Elemental impurities are residues of metallic or other elements in a medicinal product that can have no therapeutic benefit. The permitted daily exposure limits the amount of a specific element that a patient may ingest per day via a specific route of administration and is the toxicological basis for the evaluation of the medicinal product.
Sources Along Materials and Equipment
Elements may be intentionally used in a manufacturing step, for example as catalysts in active substance synthesis. However, they may also unintentionally originate from the active substance, excipients, or water. Furthermore, product-contacting parts of the equipment and the container closure system are possible sources of entry if their composition or interaction with the product is relevant.
The risk assessment therefore begins with a material and process map. It asks which elements are expected in raw materials, from which components a migration is conceivable, and whether purification steps effectively reduce the entry. Not every theoretically present metal surface automatically requires routine testing; the decisive factor is the plausible exposure in the finished medicinal product.
Calculation Path from PDE to Product Limit
For each element to be considered, ICH Q3D provides a permitted daily exposure (PDE) per route of administration. The permitted daily exposure is divided by the maximum daily dose of the medicinal product; this results in a concentration that must not be exceeded at this dosage. The calculation thus links a toxicological daily value with the actual intake amount or application of the specific product.
For a medicinal product with a very low daily dose, the same PDE value can lead to a higher concentration value than for a high-dose preparation. Conversely, a small elemental concentration can become relevant at a high daily dose. The risk assessment also considers whether several components together contribute to the entry and whether the route of administration changes the applicable PDE.
The three-step ICH approach first involves identifying potential sources of entry, then evaluating the observed or expected concentrations against the PDE, and finally establishing controls. These controls may be based on process understanding, specifications for starting materials, supplier qualification, or analytical data. Measurement of the finished product is thus one possible, but not the only, form of risk control.
When evaluating equipment, the composition of those components that actually come into contact with the product is of interest. Stainless steel, coatings, seals, and surface treatments can have different elemental profiles. Whether this results in a relevant contribution depends, among other things, on contact time, product pH, temperature, and the possibility of leaching.
A risk can also change with the formulation. The same active substance in an aqueous solution and in a solid tablet can have different contacts with the container or production plant. Product evaluation must therefore not be transferred from one dosage form to another without verification.
Differentiation from Other Impurity Groups
Elemental impurities are not to be equated with residual solvents. Residual solvents are volatile organic substances from manufacturing or purification steps and are evaluated according to a different guideline concept. Organic impurities such as starting material residues, by-products, or degradation products also have different chemical and toxicological profiles.
The ICH Q3D guideline does not apply to medicinal products in the clinical development phase. Its principles can nevertheless be used there to assess risks from catalysts, excipients, or product-contacting materials. Clinical application does not replace the subsequent full evaluation for marketing authorization, but it can scientifically guide the selection of materials and tests.
The chosen control must match the dominant entry path. For a catalyst-related residue, a purification step may be decisive, while for an excipient, the supplier specification forms the more effective control point.
Significance for Clinical Trials
In the case of investigational medicinal products, active substance batches and excipient sources are sometimes changed while the formulation and dose continue to be developed. The risk assessment for elemental impurities helps to decide whether a new source, a new mill, or a different packaging material requires additional data. For high-dose oral investigational products, the daily intake amount can have a particularly strong influence on the priority of the assessment.
Full-service CROs like Mediconomics provide support by compiling dose information, material data, and CMC changes for a traceable risk assessment. They can organize the coordination between analytics, manufacturing, and regulatory affairs when product-related testing limits or supplementary supplier data follow from the PDE calculation.
Frequently Asked Questions (FAQ)
Is the PDE the same for every element and every route of administration?
No. The permitted daily exposure is specified for each element and route of administration. The basis for evaluating an oral application cannot, therefore, be transferred to a parenteral application without further examination.
Why is the maximum daily dose required for the calculation?
It translates the permitted daily elemental amount into a product-related concentration limit. Without this dose, it would not be possible to determine how much of the medicinal product the patient actually ingests.
Do all elements have to be measured in every batch?
The guideline requires a risk-based assessment of plausible sources and exposure. From this, it is derived whether process controls, supplier data, or analytical tests are required.
Regulatory References
- ICH Q3D(R2) “Guideline for Elemental Impurities” — defines PDEs, sources of entry, and the risk-based assessment approach.
- EudraLex Volume 4, Annex 15 “Qualification and Validation” — requires the risk-based consideration of equipment and processes.
- ICH Q10 “Pharmaceutical Quality System” — describes quality system elements across the product lifecycle.