Europe – Reflection paper on the qualification of non-genotoxic impurities

The core ICH quality guidelines addressing qualification of NGI are ICH Q3A and Q3B. These guidelines state that qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations. For DNA reactive (mutagenic) impurities, elemental impurities and residual solvents specific guidance is provided (ICH M7, Q3D and Q3C, respectively). However, for non-genotoxic impurities (NGI) little guidance is available on how these impurities should be qualified. The level of any impurity present in a new drug substance that has been adequately tested in safety and/or clinical studies would be considered qualified. This is the situation for most impurities that have been present in the drug substance batches throughout development. The problem with this approach is that qualification is establishing biological safety of a drug substance or drug product with a given impurity profile, which is not the same as characterising the safety profile of an impurity. Obviously, when toxicity is observed, it is usually not possible to discriminate between toxicity attributable to the active pharmaceutical ingredient (API) and toxicity attributable to the impurities present in the drug substance batch. The safety testing only establishes that a drug substance batch with a certain impurity profile has a specific safety profile. This limits the possibilities of extrapolating the safety of a drug substance or product with a given impurity profile to a drug substance or product with the same API but with an increased level of an impurity, when no impurity-specific data are available. Also when new impurities arise due to manufacturing changes or novel degradants are discovered at a later stage of development, and these impurities cannot be controlled at a level below the qualification threshold, a lack of impurity-specific safety data complicates the qualification process…