Nitrosamine impurities in pharmaceuticals: Why excipient selection and formulation understanding must go together

by Philippe Tschopp Glatt Pharmaceutical Services – CDMO Unlimited, November 2026
This short article is based on the presentation at the HPC webinar Nitrosamine Impurities in Pharmaceuticals, 31 October 2026 and then expanded with scientific publications and regulatory sources.

A supplier reports a low nitrite value. The excipient meets its specification. The formulation performs well during development. Yet one important question remains: what happens when that material meets a susceptible drug substance, passes through manufacturing and stays in the finished product for its entire shelf life?

This was the focus of my contribution to the HPC Firm webinar on 31 October. From a formulator’s perspective, nitrosamine prevention requires us to connect information that often sits in separate places: the supplier’s analytical result, the quantity of each excipient, the chemistry of the API and the conditions inside the dosage form.

The practical challenge is to understand how these factors interact and which intervention will produce a measurable, lasting improvement.

An excipient can contribute to nitrosamine formation without containing a nitrosamine

Nitrite and nitrosamines are different substances. An excipient containing trace nitrite does not automatically contain the nitrosamine that may eventually appear in a medicine.

For the pathway considered here, nitrite provides a potential nitrosating source. A susceptible amine in the API or an API related impurity provides the reaction partner. Manufacturing and storage conditions influence whether, and how quickly, the reaction proceeds. Nitrosamine drug substance related impurities, or NDSRIs, share structural similarity with the API. [1,2]

That distinction changes the question asked of a supplier. A statement about the absence of nitrosamines cannot, on its own, answer whether an excipient contributes nitrite to a formulation. The product developer needs information relevant to the potential formation pathway.

This article concentrates on that formulation pathway. A complete assessment must also consider other routes by which nitrosamines or their precursors could enter the product. [1]

The most important number may be nanograms per tablet

Comparing excipients by their nitrite concentration alone can lead to the wrong priority. The amount used in the formulation matters just as much.

The hypothetical example from my presentation illustrates this clearly. These figures are calculation inputs, not typical market values or specifications for the named excipients.

When ppm is expressed as micrograms of nitrite per gram of excipient, the calculation is straightforward:

Nitrite input in ng = excipient quantity in mg × nitrite concentration in ppm.

Magnesium stearate has the highest concentration in this example. MCC contributes six times as much nitrite because the formulation contains much more of it. Reducing the MCC value from 0.6 to 0.2 ppm would remove 80 ng from the calculated input per tablet. Reducing the magnesium stearate value from 4 to 1 ppm would remove 15 ng.

These are useful comparisons for selecting experiments. They do not predict the amount of NDSRI formed. A conversion model would additionally need a chemically justified molar relationship and evidence about the fraction that reacts under the relevant conditions. Directly comparing 210 ng of nitrite with an acceptable intake expressed in ng of a particular nitrosamine would compare different substances.

A database helps identify priorities, while qualification establishes control

Lhasa’s 2026.1 release announced more than 3,000 nitrite results, illustrating the growing shared evidence base. Such resources help development teams identify materials worth investigating. [3]

For a commercial formulation, however, the useful unit of information is the actual material: its grade, manufacturing source, lot history and analytical method. A database entry under an excipient name cannot establish the behaviour of every product sold under that name.

My practical recommendation is to request results from several representative lots, together with the method and relevant manufacturing information. The IPEC Federation’s updated Questionnaire for Excipient Nitrosamines Risk Evaluation, version 2 from 2025, provides a standardised starting point for that supplier discussion. [4]

The conversation should also establish what will trigger notification and reassessment. If an approved source changes its manufacturing process, the development team needs to understand whether the evidence supporting its original selection still applies.

A low result is only useful if the method can support it

Blom and colleagues’ 2026 comparison involved six laboratories analysing lactose, MCC and magnesium stearate. Lactose gave consistent results. Magnesium stearate showed the greatest variability, with sonication during sample preparation contributing to differences. Matrix interference complicated the assessment of the selected MCC lots. [5]

The implication is practical: a difference between two certificates may reflect both material variability and analytical variability. Extraction conditions, recovery, specificity and the limit of quantification belong alongside the reported number.

For example, “below 0.1 ppm” and “below 0.5 ppm” provide different levels of analytical assurance. Neither means zero. When constructing a preliminary nitrite budget, a team can examine an upper bound scenario using the reporting limit for an unquantified result, explicitly identifying this as an assumption. If that assumption drives the risk conclusion, better analytical resolution becomes a development priority.

