ICH Q3D elemental impurities: behind this phrase, which anyone working in QA, QC or Regulatory Affairs meets in every dossier and every audit, sits the guideline that rewrote the control of metals and other toxic elements in medicines. The current version, ICH Q3D(R2), has applied in Europe since 24 September 2022 and sets Permitted Daily Exposures (PDEs) for 24 elements by the oral, parenteral, inhalation and — new in R2 — cutaneous routes. In this guide you will find the complete list of elements by class, the PDEs of the most critical ones, the four risk assessment options and the mistakes inspectors challenge most often.
ICH Q3D elemental impurities list: the 24 elements by class
The heart of the guideline is the classification of elements into four classes, built on two criteria: toxicity and the likelihood of occurrence in the medicinal product. This classification tells you which elements must always be considered in the risk assessment and which only if you introduce them deliberately into the process.
- Class 1 — As, Cd, Hg, Pb. The four most toxic elements for humans, whose use in pharmaceutical manufacturing is limited or absent. They must be evaluated in every risk assessment, for all routes of administration.
- Class 2A — Co, Ni, V. Toxic elements with a relatively high probability of occurrence in the product (equipment, excipients of mineral origin, environment). They too must always be evaluated.
- Class 2B — Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, Tl. Toxic elements with low natural abundance: they enter the assessment only if intentionally added, typically as synthesis catalysts.
- Class 3 — Ba, Cr, Cu, Li, Mo, Sb, Sn. Relatively low oral toxicity (oral PDE above 500 µg/day), but to be considered for the parenteral and inhalation routes or if intentionally added.
Beware of a frequent misunderstanding: the class is not an absolute measure of hazard, but a guide to deciding when an element enters the assessment. A Class 2B element added as a catalyst must be treated with the same rigour as a Class 1 element.
PDEs: what they are and the values of the most critical elements
The PDE (Permitted Daily Exposure) is the maximum daily dose of an element a patient can take without appreciable risk, expressed in µg/day and differentiated by route of administration. The values are set in Appendix 2 of the guideline; these are the most relevant in practice:
| Element (Class) | Oral PDE (µg/day) | Parenteral PDE (µg/day) | Inhalation PDE (µg/day) |
|---|---|---|---|
| Arsenic — As (1) | 15 | 15 | 2 |
| Cadmium — Cd (1) | 5 | 2 | 3 |
| Mercury — Hg (1) | 30 | 3 | 1 |
| Lead — Pb (1) | 5 | 5 | 5 |
| Cobalt — Co (2A) | 50 | 5 | 3 |
| Nickel — Ni (2A) | 200 | 20 | 6 |
| Vanadium — V (2A) | 100 | 10 | 1 |
Two practical observations. First: parenteral and inhalation PDEs are almost always stricter than oral ones, so the same excipient can be acceptable in a tablet and critical in an injectable. Second: revision R2 introduced Appendix 5 with limits for the cutaneous and transcutaneous route, closing a gap that for years had forced companies into case-by-case justifications for topical products.
Q3D limits and appendices change through revisions and corrigenda, and noticing late means redoing the risk assessment. With The Pragmatic GMP, GuideGxP's free weekly newsletter, you get regulatory updates on impurities, ICH and GMP already translated into operational actions: subscribe and be ready for the next revision.
The risk assessment: the four options and the 30% control threshold
Once the elements to evaluate are identified, Q3D asks you to estimate the patient's actual exposure and compare it with the PDE. To convert PDEs into concentration limits on materials, Section 7 offers four approaches:
- Option 1: permitted concentrations common to all components, assuming a daily product dose of up to 10 g. The simplest and most conservative route.
- Option 2a: the same common concentrations, but calculated on the product's actual maximum daily dose — useful when the dose is well below 10 g.
- Option 2b: component-specific limits, provided the sum of the contributions of all components stays below the PDE. Maximum flexibility, maximum data requirement.
- Option 3: direct analysis of the finished product and comparison with the PDE.
The result of the comparison is read against the control threshold: if the total estimated exposure from all sources stays consistently below 30% of the PDE, and the risk assessment demonstrates this with solid data, no additional routine controls are needed. Above that threshold, controls must be established — a material specification, periodic or batch-by-batch testing — to ensure the PDE is not exceeded.
As for the sources to examine, the assessment must systematically cover the API and excipients (with attention to those of mineral origin), synthesis catalysts and reagents, product-contact process equipment, container-closure systems and utilities such as process water. Analytically, the reference methods are those of the harmonised pharmacopoeial chapters — USP <232>/<233> and Ph. Eur. 2.4.20/5.20 — typically using ICP-OES or ICP-MS techniques.
The most common findings in inspections
- A “photocopy” risk assessment from the supplier: the excipient's Q3D statement is filed away without assessing the cumulative contribution of all components in your own product.
- Class 2B ignored even though a palladium catalyst appears in the API synthesis route.
- Maximum daily dose underestimated or not updated after a posology variation, leaving Option 2a limits no longer valid.
- No periodic re-evaluation: the risk assessment is frozen at registration while suppliers, sites and processes have changed.
- Topical products with no reference to Appendix 5 of R2, still anchored to pre-2022 justifications.
GuideGxP recommendation
Treat the Q3D risk assessment as a living document, not a registration annex. The method we see working in audits: an element-by-source matrix for each product, with the estimated contribution of API, excipients, equipment and packaging, the comparison against 30% of the PDE and the documented decision (no control, periodic control, specification). Link the matrix to change control: every change of supplier, synthesis route or posology must reopen it. And when exposure exceeds the control threshold, choose the most upstream control point possible — a material specification before finished-product testing.
If you want a ready-made framework, our guide Elemental and Mutagenic Impurities and Nitrosamines: Risk Assessment under ICH Q3D and M7 includes matrix templates, worked calculations for the four options and the structure of an inspection-ready Risk Management Summary.
