USP <665>: risk assessment can be a powerful tool

Patty High, Manager, Extractables & Leachables Testing; Kate Knapp, PhD, Group Leader II; Extractables & Leachables Testing, Eurofins BioPharma Product Testing

USP <665> became official on May 1, 2026, bringing updated expectations for extractables testing grounded in scientific rationale and risk-based decision making. While the chapter introduces new requirements—including qualified analytical methods—it can be implemented smoothly with thoughtful planning. The revised framework provides clearer, risk-aligned guidance that supports reliable extractables testing without unnecessary burden.

Earlier drafts lacked clarity or imposed prescriptive requirements, but the final USP <665> reflects a more balanced, practical approach. It emphasizes scientific justification, well-designed studies, and testing strategies aligned with patient risk—aimed at generating meaningful, defensible data rather than testing for its own sake.

Eurofins’ Extractables and Leachables (E&L) teams have reviewed the updated chapter, developed a strategic implementation plan, and created templated protocols aligned with its key elements to meet client challenges.

Risk assessment as the foundation

A robust, well documented risk assessment is central to any USP <665> strategy. It justifies testing decisions, aligns programs with regulatory expectations, and clarifies what requires testing—and what does not.

When applied effectively, risk assessments can reduce the number of components tested, shorten timelines, and eliminate low value work. Although this requires upfront effort, it often leads to meaningful time and cost savings. Eurofins’ E&L teams leverage extensive experience to deliver defensible risk evaluations paired with fit-for-purpose study designs.

How risk drives testing under USP <665>

The official chapter introduces clearer expectations and stronger scrutiny, with testing decisions explicitly tied to risk. As USP <665> becomes enforceable, documentation quality and scientific justification grow increasingly important.

Materials are categorized as low, medium, or high risk, with testing requirements scaled accordingly—from basic screening techniques (UV/Vis, NVR) to full orthogonal chromatographic and spectrometric analyses. This tiered approach strengthens scientific rigor while avoiding unnecessary testing.

Expanded scope beyond final packaging

USP <665> broadens extractables assessments beyond container–closure systems. Manufacturing components that contact materials are now included, reflecting their potential contribution to patient exposure. This expanded scope supports more realistic risk evaluations and reduces regulatory gaps.

Evolving expectations around AETs

Analytical Evaluation Thresholds (AETs) remain a challenge, especially for large volume or high dose products. Under USP <665>, extractables must be evaluated against a calculated AET based on clinical use and patient exposure. This may result in lower thresholds and more reportable compounds requiring
toxicological assessment.

Alternative thresholds must be scientifically justified and thoroughly documented, underscoring the need for early planning and cross functional alignment.

Manufacturing strategy matters

Successful implementation depends heavily on manufacturing strategy. Inhouse vs CMO manufacturing affects data availability, traceability, and risk assessment quality. CMOs may not always provide USP <665> ready data packages, and gaps in material information must be addressed early to avoid delays. Strong communication with manufacturing partners is essential.

Planning early for success

Effective USP <665> programs begin with early information gathering—confirming material status, understanding manufacturing strategy, and determining whether risk assessments will be conducted internally or outsourced. Internal assessments may reduce cost but require expertise; outsourced assessments are often faster and more defensible but depend on data quality. The right approach depends on internal capabilities and timelines.

Key takeaway

USP <665> is now a reality, and preparation is essential. With strategic planning, risk assessment becomes a powerful tool rather than a regulatory hurdle. Early alignment reduces cost, delays, and rework; while a strong scientific framework keeps implementation manageable.

Eurofins partners with clients to navigate this evolving landscape, applying USP <665> in a practical, fit-for-purpose manner that focuses resources where they add the most value while maintaining strong regulatory defensibility.

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