The European Medicines Agency (EMA) has announced its adoption of the International Conference on Harmonisation's (ICH) M7 guideline on controlling carcinogenic risk in pharmaceutical products when those products are made using, or are exposed during the manufacturing process to, genotoxic or carcinogenic materials.
The draft guideline, M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceutical to Limit Potential Carcinogenic Risk, was released by ICH for adoption on 7 February 2013. EMA is the first of ICH's three member regions (EU, US and Japan) to adopt the guideline, which is now in step three of the ICH process, which involves a comment process on how to improve the document.
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 that a acceptable levels needed to be set for 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. EMA's comment period closes on 20 June 2013.
EMA: ICH's M7 Guideline