As part of
the ongoing effort to define impurities in drug substance and drug products,
CDER’s has issued the Genotoxic and carcinogenic (GTI) Impurity draft Guidelines
for evaluation of mutagenic impurities for clinical drugs from IND to
registration. One of the first steps in addressing such impurities is determining potential
GTI’s. The next step is to determine the therapeutic toxicological concern TTC.
Finally, are the impurities present and at what level in the drug product or
active ingredient?
One reasonable approach for determining impurity levels would
be a paper analysis of the known GTI to show it is well below the threshold
limits. For example, a dilution scheme followed through the synthesis shows a GTI
impurity exists, if at all, well below the relevant threshold. Recent trends suggest this approach will not
be accepted as it lacks definitive data. This outcome is expected as the paper
approach is similar to determining an API-related substance is below the monitoring
threshold based on mathematics alone. GTI
impurities levels will likely need assessment with analytical methodologies and
monitored. In addition, these methodologies often require validated methods at
the ppm/ppb level.
Let me know if your thoughts on the discussion
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