ICH announces sign-off of residual solvent guideline

Regulatory NewsRegulatory News | 03 May 2021 |  By 

The International Council for Harmonization (ICH) recently announced that its guideline establishing new permitted daily exposures (PDEs) for three residual solvents had reached Step 4, meaning the guideline can now be implemented by regulators.
The ICH Q3C(R8) guideline has been revised to include permitted daily exposure (PDE) levels for 2-methyltetrahydrofuran (2-MTHF), cyclopentyl methyl ether (CPME) and tertiary butyl alcohol (TBA). The PDE for 2-methyletrahydrofuran is 50 mg/day, for cyclopentyl methyl ether 15 mg/day and tertiary butyl alcohol 35 mg/day.
According to a Step 4 training presentation on the guideline, the Q3C (R8) Expert Working Group (EWG) review of available toxicity data with 2-MTHF, also known as tert-butylmethyl ether, found no evidence for genotoxicity or reproductive toxicity and no observed effect level in repeat dose toxicity studies involving rats. For CPME, EWG’s review found no evidence of genotoxicity and no data available demonstrating carcinogenic effects. For TBA, the review found no evidence of genotoxicity and limited data available on reproductive toxicity.
ICH said that the document was unchanged from a Step 2 guidance issued last year. (RELATED: FDA consults on ICH residual solvent guideline, Regulatory Focus, 26 May 2020.)
The ICH Q3C guideline was finalized in July 1997, providing recommendations on the PDEs for less toxic solvents in the manufacture of drug substances and dosage forms. Residual solvents are considered organic volatile impurities.
A maintenance process for the Q3C guideline was set up to enable the revision of the guideline and to include new PDE levels as new toxicological data for solvents became available. As part of the maintenance process, the Q3C(R8) maintenance EWG has been working on setting PDE levels for these three residual solvents.
ICH Q3C (R8) Guideline


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