ICH Q3D Elemental Impurities Risk Assessment: How a CDMO Builds the Control Strategy

Introduction:

ICH Q3D elemental impurities risk assessment is a critical part of pharmaceutical quality management, because metals can enter drug products through raw materials, manufacturing processes, equipment and packaging. Some elements are present only at trace levels, but their potential toxicity makes systematic evaluation and control essential for patient safety.

The International Council for Harmonisation (ICH) created the Q3D guideline to give a harmonized framework for this work. It does not require the same testing for every formulation. It promotes a risk-based strategy that considers each element’s toxicity, its potential sources, the route of administration and the maximum daily dose.

A contract development and manufacturing organization (CDMO) plays an important role here. By combining formulation knowledge, process understanding, supplier information, equipment assessments and suitable analytical methods, a CDMO can build a control strategy that protects product quality without unnecessary testing.

This article explains how a CDMO runs an elemental impurity assessment, identifies contamination sources, selects analytical methods and builds a practical control strategy. At ResolveMass Laboratories Inc., a Canadian analytical CRO and CDMO with a mass spectrometry focus, we treat this assessment as the foundation of a product’s impurity control strategy rather than a one-time filing exercise.

Summary:

• An ICH Q3D elemental impurities risk assessment identifies, evaluates and controls potentially harmful elemental impurities in pharmaceutical drug products.
• A CDMO builds the control strategy by evaluating raw materials, drug substances, excipients, equipment, water and container-closure systems.
• The assessment is science- and risk-based. It determines whether elemental impurities could exceed the established permitted daily exposures (PDEs).
• Q3D covers 24 elements in four classes (1, 2A, 2B, 3) and sets PDEs by route: oral, parenteral and inhalation. Q3D(R2) adds cutaneous and transcutaneous limits.
• ICP-MS and ICP-OES testing is used when the risk assessment justifies it.
• A robust strategy combines supplier qualification, process knowledge, preventive controls, analytical testing, documentation and ongoing monitoring.
• CDMOs build elemental impurity assessment into development, technology transfer, manufacturing and regulatory documentation.

1: What Is an ICH Q3D Elemental Impurities Risk Assessment?

An ICH Q3D elemental impurities risk assessment is a systematic evaluation of whether elemental impurities in a drug product could exceed established safety-based limits. It determines which elements need control and whether existing manufacturing and analytical measures are enough.

Elemental impurities offer no therapeutic benefit, so their levels must be controlled within acceptable limits. The assessment compares the expected exposure from each relevant source with the applicable PDE. The current guideline, Q3D(R2), was adopted on 26 April 2022. It added limits for the cutaneous and transcutaneous routes (Appendix 5) and corrected PDEs for silver, gold and nickel.

The main objectives are to:

• Protect patients from harmful exposure to elemental impurities.
• Identify the elements that may be introduced during manufacturing.
• Establish scientifically justified controls based on product-specific risks.
• Decide whether routine analytical testing is necessary.
• Generate documented evidence for quality decisions and regulatory submissions.

How Are Elemental Impurities Classified Under ICH Q3D?

ICH Q3D sorts elements into classes by toxicity and likelihood of occurrence, and the class determines when an element must be included in the assessment.

The classification is a screening framework, not a substitute for source-specific evaluation. An element that is unlikely in a formulation may still need assessment if a catalyst, processing aid or equipment component credibly introduces it.

PDEs differ by route. For the highest-concern elements, the limits (µg/day) are:

Important: Consult the current ICH Q3D guideline and regional requirements for the complete element list, PDE values and route-specific requirements before using any value in a filing.

2: Why Does a CDMO Need an Elemental Impurity Control Strategy?

A CDMO needs a documented control strategy to show that potential contamination sources have been evaluated and that patient exposure stays within applicable limits. It also ensures testing and preventive controls match the product’s actual risk.

Elemental impurities can be introduced at several stages of development and manufacturing. Testing only the finished product may not explain where contamination comes from or prevent it effectively.

A structured strategy lets a CDMO:

• Identify contamination risks before commercial manufacturing.
• Qualify raw material suppliers using relevant specifications and data.
• Evaluate manufacturing equipment and process-contact materials.
• Select analytical methods based on expected concentrations and product matrices.
• Reduce redundant testing when scientifically justified.
• Support technology transfer and regulatory submissions with traceable evidence.
• Maintain control when suppliers, equipment, processes or formulations change.

