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.
  Class PDE (mg/day) Solvent Concentration Limit (ppm)
Benzene 1 - 2
Carbon tetrachloride 1 - 4
1,2-Dichloroethane 1 - 5
1,1-Dichloroethene 1 - 8
1,1,1-Trichloroethane 1 - 1500
Acetonitrile 2 4.1 410
Chlorobenzene 2 3.6 360
Chloroform 2 0.6 60
Cumene 2 0.7 70
Cyclohexane 2 38.8 3880
1,2-Dichloroethene 2 18.7 1870
Dichloromethane 2 6.0 600
1,2-Dimethoxyethane 2 1.0 100
N,N-Dimethylacetamide 2 10.9 1090
N,N-Dimethylformamide 2 8.8 880
1,4-Dioxane 2 3.8 380
2-Ethoxyethanol 2 1.6 160
Ethylene glycol 2 6.2 620
Formamide 2 2.2 220
Hexane 2 2.9 290
Methanol 2 30.0 3000
2-Methoxyethanol 2 0.5 50
Methylbutyl ketone 2 0.5 50
Methylcyclohexane 2 11.8 1180
N-Methylpyrrolidone 2 5.3 530
Nitromethane 2 0.5 50
Pyridine 2 2.0 200
Sulfolane 2 1.6 160
Tetrahydrofuran 2 7.2 720
Tetralin 2 1.0 100
Toluene 2 8.9 890
1,1,2-Trichloroethene 2 0.8 80
Xylene 2 21.7 2170

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

Increased Throughput for Trace Impurities and Residual Solvents Determination with Unattended Liquid/Headspace Switching

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

Webinar

Automate and Enhance Static Headspace Gas Chromatography Determinations

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

This application note describes the analysis of residual solvents in accordance with USP method <467> using the Thermo Scientic™ TRACE™ 1310 GC, the new Thermo Scientic™ TriPlus™ 300 Headspace autosampler, and the Thermo Scientic™ Dionex™ Chromeleon™ chromatography data system (CDS) software.


Residual solvents and volatile organic impurities literature library

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Type Title Product Focus Year
Application Note Analysis of Residual Solvents using GC/FID with Headspace and a Cyanopropylphenyl Polysiloxane Phase Gas Chromatography Mass Spectrometry 2010
Application Note Analyzing Residual Solvents in Pharmaceutical Products Using GC Headspace with Valve-and-Loop Sampling Gas Chromatography 2013
Application Note Impurity Profiling of Pharmaceutical Starting Materials Using GC Coupled with High Resolution Accurate Mass Spectrometry Gas Chromatography Mass Spectrometry 2016
Article Detecting impurities in drugs by Orbitrap MS Gas Chromatography Mass Spectrometry 2016
Blog Doctor, Doctor My Pills Smell of Residual Solvents Gas Chromatography 2015
Brochure Thermo Scientific TRACE 1300 Series Gas Chromatography Mass Spectrometry 2014
Brochure TriPlus 300 Headspace Autosampler Brochure Gas Chromatography Mass Spectrometry 2013
Case Study Sanofi evaluates and recommends new "flexible and user friendly" GC system Gas Chromatography 2012
Poster Analysis of residual solvents using GC/FID with headspace and a cyanopropylphenyl polysiloxane phase Chemistries and Consumables 2010
Poster Improving Pharmaceutical Laboratory Throughput in the Analysis of Trace Impurities and Residual Solvents with Liquid/Headspace Unattended Switching and Automated Standard Preparation Gas Chromatography 2014
Poster Note Headspace Grade Solvents for Trace Level Analyte Detection Chemistries and Consumables 2016
Product Specifications Thermo Scientific TriPlus 300 Headspace Autosampler Gas Chromatography Mass Spectrometry 2013
Webinar Automate and Enhance Static Headspace GC Determinations Gas Chromatography 2014
Webinar Pharmaceutical Impurity Profiling: Simple, Confident Analysis with New GC-MS Technology (AstraZeneca) Gas Chromatography Mass Spectrometry 2015
White Paper Advances in Process Mass Spectrometry for product drying in the pharmaceutical industry - learning lessons and applying QbD concepts to instrument design Process Analytical 2014