Genotoxic Impurities - A Mathematical Approach?

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.

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Novel MS Techniques Speed Detection of Biopharmaceutical Product and Process Impurities (an ABC Webinar)

Product and process impurities in biopharmaceuticals are often present in very low abundance and are often “lost in the noise,” making their analyses quite challenging and time-consuming.

In this webinar, learn about a novel mass spectrometer-based approach that can speed detection and quantitation while achieving the required specificity and sensitivity—and how multiple reaction monitoring (MRM) techniques can be effectively applied to CMC-related development activities.

Case studies will be cited to demonstrate how internally standardized LC-ESI-MS/MS methods can be designed and validated to meet regulatory requirements.

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