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ICH Q3D(R2) is the international guideline on elemental impurities in drug products. It sets a permitted daily exposure (PDE) for 24 elements and asks manufacturers to use a risk-based approach, built on ICH Q9 principles, to show that the total level of each relevant element in a finished product stays within control. It is a harmonised quality guideline, not a testing method: it tells you which elements to assess and what limits to apply, and leaves the choice of analytical technique to you. This page summarises the Final version (Step 4, adopted 26 April 2022) as described in the ICH text.
What ICH Q3D is and who issues it
ICH Q3D, “Guideline for Elemental Impurities”, is published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. The guideline has three parts: an evaluation of the toxicity data for each element, the establishment of a PDE for each element, and a risk-based approach to controlling elemental impurities in drug products. The ICH text notes that elemental impurities give no therapeutic benefit. They may be residual catalysts, or they may arise from processing equipment, container and closure systems, or the components of the product.
Regulators implement it through their own channels. For example, the US FDA announced the availability of the final guidance “Q3D(R2) Guideline for Elemental Impurities” in the Federal Register on 15 September 2022. That notice states that R2 revises Q3D(R1) (issued March 2020) to provide PDEs for the cutaneous and transcutaneous routes, and that the draft had included corrections to the gold, silver and nickel PDEs.
Scope and exclusions
As described in the ICH text, Q3D applies to new finished drug products and to new drug products containing existing drug substances. This includes products containing purified proteins and polypeptides, synthetic polypeptides, polynucleotides and oligosaccharides.
It does not apply to:
- herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, and whole blood and blood derivatives;
- dialysate that is not intended for systemic circulation;
- elements that are intentionally included in the product for therapeutic benefit;
- gene therapy, cell therapy and tissue engineering products;
- drug products used during the clinical research stages of development (the guideline says its principles can still be useful there).
The text also states that application to existing products was not expected before 36 months after ICH publication of the guideline.
The element classes
Section 4 sorts the elements into classes by toxicity and likelihood of occurrence in a drug product.
| Class | Elements | Character as described in the guideline |
|---|---|---|
| Class 1 | As, Cd, Hg, Pb | Human toxicants with limited or no use in manufacturing; evaluate in the risk assessment for all sources and routes. |
| Class 2A | Co, Ni, V | Relatively high probability of occurrence in the product; assess for all routes. |
| Class 2B | Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, Tl | Excluded from the risk assessment unless intentionally added. |
| Class 3 | Ba, Cr, Cu, Li, Mo, Sb, Sn | Relatively low oral toxicity; PDEs generally above 500 µg/day. |
PDE values by route
Appendix 2 (Table A.2.1) lists PDEs in µg/day for the oral, parenteral and inhalation routes, and R2 added Appendix 5 with cutaneous and transcutaneous PDEs. The Class 1 and 2A rows, as listed in Table A.2.1 of the R2 text, are:
| Element | Oral | Parenteral | Inhalation |
|---|---|---|---|
| Cd | 5 | 2 | 3 |
| Pb | 5 | 5 | 5 |
| As | 15 | 15 | 2 |
| Hg | 30 | 3 | 1 |
| Co | 50 | 5 | 3 |
| V | 100 | 10 | 1 |
| Ni | 200 | 20 | 6 |
Always take working values from the current guideline text rather than from a secondary table, because R2 itself corrected earlier values. Section 3.3 also recognises that levels above an established PDE may be acceptable in certain cases, such as intermittent dosing, short-term dosing of 30 days or less, or specific indications such as life-threatening conditions, unmet medical needs and rare diseases.
Risk assessment steps
- Identify potential sources (Section 5.3): intentionally added catalysts and reagents; the drug substance and excipients; manufacturing equipment; container closure systems; and water.
- Choose the elements to evaluate by route (Table 5.1): for the oral route, evaluate Class 1 and Class 2A; for parenteral and inhalation, evaluate Class 1, 2A and 3. Any Table 5.1 element that is intentionally added must be considered.
