Digestion of Pharmaceuticals containing very stable APIs for Elemental Impurities Analysis with ICP-MS according to ICH Q3D, USP <232>/<233> and Ph. Eur. 5.20

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Elemental impurities constitute not only a toxicological risk for the patient but also may affect the quality and efficacy of pharmaceutical products. Therefore their analysis plays an important role within the development and quality control of pharmaceuticals.

Regulatory Background

Since 2018 the use of ICP-OES or ICP-MS together with reliable sample preparation techniques such as microwave-assisted closed vessel digestion has become the current imperative for the specific quantification of elemental impurities.

The ICH (International Conference of Harmonization) Guideline Q3D step 4 classifies elemental impurities based on their toxicity and the possibility of their occurrence in drugs in four different classes - 1, 2A, 2B and 3. For each element and dosage form - oral, parenteral or inhalation - PDE (Permitted Daily Exposure) values are specified.

Particular attention is given to the impurities of class 1, the so-called "big four" - Cd, Pb, As and Hg - and the metals of class 2A - Co, V and Ni. All of them are human toxicants and therefore have low PDE limits.

For these elements a risk analysis concerning the possibility of breaching the respective PDE is mandatory, even if these metals have not been added intentionally. Depending on the outcome of this assessment a justified control strategy has to be defined.

The limits stated in USP (United States Pharmacopoeia) chapter <232> completely align with the requirements of ICH Q3D and the analytical procedure described in USP chapter <233> is also referred to in chapter <2232> for dietary supplements.

The European Pharmacopoeia Commission decided to reproduce verbatim the ICH Q3D guideline in Ph. Eur. chapter 5.20.

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