Below you will find frequently asked questions about the integrity assurance of single-use systems.
These questions have been reviewed and answered by BPSA’s Integrity Assurance Committee of industry experts.
Additional Questions: If you have additional questions, you can submit them to bpsa@socma.org. Inquiries will be reviewed by BPSA’s Committee, and the most relevant questions will be added to the FAQ page.
BPSA Resources:
- BPSA Technical Guide, 2023 Design, Control and Monitoring of SUS for Integrity Assurance, Volume 2
- BPSA Technical Guide, 2017 Design, Control and Monitoring of SUS for Integrity Assurance
Technically, some of the established test methods used for pre-use testing, such as pressure decay or flow rate measurement, can be applied post-use as well. There is however a risk of false PASS, as residual liquid/product (liquid or dried) in the SUS can impact the test result, e.g., due to blocking a defect in the SUS (also refer to Table 2 in ASTM E3244).
This also applies to helium tracer gas in sniffer mode. Helium tracer gas detection in vacuum mode is nearly impossible to apply post-use, as the evaporation of residual liquid would highly impact the generation of an appropriate vacuum level, unless the system is carefully dried. This is a complex operation that limits this post-use test to specific validation testing.
For all test methods to apply it reliably post-use, a prerequisite would be to establish a validated cleaning and drying procedure for the SUS, bringing it back to the state as it was before use.
Note that there are simple good practices expected to be in place to check for the absence of leaks during the process, such as visual checks with or without aids (see section 3.5, third paragraph of the BPSA Technical Guide, Volume 2, for further details)
When the test is considered to be an integrity test (not a leak test), the sensitivity of the test method must be established (see section 5.1 of the BPSA Technical Guide, Volume 2, for further details)
ASTM E3244-20, Standard Practice for Integrity Assurance and Testing of Single-Use Systems.
BPSA Technical Guide, 2023 Design, Control and Monitoring of SUS for Integrity Assurance, Volume 2
When pressure for the leak/integrity test is applied on a SUS (for pressure decay, but for tracer gas detection too), the surface areas of the test article that are mechanically supported by the container wall (or other supporting structures) are pressed against the structure surface. This can cause the blocking of a potential defect in this surface area, also called masking effect. More considerations about masking effect can be found in ASTM E3244-23, Table 2 and E3336-22 5.2.2.2 Note 8).
ASTM E3244-23, Standard Practice for Integrity Assurance and Testing of Single-Use Systems
ASTM E3336-22, Standard Test Method for Physical Integrity Testing of Single-Use Systems
Introduction of particulate matter, microorganisms (bioburden), moisture or oil residues are not acceptable for single-use applications. Compressed air used for pressure decay leak testing shall be produced in a manner that delivers oil free, dry air, free from particulate matter. It is best practice to additionally fit the test system with a sterilizing grade point of use filter in the flow path directly before the test article.
Integrity and leak testing of single-use systems (SUS) encompass a spectrum of tests that may be employed to ensure integrity assurance as part of a quality by design approach. Most commonly pressure decay and tracer gas leak tests are used to establish the integrity of SUS or specific components in a non-destructive manner. The test methods are developed to ensure the SUS is not damaged by the testing due to over pressurization, contamination or other means. These efforts during test method development and validation help to ensure no final drug product is lost as a result of the failure of the tested SUS or contamination of the SUS. A validation package showing the absence of impact of the leak/integrity test on the CQA (Critical Quality Attributes) of the SUS is expected to be generated by the supplier.
Further details on validation expectations associated to pressure based test methods and tracer-gas based test methods can be found in ASTM E3336-22.
Some destructive leak tests may be employed during validation or as lot release tests. Examples include microbial ingress testing or bubble leak tests. In these instances, the SUS or component subjected to the testing is not expected to be used for the end-use application.
ASTM E3336-22, Standard Test Method for Physical Integrity Testing of Single-Use Systems
This is a very important distinction, as it has a direct impact on the SUS assurance of integrity. “Integrity test” is still too often misused to name a simple leak test.
Physical testing of SUS can only provide a full integrity guarantee when the detection limit can be correlated to the barrier properties of the SUS.[2]
Barrier properties are defined according to the intended use or process compatibility of the SUS[1], maintaining the adequate barrier between the inside and outside of the SUS. Examples would be transparency to light, barrier to microbial ingress, to liquid loss or gas permeability.[1]
According to the common definitions in ASTM E3244, E3251 and E3336, only a test method with a limit of detection good enough to confirm the barrier properties of a SUS is an integrity test. A test method with inferior (less performant) or unqualified limit of detection is only a leak test.[2]
An integrity test is usually correlated to the size of an orifice/hole, which is itself correlated to the intended barrier property or Maximum Allowable Leakage Limit (MALL). See BPSA Technical Guide, Volume 2, section 5.1 for further details on MALL.
A leak test acceptance criterion can be associated to a leak size, but without the correlation to the MALL. Another typical example of leak test acceptance criterion is the maximum delta pressure allowed in case of pressure decay leak testing.
[1] BPSA Technical Guide, 2017 Design, Control and Monitoring of SUS for Integrity Assurance, section 2.2.1
[2] BPSA Technical Guide, 2023 Design, Control and Monitoring of SUS for Integrity Assurance, Volume 2, section 5.1