Risk Mitigation of Nitrosamines Formation in Drug Products: Role of Excipients – Interview with MEGGLE
MEGGLE published a study and an update on the topic of “Risk Mitigation of Nitrosamines Formation in Drug Products: Role of Excipients” in 2024.
Pharma Excipients interviewed Dr. Spellerberg from MEGGLE about the background and most important topics and findings of the study.
The whitepaper on the study is linked below this interview.
See the interview in written form:
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Can you explain the significance of nitrosamine impurities in pharmaceutical products?
The issue of nitrosamine impurities in pharmaceutical products has become quite a significant concern for both the industry and health authorities. To give you a bit of background, nitrosamines are chemical compounds and some of them can potentially cause cancer.
Back in June 2018, the FDA was alerted about the presence of N-nitrosodimethylamine (NDMA) in valsartan, a common high blood pressure medication. This discovery set off a chain reaction, leading to recalls of valsartan and later other drugs like ranitidine and metformin, all found to contain unacceptable levels of nitrosamines.
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What is the impact of recent regulatory guidelines on the industry?
Regulatory bodies like the FDA and the EMA have since issued guidelines to tackle this issue. Companies are required to first evaluate the risk of nitrosamines in their products. If a risk is identified, they must conduct testing to confirm the presence of these impurities. Should nitrosamines be found, companies need to implement risk mitigation measures and adjust their product submissions accordingly.
Currently, we are at the final stage where companies are actively implementing risk mitigation measures. To highlight the significance of this step and its implications, we can consider two recent decisions by BfArM: First, the suspension of all approvals for medicines containing ranitidine has been extended by an additional three years. Furthermore, neuraxpharm has announced a definitive decision to discontinue the sale of maprotiline due to constantly exceeding acceptable levels of nitrosamine contamination.
This whole situation pushes companies to reevaluate their manufacturing processes to comply with these new regulatory standards, highlighting the importance of continuous improvement to prevent future occurrences.
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MEGGLE is a specialist in lactose. Therefore, let’s discuss the nitrosamine topic in lactose. What do we need to keep in mind regarding nitrosamine sources?
When discussing nitrosamine concerns in drug products using lactose as filler, or any excipient for that matter, it’s important to understand the sources and formation of nitrosamines. Nitrosamines are formed when a nitroso group bonds to an amine, often through a reaction between amines and nitrous acid, which can originate from nitrite salts under acidic conditions.
It’s important to consider all potential sources of secondary and tertiary amines, which can come from starting materials, intermediates, reagents, catalysts, or solvents. In the context of excipients, nitrite impurities, even in trace amounts, can contribute to nitrosamine formation.
This is why setting scientifically derived limits for nitrite levels is crucial, especially for critical active ingredients. However, achieving completely “nitrite-free” excipients might not be feasible due to the limitations of detection methods. It is more about low nitrite grades.
So, for specialists like MEGGLE, the focus should be on effectively managing these risks by ensuring comprehensive testing for nitrite levels and establishing limits to minimize potential nitrosamine formation in drug products.
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What results for nitrite content did you observe and how do these compare to other commonly used excipients? What factors might influence these levels?
When it comes to nitrite content in our low nitrite grades, we maintain a strict specification, ensuring that the nitrite content stays below 0.10 ppm. Lactose is not prone to high nitrite levels since it is a natural material and not chemically synthesized. Unlike some other excipients, we don’t use organic solvents, catalysts, or reagents that could introduce amines and nitrite salts.
However, it’s important to note that lactose monohydrate is isolated and purified from whey, which is a by-product of cheese manufacturing. This means that trace levels of nitrite can originate from the raw materials whey and water. We do see seasonal fluctuations in the nitrite and nitrate content of our whey, but we have strict limits set during our incoming goods inspection to manage this. Water is another factor, and its nitrite levels are regulated by German law for drinking water, ensuring they remain within safe limits.
Our process for manufacturing pharma-grade lactose includes multiple washing and purification steps, along with double crystallization. These processes secure the control of nitrite levels.
Moreover, the conditions during manufacturing aren’t conducive to the formation of nitrosamines. We avoid the highly acidic conditions that could lead to their formation, and we use only indirect heating for drying, which means there’s no potential for NOx generation from combustion.
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Which strategies exist in general for mitigating nitrosamine risks in drug product manufacturing?
When it comes to mitigating nitrosamine risks in drug product manufacturing, several strategies can be considered by pharmaceutical manufacturers. One effective approach is to reformulate the manufacturing process by moving from wet granulation to direct compression. Wet granulation involves a high amount of water and intense heat conditions for drying, both can promote nitrosation reactions.
Another strategy is to reduce the tablet size, which in turn lowers the amount of excipients used. By minimizing the quantity of excipients, the potential sources of nitrosamine precursors are decreased.
Simplifying the formulation is also a key consideration. By reducing the number of excipients involved, the complexity that can contribute to nitrosamine formation is limited.
