Single-use solutions for PUPSIT: requirements, challenges, and solutions

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Operational expenditures (OPEX) are broadly comparable across the three modalities under equivalent throughput and staffing assumptions.

“By contrast, operational expenditures (OPEX) are broadly comparable under equivalent throughput and staffing assumptions.”

• AssumptionThe authors state this as an assumption: Throughput and staffing are equivalent across the three implementation modalities when comparing operational expenditures.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Across the three implementation modalities (manual, shadowboard-standardized, and fully automated), capital expenditures (CAPEX) differ materially when equipment scope, control architecture, and validation requirements are considered.

“Across the three implementation modalities (manual, shadowboard-standardized, and fully automated), capital expenditures (CAPEX) differ materially when equipment scope, control architecture, and validation requirements are considered.”

Probably not a substantial claim: may not pass S4 (based).

Design strategies for single-use systems emphasize simplicity, error-proofing, and effective wetting and flushing methods.

“Design strategies for single-use systems emphasize simplicity, error-proofing, and effective wetting and flushing methods.”

May combine two claims.

The FDA approach is risk-based under 21 CFR 211.113(b), allowing flexibility, provided sterility assurance is maintained.

“The approach is risk-based under 21 CFR 211.113(b), allowing flexibility; the provided sterility assurance is maintained.”

• cites 21 CFR 211.113(b)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Secure clamping mechanisms such as Oetiker clamps are employed to ensure tight seals while overmolding techniques further enhance reliability by eliminating crevices and potential leak paths, improving both mechanical strength and hygienic design.

“To mitigate these risks, secure clamping mechanisms such as Oetiker™1 clamps are employed to ensure tight seals while overmolding techniques further enhance reliability by eliminating crevices and potential leak paths, thereby improving both mechanical strength and hygienic design (Bio-Process Systems Alliance (BPSA), 2023).”

• cites Bio-Process Systems Alliance (BPSA), 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Option 1 (manual vent valves) requires an attached flush bag on the vent valves to collect air and droplets; otherwise there is a risk of contamination and leaking product into the cleanroom or isolator.

“Option 1 requires, for example, an attached flush bag on the vent valves of the filter to collect air and droplets of the fluid; otherwise, there is a risk of contamination of the system and a risk of leaking the product into the cleanroom or isolator.”

Probably not a substantial claim: may not pass S2 (checkable).

Mechanical strength is not an isolated requirement, but a vital component of the broader CCS.

“Mechanical strength is not an isolated requirement, but a vital component of the broader CCS.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In a broader contamination control strategy, PUPSIT represents a mitigation strategy.

“In the context of a broader contamination control strategy (CCS), where risks are assessed and managed according to quality risk management (QRM) principles described in ICH Q9 (European Medicines Agency (EMA), 2025), PUPSIT represents a mitigation strategy.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

A robust E&L strategy is not just about testing; it is about integrating material science with process design.

“However, a robust E&L strategy is not just about testing; it is about integrating material science with process design.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Incorporating a sterile air filter downstream of the primary sterile filter adds a critical component that requires post-use validation and could risk a batch.

“Incorporating a sterile air filter downstream of the primary sterile filter adds a critical component that requires post-use validation and could risk a batch.”

May combine two claims.

The PUPSIT requirement addresses the risk of filters being damaged during transport, unpacking, installation, or sterilization as well as filter flaw masking.

“This requirement addresses the risk of filters being damaged during transport, unpacking, installation, or sterilization as well as filter flaw masking, where defects could be obscured during filtration and escape detection in post-use tests.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Extractables help predict what might leach, while leachables are what actually do.

“The distinction is subtle but critical: extractables help predict what might leach, while leachables are what actually do.”

May combine two claims.

Other materials such as PEEK, PP, and silicone also play important roles, with PEEK providing excellent mechanical and thermal properties for high-performance connectors and housings, and silicone offering flexibility and biocompatibility, though it requires thorough evaluation for extractables.

