Methods / Elemental impurities
Elemental impurities
Are there heavy metals, and at what concentration?
| Technique | Microwave digestion followed by ICP-MS |
| Interference control | Collision or reaction cell |
| Routine scope | Arsenic, cadmium, lead, mercury; extended panels on request |
| Assessed against | ICH Q3D(R2) permitted daily exposure by route |
| Reported with | Numeric LOD and LOQ per element |
Elemental impurities are determined by inductively coupled plasma mass spectrometry after microwave digestion, reaching parts per billion and below. ICH Q3D(R2) classifies elements by toxicity and likelihood of occurrence, with arsenic, cadmium, lead and mercury forming Class 1. Energy-dispersive X-ray fluorescence is three to six orders of magnitude less sensitive and is a screening technique, not a compliance method.
Applied to: Peptides, Supplements, Cosmetics, Botanicals. Reference: USP <232>, USP <233>, ICH Q3D(R2).
The sample is decomposed in concentrated nitric acid, often with hydrogen peroxide or hydrofluoric acid depending on matrix, in a sealed vessel under microwave heating. Complete digestion matters: organic material left undecomposed carries analyte with it and suppresses recovery.
The digest is nebulised into an argon plasma at roughly 6000 to 10000 kelvin, which atomises and ionises essentially everything, and the ions are separated by mass to charge ratio. A collision or reaction cell removes polyatomic interferences, which is essential for arsenic at mass 75 where argon chloride overlaps directly.
Quantitation is against matrix-matched calibration standards with internal standards to correct for drift and matrix suppression, and recovery is verified with a spiked sample in every run.
Class 1 covers arsenic, cadmium, mercury and lead: significantly toxic, with limited or no therapeutic use, and plausible in any pharmaceutical supply chain. These are evaluated for every product.
Class 2A covers cobalt, nickel and vanadium, toxic and with a relatively high probability of occurrence, and is evaluated for all routes. Class 2B covers elements with low occurrence probability, evaluated only where intentionally added. Class 3 covers elements of low oral toxicity that still require assessment for parenteral and inhalation routes.
Permitted daily exposures differ by route by orders of magnitude. Lead is 5 micrograms per day orally and also 5 parenterally; arsenic is 15 micrograms per day orally and 15 parenterally; cadmium is 5 orally and 2 parenterally. A supplement result and an injectable result are therefore not interchangeable even for the same measured concentration.
| Element | Oral | Parenteral | Inhalation |
|---|---|---|---|
| Cadmium | 5 | 2 | 3 |
| Lead | 5 | 5 | 5 |
| Arsenic | 15 | 15 | 2 |
| Mercury | 30 | 3 | 1 |
Energy-dispersive X-ray fluorescence irradiates the sample and reads the characteristic emission of each element. It needs almost no preparation, is fast and inexpensive, and is genuinely useful for sorting materials or flagging gross contamination.
Its detection limits sit in the parts per million range for these elements, while ICP-MS reaches parts per trillion. When a permitted concentration is at parts per billion, an XRF result reading not detected is entirely consistent with a sample that exceeds the limit several times over. The instrument simply cannot see down to where the question lives.
USP <233> specifies ICP-MS or ICP-OES as the compendial procedures for elemental impurities, with alternative methods permitted only where validated to demonstrate equivalent performance. A screening result presented as a compliance result is the substitution of one method's convenience for another's sensitivity.
| Speciation. Total arsenic does not distinguish inorganic arsenic from the far less toxic organic forms. |
| Organic contaminants, solvents and pesticides. |
| Microbiological quality and endotoxin. |
Every method has a blind spot, and the blind spots are why a certificate lists what was not determined alongside what was. A reader who sees only results will read silence as reassurance.
Is XRF good enough for heavy metals testing?
For screening, yes. For a compliance statement against ICH Q3D limits, no. XRF detects at parts per million while the limits sit at parts per billion, so a not-detected result from XRF is compatible with a sample that fails.
Which elements are tested as standard?
The ICH Q3D Class 1 set: arsenic, cadmium, lead and mercury. Class 2A elements such as cobalt, nickel and vanadium are added where the route of administration or the supply chain justifies it.
Do supplement and injectable limits differ?
Substantially. Cadmium is permitted at 5 micrograms per day orally but 2 parenterally, and mercury at 30 orally against 3 parenterally. The same concentration can pass in one route and fail in another.
Does the result distinguish inorganic from organic arsenic?
Not by default. Standard ICP-MS reports total arsenic. Speciation requires a chromatographic separation coupled to the ICP-MS and is a separate determination.
References
- ICH Q3D(R2), Guideline for Elemental Impurities
- USP <232>, Elemental Impurities Limits
- USP <233>, Elemental Impurities Procedures
Sources
Related determinations
Updated 2026-09-01