ThermoFisher Scientific will hold a webinar regarding NDSRI analysis.
In this part online seminar part panel discussion, we will present and discuss nitrite in excipients, nitrite and NDSRI analysis methods and challenges, NDSRI risk assessment and a comprehensive and industry accessible NDSRI database hosted by Lhasa Limited. It will examine the challenge of NDSRI analysis include matrix effects and the risk of false positive results arising during sample preparation.
Speaker:
Joerg Schlingemann
Principal Expert QC Systems, Merck Healthcare KGaA
Andrew Teasdale
Senior Principal Scientist, AstraZeneca
Sebastian Hickert
Senior Manager, Merck KGaA
Giorgio Blom
Associate Principal Scientist, AstraZeneca
Grace Kocks
Senior Global Alliances Manager, Lhasa Limited
Jon Bardsley
Market Development Manager, Pharma & Biopharma, Thermo Fisher Scientific
This is an event not to be missed.
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In case you missed it, this was a fantastic webinar, and not just because of the shout out to Naiffer & the forum 
. It can still be accessed with the link provided!
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Congrats to @schlinjo1975 @AndyTeasdale @giorgio @KocksG @jon.badsley for a great workshop!! Thanks for the shout out to the community!
A summary of the discussion, but I invite you to watch it…
The sources you provided highlight a wide array of challenges that the pharmaceutical industry faces regarding nitrosamines, specifically NDSRIs:
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Ubiquity of Nitrosamine Precursors: Secondary and tertiary amines, the chemical precursors to nitrosamines, are common in many drugs. A large-scale analysis found that 41.4% of active pharmaceutical ingredients (APIs) and 33% of impurities in a drug database were either secondary or tertiary amines. These amines play vital roles in drug development: they are essential reactants in chemical reactions, contribute to drug solubility by acting as hydrogen bond donors and acceptors, and their 3D structure facilitates pharmacological interaction. Due to their prevalence and importance in pharmaceuticals, avoiding secondary and tertiary amines altogether is not a feasible solution.
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Stringent Regulatory Limits and Analytical Testing Challenges: Regulators impose strict limits on acceptable intake levels for nitrosamines, particularly NDSRIs. This creates an analytical challenge, as the required limits of quantification (LOQs) often fall in the parts per billion range, pushing the boundaries of current analytical technology. Detecting such minuscule amounts requires highly sensitive techniques and adds significant costs to the drug development process. One speaker notes that their company has spent approximately $20 million on nitrosamine-related expenses, including analytical equipment, contract labs, toxicological testing, and personnel. Extrapolating this spending to the entire pharmaceutical industry suggests a collective expenditure of around $4 billion on nitrosamine testing thus far.
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Limitations of the Ames Test: The Ames test, a widely used method to assess the mutagenic potential of chemicals, has come under scrutiny due to concerns about its sensitivity in detecting mutagenic NDSRIs. Historical data suggests that the Ames test may produce false negatives, failing to identify potentially carcinogenic NDSRIs. This has led regulators to adopt a precautionary approach, applying the stringent limits for well-known potent nitrosamines like NDMA and NDEA to NDSRIs, even though limited carcinogenicity data exists for these NDSRIs. This conservative approach further exacerbates the analytical challenges by necessitating even lower detection limits.
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Impact and Limitations of CPCA: The introduction of the Carcinogenicity Potency Characterization Approach (CPCA) in July 2023 has brought some relief by categorizing nitrosamines based on their potency scores. This categorization resulted in a wider range of acceptable intake levels, from 18 to 1500 nanograms per day, with many NDSRIs, particularly those derived from secondary amines, falling into the lower potency categories with higher acceptable intakes. While the CPCA has eased the immediate crisis, the sources point out several limitations and areas for improvement. One speaker expresses hope that the limit for category 5, currently set at 1500 nanograms per day, will be raised in the future to accommodate NDSRIs that may warrant higher limits based on emerging safety data.
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Regulatory Disparities and Uncertainties: Concerns persist about the lack of alignment between regulatory agencies, particularly between the FDA and European perspectives, on how to interpret safety data for NDSRIs. The recent update to the FDA’s guidance in September further adds to the complexity, introducing new risk factors, tightening testing requirements, and suggesting the use of mitigation strategies like scavengers and pH adjustment, the effectiveness of which is still debated within the industry. These uncertainties and discrepancies underscore the need for a more comprehensive and globally harmonized approach to NDSRI risk assessment and management.
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Nitrite Contamination in Excipients: Nitrite impurities in excipients, the inactive ingredients in drug formulations, pose a significant challenge as they can react with amines in the drug substance to form nitrosamines during manufacturing or storage. Controlling nitrite levels in excipients is therefore crucial for mitigating nitrosamine formation. A collaborative database of nitrite levels in various excipients has been established, providing valuable information about the variability in nitrite levels among different batches and suppliers. However, simply labeling excipients as “high nitrite” or “low nitrite” is insufficient, as the amount of excipient used in a formulation can significantly impact the overall nitrosamine risk. A more nuanced understanding of nitrite levels in excipients and their contribution to nitrosamine formation in the final drug product is necessary.
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Difficulties in Nitrite Testing: Analyzing nitrite content in excipients presents a significant analytical challenge due to the inherent properties of nitrite: its small size, high polarity, and reactivity. Traditional reversed-phase HPLC, a mainstay in analytical labs, is unsuitable for retaining and separating nitrite. Specific techniques like ion chromatography, often coupled with conductivity detection, are commonly employed for nitrite analysis. Another approach involves derivatization, where nitrite is chemically modified to enhance its detectability by techniques like UV spectroscopy or mass spectrometry. Careful sample preparation is crucial to avoid nitrite loss through oxidation to nitrate or artificial generation of nitrite during sample processing. A comparative study involving six labs revealed significant discrepancies in nitrite levels measured in magnesium stearate, highlighting the impact of sample preparation methods, particularly the use of ultrasonication, on the results.
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Complexity of NDSRI Testing: Analyzing NDSRIs presents unique challenges due to their low acceptable intake levels, requiring highly sensitive analytical techniques to avoid both false positives and false negatives. The risk of in-situ nitrosamine formation during sample preparation adds another layer of complexity, demanding meticulous control of experimental conditions, such as pH and solvent choice, to prevent artificial generation of NDSRIs. Furthermore, the lack of commercially available reference standards for many NDSRIs necessitates complex synthesis and purification processes to ensure the accuracy and reliability of the analysis. Synthesizing NDSRI standards comes with its own set of challenges, including the potential for unwanted side reactions that can lead to the formation of incorrect chemical structures. These challenges highlight the need for robust analytical methods and meticulous quality control measures to ensure the accuracy and reliability of NDSRI testing.
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