Investigational

Genotoxic impurities – how to detect?
NOVARTIS
The structure of impurities present at levels above the identification threshold is
known, their impact on safety of the drug substance can be appropriately assessed
But: the ICH guidance on drug substance impurities does not stipulate identification
of the structure of impurities below a level of 0.1% =1000 ppm (0.05% or 500 ppm if
daily dose is above 2 g).
1000 ppm (500 ppm) may be unacceptably high for an impurity if it is genotoxic.
‣ A 2 g daily dose of a pharmaceutical may contain 2 mg of a potential toxin
‣ E.g. 2 mg residues of an alkylating starting material would not be desired
What would happen if you spike drug substance X with 1000ppm of an alkylating
agent?
Genotoxicity tests may not be sensitive enough to detect the effect of genotoxic
impurities in a batch if the impurity is present at the 0.1% level
In other words: few genotoxic compounds have a potency e.g. in the Ames that
would enable their detection at or below 0.1% (the same is true for rodent
carcinogenicity studies)
‣ Without a structure, we do not have an idea whether we have a genotoxic impurity
problem unless we start to approach the problem from the synthesis side
L. Müller, Swissmedic, 21-Oct-2003