FDA’dan yeni, ICH Katışıklık Kılavuzu (İng) 


FDA issues new ICH Impurity Guidelines for comments 


The focus of this guideline is on DNA reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer. 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 drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products provides guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive. The purpose of this guideline is to provide a practical framework that can be applied for the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk. This guideline is intended to complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals. 

This document is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing. It also applies to new marketing applications and post approval submissions for marketed products, in both cases only where:

  • Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities;
  • Changes in the formulation, composition or manufacturing process result in new degradants or increased acceptance criteria for existing degradants;
  • Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level. 

The following types of drug substances are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin. Exceptions would be when products such as biologicals and peptides are chemically synthesized or modified (e.g., addition of organic chemical linkers, semi-synthetic products). In such cases an assessment of potential mutagenicity is warranted for chemicals likely to exist as impurities/degradants in the drug product. 

This guideline does not apply to drug substances and drug products intended for advanced cancer indications as defined in the scope of ICH S9.  Additionally, there may be some cases where a drug substance intended for other indications is itself genotoxic at therapeutic concentrations and may be expected to be associated with an increased cancer risk. Exposure to a mutagenic impurity in these cases would not significantly add to the cancer risk of the drug substance and impurities could be controlled at acceptable levels for non-mutagenic impurities. 

Excipients used in existing marketed products and flavoring agents are excluded from this guideline. Application of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used if warranted. The safety risk assessment principles of this guideline can be used if warranted for impurities in excipients that are used for the first time in a drug product and are chemically synthesized. 

This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk. It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use.