Permitted Daily Exposure (PDE) Calculation – Overview
The importance of Health-Based Exposure Limits (HBEL) such as Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) through a highly scientific toxicological risk assessment process has become a new norm in the pharmaceutical industry. Although the ADE/PDE assessment based on health is essentially started post-implementation of the European Medicines Agency’s (EMA’s) guideline (Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities), there is several other similar guidelines or publications highlighting the importance of using scientifically derived exposure limits in pharmaceutical cleaning validation process.
Permitted Daily Exposure (PDE) Calculation:
The EMA guideline insists on establishing HBELs (PDE values), which will be further used for the calculation of Maximum Allowable Carryover (MAC or MACO) and the Maximum Safe Carryover (MSC)limits for residual active substances during the manufacture of different medicinal products in shared facilities. Thus, for pharmaceutical manufacturing facilities or Contract Manufacturing Organizations (CMO), the derivation and establishment of PDE or ADE limits have become an integral part of cleaning validation programs to comply with various Regulatory or cGMP requirements.
The process of PDE calculation encompasses the systematic collection and review of scientific information and performs a robust toxicological risk assessment to derive the PDE values. 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 recommended PDE value derived from the PDE calculation is used for the calculation of MACO MAC or MSC in the cleaning validation process. The PDE limits of highly hazardous substances also help in the evaluation of dedicated and separate equipment or 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. 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).
Similar to PDE calculations, the OEL calculation is based on a systematic scientific assessment of all available data. Freyr can develop a standalone OEL report or a combined PDE and OEL report based on the requirement.
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.
Permitted Daily Exposure (PDE) Calculation
- 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 alert indications/summary.
- Review of acute toxicity (LD50 calculations), skin/eye irritation, and sensitization potential.
- Repeat-dose toxicity data
- Reproduction and developmental toxicity.
- Genotoxicity.
- Carcinogenicity.
- Review of clinical adverse effects and evidence.
- Use of Threshold of Toxicological Concern (TTC) approach for genotoxic substances [ICH-M7(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 cleaning agents, starting materials, solvents, intermediates, and complex mixtures.
- GMP audit support (post/during), including answering the Agency queries.
- Any other technical support during cleaning validation.
- Qualified team of toxicologists and experts involved in the drafting of PDE and OEL reports.
- Reports reviewed and approved by American board-certified (DABT) and European Registered Toxicologists (ERT) with extensive experience in Regulatory toxicology.
- Global delivery of 2000+ PDE/ADE reports, 1000+ OEL reports, and 1000+ 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 including priority delivery of reports within the shortest time.
- Flexibility to adapt to customer-specific templates and requirements.
