Defect Detection Sensitivity of Bubble-Point-Type Tests for Sterilizing-Grade Membrane Cartridge Filters
Open accessAbstract
Bubble point tests are widely used for assessing the integrity of sterilizing-grade membrane cartridge filters. While many authors have considered the limitations of bubble point tests as applied to cartridge filters, the level of bacterial retention assurance provided by this test as conducted with automated integrity testers (AITs) has not, until now, been quantified. Contrary to the notion that filter leaks result in a depressed bubble point, it was shown that the bubble point as reported by AITs was insensitive to defect size up until the point where the AIT either determined a gross leak failure or was not able to return a valid result. For the three AITs used in this study, the minimum laser hole defect diameter in 10-inch (25.4 cm) sterilizing-grade cartridge filters that resulted in a failing bubble point test was between about 30 and 60 µm, depending on the filter type and test conditions. These defect sizes were associated with bacterial log reduction values in the 4.0 to 4.5 range. This study supports the generally recommended practice of pairing the bubble point test (which does confirm proper pore size rating) with a complementary gas–liquid diffusion test (better suited for detecting defects) to achieve a more comprehensive assessment of filter integrity.
AI snapshot
Written from the paper’s full text.
TL;DR
Bubble-point tests run on automated integrity testers (AITs) were practically insensitive to defect size in 10-inch sterilizing-grade cartridge filters until the AIT reported a gross leak or invalid result. The minimum laser-hole defect diameter that caused a failing bubble point was about 30–60 µm depending on filter type and test conditions, corresponding to bacterial log reduction values (LRVs) of about 4.0–4.5.
Key findings
- Reported bubble point was invariant with leak rate and defect size up until the AIT either determined a gross leak or could not return a valid result; no defect produced a depressed bubble point.
- For the three AITs, the minimum laser-hole defect diameter in 10-inch sterilizing-grade cartridge filters that resulted in a failing bubble point was between about 30 and 60 µm, depending on filter type and test conditions.
- Defects as large as 60 µm could pass the bubble point test, and filters with LRVs as low as about 4–4.5 passed; all filters with 30 µm holes passed all AITs and exhibited LRVs of about 4.5–5.
- Bubble point remained sensitive to rated pore size: integral 0.45 µm cartridges had lower bubble points than 0.2 µm cartridges, while laser-hole defects did not lower reported bubble point. Air diffusion values for laser-hole filters were above vendor specifications and failed that test.
Methods
- Two 0.2 µm membrane types were evaluated in 10-inch pleated cartridges: asymmetric polyethersulfone (PES) and symmetric polyvinylidene fluoride (PVDF); 0.45 µm PES and PVDF cartridges were also tested for bubble point only.
- Controlled leaks were created by a metering-valve bypass from feed to permeate and by laser-drilled holes of nominal 20–100 µm diameter in the membrane pleat pack.
- Bubble point and diffusion tests used three commercial AITs (VA, VB, VC) with default or vendor-recommended settings, after wetting with RO water or 70:30 IPA:water; bacterial retention was measured per ASTM F838-20 with *Brevundimonas diminuta*, and LRV was calculated.
Limitations
- The paper states that “real-world” defects are not necessarily cylindrical like the laser holes, and the relationship between defect size, leak rate, and bacterial retention depends on defect geometry.
- The paper states that AIT bubble-point algorithms are proprietary and not transparent, there is no universal standard for cartridge bubble point, “gross leak” is not quantitatively defined, and results are filter-, AIT-, and potentially user-setting-specific.
- Evident from the text: the study used only three AITs, two 0.2 µm membrane types, and one artificial defect shape; diffusion-test sensitivity was not within scope, and the findings may not generalize to all cartridge filters or defect types.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 31 cited sources checked · 0 supported · 0 flagged
- Findingown data
Above a certain flow rate (or rate of upstream pressure decay), the AIT algorithm considered the flow rate to be either a "gross leak" or too high to accurately measure, resulting in a failed test.
“Above a certain flow rate (or rate of upstream pressure decay), the AIT algorithm considered the flow rate to be either a “gross leak” or too high to accurately measure (resulting in a failed test).”
Quote in the paperSubstantial claim - Findingown data
For the three AITs used in this study, the minimum laser hole defect diameter in 10-inch (25.4 cm) sterilizing-grade cartridge filters that resulted in a failing bubble point test was between about 30 and 60 μm, depending on the filter type and test conditions.
“For the three AITs used in this study, the minimum laser hole defect diameter in 10-inch (25.4 cm) sterilizing-grade cartridge filters that resulted in a failing bubble point test was between about 30 and 60 µm, depending on the filter type and test conditions.”
Quote in the paperSubstantial claim - Findingown data
The bubble point reported by automated integrity testers (AITs) was insensitive to defect or leak size up until the point where the AIT either determined a gross leak failure or was not able to return a valid result.
“Contrary to the notion that filter leaks result in a depressed bubble point, it was shown that the bubble point as reported by AITs was insensitive to defect size up until the point where the AIT either determined a gross leak failure or was not able to return a valid result.”
