Elemental impurities in drug products may arise from several sources:

  1. Present as residual catalysts that were added intentionally in synthesis
  2. Present as impurities through interactions with processing equipment or the container/closure systems
  3. They may be present in components of the drug product.

Elemental impurities do not provide any therapeutic benefit to the patient, but they may also adversely affect drug stability and shelf-life and they may lead to unwanted side effects for the end user. As such, the levels  of elemental impurities must be monitored and controlled in drug substances, intermediates, excipients, and final drug products.

The United States, United States Pharmacopeia (USP) introduced new general chapters USP<232> and USP<233> to monitor and control elemental impurities in lieu of the 100-year-old colorimetric technique defined in the chapter USP<231>, also known as “Heavy Metals testing”. USP General Chapters specifications have followed the International Conference on Harmonization (ICH) limits established in the Guideline for Elemental Impurities Q3D. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.

USP<232> includes a more comprehensive range of analytes, including catalysts and elemental contaminants from raw materials, manufacturing processes, the environment, and container closure systems (CCS). It is a risk-based approach to ensuring regulatory compliance. Metal elements are classified into three classes based on their toxicity and likelihood of occurrence. The classification scheme is intended to focus the risk assessment on those elements that are the most toxic but also have a reasonable probability of inclusion in the drug product.

ICHQ3D and USP<232> provide guidelines on Permitted Daily Exposures (PDEs) for elemental impurities. Permitted daily exposures (PDEs) for each element (Class 1, 2A, 2B, and 3) and the maximum allowable daily dosage of the drug product can be used for the evaluation of the permitted concentration of each element in that specific drug product.

The toxicity of an elemental impurity is related to its extent of exposure (bioavailability). The extent of exposure has been determined for each of the elemental impurities of interest for three routes of administration: oral, parenteral, and inhalational. These limits are based on chronic exposure.

The USP<233> chapter defines two analytical procedures for the evaluation of the levels of the elemental impurities. The chapter also describes criteria for acceptable alternative procedures (Limit Test procedures and Quantitative procedures). In the chapter, the use of modern instrumentation such as multi-element ICP-MS and ICP-OES is recommended.

CS Analytical has experts with years of knowledge and experience and state-of-the-art instrumentation to assist with all your USP<232>/ USP<233> ICHQ3D Elemental Impurities testing (Trace Metals Analysis) requirements in a cGMP, FDA-regulated setting.