A structured approach for non-mutagenic impurity qualification

In pharmaceutical development, the control of impurities is a critical component of ensuring patient safety and achieving regulatory approval. A common challenge arises during stability studies when a non-mutagenic impurity (NMI) is detected at a level that exceeds the qualification threshold outlined in ICH Q3A and ICH Q3B guidance.  Non-mutagenic impurity qualification can present a significant hurdle that requires careful management to avoid derailing project timelines.

To support this, the recent European Medicines Agency (EMA) draft reflection paper on the qualification of NMIs reinforces a more scientific and efficient path forward. It strongly favours a structured, weight-of-evidence approach to prove the biological safety of an impurity at its observed level. This process, known as ‘qualification’, can prevent costly delays and ensure project timelines are met.

Navigating the non-mutagenic impurity qualification process

The EMA paper endorses a systematic, stepwise approach to non-mutagenic impurity qualification. Here, we break down our interpretation of this recommended pathway, focusing on the key decisions drug development teams need to make.

This workflow is designed hierarchically to answer the most straightforward questions first, ensuring resources are used efficiently while building a logical and defensibly robust argument.

Step 1 – Applicability

The process begins by determining if the impurity falls within the parameters outlined in the EMA draft reflection paper. If the impurity is potentially mutagenic, falling under the specific ICH M7 guideline for control, or if other guidelines apply, such as the ICH Q3C or ICH Q3D, it should be treated accordingly. Otherwise, you then proceed with this qualification workflow.

This initial check acts as a crucial triage point, ensuring the correct regulatory pathway is followed from the start.

Step 2 – Check for metabolite data

The first review to see if the impurity can be qualified without committing to more complex assessments is to check if the impurity is a known metabolite.

According to the ICH Q3 A/B guidelines, impurities that are also significant metabolites are “generally considered qualified” and thus safe at observed levels.

Step 3 – Compare the API structure

With the metabolite status established, the following assessment focuses on comparing the impurity’s structure to the Active Pharmaceutical Ingredient (API).

If the impurity’s structure introduces no new safety alerts compared to the Active Pharmaceutical Ingredient (API), its safety profile is often considered comparable, and the impurity level is likely to be deemed ‘toxicologically acceptable’. However, a robust argument to prove the impurity is API-like needs to be implemented before this approach is used.

Step 4 – Use a surrogate for read-across

If the impurity’s safety cannot be confirmed with existing data, the next step is to find a structurally similar compound (a surrogate) with a known safety profile. You can then use a read-across assessment to build a scientifically robust argument for the safety of your impurity.

Step 5 – Apply a computational toxicology approach

In cases where no suitable surrogate can be found for a read-across, a computational toxicology (in silico) approach should be used. This method uses expert-led computer models to predict a compound’s potential toxicity for key health endpoints, providing a powerful way to assess safety without conducting new animal studies.

This approach is central to modern toxicology, allowing for a robust safety assessment while adhering to the principles of the 3Rs (Replacement, Reduction, and Refinement of animal testing).

A range of approaches, including (Q)SAR, machine learning (ML) models and Artificial Intelligence (AI) are cited in the reflection paper.

Step 6 – Make the final determination

This definitive stage consolidates all the collected evidence into a weight-of-evidence (WoE) assessment, enabling you to make a final determination on safety. If the assessment provides sufficient evidence, the impurity is qualified at its current level.

If a potential risk remains, a decision must be made on whether this risk is acceptable. If the risk is not acceptable, further work is required to either generate new safety data or lower the impurity level in the product.