- Also stated in: § 4.1. Controlled Bypass Leak · plain
“The reported bubble point was invariant with leak rate up until the point where an AIT reported an invalid or failed test.”
Quote in the paperSubstantial claim - Also stated in: § 4.1. Controlled Bypass Leak · plain
- Findingown data
The defect sizes that caused failing bubble point tests were associated with bacterial log reduction values in the 4.0 to 4.5 range.
“These defect sizes were associated with bacterial log reduction values in the 4.0 to 4.5 range.”
Quote in the paperSubstantial claim - Findingown data
Sterilizing-grade filter cartridges that contained laser hole defects as large as 60 μm in diameter exhibited passing AIT bubble point values.
“Since sterilizing-grade filter cartridges that contained laser hole defects as large as 60 µm in diameter exhibited passing AIT bubble point values, filters with LRV values as low as about 4–4.5 passed the bubble point test, as can be seen in Figure 10.”
Quote in the paperSubstantial claim
- Findingown data
Every device that contained a laser hole defect of 30 μm or smaller showed passing bubble point values for all the AITs.
“The largest defect size that resulted in a passing reported bubble point did depend on the combination of filter type and AIT vendor, although every device that contained a laser hole defect of 30 µm or smaller showed passing bubble point values for all the AITs.”
Quote in the paperSubstantial claim - Findingown data
All the filters that contained laser hole defects that were 30 μm in diameter or smaller and that exhibited an LRV as low as about 4.5, passed the bubble point test for all three AITs used in this study.
“All the filters that contained laser hole defects that were 30 µm in diameter or smaller and that exhibited an LRV as low as about 4.5, passed the bubble point test for all three AITs used in this study.”
Quote in the paperSubstantial claim - Findingreasoning
An air flow rate of 30 sccm at 40 psi is consistent with a short, cylindrical hole of about 30 μm in diameter.
“An air flow rate of 30 sccm at 40 psi (276 kPa) was consistent with short, cylindrical hole of about 30 µm in diameter.”
Quote in the paperSubstantial claim - Findingown data
For sterilizing-grade membrane cartridge filters, the bubble point reported by automated integrity testers (AITs) is practically invariant with increasing leak rate or defect size up to the point where the tester reports a gross leak or cannot determine a valid bubble point.
“Almost regardless of which of the three bubble point determination methods described above was used, the leak rate had a minimal impact on the reported bubble point (the flow rate vs. pressure curves that were the basis of the bubble point determinations in Figure 4 are shown in Appendix A). The curves associated with the leaks were nearly indistinguishable from the integral curves in terms of the”
- Also stated in: § 4.2. Filters with Controlled Laser Hole Defects · plain
“Consistent with the controlled bypass leak results (Section 4.1), bubble point was nearly invariant with defect size up until the point where the tester either ascertained a gross leak or was unable to determine a valid bubble point.”
- Also stated in: § 5. Conclusions · plain
“In this study, it was found that bubble point as determined by three different AITs was practically invariant with defect size up to the point where an AIT either determined that the filter contained a “gross leak” or was not able to produce a valid bubble point result.”
Quote in the paperSubstantial claim - Also stated in: § 4.2. Filters with Controlled Laser Hole Defects · plain
- Findingown data
The reported bubble point had minimal impact from leak rate for the tangent method, the slope change method, and the threshold diffusive flow method.
“The curves associated with the leaks were nearly indistinguishable from the integral curves in terms of the bubble point for the tangent method, the slope change method, and the threshold diffusive flow method.”
- Also stated in: § 4.1. Controlled Bypass Leak · plain
“As previously discussed, based on the algorithms used by the AITs to determine bubble point, there were no significant differences in bubble point between the integral devices and the devices containing the 30 µm defect for any of the three bubble point determination methods of Figure 5.”
Quote in the paperSubstantial claim - Also stated in: § 4.1. Controlled Bypass Leak · plain
- Findingown data
Cartridge filters containing membranes with different pore size ratings did show a relationship between bacterial retention and bubble point.
“Cartridge filters containing membranes with different pore size ratings (e.g., 0.1 µm, 0.2 µm, 0.45 µm, 0.65 µm, etc.) did show a relationship between bacterial retention and bubble point, and as can be seen from Figure 9 and Figure 11, the integral 0.45 µm cartridge filters did exhibit lower bubble point and lower LRV values compared to the corresponding integral 0.2 µm cartridge filters.”
Quote in the paperSubstantial claim - Findingreasoning
The air-water bubble point of a 30 μm hole should be about 1.4 psi.
“In accordance with Equation (1), the air–water bubble point of this hole should be about 1.4 psi (9.7 kPa).”
Quote in the paperSubstantial claim - Findingreasoning
There was no correlation between LRV and bubble point for filters with the same pore size ratings.
“Since reported bubble point was invariant with defect size until an invalid or gross leak result was reported, there was no correlation between LRV and bubble point, as shown in Figure 11 for filters with the same pore size ratings.”
