December 10, 2024

What Are Nitrosamine Drug Substance-Related Impurities (NDSRIs)?

Nitrosamine Drug Substance-Related Impurities (NDSRIs) are a specific class of nitrosamines that form during the manufacturing, storage, or degradation of drug substances. NDSRIs are structurally related to the active pharmaceutical ingredient (API) and are formed when secondary or tertiary amines in the API or its intermediates react with nitro sating agents under certain conditions. Nitrosamines, including NDSRIs, are classified as probable human carcinogens by agencies like the International Agency for Research on Cancer (IARC) due to their potential to induce DNA damage.

Common sources of nitro sating agents include residual nitrites in water, excipients, or reaction solvents. Regulatory agencies worldwide, such as the U.S. FDA, EMA, and WHO, have emphasized the need for risk assessment and mitigation strategies to control nitrosamine levels in drugs.

 

Key Challenges Facing Pharmaceutical Companies Regarding NDSRIs

1. Complexity of Detection and Quantification

  • Detecting NDSRIs is technically challenging due to their structural similarity to APIs and typically low concentrations.
  • Advanced analytical techniques like LC-MS/MS, GC-MS, and HRMS are required, but their validation for NDSRIs can be resource-intensive.

2. Limited Toxicological Data

  • Many NDSRIs are unique to specific APIs, resulting in limited toxicological data for establishing acceptable intake limits.
  • Developing robust safety thresholds, such as Acceptable Daily Intakes (ADIs) or Permitted Daily Exposures (PDEs), is a significant challenge.

3. Regulatory Compliance

  • Adhering to stringent guidelines issued by global regulatory bodies like the FDA, EMA, and Health Canada requires comprehensive risk assessments, documentation, and frequent updates.
  • Differences in nitrosamine thresholds and requirements across regions add to the complexity.

4. Supply Chain Risks

  • Variability in raw materials, excipients, and manufacturing processes can introduce nitrosamine contamination.
  • Ensuring consistent quality and minimizing nitrosamine precursors across global supply chains demands strong oversight and collaboration.

5. Time and Cost Pressures

  • Implementing changes in manufacturing processes or formulations to mitigate NDSRIs can delay product launches and increase costs.
  • Analytical testing and toxicological evaluations require significant investment in time and resources.

 

Maven’s Approach to NDSRI Risk Assessment

Maven specializes in providing comprehensive solutions for assessing and mitigating risks associated with NDSRIs. Our approach is aligned with the latest regulatory requirements and focuses on ensuring safety, compliance, and continuity in pharmaceutical production.

1. Holistic Risk Assessment Framework

We adopt a systematic framework that includes:

  • Identification of Risk Factors: Evaluating API structures, raw materials, and manufacturing processes to identify potential nitrosamine precursors.
  • Prioritization of Risks: Categorizing APIs based on the likelihood of NDSRI formation and patient exposure.
  • Analytical Testing Strategy: Developing robust testing methodologies tailored to the specific API and its impurities.

2. Regulatory Compliance Support

Our team ensures adherence to international guidelines, including:

  • FDA’s Guidance on Nitrosamine Impurities.
  • EMA’s Questions and Answers on Nitrosamines.
  • ICH M7 and M13 Guidelines for assessing mutagenic impurities.

We also provide support in generating and submitting detailed risk assessment reports to regulatory agencies.

3. Toxicological Risk Assessment

Maven’s toxicology experts:

  • Conduct in-depth evaluations to establish ADIs or PDEs for identified NDSRIs using structure-activity relationship (SAR) models, read-across data, and in silico toxicology tools.
  • Provide guidance on risk mitigation strategies to maintain impurity levels below established safety thresholds.

QSAR and In Silico Modelling

Quantitative Structure-Activity Relationship (QSAR) models and in silico tools are central to our toxicological evaluations. By predicting mutagenic and carcinogenic potential based on chemical structure, we:

  • Rapidly screen for high-risk NDSRIs.
  • Leverage predictive models to prioritize impurities for further testing.
  • Utilize advanced computational tools to minimize reliance on in vivo studies.

4. Process Optimization and Mitigation Strategies

We collaborate with clients to:

  • Optimize Manufacturing Processes: Adjust parameters to minimize nitro sating conditions.
  • Control Raw Materials: Ensure the absence or minimization of nitrite impurities in excipients and reagents.
  • Enhance Storage Conditions: Recommend packaging and storage solutions to limit nitrosamine formation.

5. Comprehensive Documentation and Training

Maven assists clients in:

  • Preparing high-quality risk assessment reports, control strategies, and technical dossiers.
  • Offering training programs for internal teams to ensure compliance and awareness of evolving nitrosamine regulations.

 

Regulatory Bodies and Their Expectations

United States: FDA

  • Requires manufacturers to conduct risk assessments and implement appropriate controls for nitrosamines, including NDSRIs.
  • Emphasizes setting Acceptable Intake (AI) limits and using validated analytical methods.

Europe: EMA

  • Mandates marketing authorization holders to perform risk evaluations and, where necessary, provide confirmatory testing and mitigation strategies.
  • Stresses compliance with ICH M7 principles.

International: ICH

  • ICH M13 Guidelines focus on developing harmonized approaches for nitrosamine control in drug products.
  • Promotes the use of computational and predictive toxicology tools for risk assessment.

Other Regions

  • Agencies like Health Canada, TGA (Australia), and PMDA (Japan) follow similar stringent guidelines.

 

Conclusion

Managing NDSRIs requires a proactive and multidisciplinary approach. Pharmaceutical companies must integrate advanced analytical methods, toxicological expertise, and robust regulatory compliance mechanisms into their workflows. Maven’s end-to-end solutions offer tailored risk assessment and mitigation strategies, ensuring the safety and efficacy of drug products while maintaining compliance with global standards. By leveraging cutting-edge tools such as QSAR and in silico modelling, Maven empowers companies to confidently navigate the complex landscape of NDSRIs and ensure patient safety.