Understanding Regulatory Frameworks For Single-Use Systems: USP <665>, USP <1665> And BPOG Extractable Guidance In Biopharmaceutical Manufacturing

The rapid expansion of single-use systems (SUS) in biopharmaceutical manufacturing has transformed how pharmaceutical and biologics manufacturers approach production efficiency, contamination control, and operational flexibility.

As the adoption of plastic-based manufacturing components continues to rise across upstream and downstream processing, regulatory agencies and pharmacopeial organizations are placing greater focus on extractables and leachables (E&L) risk management.

The introduction of USP <665> and USP <1665> marks a major regulatory milestone for pharmaceutical and biopharmaceutical manufacturers utilizing single-use technologies. These chapters establish new expectations surrounding plastic component qualification, risk assessment methodologies, and lifecycle compliance management.

At Maven Regulatory Solutions, we support pharmaceutical and biopharmaceutical companies with extractables and leachables risk assessment, single-use system qualification, supplier compliance strategy, toxicological evaluation, and global regulatory intelligence aligned with evolving international expectations.

Regulatory Landscape for Single-Use Systems

USP <665> and USP <1665> were developed to address the growing use of plastic components and systems in pharmaceutical and biopharmaceutical manufacturing environments.

Both chapters were officially approved in 2024, while the USP General Chapters Packaging and Distribution Expert Committee extended the official implementation date to May 1, 2026.

Although manufacturers still have time to prepare, organizations are strongly encouraged to begin compliance planning early to avoid operational bottlenecks, qualification delays, and regulatory risks.

Why Single-Use Systems Are Expanding Rapidly

Single-use technologies are increasingly preferred because they offer operational and contamination-control advantages compared to traditional stainless-steel systems.

Key Industry Drivers

• Reduced cleaning validation burden 
• Faster manufacturing turnaround times 
• Lower cross-contamination risks 
• Greater flexibility in biologics production 
• Improved scalability for cell and gene therapies 
• Reduced water and utility consumption 
• Increased manufacturing efficiency 

However, the increased use of plastic materials also introduces extractables and leachables risks that require structured regulatory oversight.

What Is USP <1665>?

USP <1665> provides guidance for conducting risk assessments involving plastic components and systems used in pharmaceutical manufacturing.

The chapter supports a risk-based approach for evaluating whether additional testing is necessary based on process exposure conditions and product interaction risks.

USP <1665> Covers

• Active Pharmaceutical Ingredients (APIs) 
• Drug products 
• Biologics manufacturing systems 
• Single-use systems (SUS) 
• Multi-use systems (MUS) 
• Plastic manufacturing components 

Two-Step Risk Assessment Approach Under USP <1665>

USP <1665> recommends a structured two-phase evaluation framework.

The framework emphasizes scientific justification and process-specific evaluation rather than universal testing requirements.

What Is USP <665>?

USP <665> establishes mandatory requirements for plastic components and systems used in pharmaceutical manufacturing once the chapter becomes effective in May 2026.

The chapter applies to manufacturing systems where process fluids contact plastic materials during production.

USP <665> Applies To

• Single-use systems (SUS) 
• Multi-use systems (MUS) 
• Liquid process streams 
• Semi-solid manufacturing systems 
• Plastic process-contact components 

Components Excluded from USP <665>

Certain elastomeric materials are excluded because they are covered under separate pharmacopeial chapters.

Examples Include

• O-rings 
• Gaskets 
• Rubber seals 
• Elastomeric closures 

These materials are generally addressed through standards such as USP <381> and related chapters.

Understanding BPOG Extractables Guidance

The BioPharma Operations Group (BPOG) has published widely adopted industry guidance documents for extractables and leachables testing of single-use systems.

Although BPOG guidance is not legally binding, it has become highly influential across the biopharmaceutical industry.

Major BPOG Guidance Documents

• Standardized Extractables Testing Protocol for Single-Use Systems 
• Best Practices Guide for Evaluating Leachable Risk from Polymeric Single-Use Systems 

These frameworks are commonly used for:

• Supplier qualification 
• Component evaluation 
• Risk mitigation strategies 
• E&L study design 
• Supply-chain compliance management 

USP <665> vs. BPOG: Key Differences

While both frameworks focus on extractables and leachables risk management, important differences exist.

