Overcoming elemental impurities

In order to adhere to International Council for Harmonisation (ICH) Q3D guidance and avoid compromising an end product, elemental impurity testing is imperative to consider in API development. To generate the necessary data early on and avoid challenges when ultimately seeking approval, organisations should establish a baseline of elemental impurity testing early in a project. However, this type of testing can be challenging and requires specific instrumentation, a deep understanding of regulatory guidelines and analytical expertise.

ICH Q3D requires organisations to prove there is no harmful elemental impurity (i.e., heavy metals) contamination in a drug product. Full Reference:Committee for Human Medicinal ProductsICH guideline Q3D (R1) on elemental impurities2019http://database.ich.orgDate Accessed: 28th August 2024 The regulatory guidance, which applies specifically to commercial products, provides instructionsfor how to perform testing, establishes permitted daily exposure (PDE) limits for elemental impurities, and dictates which elements to test for based on the route of administration. It defines three classes of elements based on toxicity and their likelihood of occurrence in a drug product. By beginning testing earlier in a project rather than waiting until an API nears commercial approval, organisations can ensure they test for the appropriate elements, establish a robust testing history and ensure that they have compiled all necessary data to adhere to regulatory guidance.

Controlling elemental impurities is critical not just from a regulatory perspective, but also from a safety perspective. Elemental impurities contamination can arise from a variety of sources, including metal catalysts and leaching from manufacturing equipment, or they can be carried through as impurities from raw materials. Regardless, these impurities deliver no therapeutic benefit and can be toxic when present in amounts exceeding the regulatory PDEs. Some metals, such as mercury, arsenic and cadmium, are so highly toxic that they should be considered in every process. To avoid retention of harmful metals in an end product, experience across a variety of analytical methods is critical for developing a robust testing approach that considers permitted daily exposure, route of administration, and more.

With numerous potential analytical approaches for identifying and eliminating elemental impurities, it can take some time to determine the option that will be most effective for a given compound. In addition, different projects require testing for different elements. Given that the first testing approach may not always be successful in identifying impurities, it is important to seek out appropriate alternatives while remaining conscious of key project deadlines. 

At Sterling, our extensive analytical expertise enables us to successfully test and identify elemental impurities for customers. With state-of-the-art analytical equipment and an experienced team, we work with customers to proactively advise on an appropriate testing approach for their specific requirements. All of this is supported by close scientific partnership and customer collaboration.

We have extensive analytical expertise, and have been testing in accordance with ICH Q3D and USP <232> and <233> guidelines since their implementation in 2018. Equipped with a strong understanding of the guidance in the industry and how to successfully apply it in our testing approach, we support customers in generating the data they need as they ultimately seek regulatory approval. By encouraging elemental impurity testing early on, we help customers to establish a robust testing history to satisfy regulatory requirements.

Our experience with elemental impurities is broad. We have developed analytical methods for dozens of compounds, ranging from extremely small organics to metal ion complex molecules. In addition, our sample preparation capabilities range from direct aqueous dissolution to closed-vessel microwave sample digestion. Sample digestion may require one or more types of acid, depending on the unique characteristics of the compound.

This experience enables us to tailor our approach for each customer’s project requirements. Generally, our initial aim is to analyse material in solution using inductively coupled plasma mass spectrometry (ICP-MS). If insoluble, we have the option of destructive microwave digestion to break down the sample matrix and leave remaining inorganics. Our precise control over temperature parameters and ability to work with a wide range of acid combinations enables us to achieve complete digestion for any sample.

At Sterling, our goal is to always make the best recommendations for our customers based on their specific project requirements. We provide insights based on our extensive experience and leverage a proven elemental impurity testing approach to maximise customer success. After confirming the route of administration for an API, we recommend which elements should be tested and establish specifications for each. We then obtain the representative material and perform a series of tests, keeping the customer informed of any challenges. Finally, we provide phase-appropriate technical reports suited to the needs of the customer, ranging from development reports for preclinical or early phase compounds to Quality Assured cGMP validation reports for late phase or commercial compounds. By using a standard, yet tailored, approach, we ensure our customers have all the information they need for regulatory success.