Anthony Lenk, Director of ROMIL, discusses the forthcoming USP Chapter <232>/<233> regulations for the determination of elemental impurities in pharmaceutical products and the company’s silver traceability scheme for calibration standards
Standard methods for the determination and control of heavy metal contamination in pharmaceutical products and dietary supplements have hardly altered during the past century, relying on wet chemistry and the visual interpretation of colour changes. New United States Pharmacopeia (USP) Chapter <232>/<233> regulations for the determination of elemental impurities in these products will come into force in January 2018, requiring the use of accurate and reliable analytical techniques validated using certified reference materials (CRMs) traceable to SI units. In most cases, the primary standards used to establish SI traceability are costly and expensive to produce, but ROMIL’s silver traceability scheme offers a more practical alternative.
Historically, heavy metal contamination has been determined using colorimetric methods, measuring the colour change in solutions that occurs as a result of specific chemical interactions. This approach forms the basis of USP Chapter <231> Heavy Metals Test, which relies on heavy elements — such as lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper and molybdenum — reacting with thioacetamide at pH 3–4 to precipitate a metal sulphide.1 Comparison with a lead (Pb) standard solution is then used to show that the metallic impurities do not exceed 10 ppm Pb. However, this method is time consuming and labour intensive; sample preparation involves ashing at 600 °C and acid dissolution, and recoveries are subject to operator-to-operator variation. In addition, some metals and volatile elements — such as mercury — are prone to processing losses. The visual comparison must also be performed rapidly once the precipitate has formed, and is subject to interpretational differences between operators.
Recognising these shortcomings, the USP supported a 2008 workshop to address the limitations of USP Chapter <231>.2 The general consensus was that colorimetric testing was inadequate, and that the adoption of state-of-the-art methods would offer greater specificity and sensitivity, allowing detection at levels below those of clinical or toxicological importance. The resulting USP Chapter <232> lists the elements to be tested and their toxicity limits, defined as maximum daily doses of different drug categories: oral, parenteral, inhalation and large volume parenteral.3 Analytical procedures, sample preparation and analytical methods — including a choice of two plasma-based spectrochemical techniques — are then covered in USP Chapter <233>.4
Regardless of the technique selected, the overall analytical procedure must be validated and demonstrated to be fit for purpose, using traceable CRMs to ensure the accuracy of the results. The silver traceability scheme offers a practical and affordable system of traceability. Ultra-pure silver acts as a realisation of the mole, but with just enough reactivity to enable it to link into a chain of reaction schemes with other chemical substances to create an unbroken chain of traceability. An example of this is the range of ROMIL PrimAg reference materials and multi-element reference solutions, produced using an ISO Guide 34-accredited adaptation of this well-established concept, and supported by ISO 17025 accreditation for both testing and calibration.
The adoption of advanced instrumental methods of analysis offers superior precision, specificity and sensitivity for trace element analysis. These methods must be validated prior to implementation to ensure they are fit for purpose, and the use of CRMs, traceable to SI units, is an essential part of the process.