A practical explanation of the Analytical Evaluation Threshold (AET) in extractables and leachables studies, its relationship to safety thresholds, exposure and analytical reporting.
The Analytical Evaluation Threshold (AET) is a study-specific analytical threshold used in extractables and leachables (E&L) programmes to determine the level above which detected chemical entities require appropriate identification, quantification, reporting and safety evaluation.
ICH Q3E is still a draft guideline as of October 2026, but it provides a harmonized risk-based framework for the assessment and control of extractables and leachables. The framework connects material and process understanding, analytical studies, patient exposure and toxicological assessment.
AET is not a universal concentration
An AET should not be treated as one fixed value that applies to every product. It depends on the safety threshold relevant to the scenario, the patient exposure or dose basis, analytical uncertainty and the way the study result is expressed. The same safety objective can therefore lead to different analytical reporting thresholds in different products, components or study designs.
Relationship between SCT and AET
A Safety Concern Threshold (SCT) is a safety-based exposure concept. The AET translates the applicable safety starting point into an analytical context that can be used by the laboratory. This distinction is important: the SCT is a toxicological concept, while the AET is an analytical threshold used to support study execution and interpretation.
What information affects the AET?
At a high level, the AET depends on the safety starting point and the exposure context. Relevant information can include maximum daily exposure to the drug product, study type, component or material basis, the analytical uncertainty applied to semi-quantitative results, and the reporting unit required for the study.
For a robust assessment, units and exposure bases must remain internally consistent. A threshold expressed per unit mass, volume, component, device or administration unit should be traceable back to the same patient-exposure objective.
Extractables and leachables studies use the AET differently
In an extractables study, the AET supports decisions about which detected extractable entities should be identified and reported as potential leachables. In a leachables study, it supports identification and quantification of compounds present in the drug product so that their toxicological relevance can be evaluated.
What happens when a compound is above the AET?
Being above the AET does not automatically mean that a compound is unsafe. It means that the compound has crossed the analytical threshold for further characterization. The next steps can include confirmation of identity, more accurate quantification, review of existing toxicological information and, where necessary, compound-specific safety qualification.
Compound-specific safety limits
Some leachables require compound-specific evaluation rather than reliance on a generic safety starting point. This is particularly important for substances that fall into higher-concern categories or have established health-based limits. The safety reference used for the AET should therefore be appropriate to the compound and the study context.
How LeachScan SEAL supports the workflow
SEAL is the LeachScan module focused on safety evaluation of extractables and leachables. At a high level, it organizes the study context, applicable safety references and reporting requirements to support the definition of analytical thresholds and the toxicological qualification of individual compounds. Proprietary scoring, conversion logic and internal calculation rules are not part of this public explanation.
Frequently asked questions
Is the AET a toxicological limit?
Not exactly. The AET is an analytical threshold derived from a safety objective and the study exposure context. It determines when a detected compound requires further analytical and safety attention.
Is there one AET value for all pharmaceutical products?
No. The value is study-specific and depends on the applicable safety starting point, dose or exposure basis, analytical uncertainty and reporting unit.
Does a compound above the AET automatically fail the study?
No. Crossing the AET triggers further identification, quantification, reporting and/or toxicological assessment; it is not itself a conclusion that the compound is unsafe.
What is the difference between SCT and AET?
The SCT is a safety-based exposure concept. The AET expresses the applicable safety objective in an analytical reporting context for a specific study.
Is ICH Q3E final?
No. As of October 2026, ICH Q3E remains a draft guideline and the public consultation has closed.
