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Elemental impurities per USP and ICH q3d guidelines

29 July 2024

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

ElementClassOral PDE(µg/day)Parenteral PDE(µg/day)Inhalation PDE (µg/day)
Cadmium1523
Lead1555
Arsenic115152
Mercury13031
Cobalt2A5053
Vanadium2A100101
Nickel2A200206
Thallium2B888
Gold2B3003001
Palladium2B100101
Iridium2B100101
Osmium2B100101
Rhodium2B100101
Ruthenium2B100101
Selenium2B15080130
Silver2B150157
Platinum2B100101
Lithium355025025
Antimony31,2009020
Barium31,400700300
Molybdenum33,0001,50010
Copper33,00030030
Tin36,00060060
Chromium311,0001,1003

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.

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