Nitrosamines such as N-nitrosodimethylamine (NDMA) have been shown to be genotoxic and carcinogenic in animals and are considered probable or possible carcinogens in humans.
For nitrosamine analysis, Alcami has the experience, technology, and testing platform to assist at all stages of nitrosamines assessments. As with other risk-based assessments, the exact approach is not clearly defined in the regulatory guidance. Certain APIs and Raw Materials have been identified as high risk for containing formed nitrosamines, containing secondary amines, or nitrosating agents that could result in the formation of a nitrosamine. There are 2 phases to nitrosamine compliance: assessment and testing.
All phases of the drug product manufacturing should be assessed for the nitrosamine formation risk.
- API manufacturing
- Drug Product manufacturing
- Container closure
From the paper assessment, it should be determined if formed nitrosamines may come from a source or if the formation of a nitrosamine is possible, i.e. secondary amine and nitrosating agents coexist in any step or are present in large quantities in separate processing steps. From this assessment, the identity of the potentially present nitrosamines can be determined. Alcami can assist in determining the risk of nitrosamine formation and generate a risk assessment report to outline process steps and overall nitrosamine risk.
Alcami offers two different nitrosamine assessments:
- Screening – R&D testing using Alcami’s in-house nitrosamine method to determine if nitrosamines are detected in a raw material or drug product
- Method Validation and Testing – This level of testing would be necessary when nitrosamines are detected in a material associated with the production of the drug product or the drug product itself or when the paper-based assessment indicates that the two components necessary for the formation of a nitrosamine are present in a step.
For screening, development, and method validation, Alcami has eight LCMS instruments (QQQ and QTOF) and four GCMS instruments that can be leveraged in the establishment of control methods for nitrosamines. Alcami’s mass spectrometry team offers more than 50 years of experience in mass spectrometry development or risk-based assessment testing strategies.
Acceptable Intake (AI) limits for individual nitrosamines have been proposed at levels of 26.5 – 96 ng/day. The allowed nitrosamine content in a drug substance or drug product would depend on the maximum daily dose and the period over which the drug will be used. FDA guidance suggests that methods used for nitrosamine testing should have limits of quantitation (LOQs) at or below 0.03 ppm.
Potential sources of nitrosamine precursors:
- Secondary and other amines
- APIs and intermediates
- Formulation catalysts
- Amide solvents such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, and N,N-diethylacetamide
- Impurities in amide solvents
- Impurities in quaternary amines such as tetrabutylammonium bromide
- Other reagents containing amine groups
- API degradation*
- Impurities in raw materials and solvents*
- Recovered solvents, reagents, and solvents*
- Inadequate or unvalidated cleaning procedures*
- Nitrosating agents
- Nitrous acid (used to quench residual azides)
- Nitrite salts (can form nitrous acid)
- Impurities in nitrate-containing raw materials
- Container closure system impurities, especially if they contain nitrocellulose or nitrites)*
- Potable water*
*May also contain fully formed nitrosamines.
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