Permitted Daily Exposure (PDE) Monographs

Hundreds of API substances PDEs have already been developed.

New monographs are being developed on a constant basis.

Any PDE monograph can be developed upon request.

Our rates for PDE monographs are based on several factors such as status of development of the monograph of course, but also routes of administration, veterinary or ophtalmic specificities, etc... and discounts can be granted upon scale up quantities.

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Evaluation of cross-contamination risk and calculation of the pde

The cross-contamination risk in the manufacture of different medicinal products in shared facilities has been included at the core of new European regulation with the revision of Chapters 3 and 5 and Annex 15 of the EU GMP Guide and the implementation of EMA “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)”. This new regulatory environment encourages pharmaceutical-industry actors to establish limit values for the validation of cleaning processes.

As stated in the Questions and answers EMA/CHMP/CVMP/SWP/246844/2018, Product Daily Exposures (PDE), as all Health Based Exposure Limits (HBELs), are required for all medicinal products and have to be established by experts as per methodology described in the EU Cross Contamination directive.

PDEs calculation relies on the Active Substance toxicological and pharmacological data, and requires periodical re-assessment throughout a product’s lifecycle.

Determination of a PDE involves :

• Hazard identification by reviewing all relevant data
• Identification of “critical effects”. Safety concerns detailed in the Risk Management Plan of the final product are reviewed in order to detect other critical effects in humans. Critical effects in humans from mechanistic studies and pharmacodynamics data are discussed in the report
• First-in-human-Phase 1 clinical studies are reviewed in order to identify a NOEL in humans NOEL in healthy volunteers as the highest exposure level at which there are no effects (adverse or non-adverse) has preference to calculate a PDE more than NOAEL in animals
• Use of several adjustment factors to account for various uncertainties. Specific pharmacokinetics for each drug product are considered in order to adjust bioavailability factor
• All relevant and recent articles published regarding methods of PDE calculation apart from EMA Guidelines are considered (e.g. PDE for topical ocular drugs from Journal Pharmaceutical Development and Technology 2018, intravitreal (IVT) drugs from Journal of Regul Toxicol Pharmacol. 2019)
• For each API, different PDEs are calculated considering all sensitive endpoints and sensitive species. Full reasoning for final PDE computation is detailed. Critical effects are discussed from non-clinical toxicity studies in order to clarify if findings are not relevant for humans or targeted animals