ICH guideline proposes daily limits for seven mutagenic impurities

Editor's note: This article was updated to correct the PDE for acetaldehyde, vinyl acetate and formaldehyde.

The International Council for Harmonization (ICH) on Wednesday issued its M7(R2) guideline setting new permitted daily exposure (PDE) limits for seven DNA-reactive substances to limit their carcinogenic risk. The guideline is now available for public comment.

The guideline contains 21 mutagenic impurities, adding seven substances to the 14 previously published in the ICH M7(R1) guideline, which reached Step 4 in June 2017. (RELATED: FDA Finalizes Guidance on Mutagenic Carcinogens, Regulatory Focus 13 March 2018).

The guideline includes the rationales for including the new mutagenic impurities along with their supporting monographs. A presentation released along with the M7(R2) guideline explained that because the ICH M7 guideline was reaching an unwieldy length, it has now been separated into one main guideline and an addendum containing PDEs or acceptable intake (AI) levels for each impurity, along with their monographs.

The seven newly added impurities, along with their permitted daily exposure (PDE) levels, include the following:

Acetaldehyde: (oral) 2,000 mcg/day – 185 mcg/day for all other routes
1,2 Dibromoethane: 2 mcg/day
Epichlorohydrin: 3 mcg/day
Ethyl bromide: 32 mcg/day
Formaldehyde: (inhalation) 8 mg or 215 parts per billion/day; all other routes 10 mg/day
Styrene: 154 mcg/day
Vinyl acetate PDE: (oral) 2,000 mcg/day – 758 mcg/day for all other routes

The monographs discuss these chemicals’ mutagenic and genotoxic potential as well as carcinogenic risks. The PDE limits were derived from published data, using the principles set forth in ICH M7.

These impurities were identified as potential candidates by a stakeholder survey as they are “commonly used in pharmaceutical drug manufacturing,” according to the ICH presentation on the guideline.

The remit of the M7(R2) Expert Working Group (EWG) is to set acceptable limits for new DNA mutagenic impurities and to revise limits already listed in the addendum “as new data become available,” said an ICH concept paper.

The newly released guideline is now at Step 2 of the ICH process, the step at which a consensus draft is released by the ICH Assembly to regional regulatory authorities for public comment.

Plans are for the expert working group to finalize the guideline as a Step 4 document in June 2022.

The guideline complements the ICH S1B(R1) Addendum to the Guideline on Testing for Carcinogenicity of Pharmaceuticals, which reached Step 2 for public consultations in May 2021. ICH announced plans to finalize a Step 4 document by May 2022. (RELATED: To speed drug development, ICH proposes reducing rat carcinogenicity testing, Regulatory Focus, 14 May 2021).

ICH M7(R2) addendum

ICH guideline proposes daily limits for seven mutagenic impurities

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