FDAnews Drug Daily Bulletin
Pharmaceuticals / Regulatory Affairs / Postmarket Safety

ICH Guidance Details Evaluation and Control of Mutagenic Impurities in Drugs

Oct. 2, 2015

The International Conference on Harmonisation has issued first-ever quantitative guidance on the evaluation and control of mutagenic impurities in medicines to limit potential cancer risk.

The draft guidance — an addendum to ICH M7 on genotoxic impurities — builds on the latter’s more broad-sweeping advice with acceptable intake and permissible daily exposure limits for 15 chemicals common in pharmaceutical manufacturing that are considered to be mutagenic and carcinogenic.

For each chemical, ICH has provided an acceptable AI or PDE in micrograms, the potential for human exposure, details on its mutagenicity/genotoxicity and carcinogenicity, regulatory and published limits, and rationale for selection of data for AI calculations.

For example, benzyl chloride, used in the synthesis of amphetamine-class drugs, has an allowed AI/PDE of 41 micrograms a day. Its potential for human exposure is mainly through inhalation, although some people ingest it from contaminated ground water, the guidance says.

Benzyl chloride is classified as Group 2A — possibly carcinogenic, but unlikely to pose a health risk to patients exposed to low concentrations, such as impurities in pharmaceuticals.

Also covered in the guidance are acrylonitrile, bis(chloromethyl)ether, 1-chloro-4-nitrobenzene, p-cresidine, dimethylcarbamoyl chloride, ethyl chloride, glycidol, hydrazine, methyl chloride, aniline, hydrogen pyroxide, hydroxylamine, p-chloroaniline and dimethyl sulfate.

ICH M7 was finalized in May. Read the draft addendum at www.fdanews.com/09-28-15-ICHM7Addendum.pdf. — Kellen Owings