Permitted Daily Exposure (PDE) Calculation – An Overview

The importance of Health-based Exposure Limits (HBEL) in terms of Permitted Daily Exposure (PDE) through scientific toxicological risk assessment has increased in the pharmaceutical industry. The reason for the HBEL requirement is due to the implementation of the European Medicines Agency’s (EMA’s) ‘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).’

Permitted Daily Exposure (PDE)/Acceptable Daily Exposure (ADE) Calculations

The EMA guideline insists on establishing HBELs, which will be used while evaluating the risks of possible carryover contamination of residual active substances through medicinal products. Thus, for pharmaceutical manufacturing facilities or Contract Manufacturing Organizations (CMO), the derivation and establishment of Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) have become an integral part of cleaning validation programs to comply with various Regulatory or cGMP requirements.

The potential risk of cross-contamination can be controlled or restricted using PDE/ADE values derived from a PDE calculation guideline that encompasses scientific and toxicological risk assessment of clinical and nonclinical data. The PDE calculation involves steps like hazard identification through structured and strategized literature search, identification of critical effects, the establishment of No Observed Effect Level (NOEL)/No Observed Adverse Effect Level (NOAEL) for critical effects, and the application of adjustment factors, including bioavailability correction factors for a route-to-route extrapolation as per the EMA, 2014, ICH Q3C, ISPE, and VICH GL18. The PDE limits derived from the PDE calculation are used in cleaning validation in manufacturing facilities to further determine the Maximum Acceptable Carryover (MACO values). The PDE limits of most hazardous substances, like cytotoxic drugs, hormones, steroids, etc., also help in the evaluation of dedicated and separate equipment and facilities.

Occupational Exposure Limit (OEL) Calculations and OEL Banding

Occupational Exposure Limit (OEL) refers to the maximum airborne concentration of a chemical to which most workers could be exposed without consequent adverse health effects or impacts. Exposure limits are typically expressed as milligrams of contaminant per cubic meter of air (mg/m3). Additionally, skin notation is used to indicate the possibility and contribution of skin absorption to the overall exposure. OELs are a measure for minimizing worker exposure to hazardous substances in the workplace. The OEL calculation is set by considering all available information on the hazards of a substance, particularly for its acute or chronic toxicity, carcinogenicity, mutagenicity, and toxicity to reproduction.

Although not mandated for pharmaceuticals, the OEL calculation has been recommended by the Occupational Safety and Health Administration (OSHA) and several other agencies, including the American Conference of Governmental Industrial Hygienists (ACGIH), National Institutes of Occupational Safety and Health (NIOSH), Japan Society for Occupational Health (JSOH), and the European Chemical Agency (ECHA).


Permitted Daily Exposure (PDE) Calculation - Freyr Expertise

  • PDE calculation in compliance with the EMA/CHMP/CVMP/SWP/169430/2012.
  • PDE reports, approved by board-certified (DABT/ERT) and experienced toxicologists.
  • Sound scientific knowledge and experience in the identification of critical effects, Points of Departure (POD), the NOAEL or NOEL, and the Lowest Observed Adverse Effect Level (LOAEL) from the most appropriate nonclinical/clinical studies.
  • Comprehensive PDE report encompassing the following details:
    • Hazard alter indications/summary.
    • Review of acute toxicity (LD50 calculations), skin/eye irritation, and sensitization potential.
    • Repeat-dose toxicity.
    • Reproduction and developmental toxicity.
    • Genotoxicity.
    • Carcinogenicity.
    • Clinical evidence with the sensitive and vulnerable population.
    • Use of Threshold of Toxicological Concern (TTC) approach for genotoxic substances [ICH-M3(R2)].
  • Derivation of PDE/ADE values for uncommon or other routes of exposure (e.g., nasal, ocular, otic, topical/dermal, including intravenous infusions).
  • Establishment of PDE levels for solvents and impurities.
  • GMP audit support (post/during), including answering the Agency queries.
  • Any other technical and protocol support during cleaning validation.

Permitted Daily Exposure (PDE) Calculation - Freyr Advantages

  • Qualified team of toxicologists and non-clinical experts involved in drafting the HBEL reports.
  • Reports reviewed and approved by American board-certified (DABT) and European Registered Toxicologists (ERT) with extensive experience in Regulatory toxicology.
  • Global delivery of 1500+ EMA-compliant PDE/ADE reports, 1000+ OEL reports, and 850+ combined PDE and OEL reports.
  • Established and structured literature search strategy.
  • Robust quality control checks, right from document compilation to sign-off.
  • Quick turnaround time for PDE and OEL reports per the customer’s timelines.
  • Flexibility to adapt to customer-specific templates and requirements like priority delivery of reports within the shortest time.

Our Experience in PDE Calculation

Over the years, Freyr toxicologists have developed and delivered more than 1500 high-quality PDE reports/monographs in compliance with the EMA, ISPE, ASTM, establishing NOEL/NAOEL, and other country-specific guidelines. Freyr toxicologists have developed PDE reports for oral, parenteral, inhalation, topical, and some uncommon routes like ophthalmic and otic, which have undergone strict scrutiny during GMP inspections and critical evaluations, even by in-house toxicologists of our customers.

Please CLICK HERE for the complete list of molecules/agents/PDE reports developed by Freyr. We would be happy to share the same with you soon.