Heavy metal testing by ICP/MS

The final version of the ICH Q3D Guideline (Elemental Impurities) came out in December 2014. Threshold values were established for 24 different elements based on toxicological data for various exposure paths. In a risk assessment of the production process the manufacturer has to identify known and potential sources of impurities and test for these versus the limit values.

The purpose of the Guideline is to harmonize differing regulatory requirements under various regional regulatory regimes. However, there are considerable implementation differences between the USP and EP regulations regarding both the selection of elements and the setting of limit values.

The non-selective and interference-susceptible visual heavy metals testing procedure per USP <231> (Heavy Metals) is now outdated, being over 100 years old. For all new approvals in the US, the new chapters USP <232> (Elemental Impurities Limits) and USP <233> (Elemental Impurities Procedures) are already in place. This testing became mandatory in January 2018 for release studies of existing approvals and for all monographed active and inactive substances.

In these chapters, limit values are set for 15 elements in pharmaceutical products and examination by means of ICP/MS and ICP/OES established as a standard method. The scope of testing is determined in a risk assessment of the elements that could be naturally found in, added to or unknowingly end up in the final product. Therefore, analysis of all 15 elements is not necessarily required.

EP 5.20 (Metal catalysts or metal reagent residues) establishes limit values for 14 elements from metallic catalysts or reagents. Determination method requirements are regulated in EP 2.4.20 (Determination of metal catalysts or metal reagent residues).

A helpful risk assessment tool for the manufacturing process that gives you a quick overview of the presence or absence of many elements at low cost. This allows identification of elements of interest that can then be quantified as required.

Highly effective for obtaining an initial overview of content levels of specific elements. In the risk assessment process, for example, elements subject to control can be monitored to ensure they remain below a warning limit.

• ICH-Guideline Q3D (“Elemental Impurities”)
• USP <730> (“Plasma Spectrochemistry”)
• USP <232> (“Elemental Impurities – Limits“)
• USP <233> (“Elemental Impurities – Procedures“)
• EP 2.2.58 (“Inductively coupled plasma-mass spectrometry“)
• EP 5.20 (“Metal catalysts or metal reagent residues”)
• EP 2.4.20 (“Determination of metal catalysts or metal reagent residues”)

Our method allows precise determination of element content in conformance with the above regulations.

Both EP and USP require matrix validation to be performed to establish that the analysis method is specifically usable for the respective matrix. In the respective monographs there are precise specifications regarding the parameters to be conformed with. We would be glad to advise you in this area and send you a testing proposal.