The European Medicines Agency (EMA) has started a discussion about how to qualify novel impurities based on principles and methods.
Non-mutagenic impurities in chemically synthesized medicines are the focus of the EMA’s draft reflection paper. The agency said the principles and methods should primarily be applied to 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.”
How to qualify non-mutagenic impurities is addressed by the existing guidelines of the International Council for Harmonization (ICH). According to EMA, there is limited guidance available for identifying impurities that are not covered by those guidelines. According to the agency, companies often lack advice when they discover novel impurities that were not present in the batches used in development.
The paper provides key considerations for evaluating impurities, starting with a basic outline for evaluating the risks and continuing with methods for determining an impurity’s toxicological properties.
ICH Q3A and Q3B are the core ICH quality guidelines that address qualification of NMI. They state that “qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations.” For DNA reactive (mutagenic) impurities, elemental impurities and residual solvents, specific guidance is provided in ICH M7(R2), Q3D and Q3C, respectively. For NMI outside the scope of these guidelines little guidance is available on how these impurities should be qualified. This is especially true when novel impurities are identified that were not present in the drug substance or drug product batches used in non-clinical safety and/or clinical studies during development, or when a higher level of these impurities needs to be qualified.
According to ICH Q3A/B guidelines, the level of any impurity presents in a new drug substance or drug product that has been adequately tested in safety and/or clinical studies would be considered qualified.
The limitation of this approach is that only the biological safety of a drug substance or drug product with a given impurity profile has been established (i.e. qualified), which is not the same as characterizing the safety profile of an impurity. When toxicity is observed, it is usually not possible to discriminate between toxicity attributable to the active pharmaceutical ingredient (API) and toxicity attributable to the impurities present in the drug substance or drug product batch. This contrasts with the approaches developed for mutagenic impurities, elemental impurities and solvents, as well as the approach under development for extractables and leachables (ICH Q3E), where a compound-specific approach is recommended.
EMA suggests that companies to consider in silico, in chemico, and in vitro approaches to impurity qualification that use existing data or non-animal models. Although in vivo studies are generally discouraged, as per EMA, the reflection paper outlines the method of conducting animal studies when necessary.
Masuu Global provides expert consulting and services for addressing EMA’s guidance on qualifying non-mutagenic impurities (NMI). Our team helps pharmaceutical companies navigate the complexities of identifying, assessing, and qualifying novel NMIs that emerge due to changes in manufacturing processes or higher impurity levels. We support clients in implementing risk-based evaluation frameworks, applying in silico, in chemico, and in vitro methods, and ensuring compliance with EMA and ICH guidelines for impurity safety assessments.
Draft version: Reflection Paper
Reference: https://www.ema.europa.eu/en/qualification-non-mutagenic-impurities-scientific-guideline