Permitted Daily Exposure (PDE) Calculation

Our steadfast non-clinical and toxicology team ensures your compliance with global and gold-standard guidelines. With our experienced delivery of over 1500 Permitted Daily Exposure (PDE) reports globally, we support and assure continuous Regulatory support and compliance conformity for our clientele.

Permitted Daily Exposure (PDE) Calculation – 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 is due to the implementation of the European Medicines Agency’s (EMA’s) guideline for use in risk identification in the manufacture of different medicinal products in shared facilities.

Permitted Daily Exposure (PDE) Calculation:

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) limits or Acceptable Daily Exposure (ADE) limits 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 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. 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).

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 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
  • 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

Celebrating Customers Success

 

Medicinal Products

Medical Writing

India

A big thanks to Freyr team for the support they have provided to us on priority. We really appreciate the extra effort that the Freyr team has put into providing the reports on time. We are looking forward for a continuous business association with Freyr.

Head of Quality Assurance

 

Medicinal Products

Medical Writing

India

A big thanks to the Freyr team for the support they have provided to us on priority. We really appreciate the extra effort that the Freyr team has put into providing the reports on time. We are looking forward to a continuous business association with Freyr.​

Head of Quality Assurance​

India-based, Leading Pharma Contract Manufacturing Organization​

 

Medicinal Products

Medical Writing

UK

We are extremely happy to inform you that the BLA was successfully submitted to the FDA. We convey our sincere gratitude to the Freyr team, who worked diligently, tirelessly, and very closely with our Bridgewater and Beijing teams over the past several months to accomplish this monumental feat on time. Freyr’s team went beyond the call of duty to make this BLA submission come true. We truly appreciate Freyr’s flexibility and eagerness to work with us to accomplish aggressive goals. Look forward to your perennial support and our continued relationship and beyond. ​

Global CMC Technical Lead​

China-based, Leading Innovator Pharmaceutical Company​

 

Medicinal Products

Medical Writing

USA

Thank you, Freyr team. I appreciate your professionalism, dedication, and hard work. You’ve gone above and beyond to ensure all deliverables were met ahead of schedule throughout the project and have done a great job managing a challenging group of products. I appreciate your attention to detail and follow-up on the large workload you’ve managed. It’s been a pleasure working with you, and I wish you and your family all the best in the future!​

Director, Global Labeling Management – Labeling Cluster Head Global Product ​ Development, Global Regulatory Affairs

US-based, Multinational Pharmaceutical and Biotechnology Company​

 

Medicinal Products

Medical Writing

Vietnam​

Thank you so much for being a great partner in our Regulatory compliance journey.

As Asian countries move towards having safety assessments as a key requirement, your support has helped us significantly in fulfilling those requirements well ahead of our competitors in Vietnam. ​

In fact, I shared your contact with our regulatory officers so that they can share it across the industry if the safety assessments become necessary.

Lead, R&D/Personal Care

India-based, Multinational Consumer Goods Company​

 

Medicinal Products

Medical Writing

USA

Kudos to you all for the brilliant teamwork !! Alone, we can do so little; together, we can do so much.

Look forward to the next milestone and collaboration on new projects in the future.

SVP - R&D ( Finished Dosage Form)​

US-based, CRO Company that Focuses on Material Science and Engineering for Drug Development​