Elemental Impurities — Limits and Procedures
USP <232> and <233> are the paired compendial chapters that implement elemental-impurity control in the United States. <232> sets Permitted Daily Exposure limits for elemental impurities such as arsenic, cadmium, mercury, and lead, differentiated by route of administration — oral, parenteral, and inhalation. <233> specifies the validated analytical procedures for measuring those elements, typically ICP-OES or ICP-MS, together with the validation requirements the methods must satisfy. As chapters numbered below 1000 they are mandatory, they became official on 1 January 2018, and they replaced the old wet-chemistry Heavy Metals chapter <231>.
What this does not cover
stated in the document's own scope- They do not provide the full risk-assessment methodology, which is set out in ICH Q3D.
- They do not cover residual organic solvents, which are governed by ICH Q3C and its own compendial chapters.
- They do not address organic process or degradation impurities, which fall under ICH Q3A and Q3B and are specified through ICH Q6A.
- <232> sets the limits but does not itself validate the method; the analytical procedures and their validation are the domain of <233>.
Always verify against the current published text before relying on it for a submission or inspection.
Overview
USP <232> and <233> work as a pair to control elemental impurities — trace metals that can enter a drug product from the drug substance, excipients, water, equipment, or packaging. <232> answers how much is acceptable, publishing Permitted Daily Exposure limits for the toxic elements and dividing them by route of administration. <233> answers how to measure them, describing modern instrumental procedures such as inductively coupled plasma techniques and the validation those procedures must pass. Together they replaced the century-old colorimetric Heavy Metals test <231>, which was non-specific and could not reliably quantify individual elements.
Legal basis & how it acquires force
As USP general chapters numbered below 1000, <232> and <233> are enforceable: under section 501(b) of the Federal Food, Drug, and Cosmetic Act, an official article that fails to meet applicable USP standards may be deemed adulterated. The chapters became official on 1 January 2018 and are harmonised with ICH Q3D, which the FDA and EMA adopted as guidance and which supplies the risk-assessment framework and the underlying PDE derivations. The compendial limits and the ICH guideline are intended to align.
Document structure
| Part | Covers |
|---|---|
| <232> scope and applicability | The elements controlled and the products and routes to which the daily-exposure limits apply. |
| <232> PDE limits by route | Permitted Daily Exposure values for each element, tabulated for oral, parenteral, and inhalation administration. |
| <232> options for demonstrating compliance | Use of drug-product PDE or component concentration limits derived from the maximum daily dose. |
| <233> analytical procedures | Procedure 1 and Procedure 2 instrumental methods, typically ICP-OES and ICP-MS, and sample preparation. |
| <233> validation requirements | Specificity, accuracy, precision, and the alternative-procedure equivalence criteria the method must meet. |
Key requirements
- Control elemental impurities to the Permitted Daily Exposure limits in <232>, selecting the limit set that matches the route of administration.
- Assess the drug product for the relevant elemental impurities across all potential sources: drug substance, excipients, water, equipment, and container-closure.
- Use a validated analytical procedure meeting <233>, generally ICP-OES or ICP-MS, or an alternative procedure shown to be equivalent.
- Satisfy the <233> validation requirements, including specificity via spiking, accuracy, precision, and demonstration of quantitation capability at the limit.
- Convert PDE values to concentration limits using the maximum daily dose when applying an option based on component or drug-product concentration.
- Base the control strategy on a documented risk assessment consistent with the ICH Q3D framework.
- Confirm results against the limits and investigate any elemental impurity found above its established acceptance criterion.
Implementation tips
- Build the elemental-impurity risk assessment from the ICH Q3D component approach, and keep supplier data for excipients and the drug substance on file to support it.
- Validate the ICP method with spike recoveries at the target limit and across the sample matrix, since matrix effects drive most method problems.
- Include contributions from manufacturing equipment, processing water, and container-closure in the assessment, not only the formulation ingredients.
- Reassess the elemental-impurity conclusion whenever a supplier, excipient grade, or contact material changes.
International alignment
USP <232>/<233> are harmonised with ICH Q3D on elemental impurities, which provides the risk-assessment framework and the toxicological derivation of the PDE values that <232> tabulates. Q3D is adopted as guidance by the FDA, EMA, and other ICH regions. The Ph. Eur. implements the same limits through its own general chapters. The compendial chapters carry the enforceable measurement and limit requirements, while ICH Q3D supplies the methodology for the product-specific risk assessment behind them.
USP <232>/<233>: frequently asked questions
Quick answers to common questions about USP <232>/<233>.
What is the difference between USP <232> and <233>?
<232> sets the Permitted Daily Exposure limits for elemental impurities by route of administration, while <233> provides the validated analytical procedures — typically ICP-OES or ICP-MS — and the validation requirements used to measure those elements.
When did <232>/<233> become official?
They became official on 1 January 2018, at which point they replaced the older wet-chemistry Heavy Metals chapter <231> for the products within their scope.
How do the USP chapters relate to ICH Q3D?
They are harmonised. ICH Q3D supplies the risk-assessment framework and the PDE derivations, and the USP chapters carry the enforceable limits and the measurement procedures. The numerical limits are intended to align.
Which elements and routes does <232> address?
It sets limits for toxic elements including arsenic, cadmium, mercury, and lead among others, with separate Permitted Daily Exposure values for oral, parenteral, and inhalation routes of administration.