ICH Q3D Elemental Impurities: Turn PDEs Into Supplier Limits

ICH Q3D applies to the finished drug product, not to an API sold on its own. The guideline covers "new finished drug products … and new drug products containing existing drug substances" (ICH Q3D(R2), section 2). The limits belong to your tablet, capsule or injection. The API reaches Q3D through your risk assessment.

That assessment can draw on information from suppliers of drug substances, excipients, container closure systems and equipment (ICH Q3D(R2), section 5.5). Excipients are the inactive ingredients in the formulation.

The US Food and Drug Administration (FDA) is explicit about who does what. Applicants for noncompendial new drug applications (NDAs) and abbreviated new drug applications (ANDAs) follow Q3D, and they include a summary of the risk assessment in section P.2 (Pharmaceutical Development) of the application. Routine testing of components can be performed by the drug product manufacturer or by "properly qualified suppliers", and the full risk assessment stays at the drug product manufacturing site (FDA, Elemental Impurities in Drug Products, 2018).

The practical reading is that your supplier provides numbers, and you decide whether they fit your product. As of October 2026, ICH Q3D(R2) (Step 4, adopted 26 April 2022) is the version in force.

For an oral product, assess the four Class 1 elements (arsenic, cadmium, mercury, lead) and the three Class 2A elements (cobalt, nickel, vanadium) in every case. Add any Class 2B or Class 3 element that is intentionally added, such as a catalyst metal (ICH Q3D(R2), sections 4, 5.3 and 5.4 (Table 5.1)).

ICH sorts its 24 elements into Class 1 (most toxic, limited or no use in manufacturing), Class 2A (route-dependent toxicity, likely to occur in products), Class 2B (route-dependent, assessed only if added on purpose) and Class 3 (low oral toxicity).

Class 2B also includes silver, gold, iridium, osmium, platinum, rhodium, ruthenium and selenium. Class 3 includes barium, chromium, copper, lithium, molybdenum, antimony and tin. For oral products these are assessed only when intentionally added.

Route changes the numbers sharply. Mercury's PDE is 30 µg/day orally but 3 µg/day for injected (parenteral) products. Injectable and inhalation products also bring Class 3 elements into the assessment.

Q3D does not ask you to test everything. It states that it is not expected that all components will require testing for Class 1 elements; testing applies only when the risk assessment identifies it as the right control.

A single concentration limit fails because Q3D limits are daily amounts, so the acceptable concentration moves with the daily dose. Concentration (µg/g) equals PDE (µg/day) divided by daily product intake (g/day) (ICH Q3D(R2), Equation 1). One µg/g is one ppm.

The fixed Option 1 limits in the table above assume 10 g/day and are valid only up to that intake. Option 2a uses your actual maximum daily intake. Option 2b sets different limits for different components, as long as the summed contribution stays under the PDE. Option 3 tests the finished product.

The grid below is our calculation. We divided each oral PDE from ICH Table A.2.1 by the daily intake, and took 30% of that result for the control threshold line. Each cell reads "limit at 100% of PDE / limit at the 30% line", in µg/g.

A 0.5 g/day product can carry 20 times the concentration of a 10 g/day product (and 50 times that of a 25 g/day product) for the same daily exposure. At 25 g/day the 10 g/day limits are too lenient, and Option 1 no longer applies. Our recommendation is to calculate from your own maximum daily dose and put that number in the supplier request. The same intake-to-concentration logic drives specifications for other trace impurities, as in our guide to nitrosamine impurities.

Take the tablet in ICH's own Appendix 4 example: 2.5 g daily intake, of which 0.200 g is drug substance, made with palladium and nickel catalysts. If the API carries 50 ppm palladium and the other components carry none, the API adds 50 µg/g × 0.200 g = 10 µg/day. That is 10% of the 100 µg/day oral PDE.

The control threshold is 30% of the PDE, which is 30 µg/day for palladium. The API reaches it at 30 ÷ 0.200 = 150 ppm. At 200 ppm the API alone adds 40 µg/day, or 40% of the PDE.

The same 50 ppm API exceeds the Option 1 limit (10 µg/g) and the Option 2a limit (100 ÷ 2.5 = 40 µg/g). Yet it uses only 10% of the allowance. Common limits assume every component carries that concentration, and the API is only 0.200 g of 2.5 g. Option 2b lets you set a higher API limit, paid for by lower limits elsewhere.

