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FDA Issues New Draft Guidance on Elemental Impurities

Posted 30 June 2016 | By Michael Mezher 

FDA Issues New Draft Guidance on Elemental Impurities

The US Food and Drug Administration (FDA) on Thursday issued new draft guidance on elemental impurities in drugs, with the goal of helping manufacturers comply with recent International Council for Harmonisation (ICH) and United States Pharmacopeial Convention (USP) standards.

Specifically, the guidance is meant to help sponsors of new and generic drugs comply with standards established in USP General Chapters <232> Elemental Impurities – Limits and <233> Elemental Impurities – Procedures and ICH Q3D – Guideline for Elemental Impurities, which go into effect in 2018.

Elemental impurities are traces of metals that can end up in finished drug products. These impurities can come from multiple points in the manufacturing process, such as residual catalysts from a product's synthesis or from contact with manufacturing equipment, containers and other materials.

Because these impurities do not contribute to a drugs therapeutic effect, and in some cases can cause patients harm, FDA and other regulatory and standards bodies have developed guidelines to measure and control the presence of these impurities.


While both ICH Q3D and USP General Chapters <232> and <233> are scheduled to go into effect in 2018, FDA says it encourages manufacturers to comply with the standards as early as possible, as they "provide significant improvements over existing approaches."

"In general, FDA recommends that the manufacturer of any US marketed drug product follow ICH Q3D recommendations to establish appropriate procedures for identifying and controlling elemental impurities in the drug product based on risk assessment and product-specific considerations," FDA writes.

When preparing new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for drugs with a USP monograph, FDA says drugmakers should comply with USP General Chapters <232> and <233> by their implementation date. For impurities not specified in the General Chapters, FDA expects drugmakers to follow ICH's recommendations instead.

FDA also says it expects sponsors submitting new applications for both USP compendial and noncompendial drugs to comply with ICH Q3D.

For drugs sold without an approved NDA or ANDA, such as certain over-the-counter (OTC) products, FDA says manufacturers should comply with the General Chapters and ICH Q3D by the implementation date, and says manufacturers should ensure they maintain "appropriate documentation demonstrating compliance."

Additionally, FDA says that some sponsors may need to report changes to the agency if they must make changes to their product to comply with the new standards. However, FDA says it expects that most approved drugs will not exceed the impurity thresholds in either the General Chapters or ICH Q3D.

If a product does exceed the limits in the standards, FDA says the sponsor should either consider "whether higher limits for elemental impurities should apply to the drug product or whether manufacturing changes could reduce elemental impurity amounts."

However, "FDA recognizes that the requirements described in General Chapter <232> and the recommendations in ICH Q3D are not appropriate for all drug products," such as radiopharmaceuticals where an element that would be considered an impurity in another product may be intentionally added.



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