Additionally, it’s important for pharmaceutical manufacturers to consider the suppliers they work with. Changing to a supplier with more stringent control over nitrite levels or more robust testing can further mitigate risks. By carefully selecting suppliers, manufacturers can ensure that the raw materials used in drug production meet the safety and quality standards required to minimize nitrosamine contamination.
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Talking about change of suppliers as risk mitigation strategy. What does MEGGLE offer to be the supplier of choice?
Our approach not only simplifies the risk management. It also provides our customers with confidence in meeting nitrosamine safety standards for critical products.
Our newly launched low nitrite grades, including GranuLac® 200 Low Nitrite, Tablettose® 100 Low Nitrite, and FlowLac® 100 Low Nitrite, are designed with specified nitrite limits to ease control strategies for manufacturers. Although nitrite testing isn’t a pharmacopoeia requirement, MEGGLE has developed in collaboration with the Technical University Munich and Thermo Fisher Scientific a precise method using ion chromatography to quantify nitrite levels. The quantification limit is at 0.03 ppm. We’ve validated our ability to safely specify a limit of ≤ 0.10 ppm. This is even lower than the sensitivity of IC method published in USP Application Note.
Each lot of our low nitrite grades is measured for nitrite content and included in the product specification and Certificate of Analysis, making nitrosamine risk mitigation efficient and reliable.
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How has collaboration with institutions like the Technical University of Munich contributed to advancements in nitrosamine risk assessment and mitigation?
Collaboration with institutions like the Technical University of Munich (TUM) has been instrumental in advancing our ability to determine nitrite levels, particularly in challenging matrices like lactose. TUM as well as Thermo Fischer Scientific have provided valuable assistance in method development, helping us navigate some of the common challenges in this area.
One of the primary pitfalls we’ve encountered is coelution, where compounds overlap during analysis, potentially leading to inaccurate results. Additionally, some methods can lack sensitivity, making it difficult to detect nitrites at the required low levels. Also potential other sources of nitrite, such as those from filters and labware or sample preparation during analysis processes, need to be considered.
Furthermore, the complexity of the substance matrix in pharmaceutical formulations means there isn’t a one-size-fits-all method for all substances. Each formulation may require a different approach to effectively measure nitrite levels.
This context reflects the challenge of co-elution again and sample preparation becomes another crucial aspect.
Overall, working with TUM and Thermo Fischer Scientific has significantly enhanced our capabilities to develop more sensitive and tailored strategies to ensure the safety and quality of our products.
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Now that we have discussed general possibilities for nitrosamine risk mitigation, what do you recommend as a practical strategy in the real-world scenario of researching a new formulation?
When it comes to practically mitigating nitrosamine risks in the real-world scenario of researching a new formulation, there are several strategies I would recommend.
Firstly, it’s crucial to use low nitrite excipients when formulating high risk APIs. Selecting excipients with a clearly stated nitrite content in their certificate of analysis allows for greater control over the levels present in the final product. This transparency is key to managing potential nitrosamine risks right from the outset.
Additionally, considering reformulation strategies, as previously discussed, can be highly beneficial. For example, moving towards direct compression techniques can help minimize conditions that might promote nitrosation reactions. MEGGLE supports this approach with its broad portfolio of direct compression excipients, providing enough variety to meet specific formulation needs.
Moreover, MEGGLE has established the Innovation and Formulation Campus near Munich, which serves as a hub for technical customer support. This facility is designed to assist in developing innovative solutions, providing the expertise and resources needed to tackle nitrosamine challenges effectively.
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What further research or industry-wide initiatives do you believe are necessary to address nitrosamine risks more effectively, especially concerning analytical methods and standardization?
The nitrite database developed by Lhasa and the “Nitrite in Excipients” conference organized in collaboration with IPEC have already been good initiatives, promoting industrial collaboration and research on nitrite-related topics.
However, to further enhance the realm of analytical methods and standardization, continued efforts will be crucial.
Firstly, the development of standardized methods for each excipient is crucial. Having consistent and universally accepted analytical protocols will ensure that nitrite levels are correctly detected and controlled across the board. This standardization can help eliminate deviations and improve comparability of results between different laboratories and manufacturers.
Additionally, the complexity of the matrix in which these compounds exist should not be overlooked. Each excipient has its own unique characteristics and interactions, which can affect the detection and quantification of nitrites.
Therefore, tailored approaches that consider these matrix effects are essential in developing accurate and reliable analytical methods.
The USP’s application note on this topic represents an important first step in the right direction. However, it is essential to continue refining these methods to achieve the higher sensitivity needed to detect even trace levels of nitrites.
In summary, advancing standardized, sensitive methods and considering matrix complexities are critical steps in enhancing nitrosamine risk assessment and ensuring the safety and quality of pharmaceutical products. Industry collaboration and continued research will be key to achieving these goals.