Formula 2 - APIC HBEL general calculation.docx

Calculation of HBEL as per APIC Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants (APIC, CEFIC, Revision April 2019, updated February 2021

1. HBEL[
mg
day]
=
POD[
mg
kg
day]×BW[kg]
UncertaintyFactors
Where:
HBEL (Health-Based Exposure Limit): The calculated value representing the maximum
safe daily exposure used as the input for MACO. HBEL is also known as the Permitted
Daily Exposure (PDE) or Acceptable Daily Exposure (ADE)—these terms all refer to the
same calculated health-based limit, derived from a POD, body weight and a set of
uncertainty factors and are used interchangeably in APIC and EMA cleaning validation.
POD (Point of Departure): Toxicological starting value. Commonly NOAEL (No Observed
Adverse Effect Level: Highest tested dose with no observed adverse effects.) or, if
unavailable, LOAEL (Lowest Observed Adverse Effect Level: Lowest tested dose with
observed adverse effects.)
If neither is available, a surrogate POD can be estimated from LD50 (see section 3), or
TTC may be used as a last resort.
BW (Body Weight): Usually 50 kg for adults; chosen as conservative regulatory safety
standard.
Uncertainty Factors: Composite multiplier accounting for interspecies differences,
human variability, study duration to lifetime extrapolation, data completeness, and
severity of effect. Defaults and calculation procedures are detailed in the EMA guideline
on setting health-based exposure limits (EMA/CHMP/CVMP/SWP/169430/2012) and ICH
guidance. Toxicologists may justify modifications based on available data and risk
scenario.