SC IV Q. Elemental Impurities

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has adopted the ICH Q3D guideline for elemental impurities in medicinal products.

The European Pharmacopoeia (Ph. Eur.) applies this guideline to medicinal products (referred to hereunder and in the ICH Q3D guideline as ‘drug products’), with the exception of products for veterinary use, unlicensed preparations and products excluded from the scope of the guideline. The guideline prescribes a permitted daily exposure (PDE) according to the route of administration for elements of toxicological concern which may be present in medicinal products. The guideline also describes some acceptable approaches to establishing concentrations of elemental impurities in medicinal products or components that would ensure that the PDEs for these impurities are not exceeded.

Parts of the introduction and the scope of the guideline are reproduced hereunder, and the full text is available from the ICH website.

The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of the guideline, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.

The guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. The guideline does not apply to products based on genes (gene therapy), cells (cell therapy) and tissue (tissue engineering). In some regions, these products are known as advanced therapy medicinal products.

The guideline does not apply to drug products used during clinical research stages of development. As the commercial process is developed, the principles contained in the guideline can be useful in evaluating elemental impurities that may be present in a new drug product.

Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or they may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits.

An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDEs. The PDEs established in the guideline are considered to be protective of public health for all patient populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity thresholds have been shown to have an impact on other quality attributes of the drug product (e.g., element catalysed degradation of drug substances).