Qualification of non-mutagenic impurities - Scientific guideline
HumanScientific guidelines
This reflection paper considers the safety evaluation of non-mutagenic impurities (NMI) in chemically synthesised pharmaceuticals and is intended to establish a framework to facilitate future discussions among stakeholders. Qualification of NMI may be required when data from the regular (non-)clinical development with the API batches is not considered sufficient. The aim of this paper is to complement currently available guidelines addressing qualification of NMI such as ICH Q3A and ICH Q3B. The reflection paper discusses different non-animal approaches, which may provide more compound-specific information than animal studies with API batches containing the impurities at low levels.
On 30 January 2025, EMA launched a public consultation on the draft reflection paper, with the aim of gathering input and feedback from stakeholders. This draft follows the earlier version that was published in 2018 and has been updated considerably.
The update focuses on alternative strategies for qualifying novel impurities or qualifying higher levels of impurities that were previously qualified at a lower level. The aim is to provide a practical reference for applicants regarding the qualification of novel impurities:
- arising from changed manufacturing processes,
- discovered after safety studies have been concluded, or
- when higher levels need to be qualified and existing data from safety studies are not sufficient for qualification.
See also: Webinar on reflection paper on the qualification of non-mutagenic impurities (6 March 2025)
Keywords: Non-mutagenic impurities, pharmacology, toxicology, threshold of toxicological concern, read across, animal testing, in vitro testing, 3Rs