Genotoxic Impurity Method Development and Methodological Validation

Genotoxic impurities (GTI) refer to compounds that can directly or indirectly damage cellular DNA, produce gene mutation or in vivo mutagenesis, and have the possibility or tendency to cause cancer. The fundamental purpose of studying genotoxic impurities is to control and reduce the risk that they may cause cancer in humans. Carcinogens can be divided into genotoxic carcinogens and non-genotoxic carcinogens according to their mechanism of action. Most of the carcinogens encountered in drug development and production are genotoxic carcinogens. The main mechanism of action of genotoxic carcinogens is to cause DNA damage, while the mechanism of action of non-genotoxic carcinogens is more complex, including oxidative stress, regulation of enzyme activity, cell proliferation and apoptosis. The toxicity of chemical substances that may cause cancer can be divided into three levels: genotoxicity, mutagenicity and carcinogenicity. Most carcinogens and mutagens are genotoxic, but not all genotoxic impurities are mutagenic or carcinogenic.

Genotoxic Impurity Method Development and Methodological Validation

Claasification of Genotoxic Impurities

Table 1 Impurities Classification With Respect to Mutagenic and Carcinogenic Potential and Resulting Control Actions

Genotoxic Impurity Method Development and Methodological Validation

Acceptable Intakes of Genotoxic Impurities

Table 2 Acceptable Intakes for an Individual Impurity

Duration of treatment ≤1 month >1-12 months >1-10 years > 10 years to lifetime
Daily intake [μg/day] 120 20 10 1.5

Table 3: Acceptable Total Daily Intakes for Multiple Impurities

Duration of treatment ≤1 month >1-12 months >1-10 years > 10 years to lifetime
Total Daily intake [μg/day] 120 60 30 5

Control Strategies of Genotoxic Impurities

These strategies of genotoxic impurities include: (a) redesigning the drug substance synthesis to avoid introducing problematic impurities, (b) altering relevant process parameters to remove or reduce such impurities to insignificant levels, (c) deploying process understanding to prove that a particular genotoxic impurity either cannot be formed or will be efficiently removed, (d) conducting toxicity studies to demonstrate that a suspect impurity is not harmful at the low levels envisaged for it.

Content of Development and Validation of Analytical Methods

System suitability


Limit of detection

The limit of quantitation


Linear and range



Solution stability

Our Services

CD Formulation provide genotoxic impurity testing services to detect and evaluate the potential of GIs for your API and drug substances which can support your product development from an early stage to market release. With scientists who are adept at method development and validation of suitable analytical procedures, we can overcome the challenges of low detection levels and difficult matrices.

Why Choose CD Formulation?

CD formulations use the QbD concept, refer to ICH and other guidelines, and are equipped with high detection sensitivity instruments such as GC-MS, LC-MS, and triple quadrupole mass spectrometry, and the research methods are applicable to different regulatory requirements such as USP and EP.

How to Contact us?

If you have a requirement about our services, please contact us by phone or email, our colleagues will reply to you within three working days.


  1. ICH Q2(R2):Validation of a analytical procedures.
  2. ICH M7(R1):Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk.
  3. ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances.
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