Nitrite levels may change after the excipient leaves its manufacturer

Grahek and colleagues investigated nitrite accumulation during exposure of excipients to nitrogen oxides, or NOₓ. Their results showed that uptake depended on material properties, including pH and specific surface area. They also observed increases during ambient laboratory air exposure. [6]

The study adds an important dimension to material qualification. An incoming result describes a sample at a particular point in its history. Subsequent exposure may alter the material.

For operations involving substantial airflow, such as fluid bed granulation or film coating, this provides a reason to investigate process air and exposure conditions where relevant. It does not establish that every such operation produces a significant increase in nitrite. The authors themselves identify manufacturing studies as a further need.

A useful investigation would compare incoming material, exposed intermediates and finished product under representative conditions. Air treatment should be justified by evidence that it addresses an actual source in that process.

Reducing nitrite must preserve the function of the excipient

Source reduction is a sensible first screening step. A lower nitrite material may reduce the precursor burden without introducing an additional ingredient. But an excipient substitution still needs to work in the formulation.

In the development approach presented at the webinar, that means assessing nitrite alongside functionality. For an immediate release tablet, a candidate material must retain acceptable processing and dissolution behaviour. For a modified release product, the consequences for the release profile need particular attention.

The purpose of the comparison is to identify a material that improves nitrosamine control while maintaining the required product performance. Choosing the lowest reported nitrite value without evaluating the finished dosage form leaves that decision incomplete.

The local environment can determine whether a mitigation works

FDA identifies modification of the formulation microenvironment as a possible mitigation approach. Its discussion includes sodium carbonate as an example of an excipient that can move conditions towards a neutral or basic pH and potentially suppress NDSRI formation. Suitability must be demonstrated for the particular formulation. [2]

This creates a development trade-off. A pH change intended to suppress nitrosation must also be evaluated for its effects on the drug product. Similarly, the webinar’s process assessment considers moisture, heat and exposure time together with the chemistry.

My recommendation is to use these factors to design comparative experiments. A bulk slurry pH or a single moisture result should not be treated as a complete description of the reacting environment inside a tablet. The decisive evidence is the behaviour of the actual product under relevant manufacturing and storage conditions.

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Control of Processing Air

Nitrosamine control does not stop with APIs, excipients and process parameters. The quality of the process air can also matter. NOxGuard addresses this aspect by monitoring and controlling NOx in process air, supporting a more comprehensive approach to nitrosamine risk mitigation. More information on NOxGuard by Glatt.

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Scavengers can help, but their implementation needs its own development work

The 2026 study by Mekhdjian and colleagues provides a particularly useful example. Ascorbic acid reduced formation of the studied NDSRI. Wet blending it with excipients before adding the API provided better suppression than dry blending. [7]

However, the intervention introduced further questions. Ascorbic acid degraded during processing and storage, and the researchers observed new API related substances attributed to reactions with it. These findings required additional analytical and toxicological work.

The lesson extends beyond the choice of antioxidant. Incorporation method and distribution can determine effectiveness, while compatibility determines whether the complete formulation remains acceptable. A lower nitrosamine result is one part of the evidence needed to adopt the change.

In practice, scavenger screening should therefore assess the broader impurity profile and stability of the formulation, alongside the targeted NDSRI. The published result supports investigation of this approach without establishing a universally suitable scavenger or concentration.

UV pretreatment is an interesting research direction

Minamioka and colleagues investigated UV treatment of excipients before contact with desloratadine. In their model, 365 nm irradiation reduced subsequent N-nitrosodesloratadine formation in tablets by 54–68% compared with the control under the study conditions. [8]

The attraction is the possibility of intervening before the API encounters the reactive species. The reported percentage should remain tied to that experimental system.

For industrial development, questions would include exposure uniformity through a powder bed, throughput, photochemical changes and preservation of excipient functionality. These are proposed evaluation needs, not evidence that the approach has already been qualified at manufacturing scale.

Packaging and changes after approval belong in the assessment

An additional consideration is the container closure system. FDA identifies packaging components and manufacturing equipment as potential sources of nitrite or nitrosamine impurities and recommends considering this risk in extractables and leachables assessments. [1]

The practical implication is to include the intended pack when evaluating the product’s stability. If formation changes after a packaging substitution, the investigation should extend beyond the excipient certificates.

Quantitative reformulation can also alter the nitrite burden. Charoo and colleagues modelled postapproval excipient changes in metformin sustained release and losartan film coated tablets. Under their assumptions, larger, level 2 changes increased simulated nitrosamine levels by more than 7% and 18%, respectively. Low nitrite excipients avoided a significant increase in those comparisons. These are modelling results, not measured outcomes applicable to every product. [9]

My recommendation is to retain the nitrite budget as a living part of change control. A change in quantity can matter even when the ingredient name stays the same.

