December 12, 2025

H1 Regulatory Landscape for Single-Use Systems

The new chapters from USP—USP <665> and USP <1665>—target plastic components and systems used in the manufacture of pharmaceutical and biopharmaceutical drug substances and products. These standards reflect the shift toward single-use systems (SUS) and the associated extractables/leachable (E&L) risk.

Both chapters were officially approved in 2024. The USP General Chapters – Packaging and Distribution Expert Committee has extended the effective date to May 1, 2026. Although there is some time, manufacturers are strongly advised to begin preparations now to ensure compliance and avoid delays.

H2 Scope and Purpose

USP <1665> – Guidance on Risk Assessment

This chapter offers guidance for materials and formulations—including active pharmaceutical ingredients (APIs), drug products, biologics, single-use systems, and multi-use systems. It describes a two-step approach:

  1. Initial assessment: determine whether a plastic component is suitable for its intended use and whether testing is required.
  2. Risk assessment: if significant contact between the plastic component and a process stream exists, evaluate further testing needs.

USP <665> – Requirements for Plastic Components & Systems

This chapter establishes mandatory requirements (once effective) for plastic components and systems used in manufacturing pharmaceutical drug products and biopharmaceutical drug substances.

Key points:

  • Applies to process streams that are liquids or semi-solids.
  • Apply to single-use systems (SUS) and multi-use systems (MUS) constructed of plastic, where process fluid contact occurs.
  • Excludes elastomeric components (e.g., O-rings, gaskets) which are addressed elsewhere (such as USP <381>).

H2 Other Key Guidance: BPOG Extractables Protocols

The BioPharma Operations Group (BPOG), an industry group of manufacturers and suppliers of single-use equipment, has published two major guidance documents for extractables and leachable (E&L) testing of single-use systems:

  • Best Practices Guide for Evaluating Leachable Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing
  • Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing.

These are widely used by industry for supply chain and component qualification although they are not formal regulatory monographs.

H2 Comparison: USP vs. BPOG

  • Both USP <665> and BPOG guidance use a risk-management framework focused on E&L for manufacturing processes.
  • The USP chapter is a regulatory requirement (once effective) and sets baseline expectations for industry. Meanwhile, BPOG provides the best industry-developed practices, widely embraced but not legally enforceable.
  • Testing protocols align in many areas (e.g., extraction solvents). However, differences exist: the number of replicates, time-points, and reporting thresholds differ (e.g., BPOG specifies ~0.1 µg/cm² threshold), whereas USP aligns to an analytical evaluation threshold (AET) based on justification per chapter <1663>/<1664> principles.

H1 Steps to Prepare: What Manufacturers Must Do

H2 1. Review your existing SUS components & systems

  • Identify all plastic components and systems (single-use and multi-use) used in your manufacturing lines (upstream and downstream) that meet process fluids or product streams.
  • Determine which components have been qualified under prior protocols (e.g., BPOG, vendor data) and which may need re-qualification under USP <665> requirements.
  • For components qualified under BPOG or older methods, evaluate whether the data suffice for USP compliance, or whether additional testing is needed.

H2 2. Plan and initiate risk-based extractables/leachable programmer

  • Use the two-step approach from USP <1665>: initial assessment followed by risk assessment. The risk assessment considers contact duration, process conditions (temperature, flow, fluid chemistry), material construction, downstream clearance steps, and potential impact on product quality/safety.
  • Based on risk level (low/moderate/high), select appropriate extractables testing strategy: minimal testing for low-risk parts, full extractables profiling for high-risk.
  • Ensure your extractables/leachable test design aligns with USP <665> and BPOG (or better) protocols: correct extraction solvents, justified contact area to volume ratio, replicates, time-points, reporting thresholds.

H2 3. Engage testing providers and allocate budget & timelines

  • Testing of SUS components can be complex; involve analytical services, toxicology assessment, and data interpretation.
  • Outsourcing may be necessary — plan for vendor lead times, capacity constraints as many companies ramp up for 2026.
  • Allocate budget for extractables/leachable programmers, documentation, supplier qualification, change-control updates, and regulatory submissions.
  • Start early: the effective date is May 1, 2026. Waiting may cause bottlenecks, non-compliance risks, and potential product delays.

H2 4. Update documentation, supplier agreements and regulatory submission strategies

  • Ensure vendor/supplier data for plastic components to align with USP <665> and USP <1665> expectations. Supplier declarations should cover materials of construction, manufacturing process, additive use, extractables/leachable data where available.
  • Update internal change-control and supplier qualification procedures to reflect the new chapters.
  • For regulatory submissions (e.g., CMC, validation dossiers), prepare to include qualification of plastic components as required under USP <665> (for US market) or equivalent global regulatory jurisdictions.
  • Use global regulatory intelligence: assess how other regions (EU EMA, PMDA Japan) view SUS E&L requirements, to align global strategies and submissions.

H1 Why This Matters: Strategic Benefits & Risk Mitigation

  • Compliance with USP <665> by the 2026 deadline ensures that plastic single-use systems are sufficiently characterized—reducing risk of leachability that could impact safety, efficacy or stability of drug substances or products.
  • A risk-based framework aids in efficient allocation of testing resources, focusing efforts where they matter most and avoiding unnecessary testing for low-risk components.
  • Robust E&L data supports regulatory submissions, strengthens supplier relationships, improves manufacturing robustness, and reduces potential recalls or remediation costs.
  • From the perspective of regulatory affairs and compliance consulting, being ahead of the curve enhances your market readiness, positioning for regulatory submissions and global market entry.
  • For global regulatory intelligence, understanding USP <665>/<1665> also helps benchmark your processes for other geographies, especially where SUS use is increasing (for example vaccine manufacturing, cell & gene therapies).

H1 Final Thoughts

The shift to single-use systems in biopharmaceutical manufacturing is irreversible—and the regulatory landscape is catching up with the release of USP <665> and USP <1665>. With the official effective date of May 1, 2026, manufacturers and suppliers must act now—not later—to align with the new standards. Components that might have been lightly qualified under previous protocols must now be rigorously reviewed, tested and documented under a risk-based paradigm focused on extractables and leachable.

At Maven Regulatory Solutions, we view this as a critical moment for regulatory affairs, compliance consulting, and global regulatory intelligence in the biopharma space. Whether you’re streamlining your SUS qualification strategy, preparing regulatory submissions or building your supplier qualification and global readiness framework, we can support you in navigating the complexity, interpreting the technical details, and executing a fit-for-purpose plan.