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Elemental Impurities

FDA recommends that the manufacturer of any U.S. marketed drug product follow ICH Q3D recommendations to establish appropriate procedures for identifying and controlling elemental impurities in the drug product based on risk assessment and product-specific considerations.

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Elemental impurity sources in pharmaceuticals can be categorized in these general ways:

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  • Leaching from container closure systems
  • Residual catalysts or inorganic reagents added intentionally in synthesis
  • Impurities unintentionally added through the use of impure drug substance, excipients, or reagents in the preparation of the drug products
  • Contamination or leaching from manufacturing and processing equipment

Element Classification

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Three classes of elemental impurities have been established based on their toxicity and likelihood of presence in the drug product:

  • Class 1 (As, Cd, Hg, and Pb) – Human toxicants with limited or no use in pharmaceutical manufacturing
  • Class 2 Toxicity is dependent on the administration route
  • Class 2A (Co, Ni, V) Relatively high probability of occurrence in the drug product
  • Class 2B (Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, Tl) Relatively low probability of occurrence in the drug product
  • Class 3 (Ba, Cr, Cu, Li, Mo, Sb, Sn) – Low toxicity (high PDEs) by oral administration, but inhalation and parenteral routes of administration may require risk assessment
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Other elements that do not have established PDEs but may need to be considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W, and Zn

How Can Primera Help You with Elemental Impurities and Assays

With advanced Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) systems (Agilent 7900 and 7700s), Primera offers elemental impurity analysis per USP <232>, <233>,  and ICH Q3D. Primera offers:

  • Method Development
  • Method Validation
  • Method Transfer

Primera also employs multiple CEM Mars microwave digestion systems to assist with our elemental impurity studies. These systems allow us to work with many drug products and other materials such as APIs, excipients and raw materials under controlled digestion conditions, and will provide greater accuracy and repeatability.

Some drug substances, drug products, and excipients require the assay of elements such as Calcium, Aluminum, and Phosphorus. Counter ions such as Sodium and Potassium can also be assayed. 

We also offer quick screening of 68 elements for your early development work. 

Primera Will Design Methods to Meet Your Specific Needs

ICH Q3D establishes Permitted Daily Exposure Limits (PDEs) for the elements of concern. The PDEs are based upon toxicological data obtained and vary by the route of administration.
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