The US Food and Drug Administration (FDA) issued a new guidance for immediate implementation (effective August 4, 2023), Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) which provides drug manufacturers and applicants with a recommended framework for a risk-based safety assessment of NDSRIs that could be present in approved and marketed drug products, as well as products under review by the FDA. 

The issue of nitrosamine impurities first arose in the industry in 2018, when the US Food and Drug Administration (FDA) and the European Medicines Agency initiated investigations of nitrosamine impurities in certain “sartan”-containing active pharmaceutical ingredients (APIs), used in anti-hypertensive and cardiovascular drugs, such as valsartan candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach, and later metformin extended-release products, used to treat Type II diabetes. As part of their investigations, the regulatory agencies issued guidelines for testing of products to detect nitrosamine impurities, acceptable daily intake levels, and risk evaluation and risk assessment. 

This new guidance provides applicants and manufacturers of drugs, including prescription and over-the-counter drug products, with a recommended framework for predicting the mutagenic and carcinogenic potential of NDSRIs that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs. NDSRIs, which are a subcategory of nitrosamine impurities that share structural similarity to the active pharmaceutical ingredient (API) in drug products, typically lack compound-specific mutagenicity and carcinogenicity data to inform safety assessments.  This guidance provides a recommended methodology for AI determination that uses structural features of NDSRIs to generate a predicted carcinogenic potency categorization and corresponding recommended AI limit that manufacturers and applicants can apply, in the absence of other FDA-recommended AI limits, in their evaluation of potential impurities in their drug products. 

To reflect the evolving and highly technical nature of the relevant information, FDA is providing certain updated NDSRI-specific information, in connection with this guidance. Specifically, FDA intends to include updated information on: (1) recommended AI limits for certain NDSRIs based on predicted carcinogenicity potency categorization listed by APIs that hypothetically could be at risk of forming such NDSRIs; (2) recommended AI limits for certain NDSRIs based on compound-specific data or read-across analysis from a surrogate; (3) recommended interim AI limits for certain NDSRIs; (4) recommended testing methods for confirmatory testing of certain NDSRIs; and (5) recommended safety testing methods for NDSRIs. 

Source: US Food and Drug Administration