Manufacturers should understand how both frameworks interact when developing SUS qualification programs.

Extractables And Leachables (E&L) Risks In SUS

Plastic materials may release chemical compounds into manufacturing streams under specific process conditions.

Common E&L Risk Factors

• High temperatures 
• Extended contact durations 
• Solvent exposure 
• pH extremes 
• Oxidative stress 
• Mechanical stress 
• Sterilization processes 

Poorly controlled E&L risks may affect:

• Product safety 
• Drug stability 
• Product purity 
• Manufacturing consistency 
• Regulatory compliance 

Preparing For USP <665> Compliance

Manufacturers should begin comprehensive readiness activities well before the May 2026 implementation deadline.

1. Review Existing SUS Components

Organizations should identify all process-contact plastic components used throughout manufacturing operations.

Areas To Evaluate

• Upstream bioprocessing systems 
• Downstream purification systems 
• Fluid transfer assemblies 
• Storage bags and tubing 
• Filtration systems 
• Mixing systems 
• Sampling components 

Manufacturers should also determine whether historical BPOG or vendor qualification data remain sufficient for USP <665> expectations.

2. Implement Risk-Based E&L Programs

USP <1665> emphasizes risk-based qualification strategies tailored to actual process conditions.

Key Risk Assessment Considerations

Higher-risk systems typically require more comprehensive extractables profiling.

3. Align Testing Protocols with Regulatory Expectations

Testing strategies should align with both USP <665> requirements and accepted industry practices such as BPOG.

Important Testing Parameters

• Extraction solvents 
• Contact area-to-volume ratios 
• Replicate testing 
• Exposure time points 
• Analytical evaluation thresholds (AETs) 
• Toxicological interpretation 

Manufacturers should ensure scientific justification supports all testing methodologies.

4. Engage Analytical and Toxicology Experts Early

E&L qualification programs can become highly complex and resource intensive.

External Expertise May Be Needed For

• Analytical chemistry support 
• Toxicological risk assessments 
• Data interpretation 
• Method development 
• Regulatory documentation preparation 

Because many companies are preparing simultaneously for the 2026 deadline, laboratory capacity constraints may become significant.

5. Update Supplier Qualification Programs

Supplier oversight is becoming increasingly important under modern E&L expectations.

Supplier Documentation Should Include

• Material composition information 
• Manufacturing process details 
• Additive disclosure information 
• Extractables data where available 
• Change notification procedures 
• Quality system documentation 

Robust supplier management helps reduce future compliance risks.

6. Prepare Regulatory Submission Strategies

Manufacturers should incorporate SUS qualification documentation into broader regulatory submission strategies.

Submission Areas Potentially Impacted

• CMC documentation 
• Validation reports 
• Process qualification files 
• Risk management reports 
• Change control documentation 
• Global registration dossiers 

Global harmonization planning is especially important for multinational manufacturers.

Global Regulatory Intelligence Considerations

Although USP <665> and USP <1665> are U.S.-based pharmacopeial chapters, global regulators increasingly focus on E&L risks associated with single-use systems.

Regions Monitoring Similar Concerns

• European Union (EMA) 
• Japan (PMDA) 
• Health Canada 
• WHO biologics programs 
• Global vaccine manufacturing networks 

Strong regulatory intelligence programs help manufacturers maintain consistent global compliance strategies.

Future Trends in Single-Use System Regulation

The regulatory landscape surrounding SUS qualification continues evolving rapidly.

Emerging Trends Include

• Expanded E&L toxicological modeling 
• AI-assisted risk prediction tools 
• More stringent supplier qualification expectations 
• Greater harmonization across global markets 
• Increased focus on polymer characterization 
• Enhanced lifecycle monitoring obligations 
• Expanded scrutiny for advanced therapies and biologics 

Organizations that proactively prepare will be better positioned for long-term compliance success.