The strategy should be proportional to the risks. A product made without intentionally added metal catalysts needs a different assessment from a drug substance synthesized with palladium or platinum catalysts.

3: How Does a CDMO Perform the ICH Q3D Elemental Impurities Risk Assessment?

A CDMO follows a structured, documented workflow. It moves from defining scope and identifying sources, through evaluating and calculating exposure, to implementing controls and reviewing whether they work.

Step 1: Define the Product and Assessment Scope

The first step is to establish what is needed to assess exposure. The CDMO reviews the composition, route of administration, maximum daily dose and manufacturing process. The review generally covers:

• Drug substance and excipient composition.
• Route of administration: oral, parenteral or inhalation.
• Maximum daily dose and intended patient population.
• Drug substance synthesis and purification processes.
• Equipment and product-contact materials.
• Water systems, processing aids and packaging components.
• Existing supplier declarations, certificates of analysis and analytical data.

The maximum daily dose matters because a PDE is a permitted exposure, not a concentration limit that applies identically to every formulation.

Route-specific products raise their own questions. For example, a team developing generic drug development for inhaled drug products must apply inhalation PDEs, which are often much lower than oral limits. A program built around CDMO services for generic topical and semisolid drug products must consider the cutaneous and transcutaneous limits introduced in Q3D(R2).

Step 2: Identify Potential Sources of Elemental Impurities

The CDMO evaluates every credible source that could introduce relevant elements. A source-based assessment separates theoretical possibilities from risks supported by real process information.

The CDMO should document why each credible source is included or excluded. A palladium catalyst used in synthesis creates a specific assessment requirement. An element with no plausible source can be excluded with a scientifically justified explanation.

Poorly soluble drugs often need specialized synthesis, particle engineering or solubilization steps, and these add reagents and equipment contacts. Teams working on generic drug development for poorly soluble APIs should check that these extra steps are captured in the source review.

Step 3: Evaluate the Risk of Each Relevant Element

After identifying sources, the CDMO evaluates the likelihood of occurrence and each source’s potential contribution to the finished product. The evaluation should consider:

• The element’s toxicity and the applicable PDE.
• Potential concentration in each raw material or process stream.
• Maximum daily consumption of the drug product.
• Route of administration.
• Removal or reduction during purification and manufacturing.
• Variability in suppliers, raw materials and processes.
• Uncertainty in analytical data and source information.

A useful assessment separates inherent contamination potential from the actual expected contribution to patient exposure. High-risk sources need stronger evidence and may justify extra controls or testing.

A risk matrix can support prioritization, but its scoring criteria should be defined in advance and scientifically justified. A numerical risk score alone cannot demonstrate compliance with a PDE.

Step 4: Calculate Potential Daily Exposure

The CDMO estimates exposure from concentration data, material quantities and the maximum daily dose. When a raw material contains an element at a known concentration, its contribution follows from the amount consumed daily.

For example, if an excipient contains 0.10 µg of an element per gram and a patient takes 2 g of that excipient per day:

Daily elemental exposure = 0.10 µg/g × 2 g/day = 0.20 µg/day

The CDMO then adds the contributions from all relevant sources:

Daily exposure (µg/day) = Σ (Cᵢ × Mᵢ)

where Cᵢ is the element’s concentration in source i (µg/g) and Mᵢ is the daily quantity of source i (g/day).

The calculation must account for units, the specific element and every applicable source.

Q3D also permits concentration-based control options. Option 1 applies common limits to every component for products with a daily dose of 10 g or less. Options 2a, 2b and 3 allow product-specific, component-specific or finished-product approaches.

The chosen approach should be justified against the guideline and the product’s maximum daily dose.

Step 5: Compare Exposure with the Applicable PDE

The PDE comparison shows whether estimated exposure is acceptable or whether extra controls are needed. The CDMO must use the correct PDE for each element and route, because oral, parenteral and inhalation PDEs can differ substantially.

The assessment should document:

• The applicable PDE and its source.
• The estimated contribution from each relevant source.
• The total estimated daily exposure.
• Assumptions, data gaps and uncertainty.
• The rationale for concluding the control strategy is adequate.

Q3D defines a control threshold of 30% of the established PDE in the drug product. If estimated levels stay below it, no additional controls are generally required beyond documenting the rationale. If exposure approaches or exceeds the threshold, the CDMO should investigate the source, assess how reliable the data are and identify corrective or preventive measures.

