How Impurity Profiling Is Approached When Impurity Levels Are Below ICH Reporting Thresholds

Published Feb 3, 2026 by Pharmaffiliates

How Impurity Profiling Is Approached When Impurity Levels Are Below ICH Reporting Thresholds

Impurity profiling is a critical component of pharmaceutical development and quality control. While ICH guidelines define reporting, identification, and qualification thresholds, impurities present below these limits can still have scientific and regulatory significance. A proactive, risk-based approach to profiling such impurities enhances process understanding, supports long-term control strategies, and reduces development and regulatory risk.

Significance of Sub-Threshold Impurities

Impurities detected below ICH reporting thresholds may not require immediate disclosure; however, their presence can become increasingly relevant as development progresses. Process optimization, scale-up, changes in raw materials, or modifications in manufacturing conditions can lead to an increase in impurity levels over time.

Regulatory authorities increasingly expect manufacturers to demonstrate comprehensive knowledge of impurity profiles, including low-level species, particularly for late-stage development and commercialization. Early evaluation of sub-threshold impurities supports:

• Anticipation of future ICH reporting or qualification requirements
• Prevention of late-stage development challenges
• Strengthened regulatory submissions and audit readiness
• Improved lifecycle and change-management planning

Targeted, High-Sensitivity Analytical Strategy

A targeted analytical strategy is implemented to detect, monitor, and characterize impurities present at trace levels. High-sensitivity techniques are selected based on molecular structure, synthetic route, and risk assessment.

LC–MS/MS for Trace Impurity Detection

LC–MS/MS is employed for the selective and sensitive detection of known or suspected impurities at very low concentrations. This technique is particularly effective for:

• Monitoring process-related and degradation impurities
• Trending impurity levels across development and stability batches
• Supporting early control strategy development

High-Resolution Mass Spectrometry (HRMS)

HRMS is utilized to characterize unknown or unexpected impurities through accurate mass measurement and isotopic pattern analysis. HRMS data support:

• Molecular formula determination
• Differentiation of closely related or isobaric compounds
• Scientific justification of impurity origin

Advanced NMR Techniques

When isolation or enrichment of impurities is feasible, advanced NMR techniques are applied for structural confirmation. NMR analysis contributes to:

• Structural justification and impurity identification reports
• Understanding impurity formation mechanisms
• Supporting toxicological and regulatory risk assessments

Impurity Trending and Control

Beyond detection and identification, impurities below ICH reporting thresholds are systematically trended to assess their behavior over time and under varying process conditions. Trending data enable:

• Early identification of impurity growth trends
• Correlation of impurity formation with critical process parameters
• Implementation of risk-based control strategies

This comprehensive documentation demonstrates that low-level impurities are scientifically understood and appropriately managed.

Value Across the Product Lifecycle

Profiling impurities below ICH thresholds provides significant value throughout the product lifecycle, particularly during:

• Process scale-up and technology transfer
• Late-phase clinical development and commercial readiness
• Global regulatory submissions with stringent CMC expectations
• Long-term stability and degradation assessments

Early investment in high-sensitivity impurity profiling reduces the likelihood of regulatory queries and manufacturing delays at advanced stages.

Conclusion

Approaching impurity profiling beyond minimum ICH reporting requirements strengthens pharmaceutical development and regulatory preparedness. The application of targeted LC–MS/MS, HRMS, and advanced NMR techniques enables effective detection, trending, and control of sub-threshold impurities. This proactive strategy supports robust process understanding, lifecycle management, and confident regulatory engagement.