Introduction: The Rising Need for Nitrosamine Impurity Testing for Drug Products
Nitrosamines have emerged as a major safety concern in pharmaceutical manufacturing, prompting stringent regulatory scrutiny worldwide. Regulatory bodies like the USFDA, EMA, and Health Canada have issued mandatory requirements for identifying and controlling nitrosamine impurities in human drug products. As a result, nitrosamine impurity testing for drug products has become an essential component of the pharmaceutical development and approval lifecycle. At ResolveMass Laboratories Inc., we offer end-to-end testing solutions designed to detect, quantify, and mitigate nitrosamine impurities in both active pharmaceutical ingredients (APIs) and finished drug products.
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What Are Nitrosamines?
Nitrosamines are a class of compounds recognized for their potential genotoxic and carcinogenic properties. These impurities typically form through reactions between secondary or tertiary amines and nitrosating agents under specific chemical conditions. Common nitrosamines like NDMA, NDEA, and NMBA have been detected in various drug formulations, leading to product recalls and regulatory warnings. Therefore, robust nitrosamine impurity testing for drug products is vital for ensuring patient safety and regulatory compliance.
Regulatory Expectations for Nitrosamine Impurity Testing for Drug Products
USFDA Guidelines
The USFDA mandates a structured three-step process:
- Risk Assessment
- Confirmatory Testing
- Regulatory Reporting
Any risk identified during development or commercial manufacturing must be accompanied by validated nitrosamine impurity testing for drug products, including robust analytical methods and proposed control strategies.
Health Canada and EMA Guidelines
Both agencies echo similar requirements. Health Canada emphasizes:
- Clear risk assessments
- Confirmatory data from validated methods
- Justified timelines for mitigation
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Common Sources of Nitrosamines in Drug Products
A key element in nitrosamine impurity testing for drug products is identifying potential precursors and triggers. These include:
- API synthesis pathways involving amine reagents or solvents
- Excipients such as nitrite-containing preservatives
- Manufacturing environments with acidic or oxidative conditions
- Packaging materials that may leach reactive compounds
Analytical Techniques Used for Nitrosamine Impurity Testing for Drug Products
At ResolveMass Laboratories, we use advanced instrumentation to support all phases of nitrosamine impurity testing for drug products:
GC-MS and GC-MS/MS
For volatile nitrosamines like NDMA and NDEA, our gas chromatography-mass spectrometry systems offer limits of detection (LOD) in the ppb range.
LC-MS/MS
Used for non-volatile and thermally unstable nitrosamines, particularly nitrosamine drug substance-related impurities (NDSRIs).
High-Resolution Mass Spectrometry (HRMS) for Nitrosamine Impurity Testing for Drug Products
Ideal for confirmatory analysis and structural elucidation of novel or unexpected nitrosamines.
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Step-by-Step Nitrosamine Impurity Testing for Drug Products
Step 1: Structural Risk Analysis for Nitrosamine Impurity Testing for Drug Products
- Review of API and excipient composition
- Retrosynthetic evaluation for NDSRI formation
- Identification of nitrosatable motifs
Step 2: Method Development and Validation
- Creation of tailored GC-MS or LC-MS/MS methods
- Validation parameters: specificity, sensitivity, accuracy, precision
- Matrix compatibility studies
Step 3: Confirmatory Testing and Batch Screening
- Testing across commercial and pilot batches
- Trending and stability data under ICH conditions
- Detection of trace impurities down to sub-ppb levels
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Nitrosamine Standard Synthesis for Method Validation
A key differentiator at ResolveMass is our capability to synthesize nitrosamine reference standards. This supports:
- Accurate method validation
- System suitability testing
- Impurity benchmarking
Our synthesized standards undergo full structural characterization using NMR, LC-MS, and elemental analysis.
Case Study: Mitigating Nitrosamines in a Modified-Release Product
A client faced challenges with secondary amines and nitrate salts in a modified-release matrix. Our strategy included:
- NDSRI prediction using in-silico tools
- LC-MS/MS method validation with synthesized standards
- Confirmatory testing for 3 different nitrosamines
The result: successful mitigation strategy and NDA submission approved by Health Canada.
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Why ResolveMass Laboratories for Nitrosamine Impurity Testing for Drug Products?
- Over a decade of experience in genotoxic impurity testing
- Full-service support: risk assessment, synthesis, testing, reporting
- Industry-leading instrumentation and turnaround time
- Trusted by pharmaceutical innovators and generics
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Conclusion: Securing Compliance Through Nitrosamine Impurity Testing for Drug Products
Nitrosamine impurity testing for drug products is an indispensable part of drug development, safety assurance, and regulatory compliance. From early risk assessment to confirmatory testing and impurity synthesis, ResolveMass Laboratories is your trusted partner for robust, scientifically sound nitrosamine solutions. We ensure you stay ahead of regulatory expectations and deliver safe, compliant pharmaceutical products to the market.
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ResolveMass Laboratories Inc.: Experience, Expertise, and Trust You Can Count On
ResolveMass Laboratories Inc. has established itself as a trusted name in the domain of nitrosamine testing services in Canada. With over a decade of dedicated experience, we have completed hundreds of successful nitrosamine testing and risk assessment projects for both domestic and international clients. Our scientists possess advanced degrees in analytical chemistry and pharmaceutical sciences, bringing a wealth of expertise to every project.
We are one of the few Canadian CROs to offer a complete in-house nitrosamine testing solution—from risk assessment to confirmatory analysis, regulatory documentation, and expert consultation. We continually invest in cutting-edge technologies and method development, keeping pace with evolving regulations and industry demands.
Our clients trust us because we not only deliver accurate results but also help them understand and resolve complex impurity challenges. Choose ResolveMass Laboratories for your nitrosamine testing services in Canada—where precision meets reliability.
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References
- EMA. (2021). Assessment and Mitigation of Nitrosamine Risk in Human Medicines. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf
- FDA. (2021). Control of Nitrosamine Impurities in Human Drugs. https://www.fda.gov/media/141720/download
- Health Canada. (2020). Guidance on Nitrosamine Impurities in Medications. https://www.canada.ca/en/health-canada/services/drugs-health-products.html
- ICH. (2023). ICH M7(R2) – Control of Mutagenic Impurities. https://database.ich.org/sites/default/files/M7_R2_Guideline_Step4_2023_0223.pdf
