A customer’s journey to navigating USP <665> compliance

When a biopharmaceutical company selects a new filter or single-use system (SUS), the decision goes far beyond performance specifications or lead times. Increasingly, the materials used in the manufacturing process—tubings, connectors, films, housings, and membranes that come into contact with the substance or product—are under close regulatory scrutiny. USP <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Product (1), introduces standardized testing protocols for plastic components used in single-use assemblies, ensuring consistent material characterization and supporting compliance with regulatory expectations.

For many teams, the journey towards compliance begins at the exact moment a new system is considered. The goal is not simply to purchase a piece of equipment, but to ensure that every material touching the product has been characterized with sufficient scientific rigor. The story of achieving USP <665> compliance is therefore a continuous one—moving from supplier selection, to risk assessment, to additional data generation as appropriate, and ultimately to regulatory submission.

Our extractables and leachables (E&L) strategy aligns with USP <665> and incorporates the comprehensive assessment principles outlined in USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems and USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems (2,3).

Understanding the need for extractables and leachables testing

It usually starts in process development, when a team evaluates options for a new sterile filter, filling needles, or mixing assembly. At this point, the question arises:

Will this component meet today’s regulatory expectations for polymeric materials?

USP <665> makes responsibilities clear to ensure appropriate extractables characterization for final drug product (DP): “[The] finished DP’s sponsor has the ultimate responsibility for performing and justifying the risk evaluation.”

Yet in practice, the depth and completeness of supplier support is what determines how smoothly the project moves forward.

Cytiva provides comprehensive end-to-end support for extractables and leachables assessments, from USP <665>-aligned extractable reports and process-specific extractable studies to leachables testing. These become indispensable as your teams begin assessing the suitability of a component.

Conducting the risk assessment for your single-use system

Under USP <665>, the risk assessment is central to ensure that polymeric, product-contacting components are suitable for their intended use. The objective is to assess the likelihood that process equipment-related leachables (PERLs) could migrate in the process stream and/or persist through subsequent processing steps, and ultimately affect the safety or quality of the final drug product.

Key considerations include the chemical nature of the component, the manufacturing process conditions, and the potential for downstream clearance. Factors that must be addressed are:

• The chemical composition of the component and its inherent propensity to leach under manufacturing conditions.
• The chemical composition of the process stream, including pH, solvents, buffer constituents, and excipients.
• Temperature and duration of contact, as both parameters influence extraction potential and kinetics.
• The ability of downstream process steps—such as filtration or chromatography—to remove, reduce, or clear PERLs before they reach the drug product. Cytiva provides additional guidance on this topic in our article assessing leachables risk over a complete single-use mAb process.
• Comparison of measured extractables levels with the Analytical Evaluation Threshold (AET). Cytiva recommends using USP <1664> and ICH Q3E Guideline for Extractables and Leachables (4) as a clear framework for establishing and interpreting AET values in the context of process safety.

This structured approach defines risk levels (low/medium/high) and the respective testing requirements (Fig 1). The risk matrix shown in Figure 1 is adapted from USP <665> and USP <1665> Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products (5).

Fig 1. Risk matrix for performing extractables and leachables testing.

Furthermore, we support you throughout this assessment by providing high quality extractables data for Cytiva consumables generated under a dedicated program aligned with USP <665> to support risk-based decision-making. This includes rigorous testing of single-use and filtration components. Our priority is to ensure that the components used in critical bioprocessing operations are well understood, consistently controlled, and supported by robust data packages. All industry standard extractables reports, test summaries, and supporting documentation are available through our extractables and leachables web page. Figure 2 provides an overview of initial risk assessment levels and their associated extractables testing requirements across bioprocess unit operations, from upstream operations through final drug product filling.

Fig 2. Typical allocation of initial risk assessment levels and corresponding extractables testing requirements across different bioprocess unit operations.

The quality, scope, and regulatory alignment of supplier extractables data often determines whether additional testing is required—or can be avoided entirely. Our E&L service specialists provide support with selecting relevant time points and solvents, compiling a cumulative assessment, and interpreting results. A rational report can be generated for your specific process by leveraging existing data, where available, without the need to perform additional testing.

Planning and executing extractables studies

Where gaps remain, process-specific extractables studies must be designed. This is where specialized scientific support—such as Cytiva Fast Trak™ validation services—becomes essential. Leveraging deep expertise across the relevant technologies, our team designs process-specific studies using our model solvent approach.

Every project includes comprehensive project management and scientific support before, during, and after execution. With more than 50 years of validation experience and E&L teams located around the world, we bring a deep understanding of regional regulatory expectations. Through compliance with USP <665> and BioPhorum Operations Group (BPOG) guidelines (6), combined with decades of in-house testing, we have built extensive knowledge of our materials—resulting in fewer unknowns and minimizing surprises.

Connecting extractables to process safety

USP focuses on extractables, but regulators evaluating a filing application will expect a clear understanding of leachables risk—what might actually migrate into the product under process conditions. This step bridges the controlled environment of an extractables study with the real-world manufacturing scenario.

Once an appropriate extractables data set is available, a product and process-specific safety assessment based on production batch size and dosing regimen may be conducted to evaluate patient safety aspects of extractable compounds. Read this case study to learn more about how to use Cytiva extractables data for a monoclonal antibody (mAb) manufacturing process leachables risk assessment. When the potential toxicological impact warrants further evaluation, Cytiva may conduct a targeted leachables study to support risk assessment.

Assembling the regulatory submission

By the time the filing application is being drafted, a comprehensive body of evidence has accumulated: supplier documentation, internal risk assessments, extractables studies, leachables evaluations, and change control strategies. The challenge now is organization—turning the evidence into a coherent narrative that meets health authority expectations for chemicals, manufacturing, and controls (CMC) documentation. Besides offering E&L testing data, Cytiva offers a range of regulatory support services, from strategic consulting to document authoring and publishing, meeting preparation and representation, and post-approval support.

Even with a strong submission, agencies often ask for clarification. By choosing a supplier whose testing program aligns with USP <665>, responses are typically straightforward. Detailed testing summaries, method explanations, and scientific rationales can be provided quickly, often preventing the need for additional studies.

This level of readiness accelerates the regulatory timeline and reduces the risk of delays during review cycles.

Life cycle management post-approval

The journey does not end with approval. USP <665> compliance as well as end user safety assessment responsibility demands an ongoing collaboration between drug manufacturer and supplier. Change control notifications, periodic reviews of new materials, and updates to risk assessments all ensure that the process remains compliant throughout the life cycle of the product.

Conclusion: Cytiva offers end-to-end support for USP <665> compliance

USP <665> has created a clearer path for evaluating polymeric components in biomanufacturing, but compliance requires thoughtful planning, strong supplier collaboration, and scientifically sound documentation.

With Cytiva as collaborator, you can access comprehensive—and longstanding—scientific expertise as well as regulatory support throughout the entire product life cycle. From the first purchase of a filter or single‑use system through to successful regulatory submission, Cytiva provides the depth of data and expertise you need to move forward with confidence. Our support doesn’t end with extractables testing; we also perform leachables testing and provide expert interpretation to give you a complete understanding of product safety at every stage of bioprocess development and validation, helping you bring life-changing therapeutics to market faster.

As part of our Fast Trak™ validation services, our E&L studies are conducted in-house using standardized, industry-aligned methods, ensuring data quality, consistency, and right-first-time solutions. We reduce rework, minimize regulatory risk, and keep your programs moving efficiently toward approval.

Ready to take the next step? Visit our Fast Trak™ validation services web page to learn more.

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