ICP-MS (elemental impurities)

What does ICP-MS do to a sample?

The sample is first digested, usually in strong acid in a closed vessel heated by microwaves, so every element ends up dissolved. The solution is sprayed into an argon plasma, which breaks molecules apart and strips electrons from the atoms, and the positive ions pass into a mass spectrometer that counts them at each element's characteristic isotope masses. Counts are converted into concentrations against calibration standards.

A 2024 validation study for elemental impurities in a tablet product used this sequence, noting that microwave digestion with ICP-MS is widely used because it is more sensitive than ICP optical emission spectrometry or atomic absorption, and choosing digestion conditions that reduce the loss of volatile mercury (Hao and colleagues, Journal of Analytical Methods in Chemistry, 2024).

Which elements matter, and who sets the limits?

ICH Q3D, the international guideline on elemental impurities, sorts elements into classes by toxicity and likelihood of being present. Class 1 is arsenic, cadmium, mercury and lead, which the guideline calls human toxicants with limited or no use in manufacture, usually entering through materials such as mined excipients. Class 2A is cobalt, nickel and vanadium. Class 2B covers elements such as palladium, platinum and silver, which may be left out of a risk assessment unless intentionally added. Class 3 includes copper, chromium, tin and others with low oral toxicity (ICH Q3D(R2), 2022).

ICH Q3D sets limits as permitted daily exposures (PDEs) in micrograms per day, with separate values for oral, parenteral and inhalation routes. The table shows the Class 1 values from Appendix 2 of the guideline.

A PDE is a quantity per day, not a concentration. ICH Q3D converts it into a concentration limit by dividing by the daily intake of the product (its simplest option assumes 10 grams a day), and defines a control threshold at 30% of the PDE, below which additional controls are not required. The same PDE can therefore give different µg/g limits for different products, so a certificate should state the concentration limit it used.

How do USP <232> and <233> relate to ICH Q3D?

In the United States, USP General Chapter <232> sets elemental impurity limits and <233> sets procedures. A 2020 study of elemental impurities in drug samples notes that a version of <232> harmonised with ICH Q3D became official in December 2017, that <232> specifies 24 elemental impurities, and that <233> describes determination by either ICP optical emission spectrometry or ICP-MS (Heliyon, 2020). ICH Q3D itself says pharmacopoeial procedures or suitable alternatives should be used, and that unless otherwise justified the test should be specific for each element identified for control.

Why was the old heavy metals test replaced?

The traditional heavy metals test was a colour reaction that gave one combined result for several metals without saying which were present. A 2021 study of elemental impurities in calcium carbonate notes that ICH Q3D moved control from the traditional heavy metals test to a risk-based assessment using modern instruments, and that colorimetry is not adequate for controlling low levels of elemental impurities (Frontiers in Chemistry, 2021). ICP-OES and ICP-MS both measure each element separately.

Are elemental impurities a concern for synthetic peptides?

Synthetic peptides are in scope. The European Medicines Agency's draft guideline on synthetic peptides says synthetic peptides are included in the scope of ICH Q3D, lists elemental impurities among typical specification tests (for example, where a metal catalyst is used), and classes them with process reagents and residual solvents as non-peptide impurities (EMA draft guideline on synthetic peptides, 2023). In regulated manufacture the starting point is a risk assessment rather than routine testing of every batch for every element.

Does Tested.ph offer heavy metals testing?

No, and it is not planned. The standard package covers identity, purity and amount, with endotoxin as an option, all performed by the partner laboratory when testing opens. See what a peptide test can and cannot tell you for the full list of what a record covers.