EMA Drafts Reflection Paper on the Qualification of Non-Genotoxic Impurities

Regulatory NewsRegulatory News | 26 November 2018 |  By 

The European Medicines Agency (EMA) last week unveiled a new draft reflection paper on the safety evaluation of non-genotoxic impurities (NGI) in chemically synthesized pharmaceuticals.

While noting that “little guidance is available on how these impurities should be qualified,” the draft reflection paper builds off ICH quality guidelines addressing qualification of NGI – ICH Q3A and Q3B.

The reflection paper includes a discussion of “how a more impurity-specific evaluation could be followed making use of these novel approaches” seen in recent literature. “Such an approach may provide more useful information than the generic approach of testing a batch with the specified level of impurity in a short/medium term toxicology study in animals.”

The reflection paper, however, “does not contain explicit guidance on which non-clinical approaches are most suitable. Rather it tries to establish a framework to facilitate future discussions among stakeholders.

“It is recommended to consider the approaches discussed in this reflection paper when qualification is required and data from the regular (non-)clinical development with the API batches is not considered sufficient. Also when the level of an impurity is below the qualification threshold defined in ICH Q3A/B guidelines, but a toxicological concern may still exist, the approaches discussed in this reflection paper may be considered. This could be the case when high dose pharmaceuticals are concerned, or when a  concern exists that the impurity involved is unusually potent, producing toxic or pharmacological effects at a level equal to or below that of the identification threshold,” the paper’s introduction notes.

The draft also includes sections on integrated risk assessment, dose considerations, structure activity relationships, use of pharmacological and toxicological databases, in vitro approaches, qualification of the NGI at a specified level and the reduction of animal use.

“When impurity-specific safety information is required, alternative strategies to gather this information may be followed, including the use of TTC [threshold of toxicological concern], (Q)SAR [(Quantitative) Structure Activity Relationship], RAX [read-across] and in vitro approaches. This information can be used in an integrated risk assessment. A WoE [weight-of-evidence] approach including an assessment of the level of uncertainty may be used to decide whether the NGI can be considered safe at the specified level,” the paper concludes.

The consultation on the draft reflection paper ends on 30 September 2019.

Reflection paper on the qualification of non-genotoxic impurities


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