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N-nitrosamine impurities have been in the news for some years now. Karina Boszko, head of API Regulatory Affairs and Customer Technical Support Department, explains how we at Polpharma undertake this challenge.

What are nitrosamines, and how do they affect human health?

 In July 2018, the pharmaceutical industry was shaken when nitrosamine impurities were detected in human medicines, leading to recalls of several batches of high blood pressure and heart failure med valsartan. Investigations by health authorities and drug companies revealed that nitrosamines are generated during the synthesis of active pharmaceutical ingredients (APIs). Different products containing different APIs, including metformin and rifampicin, were found to contain low levels of nitrosamine impurities.

Nitrosamines, or N-nitrosamines, refer to any nitroso functional group molecule. They are common in water and foods, including cured and grilled meats, dairy products, and vegetables. Everyone is exposed to some level of nitrosamines. They are a cause of concern because they are probable human carcinogens, and long-term exposure to high levels may increase cancer risk. Over 300 known nitrosamines, many highly potent mutagenic carcinogens, are known today.

What steps have regulators taken to check nitrosamine impurities in pharmaceutical products?

On September 26, 2019, the European Medicines Agency’s Human Medicines Committee (CHMP) requested all Marketing Authorization Holders (MAHs) review their medicines containing chemically synthesized APIs for the possible presence of nitrosamines.

The EMA recommended a three-step process. In the first step, MAHs were supposed to perform a risk evaluation of APIs and finished products by March 31, 2021. If a risk is identified, MAHs have to perform confirmatory tests. Finally, if tests confirm the presence of nitrosamines, MAHs are supposed to inform competent authorities immediately and implement risk-mitigating measures. They should also submit any changes in the manufacturing process or product specifications by September 26, 2022.

The US Food and Drug Administration (FDA) also came up with similar recommendations. Both these agencies have partnered with various other regulators to develop immediate solutions to ensure the safety and quality of drugs.

Why are nitrosamine impurities being reported so much now?

 The scientific community has been aware of nitrosamine presence for years. But every year, we have better equipment and better testing methods to detect impurities. Currently, we use the gas chromatography-mass spectrometry (GC-MS) or gas chromatography-tandem mass spectrometry (GC-MS/MS) methods due to their high selectivity and low detection levels. 

What are the potential sources of nitrosamine impurities?

 There are many ways and conditions that lead to the formation of nitrosamines. The most common is nitrosating agents in the presence of secondary or tertiary amines within the same or different steps of the manufacturing process. The use of contaminated raw materials and intermediates supplied by vendors containing residual nitrosamines or nitrosating agents is another potential source.

 Additionally, the use of contaminated recovered or recycled materials or certain packaging materials may lead to the formation of these impurities. There is also the risk of cross-contamination due to different processes being run successively on the same manufacturing line; degradation processes of raw materials, intermediates, and active substances. The lack of optimization of the manufacturing process for APIs can also lead to the formation of nitrosamines.

How is Polpharma addressing this risk?

I can confidently say our knowledge of nitrosamines in APIs is huge. Our products are thoroughly analyzed and tested with highly sensitive analytical methods developed and validated in-house. We have a dedicated team comprising our best technologists, analysts, regulatory affairs experts, and process engineers. We also have top-class analytical equipment to develop very sensitive methods for testing our APIs. At Polpharma, we use GC-MS/MS chromatographs with Headspace auto-samplers and UPLC-MS/MS (Ultra-high performance liquid chromatography-MS/MS) chromatographs to detect impurities as low as 0.001 ppm.

We continuously updated our risk assessment process and developed additional analytical methods. And, of course, we strictly follow the recommendations of the EMA and FDA.

Can you elaborate on Polpharma’s risk assessment process?

Being a vertically integrated company, we perform the risk assessment for APIs including close cooperation with our experts in FDF. We take precautionary measures to mitigate the risk of the presence of nitrosamines during the manufacture and storage of all medicinal products containing chemically synthesized APIs. Moreover, we also cooperate with our customers. Thanks to close cooperation and information exchange between drug manufacturers and MAHs, the quality and safety of the drugs can be guaranteed.

Do you see N-nitrosamine impurities getting eliminated from drug products in the future?

 Yes, it can be eliminated through good manufacturing practices (GMPs), good/safe chemistry, synthetic route modification, elimination of nitrosamine formation sources, and a holistic understanding of the entire manufacturing process.

 Some available literature reports show that commonly used antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) inhibit the formation of nitrosamines in vivo, based on data from human gastric fluid in vitro studies. A second possible approach suggests that nitrosamines are typically formed under acidic conditions. In the future, it will be possible to reduce and even eliminate N-nitrosamine impurities by using our knowledge and advanced technologies.

What has the industry done to alleviate the concerns of patients?

 With each news headline about nitrosamine impurities in drugs, people’s trust in drug safety decreases. Patients complain that there is a lack of clear information from regulators or healthcare professionals regarding the problem. To address this issue, the industry has come together to implement the best practices in communication. 

Science is constantly evolving. The industry should adopt the latest findings and technology solutions to improve patients’ lives. Our priority should be to provide them with top-quality and safe medicines.

Author: Karina Boszko, head of API Regulatory Affairs and Customer Technical Support Department

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