For over 100 years, regulatory guidelines have been in place to protect patients from elemental impurities being present in drug products. Now, with new U.S. Pharmacopeia (USP) chapters coming into force, manufacturers are allowed some choice in the analytical method used for the evaluation of levels of such impurities. This article will outline the regulatory changes and discusses the advances in testing methodologies, which can help manufacturers to ensure compliance for both new and legacy products.

New USP chapters and their impact
Catalysts involved in drug production are a key source of elemental impurities, which at higher levels can be harmful to patients. Since 1905, the pharmaceutical industry has adhered to USP , which set out a testing methodology to evaluate levels of elemental impurities using thioacetamide to visually demonstrate the presence of metallic impurities through the formation of colored sulfides. However, this approach can fail to detect key elements such as mercury at toxicologically relevant levels, and is now widely considered to lack the necessary selectivity and sensitivity for QC workflows, as well as being both time-consuming and labor intensive.

In consultation with the industry, chemists and toxicologists over the course of the past decade, the USP has developed and produced several iterations of new regulations. More recently, the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) performed a similar process, which resulted in the ICH Q3D Guideline for Elemental Impurities.

USP Elemental Impurities Limits sets new requirements for the concentration levels of elemental impurities present in drug products, while Elemental Impurities—Methods introduces changes to analytical testing techniques. From January 2018, pharmaceutical manufacturers must demonstrate compliance with these requirements for both new and legacy products.
While these are significant and welcome changes, our customers in the market have already been working to the proposed standards for some time, following best practice to anticipate the new regulations.

Which methods align with the new guidance?
USP provides manufacturers with a degree of choice when selecting an analytical technique to detect elemental impurities. Two example procedures are provided, using inductively coupled plasma atomic emission spectroscopy (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS). ICP-AES uses ICP to excite atoms in a sample to emit electromagnetic radiation; the wavelength indicates the presence of an element, while the intensity indicates the concentration. ICP-MS uses ICP in a different way, creating an ionized sample, which is separated, and any detected elements quantified by mass spectrometry.

Although these methods are employed within the industry, the total cost of instrument operation can be daunting to a number of companies. Moreover, errors in analysis can result from inadequate sample dissolution/digestion as well as from dilution errors during sample preparation. In order to address these issues, USP does permit alternative methods for elemental impurity testing, providing the technique has been validated in line with the requirements.

New and emerging technologies
Technological advances mean new testing methodologies are being developed to help pharmaceutical manufacturers to comply with new regulations. One option is X-ray Fluorescence (XRF), which has recently been admitted as a compendial technology in USP X-ray Fluorescence Spectrometry. Although not yet well known in this sector, XRF is established in other industries and may be used for both drug development and process control. The technique follows similar principles to X-ray diffraction, which is widely used in the pharmaceutical industry for a variety of applications. 

XRF offers several significant advantages over ICP as an analytical technique to evaluate levels of elemental impurities. XRF is non-destructive, which may be important when samples are in short supply—for example, in drug development. The technique involves minimal sample preparation, avoiding the dissolution/digestion and dilution errors which can occur with ICP-AES and ICP-MS. In addition to these functional benefits, solvents are not needed, meaning XRF systems have a significantly lower total lifetime cost compared to ICP instruments.

Walk-up, pre-calibrated solutions for testing catalysts used during the manufacture of drug products using XRF techniques have been developed*, which enable even non-expert users to utilize XRF to quantify elemental residues at levels required by USP .

Conclusion
With choice of analytical technique to determine elemental impurities permitted under the new USP guidance, many companies have taken advantage of other methods now available. Technological advances are providing alternatives for pharmaceutical manufacturers, which facilitate more accurate analyses and improved access to useful data, and enable higher test throughput. Looking forward, these innovations will bring more powerful data to the industry, accelerating the development of efficacious drugs which comply with new guidance. Moreover, the USP is working closely with the industry and FDA to ensure agreement on interpretation of the new regulations, to ensure that these alternative testing methods gain widespread acceptance.