How about the New Regulations for Elemental Impurities?
Question & Answer (Q&A) White Paper

Q: At what stage can these elemental impurities be introduced?

A: Metal impurities in pharmaceutical drug substances/products may originate from several sources like metal catalysts and metal reagents used during the synthesis of the active pharmaceutical substance and the excipients, impurities from manufacturing equipment, water or originating from the container closure system. This is shown in the Figure below, extracted from the ICH Q3D Guideline.


Q: Do these elemental impurities need monitoring?

A: These impurities have to be monitored in pharmaceutical laboratories for basically two reasons. Metals known to be toxic have to be controlled during the entire manufacturing process from testing of source material to quality control of finished drugs. Also, metals can affect the stability of a formulation and catalyze the degradation of drug substances.

Q: How is heavy metal testing being performed at this moment?

A: The current heavy metals limit test - as stated in pharmacopeias EP 2.4.8 and USP 231 – has been the main reference for elemental impurities testing for more than a hundred years. Basically, the method has a limit of about 10 ppm and is based on the reaction of the present ‘metal impurities’ with thioacetamide to form sulfides. The intensity of the colored sulfide precipitate is compared between the test solution and a reference lead standard. It is assumed that each of the specified metal impurities will react in the same way as the lead standard. However, it must be emphasized that the performance of this heavy metals limit test is not adequate for the purpose of controlling the levels of potentially toxic elements and consequently needs to be replaced by modern instrumental methods.


Q: What are the changes in the regulatory landscape?

A: Recent changes in the European Pharmacopoeia (EP), the United States Pharmacopoeia (USP) and ICH require companies to adopt new strategies for Heavy Metals analysis both in Europe and in the United States. Compared to the original Heavy Metal analysis, the new strategies eliminate the specificity issue, extend the range of elements detected and decrease detection levels. With the new standards, drug product/substance manufacturers will have to ensure that all their products adhere to the new requirements. Simultaneously, these companies also need to ascertain the quality of product components provided by their suppliers.



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