Quote in the paperSubstantial claim - Findingown data
In some cases, devices containing defects as large as 60 μm exhibited passing bubble point values.
“In some cases, devices containing defects as large as 60 µm exhibited passing bubble point values.”
Quote in the paperSubstantial claim - Findingreasoning
Filters with LRV values as low as about 4-4.5 passed the bubble point test.
“Since sterilizing-grade filter cartridges that contained laser hole defects as large as 60 µm in diameter exhibited passing AIT bubble point values, filters with LRV values as low as about 4–4.5 passed the bubble point test, as can be seen in Figure 10.”
Quote in the paperSubstantial claim - Findingown data
The measured air diffusion as a function of defect size shows good agreement with the model predictions.
“The measured air diffusion as a function of defect size is summarized in Figure 7 and shows good agreement with the model predictions.”
Quote in the paperNot a substantial claim - Findingown data
The largest defect size that resulted in a passing reported bubble point depended on the combination of filter type and AIT vendor.
“The largest defect size that resulted in a passing reported bubble point did depend on the combination of filter type and AIT vendor, although every device that contained a laser hole defect of 30 µm or smaller showed passing bubble point values for all the AITs.”
Quote in the paperSubstantial claim - Findingown data
There were no significant differences among the bubble point values reported by the different AITs for either filter type.
“Although each AIT had its own proprietary bubble point determination algorithm, there were no significant differences among the bubble point values reported by the different AITs for either filter type.”
Quote in the paperSubstantial claim - Findingown data
The air diffusion rates of the filters containing laser holes were elevated compared to the integral filters.
“While the laser hole defects did not result in depressed bubble points (where values were reported), the air diffusion rates of the filters containing laser holes were elevated compared to the integral filters.”
Quote in the paperSubstantial claim - Findingown data
The model predictions for LRV as a function of defect size were in good agreement with the measured values.
“For both sets of data, the model predictions were in good agreement with the measured values.”
Quote in the paperSubstantial claim - Findingown data
The bubble point values of the integral nominal 0.45 μm membrane cartridges were significantly lower than the 0.2 μm membrane cartridges.
“It was noted that the bubble point values of the integral nominal 0.45 µm membrane cartridges (measured using the VA AIT) were significantly lower, as expected, compared to the 0.2 µm membrane cartridges.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The gas-liquid diffusion test is better suited for detecting defects.
“This study supports the generally recommended practice of pairing the bubble point test (which does confirm proper pore size rating) with a complementary gas–liquid diffusion test (better suited for detecting defects) to achieve a more comprehensive assessment of filter integrity.”
Quote in the paperSubstantial claim - Premisecitation
In many cases, including in some recent studies pertaining to filter integrity testing, a bubble point test is the only test used to assess the integrity of a filter.
“However, in many cases, including in some recent studies pertaining to filter integrity testing, a bubble point test is the only test used to assess the integrity of a filter [20,21].”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
The slope of a flow vs. pressure curve prior to the onset of primarily bulk flow through pores evacuated of liquid is not affected by such a defect.
“Therefore, the slope of a flow vs. pressure curve prior to the onset of primarily bulk flow through pores evacuated of liquid is not affected by such a defect.”
Quote in the paperSubstantial claim - Premisecitation
There is a lack of published data showing a correlation between retention performance and bubble point for cartridge filters containing controlled defects.
“While bacterial retention performance has been correlated with bubble point on disk filters, there is a lack of published data * (* As remarked in a book published in 1987 but still pertinent as of this writing, “one hears stories that defects in cartridges, induced by penetration by a pin, may or may not be detectable by either diffusional air flow or bubble point measurements, depending on what”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Meltzer, T.H., and Blakie, E.W. (1987). Filtration in the Pharmaceutical Industry, Marcel Dekker.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
An AIT-based bubble point test ensures that an installed filter is of the proper pore size.
“This means that, while an AIT-based bubble point test ensures that an installed filter is of the proper pore size, it provides an uncertain level of retention assurance for the filter.”
Quote in the paperSubstantial claim - Interpretationown data
Defects in cartridge membrane filters that were large enough to easily allow the passage of bacteria could escape detection by bubble point tests.
“The results presented here, however, demonstrate that defects in cartridge membrane filters that were large enough to easily allow the passage of bacteria could escape detection by bubble point tests.”
Quote in the paperSubstantial claim- Rests on an assumption: Controlled laser hole defects are representative enough of real-world membrane defects for the study's conclusions about real-world defects to hold.
- Interpretationreasoning
The intermediate diffusion flow rates in a bubble point test at pressures that are lower than the bubble point cannot be relied on for determining filter integrity.
“Therefore, the intermediate diffusion flow rates in a bubble point test at pressures that are lower than the bubble point cannot be relied on for determining filter integrity; a formal diffusion test at the vendor-specified conditions needs to be conducted in conjunction with the bubble point test.”
Quote in the paperSubstantial claim - Interpretationreasoning
To accurately determine the true bubble point of the filter, the flow rate vs. pressure curve would need to be initiated at a pressure below 1.4 psi.
