Nitrosamines

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.

Paper Assessment:

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.

Testing:

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.