Since the Valsartan crisis in 2018, attention has shifted to an impurity that had long remained under the radar: nitrosamines. These potent genotoxic impurities, classified as probable human carcinogens, are not the result of isolated external contamination but a byproduct of specific chemical conditions during the manufacturing process. [1] Following global recall and media coverage, new quality control mandates were implemented, and Nitrosamines risk management is now a core component of drug development and quality control. What was once perceived as an API-related issue is now understood as a broader challenge, involving the entire value chain.
This evolving understanding invites us to challenge common perceptions and dive deeper into the role of suppliers.
Not all amines contribute equally to nitrosamines formation
Nitrosamines formation in drug products is influenced by many factors, but one of the main drivers are nitrites levels and conditions that promote their conversion. These include susceptible amines (secondary and tertiary), acidity, moisture, temperature, and processing or storage history. Nitrites levels can vary with excipient source and manufacturing conditions and may increase further under heat and humidity during storage.
Nitrate is indirectly risky as it is not a nitrosatable amine but can be reduced to nitrites under certain conditions.
While any formulation containing a nitrosatable amine may be at risk, the risk is not uniform across all APIs and excipients. Some excipients or suppliers may contain higher levels of nitrites than others for the same galenic role.
At an excipient level like lactose, residual nitrites can be traced back to milk/whey processing aids, water or process condition. This explains the significant intervariability between suppliers, driven by differences in raw materials, process conditions, and storage.
Beyond Europe: Nitrosamines assessment is a global regulatory expectation
Following the Valsartan recall in 2018, regulatory authorities required all pharmaceutical manufacturers to evaluate the risk of nitrosamine formation in marketed medicinal products. Since 2023, the EMA has revised monograph 2034 to include a section outlining the Ph. Eur. approach to controlling N-nitrosamine impurities. [3] In parallel, the FDA has updated its classification of nitrosamines, distinguishing well-known impurities such as NDMA (N-Nitrosodiméthylamine) and NDEA (N-Nitrosodiméthylamine) to NDSRIs (Nitroso Drug Substance-Related Impurities), while establishing associated acceptable intake limits.[4] Through these investigations, guidelines, and frameworks, the focus has gradually shifted toward a broader evaluation encompassing the entire product lifecycle.
That same year, the ICH M7(R2) guideline further supported this evolution by promoting a harmonized, risk-based approach to mutagenic impurities. As a result, control strategies now extend across the full value chain, from API synthesis to excipient selection. In this regulatory landscape, there is a stronger emphasis on traceability and impurity monitoring. [6]
This evolution has increased the role of excipient suppliers. Manufacturers now look for low-nitrite grades, tighter specifications, and suppliers who can provide reliable analytical data and consistent quality. Excipients are no longer seen as passive components. They are now part of an active risk management approach. More broadly, this shift has changed how manufacturers and suppliers work together, with greater focus on data sharing, transparency, and supply chain control.
End-to-end control is key to minimizing nitrites levels in excipients
In pharmaceutical quality control, nitrite remains the most frequently monitored parameter, as its control enables early intervention and proactive risk management upstream. The industry relies on three main analytical methods that are currently recognized for its assessment: ion chromatography (IC) for sensitive and selective quantification, Griess derivatization followed by LC-UV for trace detection in complex matrices, and headspace GC-MS for ultra-trace analysis across diverse excipients. [8]
Lactalis Ingredients Pharma consistently report pharmaceutical lactose range (Lactalpha ), nitrites levels ≤ 0.1 ppm. Nitrites testing is routinely performed on every batch, and the detailed values are included on each CoA (Certificate of Analysis). An independent external lab performs the analyses, and internally we transcribe the results and assess their relevance. , ensuring objectivity and reinforcing confidence in the data. Combined with deep expertise in dairy raw materials and processing, this approach ensures a reliable supply of low-nitrite lactose suited for highly sensitive pharmaceutical applications. [5] [7]
This enables precise and reliable nitrites quantification, while consistently low nitrite levels are achieved through tight, end-to-end control of the value chain. Leveraging strong expertise in dairy raw materials and processing, this approach supports a reliable supply of low-nitrite lactose.
In line with evolving regulatory expectations, collaboration between manufacturers and suppliers has become increasingly important. Collaboration between manufacturers and customers remains important, with standard supplier questionnaires such as IPEC being part of the baseline documentation expected in excipient quality management.
Agility is the new Quality
Regulators and manufacturers are moving toward higher standards where quality aligns with prevention. Suppliers like Lactalis are aware of this is both a responsibility and an opportunity. Showing consistently low nitrites levels and maintaining strong, continuousquality management on top of a sustainable approach, suppliers like Lactalis position themselves as strategic partners for manufacturers.
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Bibliographie
[1] Valsartan crisis: WHO recall
[2] Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation
[6] ICH Guidelines
[7] Nitrosamines Contamination in Pharmaceutical Excipients: Risks & Prevention