“Other materials such as polyether ether ketone (PEEK), polypropylene (PP), and silicone also play important roles, with PEEK providing excellent mechanical and thermal properties for high-performance connectors and housings, and silicone offering flexibility and biocompatibility, though it requires thorough evaluation for extractables (Kushwah, et al. 2022; Huang, et al. 2011; Jenke et al. 2006).”

• cites Kushwah, et al. 2022 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Huang, et al. 2011 sourceNot checked — no full text of the source
• cites Jenke et al. 2006 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Achieving both high recovery and a reliable wetting procedure can be challenging to integrate effectively in one single-use system.

“However, achieving both high recovery and a reliable wetting procedure can be challenging to integrate effectively in one single-use system.”

Classified as probably not a substantial claim. May combine two claims.

PUPSIT aims to verify the integrity of sterilized filters before use, reducing risks of defect masking and safeguarding drugs against contamination.

“PUPSIT aims to verify the integrity of sterilized filters before use, reducing the risks of defect masking and safeguarding drugs against contamination.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Regardless of the integrity test method, the wetted filter is pressurized with air, and the diffusive gas flow through the membrane is measured.

“however, regardless of the test method, the wetted filter is pressurized with air, and the diffusive gas flow through the membrane is measured.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Introducing sterile air into the capsule's inner core to facilitate recovery is a complex task.

“For example, introducing sterile air into the capsule’s inner core to facilitate recovery is a complex task.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

Compliance with international standards and industry guidelines is key to aligning materials and design with a robust CCS.

“Compliance with international standards and industry guidelines is key to aligning materials and design with a robust CCS.”

Classified as probably not a substantial claim.

In the first wetting step where the membrane is still dry, air can easily pass through the dry sterile filter membrane and leave the flow kit downstream of the filter.

“In the first wetting step of PUPSIT where the membrane is still dry, the air can easily pass through the dry sterile filter membrane and leave the flow kit downstream of the filter.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Suppliers of SUT offer product-specific generation of E&L profiles as a service, which can be used by end users in a risk-based approach to determine the level of these substances per dose of final product.

“Suppliers of SUT also offer product-specific generation of E&L profiles as a service, which can be used by the end users in a risk-based approach to determine the level of these substances per dose of final product.”

Classified as probably not a substantial claim.

A comparative analysis of single-use PUPSIT systems including manual, shadowboard-assisted, and automated PUPSIT systems illustrates how process flexibility, consistency, and safety can be achieved.

“A comparative analysis of single-use PUPSIT systems including manual, shadowboard-assisted, and automated PUPSIT systems illustrates how process flexibility, consistency, and safety can be achieved.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Annex 1 emphasizes that manufacturers must apply QRM principles, as outlined in ICH Q9, to justify their approach to PUPSIT.

“Annex 1 emphasizes that manufacturers must apply QRM principles, as outlined in ICH Q9, to justify their approach to PUPSIT.”

• cites European Medicines Agency (EMA), 2025Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

An integrity test before use requires wetting and venting of the filter, followed by pressurized air applied to the filter for integrity test measurement, typically bubble point or forward flow testing.

“an integrity test before use requires a wetting and venting of the filter, followed by pressurized air being subjected onto the filter for the integrity test measurement, typically either bubble point or forward flow testing.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Single-use technology and stainless-steel filtration systems are two commonly used options in biomanufacturing.

“Single-use technology (SUT) and stainless-steel filtration systems are two commonly used options in biomanufacturing.”

May combine two claims.

Even when not naming PUPSIT, these regulatory bodies expect integrity testing of sterilizing-grade filters pre- and post-use and clear documentation as a vital part of the contamination control strategy.

“Even when not naming PUPSIT, these regulatory bodies expect integrity testing of sterilizing-grade filters pre- and post-use and clear documentation as a vital part of the contamination control strategy.”

May combine two claims.

These materials retain mechanical strength and microbial barrier function even after gamma irradiation, making them ideal for sterile filtration systems.

“These materials retain their mechanical strength and microbial barrier function even after gamma irradiation, making them ideal for sterile filtration systems.”

• cites Kushwah, et al. 2022 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Huang, et al. 2011 sourceNot checked — no full text of the source
• cites Jenke et al. 2006 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S4 (based).

