GENOTOXIC IMPURITY – All About Drugs

All About Drugs

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An in-depth analysis of the web-based CambridgeSoft Pharmaceutical Drug Degradation Database, Pharma D3, was conducted in two phases in an attempt to generate some general rules for the prediction of alerting structures for genotoxicity that may arise as a result of degradation. The first phase involved interrogation of the database to determine the nature and frequency of alerting structures present in the degradants. This analysis revealed five functional groups, which account for approximately 70% of the alerting structures found in the degradants within the database: (1) aldehydes; (2) α,β unsaturated carbonyls; (3) aromatic amines, hydroxylamine and its derived esters; (4) epoxides; and (5) polyaromatic hydrocarbons. The second phase of the analysis involved categorizing the major chemical reactions responsible for the generation of the five most prevalent alerting structures. This two-step approach led, in turn, to a proposal for the prediction of functional groups that may have a propensity to degrade to alerting structures not necessarily present in the parent molecule.

Prediction of Drug Degradation Pathways leading to Structural Alerts for Potential Genotoxic Impurities

Stephen P. Raillard, Joel Bercu, Steven W. Baertschi and Christopher M. Riley

Org. Process Res. Dev., 2010, 14 (4), pp 1015–1020

Publication Date (Web): April 21, 2010 (Article)

DOI: 10.1021/op100007q

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http://pubs.acs.org/doi/full/10.1021/op100007q

Controlling impurities during drug development improves product quality and minimizes safety risks to the patient. Recent regulatory guidance on genotoxic impurities (GTIs) state that identified GTIs are unusually toxic and require lower reporting, identification, and qualification limits than outlined in the International Conference on Harmonization (ICH) guideline “Impurities in New Drug Substances Q3A(R2).” [ ICH Harmonized Tripartite Guideline: Impurities in New Drug Substances (Q3A), (R2); International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 2006.] Patient safety is always the underlying focus, but the overall impurity control strategy is also driven by appropriate “as low as reasonably practicable” (ALARP)(2)procedures that include assessment of process capability and associated analytical techniques. In combination with ALARP, safe and appropriate GTI levels are currently identified using chronic toxicology-based limits calculated under the standard assumption of 70-years for exposure duration. This paper proposes a risk assessment approach for developing GTI limits based on shorter-term exposure durations by highlighting marketed anticancer compounds with limited dosing schedules (e.g., 2 years). These limits are generally higher than the defaulted threshold of toxicological concern (TTC of 1.5 μg/day) and can result in more easily developed and less complex analytical methods. The described approach does not compromise safety and can potentially speed life-saving medicines to patients.