“This means that, to accurately determine the “true” bubble point of the filter, the flow rate vs. pressure curve would need to be initiated at a pressure below 1.4 psi (9.7 kPa), at which point an inflection in the flow rate vs. pressure curve could be detected, at least in principle.”
Quote in the paperSubstantial claim - Interpretationreasoning
An AIT-based bubble point test provides an uncertain level of retention assurance for the filter.
“This means that, while an AIT-based bubble point test ensures that an installed filter is of the proper pore size, it provides an uncertain level of retention assurance for the filter.”
Quote in the paperSubstantial claim- Rests on an assumption: There are no established, quantified criteria for what constitutes a gross leak or invalid test result.
- Rests on an assumption: Filter vendors do not provide specifications for gross leaks.
- Rests on an assumption: The algorithms used by AITs are usually not transparent to the user.
- Interpretationown data
If the flow rate vs. pressure drop curve was initiated at 1 psi or less, it would be possible to ascertain the true bubble point in this filter as less than 2 psi.
“This plot reveals that, if the flow rate vs. pressure drop curve was initiated at 1 psi (7 kPa) or less, it would be possible to ascertain the “true” bubble point in this filter as less than 2 psi (14 kPa).”
Quote in the paperSubstantial claim - Interpretationown data
The gas-liquid diffusion test is better able to detect filter defects.
“The gas–liquid diffusion test, which is not sensitive to pore size at pressures below the bubble point, is better able to detect filter defects.”
Quote in the paperSubstantial claim- Rests on an assumption: The gas–liquid diffusion test is not sensitive to pore size at pressures below the bubble point.
- Interpretationown data
The level of retention assurance of sterilizing-grade filters provided by the bubble point test as determined by AITs is filter- and AIT-specific (and within an AIT, potentially user-setting-specific).
“While the level of retention assurance of sterilizing-grade filters provided by the bubble point test as determined by AITs is filter- and AIT-specific (and within an AIT, potentially user-setting-specific), the results presented here showed that leaks from laser hole defects as large as 60 µm in diameter in 10-inch (25.4 cm) sterilizing-grade pleated cartridge filters and results for bacterial LR”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 19
- May combine two claims. 22
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataFor water at room temperature flowing through micromachined orifices, a Cv value of about 0.028 m3s−1Pa−0.5 was found to provide a good fit to the data.
“For water at room temperature flowing through micromachined orifices, a Cv value of about 0.028 m3s−1Pa−0.5 was found to provide a good fit to the data (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone givenThe criteria for what constitutes a gross leak are not made explicit in any user manuals of the AITs used in this study and appeared to be different among the different AITs.
“The criteria for what constitutes a gross leak—which are not made explicit in any user manuals of the AITs used in this study—appeared to be different among the different AITs.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe insensitivity of reported bubble point to leak rate was irrespective of filter type and has been observed with filters from various filter vendors (data not shown).
“This behavior was irrespective of filter type and has been observed with filters from various filter vendors (data not shown).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe leak through 30 μm laser holes shifted the flow rate vs. pressure drop curves upward but did not impact the reported bubble point of any of the AITs.
“Similar to the effect of controlled leaks shown in Appendix A, the leak through 30 µm laser holes shifted the flow rate vs. pressure drop curves upward but did not impact the reported bubble point of any of the AITs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe integral 0.45 μm cartridge filters exhibited lower bubble point and lower LRV values compared to the corresponding integral 0.2 μm cartridge filters.
“Cartridge filters containing membranes with different pore size ratings (e.g., 0.1 µm, 0.2 µm, 0.45 µm, 0.65 µm, etc.) did show a relationship between bacterial retention and bubble point, and as can be seen from Figure 9 and Figure 11, the integral 0.45 µm cartridge filters did exhibit lower bubble point and lower LRV values compared to the corresponding integral 0.2 µm cartridge filters.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAll the filters that contained laser hole defects exhibited air diffusion values that were above the vendor specifications and, therefore, failed that test.
“All the filters that contained laser hole defects exhibited air diffusion values that were above the vendor specifications and, therefore, failed that test.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll the filters that contained 30 μm holes passed the bubble point test for all the AITs, and those filters exhibited LRV values of about 4.5-5.
“All the filters that contained 30 µm holes passed the bubble point test for all the AITs, and those filters exhibited LRV values of about 4.5–5.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWhile pore size impacted the reported bubble point of the AITs for cartridge filters, the presence of defects in the filters (where valid bubble points were reported) did not.
“While pore size impacted the reported bubble point of the AITs for cartridge filters, the presence of defects in the filters (where valid bubble points were reported) did not.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFor defect sizes larger than about 60 μm, the AITs reported either an invalid result or a gross leak, but in no case did a defect result in a depressed bubble point value.
“For defect sizes larger than about 60 µm, the AITs reported either an invalid result or a gross leak, but in no case did a defect result in a depressed bubble point value.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenThe 0.45 μm PES filters had much lower reported bubble points but equal or higher LRV values than the corresponding 0.2 μm filters that contained laser hole defects.
