Toxicological evaluation

Validation of cleaning processes

Limits for the carryover of product residues

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.
Deviation from the main approach highlighted in this guideline to derive such safe threshold levels
could be accepted if adequately justified.

Limits for residue carryover should be based on a toxicological evaluation of the active materials. These evaluations should be verified by a toxicologist (or equivalent) and performed in accordance with current guidance. (Guidance may be found in EMA/CHMP/ CVMP/ 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 (pdf,169kb)).