PDE Cross-Contamination Regulations

Listed below are the current European regulations regarding potential cross-contamination of chemicals in production facilities during the manufacturing of “APIs” (active pharmaceutical ingredients):

1.) Cross-contamination guideline for human and veterinary drugs: 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)

2.) New annex 15: Qualification and Validation for GMP for medicinal products for Human and Veterinary Use Ares (2015)1380025 – 30/03/2015

3.) Questions and answers on implementation of risk-based prevention of cross-contamination in production and Guidelines 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/246844/2018)

4.) Overview of comments received on Guidelines for setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/SWP/364535/2015)

Permitted Daily Exposures (“PDEs”):

• Are required for the validation of cleaning processes for all drugs
• Must be developed in accordance with the expert cross-contamination guidelines
• Should be re-evaluated periodically throughout the product cycle

WHO (World Health Organization) Annex 2 - Points to consider when including Health Based Exposure Limits (HBELs) in cleaning validation: 

Technical report series based on the Working document QAS/20.849/Rev.1 also encourages the pharmaceutical industry to use PDEs for cleaning process validation.

To ensure the safety of all human patients and target animals exposed to residual active substances via medicinal products, as well as consumers of meat & animal products where the animal was treated with veterinary medicinal products, Health Based Exposure Limits must be established.