“Interestingly, the 0.45 µm PES filters had much lower reported bubble points but equal or higher LRV values than the corresponding 0.2 µm filters that contained laser hole defects.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenDefault or vendor-recommended test parameters were used for all the bubble point tests.
“Default or vendor-recommended test parameters were used for all the bubble point tests.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenThere is no universal standard for the determination of bubble point in cartridge filters, and the methodologies and algorithms used are specific to AIT vendors.
“However, there is no universal standard for the determination of bubble point in cartridge filters, and the methodologies and algorithms that are used are specific to AIT vendors.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLaser-drilled holes are considered to be the most practical and controllable among various methods for creating artificial leaks in thin films and membranes and have often been used for this purpose.
“While “real-world” defects can encompass a variety of forms, laser-drilled holes are considered to be the most practical and controllable among various methods for creating artificial leaks in thin films and membranes and have often been used for this purpose [11,16,17,20,30,31].”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [11] Giglia, 2016, Air-water binary gas integrity test for sterilizing and virus filters, PDA J. Pharm. Sci. Technol. source
- cites [16] Mahler, 2019, Comparing physical container closure integrity test methods and artificial leak methodologies, PDA J. Pharm. Sci. Technol. source
- cites [17] Bio-Process Systems Alliance (2017). Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance, Bio-Process Systems Alliance.
Not checked in the free run.
- cites [20] Ferrante, 2020, Test process and results of potential masking of sterilizing-grade filters, PDA J. Pharm. Sci. Technol. source
- cites [30] Brown, 2017, Container closure integrity testing—practical aspects and approaches in the pharmaceutical industry, PDA J. Pharm. Sci. Technol. source
- cites [31] Aliaskarisohi, 2019, Single-Use System Integrity I: Using a Microbial Ingress Test Method to Determine the Maximum Allowable Leakage Limit (MALL), PDA J. Pharm. Sci. Technol. source
May combine two claims.
PremisereasoningThe bubble point indicates the largest membrane pore size, which can be correlated to bacterial retention, so bubble point measurement can provide an indirect measure of retention.
“Since the bubble point indicates the largest membrane pore size, which can be correlated to bacterial retention, bubble point measurement can provide an indirect measure of retention.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductcitationBacterial retention was measured in accordance with ASTM F838-20.
“To assess the retention capability of the filters, bacterial retention was measured in accordance with ASTM F838-20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites ASTM F838-20
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationreasoningThe defect detection capability of a bubble point test is AIT-specific, and user-adjustable bubble point recipe settings can impact the defect detection sensitivity of the test.
“Therefore, the defect detection capability of a bubble point test (throughout this paper, the term “bubble point test” refers to the collection of methods as applied by different AITs) is also AIT-specific. Even within an AIT, user-adjustable bubble point recipe settings can impact the defect detection sensitivity of the test.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenA diffusion test was run at the manufacturer-specified test pressure for each filter with the respective AIT that was used to run the bubble point test for that filter, and it served to confirm the leak flow rate that was applied to the filters.
“Although ascertaining the sensitivity of the gas–liquid diffusion test was not within the scope of this study, a diffusion test was run at the manufacturer-specified test pressure for each filter with the respective AIT that was used to run the bubble point test for that filter. The diffusion test served to confirm the leak flow rate that was applied to the filters.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe bubble point measured on larger-area devices, such as 10-inch pleated cartridges, can be measured to be significantly different than on 47 mm disks due to factors including the absolute background diffusive flow rate increasing in proportion to filter area, which obscures the transition between primarily diffusive flow and the onset of convective flow through pores evacuated of wetting fluid.
“For example, it has been pointed out that the bubble point measured on larger-area devices, such as 10-inch pleated cartridges that may contain the equivalent of 500–1000 47 mm disks in terms of filtration area, can be measured to be significantly different than on 47 mm disks due to several factors. One of these factors is that the absolute background diffusive flow rate through a membrane in”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [6] Jornitz, 2001, Filter Integrity Testing in Liquid Applications, Revisited, Pharm. Technol.
Not checked in the free run.
- cites [7] Jornitz, 2001, Filter integrity testing in liquid applications, revisited--part II, Pharm. Technol.
Not checked in the free run.
- cites [26] Johnston, 1981, Certain imprecisions in the bubble point measurement, PDA J. Pharm. Sci. Technol.
- cites [27] Sundaram, 2000, Considerations in using ‘bubble point’ type tests as filter integrity tests, part I: Effect of test methodology on filter cartridge ‘bubble point’ measurements and implications for the use of ‘bubble point’ type tests as correlated tests, Pharm. Technol.
Not checked in the free run.
- cites [28] Sundaram, 2000, Considerations in using ‘bubble point’ type tests as filter integrity tests, part II, Pharm. Technol.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe term "gross leak" is rarely, if ever, quantitatively defined in the integrity test literature and in AIT operating manuals.
