By Matt Koval, Aspen Research Corporation, August 28, 2017
In the past, the USP listed a “Heavy Metals as Lead” specification for compounds and specified a wet chemical method, USP<231>, that was introduced in 1908. This method is a color comparison test that was dependent on the visual acuity of the analyst and relied on the interaction of elements present in a sample with sulfide. This is more of a screening test and is not element specific. In fact, the response of the elements in question and the sensitivity of their response to the sulfide reagent varies by element and often under-reported.
In 2009, the International Conference on Harmonization (ICH) began the process of updating the assessment of elemental impurities in drug products. As a result, on January 1, 2018, USP<232> and <233> will be implemented. USP<232> takes a toxicological approach to elemental impurities of a drug product that specifies elements and their daily exposure limits based on route of entry of the drug. USP<233> provides the guidelines for the instrumental methodology to be used and gives method validation criteria for the test methods. Companies will have 36 months after the implementation to apply the new rules to existing drugs. Methods specified in USP<233> are inductively coupled plasma optical emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectroscopy (ICP-MS). For the preparation of samples for testing, a closed vessel system is recommended to mitigate the loss of volatile elements.
The limits in USP<232> apply specifically to the drug product. Unless specified by a monograph, they do not apply to drug substances or excipients. However, elemental impurities may come from anything that is involved in the manufacture, storage, transport and administration of a drug. Because of this, drug manufactures will require information from their suppliers regarding the elemental impurities of reagents, APIs, excipients, processing equipment, packages, delivery devices, etc.