Elemental Impurities

  • What are Elemental Impurities?

    Elemental impurities analysis encompasses trace metal/heavy metal testing to evaluate pharmaceutical products for elevated concentrations of elements such as lead and arsenic that are of significant toxicological concern. In any product, impurities can delay development or can cause a recall of a product on the market. Impurity analysis is particularly critical in pharmaceutical development because impurities can impact the safety and efficacy of final therapeutic products. Various organizations such as the FDA and ICH provide recommendations regarding testing for impurities and acceptable impurity limits.

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USP 232/USP 233 and ICH Q3D

The International Council for Harmonization’s Guideline for Elemental Impurities (ICH Q3D) defines the permissible daily exposures (PDEs) for elemental impurities in pharmaceutical drug products. This includes specifications for oral, inhalation, and parenteral drug products. Dermal drug products specifications are not provided, but recent publications provide recommendations. Based on the ICH guideline, the United States Pharmacopoeia (USP) has published general chapters <232> “Elemental Impurities — Limits” and <233> “Elemental Impurities — Procedures”.

As of January 1, 2018, all NDAs and ANDAs for drug products with an official USP monograph are required to meet the requirements of USP 232 and USP 233. NDAs and ANDAs for non-compendial drug products are expected to follow the ICH Q3D guidance.

Element Classification

Following extensive toxicological study, the FDA has grouped elemental impurities into three classes.

  • 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)
    • Relatively low toxicities (high PDEs) by oral administration, but may require consideration in the risk assessment for inhalation and parenteral routes
  • Other elements do not have established PDEs but may need to be considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W, and Zn
Potential Sources of Elemental Impurities

Elemental impurity sources in pharmaceuticals can be categorized in four main ways:

  • 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 product
  • Contamination or leaching from manufacturing and processing equipment
  • Leaching from container closure systems

USP <665> provides a risk assessment and procedures for testing manufacturing and processing equipment. Extractable and leachable testing of container closure systems is performed under USP <661.2>.

Elemental Impurities Testing at EKG Labs

EKG Labs provides elemental impurity testing services to the pharmaceutical and medical device industries. Using Inductively Coupled Plasma Mass Spectrometry (ICP-MS), EKG Labs is capable of detecting elemental impurities down to an analytical parts-per-trillion level. EKG Labs can perform USP compendial and ICH testing for any or all of the elements listed above. We have experience demonstrating precise recovery even in most challenging matrices and can extract or digest your unique sample as necessary. EKG Labs can also develop and validate a risk-based, product-specific method in order to monitor one or more targeted elements.

While medical devices and other products may not require direct compliance with USP 232/USP 233 or ICH Q3D testing, EKG Labs prides itself on developing comprehensive extractable and leachable studies, many of which include ICP-MS trace metal analysis. An EKG Labs elemental survey scan can analyze over 60 elements! At EKG Labs we work with you to provide a customized solution to your impurity identification and analysis needs.

To read an EKG case study about how elemental impurities analysis identified the root cause of a syringe discoloration click here.

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