“While the term “gross leak” is replete in the integrity test literature and in AIT operating manuals, it is rarely, if ever, quantitatively defined.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe bubble point relates to the largest pore or set of pores in a membrane, and many investigators have correlated membrane bubble point to its particle retention performance.
“Since the bubble point relates to the largest pore or set of pores in a membrane, many investigators have correlated membrane bubble point to its particle retention performance [23,24,25].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [23] Johnston, 1979, Comments on Organism Challenge Levels in Sterilizing Filter Efficiency Testing, Pharm. Technol.
Not checked in the free run.
- cites [24] Leahy, 1978, Validation of bacterial retention capabilities of membrane filters, Pharm. Technol.
Not checked in the free run.
- cites [25] Blanchard, 2007, Quantifying sterilizing membrane retention performance, BioProcess Int.
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenIdentical test procedures were used for integral devices and for the devices containing controlled defects.
“Identical test procedures were used for integral devices and for the devices containing controlled defects.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenStudies correlating membrane bubble point to particle retention have typically been conducted on small disk (often 47 mm) samples.
“However, these types of studies have typically been conducted on small disk (often 47 mm) samples.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenThe bubble point test is often paired with the air-water diffusion test, and the combined defect detection sensitivity when both tests are run is at least that of the air-water diffusion test.
“The bubble point test is often paired with the air–water diffusion test (these two tests complement each other) so that the combined defect detection sensitivity when both tests are run is at least that of the air–water diffusion test.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationnone givenThe bubble point test does confirm proper pore size rating.
“This study supports the generally recommended practice of pairing the bubble point test (which does confirm proper pore size rating) with a complementary gas–liquid diffusion test (better suited for detecting defects) to achieve a more comprehensive assessment of filter integrity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBoth the gas-liquid diffusion and bubble point tests have been endorsed by regulators, with FDA guidance stating that forward flow and bubble point tests are two integrity tests that can be used to detect filter leaks, and EU guidance stating that filter integrity should be verified before use and confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or压力-
“Both tests have also been endorsed by regulators, with FDA guidance stating, for example, that for sterilizing filters, “forward flow and bubble point tests… are two integrity tests that can be used” to detect any filter leaks [2]. Similarly, EU guidance states that the “integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Food and Drug Administration (FDA) (2004). Guideline on Sterile Drug Products Produced by Aseptic Processing, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drugs and Biologics.
Not checked in the free run.
- cites [3] Eudralex, G.M.P. (2008). The Rules Governing Medicinal Products in the European Union–Volume 4-EU Guidelines to Good Manufacturing Practice–Medicinal Products for Human and Veterinary Use–Annex 1–Manufacture of Sterile Medicinal Products, European Commission.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFor the air-water diffusion test, the minimum detectable single defect size in a sterilizing-grade 10-inch (25.4 cm) cartridge filter has previously been estimated to be in the range of 5-20 μm, depending on the filter area, accuracy of the diffusive flow measurement, and variability in filter properties.
“For the air–water diffusion test, the minimum detectable single defect size in a sterilizing-grade 10-inch (25.4 cm) cartridge filter has previously been estimated to be in the range of 5–20 µm, depending on the filter area, accuracy of the diffusive flow measurement, and variability in filter properties [11,18,19].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [11] Giglia, 2016, Air-water binary gas integrity test for sterilizing and virus filters, PDA J. Pharm. Sci. Technol. source
- cites [18] Hofmann, 1984, Integrity testing of microfiltration membranes, PDA J. Pharm. Sci. Technol.
- cites [19] Schroeder, 1980, Theoretical aspects of sterile filtration and integrity testing, Pharm. Technol.
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationMany authors have considered the limitations of bubble point tests as applied to cartridge filters, but concerns have primarily focused on measurement accuracies and the subjectivity aspects involved in determining the bubble point.
“Many authors have considered the limitations of bubble point tests as applied to cartridge filters and assemblies of cartridge filters, but concerns have primarily focused on measurement accuracies and the subjectivity aspects that are involved in determining the bubble point [6,7,26,27,28].”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [6] Jornitz, 2001, Filter Integrity Testing in Liquid Applications, Revisited, Pharm. Technol.
Not checked in the free run.
- cites [7] Jornitz, 2001, Filter integrity testing in liquid applications, revisited--part II, Pharm. Technol.
Not checked in the free run.
- cites [26] Johnston, 1981, Certain imprecisions in the bubble point measurement, PDA J. Pharm. Sci. Technol.
- cites [27] Sundaram, 2000, Considerations in using ‘bubble point’ type tests as filter integrity tests, part I: Effect of test methodology on filter cartridge ‘bubble point’ measurements and implications for the use of ‘bubble point’ type tests as correlated tests, Pharm. Technol.
Not checked in the free run.
- cites [28] Sundaram, 2000, Considerations in using ‘bubble point’ type tests as filter integrity tests, part II, Pharm. Technol.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBecause achieving a sterile effluent is of critical importance, sterilizing-grade filters are typically integrity-tested after assembly and prior to use, as well as again after use, as per industry and regulatory guidelines.
