USP <467> Residual Solvents
Residual Solvents Analysis (formerly Organic Volatile Impurities)
Validation Resources conducts residual solvent testing for drug products and excipients to meet the current requirements of USP General Chapter <467> Residual Solvents.
On July 1, 2008 the United States Pharmacopoeia (USP) implemented the provisions in the new General Chapter <467> Residual Solvents (formerly entitled Organic Volatile Impurities). To meet the requirements of this chapter we offer residual solvent analysis of drug substances, products, excipients and raw materials utilizing headspace sampling and gas chromatography with flame ionization detection (FID). This analysis provides identification and quantitation of USP Class 1 and Class 2 solvents and can be adapted for Class 3 solvent analysis if necessary.
An Overview and Introduction to Residual Solvents Analysis
USP General Chapter <467> Residual Solvents applies to existing drug substances, excipients and products. Residual solvents are defined 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 following is a synopsis of the USP Chapter.
Testing should be performed when production or purification processes are known to result in the presence of residual solvents in the drug substance, excipients or drug product. It is only necessary to test for those solvents used or produced in the manufacturing process.
The term “permitted daily exposure” (PDE) is used to define the pharmaceutically acceptable intake of residual solvents. The solvents addressed in the chapter were categorized based on their possible risk to human health and placed in one of three classes:
- Class 1 – Solvents to be avoided
- Class 2 – Solvents to be limited
- Class 3 – Solvents with low toxic potential
Known human carcinogens; strongly suspected human carcinogens; environmental hazards.
Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity, such as neurotoxicity or teratogenicity; solvents suspected of other significant but reversible toxicities.
Solvents with low toxic potential to humans; Class 3 residual solvents have PDEs of 50 mg or more per day.
Class 1 Solvents
In general, USP recommends that Class 1 solvents not be used in the manufacture of drug substances, excipients or drug products due to their high toxicity and or negative environmental effects. However, if their use is unavoidable the levels should be restricted to the amounts shown in Table 1.
| Solvent | Concentration Limit (ppm) | Concern |
|---|---|---|
| Benzene | 2 | Carcinogen |
| Carbon tetrachloride | 4 | Toxic and environmental hazard |
| 1,2-Dichloroethane | 5 | Toxic |
| 1,1-Dichloroethane | 8 | Toxic |
| 1,1,1-Trichloroethane | 1500 | Environmental hazard |
When Class 1 solvents are used or produced in the manufacture of drug substances, excipients or drug products and are not removed by the process they should be identified and quantified.
Class 2 Solvents
Table 2 shows the Class 2 solvents and the permitted daily exposure (PDE). USP recommends that Class 2 solvents be limited in the production of drug substances, excipients and drug products due to their inherent toxicities.
| Solvent | Permitted Daily Exposure (mg/day) | Concentration Limit (ppm) |
|---|---|---|
| Acetonitrile | 4.1 | 410 |
| chlorobenzene | 3.6 | 360 |
| Chloroform | 0.6 | 60 |
| Cyclohexane | 38.8 | 3880 |
| 1,2-Dichloroethane | 18.7 | 1870 |
| 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 |
| Ethylene glycol | 6.2 | 620 |
| Formamide | 2.2 | 220 |
| Hexane | 2.9 | 290 |
| Methanol | 30.0 | 3000 |
| 2-Methoxyethanol | 0.5 | 50 |
| Methylbutylketone | 0.5 | 50 |
| Methylcyclohexane | 11.8 | 1180 |
| Methylene chloride | 6.0 | 600 |
| N-Methylpyrrolidone | 5.3 | 530 |
| Nitromethane | 0.5 | 50 |
| Pyridine | 2.0 | 200 |
| Sulfolane | 1.6 | 160 |
| Tetrahydrofuran | 7.2 | 720 |
| Tetralin | 1.0 | 100 |
| Toluene | 8.9 | 890 |
| Trichloroethylene | 0.8 | 80 |
| Xylene | 21.7 | 2170 |
Two options are available when assessing limits for Class 2 residual solvents.
Option One
Residual solvent concentration limits in ppm do not exceed those stated in Table 2 when applied to the components of a drug product. In other words, the drug substance along with any excipients combined in the drug product individually meet the limits as stated in Table 2. These components can then be used in any proportion and still meet the requirements of USP <467> as long as the administered doses do not exceed 10 g per day. This option can be used when the daily dose is not fixed.
Option Two
Option Two can be used when some of the components of a drug product do not by themselves meet the ppm limits of Option One but the total drug product does not exceed the PDE in mg per day as stated in Table 2. Option Two can also be used if the daily administered dose of a drug product exceeds 10 g.
If Class 2 solvents are likely to be present at greater than the Option One limits they should be identified and quantified.
Class 3 Solvents
Class 3 residual solvents are regarded as less toxic and of lower risk to human health than either Class 1 or Class 2 residual solvents. Class 3 residual solvents are listed in Table 3. USP <467> considers that amounts of these residual solvents of 50 mg per day or less would be acceptable without justification.
| Solvent | Solvent |
|---|---|
| Acetic Acid | Heptane |
| Acetone | Isobutyl acetate |
| Anisole | Isopropyl acetate |
| 1-Butanol | Methyl acetate |
| 2-Butanol | 3-Methyl-1-butanol |
| Butyl acetate | Methylethylketone |
| Tert-Butylmethyl ether | Methylisobutylketone |
| 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 |
The USP General Chapter <467> provides a method for the identification and quantitation of Class 1 and Class 2 residual solvents utilizing headspace sampling and gas chromatography with flame ionization detection (FID). Some Class 2 solvents, including formamide, 2-ethoxyethanol, 2-methoxyethanol, ethylene glycol, N-methylpyrrolidone and sulfolane, are not amenable to detection using this method and will require the development of alternative methods. For Class 3 residual solvents levels may be determined as directed under USP <731> Loss on Drying if so indicated in the monograph for the test article. If not indicated or if levels greater than 50 mg per day are expected, the analysis procedure indicated for Class 1 and Class 2 solvents with the appropriate changes made in standards or other validated procedures can be used.