Nitrosamine Impurities: Turn Intake Limits Into ppm Specs

An acceptable intake (AI) limit is the daily exposure to a nitrosamine that approximates one additional cancer case in 100,000 people over a lifetime, set per compound. FDA's guidance cites this definition from the International Council for Harmonisation (ICH) M7(R2). The FDA values include 96 nanograms per day (ng/day) for N-nitrosodimethylamine (NDMA) and 26.5 ng/day for NDEA.

Which rule applies depends on the impurity:

1. FDA publishes a value for the compound. Use it. The FDA acceptable intake page is the list, and FDA changes it as its understanding evolves.
2. No published value, and the impurity is a nitrosamine drug substance-related impurity (NDSRI). An NDSRI shares the API's structure and is generally unique to that API. Assign a potency category under the Carcinogenic Potency Categorization Approach (CPCA) and use that category's AI, then confirm it with FDA. Section IV.A of the guidance sets this out.
3. The AI cannot be determined by the approaches in Section IV.A. Only then does FDA recommend 26.5 ng/day as the default.

Small-molecule nitrosamines, which do not resemble the API, are the other class in FDA's guidance, revised in September 2024. The values above are FDA's. The European Medicines Agency (EMA) keeps its own list, so use the agency of the market where your product is approved.

Divide the AI in nanograms by the maximum daily dose (MDD) in milligrams as shown on the product label. The result is in ppm (parts per million, here nanograms per milligram). EMA's worked example for a 300 mg/day product gives 0.088 ppm for NDEA (26.5 ÷ 300) and 0.32 ppm for NDMA (96 ÷ 300).

The divisor is the dose of the active substance, not the weight of the whole tablet. EMA's answer (Q&A 10) says the ppm limit is usually expressed per active moiety in the finished product and, for a control point in the API only, per drug substance. FDA's guidance uses the same formula, ppm = AI (ng/day) ÷ MDD (mg), with the MDD typically taken from the labeling.

Read the corners. At 2,000 mg/day, a 26.5 ng/day impurity needs a method that reliably measures about 13 parts per billion. At 10 mg/day the limit is 2.65 ppm, about 200 times looser. A flat "below 1 ppm" result tells a buyer little until it is set against the product's dose and the compound named.

The per-compound AI values apply only if a product contains a single nitrosamine. FDA recommends that when more than one is identified, the total should not exceed the AI of the most potent one, or the total can be set with the flexible approach in Appendix C: express each nitrosamine as a percentage of its own AI limit and keep the sum at or below 100%. In FDA's own example for an 80 mg/day product, three nitrosamines at 0.15, 0.20 and 3.00 ppm each sit below their individual limits (0.33, 0.46 and 18.75 ppm) yet total 104.93% of their AI limits, a fail. Set the specification on the total as well as on each compound.

The API does not get the whole budget. FDA's guidance says the overall cancer risk estimate should consider all sources, from drug substance and drug product, including container closure. Our recommendation is to set the API limit below the grid value and leave headroom for excipients and process water.

Nitrosamines can form after the API leaves its manufacturer, through reactions with excipients, solvents and the atmosphere, so an API result covers only the API. In a 2020 study of 105 metformin tablet samples from 13 manufacturers, NDMA was not detected in the API tested but was found in 64 of 75 finished-product samples (85.3%).

That study shows the route exists, not how common it is across products. Proposed causes for metformin include dimethylamine in the API reacting with nitrite from excipients during wet granulation, and atmospheric nitrogen dioxide reacting with dimethylamine. FDA's guidance also names recovered solvents, reagents and catalysts, and quenching steps that use nitrous acid, as sources, and notes that nitrite is found in commonly used excipients.

For NDSRIs in approved products, FDA had set August 1, 2025 for confirmatory testing and for submitting required changes. As of 10 October 2026, FDA's page (updated 24 September 2026) says applicants who could not meet that date should provide a progress update by August 1, 2025, and that FDA intends to share further details on targeted timelines. No revised dates are listed.

Both own part of it, split by who controls the source. FDA's guidance says API manufacturers should control nitrosamine impurities so that the drug products made from their APIs can meet the AI limits. The finished-dose maker controls what happens after the API arrives. This split is our reading of those root causes.

An RFQ should ask for seven things: a dated risk assessment, a list of nitrosating agents and amines, recovered-solvent controls, shared-equipment controls, a validated method with its quantitation limit in ppm, batch results by compound and in total, and a change-notification commitment. Paste the addendum below next to your product name or Chemical Abstracts Service (CAS) number, quantity and destination.

Nitrosamine addendum

A supplier also needs a quality system to stand on; the ICH Q7 guideline on good manufacturing practice for active pharmaceutical ingredients is the benchmark to check against. Our steroid API RFQ checklist lists what else an RFQ should carry, and how to read a steroid API COA explains the result lines. The same logic applies to other API classes.

Send the addendum with your RFQ. We confirm, product by product, which items the approved manufacturing source can answer and which documents we can supply for your API and destination market. Available documents may include the certificate of analysis (COA), specifications and safety data sheet (SDS, formerly MSDS) where applicable.

We supply steroid, hormone, peptide and general pharmaceutical APIs to business buyers, including generic manufacturers, contract formulators, importers and distributors. We prepare a quotation once you give us the API name and CAS number. Our RFQ also asks for quantity, destination, grade or purity and the documents you need, so the addendum belongs on the documents line.

We support sample and evaluation quantities for qualified buyers, with quantity, price and documentation confirmed per product. Pricing depends on the API and current market conditions, so ask us for a quotation. Our guide to API quality testing explains the methods behind a COA, and API suppliers for US importers maps what importers should qualify.

To start, send your RFQ and addendum through our contact page, or write to sunil@aarisepharma.com or WhatsApp +91 9899783330.