“Because achieving a sterile effluent is of critical importance, sterilizing-grade filters are typically integrity-tested after assembly and prior to use, as well as again after use, as per industry and regulatory guidelines [1,2,3].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Antonsen, 2008, Sterilizing filtration of liquids. Technical report no. 26 (revised 2008), PDA J. Pharm. Sci. Technol.
Not checked in the free run.
- cites [2] Food and Drug Administration (FDA) (2004). Guideline on Sterile Drug Products Produced by Aseptic Processing, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drugs and Biologics.
Not checked in the free run.
- cites [3] Eudralex, G.M.P. (2008). The Rules Governing Medicinal Products in the European Union–Volume 4-EU Guidelines to Good Manufacturing Practice–Medicinal Products for Human and Veterinary Use–Annex 1–Manufacture of Sterile Medicinal Products, European Commission.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll AITs used in this study were validated by the vendor for the determination of diffusive flow rate and bubble point of sterilizing-grade filters.
“All the testers were the most recent AIT versions offered by the vendors at the time of the study, and all of them were validated by the vendor for the determination of diffusive flow rate and bubble point of sterilizing-grade filters.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAlthough the bubble point test had relatively low sensitivity to filter leaks, it did serve to confirm the pore ratings of the installed filters.
“Although the bubble point test had relatively low sensitivity to filter leaks, it did serve to confirm the pore ratings of the installed filters.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAlthough the bubble point values as reported by AITs were insensitive to defects, they were sensitive to rated membrane pore size.
“This confirms that, although the bubble point values as reported by AITs were insensitive to defects, they were sensitive to rated membrane pore size.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenAt a typical starting pressure of 40 psi, the flow rate through an orifice-like defect is choked, such that the flow rate increases linearly with pressure, just as the diffusive flow rate through the integral portion of a membrane increases linearly with increasing pressure.
“However, at a typical starting pressure of 40 psi (276 kPa), the flow rate through an orifice-like defect is choked, such that the flow rate increases linearly with pressure, just as the diffusive flow rate through the integral portion of a membrane increases linearly with increasing pressure (absent thinning of the liquid layer with increasing pressure).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationnone givenFor sterilizing-grade filters where the bubble point is typically about 50 psi or higher, it is impractical to routinely start at such a low pressure.
“However, for sterilizing-grade filters where the bubble point is typically about 50 psi (345 kPa) or higher, it is impractical to routinely start at such a low pressure.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataLeaks from laser hole defects as large as 60 μm in diameter in 10-inch sterilizing-grade pleated cartridge filters and results for bacterial LRV as low as about 4 could escape failing a bubble point test.
“While the level of retention assurance of sterilizing-grade filters provided by the bubble point test as determined by AITs is filter- and AIT-specific (and within an AIT, potentially user-setting-specific), the results presented here showed that leaks from laser hole defects as large as 60 µm in diameter in 10-inch (25.4 cm) sterilizing-grade pleated cartridge filters and results for bacterial LR”
Quote in the paperSubstantial claim
The paper relies on this without support.
No known published studies exist on the minimum detectable defect size or the level of retention assurance provided by the bubble point test as applied to 10-inch sterilizing-grade cartridge filters.
“For the bubble point test, there are no known published studies on the minimum detectable defect size or the level of retention assurance provided by this test as applied to 10-inch sterilizing-grade cartridge filters.”
“While many authors have considered the limitations of bubble point tests as applied to cartridge filters, the level of bacterial retention assurance provided by this test as conducted with automated integrity testers (AITs) has not, until now, been quantified.”
The authors state this as an assumption.
The concentration of the retained species in the liquid flowing through a defect is the same as that in the bulk feed; the defect does not retain any of the species retained in the integral portion of the membrane.
“It was assumed that the concentration of the retained species in the liquid flowing through a defect was the same as that in the bulk feed, that is, the defect did not retain any of the species retained in the integral portion of the membrane.”
The authors state this as an assumption.
The model lines assumed an integral membrane bacterial LRV > 11–11.5, which was about the assay upper limit of the retention test.
“The model lines assumed an integral membrane bacterial LRV > 11–11.5, which was about the assay upper limit of the retention test.”
The paper relies on this without support.
There are no established, quantified criteria for what constitutes a gross leak or invalid test result.
“However, as noted, there are no established, quantified criteria for what constitutes a gross leak or invalid test result.”
The paper relies on this without support.
Filter vendors do not provide specifications for gross leaks.
“Filter vendors do not provide specifications for gross leaks, so the user of an AIT must rely on the algorithm used by the AIT, the details of which are not typically transparent to the user.”
The paper relies on this without support.
The algorithms used by AITs are usually not transparent to the user.
“Filter vendors do not provide specifications for gross leaks, so the user of an AIT must rely on the algorithm used by the AIT, the details of which are not typically transparent to the user.”
The paper relies on this without support.
Controlled laser hole defects are representative enough of real-world membrane defects for the study's conclusions about real-world defects to hold.