- Evaluate the predicted level of each relevant element against its PDE, using the data you have for each source.
- Conclude and document: either the controls in place are adequate, or additional controls are needed.
For biotechnology-derived products, the guideline (Section 5.7) treats the risk at the drug substance stage as low, but excipients and environmental sources in drug product manufacture still need to be assessed.
The control threshold
Section 5.6 defines the control threshold as 30% of the established PDE in the drug product. If the total level from all sources is consistently below 30% of the PDE, no additional controls are required, provided the data have been properly assessed. Variability from the analytical method, the source and the product must be factored in. At submission, and absent other justification, the guideline expects data from three representative production-scale lots or six representative pilot-scale lots.
Illustrative arithmetic, not a real product: for an element with an oral PDE of 5 µg/day (such as Pb in Table A.2.1), 30% of the PDE is 1.5 µg/day. A product whose total oral exposure from all sources is consistently below that figure would not need additional controls for that element.
Control approaches and concentration options
Section 6 lists the ways to keep an element under control: modifying process steps, in-process or upstream controls, specification limits for excipients, materials, the drug substance or the drug product, and choosing appropriate container closure systems. Section 7 gives four options for expressing concentration limits:
| Option | How it works |
|---|---|
| Option 1 | Common permitted concentration limits (Table A.2.2) for products with a daily intake of 10 g or less. |
| Option 2a | Common limits using the actual maximum daily intake: concentration (µg/g) = PDE (µg/day) / maximum daily amount of product (g/day). |
| Option 2b | Component-specific limits, where the sum of each component’s concentration multiplied by its mass in the daily dose must meet the PDE. |
| Option 3 | Finished-product analysis against the PDE. |
Illustrative arithmetic: with an oral PDE of 5 µg/day and a maximum daily intake of 2 g/day, Option 2a gives 5 / 2 = 2.5 µg/g.
Common mistakes
- Treating Q3D as a test method. It sets limits and a risk framework; method choice and validation are separate (see ICH Q2(R2) analytical procedure validation, and ICP-MS vs ICP-OES for common techniques).
- Ignoring non-API sources such as equipment, water and container closure systems; see extractables and leachables in single-use systems for one source category.
- Applying the oral element list to a parenteral or inhalation product, when Class 3 elements must also be evaluated for those routes.
- Skipping the variability allowance when comparing results with the 30% control threshold.
- Assuming the guideline covers excluded product types or clinical-stage materials without checking regional expectations.
Related guidelines
| Guideline | Relationship to Q3D |
|---|---|
| ICH Q9 | Risk-management principles that Q3D’s risk-based approach builds on. |
| ICH Q2(R2) | Validation of the analytical procedures used to measure elemental impurities. |
| Q3D(R1) and Q3D(R2) | R2 adds cutaneous and transcutaneous PDEs and corrects several values. |
FAQ
What does ICH Q3D cover?
Elemental impurities in finished drug products: toxicity evaluation, PDEs for 24 elements and a risk-based control strategy.
What is the 30% control threshold?
If the total level of an element from all sources is consistently below 30% of its PDE, additional controls are not required, with variability factored in.
Which elements must be assessed?
Class 1 and 2A for oral products; Class 1, 2A and 3 for parenteral and inhalation products; Class 2B only if intentionally added.
Does Q3D apply to clinical-trial material?
No. The guideline states it does not apply to drug products used during the clinical research stages of development, although its principles can be useful.
Which version is current?
Q3D(R2), Final version, Step 4, adopted 26 April 2022, as described on the ICH document.
Sources
- ICH, Q3D(R2) Guideline for Elemental Impurities, Final version, adopted 26 April 2022.
- US FDA, Q3D(R2) Guideline for Elemental Impurities; ICH; Guidance for Industry; Availability, Federal Register, 15 September 2022.
Read against the sources above on 8 November 2026. Regulatory text is revised over time; consult the current ICH and regional agency documents before relying on any value.
