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48 March 2015 Tablets & Capsules The presence of elemental impuri- ties, such as catalyst residue, in drug products must be monitored to ensure they don't exceed regulatory guidelines. One method of testing for these impurities is outlined in USP <231>, a standard that dates to 1905. It entails adding thioacetamide to the sample and observing it for colored sulfides, which indicate the presence of metallic impurities [1, 2]. But this qualitative approach lacks selectivity and sensitivity, and can fail to detect mercury and other key elements at toxicologically relevant levels. It's also an outdated method that is time-con- suming and labor-intensive. Thus in 2005, USP sought to establish new limits and a new test method and, after producing several iterations of the regulation, developed chapters <232> and <233>. The first addressed the elemental impurity con- centration limits and, the second, the testing methods. Both would apply to new and legacy products. But USP delayed implementation of the chapters several times in order to align them with the standards of the International Conference on Har mo - ni zation, known as ICH Q3D Guide - line for Elemental Impurities [3]. Final - ly, in January 2015, USP set January 2018 as the date of applicability of <232> and, by reference, <233>. Chapter <233> allows manufactur- ers to select the analytical method for evaluating elemental impurity levels and provides two examples: induc- tively coupled plasma-atomic spec- troscopy (ICP-AES) and ICP-mass spectroscopy (MS). ICP-AES excites atoms in the sample, causing it to emit electromagnetic radiation. The wavelength of the radiation indicates the presence of an element, while its intensity indicates the concentration. The other method, ICP-MS, first ion- izes the sample, then separates it and quantifies the elements present. Both techniques are already used in the pharmaceutical industry, but both also have drawbacks: The need to dilute the sample can lead to errors, and the instruments are expensive. But again, alternative methods for elemental impurity testing are per- mitted, as long as the technique has been validated per <233> require- ments. One option is x-ray fluores- cence (XRF), a compendial technol- ogy cited in USP <735> that operates similarly to X-ray diffrac- tion, which is widely used in the pharmaceutical industry. While XRF isn't well known in pharma, it's well established in other industries and has several advantages over ICP spectroscopy. First, XRF is non-destructive, which is important when samples are in short supply. It also minimizes sample preparation, thereby avoiding the dilution errors possible with ICP methods. Additionally, XRF requires no solvents and thus costs less than other methods over the life of the instrument. Plus, by using a pre-cali- brated instrument, even non-experts can quantify catalyst residues or the other elemental impurities as re - quired by USP <232>. XRF instru- ments can also analyze raw materials, including excipients. By allowing the use of alternative techniques, USP is bringing greater choice to pharmaceutical manufactur- ers, and many companies are taking advantage of this opportunity to explore and adopt other methods. Moreover, ICH is working closely with the industry and regulators to reach full agreement on the interpre- tation of the new standards, thereby ensuring that alternative testing meth- ods are accepted everywhere. T&C References 1. US Pharmacopeia General Chapter <231>. www.pharmacopeia. cn/v29240/usp29nf24s0_c231.html. Accessed February 16, 2015. 2. US Pharmacopeia. Frequently asked questions: Rationale for USP's proposed standards for elemental im - purities. home/frequently-asked-questions/ frequently-asked-questions-usps- p r o p o s e d - s t a n d a r d s - e l e m e n t a l - impurities. Accessed February 16, 2015. 3. US Pharmacopeia. "General notices section 5.60.30 elemental impurities in USP drug products and dietary supplements. usp-nf/ notices/general-notices-section- 56030-elemental-impurities-usp-drug- products-and-dietary-supplements. Accessed February 16, 2015. [Editor's note: To comment on the Back Page, visit www.tabletscapsules. com.] Andrew Fussell, Ph.D., is pharmaceutical seg- ment manager at PAN- alytical, 1 Lelyweg, Almelo 7602EA, The Netherlands. Tel. +31 546 534 444. Website: www.panalytical. com. The company introduced its XRF instrument, the Epsilon 1 Pharma, at the 2014 AAPS annual meeting in San Diego, CA. b a c k p a g e New USP elemental impurity testing: Selecting a method Alternative methods for elemental impurity testing are permitted, as long as the technique has been validated per <233> requirements.

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