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)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) 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.

Comprehensive Toxicology Risk Assessment for Genotoxic ImpuritiesDear Editor:We believe that the publication by Yang et al. 1 provides an important methodology for eliminating genotoxic impurities from drug substances. However, we recommend that the risk assessment presented for methyl and ethyl chloride go beyond the staged TTC guidance as referenced in the manuscript.Dr. David Snodin's letter to the editor 2 highlighting the need for a comprehensive risk assessment for specific genotoxic impurities is relevant to the recent Yang et al. manuscript. One reason to conduct a genotoxicity test is to predict potential carcinogenicity. We acknowledge that the TTC has been an effective risk assessment tool to provide a conservative acceptable dose for genotoxic compounds when no adequate carcinogenicity information is available. However, if available, carcinogenicity data should be used to evaluate the risk.Both methyl and ethyl chloride are examples of genotoxic compounds with carcinogenicity data critical to the toxicology evaluation. The United States Environmental Protection Agency (USEPA) review of the carcinogenicity data 3 for methyl chloride indicates that renal tumors observed in male mice are a speciesspecific effect with limited relevance in humans and categorizes methyl chloride as a Group D compound (i.e., "Not classifiable as to its carcinogenicity"). USEPA has not developed an oral permissible daily exposure (PDE also referred to as a reference dose) for noncarcinogenic effects because methyl chloride exists primarily as a gas and no adequate oral toxicity data exist. While an oral PDE could be developed from inhalation data given the high rate of absorption from an inhalation perspective, the result would be several orders of magnitude greater than the TTC. 3,4 In addition, ambient exposures are well in excess of

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