Navigating EMA and FDA guidance on non-mutagenic impurities

With the recent release of its Reflection Paper on the Qualification of Non-Mutagenic Impurities (NMIs) (EMA/CHMP/543397/2024), the European Medicines Agency (EMA) has taken a notable step toward a more flexible, science-driven approach to managing these impurities.

In contrast, the U.S. Food and Drug Administration (FDA) continues to apply a broader framework for impurities, emphasizing robust process control as a cornerstone of impurity management.

For companies navigating global drug development and regulatory submissions, understanding the similarities and differences between the two key markets of Europe and America is essential to building a compliant, efficient, and scientifically sound strategy.

The EMA’s reflection paper marks a progressive shift in how NMIs can be qualified in the EU.

While traditional approaches often required extensive toxicological data, the EMA now explicitly recognizes that alternative methods, including in silico models, in vitro testing, and other New Approach Methodologies (NAMs), can provide a sufficient scientific basis for qualification under certain conditions.

This provides developers with greater flexibility, particularly when managing low-level impurities where traditional toxicology studies may be disproportionate to the potential risk.

It also aligns with broader trends in regulatory science that aim to reduce unnecessary animal testing and leverage modern tools for faster, more ethical risk assessment.

Unlike the EMA, the FDA does not currently offer specific guidance solely dedicated to NMIs. Instead, non-mutagenic impurities are addressed within broader impurity-related guidelines, including:

• ICH Q3A(R2): Impurities in New Drug Substances

• ICH Q3B(R2): Impurities in New Drug Products

These documents emphasize that all impurities, including NMIs, must be appropriately qualified based on safety data and manufacturing controls.

The FDA’s approach to impurities is deeply tied to a lifecycle management view of pharmaceutical quality and focuses on the need to minimize impurities through robust process design, control, and validation.

While the FDA has detailed guidance for mutagenic impurities, such as M7(R2) (which focuses on DNA-reactive impurities and uses tools like the Threshold of Toxicological Concern, or TTC), there remains a gap in explicit, dedicated FDA guidance on NMIs, leaving developers to interpret broader frameworks to cover these cases.

EMA and FDA alignment:

• Risk-based approaches are central to both EMA and FDA frameworks, requiring thorough understanding and control of impurities to ensure patient safety.
• Both regulators emphasize leadership accountability and expect companies to have systems in place to monitor and manage impurity risks over a product’s lifecycle.
• Adoption of emerging scientific methodologies is encouraged, signaling a shift toward integrating modern risk assessment tools like in silico models and NAMs.

Key differences:

• EMA offers more explicit flexibility for qualifying NMIs using alternative methods like computational and in vitro tools, allowing developers to take advantage of science-driven qualification strategies.
• FDA maintains a broader and stricter process-focused approach, emphasizing that impurities (including NMIs) must be addressed through comprehensive process control, validation, and lifecycle oversight. This has less emphasis on alternative qualification strategies to date.
• The EMA’s framework allows for adaptability when managing uncertainty, whereas FDA emphasizes minimizing uncertainty through upfront, robust manufacturing processes and continuous oversight.

The impact for drug developers

For pharmaceutical companies operating in both Europe and the U.S., balancing these two regulatory expectations is becoming more challenging and more critical.

On one hand, the EMA’s reflection paper opens opportunities to qualify certain NMIs more efficiently, using cutting-edge methods that could accelerate development timelines and reduce unnecessary toxicology work.

On the other hand, FDA expectations continue to emphasize process rigor, making it essential that companies do not rely solely on alternative methods without ensuring that robust process controls and comprehensive impurity management plans are in place.

Key actions for Regulatory and Quality teams

• Invest in modern risk assessment tools that support a science-based approach to impurity qualification. These methods can strengthen global submissions, particularly in the EU.
• Ensure cross-functional teams (Regulatory, Quality, CMC, Toxicology) are aligned on a global strategy that addresses both EMA and FDA expectations, avoiding a one-size-fits-all approach.
• Strengthen lifecycle impurity management systems, including proactive impurity identification, control, and ongoing monitoring, which are key to meeting the FDA’s expectations for continuous process oversight.
• Monitor evolving regulatory guidelines, as staying ahead of updates will be essential for compliant submissions.

G&L can help

At G&L Scientific, we specialize in helping pharmaceutical and biotech companies navigate complex and evolving global regulatory frameworks.

Our teams provide strategic and operational support in regulatory affairs, CMC, quality assurance, and toxicology, helping organizations:

• Develop global impurity management strategies that align with both EMA and FDA expectations.
• Integrate alternative scientific methodologies into impurity qualification packages.
• Ensure regulatory submissions are robust, defensible, and compliant with current and emerging guidelines.
• Prepare for regulatory agency interactions and respond to questions related to impurity qualification and risk management.

As the regulatory environment continues to evolve in 2025, companies that stay ahead of these shifts and align with both flexible and stringent expectations will be best positioned to succeed.

If you would like to discuss your strategy around impurity qualification or any aspect of global drug development, get in touch directly or visit www.gandlscientific.com

Referenced guidelines:

• EMA Reflection Paper on NMIs: EMA/CHMP/543397/2024
• ICH Q3A(R2) - Impurities in New Drug Substances: Link
• ICH Q3B(R2) - Impurities in New Drug Products: Link
• ICH M7(R2) - Assessment and Control of DNA Reactive (Mutagenic) Impurities: Link

Paul Kuiken is Vice President of Advisory Services at G&L Scientific.