PUPSIT systems must endure physical stresses imposed during sterilization, integrity testing, and routine handling, while preserving a sterile barrier.

“These systems must endure the physical stresses imposed during sterilization, integrity testing, and routine handling, all while preserving a sterile barrier.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Single-use flow kits for PUPSIT with sterile filters are supplied gamma irradiated and thus ready for flushing, integrity testing, and filtration.

“Single-use flow kits for PUPSIT with sterile filters are supplied gamma irradiated and thus ready for flushing, integrity testing and filtration.”

Probably not a substantial claim: may not pass S4 (based).

The choice of membrane type and filter size, tubing diameter, and recovery methods impacts product recovery.

“The choice of membrane type and filter size, tubing diameter, and recovery methods impacts the product recovery.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The orientation of both sterile and vent filters is important to maintain vertical venting of the system.

“The orientation of both sterile and vent filters is important to maintain vertical venting of the system.”

May combine two claims.

Pressure-decay testing pressurizes the assembly and observes loss of pressure over time; semi-automated systems have improved sensitivity and consistency, making this method widely applicable in routine operations.

“One of the most practical options for IT is pressure‑decay testing, in which the assembly is pressurized and observed for any loss of pressure over time; semi‑automated systems have improved both sensitivity and consistency, making this method widely applicable in routine operations (Waldron et al. 2025).”

• cites Waldron et al. 2025 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S4 (based).

It is essential that materials retain functional properties to ensure sterility and reliability of the process, including mechanical strength, dimensional stability, and low extractables and leachables.

“It is essential that these materials retain their functional properties to ensure the sterility and reliability of the process. This includes maintaining mechanical strength, dimensional stability, and a low amount of extractables and leachables that could contaminate the product.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Integrity testing of single-use assemblies broadly falls into two categories: general integrity tests, which use pressure-decay, vacuum-decay, or gas-flow methods to identify gross and moderate leaks in a practical, non-destructive manner; and helium-based integrity tests, which provide high-sensitivity detection of micro-defects and establish a direct, quantitative link between physical leakage和?

“Integrity testing of single-use assemblies broadly falls into two categories: general integrity tests, which use pressure-decay, vacuum-decay, or gas-flow methods to identify gross and moderate leaks in a practical, non-destructive manner; and helium-based integrity tests, which provide high-sensitivity detection of micro-defects and establish a direct, quantitative link between physical leakage”

Probably not a substantial claim: may not pass S3 (load-bearing).

These frameworks provide a structured approach to assessing the safety of materials used in contact with drug products.

“These frameworks provide a structured approach to assessing the safety of materials used in contact with drug products.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Common filter integrity test methods include bubble point, diffusive flow, water intrusion, and pressure hold tests.

“Common methods include bubble point, diffusive flow, water intrusion, and pressure hold tests (European Medicines Agency (EMA), 2022).”

• cites European Medicines Agency (EMA), 2022Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Regulators expect clear evidence that the chosen approach maintains sterility assurance and complies with GMP principles.

“Regulators expect clear evidence that the chosen approach maintains sterility assurance and complies with GMP principles.”

May combine two claims.

For product-wet processes, the system design can be simpler as only one product inlet is required, and a flush bag becomes optional.

“For product-wet processes, the system design can be held simpler as only one product inlet is required, and a flush bag becomes optional (Fig. 1b).”

Classified as probably not a substantial claim.

Design principles aim to eliminate areas where fluids can stagnate, such as dead legs, which do not easily allow for full product recoveries.

“Design principles aim to eliminate areas where fluids can stagnate, such as dead legs, which do not easily allow for full product recoveries.”

Classified as probably not a substantial claim.

In both water-wet and product-wet scenarios, air must be removed from the capsule during wetting and priming before and after the integrity test.

“In both scenarios, air must be removed from the capsule during wetting and priming before and after the integrity test.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The flush liquid can either be collected in a biocontainer or exit the filter flow kit by using hydrophobic/hydrophilic barrier filters.

