As highlighted in the GMP guideline revised by EMA on June 01 2015, companies that manufacture different medicinal products in shared production facilities must set Permitted Daily Exposure (PDE) Limits for health risk identification.

Companies that manufacture different multiple medicinal products in shared production areas should have PDE values for their products for the cleaning validation approach.

PDE reports are requested during local and international authority inspections in your facility. PDE values are calculated based on the ICH Guideline (Q3D) dated February 4, 2011.

PDE values are obtained using scientific NO(A)EL or LO(A)EL results of animal studies.

PDE Calculation takes place in 4 steps;

  • Phase 1: Hazard Identification
  • Stage 2: Critical Effects
  • Phase 3: NOEL Identification
  • Phase 4: Implementation of Security Factors

PDE Calculation: NO(A)EL x Weight is variable is divided by various adjustment factors (also known as safety-, uncertainty-, assessment-, or modifying factors) in order to adjust the data for uncertainties and to allow extrapolation to human population (or target animal population).

Adjustment factors F1 to F5 are addressing the following uncertainties:

  • F1: For Extrapolation between species
  • F2: For Variability between individuals
  • F3: For Short duration repeat-dose studies
  • F4: For Severe toxicity (i.g. neurotoxicity, non-genotoxic carcinogenicity, etc.)
  • F5: May be applied for extrapolation if the no-effect level was not established (if only LOEL is available)

As stated in the guideline, the lowest of the PDE values calculated according to the different species should be taken into account.

We will be happy to assist you with the preparation of the Permitted Daily Exposure Report, which is requested by the inspectors who inspect your facility during local and international authority inspections on common production areas!

The relevant calculations are carried out by the Toxicologist who is certified by the European Registered Toxicologist by the International Union of Toxicology (IUTOX) and the European Societies of Toxicology (EUROTOX).

The European Registered Toxicologist title is evaluated every 5 years considering the Academic activity.

All pharmacological and toxicological data (preclinical and clinical data) related to the active pharmaceutical ingredient should be evaluated scientifically.