Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-Nitrosodiethylamine (NDEA)

The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines. •N-Nitrosamines are part of the ICH M7 cohort of concern (COC) class of impurities.•ICH M7 provides a framework for less-than-lifetime (LTL) acceptable intake (AI) derived from a lifetime AI.•N-Nitrosodiethylamine (NDEA) exposures at the ICH M7 LTL AIs are of negligible excess cancer risk.•The ICH M7 LTL AI guidance should be used to limit exposures to N-nitrosamines.