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The control of elemental impurities in drug products is critical for patient safety. The general section of USP〈232〉 defines the limits and classification of elements, while USP〈233〉 defines the analytical procedures to be used in determining these impurities.
USP〈232〉 classifies elements into four classes based on their toxicity profiles and the likelihood of their occurrence in drug manufacturing.
Class 1: Elements Posing the Highest RiskThese are elements with high toxicity whose use in drug manufacturing is restricted or prohibited. They must be evaluated on a product-by-product basis.
These are elements that are relatively common in pharmaceutical manufacturing and may exhibit toxic effects. They are addressed as a priority in risk assessments.
These elements tend to occur naturally at low levels. Unless intentionally added during the manufacturing process, they can generally be excluded from the assessment.
These are elements with relatively low toxicity when administered orally. They should be evaluated separately in products administered parenterally or by inhalation.
The limits are based on the PDE (Permitted Daily Exposure) approach. The table below summarizes the applicable PDE values for orally administered drug products. Different PDE values apply to products administered parenterally or by inhalation.
| Element | Class | Oral PDE (µg/day) |
|---|---|---|
| Cadmium (Cd) | 1 | 5 |
| Lead (Pb) | 1 | 5 |
| Arsenic (As) | 1 | 15 |
| Mercury (Hg) | 1 | 30 |
| Vanadium (V) | 2A | 10 |
| Cobalt (Co) | 2A | 50 |
| Nickel (Ni) | 2A | 200 |
| Thallium (Tl) | 2B | 8 |
| Gold (Au) | 2B | 100 |
| Iridium (Ir) | 2B | 100 |
| Osmium (Os) | 2B | 100 |
| Palladium (Pd) | 2B | 100 |
| Platinum (Pt) | 2B | 100 |
| Rhodium (Rh) | 2B | 100 |
| Ruthenium (Ru) | 2B | 100 |
| Silver (Ag) | 2B | 150 |
| Selenium (Se) | 2B | 150 |
| Barium (Ba) | 3 | 1400 |
| Antimony (Sb) | 3 | 1200 |
| Copper (Cu) | 3 | 1300 |
| Lithium (Li) | 3 | 550 |
| Molybdenum (Mo) | 3 | 3000 |
| Tin (Sn) | 3 | 6000 |
| Chromium (Cr) | 3 | 11,000 |
Note: PDE values vary depending on the route of administration (oral, parenteral, inhalation). Refer to the original text of USP〈232〉 for current values.
USP〈233〉 defines two basic analytical procedures to be used in the determination of elemental impurities.
Procedure 1: ICP-OESInductively Coupled Plasma Optical Emission Spectrometry is based on the principle of exciting the elements in the sample within a plasma environment and measuring the light they emit according to its wavelength.
Procedure 2: ICP-MSInductively Coupled Plasma Mass Spectrometry is based on the principle of separating and measuring elements ionized in the plasma according to their mass-to-charge ratios.
USP〈233〉 defines specific system suitability criteria to demonstrate the validity of the analytical method:
