Residual Solvent Analysis Information

Pharmaceutical volatile organic impurity testing

Residual solvents in pharmaceuticals are volatile organic compounds used or created during the manufacture of drugs and pharmaceutical additives. Manufactures are forced by regulation to ensure pharmaceuticals are free from toxicologically significant levels of volatile organic compounds. Typically, headspace gas chromatography is employed (GC) for this task, and often together with identification and quantification using mass spectrometry (GC-MS).

Regulations for residual solvents analysis: ICH Q3C & USP <467>

Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process.

In 1988, the United States Pharmacopoeia (USP) provided control limits and testing criteria for seven organic volatile impurities (OVIs) under official monograph USP <467> Residual Solvents. The compounds were chosen based on relative toxicity and only applied to drug substances and some excipients. They have since extended the compound list in General Chapter <467> Residual Solvents, and harmonized their efforts by aligning limits with the International Council for Harmonization (ICH) guidelines ICH Q3C Guideline for Residual Solvents.

Allowable limits or Permitted Daily Exposure (PDE) for residual solvents are defined in ICH Q3C. The PDE is based on the toxicity of the solvent. Solvents are defined into three class:

  • Class 1 solvents: Solvents to be avoided—known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
  • Class 2 solvents: Solvents to be limited—on-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
  • Class 3 solvents: Solvents with low toxic potential—solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.
 ClassPDE (mg/day)Solvent Concentration Limit (ppm)
Benzene1-2
Carbon tetrachloride1-4
1,2-Dichloroethane1-5
1,1-Dichloroethene1-8
1,1,1-Trichloroethane1-1500
Acetonitrile24.1410
Chlorobenzene23.6360
Chloroform20.660
Cumene20.770
Cyclohexane238.83880
1,2-Dichloroethene218.71870
Dichloromethane26.0600
1,2-Dimethoxyethane21.0100
N,N-Dimethylacetamide210.91090
N,N-Dimethylformamide28.8880
1,4-Dioxane23.8380
2-Ethoxyethanol21.6160
Ethylene glycol26.2620
Formamide22.2220
Hexane22.9290
Methanol230.03000
2-Methoxyethanol20.550
Methylbutyl ketone20.550
Methylcyclohexane211.81180
N-Methylpyrrolidone25.3530
Nitromethane20.550
Pyridine22.0200
Sulfolane21.6160
Tetrahydrofuran27.2720
Tetralin21.0100
Toluene28.9890
1,1,2-Trichloroethene20.880
Xylene221.72170

ICH Q3C and USP <467> are harmonized in their approach with a salient exception: whereas ICH Q3C applies only to new drug products, USP <467> applies the same requirements to all new and existing drug products.

To meet low levels in regulated analytical protocols, many modern methods employ valve and loop style headspace auto-samplers, gas chromatographs with flame ionization or mass spectrometric detection and compliant chromatography data software.

For more information on these technologies, please visit our Volatile Organic Impurities section of web content.


Monitoring product drying to minimize residual solvents

A key stage in many pharmaceutical processes is the complete or partial removal of a solvent or solvents from a product or intermediate. This drying process can occur in a variety of process vessels, including vacuum dryers, tray dryers and rotary dryers. Many API drying processes involve the removal of two or more solvents from a potential list of over thirty compounds. This requires complex chemometric modelling to turn the spectroscopic data into process friendly concentration data. Gas analysis by MS offers significant advantages of simplicity in both sampling and data manipulation for the solvent drying application.


Featured USP <467> & ICH Q3C learning content

Webinar

Learn how to increase throughput of residual solvent determination with novel autosampler technology.

Webinar

Learn how the latest robotic sample handling autosampler can increase your throughput for headspace and SPME analysis, all within a fully compliant software environment. Understand the effect of sampling time, salting and other variables in the optimization of your volatile organic impurity analyses.

Poster note

Water is the most common solvent to dissolve a drug formulation in for residual solvent deteremination; however many drug APIs or formulations are insoluble in water. Consequently headspace grade solvents are required. Here we evaluate five different solvents for headspace GC analysis. The solvents are water, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and 1-methyl-2-pyrrolidinone (NMP).

Application note

This application note describes the use of the new Thermo Scientifi­c TriPlus 500 Headspace autosampler, which is based on Valve-and-Loop technology, for the analysis of residual solvents in accordance with USP method <467>. Discover the benefits of direct column connection and highly precise pneumatic control in delivering the best analytical performance, combined with this autosampler's routine grade robustness.


Residual solvents and volatile organic impurities literature library

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TypeTitleProduct FocusYear
Application NoteAnalysis of Residual Solvents using GC/FID with Headspace and a Cyanopropylphenyl Polysiloxane PhaseGas Chromatography Mass Spectrometry2010
White PaperInvestigation of Key Parameters for a Smooth Method Transfer to the TriPlus 500 Headspace AutosamplerGas Chromatography2019
Application NoteImpurity Profiling of Pharmaceutical Starting Materials Using GC Coupled with High Resolution Accurate Mass SpectrometryGas Chromatography Mass Spectrometry2016
Application NoteGenerating Reliable Quantitative Solvent Drying Process Data in the Pharmaceutical IndustryProcess Analytical2014
Application NoteRoutine-grade Residual Solvents According to USP 467Gas Chromatography2018
Application NoteGenotoxic Impurities in Valsartan by GC-MSGas Chromatography Mass Spectrometry2019
ArticleDetecting impurities in drugs by Orbitrap MSGas Chromatography Mass Spectrometry2016
BlogDoctor, Doctor My Pills Smell of Residual SolventsGas Chromatography2015
BlogWhat is in my medicine?Gas Chromatography2019
BrochureThermo Scientific TRACE 1300 SeriesGas Chromatography Mass Spectrometry2014
BrochureTriPlus 300 Headspace Autosampler BrochureGas Chromatography Mass Spectrometry2013
BrochureTriPlus 500 GC Headspace AutosamplerGas Chromatography2019
Case StudySanofi evaluates and recommends new "flexible and user friendly" GC systemGas Chromatography2012
Case StudyCase Study SGS on Enhanced Productivity and Reliability in Pharmaceutical LaboratoriesPharmaceutical2019
PosterAnalysis of residual solvents using GC/FID with headspace and a cyanopropylphenyl polysiloxane phaseChemistries and Consumables2010
PosterImproving Pharmaceutical Laboratory Throughput in the Analysis of Trace Impurities and Residual Solvents with Liquid/Headspace Unattended Switching and Automated Standard PreparationGas Chromatography2014
Poster NoteHeadspace Grade Solvents for Trace Level Analyte DetectionChemistries and Consumables2016
Product SpecificationsThermo Scientific TriPlus 300 Headspace AutosamplerGas Chromatography Mass Spectrometry2013
Product SpecificationsTriPlus 500 Gas Chromatography Headspace AutosamplerGas Chromatography2019
Technical NoteSimplified, Cost-Effective Headspace GC Method for Residual Solvents Analysis in Pharmaceutical ProductsGas Chromatography2019
Technical NoteRoutine-Grade Quantitative Performance of TriPlus 500 HS Coupled to TRACE 1310 GC-FIDGas Chromatography2018
WebinarGas Chromatography2014
WebinarPharmaceutical Impurity Profiling: Simple, Confident Analysis with New GC-MS Technology (AstraZeneca)Gas Chromatography Mass Spectrometry2015
CMD SchemaApp code