Numerous organic solvents were utilized in the synthesis of drug substances or drug products. These organic solvents have poisonous properties also harmful to the environment. During manufacturing, it’s very difficult to get rid of organic solvents completely from the finished product. If organic solvents aren’t removed completely from the finished product then the quality and safety of the product are at risk and finally unsafe to the consumer.
What is a Residual Solvent?
Residual solvents in pharmaceuticals are those organic volatile compounds that are used during the manufacturing of drug products or formed during the manufacturing of drug substances or excipients.
Classification of Residual Solvents by Risk Assessment:
There are certain guidelines issued by the regulatory authority to make sure that it’s safe to use organic solvents. Permitted daily exposure (PDE) is defined as a pharmaceutically suitable consumption of residual solvents.
| Class 1 Solvents | Class 2 Solvents | Class 3 Solvents |
| Class-1 solvents are to be avoided because of their predictable and assumed to be human carcinogens and environmental risks. | Class-2 solvents are a smaller amount of genotoxic carcinogens agent of other irrevocable toxicity like neurotoxicity. | Class-3 solvents with less poisonous and at lesser risk to human health. |
| The class-1 solvent should be avoided within the manufacture of drug substances, excipients, and drug products. | Class-2 solvents are assumed as further substantial but revocable toxicities. PDEs are stated to the adjacent 0.1 mg/day, and concentrations are given around 10ppm. | Class-3 solvents are safe for humans with their generally accepted limit in drugs. PDEs are specified as 50 mg per day (5000ppm) would be acceptable without justification. |
| e.g. Benzene, Carbon tetrachloride, 1,2-Dichloroethane 1,1-Dichloroethene, 1,1,1-Trichloroethane | e.g. Acetonitrile, Chlorobenzene, Cyclohexane, Dichloromethane, Hexane, Methanol, N-Methylpyrrolidone, Tetrahydrofuran, Toluene, Xylene | e.g. Acetic acid, Acetone, Anisole, 1-Butanol, 2-Butanol, Butyl acetate, tert-Butylmethyl ether, Dimethyl sulfoxide, Ethanol, Ethyl acetate, Ethyl ether, Ethyl formate, Formic acid, Heptane, Isobutyl acetate, Isopropyl acetate, Methyl acetate, 3-Methyl-1-butanol, Methylethyl ketone, Methyl isobutyl ketone, 2-Methyl-1-propanol, Pentane, 1-Pentanol, 1-Propanol, 2-Propanol, Propyl acetate. |
Recently International Council for Harmonisation (ICH) published a draft guideline ICH Q3C(R8) for establishing new permitted daily exposures (PDEs) for three residual solvents.
2-methyltetrahydrofuran (Class-3), Cyclopentyl methyl ether (Class-2) and Tertiary butyl alcohol (Class-2).
References:
- ICH, Q3C(R6) Impurities: Guideline for Residual Solvents,
- ICH, Q3C(R8) Impurities: Guideline for Residual Solvents, PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether and Tertiary-Butyl Alcohol, Draft Version,
- The United States Pharmacopeia (USP) general chapter <467> Residual Solvents,
- Posiva Panovska; Acevska J; Stefkov G; Breszovska K; Petkovska R; Drimitrovska. A, Optimization of HS-GC-FID-MS Method for Residual Solvent Profiling in Active Pharmaceutical Ingredients Using DoE, Journal of Chromatographic Science, 54, 2016,
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