Nitrosamines: understanding carcinogenic risk and control strategies
- 6 days ago
- 2 min read
Since the sartans crisis in 2018, the detection of nitrosamines has highlighted systemic gaps in identifying contamination pathways across pharmaceutical supply chains.
As impurities belonging to the “cohort of concern” following ICH M7 (R2), nitrosamines present exceptionally high carcinogenic potency. Their mechanism of action relies on metabolic activation leading to the formation of adducts. If these lesions escape cellular repair systems, they can induce irreversible genetic mutations and carcinogenesis.
With a TD50 typically below 1.5 mg/kg/day, this extreme toxicity prevents the application of the standard Threshold of Toxicological Concern (TTC) of 1,500 ng/day defined in ICH M7(R2).
Acceptable Intake (AI) and carcinogenic potency assessment
Patient safety is ensured through the establishment of an Acceptable Intake (AI), calculated for a theoretical excess cancer risk of 1 in 100,000 over a 70-year exposure.
For compounds with sufficient data, the AI is derived through linear extrapolation from the most conservative TD50 values obtained in the most sensitive species.
For NDSRIs (nitrosamines related to the active substance) lacking in vivo data, the CPCA (Carcinogenic Potency Categorisation Approach) recommended by the EMA is applied. This method classifies nitrosamines into five potency categories based on structural characteristics influencing metabolic activation.
Alternatively, a negative Enhanced Ames Test (EAT) can justify the application of a limit of 1,500 ng/day.
Sources and formation of nitrosamines
Control of these impurities requires a rigorous strategy. Nitrosamine formation generally results from the combination of amines with nitrosating agents under acidic conditions.
Identified sources include:
Contaminated or degraded solvents
Nitrites present in excipients
Risk management strategy
Risk management follows three main steps:
Proactive assessment
Confirmatory testing
Implementation of CAPA
According to ICH M7, omission of specification may be considered if levels remain consistently ≤10% of the AI. Batch-by-batch control is required when levels are between 30% and 100% of the AI.
When multiple nitrosamines are present, summation strategies must ensure that cumulative risk never exceeds the 1:100,000 threshold.
Mitigation options
Reformulation can be an effective mitigation strategy. The addition of nitrite scavengers or pH adjustment can slow nitrosation reactions. In some cases, these modifications may benefit from simplified procedures and avoid new bioequivalence studies.
CEHTRA Expertise
At CEHTRA, we mobilise our toxicology expertise and QSAR tools to support partners in the qualification of these impurities.
This topic was presented during our latest webinar dedicated to nitrosamines and related regulatory expectations.Follow us to stay informed about upcoming webinars and publications.
