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Regulatory Focus™ > News Articles > EMA Regulators Release ICH Guideline on Genotoxic, Carcinogenic Starting Materials

EMA Regulators Release ICH Guideline on Genotoxic, Carcinogenic Starting Materials

Posted 25 February 2013 | By Alexander Gaffney, RAC

EU regulators have released for public consultation a guideline under development by the International Conference on Harmonisation (ICH) intended to establish the best practices for controlling carcinogenic risk in pharmaceutical products when those products are made using genotoxic or carcinogenic starting materials.

That guideline, M7 Guidelines on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to limit Potential Carcinogenic Riskfirst cleared the ICH's Step 2 in December 2012, and the European Medicines Agency's (EMA) 22 February 2013 release of the guideline marks the start of the third of a five-step process.

During step four, the various entities that make up the ICH-among them EMA, the US Food and Drug Administration (FDA) and Japan's Ministry of Health, Labour and Welfare (MHLW)-will formally adopt the ICH guideline. The final step, step five, sees it formally implemented across all three ICH regions.

EMA said it will be accepting comment through 23 April 2013, part of a six-month consultation process set to end in August 2013.

The Guideline

The guideline, unlike similar ones which deal with drugs that are themselves genotoxic or carcinogenic, pertains to products that are only manufactured with the assistance of genotoxic or carcinogenic starting materials, intermediates and reagents.

While the manufacturing process is not intended to leave any of these materials in the final drug product, low levels of impurities can nevertheless be present at the end of the manufacturing process.

The larger question, explained Warren Ku, the ICH Rapporteur on the M7 guideline and the section head of integrative toxicology at Boehringer-Ingelheim Pharmaceuticals, is how regulators should best manage risk and quality at all stages of the product lifecycle.

The guideline follows a 2010 concept paper that called for its need, saying that while many ICH guidelines touched on the topic, none confronted its core premise: the need for acceptable levels of genotoxic impurities.

While some regional regulatory bodies have published guidance and guidelines on the specific topic, there are some inconsistencies and clashes between the EMA, FDA and ICH documents.

What are Acceptable Limits?

The draft M7 guideline established what Ku called a "Threshold of Toxicological Concern (TTC) concept as a basis for characterizing risk."

For all chemicals for which there is no "appreciable risk to human health," residue exposure should be capped at 1.5 ug/day.

For chemicals and substances known to cause cancer, sponsors of products will need to justify acceptable limits, depending on a variety of factors including frequency of dosing and length of dosing. The guideline notes that for drugs intended to be taken for less than a month, regulators might accept a daily intake limit of 120 ug/day. For drugs intended to be taken for up to 10 years, that acceptable tolerance falls to just 1.5 ug/day for individual impurities. Total impurity acceptances are slightly higher (5 ug/day for a 10-year or lifetime pharmaceutical product).

These levels may be adjusted based on a  number of considerations, such as whether humans are likely to encounter those impurities in the course of their normal lives (such as through food consumption), or if the chemical is extraordinarily toxic, requiring a vastly lower threshold for intake.


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