Elemental impurities are traces of metals carried from raw materials, residual catalysts, manufacturing equipments, process water, excipients, containers that can be observed in finished drug products.
These elemental impurities do not have any therapeutic effect and is harmful to patients due to their toxicity beyond certain limit.
The presence of trace elements were tested classically by using USP's Heavy metals test, <231> , which uses as a colorimetry test by forming as a sulphide precepitate with elements.
In the last decade, PDE (permitted daily exposure) of almost all elements are found which leads to monitor and control the individual elements in the drugs by measuring their level by using modern instruments like ICP OES, ICP MS etc.
ICH developed a guideline specifically on Elemental impurities as Q3D and list the PDE values for each element. Based on PDE value and the route of administration ( orals, parenteral, nasal) values are differently set for each elemental impurity.
Following ICH Q3D guideline, USP has developed new standards in general chapters, <232> Elemental impurities - Limits and <233> Elemental Impurities - Procedures inplace of <231>.
Elements are classified into 3 categories based in their toxicity data.
Class 1 elements - To be avoided in the process as they're human toxicants, includes Arsenic, Lead, Cadmium and Mercury.
Class 2 have two sub-classes.
Class 2A elements have high probability of occurrence in the drug products. The presence of these elements are common in oral and parenteral drugs. Class 2A elements includes Cobalt, Nickel and Vanadium.
Class 2B elements have less probability to occur due to their low abundance and low potential to co-elute with other materials during crystallization.The elements in this class ares Silver, Gold, Iridium,o Osmium, Palladium, Platinum, Rhodium, Ruthenium, Seleniuma and Thallium.
Class 3: The elements in this class have low toxicity and the PDE's are high, more than 500 MCG/day.
All the drug products of oral administration shall be screened for class 1, 2A elements.
All the drug products of parenteral and nasal products shall be screened for class 1, 2A and some of class 3 elements.
Class 3 elements shall be tested if they are intentionally added in the manufacturing process.
Initially risk assessment must be made for the drug products based on the drug substance, excipients, container closure system, equipment used etc. for possible presence of elemental impurities. On assessment, if there are no chances of presence of elemental impurities, only class 1, class 2A will be screened for oral products and some of class 3 elements will be screened additionally for parenteral and nasal products.
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