Overview of single-use system integrity assurance

Assuring the integrity of single-use systems (SUS) is a foundational element of today’s biopharma drug manufacturing, and it is critical to sterility assurance, contamination control, and patient safety. SUS integrity assurance must be approached as an end-to-end, life cycle process, grounded in quality risk management (QRM) and aligned with regulatory expectations and industry best practices. To assure the integrity of a single-use system, manufacturers must fully understand its life cycle—starting with the components and materials it is constructed from, to its usage in drug product manufacturing.

Single-use systems have come a long way since their origins more than 35 years ago, when early iterations were relatively simple biocontainer bags. Today, SUS can be as simple as a transfer set, such as tubing with a sterile connector, or as complex as a bioreactor complete with mixer and sensor probes. Simple or complex, assurance of integrity both at the SUS supplier and final end user facility requires a holistic view of the entire SUS life cycle, recognizing that materials, components, packaging, transport, and handling at every stage can lead to deviations if risk isn’t mitigated. Loss of integrity at any point in the SUS life cycle can directly compromise product quality, operator safety, and business continuity.

This reality demands a holistic integrity assurance strategy that spans design, manufacture, packaging, transport, installation, use, and disposal. A QRM approach that incorporates all these elements is fundamental to defining an appropriate integrity assurance strategy.

Effective single-use system integrity assurance includes entire SUS life cycle

Single-use integrity cannot be assured without a comprehensive understanding of the full SUS life cycle. From raw materials and component fabrication through final use in a validated manufacturing process, each phase introduces possible integrity risks that must be identified, assessed, and controlled.

Adopting a life cycle perspective helps ensure effective integrity controls. Integrity assurance extends well beyond leak testing of single-use systems alone. Materials of construction, junctions, assembly processes, packaging design, shipping conditions, storage practices, and operator handling all influence the ability of a SUS to maintain its intended function (Fig 1).

Fig 1. Illustration of the SUS life cycle.

Where can single-use system integrity be compromised?

Closer scrutiny of the end-to-end life cycle can reveal areas where integrity could potentially be compromised and where mitigation strategies should be applied. These are:

SUS components

Bag chambers (biocontainers), tubing, connectors, and junctions must prevent leaks or defects that could allow risk of microbial ingress or liquid loss. These risks must be evaluated and mitigated to ensure patient safety, decrease operator exposure, and prevent environmental impact. Some questions to ask include: Have SUS components and assemblies been tested and validated? Are there leaks in biocontainers or junctions that could allow microbial ingress? Is there a potential risk of product contamination (patient risk) or of operator contamination (operator safety), and have these been mitigated?

Packaging of SUS

Packaging must protect the SUS throughout handling, storage, and transport. It should be designed to reduce movement, protect drug product during shipping and storage, and prevent risks of damage (e.g., due to film folding or contact of edgy parts with softer, more fragile ones). Robust design and reproducible packaging practices are key to risk reduction.

Shipping of SUS

Transportation validation should demonstrate that shipping conditions present minimal risk of damage that could compromise integrity prior to use.

End user training in SUS

Operators should be trained in correct handling, installation, and use of SUS components. Clear procedures, visual inspection criteria, and effective operator training are therefore essential elements of the integrity control strategy.

Defining a single-use system integrity assurance strategy

Current industry best practice recognizes that SUS integrity assurance must be a risk-based and application-specific approach. A robust strategy evaluates both supplier and end user controls and considers the benefits and limitations of available test methods. Demonstrating a sufficient SUS integrity assurance strategy should include a risk assessment that evaluates the SUS supplier manufacturing process, validation and routine integrity control points, and the intended application. It should assess risks versus benefits of existing test methods and ask the question, are other tests required?

Industry guidance: Bio-Process Systems Alliance and SUS integrity

Collaborative industry groups made up of suppliers and manufacturers have recognized the need for control and standardization for SUS. The Bio-Process Systems Alliance (BPSA) developed a recommended approach to risk assessment in their technical guide, Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance, Volume 1 (2017) . Volume 1 established core principles for risk assessment and control strategy definition, while Volume 2, issued in 2023, provides case studies based on principles discussed in Volume 1, as well as updates to key technologies and regulatory guidance (1). Many suppliers and end users of SUS follow this approach to define their strategy for SUS integrity assurance.

The BPSA risk management approach considers:

• The intended application of the SUS and its criticality in terms of patient safety, drug safety, operator safety, and/or business impact.
• The whole life cycle of the SUS, from its design and manufacture at the supplier site to its disposal at the drug manufacturing facility.
• The supplier qualification and manufacturing practices, including:
  • Quality by design (QbD) approach, validation/verification tests (e.g., junction tests)
  • Packaging and transportation validation tests
  • Operator training
  • Routine testing and controls (e.g., visual inspection and leak testing/integrity testing)
• The drug manufacturer qualification and manufacturing practices, including:
  • Verification of SUS attributes against the requirements for the intended use, also referred to as the User Requirement Specifications (URS)
  • Procedures for storage, unpacking, installation, and use of the SUS, including visual inspection, operator training, and leak testing/integrity testing

Industry guidance: ASTM E3244-20 and SUS integrity

ASTM International’s E3244-20: Standard Practice for Integrity Assurance and Testing of Single Use Systems (2) further reinforces a QbD and QRM based approach to integrity assurance. Published in May 2020, the guidance is the outcome of several years of collaboration among individuals on the ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products, a group that includes SUS suppliers, end users, and the US Food and Drug Administration (FDA).

This standard practice provides useful recommendations on how to manage integrity of SUS, with an approach that follows QbD and QRM principles. In this document, integrity assurance is associated to microbial integrity and bioburden control (risk to product quality) as well as liquid product loss (risk to operator and environment).

The ASTM practice also recommends performing a risk assessment by following a holistic end-to- end approach, based on the life cycle of the SUS, from the first manufacturing steps of the SUS until its disposal. This end-to-end approach requires close communication and collaboration between the supplier and the end user. The standard also covers the different elements to consider when building and maintaining integrity assurance of the SUS, defining precise user requirements as a starting point. It also covers the challenges in setting up the requirements for integrity, explains why a one-size-fits-all standard does not exist, and why different controls and methods are likely to be applied at different stages of development (design, qualification, validation, commercial production). In addition, it emphasizes the need for in-depth communication between supplier and end user when applying a QbD approach in qualification or defining suitable testing parameters to meet the user requirements.

The standard also provides an extended overview of the test methods best suited to evaluate the integrity of the SUS, at development, validation, or routine use stages. By focusing on SUS, this ASTM standard practice provides an interesting complement to USP <1207> Package Integrity Evaluation–Sterile Products (3), which explicitly excludes “packaging systems and processing equipment used in the preparation, storage, and manufacture of sterile pharmaceutical products.” In other words, ASTM E3244-20 complements, rather than overlaps with, USP <1207>, which excludes single use processing equipment from its scope.

Fig 2. Potential control points in the SUS life cycle.

Conclusion: single-use system integrity assurance is a risk-based, life cycle approach to contamination control

Assuring the integrity of single use systems is not a one-time activity, but a continuous, risk-based life cycle process. It thus becomes a shared responsibility between the supplier and the drug manufacturer, requiring a strong collaboration and continued relationship as well as a deep understanding of the SUS application requirements. Awareness of the complete SUS life cycle creates opportunity to mitigate risk at critical points—from pre-assembly stage to final disposal. By controlling integrity risks at critical life cycle points, suppliers and manufacturers alike can strengthen sterility assurance, protecting patients and operators while supporting compliant drug product manufacturing operations.