An effort to increase the sensitivity and specificity of the analyses of toxic metal impurities in drug articles (including natural source and rDNA biologics), dietary supplements and excipients is advancing, and could benefit makers of Inductively Coupled Plasma–Optical Emission Spectroscopy (ICP-OES), ICP-MS and microwave digestion systems. The January/February issue of the US Pharmacopeia’s (USP) Pharmacopeial Forum features proposals for the new General Chapter 231 of the USP–National Formulary (USP–NF) for elemental impurities, including the elements to be monitored and limits for these elements (Chapter 232) and new analysis procedures (Chapter 233).

USP is a nonprofit public health organization that sets standards for medicines, health care products, food ingredients and dietary supplements sold in the US. Medicines must meet USP standards to be sold in the US. The USP–NF is the official publication of monographs for products. Tests and procedures featured in multiple monographs are described in the USP–NF’s General Chapters.

The proposed revision describes limits for lead, mercury, arsenic and cadmium, as well as for metal catalysts that may be added during production. New referee procedures for multielement analysis that would replace the current wet chemistry method utilize ICP-OES and ICP-MS. Dr. Anthony DeStefano, vice president of General Chapters for the USP, told IBO, “the Elemental Impurities—Procedures Chapter <233> has detailed procedures for analyses by ICP-OES and ICP-MS and provides acceptance criteria for validation of alternative procedures.” In defining a referee procedure, he stated, “in all cases, a procedure described in the USP, whether in monographs or in General Chapters, is the official (referee) procedure if there is a difference in results between the USP procedure and an alternative.” Labs can chose any analysis technique, but must show that it is equivalent or better than the USP procedure. Closed vessel microwave digestion is the proposed referee method for sample preparation for samples requiring digestion.

Many larger drug companies are already using ICP-OES and ICP-MS for testing of elemental impurities, according to Zoe Grosser, PhD, director of Food and Environmental Applications for PerkinElmer, a provider of ICP-OES and ICP-MS systems. Other labs do not need to use them. “Some of the excipient manufacturers find the current methodology sufficient and do not necessarily need to move to the new technology. Especially if only a small amount of their product is used in the final formulation, it won’t exceed the daily exposure based on dosage.” Nonetheless, the new procedures have many advantages. “The sample size needed for ICP-OES or ICP-MS is much smaller than the colorimetric method, saving the cost of destroying large amounts of sample,” she noted. “The specificity of ICP-OES and ICP-MS yields more information that can be used to solve a problem if the level of metal detected is too high.” Asked about the barriers to adoption, she said, “the initial investment is more than for the older method, which required a UV/Vis for quantitation. The skill level and training required for the operator is somewhat higher.” But, as she noted, the investment can be worth it. “The payback of the initial investment is rapid, if enough samples are run to make good use of the productivity feature of the instrument. In a production laboratory, this is easier to achieve than in a small company, where only a few samples would need to be measured.”

Although ICP-MS is widely used at drug companies for drug development and manufacturing, other techniques are also used. “[M]any pharmaceutical labs still use graphite furnace atomic absorption for monitoring metals. Even though it has limited dynamic range and low sample throughput, especially for multielement analysis,” said Don Potter, worldwide marketing manager for ICP-MS at Agilent, which offers ICP-MS but not ICP-OES. One of the advantages of ICP-MS is its use for speciation, according to Mr. Potter. “[T]he proposed method USP 2232 (for dietary supplements) requires speciation measurement for arsenic and mercury if these elements are present above the threshold limit. ICP-MS is much better suited to speciation measurement than ICP-OES due to better sensitivity and interference removal.” Although ICP-MS is more expensive to purchase and operate than ICP-OES, he noted, “this gap is smaller than it used to be. Better performance for the key elements justifies the higher initial price of ICP-MS compared to ICP-OES.”

Public comments on the new General Chapter will be accepted until April 15. A delayed implementation program is set to begin in September 2013.