“The flush liquid can either be collected in a biocontainer or exit the filter flow kit by using hydrophobic/hydrophilic barrier filters.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Annex 1 acknowledges that PUPSIT may not always be possible, with processing of very small volumes given as an example, but volumes are not specified.

“Annex 1 acknowledges that PUPSIT may not always be possible. Processing of very small volumes is given as example, but volumes are not specified.”

• cites European Medicines Agency (EMA), 2022Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Burst pressure testing determines the maximum pressure the system can withstand before failure, while tensile strength testing evaluates the material's resistance to pulling forces.

“Burst pressure testing determines the maximum pressure the system can withstand before failure, while tensile strength testing evaluates the material’s resistance to pulling forces.”

Probably not a substantial claim: may not pass S3 (load-bearing).

QRM ensures that decisions regarding filter integrity testing are science-based, systematic, and documented, reducing the risk of microbial contamination in sterile medicinal products.

“QRM ensures that decisions regarding filter integrity testing are science-based, systematic, and documented, reducing the risk of microbial contamination in sterile medicinal products.”

• cites ICH Q9Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

This leads to chain scission, crosslinking, and uneven structural changes that generate internal stress.

“This in turn leads to chain scission, crosslinking, and uneven structural changes that generate internal stress.”

May combine two claims.

FDA guidance (2004) requires post-use integrity testing for batch release but does not mandate PUPSIT and does recommend it as a best practice.

“In the USA, the Food and Drug Administration’s (FDA) guidance (2004) requires post-use integrity testing for batch release but does not mandate PUPSIT and does recommend it as a best practice however.”

• cites FDA guidance (2004)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Materials used in PUPSIT assemblies must be resilient to the desired sterilization methods, high pressure, and chemical exposure of the drug and excipients.

“As part of this life cycle, materials must be resilient to the desired sterilization methods, high pressure and chemical exposure of the drug and excipients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Venting through dedicated vent filters is a safe and convenient option since air filters are also needed to connect the integrity test machine when performing the filter integrity test.

“Venting through dedicated vent filters is a safe and convenient option since the air filters are also needed to connect the integrity test machine when performing the filter integrity test.”

Probably not a substantial claim: may not pass S3 (load-bearing).

ISO 13408-1, ISO 11137, and USP chapters provide a solid framework for ensuring product safety and efficacy.

“Additional standards such as ISO 13408-1 for aseptic processing (International Organization for Standardization (ISO), 2023), ISO 11137 for radiation sterilization (International Organization for Standardization (ISO), 2025), and USP chapters on microbial and particulate contamination provide a solid framework for ensuring product safety and efficacy (United States Pharmacopeial Convention (USP),”

• cites International Organization for Standardization (ISO), 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites International Organization for Standardization (ISO), 2025Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites United States Pharmacopeial Convention (USP), 2025Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

SUTs are now widely used across the entire product life cycle from development to commercial manufacture.

“While processes were historically built in steel facilities, SUTs are now widely used across the entire product life cycle from development to commercial manufacture.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Industry-specific recommendations from DECHEMA and supplier validation guides offer practical insights into the selection and qualification of materials for single-use systems.

“Industry-specific recommendations, such as those from DECHEMA (DECHEMA Expert Group Single-Use Technologies 2020) and validation guides from suppliers, offer practical insights into the selection and qualification of materials for single-use systems.”

• cites DECHEMA Expert Group Single-Use Technologies 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Sustainable materials and designs for single-use systems gain importance due to increasing focus on the environmental footprint of drug manufacturing.

“With increasing focus on environmental footprint of drug manufacturing, sustainable materials and designs for single-use systems gain importance.”

Probably not a substantial claim: may not pass S2 (checkable).

In pharmaceutical manufacturing, especially within PUPSIT, scrutiny of materials for extractables and leachables is a matter of patient safety and product integrity.

“In pharmaceutical manufacturing, especially within the framework of PUPSIT, the scrutiny of materials for extractables and leachables (E&L) is not just a regulatory checkbox; it is a matter of patient safety and product integrity.”

Classified as probably not a substantial claim.

Mechanical integrity of PUPSIT assemblies is essential for ensuring operational reliability and maintaining contamination control.

