Pharma, Veterinary and API

Pharma, Veterinary and API

The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated veterinary medicinal products (VMPs).

Recent guidelines and documents have been published by regulatory authorities providing recommendations on the use of non-animal testing methods for the hazard assessment of drug impurities, i.e. the ICH M7 Guideline on the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals, the related EMA guideline on assessment and control of DNA reactive (mutagenic) impurities in veterinary medicinal products, and the EMA reflection paper on the qualification of non-genotoxic impurities.

Genotoxic impurities

The assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals is regulated under the ICH M7 guideline, which was used as a template for the related EMA guideline on assessment and control of mutagenic impurities in veterinary medicinal products, with amendments introduced in order to cover the issues specific to VMPs.

GI Hazard assessment elements

We can support you meeting ICH M7 requirements with a range of solutions and services:

  • Database search and expert review of experimental carcinogenicity and mutagenicity data
    • Search of experimental carcinogenicity and mutagenicity data from toxicological databases
    • Expert assessment of toxicological studies (publicly available and/or proprietary)
    • Classification of impurities
    • Documentation of results
  • ICH M7-compliant (Q)SAR predictions for bacterial in vitro mutagenicity (Ames test)
    • (Q)SAR predictions by employing statistical-based and expert rule-based methods
    • Expert assessment of prediction’s reliability and adequacy following OECD and ECHA guidelines
    • Classification of impurities
    • Documentation of results in compliance with regulatory requirements (OECD and ECHA)
  • Justification study for classification in Class 4
  • Feasibility study for classification of impurities into Class 4 (to be treated as non-mutagenic). Prerequisite for the Justification study are: i) identification of a suitable analogue (API or related compound) sharing the same structural alert (in the same position and chemical environment) of the target impurity; ii) availability for the identified analogue of a negative Ames test study (OECD 471 compliant)
  • Documentation of the justification study, to be integrated with the (Q)SAR-based assessment of the impurity

Workflow for ICH M7 compliant (Q)SAR assessment of GI 

Non-Genotoxic impurities

EMA recently published a reflection paper on the qualification of non-genotoxic impurities (NGIs) in chemically synthesized pharmaceuticals, addressing open issues in the current qualification approach outlined in the ICH Q3A/Q3B guidelines and providing recommendation for the use of alternative non-animal testing methods.

According to these guidelines, qualification establishes the biological safety of a drug substance batch or drug product with a given impurity profile, but not characterizes the safety profile of individual impurities. Thus, when toxicity is observed, it is not possible to discriminate between toxicity attributable to the API and toxicity attributable to the impurities present in the drug substance batch. This limits the extrapolation of the safety of a drug substance or product with a given impurity profile to a drug substance or product with the same API but with an increased level of an impurity, when no impurity-specific data are available. In addition, when new impurities arise due to manufacturing changes or novel degradants are discovered at a later stage of development, and these impurities cannot be controlled at a level below the qualification threshold, a lack of impurity-specific safety data complicates the qualification process.

The EMA paper acknowledges that ICH Q3A/Q3B provide little guidance on which criteria and methods should be applied to qualify NGIs, and expresses some concerns from a scientific and 3R’s perspective on the current approach. When qualification of NGIs is required and data from the regular (non-)clinical development with the API batches is not considered sufficient, a recommendation to consider non-animal testing strategies to evaluate the toxicity of individual NGIs is provided. An integrated risk assessment (IRA) is proposed, to be assessed case-by-case, which encompasses several approaches, including TTC, (Q)SAR and read-across, as well as in vitro methods.

We can support you in the qualification process of non-genotoxic impurities with a range of solutions and services:

  • Strategy definition for the hazard assessment of non-genotoxic impurities
    • Analysis of existing information on the API (e.g., use and route of administration) and related impurities
    • Identification of relevant endpoints
    • Analysis of the structural similarity between the target NGI and the API
    • Definition of the workflow to characterise the safety profile of individual NGIs making the best use of non-testing methodologies
  • Database search and expert review of experimental toxicological data
  • TTC assessment
  • Alert profiling
    • Identification and assessment of toxicologically relevant structural alerts to understand toxicity mechanism and mode of action
  • (Q)SAR predictions
  • Read-across predictions