Genotoxic Impurities- Regulatory Updates

Drafting ICH M7 guidance on genotoxic impurities will require a lot of work from industry and regulators but has the potential to resolve a number of issues.

Guidelines for Genotoxic impurities, those which damage DNA and potentially cause cancer, have been formed in recent years and the International Conference on Harmonisation (ICH) is now to draft its document.

ICH M7 will “require an awful lot of commitment” from industry and authorities alike, said Andrew Teasdale, senior quality assurance executive at AstraZeneca. Teasdale was speaking at a US Pharmacopeia (USP) workshop on genotoxic impurities at AAPS 2010.

Discussion of M7 was initiated by the ICH at its steering committee meeting in Japan. Speaking days after the ICH meeting finished Teasdale highlighted areas M7 can build on US Food and Drug Administration (FDA) and European Medicines Agency (EMA) genotoxic impurity guidance.

Intermediates and excipients

Gopi Vudathala, associate vice president of global regulatory affairs at Sanofi-Aventis, spoke for the US pharma industry at the workshop. Challenges for those drafting guidelines include how to apply them to oncology products, said Vudathala, and starting materials and intermediates.

Vudathala said excipients are being considered in drafting M7 but they face a number of unique issues. For instance, limit identification and testing of excipients may need a different approach. The panel also questioned the need for limits on excipients that have been used for decades.

The FDA has issued draft guidance on how manufacturers should evaluate the safety of products that contain genotoxic and carcinogenic impurities.

Genotoxic and carcinogenic properties can be acceptable traits of active pharmaceutical ingredients (APIs) but when these are impurities, which generally do not have a beneficial effect, their presence should be minimised.
To help manufacturers achieve the lowest technically feasible levels of these impurities, or reduce them to quantities that convey no significant cancer risk, the US Food and Drug Administration (FDA) has issued guidance on the subject.

By following the guidelines manufacturers should understand what the FDA requires to approve applications at various developmental stages and how these standards can be achieved.

One recommendation is that manufacturers change the synthetic or purification routes to reduce impurity formation or increase its removal.

Further characterisation of the risks posed by the impurities by studying the mechanism of action or performing weight-of-evidence approaches can also add support to impurity specifications.

Products released prior to the issuing of the guidance are covered by it if a specific safety signal highlighting increased risk is detected.

Supplemental applications in previously approved products are also covered if they require a significant change to the labelling that suggests potential for increased carcinogenic risk.

The FDA regards 1.5μg per day as an acceptable level for impurities but this may not be appropriate in every case. In addition, higher levels may be allowed during clinical development.