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Elemental Impurities: Updated Regulatory Requirements

In 2013, the International Conference on Harmonization (ICH) approved ICH Q3D, a Guideline for Elemental Impurities, which replaced wet chemistry "heavy metals" limit test, such as USP <231>, with new analytical technology, specifically inductively coupled plasma (ICP) - based technologies, and mandated conformance to new and specific limits for individual elements. This action by the ICH triggered prompt reactions by the U.S. Food and Drug Administration (FDA), United States Pharmacopeia (USP) and European Pharmacopeia (EP) to harmonize with the ICH requirements.

After the adoption of Q3D by the ICH, both the FDA and USP moved quickly to harmonize U.S. regulations with the new requirements. Among the new requirements was the setting of individual limits for metals and the defining of the Permissible Daily Exposure (PDE) which is the amount of a metal contaminant in daily dosage that will likely not cause an adverse event during a lifetime exposure. In ICH Q3D, the PDE is defined for specific elements depending upon their toxicity, and a formula is provided as a guideline for calculating the PDE if an
element is not listed in the guidance. A summary of current PDE limits are shown in the table below:


In response to the regulatory changes, Alcami will begin phasing out wet chemistry heavy metals testing in 2017, therefore recommending current and future clients that all heavy metals testing transition to align with USP <232>, <233>, Ph. Eur. and ICH Q3D. This will require the development of ICP-OES, ICP-MS or other appropriate analytical methods and subsequent validation in accordance with ICH Q2 (R1), Validation of Analytical Procedures: Text and Methodology.

Please note that, analysis for the presence of all metals may not be required. The FDA recommends a risk-based estimation be used to determine which elemental impurities may be present in the product from a thorough review of possible sources; it is these metals that should be quantified in both API and drug product. However, arsenic, lead, cadmium and mercury are excluded from the risk-based evaluation and must always be considered possible contaminants. A manufacturer need not test for certain contaminants if it can be proven that they cannot exist in the final product.