The first version of the ICH Q3D guidance was published in 2016, to control elemental impurities in medicinal products for human use within acceptable limits. For veterinary medicinal products, it was recently published in early 2020.
The presence of elemental impurities in pharmaceuticals has traditionally been monitored by the so-called heavy metal test. This test only detected certain elemental impurities and due to its limitations, it is now considered obsolete. In contrast, the ICH Q3D Guideline provides a fully detailed evaluation with updated, much more sensitive and robust analytical methods (ICP-MS, ICP-OES etc.).
The guidance covers the evaluation of toxicity data for potential elemental impurities, the establishment of a Permissible Daily Exposure (PDE), and the application of a risk-based approach to control impurities. The EDPs set out in this guidance are considered to be protective of public health.
Elemental impurities in pharmaceuticals can arise from several sources:
- Residual catalysts that are intentionally added in the synthesis.
- Present as impurities (e.g. through interactions with manufacturing equipment, packaging systems, or in components of the drug product itself).
According to their toxicity and probability of occurrence, elemental impurities are classified into 4 categories:
- Class 1 (As, Hg, Pb, Cd): they show toxicity by all routes of administration. Therefore, it is considered that they should always be included in the risk analysis.
- Class 2: includes elements whose toxicity depends on the route of administration. This category is subdivided into two subgroups according to the probability of occurrence.
- Class 2A (Co, Ni, V): have a high probability of occurrence and therefore should also always be included.
- Class 2B (Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl): have a lower natural abundance and therefore a lower probability of occurrence. They are included in the risk analysis only if they are intentionally added.
- Class 3 (Li, Sb, Ba, Mo, Cu, Sn, Cr): This category includes elements that have relatively low toxicity when administered orally, but should be evaluated when the product is administered parenterally or inhaled, and also if intentionally added.
In the case of products for veterinary use, any impurities that may have a toxicological risk for the target species must also be included.
ICH Q3D presents a process to assess and control elemental impurities in the drug product using the risk management principles described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.
In any case, the control strategy shall be established on the basis of the outcome of the risk analysis on a case-by-case basis.
It is very important to evaluate any changes in the production process of the medicinal product throughout its life cycle. A change could lead to an update of the control strategy (if any), to control elemental impurities and not to exceed the EDP in any case.