Novel analytical approach could aid quality control during nitrosamine analysis

A set of highly sensitive and specific generic liquid chromatography-mass spectrometry (LC-MS/MS) approaches could streamline method development when analysing small molecule N-nitrosamines in oral solid dosage forms (tablets).

The innovative in silico approach, proposed by a team of Belgium researchers, is based on quantitative structure retention relationship (QSRR) modelling and aims to address regulatory concerns regarding N-nitrosamine contamination.

“In trace analysis, the development of analytical methods poses considerable challenges as they must achieve sufficient sensitivity to reliably detect and quantify trace levels of analytes,” Zhang et al. noted.

While LC-MS/MS or GC-MS/MS, are frequently reported in literature, chromatographic development can be time-consuming and QSRR modelling offers a potential tool for predicting retention time.

As such, the proposed approach represents a significant advancement in method development by providing a reliable and robust analytical approach within an industrial framework.

Key study findings

The development process includes screening and optimisation phases, offering flexibility in targeting N-nitrosamines and addressing the challenges related to the matrix effect.

For instance, “the LC-MS/MS method provides a proof-of-concept for the QSRR-based approach when applied to a real case involving a finished product, where the significant presence of a component led to a pronounced matrix effect”.

According to Zhang et al., validation results demonstrated the method’s adequate quantitative performance, establishing a validated dosing range from 1 to 30 ng/mL for all N-nitrosamines.

The estimated detection limit ranged from 0.75 pg/mL to 0.02 ng/mL. Detection and quantification limits for each N-nitrosamine met the EMA N-nitrosamine investigation approach requirements.

The proposed method was also shown to be suitable for both limit testing and quantitative analysis of five N-nitrosamine impurities. Data showed that all required quantitative validation criteria were fulfilled.

Zhang et al. investigated flexible experimental conditions, including pH and gradient time, to optimise the LC separation of N-nitrosamines based on formulation compositions. 

Overall, the proposed approach supports marketing authorisation holders (MAHs) to comply with evolving regulatory requirements and overall manage N-nitrosamines impurities in pharmaceutical processes.

The paper was published in Journal of Pharmaceutical and Biomedical Analysis Open