A result below the PDE does not automatically remove all quality-control obligations. The conclusion must also reflect the chosen control option, regional requirements and the strength of the underlying evidence.

Step 6: Select an Appropriate Analytical Strategy

Analytical testing provides evidence when supplier information, process knowledge or existing controls cannot fully support the assessment. Two techniques are widely used.

The choice depends on the target elements, expected concentrations, acceptance limits, sample matrix and potential interferences. Methods are typically validated following pharmacopoeial principles such as USP <232>/<233> and Ph. Eur. 2.4.20 and 5.20.

The CDMO must also evaluate sample digestion, recovery, contamination during preparation, matrix effects, calibration and the suitability of the reporting limit. Testing should answer a specific risk question. It should not be added simply because the technique is available. Because ResolveMass specializes in mass spectrometry, we design the testing plan to reflect the real risk profile rather than a generic panel.

Step 7: Establish Preventive and Detective Controls

The final strategy combines measures that stop elemental impurities entering the product with measures that detect unacceptable levels.

Preventive controls

• Qualified suppliers and suitable raw material specifications.
• Defined catalyst-removal and purification steps.
• Appropriate equipment and product-contact materials.
• Maintenance and corrosion prevention.
• Control of process water and processing aids.
• Change control for relevant materials and operations.

Detective controls

• Supplier analytical data and certificates of analysis.
• Risk-based raw material testing.
• In-process or intermediate testing where justified.
• Finished-product elemental impurity testing when required.
• Periodic review of process and analytical trends.

The CDMO should document how each control addresses a specific identified risk. Where existing controls reliably demonstrate acceptable exposure, routine finished-product testing may not always be necessary. Any decision to omit testing must be justified and consistent with applicable requirements.

Q3D also notes that applicants are not expected to tighten limits based on process capability, provided levels stay within the PDEs. Lower levels may still be warranted when metals affect other quality attributes, for example by catalyzing degradation of the drug substance.

4: How Does Elemental Impurity Control Fit into ANDA and Generic Drug Programs?

Elemental impurity control fits into an ANDA program as a defined section of the quality and CMC package. It needs to be planned early, so that suppliers, equipment and methods are qualified before submission rather than during review.

Sponsors choosing a development partner often weigh CRO vs in-house ANDA development. The Q3D assessment is a good test case. It needs toxicology, process chemistry, quality and analytical expertise working together, and few small teams have all of these in-house.

An experienced generic drug development CRO for ANDA can run the assessment alongside formulation work. That keeps the risk conclusions consistent with the process as it evolves. Finally, the documented assessment must be written up for submission, which is where regulatory support for generic drugs in the US and Canada helps align the report with both agencies’ expectations.

What Are Common Pitfalls in Elemental Impurity Risk Assessments?

The most common pitfalls are ignoring excipient and water contributions, skipping intentionally added catalysts, relying on outdated supplier data and failing to reassess after changes.

• Assuming the drug substance is the only meaningful source.
• Applying Option 1 limits to a product whose daily dose exceeds 10 g.
• Leaving out Class 2B elements used as catalysts earlier in the route.
• Treating the assessment as a static document rather than a living record.
• Weak documentation that does not explain why a source was ruled out.

How Does Lifecycle Management Keep the Assessment Current?

Lifecycle management keeps the assessment current by tying it to change control, periodic review and ongoing data collection, in line with ICH Q9 quality risk management.

Each new batch, supplier lot or process change is a chance to confirm or update the conclusions. A CDMO that holds manufacturing and analytical data together can spot trends early, such as a slow rise in nickel from ageing equipment, and act before it becomes a specification failure.

Conclusion:

A strong ICH Q3D elemental impurities risk assessment identifies every credible source, compares realistic exposure with PDE limits, verifies the conclusions with validated analytical data and stays current through change control. When a CDMO builds this work into process development and analytical testing, sponsors get a control strategy that stands up to regulatory review and protects patients.

Frequently Asked Questions:

Reference

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• Teasdale A, Thompson S. ICH Q3D elemental impurities. ICH quality guidelines: an implementation guide. 2017 Sep 27:233-80.https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118971147.ch8
• Lutfor M. Strategic impurity control in next-generation pharmaceuticals: Analytical technologies, toxicological assessment, and regulatory integration. Journal of Angiotherapy. 2025 Jul 16;9(1):1-5.https://publishing.emanresearch.org/CurrentIssuePDF/EmanPublisher_1_6041biomedical-9110292.pdf
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About the Author

Priyal Darji