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Permitted Daily Exposure (PDE) determinations

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Being the manufacturers of a variety of medicinal products in shared facilities, it is customatory for Pharmaceutical industry to implement the guidelines of European Medicines Agency (EMA) with regards to Health Based Exposure Limits (HBEL) to prevent toxicological risk.

One such threshold value: permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a systematic and critical scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical reports of that specific substance/compound.


Sugen Life Science prepares three types of toxicological assessment reports :

  • Permitted Daily Exposure (PDE) limit determinations
  • Cleaning Validations (CV)
  • Occupational Exposure Limit (OEL)

The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose daily for lifetime. Establishment of PDE also known as Acceptable Daily Exposure (ADE) has become an integral part of cleaning validation program due to the risks of possible carryover contamination of residual active substances so as to comply with various Regulatory or cGMP requirements.


The PDE calculation involves complex steps such as systemic hazard identification through organized, strategized literature search; identification of critical effects; establishment of NOEL (no observed effect level)/NOAEL (no-observed-adverse-effect level) for critical effects and application of adjustment factors including bioavailability correction factors for 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).


Occupational Exposure Limit (OEL) refers to the maximum airborne concentration of a chemical to which most workers could be exposed, without consequent adverse health effect or impact. OELs are a measure for minimizing the worker exposure to hazardous substances in the workplace. The OEL calculation is set considering, all available data on the hazards of a substance, particularly with respect to its acute and/or chronic toxicity, carcinogenicity, mutagenicity and toxicity to reproduction.


Though not mandated for pharmaceuticals, the OEL calculation has been recommended by several Agencies including, Occupational Safety and Health Administration (OSHA), 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).


Criteria for Sugen's toxicology reports:

  • PDE calculation is in compliance with EMA/CHMP/CVMP/SWP/169430/2012
  • PDE reports are certified by the Diplomate of American Board of Toxicologists (DABT).
  • Thorough scientific knowledge and experience in identification of critical effects, point of departures (PODs), NOEL, NOAEL and/or LOAEL (lowest observed adverse effect level) from most appropriate non-clinical/ clinical studies.

Sugen' s PDE reports contain the following information

  • Hazard alters indications/summary
  • Review of acute toxicity (LD50 calculations), skin/eye irritation and sensitization potential
  • Thorough scientific knowledge and experience in identification of critical effects, point of departures (PODs), Repeat Dose toxicity
  • Reproduction and Developmental toxicity
  • Genotoxicity
  • Carcinogenicity
  • Clinical evidence with sensitive and vulnerable population
  • Use of Threshold of Toxicological Concern (TTC) approach for genotoxic substances.
  • Derivation of PDE/ADE values for uncommon or other routes of exposure (example, nasal, ocular, otic, topical/dermal including intravenous infusions)

Key points of toxicological assessment by Sugen's team

  • Qualified and experienced team of toxicologists and data scientists.
  • Certified by DABT
  • Established and structured literature search strategy.
  • Robust quality control checks.
  • Quick turnaround time.
  • Audit support (post/during) including answering the Agency queries.

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