Supplier high sensitivity integrity test for single-use systems used in critical applications for enhanced patient safety
Single-use technologies have gained strong market acceptance in both clinical and manufacturing operations. Nevertheless, patient safety, as well as protection of operator and facility must be secured. A suitable strategy to assure the integrity of the single-use system during the life cycle is essential. This strategy includes the manufacturing process and the supply chain.
The helium integrity test (using Pall HIT™ technology) or single-use system leak testprovides the highest level of control that the single-use system leaving the factory is 100% integral. The size of detectable defects is correlated to microbial ingress. The test can be requested for Allegro biocontainer systems, Allegro mixer biocontainer systems, and single-use filling sets.
As single-use systems are delivered as ready-to-use systems, the SUS supplier has an increased responsibility in the design, manufacture, and validation of SUS. That is different compared to conventional reusable stainless-steel systems, where the end-user is responsible for their life cycle, from design to maintenance, including validation, routine operation tests, etc. With SUS, the responsibility is shared between the supplier and the end-user.
To develop a suitable strategy for the assurance of the integrity of SUS, in addition to the SUS application-specific requirements, all the steps in the life cycle of the SUS should be considered, from its design and manufacture at the supplier to its disposal by the end-user. A proper riskassessment should be performed to define the most appropriate risk mitigation strategy. This risk-based approach is recommended in the Bio-Process Systems Alliance (BPSA) guide on ‘Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance’.
Quality by Design (QbD) principles, junction tests, visual inspection, quality control tests, and validated processes are used for all Pall manufacturing procedures to ensure robustness and integrity of manufactured SUS. Additionally, Pall can perform the helium integrity test (using Pall HIT technology) upon request for Allegro single-use (SU) assemblies. The HIT method provides the highest level of control of integrity for SUS incorporated into the most critical steps of drug substance or drug product bulk storage.
The helium integrity test or integrity test for single-use systemsoccurs at the Pall site during the manufacturing of Allegro SUS. Figure 1 shows the life cycle of a Pall Allegro SUS with the Pall manufacturing steps in the upper region and the SUS deployment steps at the end-user site in the lower region of the figure.
SUS life cycle with Pall and end-user steps
When dealing with complex SUS, additional tests using a high sensitivity pressure decay test may be required on the SUS fluid transfer parts. Pall can also offer these tests on request.
Single-use systems for the clinical and commercial production of drugs
- Aseptic processes in vaccines, gene and cell therapy applications
- Bulk storage of mAbs, vaccines, r-proteins, etc.
- Aseptic filling processes
End-user point-of-use in-situ leak testing is vital to confirm that no damage has occurred during shipping, handling or installation of the single-use system. We set very high standards with regards to the design and validation of the manufacturing process for Allegro SUS to deliver integral SUS. At end-user’s sites, operators should be well-trained in unpacking, handling, and installing single-use systems. However, there may be still a need to confirm the absence of leaks prior to or after use from a risk management perspective. By performing an easy and reliable point-of-use leak test, end-users can check that the SUS has not been damaged during the installation, and/or use or storage process. This point-of-use test complements Pall’s manufacturing tests and provides an additional level of assurance of integrity.
The Palltronic® Flowstar LGR Test Instrument enables in-situ, post-installation point-of-use leak testing of single-use systems up to 200 L nominal volume and provides the ability to test filter integrity. It allows end users to test endless configurations of single-use systems and filters with one device, without compromising system sterility. It is more specifically designed for use in the vaccines, biotech, and pharmaceutical markets and with a specific focus on formulation and filling applications.
Palltronic® Flowstar LGR Test InstrumentView Details »
Working principle of the HIT method
Pall has developed a highly sensitive integrity test system using helium as a tracer gas.
The tracer gas detection method, in vacuum mode, is the method of choice recommended by USP <1207.2>1 on package integrity leak test technologies. Helium is used as a tracer gas, due to its favorable properties (inertness and small atomic size), in an inside-out test method, where helium leaking from the defects is collected in the test chamber (Figure 2).
Test chamber schematic
A highly sensitive mass spectrometer (MS) connected to the test chamber quantifies helium gas concentration. A leak rate calculated from the helium concentration in the test chamber is compared to an acceptance criterion (threshold value) to determine whether the tested SUS assembly passes or fails the test (Figure 3).
Leak rate measurement
The Pall HIT method is a non-destructive test method. The method and acceptance criteria have been fully validated to detect down to a 2 μm defect with assemblies including Allegro biocontainers ranging in size from 50 mL to 50 mL to 200 L and Allegro mixer biocontainers in sizes up to 200 L.
For filling set assemblies the method is validated to detect down to a 10 μm defect.
Both comply with the MALL (Maximum Allowable Leakage Limit defined in USP<1207>1) approach and are correlated to microbial ingress2
Key Elements of SUS Integrity
Pall has very high standards with regards to the design (QbD) and validation of the manufacturing process for Allegro SUS. Additional key elements of the Pall approach for assurance of integrity are the HIT test and pressure decay test at the supplier as well as a SUS leak test at the end-user (Figure 4).
End-user point-of-use in-situ leak testing to confirm that no damage occurred during shipping, handling, or installation of the single-use system Should there be a need to confirm the absence of leaks prior to use from a risk management perspective an easy and reliable point-of-use leak test can demonstrate that the SUS has not been damaged during installation. This point-of-use test at the end-user complements Pall manufacturing tests and provides an additional level of assurance of integrity. For further information please refer to Pall datasheet reference USD3015 - Palltronic® Flowstar LGR Test Instrument.
The Palltronic® Flowstar LGR test instrument enables in-situ, post-installation point-of-use leak testing of single-use systems up to 200 L nominal volume and provides the ability to test filter integrity. It allows end-users to test endless configurations of single-use systems and filters with one device, without compromising system sterility. It is more specifically designed for use in vaccines, biotech, and pharmaceutical applications with a specific focus on formulation and filling operations.
1. United States Pharmacopiea <1207.2> General Chapter, Package Integrity Evaluation – Sterile Products – Package integrity leak test options
2. Pall Biotech data - Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance, BPSA, July 2017