ICH Q3D: Elemental Impurities and the Risk Assessment

ICH Q3D governs elemental impurities in drug products. It replaced the old USP <231> heavy metals wet-chemical test, which detected a handful of elements poorly and said nothing about the rest.

The replacement is not another test. It is a risk assessment, and that is the part organisations underestimate.

Permitted daily exposures

Q3D sets a permitted daily exposure (PDE) in µg per day for each element, varying by route of administration: oral, parenteral and inhalation, with inhalation generally the most restrictive.

Elements are grouped by toxicity and likelihood of occurrence:

• Class 1: arsenic, cadmium, mercury, lead. Human toxicants with limited use in manufacturing. Always assessed.
• Class 2A: cobalt, nickel, vanadium. Relatively high probability of occurrence, so always assessed.
• Class 2B: elements with low probability of occurrence due to low abundance, assessed only if intentionally added.
• Class 3: relatively low toxicity by oral route, but requiring assessment for parenteral and inhalation.

The three options for setting limits

Option 1. A common permitted concentration across components, based on a maximum daily dose of 10 g per day. Simple, and conservative.

Option 2a. Permitted concentration calculated from the product's actual maximum daily dose. Less conservative than Option 1 where the dose is small.

Option 2b. Limits set per component, allowing a higher concentration in one component where others contribute little. Requires knowing every component's contribution.

Option 3. Testing the finished product against the PDE directly.

Most products use Option 1 or 2a. Option 2b earns its complexity only where a single excipient would otherwise fail.

Where elements actually come from

The risk assessment has to consider every route in, and the one that gets missed is rarely the drug substance.

• The drug substance itself, and catalysts used in its synthesis. Palladium and platinum residues from catalytic steps.
• Excipients. Mined excipients such as talc, magnesium stearate, calcium carbonate and titanium dioxide carry naturally occurring elements, and their levels vary by source.
• Water.
• Manufacturing equipment. Stainless steel contributes chromium, nickel and iron, particularly with abrasive processes or long contact times.
• Container closure. Glass contributes, and this matters most for parenterals in prolonged contact.

A risk assessment that covers the drug substance and stops has skipped the sources most likely to matter.

What the assessment produces

A documented conclusion, per element, that the level is below the control threshold of 30% of the PDE, with data supporting it. Where it is not, you establish a control: a specification on a component, a supplier requirement, or finished product testing.

The conclusion belongs in the dossier, and a change to a supplier or a component source is a change to its inputs, which makes it a change control question.