Nitrosamine Acceptable-Intake Limit Calculator
Convert a nitrosamine’s acceptable intake (ng/day) into the concentration limit (ppm) permitted in a specific product given its maximum daily dose — limit = AI ÷ MDD — and check a measured level against it. Aligned to ICH M7(R2) and the EMA/FDA nitrosamine guidance.
OUTPUT
TIME
Limitations — read before you rely on this
- AI values change as regulators re-evaluate compounds, and NDSRI-specific values follow the CPCA approach — confirm the AI against the live regulator table on the day you use it.
- The calculation covers one nitrosamine at a time; it does not implement combined-nitrosamine rules, less-than-lifetime adjustments, or interim limits.
- This calculator is transparent but it is not a validated system; treat its output as a check, not a record.
- Reproduce the result in your own qualified system before using it in a submission, batch disposition, or CAPA record.
WHAT THIS CALCULATES
Converts a nitrosamine’s acceptable intake (ng/day) into the concentration limit in ppm permitted in a specific product at its maximum daily dose, and reports the margin against a measured level.
THE METHOD
Limit = AI / MDD Margin = Limit / Measured- Limit
- The maximum permitted nitrosamine concentration in the product, in ppm (equivalently µg/g or ng/mg).
- AI
- The acceptable intake for the specific nitrosamine, in ng/day, from the regulator’s published table or derived per ICH M7(R2).
- MDD
- The maximum daily dose of the product, in mg/day, per the approved labelling (including any titration maximum).
- Margin
- The dimensionless ratio of the limit to the measured level; values above 1 mean the measurement sits below the limit.
- Measured
- The analytically determined nitrosamine concentration in the product, in ppm, from a suitable validated method.
AI in ng/day divided by MDD in mg/day yields ng/mg, and 1 ng/mg = 10⁻⁶ = 1 ppm, so no further scaling factor is applied. Worked check: 96 ng/day ÷ 2000 mg/day = 0.048 ppm. Where several nitrosamines are present, regulators apply additional combined-risk rules this single-compound calculation does not implement.
THE INPUTS, AND WHAT THEY MEAN
- Acceptable intake (AI)
- The regulator-published or ICH M7(R2)-derived acceptable daily intake for the specific nitrosamine, in ng/day, for your filing jurisdiction.
- Maximum daily dose (MDD)
- The highest daily dose of the finished product permitted by the approved label, in mg/day, including any titration maximum.
- Measured level (optional)
- The nitrosamine concentration actually found in the batch or stability sample, in ppm, from a validated analytical method. Leave blank to compute the limit only.
Concentration limit from an acceptable intake.
Enter the nitrosamine’s acceptable intake (AI) and the product’s maximum daily dose. SPEQ computes the concentration limit in ppm — AI divided by MDD — and, if you add a measured level, the margin of safety against it.
HOW TO READ THE OUTPUT
- The output is the concentration ceiling for that nitrosamine in that specific product; the same compound has a different ppm limit in every product because the maximum daily dose differs. The AI values are the regulator’s thresholds, not SPEQ’s.
- A margin above 1 means the measured level is below the limit; a margin near 1 leaves no analytical or process headroom and usually warrants root-cause and mitigation work even without a formal breach.
- A margin below 1 signals a level above the acceptable limit, which drives batch disposition, reporting to the authority, and potentially recall decisions depending on jurisdiction and any interim-limit policy.
- The AI is a lifetime-exposure basis; less-than-lifetime allowances under ICH M7(R2) may apply in remediation scenarios, which this standard-case calculation does not model.
WORKED EXAMPLE
A metformin extended-release product with a 2000 mg/day maximum label dose is screened for NDMA.
- AI (NDMA)
- 96 ng/day
- MDD
- 2000 mg/day
- Measured
- 0.010 ppm
RESULT
The batch sits at roughly one-fifth of the permitted NDMA concentration, supporting release from a nitrosamine standpoint — but the result belongs in the product’s nitrosamine risk-assessment record, not just the certificate of analysis.
REGULATORY BASIS
- ICH M7(R2)
- Establishes the TTC-based framework for acceptable intakes of mutagenic impurities from which nitrosamine AI values are derived.
- FDA Guidance — Control of Nitrosamine Impurities in Human Drugs
- Publishes the US acceptable-intake table and the recommended AI ÷ MDD limit calculation.
- EMA nitrosamine guidance (Art. 5(3) referral Q&A)
- Publishes EU acceptable-intake values for individual nitrosamines and the rules for converting an AI to a product limit.