Elemental impurities per USP and ICH q3d guidelines
Elemental impurities in a drug product may arise from several sources. These sources may include impurities in starting raw material, reagents, catalysts intentionally added during synthesis, contaminants due to interaction with components in the manufacturing processes or container closure systems. To keep the number of elemental impurities within the limits provided by United States Pharmacopeia (USP) 232, the concentration of these impurities should be monitored. The raw materials should be tested before they are used for manufacturing. The manufacturing components coming in contact with the drug product should also be tested for these elemental impurities since they can also be a contributing factor, especially if exposed to elements further the process, closer to the final product. These elemental impurities, —in addition to having potential toxicological effects, —may adversely impact a drug’s stability, leading to loss of efficacy or other unintended effects.
USP 232 and ICH Q3D guidelines provide the limit of each element’s permitted daily exposure (PDE) in final parenteral products, oral products and inhalation products. The elemental impurities are classified per ICH Q3D in three classes. Detailed below, the classification scheme is intended to focus the risk assessment on the elements that are most toxic but have reasonable probability of being included in the drug product.
Class I: Elemental impurities of significant toxicity
Class 2: Elemental impurities that are toxic to a greater or lesser extent based on route of administration include:
2A: Elements with a high probability of occurrence, thus requiring risk assessment. The elements included in Class 2A are cobalt, nickel and vanadium.
2B: Elements with a low probability of occurrence due to their low abundance. The elements in class 2B are silver, gold, iridium, osmium, palladium, platinum, rhodium, ruthenium, selenium, and thallium
Class 3: Elemental impurities of relatively low toxicity include barium, chromium, copper, lithium, molybdenum, antimony and tin.
Per Table A.2.1 of ICH Guidelines for Elemental Impurities
Permitted Daily Exposure for Elemental Impurities
| Element | Class | Oral PDE(µg/day) | Parenteral PDE(µg/day) | Inhalation PDE (µg/day) |
|---|---|---|---|---|
| Cadmium | 1 | 5 | 2 | 3 |
| Lead | 1 | 5 | 5 | 5 |
| Arsenic | 1 | 15 | 15 | 2 |
| Mercury | 1 | 30 | 3 | 1 |
| Cobalt | 2A | 50 | 5 | 3 |
| Vanadium | 2A | 100 | 10 | 1 |
| Nickel | 2A | 200 | 20 | 6 |
| Thallium | 2B | 8 | 8 | 8 |
| Gold | 2B | 300 | 300 | 1 |
| Palladium | 2B | 100 | 10 | 1 |
| Iridium | 2B | 100 | 10 | 1 |
| Osmium | 2B | 100 | 10 | 1 |
| Rhodium | 2B | 100 | 10 | 1 |
| Ruthenium | 2B | 100 | 10 | 1 |
| Selenium | 2B | 150 | 80 | 130 |
| Silver | 2B | 150 | 15 | 7 |
| Platinum | 2B | 100 | 10 | 1 |
| Lithium | 3 | 550 | 250 | 25 |
| Antimony | 3 | 1,200 | 90 | 20 |
| Barium | 3 | 1,400 | 700 | 300 |
| Molybdenum | 3 | 3,000 | 1,500 | 10 |
| Copper | 3 | 3,000 | 300 | 30 |
| Tin | 3 | 6,000 | 600 | 60 |
| Chromium | 3 | 11,000 | 1,100 | 3 |
Labcorp has intensive capabilities in elemental analysis, with of over 40 years of industry experience evaluating medical devices and pharmaceutical products.
- Our laboratory is equipped with ICP/MS, inductively coupled plasma optical emission spectrometry and atomic absorption spectroscopy (ThermoFisher Scientific iCE 3500 GF)
- Our methods are fully validated to support the evaluation of elemental impurities
- Our in-house toxicologists can provide guidance for this evaluation and assist in the interpretation results to specific applications
Our analytical instrumentation, along with our closed vessel microwave digestion system, provides for the low detection levels (parts per billion (ppb)) of the elements. We have extensive experience with a variety of sample types including liquid, solid, polymer and biological matrices.