Introduction of the term PDE

In the context of setting health-based exposure limits for the prevention of cross-contamination of different medicinal products, the term permitted daily exposure (PDE) was first defined in the European Medicines Agency (EMA) Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (hereafter referred to as the “HBEL guideline”) in December 2012 (draft version). And, that guideline went into effect on 01 June 2015. In the EMA’s HBEL guideline, the term permitted daily exposure was defined as follows:

“The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.”

The HBEL guideline then proceeded to present the following equation for the derivation of the PDE = (NOAEL x Weight Adjustment) / (F1 x F2 x F3 x F4 x F5):

While it may be tempting to believe that this is a newly introduced method, in reality, this equation has been in use for many years. Most notably in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Impurities: Guideline for Residual Solvents document, otherwise known as ICH Q3C. Additionally, prior to ICH Q3C, a similar method was presented in the procedures for setting exposure limits in pharmaceuticals (Pharmacopeial Forum, Nov-Dec 1989).

Reviewing the definition of Permitted Daily Exposure

When reviewing the definition of a PDE, it’s important to use critical thinking skills and carefully examine what is meant by every word or phrase in the definition. For example, as follows:

• “Substance-specific dose” means that this is a molecule specific calculation; therefore, you need to have scientific data related to that specific molecule.
• “Unlikely to cause an adverse effect” means any unintended effect, but by using the word “unlikely” it doesn’t eliminate the possibility that there could be an effect.
• “If an individual is exposed” means any individual, including newborns, infants, children, adults or the elderly. And “exposed” means by any route of exposure, including oral, inhalation, dermal, injection, or I.V.
• “Every day for a lifetime” means every day from birth to death.

Conclusion

In conclusion, it’s important to thoroughly understand the basic definition of a PDE so that when you begin performing the calculations you understand what and who you are trying to protect.

Contact Affygility Solutions If you have any questions, need additional information, or would like to request a quote for a PDE report.

Published July 18, 2019 / Updated November 8, 2021

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