Nitrosamine Impurities: Quality Impact, Awareness, and Risks

by Alfredo Vannini, Operations Manager - GMP-API Auditor @PQE Group

What Are Nitrosamines and Why Is The Industry Concerned? 

Since 2018, the pharmaceutical industry has been closely monitoring nitrosamines, especially NDMA, following their discovery in certain batches of Valsartan, a high blood pressure treatment produced by Zhejiang Huahai Pharmaceutical (ZHP). Valsartan, an angiotensin II receptor blocker, helps regulate blood pressure by inhibiting these receptors, which leads to the relaxation and widening of blood vessels, coupled with a decrease in sodium retention. This discovery ultimately led the European Medicines Agency (EMA) and the FDA to broaden their scrutiny of pharmaceutical manufacturing processes and products with the aim of enhancing patient safety by evaluating contamination levels and ensuring impurity levels remain within acceptable limits. Since the presence of hazardous substances is not limited to inherently risky products but also extends to those that should not contain these dangerous elements, this situation has led to calls for more rigorous quality control measures by regulatory bodies to safeguard patients. 

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Understanding The Formation of Nitrosamines 

Various factors can lead to the formation of harmful contaminants like nitrosamines during the production of pharmaceutical products. The risk of contamination, present throughout multiple stages of the manufacturing process, underscores the importance of stringent quality control measures. The presence of impurities in raw materials and other components used in pharmaceutical production can introduce nitrosamines, potentially compromising medication safety and efficacy. The risk of contamination during production is so high that even a small amount of impurities in the container-closure system for the finished drug product has the potential to adversely impact product quality and patient health by introducing nitrosating agents like nitrile and nitrocellulose elements. 


Regulatory Expectations By The FDA & EMA Regarding Nitrosamines 

Following the discovery of nitrosamines in medications such as angiotensin II receptor blockers (ARBs), the FDA and EMA have prepared guidelines for API and drug manufacturers to meet regulatory expectations regarding nitrosamine impurities in pharmaceutical products. Pursuant to these guidelines, manufacturers are mandated to assess the risk of nitrosamine formation or contamination in their products and implement necessary testing to detect these impurities. 


FDA Recommendations 

Given the carcinogenic potential of nitrosamines, the FDA advises manufacturers to thoroughly assess and mitigate their formation in Active Pharmaceutical Ingredients (APIs) and drug products. This detailed approach requires the investigation of both established and potential pathways for nitrosamine formation, underlining the need to prioritize assessments based on key factors such as the drug's dosage, duration of treatment, and extent of patient exposure. In line with these guidelines, if nitrosamines are detected, a thorough investigation must be conducted to determine their origins. Subsequently, necessary adjustments to manufacturing protocols should be made to minimize or eliminate such risks. This process demands a collaborative effort between API producers and drug product manufacturers to effectively identify and address risks. 


EMA Recommendations 

The EMA's guideline on nitrosamines recommends that manufacturers minimize or control the presence of N-nitrosamines below the acceptable intake (AI) limits. These limits have been determined or can be predicted based on the decision tree present in the guideline, aligning with ICH M7(R1) principles for "cohort of concern" substances while considering lifetime exposure. 

The guideline also requires manufacturers to valuate the risk of nitrosamines in their products and conduct confirmatory testing if a risk is identified, this includes assessments for both new and existing medicinal products with chemically synthesized APIs and biological products, focusing on manufacturing processes and potential contamination sources. According to the guideline, If multiple N-nitrosamines are detected, the total risk should not exceed a 1 in 100,000 lifetime risk, requiring a calculated limit for each detected nitrosamine. For products where N-nitrosamines exceed acceptable levels, manufacturers are required to report to competent authorities, detailing root causes, corrective actions, and impact on the benefit to risk balance. The same guideline also specifies control strategies for both APIs and finished products to minimize nitrosamine risk, mandating compliance with current scientific and manufacturing standards. With regards to analytical methods for detecting nitrosamines, the guidelines require compliance with specified sensitivity requirements, taking into account routine control, skip testing, and specification omission. 


Impurity Risk & Drug Supply Challenges  

The omnipresent risk of contamination in pharma production and the complex global supply chain means pharmaceutical companies must now more than ever rigorously adhere to Good Manufacturing Practices (GMP) to ensure product safety, efficacy, and quality throughout the manufacturing process to avoid shortages and product recalls. While the presence of a significant amount of nitrosamine in drugs such as valsartan, ranitidine, and metformin is alarming enough on its own due to the carcinogenic nature of these impurities, it is vital for the same level of scrutiny to be extended to other pharmaceutical products and product families to ensure the safety of all medications. This includes a thorough assessment of vulnerable amines present in active pharmaceutical ingredients (APIs) and excipients, to mitigate any potential risk and safeguard patient health. Although regulatory agencies have established guidelines and standards to address these concerns, it is ultimately the responsibility of manufacturers to implement and consistently uphold these standards. Hence, effectively addressing the challenges associated with contamination and the complexities of the global supply chain highlights the vital necessity for a collaborative partnership between regulatory bodies and manufacturers. Such cooperation is paramount for enhancing public health safety and ensuring the integrity of the pharmaceutical supply chain.  

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