Residual Solvents Under USP 467 (ICH Q3C) Guidelines

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Residual solvents in pharmaceuticals are defined by the ICH as organic volatile chemicals that are used or produced in the manufacture of drug substances, excipients, or in the preparation of drug products. In general, solvents are not completely removed by practical manufacturing techniques.  Solvents provide no therapeutic benefit, therefor all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Appropriate selection of solvent for processing of a drug substance may enhance the yield, allow isolation of a preferred crystal form, improve purity, or enhance solubility. Therefore, the solvent can play a critical role in the synthetic process. Given the presence of solvents in most pharmaceutical processing steps, the content of solvents in pharmaceutical products should be evaluated.

Drug products should contain no higher levels of residual solvents than can be supported by safety data. Commonly used solvents have been grouped by toxicity under the ICH Q3C guidance. The most toxic solvents (Class 1, table below) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity (Class 2, table below) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3, table below) should be used where
practical.

 

Class 1: Most Toxic Solvents
Solvent Limits (ppm) Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and environmental hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Environmental hazard
Class 2: Less Toxic Solvents
Solvent Permissable Daily Exp. mg/day Limits (ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
Dichloromethane 6.0 600
1,2-Dimethoxyethane 1.0 100
N,N-Dimethylacetamide 10.9 1090
N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380
2-Ethoxyethanol 1.6 160
Ethyleneglycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3000
2-Methoxyethanol 0.5 50
Methylbutyl ketone 0.5 50
Methylcyclohexane 11.8 1180
N-Methylpyrrolidone 15.3 530
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetrahydrofuran 27.2 720
Tetralin 1.0 100
Toluene 8.9 890
1,1,2-Trichloroethene 0.8 80
Xylenes 21.7 2170
Class 1: Safest Solvents. 5000ppm limits, PDE 50mg/day
Solvent Solvent
Acetic acid Heptane
Acetone Isobutyl acetate
Anisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl acetate Methylethyl ketone
tert-Butylmethyl ether Methylisobutyl ketone
Cumene 2-Methyl-1-propanol
Dimethyl sulfoxide Pentane
Ethanol 1-Pentanol
Ethyl acetate 1-Propanol
Ethyl ether 2-Propanol
Ethyl formate Propyl acetate
Formic acid