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The EMA 2026 Reflection Paper on Non-Mutagenic Impurities introduces a new risk-based framework for the qualification of non-mutagenic impurities (NMIs) in chemically synthesised pharmaceuticals.
Furthermore, the updated guidance provides pharmaceutical manufacturers with clearer expectations for impurity assessment, including the use of New Approach Methodologies (NAMs), exposure-based evaluation and scientifically justified safety assessments.
The updated framework is particularly relevant when impurity levels exceed the qualification thresholds described in ICH Q3A and ICH Q3B, either because a new impurity is identified or because a known impurity increases above previously qualified levels.
For pharmaceutical manufacturers, the key message is clear: impurity qualification is moving towards a risk-based, exposure-driven approach that prioritises scientific justification and modern non-animal methods.
Specifically, the 2026 update introduces three major developments:
Overall, these changes reshape how manufacturers should approach NMI assessments and regulatory submissions.
First, before generating new data, assessors should first determine whether sufficient information already exists.
To achieve this, manufacturers should evaluate whether:
As a result, this first step avoids unnecessary testing and ensures available scientific evidence is fully considered.
Next, EMA introduces a formal two-stage Level of Concern (LoC) evaluation:
In addition, the assessment considers multiple factors, including:
Consequently, this approach moves impurity qualification away from fixed limits and towards a patient-relevant risk assessment.
Importantly, before considering animal studies, EMA expects manufacturers to evaluate scientifically valid non-animal approaches.
These may include:
In vivo studies should only be considered when non-animal approaches cannot adequately address the remaining uncertainty.
The updated EMA framework significantly strengthens expectations around modern toxicology approaches.
To ensure reliable interpretation, QSAR predictions should be supported by:
In other words, simply generating a computational prediction is no longer sufficient; manufacturers must demonstrate why the model is appropriate for the impurity being assessed.
Similarly, EMA provides clearer expectations for read-across assessments, including:
As a result, this represents a shift from generic similarity arguments towards scientifically justified impurity-specific assessments.
Futhermore, modern in vitro approaches can support impurity qualification by providing mechanistic and human-relevant information.
For instance, examples include:
Ultimately, these approaches help improve confidence while reducing unnecessary animal testing.
Moreover, where scientifically appropriate, Quantitative In Vitro–In Vivo Extrapolation (QIVIVE) can help translate laboratory findings into human-relevant exposure estimates.
This supports more accurate risk characterisation and improves regulatory decision-making.
The EMA 2026 update further aligns impurity qualification with actual patient exposure.
The revised framework provides greater clarity on TTC application across different administration routes, including:
Therefore, this helps ensure that impurity limits reflect realistic exposure scenarios.
EMA introduces a more refined approach for establishing Acceptable Levels (ALs).
More specifically, AL calculations incorporate assessment factors (AF1–AF7), considering uncertainties such as:
Overall, this represents a move beyond traditional impurity percentage limits towards scientifically justified exposure-based evaluations.
EMA reinforces the principles of the 3Rs (Replacement, Reduction and Refinement).
Therefore, animal studies should only be performed when necessary and when remaining uncertainties cannot be addressed through alternative methods.
Where required, studies should:
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The EMA 2026 Reflection Paper introduces new expectations for non-mutagenic impurity qualification. To successfully implement these requirements, manufacturers need a combination of regulatory understanding, toxicology expertise and practical dossier experience.
Agirad helps pharmaceutical manufacturers translate the updated EMA framework into clear, scientifically justified and submission-ready impurity assessments.
Our support includes:
Gap Analysis
Review and upgrade existing impurity dossiers to align with EMA 2026 expectations.
NMI Risk Assessment
Develop impurity-specific scientific justifications covering Acceptable Levels, exposure assessment and read-across strategies.
Study Oversight
Support CRO selection, protocol development, study monitoring and generation of regulatory-ready documentation.
Ultimately, with the right strategy, manufacturers can meet evolving EMA expectations while reducing unnecessary testing and strengthening regulatory confidence.
The EMA 2026 Reflection Paper on Non-Mutagenic Impurities provides updated guidance on how pharmaceutical manufacturers should assess and qualify non-mutagenic impurities (NMIs) in chemically synthesised active pharmaceutical ingredients (APIs) and medicinal products. The framework introduces a more structured, risk-based approach that considers patient exposure, toxicological relevance and the use of modern non-animal methods.
The EMA framework applies when non-mutagenic impurity levels exceed the qualification thresholds described in ICH Q3A/Q3B, either because a new impurity is identified or because a previously known impurity increases to a higher level requiring additional assessment.
The key changes include:
No. The EMA 2026 framework emphasises that non-animal approaches should be considered before in vivo studies. Manufacturers should first apply scientifically valid methods such as QSAR, read-across, in vitro testing and mechanistic toxicology approaches. Animal studies should only be performed when remaining uncertainties cannot be addressed through alternative methods.
New Approach Methodologies (NAMs) support impurity qualification by providing mechanistic and human-relevant information without relying solely on traditional animal testing. Examples include:
These methods can help demonstrate safety while improving scientific justification.
The EMA 2026 approach expects manufacturers to provide scientifically robust justification when using QSAR or read-across. This includes demonstrating chemical similarity, relevance of toxicological endpoints, applicability of models, mechanistic plausibility and reliability of supporting data
Acceptable Levels (ALs) represent exposure-based impurity limits derived through a structured assessment process. The calculation considers uncertainty factors related to issues such as species differences, human variability, exposure duration, effect severity and confidence in available data.
Manufacturers should review existing impurity assessments and identify potential gaps against the updated framework. Preparation may include:
Agirad supports pharmaceutical manufacturers in implementing the updated EMA expectations through scientific and regulatory expertise. Services include impurity dossier gap assessments, NMI risk assessments, read-across strategies, exposure evaluations and study oversight to support submission-ready documentation.