criteria are not met, repeat the checking steps (350) until the stopping criteria are met; If the stopping criteria are met, the determined flow rate is compared with the flow rate threshold (260): If the determined flow rate is greater than or equal to the flow rate threshold, then the filter is determined to be incomplete; and If the determined flow rate is less than the flow rate threshold, then the filter is determined to be complete. in: The stopping criteria include a stable range and a voltage drop threshold; Determining whether the stopping criteria are met includes: Determine the stability indicators for the determined flow rate; The instantaneous pressure at the upstream side of the filter is measured to obtain a measured pressure drop as the difference between the test pressure and the instantaneous pressure; The stability index is compared with the stability range, and the measured voltage drop is compared with the voltage drop threshold; and The stop criterion is not met when the stability index is outside the stability range and / or the measured voltage drop is less than the voltage drop threshold. The stopping criterion is met when the stability index is within the stability range and the measured voltage drop is greater than or equal to the voltage drop threshold.
2. The method according to claim 1, wherein, The stability range is a numerical interval centered on the determined flow rate corresponding to the c-th executed check step, and the stability index is the value relative to the flow rate of the c-th executed check step. Each inspection step corresponds to The average of a subset of the determined flow rates.
3. The method according to claim 1 or 2, wherein, The fluid is a gas, and the flow rate is a diffusion flow rate.
4. The method according to claim 1 or 2, wherein, The fluid is water, and the flow rate is a volumetric flow rate.
5. The method according to claim 1 or 2, further comprising: Before performing the inspection step, after pressurizing the upstream side of the filter, a stabilization time (140) is waited, wherein: The settling time is retrieved from the table based on the test pressure and the volume on the upstream side of the filter.
6. The method according to claim 1 or 2, wherein, The flow range is a first flow range, and if the determined flow range is further within a second flow range, then the stop criterion is set to the second stop criterion, wherein the first flow range is included in the second flow range; The method further includes setting the stop criterion as a third stop criterion if the determined flow rate is outside the second flow rate range.
7. A computer program product comprising computer-readable instructions that, when executed on a computer system, cause the computer system to perform the method according to any one of the preceding claims.
8. A system for testing the integrity of a filter, the system comprising: At least one processor; Memory; A communication channel configured to be connected to the filter; Wherein, the at least one processor is configured as follows: Apply pressure (130) to the upstream side of the filter to the test pressure; Perform the inspection steps, including: - Determine (240) the flow rate of the fluid from the upstream side of the filter to the downstream side of the filter; - Compare the determined flow rate with the flow rate range that includes the flow rate threshold (310). - A stopping criterion is set based on the comparison, wherein the stopping criterion includes at least one quantitative constraint indicating the reliability of the determined flow rate, and wherein: If the determined flow rate is within the specified flow rate range, then the stop criterion is set (320) as the first stop criterion; and If the determined flow rate is outside the flow rate range, then the stop criterion is set (330) as the second stop criterion; - Determine whether (340) meets the stopping criteria; If the stopping criteria are not met, repeat the checking steps (350) until the stopping criteria are met; If the stopping criteria are met, the determined flow rate is compared with the flow rate threshold (260): If the determined flow rate is greater than or equal to the flow rate threshold, then the filter is determined to be incomplete; and If the determined flow rate is less than the flow rate threshold, then the filter is determined to be complete. in: The stopping criteria include a stable range and a voltage drop threshold; and The at least one processor is further configured to: Determine the stability indicators for the determined flow rate; The instantaneous pressure at the upstream side of the filter is measured to obtain a measured pressure drop as the difference between the test pressure and the instantaneous pressure; The stability index is compared with the stability range, and the measured voltage drop is compared with the voltage drop threshold; and The stop criterion is not met when the stability index is outside the stability range and / or the measured voltage drop is less than the voltage drop threshold. The stopping criterion is met when the stability index is within the stability range and the measured voltage drop is greater than or equal to the voltage drop threshold.
9. The system according to claim 8, wherein, The stability range is a numerical interval centered on the determined flow rate corresponding to the c-th executed check step, and the stability index is the value relative to the flow rate of the c-th executed check step. Each inspection step corresponds to The average of a subset of the determined flow rates.
10. The system according to claim 8 or 9, wherein, The fluid is a gas, and the flow rate is a diffusion flow rate.
11. The system according to claim 8 or 9, wherein, The fluid is water, and the flow rate is a volumetric flow rate.
12. The system according to claim 8 or 9, wherein, The at least one processor is further configured to: Based on the test pressure and the volume on the upstream side of the filter, the stabilization time is retrieved from the table; as well as Before performing the inspection steps, after pressurizing the upstream side of the filter, a stabilization period is allowed.
13. The system according to claim 8 or 9, wherein, The flow range is a first flow range, and if the determined flow range is further within a second flow range, the stop criterion is set to the second stop criterion, the first flow range being included in the second flow range; and the at least one processor is further configured to set the stop criterion to a third stop criterion if the determined flow is outside the second flow range.