FDA Releases Final Guidance on Mutagenic Impurities

Sponsors looking to determine whether their drugs have impurities that might lead to cancer-causing mutations in human DNA should conduct two toxicology assessments using mathematical models that base this probability on the drug’s chemical structure.

One of these tests should be rule-based, while the other should be based on statistical models, the agency says in final guidance harmonizing assessment and control methods for DNA-reactive impurities with International Conference on Harmonization recommendations.

The guidance, which makes no substantive changes to a 2013 draft, applies to new drug substances, products in clinical development and already-marketed drugs in which dosing or indication changes might increase cancer risks. It also applies to drugs in which changes to the formula, manufacturing process or composition may create new impurities or raise the acceptance criteria for existing ones.

If neither test finds any structural alerts, sponsors can safely conclude their drugs have no mutation risks, the FDA says.

If, however, either test suggests the existence of impurities, sponsors should test whether the drug substance can reverse mutations in common bacteria such as salmonella and E. coli. If so, companies should establish control strategies to ensure the risk is below acceptable thresholds.

The FDA says it will accept some flexibility in risk levels. In earlier phases of development when control strategies are less advanced, a one-in-one-million cancer risk may suffice, the guidance says. In later stages of development and after the drug is on the market, the acceptable risk narrows to one in 10,000.

Read the final guidance at www.fdanews.com/05-27-15-M7guidance.pdf. — Lena Freund