“The mechanical integrity of PUPSIT assemblies is essential for ensuring operational reliability and maintaining contamination control.”

May combine two claims.

To withstand these conditions, tubing materials must offer both flexibility and high tensile strength, so reinforced silicone and braided thermoplastic elastomers are commonly used because they maintain structural integrity under pressure and are compatible with most sterilization methods.

“To withstand these conditions, tubing materials must offer both flexibility and high tensile strength, so reinforced silicone and braided thermoplastic elastomers (TPE) are commonly used because they maintain structural integrity under pressure and are compatible with most sterilization methods.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Vacuum-decay testing evaluates changes in vacuum rather than pressure and is recognized among standard leak-testing tools, particularly for components that tolerate vacuum without deformation.

“A related approach, vacuum‑decay testing, evaluates changes in vacuum rather than pressure and is recognized among standard leak‑testing tools, particularly for components that tolerate vacuum without deformation (ASTM International 2024).”

• cites ASTM International 2024Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Other major regulatory bodies align with PIC/S principles (2023), including Health Canada (2025), Japanese PMDA (2011), South Korean MFDS (2016), and Chinese NMPA (2011).

“Other major regulatory bodies align with Pharmaceutical Inspection Co-operation Scheme (PIC/S) principles (2023), which includes Health Canada (2025), the Japanese Pharmaceuticals and Medical Devices Agency (2011), the South Korean Ministry of Food and Drug Safety (MFDS 2016), and the Chinese National Medical Products Administration (NMPA 2011).”

• cites Pharmaceutical Inspection Co-operation Scheme (PIC/S) principles (2023)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Health Canada (2025)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Japanese Pharmaceuticals and Medical Devices Agency (2011)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Weld-free, pre-assembled single-use systems offer additional benefits by simplifying installation and reducing the potential for human error.

“Weld-free, pre-assembled single-use systems therefore offer additional benefits by simplifying installation and reducing the potential for human error.”

May combine two claims.

Important factors when performing a process risk assessment are the chance of a present filter damage being masked and whether the process fluid can plug and thereby mask this damage.

“Important factors when performing a process risk assessment are the chance of a present filter damage being masked and whether the process fluid can plug and thereby mask this damage (Ferrante et al. 2020).”

• cites Ferrante et al. 2020 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

While PUPSIT may not be strictly mandatory, drug manufacturers are expected to assess and explain any exceptions very carefully in a risk assessment.

“While PUPSIT may not be strictly mandatory, drug manufacturers are expected to assess and explain any exceptions very carefully in a risk assessment.”

Classified as probably not a substantial claim.

In cases where PUPSIT is not possible, a thorough risk-based rationale must be documented, supported by process knowledge and supplier data.

“In such cases, a thorough risk-based rationale must be documented, supported by process knowledge and supplier data.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Assemblies that fail under pressure or mechanical stress can compromise sterility, introduce contaminants, and disrupt process continuity.

“Assemblies that fail under pressure or mechanical stress can compromise sterility, introduce contaminants, and disrupt process continuity.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

For wetting with water, an additional water inlet must be integrated as well as a bigger flush bag to collect the water after wetting.

“For wetting with water, an additional water inlet must be integrated as well as a bigger flush bag to collect the water after wetting (Fig. 1a).”

May combine two claims.

Implementing PUPSIT introduces significant technical and operational challenges, including more complex wetting and venting procedures that may bring increased risk of contamination and susceptibility to human error.

“However, implementing PUPSIT introduces significant technical and operational challenges, including more complex wetting and venting procedures that may bring increased risk of contamination and susceptibility to human error.”

• cites BioPhorum Operations Group (BPOG), 2024 sourceNot checked — no full text of the source

May combine two claims.

The revised Annex 1 has been adopted by PIC/S, which now requires drug manufacturers outside the EU to assess and implement PUPSIT.

“The new revision has also been adopted by PIC/S (Pharmaceutical Inspection Co-operation Scheme), which now also requires drug manufacturers outside of the EU to assess and implement PUPSIT.”

