Residual Solvent Analysis of Pharmaceutical Products

Organic solvents constitute a major fraction in the synthesis of pharmaceutical products. The manufacturing process for active pharmaceutical ingredients (APIs) may contribute to residual solvents remaining in the final product. Producers need to monitor and control the levels of residual solvents for several reasons—including safety, effect on crystalline form, solubility, bio-availability, and stability.

Therefore, all products must be tested to assess whether the solvents used during the manufacturing processes are within the accepted limits. Quality assurance laboratories routinely use the United States Pharmacopeia (USP) Method <467>.


Procedures for identification and quantification

The USP <467> monograph specifies the different classes of solvents per their toxicity, sets the concentration limits according to their health hazard, and describes the assay procedure for the solvents. A complete list of all the solvents that may be used in manufacturing processes is not mentioned under these classes. Therefore, the final products should be screened according to the solvents used during their specific manufacturing process.

The method is composed of three analytical procedures for identification and quantification.

  • Procedure A: Identification and limit testing. Uses a G43 phase (624-type column).
  • Procedure B: Confirms whether or not an identified solvent is above the regulated limits. Uses a G16 phase (WAX-type column).
  • Procedure C: Quantitative test using a G43 phase or G16 phase, depending on which produced fewer coelutions.


USP <467> analytical flowchart for residual solvent analysis.


Columns for excellent performance

Agilent J&W DB-Select 624 UI columns have shown excellent performance for residual solvent analysis according to USP <467> Procedure A. Repeatability was generally better than 2.5% RSD for Class 1, Class 2A, and Class 2B solvents. Once a residual solvent was identified above the permitted daily exposure (PDE) limit, Procedure B is performed to confirm analyte identity. The Agilent J&W DB-WAX UI GC column has been successfully used as a confirmation column, because it yields an alternate selectivity compared to that of a G43 column.

Agilent J&W DB-Select 624 UI columns


Recommended instruments

For this method, Chemetrix can recommend state-of-the-art analytical instruments. With best-in-class technology and powerful software, the Agilent 7697A headspace sampler is packed with the latest productivity-boosting features.  It’s unique sampling design allows you to use hydrogen as a carrier gas, delivering optimal chromatography and helping to future-proof your lab.

Agilent 7697A Headspace Sampler


Based on the Agilent Intuvo 9000 GC system, Agilent Residual Solvent Analyzers are factory pretested and preconfigured to deliver results, fast, while saving precious startup time. What’s more, their analytical precision exceeds USP method requirements for the three classes of residual solvents. It’s chemically tested to ensure optimal analysis of class 1 and class 2A/B solvents and labs can begin system calibration and validation immediately following installation.

Agilent Intuvo 9000 GC


A critical process

Residual Solvent Analysis is a must in any manufacturing environment where solvents form part of the production process. Because this process is so critical, using the correct instruments suited for the lab requirements can save time and boost accuracy.


Quality control at the heart of it all

At every stage of the quality control process, Chemetrix can assist labs with full end-to-end solutions for your residual solvent analysis. Our team of qualified professionals can share a comprehensive portfolio of solutions, including different instrument models, software and consumables, that work together to provide accurate and reproducible results.


Looking for more information on Residual Solvent Analyis? Watch our webinar >


Analytical Strategies for USP Residual Solvents Analysis

In this presentation, we will present the relevant GC/FID and GC/FID/MS based analytical strategies to confidently detect and quantify Class 1, 2, and 3 as well as unknown solvents in drug products. Learn how taking advantage of dual channel configuration and Agilent’s Smart, Connected, and Self-Aware systems can help you successfully meet your requirements for residual solvent analysis and ensure your testing is right first time and every time.


What will you learn

  • Understand what residual solvent impurities are and why it’s important to characterise and quantify them, even when present in trace amounts
  • Understand the current regulatory guidelines for residual solvent analysis in drug substance and product
  • Learn about the approaches for the confident identification and quantification of residual solvents


Who should attend this webinar

  • Laboratory managers
  • Chromatographers
  • Analytical chemists and scientists
  • New product developers
  • Pharma quality control managers


Ian Eisele
Applications Chemist,
Gas Phase Separation Division,
Agilent Technologies


Youjuan Zhang
Applications Chemist,
Gas Phase Separation Division,
Agilent Technologies


Register and watch on demand >


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Residual solvent impurities in pharmaceuticals are trace amounts of volatile organic compounds used in drug production that remain in the final drug product. Strict regulations require close monitoring on the presence of residual solvent, as even trace amounts can impact drug safety and efficacy.



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