Elemental impurities (EI) in drug products may arise from several sources. They can be intentionally added or contaminants. EIs do not provide any therapeutic benefit to the patient, therefore, their levels should be controlled within acceptable limits in the drug product (DP).
The ICH guideline Q3D(R1) on elemental impurities provides an appropriate process to assess and control elemental impurities in pharmaceuticals. The guideline gives toxicological information for 24 Elemental Impurities and for these, establishes Permitted Daily Exposures (PDEs) for drug products administered by the oral, parenteral and inhalation routes of administration.
The guideline states that for the other routes of administration, more appropriate PDEs can be derived taking into consideration specific toxic endpoints, peculiar for other routes, and differences in absorption. Products administered on skin and its appendages (e.g., hair, nails) remain the largest area where PDEs for EIs have not been established. The Expert Working Group (EWG) is working on the implementation of the existing guideline for the cutaneous and transdermal route of administration for products administered by the cutaneous and transdermal routes of administration. However, the revised guideline is still missing.
To define specific PDEs for EIs in topical drugs, differences in absorption between local and oral routes, suggested as an appropriate starting point by the ICH Q3D(R1) guideline, should be considered.
The skin provides a formidable barrier to exogenous materials. In particular, the stratum corneum is highly lipophilic and contains very little water. As a result, penetration of hydrophilic or charged molecules is particularly difficult, and such species are effectively unable to partition into the lipid layer and hence pass through the skin at significant levels. Thus, dermal absorption data may allow re-evaluations of some oral PDEs.
Different considerations should be made for the mucosal routes, such as the oral or vaginal mucosa. Mucose are not efficient barriers. The mucous membranes generally consist of a very permeable lining epithelium and an innermost layer, the lamina propria, rich in blood and lymphatic vessels. Therefore, higher PDEs are more appropriate for mucosal drugs (i.e. mouthwashes, oral spray, suppository, pessaries).
Moreover, specific evaluations should be made on excipients in the formulation, especially if used to enhance the PD bioavailability.
One other key point to consider in the EI Risk Assessment and to define appropriated PDEs is the evaluation of specific toxic endpoints, such as skin sensitization. Skin sensitization has been identified as a cause of potential safety issue for a few EIs. The consideration of concentration limits, in addition to PDEs, may increase the safety of EIs for their overall dermal safety evaluation.
To determine safety exposures regarding sensitization, when no experimental data are available a Dermal Sensitisation Threshold (DST) of 900 µg/cm2 for humans can be used. The use of the TTC approach for dermal sensitization was proposed based on a probabilistic analysis of available sensitization data using the ELINCS data set and a compilation of data on the Local Lymph Node Assay (LLNA) in mice.
When animal or human data, including absorption, is available, specific limits can be calculated.
Marinovich M et al. Metals in cosmetics: an a posteriori safety evaluation. Regul Toxicol Pharmacol. 2014;69(3):416-424. doi:10.1016/j.yrtph.2014.05.005
Safford RJ. The Dermal Sensitisation Threshold- a TTC approach for allergic contact dermatitis. Regul Toxicol Pharmacol. 2008;51(2):195-200. doi:10.1016/j.yrtph.2008.02.010