Regulatory Focus™ > News Articles > ICH Manufacturing Impurities Guideline Goes to FDA, EMA, MHLW for Consideration

ICH Manufacturing Impurities Guideline Goes to FDA, EMA, MHLW for Consideration

Posted 07 February 2013 | By Alexander Gaffney, RAC

The International Conference on Harmonisation (ICH), the international pharmaceutical regulatory harmonization body, has released a draft guidance on the best practices for controlling carcinogenic risk in pharmaceutical products when those products are made using genotoxic or carcinogenic starting materials.

That draft guideline, M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceutical to Limit Potential Carcinogenic Risk, is now awaiting acceptance by the European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and Japan's Ministry of Health, Labour and Welfare (MHLW) under Step 2 of ICH's 5-step guideline process.

Once accepted, it will undergo a six-month consultation process, during which EMA, FDA and MHLW will solicit public comment on ways to improve the guideline.

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.

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.

The entire guideline may be found online here or here.

Tags: M7 Guideline

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