PharmaCalc

A Health-Based Exposure Limit (HBEL) — expressed as a Permitted Daily Exposure (PDE), numerically the same quantity as an Acceptable Daily Exposure (ADE) — is the daily dose of a substance that is unlikely to cause an adverse effect if an individual is exposed to it, by any route, every day for a lifetime. It is derived from a point of departure in the toxicology data (a NOAEL, or a LOAEL when no NOAEL is available) divided by a series of adjustment factors that account for the uncertainties in extrapolating from that study to chronic human exposure. The HBEL/PDE is the health-based input to cleaning-validation limits (Method 3 of the MACO calculation).

Where this is used:

• Setting health-based cleaning-validation limits for shared facilities (operative authority: EMA/CHMP/CVMP/SWP/169430/2012).
• Occupational and cross-contamination risk assessment for actives and intermediates.
• The F1–F5 adjustment-factor scheme originates in ICH Q3C (residual solvents) and is carried into ICH Q3D (elemental impurities) and the EMA HBEL guideline.

Scope note: ICH M7 governs mutagenic impurities via the threshold of toxicological concern (TTC) and is not the authority for the F-factor PDE scheme. M7 is relevant only as a pointer for mutagenic/genotoxic compounds, where a TTC-based limit may apply instead of, or alongside, a PDE.

Adjustment factors (ICH Q3C(R8), Appendix 3 / EMA HBEL guideline):

Scenario: a compound handled on shared equipment has a published NOAEL of 50 mg/kg/day from a 90-day oral rat study; at the next dose level, reversible effects were seen. A PDE is needed as the health-based input to cleaning-validation limits.

1. Identify the point of departure: a clear NOAEL exists, so the POD is the NOAEL and F5 = 1.
   Example Data

   Study: 90-day oral rat study
   NOAEL = 50 mg/kg/day (POD)
   Effects at the next dose level: reversible (mild)
2. Set the reference body weight: the EMA HBEL guideline specifies 50 kg.
   Parameters

   BW = 50 kg (EMA reference)
3. Assign the adjustment factors from ICH Q3C(R8) Appendix 3.
   Factor Assignment

   F1 = 5 (rat → human)
   F2 = 10 (interindividual variability)
   F3 = 5 (90-day rodent study)
   F4 = 1 (effects mild and reversible)
   F5 = 1 (NOAEL available)
4. Compute the factor product.
   Calculation

   F1 × F2 × F3 × F4 × F5 = 5 × 10 × 5 × 1 × 1 = 250
5. Apply the PDE formula.
   Calculation

   PDE = (50 mg/kg/day × 50 kg) / 250
   = 2,500 / 250
   = 10 mg/day
6. Interpret and apply: the PDE feeds directly into Method 3 of the MACO calculation as the ADE/HBEL term. A PDE is compound- and data-specific — document the basis for every factor chosen. For mutagenic/genotoxic actives, check whether an ICH M7 TTC-based limit applies before using an F-factor PDE.
   Sensitivity

   Had only a LOAEL of 50 mg/kg/day been available, F5 would rise to as much as 10, lowering the PDE proportionally — to as little as 1 mg/day.

• Reference body weight: the EMA HBEL guideline uses 50 kg; older practice and some MACO worksheets use 70 kg. The choice changes the PDE by 1.4×. Pick one, justify it, and keep it consistent through the entire MACO chain.
• Point-of-departure quality: a LOAEL-based POD carries real added uncertainty, captured by F5.
• Route and bioavailability: route-to-route or bioavailability corrections are applied separately where justified.
• Terminology: ICH Q3C uses NOEL/LOEL; ICH Q3D and EMA use NOAEL/LOAEL. The adverse-effect basis (NOAEL) is the intended point of departure.

• ICH Q3C(R8), Impurities: Guideline for Residual Solvents, Appendix 3. database.ich.org
• ICH Q3D(R2), Guideline for Elemental Impurities. database.ich.org
• EMA, Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, EMA/CHMP/CVMP/SWP/169430/2012. ema.europa.eu
• ICH M7(R2), Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals — mutagenic compounds only. database.ich.org