CH 12 · notes
How it works
The CPCA wizard follows EMA Appendix 2 Figure 2: no α-hydrogens, not more than one α-hydrogen on either side, or a tertiary α-carbon maps to Category 5 (AI 1500 ng/day). Otherwise the Potency Score is α-Hydrogen Score (Table 2) plus deactivating (Table 3) and activating (Table 4) feature scores. Score ≤1 → Cat 1 (18 ng/day), 2 → Cat 2 (100), 3 → Cat 3 (400), ≥4 → Cat 4 (1500). FDA August 2023 uses the same categories but recommends 26.5 ng/day for Category 1 in the US.
AI to ppm uses EMA Q&A 10: Limit (ppm) = AI (ng/day) ÷ MDD (mg/day). The LOQ target shown is 10% of that limit. Multiple nitrosamines use the flexible sum Σ(level ÷ limit) ≤ 1; optional interim LTL factors during CAPA come from Q&A 22 (13.3× or 6.7× AI). ICH M7 mode shows the TTC 1.5 µg/day and Table 2 LTL intakes by treatment duration.
Worked example
Invented structure with α-H counts 2,2 and a morpholine ring feature (+1) gives Potency Score 2 → Category 2, AI 100 ng/day. With MDD 200 mg/day that is 0.5000 ppm and LOQ target 0.05000 ppm. Two invented levels 0.04 and 0.03 against limits 0.1 and 0.1 sum to 0.7000 (pass).
Sources
- EMA Appendix 2 CPCA (EMA/451665/2023, 12 Oct 2023) — Figure 2, Table 1, Annex A Tables 2–4
- FDA Recommended AI Limits for NDSRIs (Aug 2023) — Table 1, Appendix A; Cat 1 = 26.5 ng/day for US products
- FDA CDER nitrosamine impurity AI limits (updated lists) — do not hard-code compound tables here
- EMA nitrosamine impurities hub / Q&A — Q&A 10 (ppm, multiple), Q&A 22 (interim LTL)
- ICH M7(R2) — §7.1 TTC 1.5 µg/day; §7.3 Table 2 LTL
Last checked 2026-10-16. This page does not replace regulatory judgment.
Related tools
Assay precision is on the RSD calculator. Relative response factors are on the RRF calculator.
FAQ
What is the CPCA?
The Carcinogenic Potency Categorisation Approach assigns an N-nitrosamine to predicted potency Categories 1–5 from α-hydrogen counts and activating or deactivating structural features. This page follows EMA Appendix 2 Figure 2 and Tables 1–4. FDA August 2023 uses the same scoring with 26.5 ng/day for Category 1 in the US.
How do I convert AI to a ppm specification?
EMA Q&A 10: Limit (ppm) = AI (ng/day) ÷ maximum daily dose (mg/day). The LOQ target shown is 10% of that limit when justifying omission of a specification.
How are multiple nitrosamines checked?
EMA Q&A 10 flexible approach: the sum of each measured level divided by its limit must be at most 1. Optional interim LTL multipliers during CAPA (13.3× or 6.7× AI) follow Q&A 22 and are temporary after authority consultation.
Does this page replace an official AI table?
No. Compound-specific AI lists are not hard-coded. Use the linked FDA and EMA pages (last checked 2026-10-16). The calculator does not replace regulatory judgment.