“As previously noted, “real-world” defects in membrane filters are not necessarily cylindrical in shape as with the controlled laser hole defects in this study. The relationship between defect size, leak rate, and bacterial retention depends on the specific geometry of a defect or defects. The results presented here, however, demonstrate that defects in cartridge membrane filters that were large”
The paper relies on this without support.
The gas–liquid diffusion test is not sensitive to pore size at pressures below the bubble point.
“The gas–liquid diffusion test, which is not sensitive to pore size at pressures below the bubble point, is better able to detect filter defects.”
Cites
Low-pressure membrane integrity tests for drinking water treatment: A review
Guo, H., Wyart, Y., Pérot, J., Nauleau, F., & Moulin, P. (2009) · Water Research · doi:10.1016/j.watres.2009.09.032 · Cited by 207 · see citing works
High sensitivity binary gas integrity test for membrane filters
Giglia, S., & Krishnan, M. (2008) · Journal of Membrane Science · doi:10.1016/j.memsci.2008.06.017 · Cited by 39 · see citing works
Self-citationCurrent and Emerging Techniques for High-Pressure Membrane Integrity Testing
Ostarcevic, E., Jacangelo, J. G., Gray, S. R., & Cran, M. J. (2018) · Membranes · doi:10.3390/membranes8030060 · Cited by 37 · see citing works
Container Closure Integrity Testing—Practical Aspects and Approaches in the Pharmaceutical Industry
Brown, H., Mahler, H.-C., Mellman, J., Nieto, A., Wagner, D., Schaar, M., Mathaes, R., Kossinna, J., Schmitting, F., Dreher, S., et al. (2017) · PDA Journal of Pharmaceutical Science and Technology · doi:10.5731/pdajpst.2016.006999 · Cited by 19 · see citing works
Sterilizing filtration of liquids. Technical report no. 26 (revised 2008).
Hr, A., Awafo, Jl, B., Carter, J. R., Rs, C., Egli, S., Tm, F., Jornitz, M. W., Kearns, M., Levy, R. V., et al. (2008) · PubMed · Cited by 17 · see citing works
Principles of integrity testing hydrophilic microporous membrane filters part ii
Emory, S. F. (1989) · Pharmaceutical technology · Cited by 11 · see citing works
Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies
Peláez, S. S., Mahler, H.-C., Herdlitschka, C., Wertli, T., Kahl, M., Koulov, A., Matter, A., Singh, S. K., Widmer, M., Germershaus, O., et al. (2019) · PDA Journal of Pharmaceutical Science and Technology · doi:10.5731/pdajpst.2018.009332 · Cited by 9 · see citing works
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Quality control of absolute bacteria removal filters.
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Test Process and Results of Potential Masking of Sterilizing-Grade Filters
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Air-Water Binary Gas Integrity Test for Sterilizing and Virus Filters
Giglia, S., Caulmare, J., Nhiem, D., & Porreca, D. (2016) · PDA Journal of Pharmaceutical Science and Technology · doi:10.5731/pdajpst.2016.006437 · Cited by 2 · see citing works
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Preuse/Poststerilization Integrity Testing (PUPSIT): To Do or Not to Do?
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(1984) · PubMed
(1981) · PubMed
Flagged first, then by citations
5 of the 21 references couldn’t be matched to a known paper.
Research works printed but not linked: 10
- Emory, 1989, Principles of integrity-testing hydrophilic microporous membrane filters, part I, Pharm. Technol., 13, 68
- Jornitz, 2001, Filter integrity testing in liquid applications, revisited--part II, Pharm. Technol., 25, 24
- Scheper, T., and Jornitz, W.M. (2006). Sterile Filtration. Advances in Biochemical Engineering/Biotechnology, Springer.
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- Leahy, 1978, Validation of bacterial retention capabilities of membrane filters, Pharm. Technol., 2, 64
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- Sundaram, 2000, Considerations in using ‘bubble point’ type tests as filter integrity tests, part II, Pharm. Technol., 24, 108
Cited by
Sorted by citations
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Regulatory landscape of ophthalmic products
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- Authors
- Giglia, S., Alembath, A., & Hersey, J.
- Affiliations
- MilliporeSigma (United States) (US)
- Corresponding author
- Giglia, Sal
- Venue
- Membranes
- Publisher
- MDPI AG
- Published
- 2023-01-10
- Volume
- 13
- Issue
- 1
- Pages
- 88
- ISSN
- 2077-0375 (ISSN-L)
- PMC
- PMC9865406
- OpenAlex
- W4315646971
- Semantic Scholar
- 04131aed793753cef0bf2fdaf18b10860709cda5
- Cited by
- 3
- References
- 21
- Citations by year
- 2025: 2 · 2024: 1
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Membranes (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Physical Sciences › Environmental Science › Water Science and Technology › Membrane Separation Technologies
- Physical Sciences › Engineering › Electrical and Electronic Engineering › Aerosol Filtration and Electrostatic Precipitation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Keywords
- filter integrity testing, defect detection sensitivity, bacterial retention, log reduction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.
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