Quick Facts

• USP <665> becomes effective May 1, 2026 
• USP <1665> provides risk assessment guidance for SUS qualification 
• BPOG guidance remains highly influential across industry 
• Extractable and leachables risk management is central to compliance 
• Risk-based qualification strategies are strongly encouraged 
• Supplier qualification plays a critical role in compliance success 
• Early preparation helps avoid future testing bottlenecks 

Why This Matters

Single-use systems are now foundational to modern biopharmaceutical manufacturing.

Organizations that fail to establish robust E&L compliance programs may be faced:

• Delayed regulatory approvals 
• Product quality risks 
• Increased remediation costs 
• Manufacturing disruptions 
• Supplier qualification gaps 
• Inspection findings 
• Market access delays 

Proactive SUS qualification and extractables risk management are essential for maintaining patient safety, product integrity, and regulatory confidence.

How Maven Regulatory Solutions Supports SUS Compliance

Our Services

• USP <665> readiness assessments 
• USP <1665> risk assessment support 
• Extractables and leachables strategy development 
• Supplier qualification consulting 
• Toxicological evaluation support 
• Regulatory intelligence monitoring 
• Global compliance strategy development 
• Documentation and submission support 
• Change control program review 

Why Choose Maven

• Deep expertise in pharmaceutical regulatory affairs 
• Strong extractables and leachables knowledge 
• Global regulatory intelligence capabilities 
• Risk-based compliance approach 
• End-to-end lifecycle support 
• Experience supporting biologics and advanced therapies 

Learn more at Maven Regulatory Solutions.

Preparing For USP <665> Compliance Before The 2026 Deadline?

Maven Regulatory Solutions helps pharmaceutical and biopharmaceutical manufacturers simplify single-use system qualification and strengthen extractables and leachables compliance strategies.

We Support You With

• USP <665> gap assessments 
• E&L risk evaluation programs 
• SUS qualification strategy 
• Supplier compliance management 
• Toxicological justification support 
• Regulatory documentation preparation 
• Global regulatory intelligence monitoring 

Partner With Maven Regulatory Solutions To:

• Strengthen SUS compliance readiness
• Reduce E&L regulatory risks
• Improve supplier qualification systems
• Support successful regulatory submissions
• Enhance manufacturing robustness
• Prepare for evolving global expectations

Contact Maven Regulatory Solutions today to build a future-ready single-use systems compliance strategy.

Final Thoughts

The growing adoption of single-use systems has transformed modern biopharmaceutical manufacturing, and regulatory frameworks are rapidly evolving to address associated extractables and leachables risks.

USP <665> and USP <1665> represent a major shift toward structured, science-based, risk-focused compliance expectations for plastic manufacturing systems.

With May 1, 2026, implementation deadline approaching, manufacturers should act now to:

• Review of SUS qualification strategies 
• Strengthen extractables and leachables programs 
• Update supplier qualification frameworks 
• Align testing methodologies 
• Prepare global regulatory documentation 

Organizations that proactively invest in compliance readiness will be better positioned to maintain operational efficiency, regulatory confidence, and uninterrupted global market access.

FAQs

1. What is USP <665>?

USP <665> establishes requirements for plastic components and systems used in pharmaceutical and biopharmaceutical manufacturing.

2. What is USP <1665>?

USP <1665> provides guidance for risk assessment and evaluation of plastic process-contact materials.

3. When does USP <665> become effective?

The official implementation date is May 1, 2026.

4. What are extractables and leachables?

Extractables and leachables are chemical compounds that may migrate from manufacturing materials into pharmaceutical products or process streams.

5. Is BPOG guidance legally mandatory?

No. BPOG guidance is considered industry best practice in the industry rather than a legally enforceable requirement.

6. Why are single-use systems important in biopharmaceutical manufacturing?

They improve flexibility, reduce contamination risks, and support efficient biologics manufacturing processes.

7. How can Maven help with USP <665> compliance?

Maven supports risk assessments, SUS qualification strategies, supplier compliance, toxicological evaluation, and global regulatory readiness programs.