Dr. Pramod Kr. Pandey is a distinguished Analytical Research Expert with over three decades of extensive experience in the pharmaceutical industry. He has contributed his expertise to both leading Indian and global pharmaceutical companies, consistently driving innovation and excellence in analytical research
Explore expert insights on nitrosamine impurities in pharmaceuticals, including their toxicity, formation during manufacturing, detection challenges, and effective control strategies. Learn through case studies and FAQs
Control of Nitrosamine Impurities in Pharmaceuticals: Learn Easily in 7 Minutes
Strategies for Controlling Nitrosamine Impurities in Pharmaceuticals: Guidelines for Detection, Limits, and Risk Management
Nitrosamine impurities in pharmaceuticals have emerged as a significant challenge due to their toxicity and stringent acceptance limits. Unlike other impurities, nitrosamines cannot be effectively detected using common analytical techniques like chromatography and spectroscopy. These impurities have no industrial use, yet their presence in pharmaceutical products can lead to severe safety concerns. In this article, I will share my expertise on nitrosamine impurities, covering essential topics such as the types of nitrosamines, their toxicity, how they form during manufacturing, and effective control strategies. Additionally, I will discuss real-world case studies and provide answers to frequently asked questions, offering valuable insights for professionals looking to better understand and manage these critical impurities in drug production.
Nitrosamine Impurities in Pharmaceuticals
R2N-N=O
Nitrosamine impurities or N-nitrosamine impurities are compounds containing a nitroso group at the dialkyl-substituted amine group
Common Nitrosamine Impurities and their structures
The following are the 7 nitrosamine impurities
N-Nitrosodimethylamine (NDMA)
N-Nitrosodiethylamine (NDEA)
N-Nitroso-N-methyl-4-aminobutanoic acid (NMBA)
N-Nitrosoisopropylethyl amine (NIPEA)
N-Nitrosodiisopropylamine (NDIPA)
N-Nitrosodibutylamine (NDBA)
N-Nitrosomethylphenylamine (NMPA)
Nitrosamine Impurities structures
Toxicity of Nitrosamine Impurities
Nitrosamines contain nitroso group and molecules having this functional group fall into the Cohort of concern due to their high potential carcinogenic nature. Their intake even below the TTC would theoretically be associated with the potential for a significant carcinogenic risk. That is why they are toxic and are excluded from the TTC approach.
Why is control of Nitrosamine impurities required in pharmaceuticals?
Nitrosamine impurities are probable human carcinogens. Secondly, no specific treatment exists for nitrosamine intoxication. That is why control of Nitrosamine impurities is required in pharmaceuticals.
There are various sources of Nitrosamine impurities such as:
Processed meat
Can form in the stomach: If a food contains precarser of the corresponding nitrosamine
Alcoholic beverages, cosmetics and cigarette
During the disinfection of drinking water: Dichloramines are used during disinfection of the drinking water and it may result in the formation of a trace amount of nitrosamine
Nitrosamine may form in the synthesis of pharmaceuticals : Nitrates, Nitrites and certain amines may lead to the formation of Nitrosamine impurities
Nitrosamine Impurities Formation in the Process
Nitrosamine Impurities may form in the process due to the following reasons:
Use of Nitrate, Nitrites and certain amines in the process
Presence of DMA (dimethyl amine) in DMF (dimethyl formamide (if DMF is the component of the synthetic process)
General conditions that lead to nitrosamine formation
Sources of secondary, tertiary, and quaternary amines that can form nitrosamines
Contamination in vendor-sourced raw materials
Recovered solvents, catalysts, and reagents as sources of contamination
Quenching process as a source of Nitrosamine contamination
Lack of process optimization and control
If nitrous acid is used to quench residual azide during tetrazole ring formation
Introduction of azide functional group into a molecule
Presence of Amines (maybe API, degradants, intermediate and purchasing material)
Presence of Amide solvents: e.g. N,N-dimethylformamide, N-methyl pyrrolidone, N,N-dimethylacetamide, and N,N-dimethylacetamide
How do nitrites turn into nitrosamines?
Nitrosamine Impurities form by following reaction mechanism:
Formation of Nitrosamine Impurities
Can the formation of nitrosamine impurities be prevented?
No but some extent. Formation of Nitrosamines can be inhibited by Ascorbic acid. Ascorbic acid (vitamin C) is known to prevent the formation of nitrosamines.
How to control nitrosamine impurities in pharmaceuticals?
Pharmaceuticals manufacturers should optimize the design of the manufacturing process for pharmaceuticals during the route of synthesis (ROS) selection to minimize or prevent the formation of nitrosamine impurities.
Avoid the reaction conditions that may produce nitrosamines whenever possible; When not possible, demonstrate that the process is adequately controlled and capable of consistently reducing nitrosamine impurities through appropriate and robust fate and purification studies.
Use bases other than secondary, tertiary, or quaternary amines (when possible) if ROS (route of synthesis) conditions can form nitrosamines.
Be careful when ROS involve the use of amide solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone)
Replace nitrites with other quenching agents for azide decomposition processes
Design a manufacturing process that facilitates purification of nitrosamine impurities in subsequent processing steps.
