The requirements for testing of pharmaceutical products for elemental impurities has been in a state of flux for several years.
Impending changes to United States Pharmacopeia (USP) chapters <232> and <233>, the International Conference on Harmonisation (ICH), the European Medicines Agency (EMA), and the European Pharmacopoeia (EP) will have a significant impact on the pharmaceutical industry and its suppliers. Until those changes are adopted as official
and implemented, it is difficult to know how to plan or proceed in anticipation of what will come. This article covers the
changes so far, impending changes, and options for preparing for those changes.
In the past 10 years, the subject of metals analyses in pharmaceuticals has gained considerable interest. The publication
of the European Medicines Agency (EMA) "Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents" (1), new United States Pharmacopeia (USP) chapters <232> "Elemental Impurities: Limits" and <233> "Elemental Impurities: Procedures" (2,3), and European Pharmacopoeia (EP) 5.20 (4) have forced the industry to begin looking more carefully at the metals content of various materials used in the
manufacture of pharmaceuticals. While there are differences between USP <232> and the EMA and EP documents, they are, none-the-less, significantly harmonized.
Following behind the EMA, USP, and EP, the International Conference on Harmonisation (ICH) recently moved to a step 3 document for Q3D: "Elemental Impurities" (5). ICH-Q3D completed the public comment period on December 31, 2013. ICH-Q3D adds many more elements to the listing of elements of interest, and is not well-harmonized with the USP, EMA, or EP documents. Furthermore, although ICH-Q3D has not yet advanced to step 4, the EMA has indicated that it will harmonize with the ICH document when it is finalized. To that end, the EMA has delayed implementation of the "Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents"
for marketed drug products, pending finalization of ICH-Q3D. This will result in significant changes to the EMA and EP documents in the future. Likewise, USP has delayed implementation of chapters <232> and <233> and will revisit <232> once ICH-Q3D is finalized as well, which could also lead to potential changes to <232> in the future.
To say that the status of elemental impurities in pharmaceuticals is in limbo is an understatement. The word limbo has two widely recognized meanings: "an intermediate state or place" (6); and "a West Indian dance where the players keep
bending over backward and passing under a pole that is lowered" (6). Both definitions fit the current state of elemental impurities
in pharmaceuticals, where compliance requirements are "on hold," and the position of the "bar" keeps changing, causing those
analysts who had hoped to be proactive in meeting compliance requirements to, in some instances, totally revisit their approaches
to compliance. As a result of the disparity between the various documents — especially, with ICH-Q3D not yet finalized and with no projected implementation date for it, the EMA, or the EP, and with a projected date of December 2015 implementation for the USP —many in the industry are both frustrated and confused as to how to proceed to prepare their companies and products to comply
with what certainly promise to be significant changes in the way metals analysis in the pharmaceutical industry is performed.
This article will provide some background and suggestions regarding how to prepare for compliance, as well as ways to leverage
the documents currently in limbo to save resources.