What are Nitrosamines?
Nitrosamines are a group of highly potent mutagenic and carcinogenic compounds. These DNA-reactive impurities are closely regulated in pharmaceuticals under ICH M7 guidelines due to their high mutagenic and carcinogenic potential. They belong to the “cohort of concern” (COC) category, which includes compounds such as NDMA (N-nitrosodimethylamine), NDEA (N-nitrosodiethylamine), and N-nitrosoethylpropylamine, among others.
Nitrosamines can form through the nitrosation of the active pharmaceutical ingredient (API) or excipients, which poses significant risks to drug safety. These impurities may remain stable or increase over time, influenced by factors such as temperature, moisture, and storage conditions. Given the variability in nitrosamine formation, robust, stringent monitoring and control are essential to ensure the safety and quality of pharmaceutical products.
Ensure Safety and Compliance with Advanced Nitrosamine Testing
Partner with Emery Pharma to safeguard your pharmaceutical products from harmful nitrosamine impurities. We provide comprehensive analytical testing and quantitation services that meet regulatory standards, ensuring your products comply with US FDA, EMA, and Health Canada guidelines.
Why Choose Emery Pharma for Nitrosamine Risk Analysis in Your Biopharma, Drug Substance, or Drug Product Testing?
Analyzing nitrosamines can be extremely challenging, requiring the detection of ultra-low levels—often in trace, nanogram quantities—within complex drug matrices. Precision in method development is critical, followed by rigorous validation to meet GMP requirements.
Emery Pharma brings a distinguished history in nitrosamine testing, including our pioneering work in root cause analysis for the ranitidine molecule. With our extensive experience, as evidenced by our industry reputation and online presence, we are well-equipped to address these complexities.
Our advanced instrumentation includes state-of-the-art liquid chromatography-mass spectrometry (LC-MS/MS), gas chromatography-mass spectrometry (GC-MS), and high-resolution Orbitrap mass spectrometry (HR-MS), enabling us to detect, differentiate, and quantify nitrosamines with precision. In addition, we also employ a comprehensive toxicological and analytical risk assessment framework to evaluate drug substances and drug products.
Additionally, Emery Pharma will assist with risk analysis for both chemistry and toxicology, support you in developing acceptable intake limits, and perform limit calculations. We provide method validation for stability testing and continuous monitoring of nitrosamines over time. Our team can evaluate nitrate and nitrite levels in excipients, drug substances, or final products and offer advanced screening methods to assess nitrosamine-related risks.
Emery Pharma is uniquely equipped to handle both method development and validation of nitrosamine testing.
Our integrated team of analytical chemists and regulatory experts has deep knowledge in designing, optimizing, and validating analytical methods in accordance with ICH Q2(R1) guidelines.
Stepwise Approach to Method Development and Validation at Emery Pharma:
- Feasibility Assessment
- Identify the nitrosamines of concern based on API, excipients, and manufacturing process
- Select the most appropriate analytical platform (e.g., LC-MS/MS, GC-MS, HR-MS) based on expected analyte characteristics and sensitivity requirements
- Perform a risk assessment to determine potential nitrosamine formation pathways
- Review current regulatory expectations (e.g., FDA, EMA, WHO) for nitrosamine testing and control strategies
- Method Development
- Identify the nitrosamines of concern based on API, excipients, and manufacturing process
- Select the most appropriate analytical platform (e.g., LC-MS/MS, GC-MS, HR-MS) based on expected analyte characteristics and sensitivity requirements
- Perform a risk assessment to determine potential nitrosamine formation pathways
- Review current regulatory expectations (e.g., FDA, EMA, WHO) for nitrosamine testing and control strategies
- Method Optimization and Preliminary Testing
- Perform spike-recovery experiments, specificity assessments, and preliminary limit of detection (LOD) evaluations
- Establish linearity, signal-to-noise ratios, and reproducibility across relevant concentration ranges
- Assess interference from related substances and potential degradants
- Method Validation (as per ICH Q2(R2))
- Validate the following parameters:
- Accuracy
- Precision (repeatability and intermediate precision)
- Specificity
- Linearity
- LOD and LOQ
- Robustness
- System suitability
- Include matrix effect assessment if applicable
- Perform cross-validation if the method is to be implemented across multiple labs or platforms
- Document all results in a formal validation report with predefined acceptance criteria and a raw data summary
- Validate the following parameters:
- Transfer and Implementation
- Transfer validated methods to partner laboratories or manufacturing organizations, as needed
- Prepare a method transfer protocol including predefined acceptance criteria
- Support method transfer to contract manufacturing organizations (CMOs), partner labs, or internal QC groups
- Provide SOPs, training materials, and troubleshooting support to ensure smooth implementation
- Offer verification support during batch release, stability studies, and routine QC testing
- Ongoing Support and Lifecycle Management
- Monitor method performance trends using system suitability and QC data
- Reassess and requalify methods in response to manufacturing changes, formulation updates, or regulatory shifts
- Support deviation investigations (e.g., OOS/OOT results) and provide documentation for regulatory responses
- Update documentation and training materials as needed to reflect method improvements or revisions
Regulatory Strategy and Testing Requirements per European Medicines Agency and US FDA in developing a “Nitrosamine Risk Statement”
The regulatory strategy can simply be broken down into three critical steps:
- Evaluation of Nitrosamine Presence in API Manufacturing:
All synthetic procedures used to manufacture the API must be carefully assessed to ensure that no materials capable of forming nitrosamines are involved in the process. - Assessment of API and Component Nitrosatability:
It is essential to evaluate the potential nitrosatability of the API, excipients such as Carboxymethyl Cellulose (CMC), Microcrystalline Cellulose (MCC), etc and other components, as well as methodology to measure Nitrite and control their levels. This requires the development and validation of a robust analytical method to accurately assess this risk. - Implementation of Quality Controls to Mitigate Nitrosamine Formation:
Effective quality control measures should be put in place to minimize nitrosamine formation. Special attention must be given to highly volatile nitrosamines, such as NDMA or NDEA, as well as the potential nitrosation of APIs, excipients, or other components.
These guidelines emphasize the importance of thorough risk management and continuous monitoring to ensure drug products meet safety standards and remain compliant with regulatory expectations.
Tailored Testing Solutions
Whether you need routine screening or advanced impurity characterization, our customized partnership models support your unique needs. From fee-for-service to collaborative testing programs at Emery Pharma, to providing you a full FTE at your facility or at Emery Pharma’s facility, we are ready to scale with your operations.
Commitment to Patient Safety
By partnering with Emery Pharma, you can confidently deliver safe, compliant products to market while prioritizing patient safety and regulatory compliance every step of the way.