What are the genotoxic impurities in API?

Based on the route of synthesis for salmeterol xinafoate, bromo acetyl bromide and 1,6-dibromo hexane are suspected genotoxic impurities. TTC values indicate the permitted level for both of these impurities is 1500 parts per million (ppm) (see Figure 4).

Is benzene a genotoxic impurity?

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

What are the genotoxic impurities?

Genotoxic impurity (GI) analysis is critical to address the purity, safety and quality of drug substances or finished drug products. The ICH M7(R1) defines genotoxicity as “A broad term that refers to any deleterious change in the genetic material regardless of the mechanism by which the change is induced”.

How many types of genotoxic impurities are there?

According to ICH guidelines, impurities related to drug substances can be classified into three main categories: organic impurities, inorganic (elemental) impurities, and residual solvents.

What is the limit for genotoxic impurity?

A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals. From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose.

How can genotoxic impurities be controlled?

These strategies 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 …

How do you identify genotoxic impurities?

Guided by existing genotoxicity data or the presence of structural alerts, potential genotoxic impurities should be identified. When a potential impurity contains structural alerts, additional genotoxicity testing of the impurity, typically in a bacterial reverse mutation assay, should be considered (Dobo et al.

What is TTC level?

The Threshold of Toxicological Concern (TTC) is a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data.

What are genotoxic agents?

A genotoxin is a chemical or agent that can cause DNA or chromosomal damage. Such damage in a germ cell has the potential to cause a heritable altered trait (germline mutation). DNA damage in a somatic cell may result in a somatic mutation, which may lead to malignant transformation (cancer).

What is TTC in pharma?

The cancer TTC (Threshold of Toxicological Concern) concept is currently employed as an aid to risk assessment of potentially mutagenic impurities (PMIs) in food, cosmetics and other sectors.

What is TTC in genotoxic impurity?

What is genotoxic effect?

Abstract. A genotoxin is a chemical or agent that can cause DNA or chromosomal damage. Such damage in a germ cell has the potential to cause a heritable altered trait (germline mutation). DNA damage in a somatic cell may result in a somatic mutation, which may lead to malignant transformation (cancer).

What is genotoxicity example?

The genotoxic substances induce damage to the genetic material in the cells through interactions with the DNA sequence and structure. For example, the transition metal chromium interacts with DNA in its high-valent oxidation state so to incur DNA lesions leading to carcinogenesis.

What are 3 types of mutagens?

Mutagens – Physical, Chemical and Biological Mutagenic Agents.

What is ICH M7?

The ICH M7 guidelines are for the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals and they provide a practical framework that can be applied to the identification, categorization, qualification and control of mutagenic impurities to limit potential carcinogenic risk.

What is ICH m7 guideline?

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.

How can genotoxicity be prevented?

EURL ECVAM strategy to avoid and reduce animal use in genotoxicity testing

  1. enhance the performance of the in vitro testing battery so that fewer in vivo follow-up tests are necessary and.
  2. guide more intelligent in vivo follow-up testing to reduce unnecessary use of animals.

What are genotoxic drugs?

Genotoxic chemicals exert their adverse effect through interaction with genetic material (DNA) of cells. Genotoxicity tests are designed to detect drugs which can induce genetic damage directly or indirectly by various mechanisms of action.

What are genotoxic chemicals?

Genotoxic chemicals are substances that interact with DNA and may subsequently induce mutations. Owing to their DNA interaction properties, genotoxic chemicals are not considered to have a safe threshold or dose (2–4).

What are 5 mutagens?

Some of the common examples of mutagens are- UV light, X-rays, reactive oxygen species, alkylating agents, base analogs, transposons, etc.

What are 2 examples of mutagens?

Examples of mutagens include radioactive substances, x-rays, ultraviolet radiation, and certain chemicals.

What is ICH M7 R1?

M7(R1) Addendum to ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk; Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes | FDA. The .gov means it’s official.

How do you test for genotoxicity?

The most commonly applied methods for detecting genotoxicity include the bacterial Ames test, DNA strand break measurements in cells (e.g. comet assay, alkaline unwinding and hydroxyapatite chromatography, alkaline elution), and cytogenetic assays (micronucleus and chromosomal aberration assays, including the use of …

Which chemicals are mutagens?

Definition. A mutagen is a chemical or physical agent capable of inducing changes in DNA called mutations. Examples of mutagens include tobacco products, radioactive substances, x-rays, ultraviolet radiation and a wide variety of chemicals.

How is TTC limit calculated?

For substances that have the potential to be DNA-reactive mutagens and/or carcinogens based on the weight of evidence, the relevant TTC value is 0.0025 μg/kg body weight (bw) per day. For organophosphates or carbamates, the relevant TTC value is 0.3 μg/kg bw per day.