Embracing Q3D: FDA's New Elemental Impurities Guidance

• By: Staff Editor
• Date: November 11, 2016
• Source: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm371025.pdf

The guidance applies to new finished drug products as defined in ICH Q6A and Q6B and new drug products containing existing drug substances.  However it does not apply to:

• Herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit.
• Products based on genes (gene therapy), cells (cell therapy), and tissue (tissue engineering).
• Drug products used during clinical research stages of development.

Elemental Impurities Classification

The elements included in this guidance are categorized into three classes based on their toxicity (permitted daily exposure) and likelihood of occurrence in the drug product. These are:

Class 1: Arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) are the elements included in this class. These elements are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Because of their unique nature, these four elements should be evaluated during the risk assessment, across all potential sources of elemental impurities and routes of administration.

Class 2: Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product.

• Class 2A elements have relatively high probability of occurrence in the drug product, thus should be evaluated in the risk assessment across all potential sources of elemental impurities and routes of administration. The class 2A elements are: cobalt (Co), nickel (Ni), and vanadium (V).
• Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they can be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients or other components of the drug product. The elemental impurities in class 2B include: silver (Ag), gold (Au), iridium (Ir), osmium (Os), palladium (Pd), platinum (Pt), rhodium (Rh), ruthenium (Ru), selenium (Se), and thallium (Tl).

Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 μg/day) but could warrant consideration in the risk assessment for inhalation and parenteral routes. The elements in this class include: barium (Ba), chromium (Cr), copper (Cu), lithium (Li), molybdenum (Mo), antimony (Sb), and tin (Sn).

Other elements: Some elemental impurities for which permitted daily exposure (PDEs) have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guidance. Some of the elements considered include: aluminum (Al), boron (B), calcium (Ca), iron (Fe), potassium (K), magnesium (Mg), manganese (Mn), sodium (Na), tungsten (W), and zinc (Zn).

While both Q3D and USP General Chapters <232> and <233> will be effective from January 1, 2018, FDA says it encourages companies to comply with the standards as early as possible, as they "provide significant improvements over existing approaches”.

Related Training:

Understanding and Implementing the New ICH/USP Elemental Impurity Guidelines