Below table represents the acceptable limits for nitrosamine impurities-
The limits shown in the above table are applicable for drug products containing a single nitrosamine. If multiple impurities are identified and the summation of individual nitrosamine impurities exceeds 26.5 ng/day based on MDD then the manufacturer should contact FDA for further evaluation. API and drug product manufacturers should use the methods with LOQs at or below 0.03 ppm.
API manufacturers need to develop a control strategy when a nitrosamine impurity is present above LOQ to confirm that nitrosamine impurity level remains within the AI (Acceptable Intake). Risk assessment needs to be performed by drug product manufacturers by collaborating with API vendors to identify the API synthesis and process conditions that may potentially generate nitrosamine impurities. Further, the risk assessment should also include determination of any degradation pathway that may produce nitrosamine impurities during the manufacture and storage of the drug product (1).
US-FDA recently published a guidance in August 2023, ‘Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)’ and recommended acceptable intake (AI) levels for NDSRIs. NDSRIs exhibit a structural similarity to the API or its fragment and therefore are distinctive to each API. NDSRIs are produced in the drug product by a nitrosation reaction of APIs (or its fragments) containing secondary or tertiary amines when exposed to nitrosating agents present in the drug product formulation. Thus, the guidance proposes a risk-based safety assessment of NDSRIs for identification of AI limits in presence of excipients used in the formulation. The Nitrosamine Guidance introduced a three-step process that manufacturers and applicants should take to mitigate nitrosamine impurities in their drug products: (i) conduct risk assessments for nitrosamines in their APIs and drug products; (ii) conduct confirmatory testing if risks are identified; and (iii) report changes implemented to prevent or reduce the presence of nitrosamine impurities in APIs and drug products in approved and pending NDAs and ANDAs. The guidance classifies NDSRIs in to five (5) potency categories based on carcinogenicity. The five categories are ranked based on high to low carcinogenic potency with Category 1 being the most and Category 5 being the least potent.
The limits mentioned in the table above are applicable when a single NDSRI is present in the drug product. When more than one NDSRI is identified, and the total limit of nitrosamines exceeds the recommended AI limit for most potent nitrosamine then the manufacturer should contact the Agency. Further, FDA has recognized certain APIs containing secondary or tertiary amines at risk of forming NDSRIs. FDA has categorized these APIs based on their ability to form nitrosamine impurities and their subsequent carcinogenic potential. The Nitrosamine Guidance introduced a three-step process that manufacturers and applicants should take to mitigate nitrosamine impurities in their drug products: (i) conduct risk assessments for nitrosamines in their APIs and drug products; (ii) conduct confirmatory testing if risks are identified; and (iii) report changes implemented to prevent or reduce the presence of nitrosamine impurities in APIs and drug products in approved and pending NDAs and ANDAs (2).
References
1. Control of Nitrosamine Impurities in Human Drugs, Guidance for Industry
(guidance dated February 2021) by US-FDA’.
2. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs), Guidance for Industry (dated August 2023) by US-FDA’