Elemental Impurities Analysis Information

For over 100 years regulators have demanded the testing of heavy metal impurities in pharmaceutical products. Recently, global regulators have issued modern revised methodologies and guidelines—such as USP 232 Elemental Impurities & ICH Q3D—for monitoring a range of metal elemental impurities in pharmaceutical materials using inductively coupled plasma (ICP) optical emission spectroscopy (ICP-OES) or mass spectrometry (ICP-MS).

The US Pharmacopeial (USP) Convention proposed three new elemental impurities general chapters in 2010 covering impurity limits, analytical procedures in pharmaceutical products and raw materials, and elemental contaminants in dietary supplements:

• Chapter <232> Elemental Impurities in Pharmaceutical Products —Limits
• Chapter <233> Elemental Impurities in Pharmaceutical Products — Procedures
• Chapter <2232> Elemental Contaminants in Dietary Supplements

These revisions focused on two main areas of work:

1. Updating the methodology used to test for elemental impurities in drugs and dietary supplements to include procedures that rely on modern analytical technology.
2. Setting limits for acceptable levels of metal impurities (including, but not limited to, lead, mercury, arsenic, and cadmium) in drugs and dietary supplements.

While no specific event triggered the revision of elemental impurities standards, USP’s scientific experts concluded that these standards should be updated to incorporate modern analytical methods and current health information on these impurities.

An announcement on January 14, 2015 established January 1, 2018 as the new date of applicability for General Chapters <232>, <233> and <2232>. This was intended to align implementation closely with limits and timelines set down by other global pharmaceutical and medical agencies including the ICH Q3D Guidelines for Elemental Impurities. The intention was to provide a buffer period where users could either continue to utilize the existing Chapter <231> approach, or implement the methodology outlined in the new chapters <232>, <233> and <2232>. In the period up to 2018, the USP will be engaging in an ongoing dialogue with the pharmaceutical industry, the FDA, and the ICH to ensure this alignment process goes as smoothly.

A total of twenty four elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt, Li, Sb, Ba, Mo, Cu, Sn, and Cr) are specified with their toxicity limits, defined as maximum permitted daily exposure (PDE) levels in μg/day for the four major drug delivery categories. The PDE limits are shown in the table below.

To meet these low regulated levels, new analytical protocols for measuring elemental impurities using spectroscopic techniques are employed using either:

• Inductively coupled plasma optical emission spectroscopy (ICP-OES)
• Inductively coupled plasma mass spectrometry (ICP-MS)
• Graphite furnace atomic absorption (AA)