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.
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.
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 complete guidance can be found here .