ICP- MS Analysis and USP Elemental Impurities Testing

USP General Chapters <232> and <233>

The United States Food and Drug Administration (FDA) and similar international health agencies have had long-standing regulations in place for controlling harmful elemental impurities in pharmaceutical products marketed for human consumption.

Since the early 1900s the United States Pharmacopeia (USP) has operated under a procedure known as General Chapter <231> - Heavy Metal.  Since this standard had been used for more than a century, regulatory agencies have now established new mandatory guidelines that will utilize more modern testing methods and instrumentation, and thus provide a higher level of control of potential toxic impurities in drugs.

On January 1, 2018, The United States Pharmacopeia (USP) officially abandoned the general chapter <231> Heavy Metals due to its lack of specificity and ability to accurately quantify individual inorganic elemental impurities.  The wet chemical methodology of general chapter <231> Heavy Metals was abandoned in favor of a more sophisticated quantitative instrumental technique with the chapters <232> Elemental Impurities-Limits and <233> Elemental Impurities-Procedures, which define the limits and procedure in screening for elemental impurities that may be present in drug products. 

What are the Elemental Impurities Testing Requirements?

The FDA released a Guidance for Industry, Q3D Elemental Impurities, that clarifies the testing requirements with regards to elemental impurities in new drug applications and abbreviated new drug applications.

Arsenic (As), Cadmium (Cd), Mercury (Hg), and Lead (Pb) are designated as Class 1, which must be evaluated under all circumstances. There are three primary reasons for this: There is no significant use of these elements in the Approved Pharmaceutical Ingredient (API) or in excipient manufacture, all four are highly toxic, and they cannot be easily removed from many materials.

Class 2 consists of elemental impurities considered to be toxic to a greater or lesser extent, based on route of administration. The guideline then subdivides Class 2 into two groups, 2A and 2B. These elements are less toxic than those in Class 1.

Subclass 2A consists of the elements Cobalt (Co), Nickel (Ni) and Vanadium (V). These elements should be evaluated and/or included in risks-based assessments due to their ubiquity, relative toxicity and likely occurrence in drug products.

Subclass 2B consists of Gold (Au), Thallium (Tl), Palladium (Pd), Platinum (Pt), Iridium (Ir), Rhodium (Rh), Ruthenium (Ru), Osmium (Os), Selenium (Se) and Silver (Ag). These elements have a lower probability of occurring in drug products and only need be evaluated if they are intentionally added in the process of manufacturing the drug product. An example would be an API or excipient that is produced using any one of these metals as a potential catalyst.

Class 3 elemental impurities have relatively low toxicity by oral administration but require assessment if delivered through the parenteral or inhalational routes. This class includes Antimony (Sb), Barium (Ba), Lithium (Li), Chromium (Cr), Copper (Cu), Tin (Sn), and Molybdenum (Mo).

These are other elements for which a potential daily exposure (PDE) has not been established, due to their low inherent toxicity and/or regional regulations. There is currently no assessment requirement for these elements. These elemental impurities include Boron (B), Iron (Fe), Zinc (Zn), Potassium (K), Calcium (Ca), Sodium (Na), Manganese (Mn), Magnesium (Mg), Tungsten (W), and Aluminum (Al).

Elemental Impurities at RD Laboratories

USP <233> Elemental Procedures offers the option of using Inductively Coupled Plasma with Optical Emission Spectroscopy (ICP-OES) or Mass Spectrometry (ICP-MS).  R.D. Laboratories is committed to maintaining state-of-the-art instrumentation and providing full-service contract service testing to satisfy the regulatory needs of our clients.  R.D. Laboratories utilizes an ICP-MS as we believe the ICP-MS offers significant sensitivity advantages over the ICP-OES.  This equipment, together with a closed vessel microwave digestion system will provide optimum sensitivity, precision, and accuracy.

We at R.D. Laboratories are committed to being your partner in meeting the Elemental Impurities requirements mandated by both the FDA and the USP. For more than 35 years, our specialty has been providing analytical services for the pharmaceutical industry. Throughout our history, we have made it a priority to master the latest methodologies and technologies needed to deliver the most accurate and timely results possible, all the while maintaining our reputation for superior customer service and communication.