How to set Specifications for Genotoxic, Metallic Impurities and Residual Solvents in APIs?

The EMA has recently published three new Questions and Answers documents under the heading "Impurities - Harmonisation of policies on setting specifications for potentially genotoxic impurities, heavy-metal-catalyst residues and class-1 solvent residues". The goal of the EMA is to provide a uniform and structured approach to the setting of specifications for these three types of impurities in APIs. The reason behind that approach is the fact that the class-1 metals and the class-1 solvents have high toxic potentials and PDE values (PDE: permitted daily exposure) that approach the level of TTC (threshold of toxicological concern) applied for genotoxic impurities. Therefore it is preferable to have a harmonised strategy for setting specifications for these impurities:

  • Genotoxic impurities
  • Heavy-metal-catalyst residues 
  • Class-1 solvent residues (e.g. benzene and 1,2-dichloroethane, solvents with carcinogenic potential).

Each Questions and Answers document describes a strategy to set specifications based on the same logic and presenting three examples.

Genotoxic Impurities

  • A potential genotoxic impurity based on theoretical considerations but not found in practice.
    In this case, the impurity doesn't need to be included in the drug substance / or intermediate specification.
  • A (potentially) genotoxic impurity is formed or introduced prior to the final step of the synthesis.
    The impurity mustn't be included in the API specification or intermediate if it can be demonstrated by analysis results that presence of this impurity doesn't exceed 30% of the defined acceptable limit ("threshold of toxicological concern; TTC"). For this, data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If the impurity exceeds the 30%- limit, it has to be included in the drug substance specification and the test at an intermediate stage of the synthesis has to be carried out on a routine basis.
  • A (potentially) genotoxic impurity is formed or introduced in the last synthesis step.
    The impurity has to be included in the drug substance specification. However, if the level of the impurity doesn't exceed 30% of the toxicological limit, skip testing is acceptable. For this, data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If the impurity exceeds the 30%- limit, a routine test has to be carried out.

Heavy-metal-catalyst residues (class-1 metal)

  • A class-1 metal is not used or suspected to be present in a synthesis process.
    The metal doesn't need to be included as an impurity in the drug substance / or intermediate specification.
  • The class-1 metal is introduced prior to the final step of the synthesis.
    The metal doesn't have to be included in the drug substance / or intermediate specification if it can be demonstrated by analysis results that its concentration doesn't exceed 30% of the acceptable limit mentioned in the "Heavy Metal Guideline" (EMEA/CHMP/SWP/4446/2000). Skip testing is acceptable when the metal concentration doesn't exceed 30% of the Guideline limit for intermediates. For this, data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If the metal concentration exceeds the 30%- limit, it has to be included in the drug substance specification and a test at an intermediate stage of the synthesis has to be carried out on a routine basis.
  • The class-1 metal is introduced in the last synthesis step.
    The metal has to be included as impurity in the drug substance specification. If the level doesn't exceed 30% of the Guideline limit for APIs, skip testing is acceptable. For this, data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If the 30%- limit is exceeded, a routine test has to be carried out.

Solvent residues (class-1)

  • A class-1 solvent is not used or suspected to be present in a synthesis process.
    The solvent doesn't need to be included as impurity in the drug substance / or intermediate specification.
  • The class-1 solvent is formed or introduced prior to the final step of the synthesis.
    The solvent doesn't have to be included as an impurity in the drug substance / or intermediate specification if it can be demonstrated by analysis results that its concentration doesn't exceed 30% of the acceptable limit mentioned in the "Solvent Residues Guideline (Annex)" (CPMP/QWP/450/03). Skip testing is acceptable when the solvent concentration doesn't exceed 30% of the Guideline limit for intermediates. For this, data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If the solvent concentration exceeds the 30%- limit, it has to be included in the drug substance specification and the test at an intermediate stage of the synthesis has to be carried out on a routine basis.
  • A class-1 solvent is formed or introduced in the last synthesis step.
    The solvent has to be included as an impurity in the drug substance specification. If the level doesn't exceed 30% of the Guideline limit for APIs, skip testing is acceptable. For this, data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches.

The positions of the EMA regarding the setting of drug substance specifications aren't really new. They have to be seen as a uniform and structured summary of the respective "Scientific Guidelines". In the end, this is a relief for marketing authorisation applicants who have to gather all the information for the dossier but also for the assessor on the authority side who has to review the dossier.

Please also visit the EMA's Q&As on quality of medicines.

Note: The question of "metallic impurities" will be addressed in a parallel session of the "15th APIC/CEFIC European Conference on Active Pharmaceutical Ingredients" taking place in Budapest, Hungary, from 9-11 November 2012 . There, you will receive first-hand information about the upcoming ICH Q3D guideline.

Author:
Dr Gerhard Becker
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

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