CH 16 · notes
How it works
The ICH Q3E Step 2 draft (endorsed 01 August 2025) defines an analytical evaluation threshold (AET) as a study-specific level that equates to the same patient exposure: safety concern threshold (SCT, µg/day) multiplied by the analytical uncertainty factor (UF; §5.1). SCT is the lower of the mutagenic threshold of toxicological concern (TTC, ICH M7) and the non-mutagenic qualification threshold (QT) for the route and exposure duration (§6.1, Table 1). For inhalation, SCT also applies the Table 1 local threshold of 5 µg/day (§6.4). Dermal (500 ppm) and subcutaneous or intradermal (50 ppm) local thresholds in Table 1 are concentrations and are not applied in this calculator. Appendix 3 gives unit conversions for manufacturing extractables (filters) and container-closure extractables (stoppers), plus leachables in liquid products.
Worst-case dosing uses the maximum approved daily dose and the minimum batch size to obtain doses per batch, or the maximum volumetric daily dose for liquid products. For the simple approach, UF may be no greater than 0.5 (§5.1); a response-factor database that yields a different UF is outside this tool's scope. Last checked 2026-10-22.
Sources
- ICH Q3E Extractables & Leachables (Step 2 draft, endorsed 01 Aug 2025) — §5 AET; §5.1 UF; §6.1 Table 1 SCT; Appendix 3 AET calculation examples
- ICH Q3E EWG work plan (Jul 2027 Step 3/4 sign-off target) — timeline context only; calculations use the Step 2 draft
- Norwood & Nagao AET (OINDP reference; not used for numbers) — OINDP context and historical SCT 0.15 µg/day; this tool follows ICH Q3E Step 2 draft only
FAQ
What is the difference between SCT and AET?
In the ICH Q3E Step 2 draft, the safety concern threshold (SCT) is the daily exposure (µg/day) below which a leachable is considered negligible for mutagenic and non-mutagenic concerns (§6.1). The analytical evaluation threshold (AET) applies SCT and the analytical uncertainty factor (UF) to a specific extractable or leachable study, expressed in study units such as µg/component or µg/mL (§5, Appendix 3).
What is the UF ceiling in the simple approach?
Section 5.1 states that when semi-quantitative methods are used, an acceptable approach is to multiply by a UF of no greater than 0.5 to account for underestimation from response-factor differences. That value is a ceiling for the simple approach, not a required default. Deriving UF from a response-factor database is outside this tool's scope.
Is this page based on the final ICH Q3E guideline?
No. Calculations follow the ICH Q3E Step 2 draft (endorsed 01 August 2025). The guideline is not final; the ICH Q3E work plan targets Step 3 and Step 4 sign-off in July 2027. Confirm thresholds with the current text and your regional authority.