The Story of Nitrosamines

Nitrosamines occurring in pharmaceuticals became a developing problem in 2018, and regulatory agencies have been working with pharmaceutical companies since to mitigate the risk of these cancer-causing chemicals in drug products. Over the years, Pharmaceutical Technology® has covered the issue through news reports, interviews, and technical articles. PharmTech's nitrosamine coverage can be found in the reference list below.

Click the above audio summary to learn about how the nitrosamines situation began and is continuing. And check out the video summary below.

Editor’s Note: This media was created using NotebookLM using articles found on PharmTech.com. Please see below list of references. AI-generated content may not be correct.

The graphic below breaks down some of the basics involved and what manufacturers should look out for.

Video summary

The discovery of nitrosamine impurities in pharmaceutical drugs, beginning in 2018, has prompted extensive regulatory action and industry-wide changes to ensure patient safety (1,2). The issue first came to light when N-nitrosodimethylamine (NDMA), a probable human carcinogen, was found in valsartan, an angiotensin receptor blocker (ARB), from a Chinese active pharmaceutical ingredient (API) manufacturer, Zhejiang Huahai Pharmaceutical Company (1, 3). This led to widespread recalls of sartan-based medicines (1).

Investigations soon revealed other nitrosamines, like N-nitrosodiethylamine (NDEA), in different sartan drugs, including losartan and irbesartan (1,4). The contamination was traced to specific manufacturing processes, particularly those involving certain solvents, reagents, and recycled materials (5, 6,7). The problem was not isolated to sartans; NDMA was later found in other widely used drugs such as ranitidine (Zantac), metformin, and pioglitazone, triggering further recalls and investigations (3,9). One study suggested the ranitidine molecule itself might be inherently unstable, capable of forming NDMA under conditions mimicking the human stomach (9).

In response, global regulators, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have issued comprehensive guidance (10, 11). They now require pharmaceutical companies to conduct rigorous risk assessments for all chemically synthesized APIs to identify and mitigate nitrosamine risks (3, 10, 7). Both agencies have established acceptable daily intake limits for various nitrosamines and mandated confirmatory testing if a risk is identified (3, 12). The FDA has also developed advanced analytical methods, such as liquid chromatography-mass spectrometry (LC-MS), to detect trace levels of these impurities and avoid false positives that could occur with older testing protocols (1, 9, 13). This ongoing challenge has underscored the critical need for continuous safety surveillance and robust quality control throughout the pharmaceutical supply chain (3, 14).

Editor’s Note: This summary was created with NotebookLM using articles found on PharmTech.com. AI-generated content may not be correct.

References

1. Shanley, A. After Valsartan Recalls, Regulators Grapple with Nitrosamine Contamination in APIs. PharmTech.com, Sept. 26, 2018.

2. James, A. Detecting Apparent Total Nitrosamine Content in Pharmaceutical Drugs. Pharmaceutical Technology, 2022 46(8), 29–31.

3. Thomas, F. Complying Confidently? Learning Lessons from Nitrosamine Impurities. Pharmaceutical Technology, 2020 44(5), 30–31.

4. PharmTech Editors. FDA Hits Valsartan Manufacturer with Warning Letter. PharmTech.com, Dec. 12, 2018.

5. PharmTech Editors. FDA Gives Update on NDMA Investigation. PharmTech.com, Jan. 28, 2019.

6. Shanley, A. FDA Releases List of 'Safe' Valsartan and ARBs While Experts Explore and Debate Root Causes of Contamination. PharmTech.com, April 9, 2019.

7. Milmo, S. Investigating NDMA Impurities at EMA’s Request. Pharmaceutical Technology, 2019 43(11), 9–11.

8. Mirasol, F. Pharma Industry Contends with Contamination-Based Recalls. Pharmaceutical Technology, 2021 Supplement(2), 2021 s32–s34.

9. Shanley, A. Problems With Ranitidine May Transcend Manufacturing Issues. PharmTech.com, Oct. 2, 2019.

10. PharmTech Editors. EMA Issues Final Opinion on Nitrosamines. PharmTech.com, July 16, 2020.

11. PharmTech Editors. FDA Publishes Guidance on Control of Nitrosamines. PharmTech.com, Sept. 2, 2020.

12. Snow, S. and Panesar, N. Nitrosamine Impurities in Medicinal Products. Pharmaceutical Technology, 2020 44(12).

13. Bhalgat, M. Understanding Nitrosamine Impurities in the Pharmaceutical Industry. Pharmaceutical Technology, 2023 47(7), 46–49.

14. Haigney, S. What Goes Wrong When API Quality is Compromised? Pharmaceutical Technology, 2022 46(8), 16–19.

Additional references

• Angrish, P. and Mani, C. Development of a Validated Method of Testing for NDMA in Ranitidine. Pharmaceutical Technology, 2020 44(10), 42–47.

• Curran, T. and Bercu, J. P. (2021, March 15). Managing the Risk of Nitrosamine Impurities. Pharmaceutical Technology eBook, 2021 March, 28–35.

• Haigney, S. European Pharmacopoeia Updates: EDQM Tackles Nitrosamine Impurities. Pharmaceutical Technology, 2021. 45(10).

• Haigney, S. N-Nitrosamine Impurities and FDA’s Recommendations for Acceptable Intake Limits. PharmTech.com, April 4, 2025.

• Haigney, S. Strategies for Mitigating Nitrosamine Risk. PharmTech.com, May 7, 2025.

• Haigney, S. The Continuous Challenge of Nitrosamines. PharmTech.com, Sept. 18, 2025.

• Husni, D. G. FDA Releases Guidance on Intake Limits for Nitrosamine Drug Substance-Related Impurities. PharmTech.com, Aug. 11, 2023..

• PharmTech Editors. European Authorities Continue Work to Prevent and Manage Nitrosamine Impurities. PharmTech.com, March 6, 2020.

• PharmTech Editors. Sartan Manufacturers Should Review Manufacturing Processes, Says EMA. PharmTech.com, Feb. 9, 2019.

• PharmTech Editors. FDA Approves New Generic Valsartan. Pharmaceutical Technology. PharmTech.com, March 12, 2019.

• PharmTech Editors. EMA Provides Guidance on How to Avoid Nitrosamines in Human Medicines. PharmTech.com, Sept. 20, 2019.

• PharmTech Editors. FDA Expands Scope of API Impurity Investigation. PharmTech.com, Aug. 29, 2019.

• PharmTech Editors. Latest ARB Recall Triggered by New Impurity. PharmTech.com, March 7, 2019.

• PharmTech Editors. Metformin HCl Extended Release Tablets Recalled. PharmTech.com, Nov. 3, 2020.

• PharmTech Editors. Nostrum Laboratories Expands Recall of Metformin HCl Extended Release Tablets. PharmTech.com, Jan. 11, 2021.

• Srinivasan, A. What Does the FDA's Recent Update of the Nitrosamine Guidance Convey? PharmTech.com, Oct. 23, 2024.

• Srinivasan, A. and Lambert, C. Nitrosamides–Should They Be Treated the Same as Nitrosamines? Pharmaceutical Technology, 2022 October eBook(3), 42–50.