Implementation Of USP New Chapters <232> and <233> On Elemental Impurities In Pharmaceutical Products

For more than 100 years, the standard method for measuring elemental impurities in pharmaceutical products sold in the United States has been the “Heavy Metals Test,” described in Chapter 231 of the United States Pharmacopeia’s (USP) National Formulary (NF). This test is based on a sulfide precipitation of the analyte elements with a thioacetamide (C2H5NS) solution, and assumes that all analytes behave in  a similar manner to a lead standard with which samples are compared. When the USP heavy metals method was first published, it was only intended as a screening tool with results being reported as < 10 ppm Pb. Additionally, although USP Chapter <231> is listed as a “Heavy Metals Test,” it was initially intended to detect a larger group of elements like Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, Mo, and Se, but there was no clear definition of which individual elements the method was expected to detect.

One of the many limitations of this approach is the assumption that the reaction mechanism for the formation of the sulfides in the sample is very similar to the formation of lead  sulfide in the standard solution and is not impacted significantly by the sample matrix. However, since many metals’ sulfides can form colloids, which behave very differently to  solutions, the method requires that the visual comparison is performed in a relatively short period of time (< 5 mins.) after the precipitate has formed but before the sample starts to become unstable.

The problem is that different analysts can differ in their interpretation of a result by how they perform the visual comparison, and it is fairly typical that inexperienced analysts
may not understand the subtleties of how to accurately and consistently read the sample and standard solutions each time. Another limitation of the technique is that ~ 2 g of sample is required in order to achieve the desired detection capability. Such a large sample weight is often difficult to acquire at the early stages of drug development due to the very limited
supply.