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Why health-based exposure limits matter
The importance of Health-Based Exposure Limits (HBEL), such as Permitted Daily Exposure (PDE) Calculation or Acceptable Daily Exposure (ADE), through a highly scientific toxicological risk assessment process has become a significant step in the medicinal product’s lifecycle across the pharmaceutical industry.
How a PDE is derived and used
The EMA guideline emphasizes establishing HBELs (PDE values) for residual substances in manufacturing. For facilities or CMOs, deriving PDE or ADE limits is essential for cleaning validation and Regulatory compliance.
The PDE calculation process involves systematic collection and review of scientific information, followed by a comprehensive toxicological risk assessment to derive PDE values. The recommended PDE value (s) derived from the PDE calculation are used to calculate MACO, MAC, or MSC during the cleaning validation process. The PDE limits for highly hazardous substances help determine whether dedicated and separate equipment or facilities are required.
Our Experience in PDE Calculation
Freyr toxicologists have developed and delivered high-quality PDE reports/monographs in compliance with the EMA, ISPE, ASTM, establishing NOEL/NAOEL, and other country-specific guidelines. Our experts have developed PDE reports for common and some uncommon routes, such as ophthalmic and otic, which have undergone strict scrutiny during GMP inspections and critical evaluations. Your molecule may already be assessed: download our catalog of available molecules and a sample PDE report to check. If it isn’t listed, request a customized assessment below.
Ensure Regulatory Compliance with Expert PDE Calculations
Occupational Exposure Limit (OEL) Calculations and Banding
Like PDE calculations and HBEL reports, 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).
OEL calculations rely on a scientific assessment of all data. Our toxicologists can create an independent OEL report or a combined PDE and OEL report.
Our PDE 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 identifying 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).
- Establish 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 drafting 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.
Streamline Your HBEL Compliance
Frequently Asked Questions
01. What is a Permitted Daily Exposure (PDE) value?
A PDE is the maximum dose of a substance a person can be exposed to daily, over a lifetime, without an appreciable health risk. It is derived from the most relevant point of departure (usually a NOAEL) divided by five adjustment factors, and is expressed in mg/day or micrograms per day.
02. What is the difference between PDE and ADE?
PDE and ADE describe the same health-based exposure limit. PDE is the term used in EMA guidance and in ICH Q3C and Q3D; ADE originates in the ISPE Risk-MaPP guide and is more common in US practice. Regulators accept either, provided the derivation is scientifically justified and fully documented.
03. Who is required to have PDE reports?
Any manufacturer producing more than one product using shared facilities or shared equipment. Since June 2016, EMA guideline EMA/CHMP/CVMP/SWP/169430/2012 has required health-based exposure limits for all active substances in human and veterinary medicinal products. This covers API manufacturers, finished-dose manufacturers, CMOs and CDMOs.
04. Who is qualified to write a PDE report?
EMA expects the assessment to be carried out by someone with adequate expertise and experience in toxicology or pharmacology. Inspectors typically look for board certification (DABT or ERT) and for the assessor’s CV to be available on request. An unsigned or uncredentialed report is a common inspection finding.
05. How is a PDE value used in cleaning validation?
The PDE feeds the Maximum Allowable Carryover calculation: MACO equals the PDE multiplied by the minimum batch size of the next product, divided by that product’s maximum daily dose. MACO is then converted to a surface residue limit per unit area, giving the swab or rinse limit the analytical method must detect.
06. What is the difference between a PDE and an OEL?
A PDE protects the patient from cross-contamination carried into the next product. An OEL protects the worker from airborne exposure inside the manufacturing environment. They draw on overlapping toxicology data but model different exposure scenarios, apply different adjustment factors, and are expressed in different units: mg/day against micrograms per cubic meter.
07. Do you already have a PDE report for my molecule?
Freyr maintains a catalog of molecules for which PDE and ADE assessments have already been completed. Where your active substance is covered, the report is issued faster. Download the catalog index to check, or send us the molecule name and route and we will confirm.
