Applicability of the ICH M7 guidelines for assessing less-than-lifetime exposure to nitrosamine impurities in drug...

Global regulators identified several data gaps that precluded acceptance of the ICH M7 framework for assessing less-than-lifetime (LTL) exposures to N-nitrosamine (NA) impurities in drug products. Building on prior analyses confirming that NA carcinogenic potency is driven by lifetime cumulative dose, this work addresses additional data gaps on whether: (1) higher daily LTL doses could overwhelm DNA repair; (2) polypharmacy could create unacceptable combined NA exposure; (3) reports of tumors after one/few doses undermine LTL principles; (4) LTL principles hold true for intermittent exposures; and (5) ICH M7 duration tiers and adjustment factors are sufficiently protective for NAs. Comparisons of in vivo mutagenicity data with LTL exposures show large margins of safety, indicating that DNA repair is not overwhelmed, including in the case of polypharmacy. The concern for polypharmacy is further mitigated by data showing reduced carcinogenic potency when exposure occurs later in life. Analyses of studies involving single/few doses demonstrate that these studies involve very high doses that have questionable relevance to human exposures and do not raise a concern for LTL exposures. Finally, conservative safety factors are incorporated into the ICH M7 LTL framework such that these analyses support its application to NA impurities without modification.