Permitted Daily Exposure determination
When different medicinal products are produced in shared facilities, the potential for cross contamination is a concern. Medicinal products provide a benefit to the intended patient or target animal; however as a cross contaminant, they provide no benefit to the patient or target animal and may even pose a risk. Hence, the presence of such contaminants should be managed according to the risk posed which in turn are related to levels that can be considered safe for all populations. To this end, health based limits through the derivation of a safe threshold value should be employed to identify the risks posed. The derivation of such a threshold value (e.g. permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data.
Determination of a PDE involves: hazard identification by reviewing all relevant data, identification of critical effects, determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical, and use of several adjustment factors to account for various uncertainties, according to the EMA requirement. For compounds with limited or no toxicity information for example for chemicals, raw materials, starting materials, intermediates or API’s in early phase clinical trials, the PDEs are based on application of the TTC principle, in which levels of human exposure are estimated that pose no appreciable risk to human health.
ToxHub provides high-quality PDE reports for active pharmaceutical ingredients (APIs) or other potential contaminants in shared facilities, authored by senior toxicologists and European Registered Toxicologists (ERT) as recommended by regulatory authorities.
- EMA/CHMP/SWP/169430/2012 “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/246844/2018. Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘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)
- Dolan DG, Naumann BD, Sargent EV, Maier A, Dourson M. Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations. Regul Toxicol Pharmacol. 2005 Oct;43(1):1-9. doi: 10.1016/j.yrtph.2005.06.010. Erratum in: Regul Toxicol Pharmacol. 2006 Mar;44(2):189. PMID: 16099564.
- Faria EC, Bercu JP, Dolan DG, Morinello EJ, Pecquet AM, Seaman C, Sehner C, Weideman PA. Using default methodologies to derive an acceptable daily exposure (ADE). Regul Toxicol Pharmacol. 2016 Aug;79 Suppl 1:S28-38. doi: 10.1016/j.yrtph.2016.05.026. Epub 2016 May 24. PMID: 27233926.