Nitrosamines became a hot topic in the pharma industry when small amounts were detected in a number of drug products a few years ago. They are classified as Class 2A carcinogens because of their known reactivity with DNA, and they are also mutagenic.
The issue first came to light in 2018, when N-nitrosodimethylamine, or NDMA, was detected in several brands of the generic blood pressure lowering agent valsartan, leading to product recalls. A year later, the same problem was found with the generic antiulcer drug ranitidine. Cue more recalls and, ultimately, the drug was withdrawn, as in this case the NDMA was not a contaminant – it was a degradation product of the drug itself.
Unsurprisingly, the regulators started to require routine testing of drug products for NDMA, and some batches of the diabetes drug metformin were also recalled. Various other drugs have also been affected, including antibiotics.
Regulatory authorities, including FDA and EMA, now require risk assessments to be carried out as part of the qualification process for both drug products and intermediates. It is not enough simply to screen the products for nitrosamines at product release stage: the possibility of growth under relevant storage conditions must be carefully considered too. Pharma companies and any CDMOs they work with share the responsibility of ensuring the nitrosamine risk is fully understood, and any risk is mitigated such that any nitrosamine impurities remain within acceptable limits.
The risk factors
There are three risk factors for nitrosamine formation in drug products, and if all three are present, then alarm bells should be ringing. First, a secondary amine needs to be present, whether this is aliphatic or aromatic, a free base or a salt. It could be found in the API itself, a degradation product, or a contaminant arising from traces of solvent, intermediates, reagents or catalysts. Secondary amines are far more likely to form nitrosamines than tertiary, quaternary or primary amines.
Second, the conditions need to be conducive to the reaction. Temperature, pH, concentration, kinetic energy, and the presence of water or nitrosation catalysts might all have an impact. And finally, there will need to be some form of nitrosating agent present. This might be a reagent, such as nitrites, nitric acids, nitrosoalkyls or nitroalkyls. It could be an inorganic nitrite from an excipient, a trace contaminant in water, or even from the degradation of the API or an intermediate.
The presence of nitrites in a drug product, even as mere traces, would be sufficient to cause nitrosamine formation if the other two risk factors are met. They may arise during API synthesis, but could also come from the reagents, solvents (particularly if water or an organic amide solvent is used), or from quenching agents. On the drug product side, nitrite contaminants might also come from process aids, with water again a potential culprit, as are other solvents, particularly if they have been recycled. Nitrocellulose may be present in the packaging, and inadequate equipment cleaning might lead to carryover.
Perhaps the biggest hidden source of nitrites, however, is the excipients used during product formulation. Suppliers now regularly test for nitrites, but amounts can vary widely according to the excipient source.
Assessing the risk
A robust risk assessment strategy is essential for every drug product. At Lonza, we have developed a structured and science-driven process to reliably identify, evaluate, and mitigate risks, helping our customers safeguard both products and patients.
The process begins with a simple screening step: determining whether the API or excipients contain amine groups. If none are present, the risk of nitrosamine formation can be confidently ruled out.
When amines are identified, we move to a paper-based assessment. Using data from excipient suppliers, we estimate potential nitrite levels in the drug product. We then identify suitable surrogate compounds with established acceptable intake limits and calculate whether these thresholds might be exceeded, based on the projected nitrite and amine levels.
If the acceptable intake could be exceeded, we will work together with our clients to establish a confirmatory testing strategy that delivers reliable and actionable results.
Where nitrosamines may be present above 10% of the acceptable level, we establish specification limits and implement a targeted mitigation strategy. This may include reformulation, changes to the process, or using different packaging, always with the goal of reducing risk effectively and sustainably.
By embedding this process early in development, well before process performance qualification, we help ensure that risks are controlled, regulatory expectations are met, and most importantly, patient safety is protected.
Managing the risk of nitrosamine formation requires foresight, expertise, and a structured approach. With Lonza’s proven risk assessment and mitigation process, you gain a trusted partner who can help you navigate complexity, ensure patient safety, and accelerate development with confidence.
Partner with Lonza to ensure your drug products meet the highest standards of safety and compliance. Connect with our experts today to learn how we can support you.