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. We also provide PDE for veterinary medicines in shared facilities.

Relevant literature

  • 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.