Remove the quenching steps (when there is a risk of nitrosamine formation)
Audit supply chains from the raw materials, starting materials, and intermediates are used in the process
Avoid cross-contamination when recovered materials such as solvents, reagents and catalysts are used in the manufacturing process. Recovered material should be used only at the same stage or in an earlier stage of the same process from which it was collected.
Be aware that potable water used in API manufacturing should be free from nitrites.
Pharmaceutical batches may be reprocessed or reworked to control the levels of nitrosamine impurities as provided inICH Q7 for modifications and controls in such operations.
If a nitrosamine impurity is detected above the detection limit (DL), the Pharmaceutical manufacturer should develop a vision-based strategy to control the same
Make sure Nitrosamine level reliably remains well below the AI limit in the Pharmaceuticals
Any Pharmaceuticals batch found to contain levels of nitrosamine impurities above the recommended AI should not be released.
Apply an effective lesson-learned approach
Analytical Challenges in controlling Nitrosamine Impurities
Nitroso amine Impurities can not be controlled by common analytical techniques like chromatographic techniques and spectroscopic techniques due to their low limit. LC-MS and GC-MS are widely used in the industries to control these impurities.
Case studies related to Nitrosamine Impurities
APIs prone to Nitrosamine Impurities
For which azide or nitrite is used in synthesis such as Metronidazole, Cilostazol, Cefazolin etc.
Sartans with a tetrazole ring such as Valsartan, irbesartan, Losartan, Olmesartan, candesartan etc
Warning letters
Several warning letters have been given in past by different authorities due to inadequate control of Nitrosamine impurities
Deficiency letters
Several Deficiency letters (DLs) have been given in past by different authorities due to failure to control of Nitrosamine impurities
Conclusion
In conclusion, controlling nitrosamine impurities in pharmaceuticals is a critical challenge that requires careful attention to manufacturing processes, rigorous testing, and adherence to regulatory standards. Given their toxicity and the difficulties in detecting them using traditional analytical methods, it’s essential for pharmaceutical companies to implement robust control strategies to minimise the risk of contamination. By understanding the types of nitrosamines, their formation pathways, and effective mitigation techniques, companies can safeguard the safety and quality of their products. The case studies and strategies discussed in this article provide valuable guidance for tackling these impurities, ensuring compliance, and ultimately protecting public health
You may also want to check out other articles on my blog, such as:
Nitrosamine impurities are compounds containing a nitroso group at the dialkyl-substituted amine group. They are highly toxic.
How, where and at what level should Impurities be controlled?
LC-MS and GC-MS are widely used to control nitrosamine impurities. Nitrosamine impurities coming from raw materials should preferably be controlled in the raw material. Nitrosamine impurities formed in the process should preferably be controlled at the same stage. Nitrosamine impurities that cannot be controlled in intermediate stages or in the (N-1) stage, or in the raw material stage that must be controlled in the API stage. Nitrosamine impurities formed due to degradation of the API must be controlled in the API stage.
How are Nitrosamines formed in pharmaceuticals?
Nitrosamines may form in pharmaceuticals due to the following reasons:
Use of Nitrate, Nitrites and certain amines in the process
Presence of DMA (dimethyl amine) in DMF (dimethyl formamide (if DMF is the component of the
Sources of secondary, tertiary, and quaternary amines that can form nitrosamines
What is the Ich guideline for nitrosamine impurities?
ICH M7
What are the 7 nitrosamine impurities?
The following are the 7 nitrosamine impurities
N-Nitrosodimethylamine (NDMA)
N-Nitrosodiethylamine (NDEA)
N-Nitroso-N-methyl-4-aminobutanoic acid (NMBA)
N-Nitrosoisopropylethyl amine (NIPEA)
N-Nitrosodiisopropylamine (NDIPA)
N-Nitrosodibutylamine (NDBA)
N-Nitrosomethylphenylamine (NMPA)
What products contain nitrosamines?
Products in whose synthesis azide or nitrite are used such as metronidazole, cilostazol, cefazolin etc. and sartans having tetrazole ring such as valsartan, irbesartan, losartan, olmesartan, candesartan etc. are prone to nitrosamines.
What are common sources of nitrosamines?
Nitrosamine may be present in processed meat, alcoholic beverages, cosmetics, cigarettes and treated and drinking water. Nitrosamine may form in the synthesis of pharmaceuticals where Nitrates, Nitrites and certain amines are used.
How do you remove nitrosamines?
Avoid the reaction conditions that may produce nitrosamines whenever possible; When not possible, demonstrate that the process is adequately controlled and capable of consistently reducing nitrosamine impurities through appropriate and robust fate and purification studies. Use bases other than secondary, tertiary, or quaternary amines (when possible) if ROS (route of synthesis) conditions can form nitrosamines.
What do nitrosamines do to your body?
Nitrosamines damage DNA which can cause cancer. This is why nitrosamines are genotoxic in nature and fall under the group of concern (COC).
What are the symptoms of nitrosamines?
N-nitrosomethylamine can cause liver damage in humans, symptoms of which include nausea, vomiting, headache and malaise, and decreased platelet counts.
