Revised Final Guidance on Nitrosamines Offers New Recommendations for Assessment and Control

Last week, FDA revised one of its two guidances relating to nitrosamines, Control of Nitrosamine Impurities in Human Drugs. Nitrosamines are impurities that can form during drug manufacturing and are considered potentially potent carcinogens. One specific kind of nitrosamines called N-nitrosamine drug substance-related impurities, or NDSRIs, are especially vexing to FDA and to industry because they mimic the structure of the specific active pharmaceutical ingredients (API), making them difficult to detect.

The new final guidance includes a description of some of the various circumstances under which nitrosamines form. It’s these varied scenarios that give quality managers nightmares. For example, depending on the manufacturing process for a specific human drug, the use of some specific solvents, reagents, and catalysts may trigger the formation of these possible carcinogens. But risk also lurks from vendor-sourced raw materials containing nitrosamine impurities, or from simple deviations in temperature or pH.

The revised guidance that was published last week aims to offer some new tools to help industry address these issues. FDA starts by setting the limit of what it views as acceptable intake (AI) limits, so that manufacturers and applicants can know what targets they should hit. Using the guidelines found in the ICH M7(R2), FDA set an AI threshold of 1.5 micrograms per day “for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects.” FDA says that highly potent compounds – again, as defined in ICH M7(R2) – pose risks below that limit.

We note that the other FDA guidance document on nitrosamines addresses NDSRIs. We wrote about 2023’s Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs), which also advised on how to review drug products and take appropriate action. This new revision acts as a companion piece to that guidance, providing additional details on identifying potential root causes and mitigation strategies.

FDA’s latest guidance has three key aspects: assessment, control, and reporting. First, firms should undertake risk assessments of their APIs, finished products, and products under approved or pending applications. We’ve seen this measure well underway at many impacted companies. Second, the guidance provides some new tactics for industry to control nitrosamine impurity risks through, for example, sensitive, product-specific chromatographic testing. Third, FDA offers new recommendations on how to report revised specifications that assessment and control might affect, which might include making amendments to approved or pending applications or drug master files where appropriate. Note here that those initial risk assessments need not be reported, but FDA recommends that firms do report resulting changes to drug specifications like stability or bioequivalence.

Last week’s guidance is featured on FDA’s new nitrosamines webpage and recommends that manufacturers implement revisions to control measures by August 1, 2025, noting that manufacturers and sponsors of approved products were expected to complete evaluations for small molecule nitrosamines last year. The revisions due in 2025 include testing for NDSRIs.

FDA recognizes that nitrosamine detection and remediation are complicated undertakings for quality managers. However, in light of its detailed and newly revised guidances, we doubt the Agency will offer too much in the way of leniency for firms that don’t respond with substantial effort.