Pharmaceutical nitrosamine analysis: from risk to targeted quantification

Mastering nitrosamine risks has become a major challenge for pharmaceutical manufacturers, both in development and in production, in deviation investigations, change control, or litigation contexts. After risk assessment, it is often necessary to confirm the presence or absence of target compounds, to look for unlisted NDSRI, and then to quantify them at trace levels compatible with regulatory expectations. This approach requires a robust analytical strategy, tailored to the matrix, the active substance, the excipients, and the finished product. In this context, nitrosamine analysis must make it possible to quickly guide quality decisions, document compliance, and secure investigations in a GMP environment. To complement a global impurity approach, it may be relevant to combine this work with GMP analysis and, depending on the needs, with a pharmaceutical ICP analysis for other critical impurity families.

Industrial needs are not limited to the best-known nitrosamines. In practice, the investigation may concern nitrosamines monitored by regulation, but also specific compounds related to the process, the amines present, solvents, synthesis aids or storage conditions. A tailor-made approach makes it possible to search for nitrosamines not initially listed, including NDSRI, when the risk assessment highlights a plausible formation scenario. High-resolution screening then becomes a useful tool for guiding the next analytical steps.

The choice of technique depends on the nitrosamine profile, the complexity of the matrix and the expected trace level. Qualitative and semi-quantitative screening can be carried out by LC-HRMS using an Orbitrap system to detect known or suspected compounds. For targeted quantification, LC-MS/MS and GC-MS/MS approaches provide the required selectivity and sensitivity. Depending on the case, total nitrosamine analysis may also be considered using an ATNC method for complementary assessment. This instrumental foundation is part of a broader laboratory characterization offering, including for example the Laboratoire analysis Met for advanced surface or material characterization needs when the project context requires it.

Nitrosamine testing requires rigorous quality organization, strong document traceability and practices compatible with the expectations of the pharmaceutical sector. An expert laboratory operating in a GMP environment provides a framework suited to sample management, securing analytical data and delivering results that can be directly used by quality, production and regulatory affairs teams. This approach is particularly useful during a supplier change, a deviation, an OOS, a complaint investigation or a variation dossier.

An expert laboratory supports manufacturers of raw materials, active substances and finished products in the search for, identification of, targeted quantification of and method validation for many nitrosamines. Services cover qualitative and semi-quantitative screening, trace-level quantification, development of methods specific to a molecule or matrix, as well as analytical validation according to ICH Q2 (R2). analysis may focus on frequently monitored compounds such as NDMA, NDEA, NMBA, NPIP, NMOR, NPYR, NDBA, NDIPA or other product-related substances. Validation work for a quantification limit of 0.1 microgram per kilogram, i.e. the ppb level, can also be carried out when the criticality of the file requires it. To place these requirements in the context of the compliance timeline, see also Dosage Des Nitrosamines Rappel Des Echeances.

Targeted quantification can be performed on raw materials, active substances, intermediates, excipients and finished products. Compounds such as NDMA, NDEA, NEIPA, NDIPA, NMBA, NDBA, NMOR, NPYR, NPIP, NDELA or other nitrosamines can be quantified depending on the nature of the sample and the target thresholds. When needed, the study may include verification of the quantification limit, confirmation using a second technique and the use of results for investigation or conditional release purposes.

The expected performance in pharmaceutical analysis requires control of the method’s specificity, accuracy, precision, linearity, and robustness. An expert laboratory can develop and then validate the method according to ICH Q2 (R2), with estimated quantification limits from 0.1 to a few ppb depending on the substance and the matrix. This capability is decisive for compliance dossiers, batch comparison studies, contamination investigations, and requests from customers or authorities.

The effectiveness of a nitrosamine analysis campaign also depends on the availability of equipment and expertise. An analytical platform made up in particular of UPLC-MS/MS, LC-ORBITRAP, LC-QTOF, GC-MS and GC-MS/MS systems, combined with a large technical team with dedicated specialists, makes it possible to handle both standard requests and complex issues. This capability promotes responsiveness, the development of specific methods and the handling of multiple matrices within the same project.

To initiate your project, you should provide the product type, development stage, matrix, suspected or targeted nitrosamines, expected thresholds, as well as the quality or regulatory context. Based on these elements, an expert laboratory can define the analytical strategy, propose screening or targeted assay, specify the method development or validation needs, and establish a suitable test plan. Depending on your file, it is also possible to integrate complementary chemical impurity analysis, for example via Analyse Icp Pharmaceutique.