How it works
Regulators set nitrosamine limits as an acceptable intake (AI) in nanograms per day. To compare a test result with it, divide the AI by the maximum daily dose in milligrams: the answer is the limit in ppm (µg per g of drug). A product dosed at 500 mg/day with NDMA (AI 96 ng/day) has a limit of 0.192 ppm. The same AI gives a tighter ppm limit as the dose goes up.
For a nitrosamine drug substance-related impurity (NDSRI) with no compound-specific AI, the Carcinogenic Potency Categorization Approach (CPCA) assigns a category from the structure: 26.5, 100, 400, 1500 or 1500 ng/day for categories 1 to 5. The small nitrosamines in the list use their published values. Use the last option to type in a compound-specific AI from the FDA or EMA list.
When more than one nitrosamine is present there are two common ways to set a limit. The more conservative keeps the total of all nitrosamines at or below the limit of the most potent one. The flexible approach, now accepted by FDA and EMA, lets each nitrosamine stay within its own limit as long as the combined risk does not exceed 1 in 100,000, which is the same as the fractions of each limit adding up to no more than 100%. Under the EMA Q&A, a nitrosamine consistently below 10% of its AI is considered negligible and need not be counted, which is also why the method LOQ is often set at or below 10% of the limit.
AI values and policies are revised often, and less-than-lifetime or interim limits are not covered here. Check the current FDA guidance (Control of Nitrosamine Impurities in Human Drugs) and the EMA Q&A (EMA/409815/2020) before you set a specification.