EMA's Reflection Paper on the Qualification of Non-Genotoxic Impurities

The qualification of impurities is an important part of the quality documentation of APIs and medicinal products. A scientifically sound safety evaluation of the preparation can only be performed through precise knowledge of the impurity profile. The basic requirements for the qualification of non-genotoxic impurities (NGIs) with regard to biological safety can be found in the ICH Q3A(R2) and Q3B(R2) guidelines. Regarding genotoxic (mutagenic) impurities as well as residual solvents and elemental impurities, the requirements specified in ICH M7(R1), ICH M7-Addendum, ICH Q3C(R7) and ICH Q3D must be observed.

The ICH Q3A-D guidelines describe the qualification of the biological safety of NGIs at the level of API or medicinal product batches in the development phase. The biological safety profile of the batch is determined in pre-clinical/clinical studies from such development batches with a certain impurity profile. However, the data from these studies cannot easily be transferred to the safety profile of the impurity itself. If the safety profile of a batch with a specific impurity profile is known, it is not possible to extrapolate the safety profile of another batch with the same active substance but with a higher proportion of impurities because the impurity specific safety data are missing.

To close this gap, the European Medicines Agency (EMA) published a draft document entitled "Reflection paper on the qualification of non-genotoxic impurities" in November last year. This document provides guidance on how to proceed when

• Data from (non-)clinical studies with API batches are not sufficient for qualification, or
• The impurity content is below the threshold for qualification according to ICH Q3A/B, but toxicological concerns remain:
  - For preparations administered in high doses,
  - For impurities of unusually high potency which are suspected to cause already toxic or pharmacological effects at concentrations equal
     to or below that of the identification threshold.

The individual chapters of the document describe different approaches and methods for the qualification of impurities, e.g. by (Q)SAR ((Quantitative) Structure Activity Relationship), in silico studies, risk considerations on dosage, PDE values and duration of exposure, evaluation of databases, in vitro tests, etc.

The Reflection Paper refers exclusively to the safety evaluation of chemically synthetised APIs. Solvents, elemental impurities and impurities of biological medicines, oligonucleotides and synthetic peptides are outside the scope of application.

The comment period for this Reflection Paper will end on September 30, 2019.