EMA: Reflection Paper on the Qualification of Non-Mutagenic Impurities (NMIs)

The EMA has published a new reflection paper outlining its current thinking on the qualification of non-mutagenic impurities (NMIs). The paper addresses recommended approaches for evaluating the safety of new or increased impurity levels, particularly when such impurities exceed the ICH Q3A/Q3B qualification thresholds and are identified after completion of non-clinical toxicology studies.

The scope is limited to chemically synthesised pharmaceuticals and includes impurity changes arising from drug substance or drug product-related modifications, such as manufacturing process changes. The reflection paper does not reflect further on the ALARP principle (As Low As Reasonably Possible) for the limits of impurities, but specification levels should generally be based on batch data and not only be guided by toxicologically qualified levels. 

The paper complements existing guidance, notably ICH Q3A(R2), ICH Q3B(R2) and ICH M3(R2), by proposing alternative, non-animal qualification strategies. Depending on the level of concern, the data requirements may range from no additional information to impurity-specific experimental studies. 

The EMA highlights that when impurity-specific safety information is needed, alternative approaches beyond additional in vivo general toxicology studies may be applied. These include threshold of toxicological concern (TTC), (quantitative) structure activity relationship ((Q)SAR), read-across and in vitro approaches, which can be combined within an integrated risk assessment. A weight-of-evidence approach may be sufficient to conclude that an NMI is safe at the specified level.

Source:

EMA: Qualification of non-mutagenic impurities - Scientific guideline