Elemental impurities
• Elemental impurities are metallic contaminants in drug products that
can be toxic to patients. They can occur naturally, be added
intentionally, or be introduced inadvertently. Sources of elemental
impurities include:
Processing equipment: Equipment used in processing, holding,
transferring, and packaging can contaminate drugs.
Catalysts: Residual catalysts added intentionally in synthesis can
contaminate drugs.
Environmental contaminants: Environmental contaminants can
contaminate drugs.
• Elemental impurities can be metals or non-metals, and some are
essential elements or compounds that play a physiological role in the
human body. However, when their concentrations exceed permitted
levels, they can develop an illness profile or a non-desirable situation.
• To analyze elemental impurities, the most commonly used techniques
are inductively coupled plasma–mass spectrometry (ICP–MS) or
inductively coupled plasma–optical emission spectroscopy (ICP–OES).
Quality Guidelines (Q3A-Q3D: impurities)
• Q3A(R2) Impurities in New Drug Substance
• Q3B (R2) Impurities in New Drug Products
• Q3C(R5) impurities: Guideline for Residual Solvent
• Q3D Guideline for Elemental Impurities
Classification of elemental impurities
• Elemental impurities are classified into three classes based on their
toxicity and likelihood of occurrence in a drug product.
Class 1: These impurities are highly toxic across all routes of
administration. Examples include arsenic (As), cadmium (Cd), mercury
(Hg), and lead (Pb).
Class 2: These impurities are toxic to varying degrees depending on the
route of administration. Class 2 is further divided into two sub-classes,
2A and 2B:
Class 2A: These elements have a relatively high probability of
occurrence in the drug product. Examples include cobalt (Co), nickel
(Ni), and vanadium (V).
• Class 2B: These elements have a reduced probability of occurrence in
the drug product. Examples include silver (Ag), gold (Au), iridium (Ir),
osmium (Os), palladium (Pd), platinum (Pt), rhodium (Rh), ruthenium
(Ru), selenium (Se), and thallium (Tl).
• Class 3: These impurities have relatively low toxicity by the oral route
of administration. Examples include barium (Ba), chromium (Cr),
copper (Cu), lithium (Li), molybdenum (Mo), antimony (Sb), and tin
(Sn).
• Other Elements: some elemental impurities for which PDEs have not
been established due to their low inherent toxicity and or differences
in regional regulations are not addressed in this guideline.(Eg Al for
compromised renal function; Mn and Zn for patients with
compromised hepatic function),or quality consideration (Eg presence
of W impurities in therapeutic proteins) for the final drug product.
Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn,
Na, W, and Zn.
control of elemental impurities