Mutagenicity Assessment of Impurities and their classification as per ICH M7

ICH M7 guideline provides the internationally harmonized framework for identification, classification and control of mutagenic impurities (DNA reactive compounds).  It describes the risk assessment and control of DNA reactive/mutagenic impurities (genotoxic impurities) in pharmaceuticals to limit potential carcinogenic risk.

Our Mutagenicity Assessment Service uses state-of-the-art computational toxicology to predict the mutagenicity of impurities in pharmaceutical compounds. This service is essential for companies aiming to ensure the safety and quality of their products while adhering to regulatory standards.

We use two (Q) SAR Software as per recommendation given, for computational toxicology.

  1. Statistical-Based Models
  2. Expert Rule-Based Models

Veeprho’s Comprehensive Mutagenicity Assessment Service

We offer services on Computer Assisted Control Strategy for Genotoxic & Nitrosamine impurities, in Line with Requirement of ICH M7 & FDA guidance.

If your Drug Manufacturing Process involves  the use of highly reactive  reagents their reactivity can lead to formation of mutagenic process impurities, in case they are not removed efficiently. We can support the precise assessment on removal of such a material using a computer assisted tool. The tool can be used for de-risking the formation of nitrosamine as well.

  • Comprehensive Mutagenicity Assessment: Employing (Q)SAR methodologies for accurate prediction and classification of genotoxic impurities.
  • Regulatory Submission Support: Providing detailed reports including classification of impurities, scientific rationale, and support for regulatory submissions.
  • Expert Summary: Offering an expert summary that outlines the classification of impurities and provides a scientific rationale based on computational toxicology.

Our value proposal

The M7 guideline defines the approach for control strategy of process related impurities and also recommends understanding process parameters and impact on residual impurities. This includes fate and purging with sufficient confidence that the level of impurity in the final drug substance will be below the acceptable level so that analytical testing is not required. Likewise, the FDA guidance document recommends a similar mitigation strategy for the presence of nitrosamine impurities in API.

The fate and purge assessments involve the application of understanding of physicochemical properties to an impurity in relation to the reaction and subsequent purification conditions to which it is exposed.

A computer assisted tool allows for a rapid, reproducible semiquantitative measure of this risk assessments of mutagenic impurities, including Nitrosamine.

The Final Assessment Report includes: 

  • The purge calculation, 
  • Scientific rationale
  • Supporting evidence to aid in the submission to regulators.

The assessment report can save substantial amounts of time and resource without increasing risk to patients.

Why are Mutagenicity Assessments required?

Impurity risk assessment is an important process. Actual and potential impurities that are likely to arise during the synthesis and storage of a new drug substance, and during manufacturing and storage of a new drug product should be assessed. 

  • Mitigating Risk: Identifies chemical compounds (impurities) that could cause DNA damage, crucial for maintaining the safety and quality of pharmaceuticals.
  • Regulatory Compliance: Necessary to meet regulatory guidelines that demand control of such impurities at low levels.
  • Ensuring Product Safety: Helps ensure the quality and safety of pharmaceutical products, protecting patient health.

Impurity identification

Potential impurities in the drug substance can include starting materials, reagents and intermediates in the route of synthesis from the starting material to the drug substance. Potential degradation products in the drug substance and drug product are those that may be reasonably expected to form during long term storage conditions. Other impurities include starting material impurities, reagents, carry-forward impurities.

Why Choose Veeprho?

  • Regulatory Compliance: Our service is specifically designed to meet the stringent requirements of ICH M7, ensuring your pharmaceutical products comply with global regulatory standards for genotoxic impurities.
  • Expertise in Computational Toxicology: Leverage the expertise of our team in computational toxicology to gain insights into the genotoxic potential of impurities, facilitating informed decision-making and strategic planning.
  • Efficiency and Cost-Effectiveness: (Q)SAR methodologies provide a rapid and cost-effective alternative to traditional mutagenicity testing, reducing the need for extensive laboratory testing without compromising on accuracy or reliability.
  • Tailored Support: From the initial assessment to the final regulatory submission, we offer tailored support to address your specific needs, ensuring a seamless and successful evaluation process.

Compliance with drug safety and regulations

To fulfil the requirement of the guideline, the structure-based assessments are useful for predicting bacterial mutagenicity. Further impurities classification with respect to mutagenic and carcinogenic potential can be performed as follows:

  • Class 1. Known mutagenic carcinogens. Also known as Cohort of concern
  • Class 2. Known mutagens with unknown carcinogenic potential (bacterial mutagenicity positive, a no rodent carcinogenicity data)
  • Class 3. Alerting structure, unrelated to the structure of the drug substance; no mutagenicity data.
  • Class 4. Alerting structure, same alert in drug substance or compounds related to the drug substance (e.g., process intermediates) which have been tested and are non-mutagenic.
  • Class 5. No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicity.

The guideline outlines how a hazard assessment should be performed for the assignment of each impurity to one of five classes. If data for such a classification are not available, an assessment of Structure-Activity Relationships (SAR) that focuses on bacterial mutagenicity predictions should be performed. A computational toxicology assessment should be performed using (Q)SAR methodologies that predict the outcome of a bacterial mutagenicity assay. 

The process flow for performing Mutagenicity Assessments


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Frequently Asked Questions About our Mutagenicity Assessment Services

What is Mutagenicity?

The risk posed by chemical compounds (impurities) that cause DNA damage.

Why Perform a Mutagenicity Assessment?

Regulatory guidelines require such impurities in pharmaceutical compounds to be controlled at low levels to ensure product safety.

Benefits of Mutagenicity Assessment?

Helps ensure the quality and safety of pharmaceuticals, critical for protecting public health.

Consequences of Skipping Mutagenicity Assessment?

Failure to perform appropriate assessments can result in 483s or warning letters from health authorities due to unacceptable levels of mutagenic impurities.

Do Pharmacopoeia Impurities Require Assessment?

Yes, all impurities related to APIs and formulations, including process-specific and pharmacopeial impurities, need to be assessed.

Classification of Impurities?

QSAR analysis allows for the classification of impurities as genotoxic or non-genotoxic based on their structural alerts.

Impact of Classification on QA and Regulatory?

Impurities classified as genotoxic require strict quality control measures. Regulatory submissions must detail the classification of all impurities and their control strategies.

Tools for Mutagenicity Assessment?

We use computational assessment tools for QSAR analysis as per ICH M7 requirements, including statistical and expert rule-based analyses.

Interpretation and Conclusion?

Every report is provided with a classification, justification, and conclusion for all listed impurities, supporting quality assurance and regulatory compliance.

Our Approach

Our mutagenicity assessment process is grounded in a thorough understanding of the chemical structure of impurities, leveraging (Q)SAR models to predict their potential genotoxic effects accurately. This approach is complemented by our team’s expertise in computational toxicology and regulatory requirements, ensuring a comprehensive assessment that supports your product’s safety and compliance.

Contact Veeprho For Mutagenicity Assessment Services

To learn more about how our Mutagenicity Assessment Service can support your pharmaceutical development and manufacturing processes, contact us today. Our experts are ready to assist you in navigating the complexities of ICH M7 compliance and ensuring the safety of your products.

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