Elemental Impurities: The Risk-Based Approach

The U.S. Pharmacopeia (USP) intends to remove the existing wet chemistry heavy metals methods outlined in USP General Chapter <231> by January 2018. Although the existing wet chemistry methods have been in effect for nearly 100 years, the methods are non-specific and frequently fail to detect or underestimate the presence of some toxic elements that are potentially present in pharmaceutical ingredients. The USP requires Plasma Spectrometry (ICP-MS or ICP-OES) as the technique to screen and/or accurately quantitate the presence of any elemental impurities of interest.  From a compliance perspective, the new guidance for elemental impurities (USP<232>and ICH Q3D) only applies to the drug product.  There are currently two strategies to meet the requirements for elemental impurities, with the first being a risk-based approach.

ICH Q3D and FDA advocate the use of a risk-based approach for assessing and controlling the potential presence of elemental impurities in drug products and is the preferred filing strategy by regulatory agencies.


Manufacturers should consider all potential sources of elemental impurities, such as elements
intentionally added (catalysts), elements potentially present in the materials used to prepare drug product, and elements potentially introduced from manufacturing equipment or container closure systems. Manufacturers should then evaluate each elemental impurity likely to be present in the drug product determining the observed level of the elemental impurities and comparing it with the established Permitted Daily Exposure (PDE). If the risk assessment test results demonstrate that the elemental impurity levels are consistently less than the control threshold for all lots tested (defined as being 30% of established PDE in at least three lots of drug product [three registration batches or six pilot batches]), then no testing may be required for future manufactured batches.

Manufacturers should include a summary of the risk assessment in the documentation related to the control of elemental impurities. Alcami’s recommendation for risk assessment is to analyze three lots of the drug substance, three lots of two to three major excipients (plus any excipient of mining origin if >5% in the formulation), and three lots of drug product.  The Alcami risk assessment method demonstrates linearity, accuracy, precision, and sensitivity by performing limited validation studies (regulatory requires that the method for risk assessment should be validated, but the extent of validation and acceptance criteria will depend on the analytical procedure’s intended use).

  • Elements should be at a minimum those required by the ICH/USP
  • Linearity is part of system suitability
  • Accuracy/precision demonstrated by recovery single preparation at 3 levels [30%, 100%, and 200% of limit (option 1 or calculated)].  Acceptance criteria for recovery is 70 – 150%, for precision the %RSD of recovery results from all levels combined is NMT 20%
  • Sensitivity is demonstrated at 30% of the limit
  • At the client’s request, Alcami can provide a risk assessment report to support the FDA filing

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Topics: Regulatory Compliance Elemental Impurities