Lakhasly

A worldwide crisis with nitrosamine contamination in medical products began in
2018 [1]. Since then, widespread investigations by regulatory agencies, including the European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA),
were undertaken. In drugs such as angiotensin II receptor blockers (ARBs), ranitidine, metformin, rifampin, rifapentine, and, recently, verenicline, N-nitrosodimethylamine (NDMA)
and other nitrosamines have been detected [2,3]. Nitrosamines are known as probable
human carcinogens (IARC 2A group for NDMA), potent genotoxic agents, and “cohort
of concern” compounds according to ICH M7 guidance [4,5]. They can form in reaction
of amine source (e.g., 2◦
, 3◦ amines, amidines, hydrazines) and nitrosating agents (e.g.,
nitrite in acidic conditions, nitrogen oxide, nitrous acid). According to newly established
guidelines, every marketing authorization holder has to identify the risk of nitrosamine
formation or cross-contamination in the manufacturing/storage of chemical and biological
medicines. Root causes of nitrosamine impurities in APIs (active pharmaceutical ingredients) and drug products can be manufacturing process related as well as stability of the
drug substance/product or excipient compatibility related (Figure 1) [6–8].
hydrazines) and nitrosating agents (e.g., nitrite in acidic conditions, nitrogen oxide, nitrous acid). According to newly established guidelines, every marketing authorization
holder has to identify the risk of nitrosamine formation or cross-contamination in the
manufacturing/storage of chemical and biological medicines. Root causes of nitrosamine
impurities in APIs (active pharmaceutical ingredients) and drug products can be manufacturing process related as well as stability of the drug substance/product or excipient
compatibility related (Figure 1) [6–8].
The scale of the problem is revealed by the fact that, till now, more than one thousand batches of medical products have been recalled from the market due to the detection of harmful nitrosamines [9].
A large number of studies also resulted in the introduction of new, more restrictive
legislation that regulated the concentration of nitrosamines in drug products. Therefore,
trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field
of quality control. Till now, a wide range of quantitative analytical methods to measure
nitrosamine traces in pharmaceuticals have been established, including gas chromatography with single quadrupole or tandem mass spectrometers (GC-MS/MS) with a headspace system or direct injection [10–12], liquid chromatography–tandem mass spectrometers (LC-MS/MS) or high-resolution mass spectrometers [13–16], and liquid chromatography with UV detectors and supercritical fluid chromatography (SFC) [17–19].
Solid-phase extraction (SPE), solid-phase microextraction (SPME), and dispersive liquid–liquid microextraction (DLLME) are also commonly used with GC-MS to produce
comparable results of the LOQ (range 0.5–1.5 ppb) to LC-MS/MS [20–22]. Many already
established methods are complex and can be applied to only one drug product/API, such
as ranitidine and metformin. Our newly established, sensitive analytical screening procedure involving microextraction is fast, simple, environmentally friendly, and with
limits of quantitation (LOQs) close to multi-step methods involving SPME or SPE extraction. Moreover GC-MS offers low operational costs, and is commonly used for analysis of volatile impurities in APIs. We demonstrate, for the first time, that our analytical
procedure can be successfully applied for various APIs selected for quantitative testin