Understanding the Revisions to USP Monograph <467>: Residual Solvents

Importance of the Topic

Residual solvent analysis in pharmaceutical products ensures patient safety by controlling potentially harmful organic volatile impurities. Revisions to USP chapter <467> harmonize testing criteria with ICH Q3C risk‐based guidelines, updating exposure limits and streamlining analytical workflows.

Objectives and Study Overview

This article reviews the key changes in the revised USP <467> monograph and evaluates gas chromatographic methods for identification and quantification of Class 1, 2, and 3 residual solvents. It compares Procedures A and B for qualitative screening, Procedure C for quantitation, and explores advanced GC and GC/MS strategies to improve throughput and specificity.

Methodology and Instrumentation Used

The USP <467> monograph specifies:

• Procedure A (Zebron ZB-624 phase) and Procedure B (Zebron ZB-WAXplus phase) for qualitative headspace GC‐FID screening.
• Procedure C for quantitation using the phase with minimal co-elutions.

System suitability criteria include signal‐to‐noise ratios >5 for key analytes and resolution >1.0 between critical peak pairs. Alternatives such as dual‐column configurations and bench‐top GC/MS (MSD detection) were assessed to reduce analysis time and eliminate misidentifications.

Main Results and Discussion

Under monograph conditions, GC‐FID screening of seven Class 1 and two Class 2 solvents required more than three hours per sample when all three procedures were run sequentially. Resolution and sensitivity targets were met, but throughput constraints led to method optimization:

• Selection of efficient column dimensions (shorter length, narrower internal diameter, optimized film thickness) with G43 and G16 phases to resolve target analytes in under 20 minutes.
• Parallel dual‐column setup splitting a single injection into two phases to achieve simultaneous Procedures A and B (and potentially C), reducing cycle time to under 10 minutes.
• Adoption of GC/MS with Zebron ZB-WAXplus to leverage mass spectral confirmation, distinguishing co-eluting compounds (e.g., ethyl formate vs. methyl acetate) and screening all Class 1–3 solvents in a single run of approximately five minutes.

Benefits and Practical Applications of the Method

The optimized approaches deliver:

• Significant reductions in sample analysis time and instrument usage.
• Improved specificity through orthogonal column selectivity or mass spectral identification.
• Adaptable workflows tailored to company‐specific solvent use and sample throughput requirements.
• Compliance readiness for existing marketed drugs and new submissions, minimizing revalidation efforts.

Future Trends and Opportunities

Emerging trends include broader adoption of compact GC/MS platforms, integrated dual‐column ovens, and automated headspace samplers. Ongoing dialogue between industry and USP will refine method text and address practical concerns. Further harmonization with global regulatory guidelines may enable unified testing standards and greater instrument flexibility.

Conclusion

Revised USP <467> aligns with ICH Q3C to enhance patient safety through updated PDE limits and risk‐based testing. While the monograph provides a robust framework, laboratories can optimize column selection, dual‐column configurations, or GC/MS detection to boost throughput and confidence in solvent identification and quantitation.

Reference

Countryman S. Understanding the Revisions to USP Monograph <467>: Residual Solvents. Phenomenex Inc., Torrance, CA, 2007.