Instead of the previously used criteria, such as 10 ppm or 1/1000 of the therapeutic dose of the foregoing product, now the sole admissible criterion is a toxicological risk assessment based on PDE values. No matter whether you prepare the required assessments yourself or have them prepared by external toxicologists, you should know the answers to these two questions: What elements must a PDE report contain? What do GMP inspectors look for?
The following overview shows which specific requirements national and international regulatory documents place on PDE reports.
Figure 1 Example for an initial page of a PDE report (Source: EMA PDE Guideline)
Knowledge-based toxicological evaluation of the active substances used:
An HBEL (PDE) assessment report should have:
The conclusions recorded in the summary should be drawn from specific points made in the text of the document and should not have excluded any points made without clear justification.
Is there a plausible explanation of why the search used was considered most appropriate?
Does the report account for the data found through the search? Are aspects searched, where no information was found related to the product, also recorded e.g. carcinogenicity?
Typically, the lowest HBEL value obtained will be used. If not, this should be justified. If concerned about this, you may wish to seek an expert opinion should the control of the product in shared facilities be high risk.
A rationale for the selection of AFs should be recorded in support of the HBEL calculation. An explanation should be provided for the effect on HBEL for differentroutes of administration (of potentially contaminated products) and for Veterinary Medicinal Products, any susceptibility for specific species.
A CV should provide evidence of the qualifications (typically pharmacy, pharmacology or other relevant pharmaceutical science degree), background in toxicology with reasonable previous experience indetermination of health-based exposure assessments such as:
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, 2014 – GMP Compliance Adviser, Chapter C.3.3.7
Aide Mémoire 07120104 der ZLG: Überwachung von Arzneimittelherstellern (Formular 071201_F01_02, optionale Berichtsvorlage, 2019),
PIC/S Aide-memoire for Inspection of Health Based Exposure Limit (HBEL) Assessments and Use in Quality Risk Management (PI 052-1, 2020),
As of June 1st 2016, health based exposure limits have to be determined for all APIs of human and veterinary medicinal products produced in multi-purpose facilities.
The PDE reports must comply with the respective EMA guideline.
„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)
Currently, GMP-Verlag can supply PDE reports for more than 1,900 already available APIs and new APIs upon request.
Our service includes:
1. Issuing of the PDE report
2. Brief explanation/training of the report (10-15 min) in English by a toxicologist after delivery of the report (via Skype)