Analysis of Non-Mutagenic Substances in the Context of Drug Impurity Assessment—Few are Potent Toxicants (S13-6)

This presentation was created by Dr. Catrin Hasselgren. It will be presented by her colleague, Dr. Paul Cornwell.

The ICH Q3A / B guidelines outlining qualification thresholds for impurities or degradation products note
that there are certain impurities / degradation products that may warrant further safety evaluation for
being unusually potent or toxic. The purpose of this study was 1) to evaluate if especially toxic non-
mutagenic compounds are rare and 2) to identify classes of non-mutagenic compounds that could
warrant lower qualification thresholds. A total of 2,815 compounds were evaluated, of which 2,213
were considered non-mutagenic. A conservative approach was taken and compounds were considered
potent when there was a point of departure value of ≤ 0.2 mg/kg/day. This was based on the
qualification threshold (1 mg/day or 0.02 mg/kg/day for a 50 kg human) in a new drug substance, with
an additional 10-fold safety margin. Only 54 of the entire set (2.4%) would be considered potent based
on this conservative potency analysis, confirming that the existing qualification thresholds are
appropriate for the vast majority of impurities. The number of compounds is 14 (0.6%), if the actual
threshold without the 10-fold safety margin is used. Very few non-mutagenic structural classes were
identified that correlate with potential high potency, consistent with prior publications, however further
safety investigations or lower qualification thresholds may be warranted for impurities belonging to one
of those classes.