• cites Pharmaceutical Inspection Co-operation Scheme (PIC/S)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

A robust E&L strategy involves selecting the right materials, understanding their behavior under sterilization and operational conditions, and ensuring that potential leachables are within safe limits.

“It involves selecting the right materials, understanding their behavior under sterilization and operational conditions, and ensuring that any potential leachables are within safe limits.”

May combine two claims.

Automation facilitates real-time parameter verification against validated ranges and direct MES connectivity for contemporaneous documentation.

“Automation also facilitates real-time parameter verification against validated ranges and direct manufacturing execution system (MES) connectivity for contemporaneous documentation.”

May combine two claims.

Offline or benchtop testing of housings can minimize production line downtime, and a shadowboard can support this by enabling multiple housings to be prepared for testing in parallel.

“Offline or benchtop testing of housings can also be used to minimize production line downtime, a concept where a shadowboard can support by enabling multiple housings to be prepared for testing in parallel (Stering 2014).”

• cites Stering 2014Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S4 (based).

The biopharmaceutical industry, including drug manufacturers, suppliers, and industry groups, has developed a range of options and best practices for system design, material selection, and process operation to meet requirements around performing PUPSIT.

“Since decades and even more now with Annex 1 updated in 2022, the biopharmaceutical industry, including drug manufacturers, suppliers, and industry groups, have developed a range of options and best practices for system design, material selection, and process operation to meet these new requirements around performing PUPSIT.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Technical challenges can be addressed by best practices in process design and material selection.

“Technical challenges can be addressed by best practices in process design and material selection.”

May combine two claims.

Integrating helium leak testing into the overall CCS allows manufacturers to significantly reduce the risk of undetected leaks and ensure the robustness of single-use systems used in aseptic processing.

“By integrating helium leak testing into the overall CCS, manufacturers can significantly reduce the risk of undetected leaks and ensure the robustness of single-use systems used in aseptic processing.”

May combine two claims.

Fully automated systems minimize contamination risk, speed up setup and testing, and handle electronic records natively.

“They minimize contamination risk, speed up setup and testing, and handle electronic records natively.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

By detecting filter damage after sterilization but before use, PUPSIT mitigates the risk of defect masking during filtration and helps prevent product contamination, thereby strengthening sterility assurance.

“By detecting filter damage after sterilization but before use, PUPSIT mitigates the risk of defect masking during filtration and helps prevent product contamination, thereby strengthening sterility assurance.”

May combine two claims.

Both the 2 μm and 10 μm detection limits comply with the MALL (maximum allowable leakage limit) defined in USP 1207.

“Both comply to the MALL (maximum allowable leakage limit, defined in USP 1207 (United States Pharmacopeial Convention (USP), 2025) (ASTM International 2023).”

• cites United States Pharmacopeial Convention (USP), 2025Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites ASTM International 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Manual single-use systems can meet Annex 1 requirements but lean heavily on operator skill, environmental discipline, and meticulous documentation.

“When looking at the intent of Annex 1 and what inspectors focus on, manual single-use systems can meet the requirements, but they lean heavily on operator skill, environmental discipline, and meticulous documentation.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These materials are evaluated using ISO 14040:2006 and ISO 14044:2006 for life cycle assessment and for recyclability.

“These materials are evaluated using ISO 14040:2006 and ISO 14044:2006 (International Organization for Standardization (ISO), 2006) for life cycle assessment and for recyclability.”

• cites International Organization for Standardization (ISO), 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Shadowboard systems cut down on assembly errors and make execution more consistent by standardizing layout and physically encoding process steps.

“They do not automate the process, but by standardizing the layout and physically encoding the process steps, they cut down on assembly errors and make execution more consistent.”

May combine two claims.

Vendor and engineering-method documentation show that mass-flow approaches are particularly suited for higher-flow or large-volume components, while high-range mass-flow methods are specifically applied when large leaks are present and fine-defect sensitivity is less critical.

“Vendor and engineering‑method documentation show that mass‑flow approaches are particularly suited for higher‑flow or large‑volume components, while high‑range mass‑flow methods are specifically applied when large leaks are present and fine‑defect sensitivity is less critical (Hogreve 2023).”

