Atmospheric NOₓ may contribute to NDSRI formation, study shows

Nitrite levels in excipients commonly used in solid oral dosage forms, should be regarded as dynamic values influenced by atmospheric NOₓ exposure, “not static material attributes”, according to a new study by scientists from Merck Healthcare KGaA and Lek Pharmaceuticals (a Sandoz company). 

The findings follow recent reports documenting nitrite impurities in excipients “as a root cause for nitrosamine formation”. This has led excipient manufacturers to begin “listing nitrite content in their IPEC declarations, with some now offering explicitly labelled ‘low-nitrite’ grades”.

According to the paper’s authors Grahek et al., analytical data compiled from a consortium of pharmaceutical companies through the Lhasa Nitrite Excipient Database, illustrate “the substantial batch-to-batch and manufacturer-to-manufacturer variability in excipient nitrite content”.

Notably, the study findings suggest that this ‘lower-nitrite grade’ “may not be sufficient to ensure consistently low nitrite levels in the drug product, but other elements of risk mitigation may be required as well, eg, additional control of critical process steps such as tablet coating”.

Therefore, overall risk for a pharmaceutical dosage form will strongly depend on multiple factors, including the excipient itself, ie, “excipients with moderate tendency for nitrite uptake may exhibit a higher risk to the dosage form if they are abundant in the formulation”.

[process air quality is] a critical, and often underappreciated, control variable in excipient manufacturing for effectively mitigating nitrosamine formation risk in pharmaceutical products”

Another key observation from the study was process air quality being a “critical, and often underappreciated, control variable” in excipient manufacturing for effectively mitigating nitrosamine formation risk in pharmaceutical products.

Together, the results have several practical implications for risk assessment and control of nitrosamine formation in solid oral products:

• Excipients differ intrinsically in their ability to form and retain nitrite upon NOx exposure, as findings showed “exposure to NO2 consistently produced greater nitrite formation than exposure to NO”
• Basic carbonate-type excipients may accumulate nitrite substantially without proportionally increasing nitrosamine formation risk because the nitrite is trapped and the carbonates create a basic micro-environment unfavorable for nitrosamine formation. On the other hand, starch or cellulose derivatives can present higher practical concern due their combination of moderate nitrite uptake potential and high content in typical formulations.
• High-air-throughput operations, including fluid-bed drying, granulation and film coating, may represent relevant sources of NOx exposure and should be considered during nitrosamine risk assessments
• Handling practices are important when dealing with small sample as in analytics. Minimising open exposure of NOx-susceptible materials to ambient air can reduce nitrite pickup and reduce unexpected variability of results.

However, the authors noted their findings should “provide relative, not absolute, metrics of nitrite uptake susceptibility”.

Grahek et al. therefore recommended a risk-based assessment of a drug product and process that considers “not only initial nitrite contents of used excipients, but also manufacturing-related risks and the intrinsic properties of formulation components.”

The paper is due to be published in the Journal of Pharmaceutical Sciences in November 2026.