COMMENT
Simplifying impurity analysis
S
tandard methods for the determination and control of heavy metal contamination in pharmaceutical products and dietary sup- plements have hardly altered over the past
century. Historically, heavy metal contamination has been determined using colorimetric methods, measuring the colour change in solutions that result from specific chemical interactions. This standard approach relies on a precipita-
tion reaction at pH 3-4 between thioacetamide and a heavy metal to form a metal sulphide. Comparison with a lead standard solution is then used to show that the metallic impurities do not exceed 10ppm Pb under the specified test conditions. The test can be used to determine the presence of elements such as lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper and molybdenum. However, this approach is labour intensive and
time consuming, as well as being subjective. The multi-step sample preparation involves ashing at 600°C and acid dissolution of the sample residue. Volatile elements, such as mercury, can be lost in the process, and metal loss is also matrix dependent, with recoveries subject to operator- to-operator variation. In addition, interpreting the colour change is challenging. The visual compari- son must be performed rapidly after precipitation, since the various metals behave differently, and analysts may not read the sample and standard solutions accurately and consistently. Recognising these shortcomings, the United
States Pharmacopeia (USP) supported a 2008 workshop where it was generally agreed that colorimetric testing was inadequate, and that the adoption of state-of-the-art instrumental meth- ods would offer greater specificity and sensitivity for a wide range of metals of interest, allowing detection at levels below those of clinical or toxicological importance. A chapter revision was in order, outlining toxicity limits for the metals to be tested, and aligning with guidelines from the International Conference on Harmonization and other major pharmacopeias to ensure a global industry standard. The resulting USP Chapter <232> lists the
elements and their toxicity limits, expressed as maximum daily doses of different drug categories: oral, parenteral, inhalation and large volume par- enteral. The following chapter, USP Chapter <233>, covers recommended analytical procedures, sample preparation and instrumental methods of analysis, including a choice of two plasma-based spectrochemical techniques – inductively coupled
plasma atomic emission spectroscopy (ICP-AES or ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS). Regardless of the technique selected, the
overall analytical procedure must be validated and demonstrated fit for purpose, using an ap- propriate system suitability protocol and tracea- ble certified reference materials (CRMs) to ensure the accuracy of the results. In analytical chemis- try, traceability is typically based on the mole, the mass of a substance containing the same number of discrete particles – in this case atoms – within 12.000g of the pure isotope carbon-12. However, carbon’s non-reactivity makes the production of CRMs for trace element analysis a complex pro- cess and a new ‘practical mole’ is needed. ROMIL’s silver traceability scheme offers such a solution, as well as being a more affordable ap- proach to traceability. In most cases, the primary standards used to establish SI traceability are generally only available from national metrol- ogy institutes. With similar stability to carbon, ultra-pure silver has 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 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 base accreditation for both testing and calibration.
The new USP regulations, which come into
force in January 2018, will require accurate, reliable testing, involving advanced methods of instrumental analysis validated using CRMs traceable to SI units. They welcome the adoption of advanced instrumental methods of analysis, offering superior precision, specificity and sensi- tivity 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.
About USP <232>/<233> USP Chapter <232> details the measurement of lead, mercury, arsenic and cadmium at toxi- cologically relevant concentrations, and also includes metal catalysts. Chapter <233> covers analytical procedures, demanding accurate, reliable testing with advanced instrumental methods, validated using certified reference materials.
The new USP regulations will require accurate, reliable test- ing, involv- ing advanced methods of instrumental analysis vali- dated using CRMs tracea- ble to SI units. They welcome the adoption of advanced instrumental methods of analysis, offering supe- rior precision, specificity and sensitivity for trace ele- ment analysis
09 | 2017 37
Anthony Lenk director, ROMIL
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