FDA has published an 11-page draft guidance on elemental impurities that provides recommendations regarding their control in human drug products marketed in the United States. The draft document is set up in consistence with ICH Q3D, published in August 2015 by the ICH (International Council for Harmonisation). The FDA draft guidance intends to help manufacturers to comply with ICH and United Pharmacopeial Convention (USP) standards.
The FDA Guidance “Elemental Impurities in Drug Products” makes recommendations on:
- How applicants should submit new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for noncompendial drug products should control elemental impurities according to ICH Q3 (risk-based approach, permitted daily exposure (PDE)).
- How manufacturers of compendial drug products that are not marketed under an approved NDA or ANDA can comply with USP General Chapters <232> and <233>.
- How holders of NDAs and ANDAs for compendial products should report changes in chemistry, manufacturing and controls specifications to FDA to comply with USP General Chapters <232> and <233> and 21 CFR 314.70.
- How manufacturers of noncompendial drug products that are marketed without an approved NDA or ANDA should control elemental impurities.
This guidance does not include:
- Specific recommendations on the evaluation of toxicity data for potential elemental impurities, application of a risk-based approach to control elemental impurities in drug products, or PDE. For this information, reference is made to ICH Q3D.
- Biological products in general.
Holders of approved or pending biologics license applications should also refer to ICH Q3D.
USP worked closely with ICH to align its new General Chapters with ICH Q3D. General Chapter <232> also endorses a risk-based approach to control elemental impurities. Of the 24 elements for which ICH Q3D provides a PDE, 15 are covered by General Chapters <232> and <233>. The ICH Q3D PDE values for those 15 elements were adopted in the General Chapters.
In general it can be said, that FDA recommends manufacturers of any US marketed drug to follow ICH Q3D recommendations. When preparing new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for drugs with a USP monograph drugmakers should comply with USP General Chapters <232> and <233> by their implementation date. For impurities not specified therein, FDA expects drugmakers to follow ICH Q3D.
FDA: Guidance for Industry: Elemental Impurities in Drug Products