• cites Hogreve 2023 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing).

The implementation of helium leak testing is guided by ASTM E3244-23, which outlines procedures for calibration, sensitivity verification, and validation of helium leak detection systems.

“The implementation of helium leak testing is guided by standards such as ASTM E3244-23, which outlines procedures for calibration, sensitivity verification, and validation of helium leak detection systems”

• cites ASTM International 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Environmental regulatory pressure in multiple jurisdictions is accelerating the transition away from PFAS materials.

“On another front, environmental regulatory pressure in multiple jurisdictions is accelerating the transition away from PFAS (per‑ and polyfluoroalkyl substances) materials (ECHA European Chemicals Agency 2023).”

• cites ECHA European Chemicals Agency 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The helium method and acceptance criteria have been fully validated by some suppliers to detect a defect down to 2 μm with assemblies including biocontainers ranging in size from 50 mL to 200 L and mixer biocontainers up to 200 L.

“The method and acceptance criteria have been fully validated by some suppliers to detect a defect down to a 2 µm with assemblies including biocontainers ranging in size from 50 mL to 200 L and mixer biocontainers in sizes up to 200 L (Bio-Process Systems Alliance (BPSA), 2023).”

• cites Bio-Process Systems Alliance (BPSA), 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

This aligns with the PDA body of work that correlates gas-flow behavior through micro-defects with maximum allowable leakage limits (MALL) and demonstrates that validated gas-flow measurements can be mapped to microbiological risk thresholds, thereby justifying air/nitrogen tests in use-cases that do not demand ultra-trace sensitivity.

“This aligns with the PDA body of work that correlates gas‑flow behavior through micro‑defects with maximum allowable leakage limits (MALL) (Hogreve 2023) and demonstrates that validated gas‑flow measurements can be mapped to microbiological risk thresholds, thereby justifying air/nitrogen tests in use‑cases that do not demand ultra‑trace sensitivity.”

• cites Hogreve 2023 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Automated helium integrity testing systems reduce operator variability and improve detection accuracy.

“these systems reduce operator variability and improve detection accuracy.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Shadowboard systems make conversations with inspectors easier because users can point to a tangible, standardized practice designed to control risk.

“Additionally, they make conversations with inspectors easier because users can point to a tangible, standardized practice designed to control risk.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Next-generation sterilizing-grade filters are increasingly subject to sustainability evaluations aligned with internationally recognized standards, such as ISO 14067 for carbon footprint quantification.

“Next-generation sterilizing-grade filters are increasingly subject to sustainability evaluations aligned with internationally recognized standards, such as ISO 14067 for carbon footprint quantification (International Organization for Standardization (ISO), 2018), enabling end users to systematically assess and optimize the environmental impact of their filtration processes.”

• cites International Organization for Standardization (ISO), 2018Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Mass-flow leak testing measures the gas required to maintain stable pressure conditions and is widely used for applications involving larger leak rates.

“Mass‑flow leak testing offers another useful pathway and measures the gas required to maintain stable pressure conditions. It is widely used for applications involving larger leak rates.”

May combine two claims.

Fully automated PUPSIT systems minimize manual interventions on the sterile side, improve repeatability of test conditions, and embed alarm handling and interlocks that halt execution or trigger preprogrammed mitigation upon deviation.

“These features minimize manual interventions on the sterile side, improve repeatability of test conditions, and embed alarm handling and interlocks that halt execution or trigger preprogrammed mitigation upon deviation.”

Classified as probably not a substantial claim. May combine two claims.

Suppliers of fully automated PUPSIT machines describe systems that natively execute both PUPSIT and post-use integrity tests and can incorporate leak tests of the single-use flow path prior to product commitment, aligning with Annex 1 while reducing contamination risk from handling.

“Suppliers of those machines describe systems that natively execute both PUPSIT and post-use integrity tests and can incorporate leak tests of the single-use flow path prior to product commitment, aligning tightly with Annex 1 while reducing contamination risk from handling.”

May combine two claims.

Shadowboard systems remain subject to the same downstream sterility controls as fully manual rigs and still require high-quality training and supervision.

