The 4 pivotal questions you have on PDEs answered: A shared concern on how to create scientifically-based PDEs.
From a safety perspective, all companies with multifunctional pharmaceutical and chemical production facilities must be able to adequately determine cleaning limits and permitted daily exposures (PDEs) by characterizing the effects of possible cross-contamination in the non-intended patient population via calculation of health-based carry-over exposure limits (ICH Q3D, EMA). This may enforce renewed cleaning validation activities, test method detection and sampling, and potentially lower detection limits. So what are the greatest obstacles in setting the PDEs so far? We answer the four most commonly asked questions:
Q: What do you do when there is insufficient data on NOAELs, dose and toxicities?
A: Initiate a practical approach; include relevant internal IBs, CTD’s, etc. and conduct literature research to evaluate the data that is available from public libraries. Find the appropriate product characteristic or patient information and determine the therapeutic dosages and adverse effects. It’s a question of knowing where to look!
Q: Does human data not always supersede non-clinical data?
A: Human data is of course very valuable, but both studies should complement each other in the derivation of a sound PDE. For example, human data can be scarce if the product is relatively new, in which case non-clinical data could be more appropriate in setting your PDE. In addition, reproductive toxicity is mostly investigated non-clinically, thereby making it an essential asset in completing your toxicological evaluation.
Q: Do you need single-dose studies (i.e. the MTD/LD50/etc.) for the PDE derivations?
A: Even though all data should be considered, the derivation of the PDEs should be reflective of your lowest limits at which adverse effects can occur. This implies that maximum tolerated dosages or non-clinical LD50 dosages might be less relevant in determining your critical PDE.
Q: There is more than one relevant PDE, what do I do?
A: Your PDE report can, and sometimes even should provide more than one PDE as it can be derived from various clinical or non-clinical studies, different routes of dosing, and/or multiple types of adverse effects. The most critical factors should be considered, i.e. incidence, severity, and dose level, with which a critical PDE can be selected.
If you need any help in implementing the guideline on PDEs, let us at 3D-PharmXchange help you integrate these type of questions into one clear scientific based evaluation with our peer-proofed PDE template, which can be readily implemented and ensures complete compliance with regulatory requirements and standards.