This is our model, built on ICH's tablet. We set excipient contributions to zero to isolate the API. In a real product, excipients, water, equipment and container closure systems add to the total, and ICH says equipment and container contributions are subtracted from the PDE before limits are calculated. Our judgement is to set the API limit below the single-source ceiling so the excipients have room. If the API were the only source, that ceiling at the 30% line for a 0.200 g API dose is 7.5 ppm for lead or cadmium, 22.5 ppm for arsenic and 150 ppm for palladium.

Data support matters as much as the arithmetic. In the absence of other justification, level and variability can be established with three representative production-scale lots or six representative pilot-scale lots. Mined excipients can need more data (ICH Q3D(R2), section 5.6).

Run six tests on the certificate of analysis (COA), the lot-specific document listing an API's tests and results. A failure on any one means you cannot yet use the certificate as Q3D evidence. The pass and fail lines, and the limit of quantitation rule, are our recommendation built on Q3D.

Does the certificate report each element separately?

Yes is the only passing answer: arsenic, cadmium, mercury, lead, cobalt, nickel and vanadium must each appear as their own value. A single combined "heavy metals" line fails, because PDEs are set per element and a combined figure cannot be compared with any of them.

Does it cover every catalyst metal in the route?

A passing certificate reports every metal used in the synthesis, for example palladium, platinum, ruthenium, rhodium or nickel. It fails if a metal is named in the route but missing from the certificate. Catalyst metals are the elements ICH treats as intentionally added, so they enter the assessment whatever their class.

Does it state the method and a limit of quantitation low enough to matter?

It passes when the method is named and the limit of quantitation (LOQ, the lowest concentration the method measures reliably) sits at or below your 30% line. The method is usually ICP-MS or inductively coupled plasma optical emission spectrometry (ICP-OES). It fails if it says "not detected" with no LOQ, or if the LOQ is above your 30% line, since "not detected" then says nothing useful about your limit.

Do the results cover enough lots?

Passing means results for three production-scale lots or six pilot-scale lots. A single lot fails, unless the supplier justifies fewer. These counts come from ICH Q3D(R2), section 5.6, where they apply "in the absence of other justification".

Do the numbers hold at your dose?

It passes when the measured value × API grams per day, plus excipients and other sources, totals consistently below 30% of the PDE, with lot-to-lot variability allowed for. It fails when the data cannot be turned into µg/day, or when the total is not consistently below 30%, in which case ICH expects controls to be established.

Is the method validated?

A pass is a validation summary available against United States Pharmacopeia (USP) General Chapter <233> criteria or equivalent. Q3D does not mandate a method, but FDA notes that <233> describes criteria for acceptable analytical procedures (FDA, 2018). No validation summary available is a fail.

A passing certificate also depends on the quality system behind it. Our ICH Q7 guide shows how to check a supplier against the good manufacturing practice (GMP) guideline for APIs. Our guide to reading an API certificate of analysis covers batch-release logic for the other lines on the page.

A Q3D data request should name the product, your daily dose and the elements you need, then ask for lot-level results with method and LOQ. First do the sums: limit = PDE ÷ daily intake; 30% line = 0.3 × limit. Then paste the figures into this message.

Send the API name or CAS number, quantity, grade, destination country and your daily dose. We confirm product by product which documents exist (COA, specification, SDS/MSDS where applicable) and whether element-level data from the manufacturing source is available for the lot.

Availability of element-level results, lot counts and route information depends on the API and its approved source, and is confirmed in the quotation. Attaching the request above tells us which items you need. The safety data sheet (SDS, also written MSDS) covers handling and hazards.

We support evaluation quantities for qualified B2B buyers, subject to the specific API, availability and applicable regulatory requirements. Sample quantity, pricing and documentation are confirmed per product. After successful evaluation and approval, we can support commercial and bulk requirements. We also provide documentation and supply support for US importers.

Pricing depends on chemical rates and market conditions, and there is no single range across our portfolio, so ask us for a quote. Our API quality testing guide explains the tests behind a COA. To start, contact our team with the API name, CAS number, your daily dose and the elements you need.