ICH Q3C(R9) - Residual Solvents

What it says

Residual solvents used or produced during manufacture of drug substances or excipients must be controlled according to a three-class toxicological categorisation, with Class 1 solvents avoided wherever possible, Class 2 solvents limited by permitted daily exposure, and Class 3 solvents permitted at higher levels reflecting their lower toxicity.

Paraphrased for plain-language clarity. Always verify against the current published regulation text.

What it means in practice

• The three-class system means the same raw residual solvent level can represent very different levels of concern depending on the specific solvent's toxicological classification, requiring solvent-specific rather than uniform limits.
• Class 1 solvents, known human carcinogens or environmentally hazardous substances, are expected to be avoided in the manufacturing process entirely wherever a suitable alternative exists, not simply controlled to an acceptable residual level.
• Permitted daily exposure limits for Class 2 solvents are calculated based on the product's maximum daily dose, meaning the same residual solvent concentration can be acceptable for one product and unacceptable for another depending on dosing.

What inspectors look for

• Whether the manufacturing process avoids Class 1 solvents wherever a suitable alternative genuinely exists, rather than continuing their use based on historical process convenience.
• Whether permitted daily exposure calculations for Class 2 solvents correctly reflect the product's actual maximum daily dose.
• Whether analytical methods used to detect and quantify residual solvents have adequate sensitivity relative to the applicable limits.

Related regulations