With 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)’, the importance of Health-based Exposure Limits (HBEL) through scientific toxicological risk assessment has increased in the pharmaceutical industry.

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 product. Thus, for pharmaceutical manufacturing facilities or Contract Manufacturing Organization (CMO), derivation and establishment of Permitted Daily Exposure (PDE) also known as Acceptable Daily Exposure (ADE) has become an integral part of cleaning validation program to comply with various Regulatory or cGMP requirements.

The potential risk of cross-contamination can be controlled or restricted by the use of PDE/ADE values derived by a scientific and toxicological risk assessment of clinical and non-clinical data. The PDE calculation involves steps like hazard identification through structured and strategized literature search, identification of critical effects, establishment of NOEL/NOAEL for critical effects and 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/ADE values are used in cleaning validation in manufacturing facilities to further determine the maximum acceptable carryover (MACO values). The PDE/ADE values of most hazardous substances like cytotoxic drugs, hormones and steroids etc., also help in determination 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 also used to indicate the possibility of skin absorption and the contribution of skin absorption in 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 with respect to 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 European Chemical Agency (ECHA).


Freyr Expertise

  • PDE calculation in compliance with EMA/CHMP/CVMP/SWP/169430/2012.
  • PDE reports approved by board-certified (DABT / ERT) and experienced toxicologists.
  • Sound scientific knowledge and experience in identification of critical effects, point of departures (PODs), the no-observed-adverse-effect level (NOAEL) or no observed effect level (NOEL) and lowest-observed-adverse-effect-level (LOAEL) from most appropriate non-clinical / clinical studies.
  • Comprehensive PDE report encompassing the following details:
    • Hazard alters 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 (example, 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

Freyr Advantages

  • Qualified team of toxicologists and non-clinical experts involved in the drafting of the 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/OEL reports.
  • Established and structured literature search strategy
  • Robust quality control checks right from document compilation to sign-off stages
  • Quick turnaround time for PDE and OEL reports as per client’s timelines
  • Flexibility to adapt to client-specific templates and requirements including priority deliveries of the reports within the shortest time.

Our Experience

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

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.

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