E&L System Suitability Standard Development

Understanding the E&L Challenge

Container closure systems, drug delivery devices, and manufacturing equipment involve complex materials: polymers, elastomers, adhesives, coatings, and lubricants. Each contains numerous chemical constituents:

• Monomers and oligomers
• Plasticizers and stabilizers
• Antioxidants and UV absorbers
• Processing aids and catalysts
• Degradation products
• Reaction by-products

Any of these might leach into pharmaceutical products under storage or use conditions. The complexity of modern materials and devices means potentially hundreds of extractable compounds could be present, each with potential to become a leachable that impacts patient safety or product efficacy.

Non-targeted screening must cast a wide analytical net, detecting compounds across this diversity without prior knowledge of what might appear.

The UPLC-HRMS Screening Approach

For low-volatility organic compounds (the majority of E&L concerns), Resolian employs ultra-performance liquid chromatography coupled with high-resolution accurate mass spectrometry.

Why UPLC?

• Efficient separation of complex mixtures
• Wide polarity range compatibility
• Fast analysis enabling high sample throughput

Why high-resolution accurate mass spectrometry?

• Accurate mass measurement enabling elemental composition determination
• High mass resolution distinguishing compounds with similar nominal masses
• Full-scan acquisition capturing all detectable compounds
• Retrospective data analysis capability

Why both ESI and APCI ionization? Different compounds ionize preferentially by different mechanisms. ESI excels for polar, ionic compounds while APCI better ionizes less polar, neutral species. Using both ionization modes expands the range of detectable compounds, critical for comprehensive E&L screening.

The System Suitability Imperative

Before analyzing precious samples where results determine patient safety decisions, the analytical system must demonstrate readiness. System suitability testing provides this verification by analyzing standard reference materials to confirm:

• Adequate chromatographic resolution
• Expected retention time behavior
• Appropriate sensitivity
• Acceptable peak shapes
• Stable ionization efficiency
• Precision of measurements

But what compounds should comprise the system suitability standard for non-targeted E&L screening?

The USP-Guided Selection Approach

The United States Pharmacopeia provides recommendations for selecting system suitability standard compounds for E&L applications. The guidance emphasizes choosing analytes that represent diverse chemical classes and fulfill specific verification functions.

Cheryl’s development process followed this approach, screening over 30 potential candidates to identify compounds that collectively provide comprehensive system verification.

The Seven Functional Categories:

1. Potentially Toxic Substances Compounds representing classes with known toxicological concern, verifying the system can detect safety-critical compounds
2. Chemical Diversity Representatives Compounds spanning diverse chemical functionalities: acids, bases, neutrals, varying polarities, different ionization behaviors
3. Anchor Compounds Stable, well-retained compounds verifying basic chromatographic and detection functionality
4. Critical Pairs Compound pairs with similar properties but requiring chromatographic resolution, testing the system’s separation capability
5. Sensitivity Markers Compounds used to verify detection limits meet requirements for trace-level E&L analysis
6. Overlapping Compounds Species detected by both ESI and APCI, verifying both ionization modes function properly
7. Precision Indicators Compounds used to assess measurement reproducibility and variation

Each category addresses a specific aspect of method fitness-for-purpose for E&L screening.

From 30+ Candidates to 15 Standards

The development process involved:

• Initial candidate screening:
  Over 30 compounds representing diverse E&L chemical classes were evaluated for:
  • Stability in standard solutions
  • Appropriate retention under UPLC conditions
  • Ionization behavior in ESI and APCI
  • Availability and purity of reference standards
  • Relevance to actual E&L findings
• Functional assessment:
  Each candidate was evaluated for which USP-defined functions it could fulfill
• Mixture optimization:
  Candidates were combined and tested as mixtures to ensure:
  • Adequate chromatographic separation of all components
  • No unexpected interactions or suppression effects
  • Stable mixed standard solution
  • Appropriate concentration ratios for all functions
• Final selection:
  15 compounds were selected that collectively:
  • Represent structural, functional, and chemical diversity expected in E&L screening
  • Fulfill all seven USP-recommended functional categories
  • Provide redundancy (multiple compounds per function) for robust verification
  • Are detectable by both ESI and APCI where appropriate

Critically, each compound in the final mixture successfully performs one or more relevant verification functions. This ensures efficient use of chromatographic space while providing comprehensive system verification.

Building Confidence in E&L Results

The value of a well-designed system suitability standard extends beyond regulatory compliance. It provides:

• Method readiness verification:
  Confirmation that chromatography, detection, and data acquisition systems are performing appropriately before sample analysis
• Troubleshooting diagnostic:
  When system suitability standards fail, they indicate specific system issues (poor resolution, low sensitivity, ionization problems) enabling targeted troubleshooting
• Result confidence:
  When system suitability passes, analysts and reviewers can trust that subsequent sample results reflect true sample composition rather than analytical artifacts or system failures
• Cross-laboratory consistency:
  Standardized system suitability criteria enable comparable performance across multiple laboratories or instrument systems

For E&L screening where patient safety decisions depend on comprehensive detection, this confidence is essential.

The Recognized Compound Advantage

Cheryl emphasizes using recognized extractable and leachable compounds in the system suitability mix. These aren’t arbitrary chemical standards but actual compounds commonly encountered in E&L studies. This means:

• System suitability verification uses chemically relevant representatives
• Retention behavior and ionization characteristics reflect real E&L analytes
• The standard provides realistic assessment of method capability for intended applications

This relevance strengthens the confidence that system suitability verification truly indicates fitness-for-purpose for E&L screening.

Advancing E&L Testing Standards

Cheryl’s work represents broader commitment to improving analytical standards and result integrity in E&L testing. As pharmaceutical products become more complex and delivery devices more sophisticated, E&L analysis must evolve to meet these challenges.

Systematic approaches to system suitability standard development, following pharmacopeial guidance and incorporating recognized E&L compounds, ensure that analytical methods keep pace with increasing complexity.

Expert E&L Analysis with Rigorous Standards

Resolian’s extractables and leachables team combines comprehensive screening capabilities with rigorous analytical standards:

• UPLC-HRMS instrumentation with ESI and APCI ionization
• Non-targeted screening workflows for unknown compound detection
• Systematic system suitability verification before sample analysis
• USP-guided standard development and validation
• Experience across diverse container closure systems and delivery devices
• Global laboratory network supporting multi-region studies

Whether you need routine E&L screening, method development for novel materials or devices, or consultation on system suitability approaches, we bring the technical rigor and commitment to patient safety that E&L testing demands.