The FDA update changes the intake assessment, while formulation control remains necessary

FDA’s 24 September 2026 guidance allows consideration of less than lifetime adjustments to recommended lifetime nitrosamine acceptable intake limits. The factors are 80 for treatment of up to one month, 13.3 for more than one month up to twelve months, and 6.67 for more than one year up to ten years. Longer treatment uses the lifetime limit. [10]

Applicability depends on the labelled treatment duration. Repeated or intermittent treatment requires consideration of total dosing days. FDA does not recommend applying these adjustments to interim acceptable intake limits, and implementation must follow the applicable regulatory process.

For excipient selection, the distinction is essential. These factors adjust nitrosamine intake limits for eligible drug products. They do not establish an equivalent multiplier for an excipient’s nitrite specification. The product still needs a justified assessment of formation and control through shelf life.

The useful endpoint is a formulation that remains controlled

The central message of my webinar contribution is that a universal nitrite threshold cannot replace understanding of the product. A value such as 0.1 ppm acquires meaning when it is connected to the amount of excipient, the susceptible chemistry and the evidence from the finished dosage form.

I would start by identifying the likely formation pathway and quantifying the material inputs. I would then use that information to select the most relevant experiments, comparing source reduction with changes to formulation or processing where needed. The final decision should account for the entire product, including its performance and stability.

This connects with the theme of my earlier article, From Development to Commercial Products: Mind the Gaps. Here, the critical interfaces run from supplier data to formulation decisions, and from manufacturing conditions to stability results.

Closing those gaps gives an excipient specification its practical value: evidence that the selected material contributes to a drug product whose nitrosamine risk remains controlled.

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By Philippe Tschopp
Philippe Tschopp writes about pharmaceutical excipients, formulation and oral drug delivery, with a focus on excipient functionality, practical formulation considerations and lesser-known material properties.

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Source:

Presentation basis: Philippe Tschopp, Nitrosamine Impurities in Pharmaceuticals: The role of excipients and practical strategies for prevention. HPC Firm webinar, 31 October 2026.

1. FDA. Control of Nitrosamine Impurities in Human Drugs. Guidance for Industry, September 2024, Revision 2. Guidance PDF.

2. FDA. Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products. FDA source.

3. Lhasa Limited. Lhasa announces >3000 nitrite data results in 2026.1 release. Release announcement.

4. IPEC Federation. Updated: IPEC Federation Questionnaire for Excipient Nitrosamines Risk Evaluation. Version 2, 2025. Questionnaire announcement.

5. Blom G. et al. Analysis of nitrite in pharmaceutical excipients: A multi-laboratory comparative study. European Journal of Pharmaceutical Sciences. 2026;221:107516. https://doi.org/10.1016/j.ejps.2026.107516.

6. Grahek R. et al. Excipient nitrite levels are not static material attributes: Nitrite generation from environmental NOx and implications for drug product manufacturing. Journal of Pharmaceutical Sciences. 2026;115(11):104482. https://doi.org/10.1016/j.xphs.2026.104482.

7. Mekhdjian A. et al. Advantages and limitations of the inclusion of ascorbic acid on nitrosamine mitigation in pharmaceutical drug products. Journal of Pharmaceutical Sciences. 2026;115(4):104190. https://doi.org/10.1016/j.xphs.2026.104190.

8. Minamioka S. et al. Efficacy of ultraviolet irradiation of pharmaceutical excipients in mitigating N-nitrosamine generation. Journal of Pharmaceutical Sciences. 2026;115(9):104435. https://doi.org/10.1016/j.xphs.2026.104435.

9. Charoo N.A., Untoo S.A., Rahman Z. Impact of post approval quantitative changes in excipient composition on nitrosamine formation: De-risking strategy. European Journal of Pharmaceutics and Biopharmaceutics. 2026;223:115058. https://doi.org/10.1016/j.ejpb.2026.115058.

10. FDA. Application of Less-Than-Lifetime Adjustment to Nitrosamine Impurities. 24 September 2026. Guidance PDF.

Scientific and regulatory sources checked on 1 November 2026. Practical recommendations and illustrative calculations are identified as such.

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Disclaimer

This article is based on publicly available information and industry sources at the time of writing and supported by AI. While every effort has been made to ensure accuracy, completeness, and fair representation, the author does not guarantee that all information is current, error-free, or reflective of the latest developments.

The content is provided for informational and educational purposes only and does not constitute technical, regulatory, or commercial advice. No liability is accepted for decisions made based on this material. Readers are encouraged to consult the original manufacturers and official sources to verify details before making professional or business decisions.