Nitrosamines: A new systematic review

The publication “Nitrosamines crisis in pharmaceuticals - insights on toxicological implications, root causes and risk assessment: A systematic review” is readily available online and accessible with an open access format.

Overall, the article provides an extensive examination of the nitrosamines crisis within the pharmaceutical industry.

• The article explores the ramifications of nitrosamines from a toxicological standpoint, delving into the most recent updates regarding the toxicity profiles of N-nitroso compounds.

• Additionally, the publication thoroughly discusses the root causes behind the nitrosamines crisis, alongside comprehensive risk assessment strategies and mitigation approaches specifically designed for pharmaceutical manufacturers.

• The authors shed light on the utilization of Gas Chromatography (GC) and Liquid Chromatography (LC) methods for the precise detection and quantification of N-nitroso compounds present in pharmaceutical products.

• An underlying emphasis throughout the article revolves around the imperative need to develop pharmaceutical products free from nitrosamine contaminants, ensuring adherence to regulatory standards.

Within this review, it’s important to underscore the authors’ mention of significant challenges encountered during the development of analytical methods.

These challenges stem from issues such as inadequate ionization of analytes and interference from matrices.

Specifically, in the context of NDSRIs, complexities arise due to molecular weights, intricate structures, and the scarcity of readily available standards.

Furthermore, the authors have mentioned our coummunity: “To address the nitrosamine crisis, the USP is hosting a virtual platform called the “nitrosamines exchange” (…). Additionally, USP has established a “nitrosamine analytical hub” to provide updates on novel analytical methods for testing nitrosamines.

It’s an evolving subject that matures daily, evolving through each new discovery and discussion.

What caught your attention the most in the article?

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Having read this I think it is a reasonable introduction to parts of the problem, but there are some flaws and omissions.

I didn’t see anything around the new different categories for NDSRIs, which is the most significant step forward that we have seen in the issue to date - though I am hopeful that things that seem to be in the pipeline may push the boundaries even further soon.

The premise is probably over-optimistic - the complete removal of nitrosamines. There are hundreds of impacted APIs (and degradants of APIs) spanning thousands of different products and involving thousands of different excipients/grades/suppliers/ratios in different dosage forms. Even with all of the techniques that are available to formulators (changes in methods of manufacture, use of scavengers, changing the pH of the formulation, low nitrite excipients, packaging changes) reaching zero nitrosamine formation both on manufacture and throughout the shelf-life of all products is most likely a pipedream. We can aim for it of course, but targeting control to known, safe levels is much more realistic and potentially achievable, without resulting in products being removed from the shelves.

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@MarkS , the challenge of handling numerous impacted APIs across various products is quite complex. Aiming for absolute zero nitrosamine formation throughout manufacturing and shelf-life might be overly ambitious due to the numerous factors involved.

I agree with your suggestion of implementing targeted control to maintain safe and known levels. It’s crucial to set realistic goals that prioritize safety without compromising the availability of essential products in the market.

Recognizing practical limitations and striving for achievable control measures offers a more sustainable approach.

There’s a need for a balanced strategy that acknowledges the issue’s complexity while actively seeking continuous improvements and refinements.

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While I appreciate the authors approaches to nitrosamine impurities I do have a few criticisms most in terms of interpretation of toxicology. First and foremost, complete removal should not be a goal but removal below acceptable limits. Zero is an impossible goal for moving forward as it is all depending on your limit of detection.

Second, when looking at Figure 1, it appears that NMOR, and MeNP are labeled as NDSRIs. I think that would be more correct to call them nitrosamine impurities.

I wish they would have considered other AIs using a more complete and scientific approach than the the regulatory limits provided. For example it would have been nice to include in Figure 2 nitrosamine limits by EFSA and Bercu et al., 2023 https://www.sciencedirect.com/science/article/pii/S0273230023000831?via%3Dihub

In section 2.1 study selection it says " total of 180 articles spanning from 1960 to the present day, including original research , reviews, case reports and studies reporting nitrosamine impurities above the no-observed-adverse-effect levels (NOAEL) established by regulatory agencies, were initially screened." It is important to note the regulatory limits are acceptable intakes based on low dose linear extrapolation. It is more conservative than applying a NOAEL, which implies a threshold. Low dose linear extrapolation assumes any dose can be carcinogenic, but then a risk of cancer above background is then developed. If delving into the toxicology it would have been good to discuss the existence of a threshold for carcinogenicity and/or mutagenicity and how that relates to the acceptable intake.

Figure 4 shows several mechanisms of toxicity, but I don’t believe we can attribute many of these to to overall carcinogenicity but more general toxicity. For example nitrosamines may cause impairment of fatty acid oxidation but the overall carcinogenicity is attributed more to DNA alkylation and disruption of key genes. Its a really cool figure but I am unsure the accuracy.

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@jbercu, your observations regarding toxicology are insightful as they provide valuable points for deeper reflection on the subject. This is an ongoing discussion, where clarity and precision of data are paramount, especially within the context of a review article. Your suggestion to incorporate nitrosamine limits established by organizations and publications is highly relevant and could significantly enhance the discussion presented in the work. This addition would broaden the study’s scope and offer a more comprehensive view of current regulatory guidelines.

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Thank you for sharing this paper.

I am looking for recent publications (for the analysis) of nitrosamines in blood. Currently I work in dialysis RD (peritoneal dialysis fluids)- and the challenges are significant for the testing/detection of nitrosamines. The exposure is also significant due to the volume of solutions each patient receives per day, our cut off for NDMA is 2.5 ng/L not an easy target by LCMSMS APCI.

Appreciate any insight.

Dear @k8evans, have you checked out this article (A Bioanalytical Method for Quantification of N-nitrosodimethylamine (NDMA) in Human Plasma and Urine with Different Meals and following Administration of Ranitidine)?

The authors outline the development and validation of a bioanalytical method for quantifying NDMA in human plasma and urine. The method, developed using LC-MS/MS, was validated following FDA guidelines. It requires a low sample volume and is suitable for analyzing samples from clinical studies. As highlighted by the authors, this method can be used to monitor NDMA levels in pharmaceutical manufacturing and could potentially be adapted for other biological matrices. I hope it helps.

Hello this is useful thank you- I just checked this feed, thank you for sharing this article.