“The approach remains subject to the same downstream sterility controls as fully manual rigs, and it still requires high-quality training and supervision.”

May combine two claims.

ICH Q9 necessitates formal risk assessments for choices such as test location, and any justified omission of PUPSIT where volumes are extremely small.

“These should be consistent with ICH Q9, which necessitates formal risk assessments for choices such as test location, and any justified omission of PUPSIT where volumes are extremely small.”

• cites ICH Q9Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Shadowboard systems reduce assembly variability and setup errors, increase product recovery and product yield, improve ergonomics, and enable faster, more reproducible execution relative to ad hoc manual single-use rigs.

“The benefit is a reduction in assembly variability and setup errors, increased product recovery and product yield, improved ergonomics, and faster, more reproducible execution relative to ad hoc manual single use-rigs (International Society for Pharmaceutical Engineering (ISPE), 2018).”

• cites International Society for Pharmaceutical Engineering (ISPE), 2018Not checked yet

  Not checked in the free run.

May combine two claims.

ASTM E3336-22 standardizes physical integrity testing of single-use systems and details pressure-based methods and apparatus/validation requirements for empty, dry SUS, enabling routine integrity/leak testing without specialty tracers.

“ASTM E3336‑22 (ASTM International 2023) explicitly standardizes physical integrity testing of single‑use systems and details pressure‑based methods and apparatus/validation requirements for empty, dry SUS, enabling routine integrity/leak testing without specialty tracers.”

• cites ASTM International 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

EU inspectors increasingly expect procedural elements for manual single-use PUPSIT to sit inside a documented CCS and QRM framework.

“EU inspectors increasingly expect these procedural elements to sit inside a documented CCS and QRM framework.”

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Manual single-use systems tend to the needs in lower-volume settings or where agility matters, provided every design choice is backed by a strong CCS and QRM rationale.

“They tend to the needs in lower-volume settings or where agility really matters, provided every design choice is backed by a strong CCS and QRM rationale.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Manufacturers are increasingly adopting recyclable materials and modular designs to reduce waste, according to the UN's 17 sustainable development goals.

“Manufacturers are increasingly adopting recyclable materials and modular designs to reduce waste (Shann 2024) according to the 17 goals established by the United Nations (UN) and adopted by all UN member states in 2015 (United Nations (UN), 2015).”

• cites Shann 2024Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites United Nations (UN), 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

These protocols ensure consistency and reliability across different testing platforms and applications.

“and these protocols ensure consistency and reliability across different testing platforms and applications.”

May combine two claims.

Single-use system options that allow for manual, shadowboard-based, or fully automated PUPSIT and filtration offer simplicity and robustness and enable successful implementation of a safe and effective PUPSIT strategy.

“Single-use system options that allow for either a manual, shadowboard-based or fully automated PUPSIT and filtration process offer simplicity and robustness and enable a successful implementation of a safe and effective PUPSIT strategy.”

May combine two claims.

The trade-off of fully automated systems is higher upfront investment along with the need for formal software validation and recipe lifecycle management.

“The trade-off is higher upfront investment along with the need for formal software validation and recipe lifecycle management.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The implementation of PUPSIT in critical sterile filtration has become a critical requirement and marks an advancement in quality assurance within biopharmaceutical manufacturing.

“The implementation of PUPSIT in critical sterile filtration has become a critical requirement and marks an advancement in quality assurance within biopharmaceutical manufacturing.”

May combine two claims.

The primary strengths of manual single-use PUPSIT are flexibility and, relative to more automated options, low capital cost, which can be attractive for development or low-throughput operations.

“The primary strengths of this approach are flexibility and, in relation to more automated system options, low capital cost, which can be attractive for development or low-throughput operations.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

Fully automated systems remain justified on the basis of application safety, offering superior repeatability, data integrity, and risk control consistent with contemporary expectations for contamination control and closed processing.

“Despite these economic nuances, fully automated systems remain justified, as mentioned, on the basis of application safety, offering superior repeatability, data integrity, and risk control consistent with contemporary expectations for contamination control and closed processing.”