FDA Sets a Recommended Framework for Predicting the Mutagenic and Carcinogenic Potential of Nitrosamine Drug Substance-Related Impurities

August 9, 2023By Douglas B. Farquhar & Richard A. Lewis, Senior Regulatory Device & Biologics Expert

Please sing to the tune of “Honesty,” by Billy Joel:

Nitrosamines, it’s such an ugly word,

In pharmaceuticals’ impurity.

Nitrosamines are hardly ever good,

Now FDA has issued policy.

Failure to detect nitrosamines, failure to notify FDA when nitrosamines appear in finished drug products, failure to identify impurities in drugs that may be nitrosamines, even having a deviation in pH of an Active Pharmaceutical Ingredient that might conceivably contribute to the formation of nitrosamines in a finished drug product.  All of these deviations discussed in FDA inspectional observations and Warning Letters have caused serious issues for manufacturers of APIs or finished drug products.

Now, just two weeks after we blogged on nitrosamines, and a week before a PharmaConference where we will talk about the importance of impurities in FDA enforcement, FDA has issued a final guidance, entitled, “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs).”  NDSRIs are a particular focus for FDA, because they are a nitrosamine subcategory that share structural similarity to drug API.

The Guidance, which provides details about nitrosamines and FDA’s experience regulating them, explicitly applies to all finished drug products (including Rx, OTC, and unauthorized drugs), to “prescription and OTC drug products in clinical development,” and to both API and drug manufacturers.  In other words, it’s a sweeping application across the industry.  An earlier FDA guidance, revised in 2021. urged manufacturers to conduct risk assessments for nitrosamines in APIs and drug products; (2) conduct confirmatory testing if risks are identified; and (3) report changes in formulation or manufacturing as required in approved and pending NDAs and ANDAs.  There were tables in each guidance that appear to be consistent where they overlap, but also include different nitrosamines/NDSRIs (FDA guidances are not generally binding law, but, rather, express FDA policy.)

The new final guidance, by its own terms, establishes “a recommended framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs.”  It further defines the AI as being “a level that approximates an increased cancer risk of one additional case in 100,000 people based on a conservative assumption of daily exposure to the impurity over a lifetime (70 years).”

The Guidance then goes on to categorize the types of NDRSIs and to suggest the appropriate acceptable intake limits for drugs, and sets a timetable for manufacturers – or those with pending applications – to review their drug products and take appropriate action.

This second half of this guidance beginning with the “Flowchart to Predict the Carcinogenic Potency Category of an NDSRI and Identify an Associated Recommended AI Limit” takes one back to basic organic chemistry and breaks down the key structural and electronic considerations into a step-by-step guide.  The substitution of the α-carbons and the electronic effects of the “Deactivating” or “Activating” groups yield tangible scores that one can apply to determine a “Potency Score” and therefore the recommended acceptable intake.  Perhaps most importantly, the guidance concludes with examples of how manufacturers would apply this framework to Nitroso compounds.

All drug manufacturers and API manufacturers would be well served to examine the guidance, and perform analysis suitable for their products, to determine whether further assessment is necessary.