CH 15 · notes
How it works
ICH Q3D(R2) sets permitted daily exposures (PDE, µg/day) for 24 elemental impurities by oral, parenteral, and inhalation routes (Table A.2.1 p.23 (PDF p.26)) and cutaneous / transcutaneous PDEs (Table A.5.1 p.83 (PDF p.86)). Class 1, 2A, 2B, and 3 guide which elements to consider in a risk assessment when they are not intentionally added (Table 5.1 p.9 (PDF p.12)).
§7 Option 1 converts a PDE to a common concentration assuming a product dose of 10 g/day or less: µg/g = PDE ÷ 10 (Table A.2.2 p.24 (PDF p.27)). Option 2a uses the actual maximum daily dose (MDD) in g/day: µg/g = PDE ÷ MDD. Option 2b multiplies each component's concentration (µg/g) by its mass per day (g), sums to µg/day, and compares that sum with the PDE. For cutaneous Ni and Co in Option 1 and 2a, the applied concentration is the lower of the PDE-based value and the 35 µg/g CTCL (Table A.5.1 footnote 4). In Option 2b the CTCL applies to the drug-product concentration Σ(Ci × Mi) ÷ ΣMi (Appendix 5 §7), not to each component.
A control threshold of 30% of the PDE (§5.6; Appendix 5 §6 for cutaneous) helps decide whether additional controls are typically needed. For cutaneous Ni and Co, a cutaneous and transcutaneous concentration limit (CTCL) of 35 µg/g also applies, with a 30% CTCL threshold of 10.5 µg/g (Appendix 5 §6).
Worked example
Invented oral product with palladium (Class 2B, oral PDE 100 µg/day). Drug substance 0.2 g/day at 10 µg/g contributes 2 µg/day. Excipient blend 2.3 g/day at 2 µg/g contributes 4.6 µg/day. The sum is 6.6 µg/day, which is at or below 100 µg/day (PASS) and below the 30 µg/day control threshold. Option 1 for the same element and route is 10 µg/g. With MDD 2.5 g/day, Option 2a is 100 ÷ 2.5 = 40 µg/g.
Sources
- ICH Q3D(R2) Elemental Impurities (Step 4, 26 April 2022) — Tables A.2.1 p.23 (PDF p.26), A.2.2 p.24 (PDF p.27), 5.1 p.9 (PDF p.12), A.5.1 p.83 (PDF p.86), A.5.2 p.84 (PDF p.87); §5.6; Appendix 5 §6 for cutaneous control threshold; §7 Options 1 / 2a / 2b
Last checked 2026-10-18. This page does not replace regulatory judgment.
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FAQ
What is the difference between Option 1, 2a, and 2b?
ICH Q3D(R2) §7 describes three options. Option 1 gives a common concentration (µg/g) assuming the daily product dose is 10 g or less: concentration = PDE ÷ 10. Option 2a uses your actual maximum daily dose: concentration = PDE ÷ MDD. Option 2b uses component-specific masses and concentrations, sums Ci × Mi in µg/day, and compares that sum with the PDE. For cutaneous Ni and Co in Option 1/2a, the applied concentration is the lower of the PDE-based value and the 35 µg/g CTCL (Table A.5.1 footnote 4). In Option 2b the CTCL applies to the drug-product concentration Σ(Ci × Mi) ÷ ΣMi (Appendix 5 §7), not to each component.
What does the 30% control threshold mean?
ICH Q3D(R2) §5.6 (and Appendix 5 §6 for cutaneous) defines a control threshold as 30% of the PDE (and, for cutaneous Ni and Co, also 30% of the CTCL = 10.5 µg/g). If the measured or predicted daily amount is consistently below that threshold and variability is adequately assessed, additional controls are typically not required. At or above the threshold, additional controls should be considered.
Why do routes have different PDEs?
Oral, parenteral, and inhalation PDEs in Table A.2.1 p.23 (PDF p.26) reflect different systemic exposure and toxicity data. Cutaneous / transcutaneous PDEs in Table A.5.1 p.83 (PDF p.86) are derived mainly from parenteral PDEs with a cutaneous modifying factor; Ni and Co also have a CTCL of 35 µg/g for already sensitized individuals.
Does this page replace regulatory judgment?
No. Confirm PDEs and concentrations with the current ICH Q3D(R2) text and the applicable authority. Values were last checked 2026-10-18. The calculation stays in the browser.