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The presence of toxic nitrosamine impurities in drug substances and drug products has become a significant focus for the pharmaceutical industry following their identification above permitted limits in common drug products prescribed for type 2 diabetes, high blood pressure and heartburn. To learn more about the situation, we interviewed David Elder – CMC consultant – who explained what we know about nitrosamine impurities, how they form, and the steps formulators can take to minimize the risk of formation in existing drug products and future developments.
Elder has 45 years of service within the pharmaceutical industry, with Sterling, Syntex and 23 years with GSK. He is now an independent CMC consultant and has broad based experience in impurity control, formulation (including stabilization strategies) and analytical method development.
David Elder, Ph.D.
Elder obtained his Ph.D. in crystallography from the University of Edinburgh. Elder is a visiting professor at King’s College, London. He is a Fellow of the RSC and chartered chemist and scientist. He is an expert member of the British Pharmacopoeia. He is the immediate past chair of JPAG (Joint Pharmaceutical Analysis Group). He is a member of the Editorial Advisory Board for the Journal of Pharmaceutical Sciences and the European Pharmaceutical Review. He has published 18 book chapters, 160 papers in international journals and has presented 22 webinars and over 182 presentations at national/international symposia. He has 9 patents to his name.
He has co-edited a book on the Analytical Characterisation and Separation of Oligonucleotides and their Impurities (with George Okafo and Mike Webb) and a second on the ICH Quality Guidelines (with Andy Teasdale and Ray Nims).
1. Can you explain what we know about nitrosamines so far?
Nearly four years after the first discovery of N-nitrosamines in valsartan – a medication commonly used to treat high blood pressure – nitrosamine impurities continue to impact the pharmaceutical industry. Nitrosamines are a class of compounds that can generally react with DNA to potentially cause mutations which increase the risk of developing cancer. They are therefore considered potential human carcinogens and can be toxic at extremely low levels. Originally, the problem was thought to be linked to N-nitrosodimethylamine (NDMA) contamination in valsartan. But it became rapidly apparent that other toxic nitrosamines, including NDEA (N-nitrosodiethylamine), NMBA (N-nitrosodibutylamine), NMPA (N-nitrosomethylphenylamine), NIPEA (N-nitrosoisopropylethylamine) and NDIPA (N-nitrosodiisopropylamine) are at risk of forming in drug products too1. Additionally, the crisis did not just impact valsartan, but other sartans, metformin, ranitidine, etc. More recently, it has become apparent that N-nitrosamine derivatives of APIs can also form2.
The crisis has caused thousands of drug product recalls, significant revenue losses and reputational damage – not to mention the temporary withdrawal of treatment from many patients globally. This has made nitrosamine mitigation a key priority for global agencies to address and an essential focus for drug developers worldwide.
2. How is the crisis affecting the pharmaceutical industry, and what can be done in the short term to mitigate it?
The crisis has impacted almost all commercial drug products in the most significant markets, including Europe and the US. To help drug formulators address the challenge, the Food and Drug Administration (FDA) updated guidance in February 2021 to specify allowable timeframes for completing nitrosamine mitigation activities by marketing authorization holders (MAHs). Their proposed strategy includes risk assessment (step 1), confirmatory testing if risks are identified (step 2) and reporting the changes that will be implemented to prevent or reduce the presence of nitrosamine impurities in approved drug products, pending new drug applications (NDAs) and abbreviated new drug applications (ANDAs) (step 3). FDA recommends completion of these steps by October 2023. The European Medicines Agency (EMA) has advised MAHs to complete confirmatory testing and submit variation applications by September 2022 for chemical medicines and July 2023 for biological products.
Should MAHs discover a risk of nitrosamine formation in their drug substance or products, they should work with Agencies to mitigate that risk. It is recommended that developers explore the root cause of the nitrosamine formation to inform and implement a long-term strategy that will successfully tackle the issue. Agencies may be prepared to tolerate higher limits in the short term to ensure the continuation of drug supply, with the expectation that the long-term limits are aligned with regulatory expectations.
3. How are nitrosamines formed in drug products? Are there any production processes (or formulation steps) in particular that you think could cause critical issues related to nitrosamine formation?
The development of short-chain alkyl nitrosamines – like NDMA and NDEA – is possible in drug substances in the presence of secondary, tertiary or quaternary amines and nitrosating agents, like nitrous acid, especially under acidic conditions. Here, nitrous acid reacts with alkyl amines, forming the corresponding N-nitrosamine impurity.
Starting materials, intermediates and the API can all contain secondary or tertiary amine functionalities. The same can be said for catalysts and reagents. Moreover, many common high boiling point amide solvents, like N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and N-diethylacetamide, contain secondary amines with the potential to form volatile impurities. For example, sartan pharmaceuticals containing a tetrazole ring carry a potential risk for nitrosamine contamination. This is because the excess amount of sodium nitrite used to purge residual sodium azide when synthesizing sartan APIs can react with residual secondary amines – unintentionally generating nitrosamines.,
Nitrites, the other necessary reagent for nitrosamine formation in drug products, are often present as an impurity in many common excipients and water. This can lead to nitrosamine impurities forming in drug products under acidic conditions during the manufacturing process itself or during storage. In addition, some drug products can undergo degradation pathways during storage, which increases the risk of nitrosamine formation. Issues can also arise from poor GMP compliances, where starting materials and raw materials are contaminated, or recovered reagents, solvents and catalysts contain nitrosamine impurities. Consequently, it can sometimes be difficult to determine the source of the nitrosamine formation.
4. What can marketing authorization holders do to overcome nitrosamine formation and prevent their drug products from being recalled?
Regulatory agencies quickly realized the nitrosamine crisis’s potential negative implications on global supply chains. They requested that manufacturers prioritize considering the source of nitrosamine impurities in all APIs and drug products, not just affected pharmaceuticals. If developers find no possibility of nitrosamine formation, then there is no requirement to take further action. If impurities are detected, a mitigation strategy must be implemented immediately to remove the risk.
Drug developers could look to optimize the processing of drug products. But even that may not completely prevent nitrosamine formation. Nitrosamines formed during drug substance processing need to be purged in subsequent or additional purification steps. Importantly, nitrosamines formed in the drug product cannot be readily purged. For these reasons, manufacturers may look to block nitrosamine formation in drug products entirely. This is considered the best way to mitigate the risk and ensure that impurity levels are below allowable limits – an acceptable daily intake of 18 ng for newly emerging nitrosamine impurities according to current EU regulatory guidance and 26.5 ng/day according to current US regulatory guidance6.
Adding specific antioxidants – like ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) – to formulations as nitrosamine formation inhibitors is recommended by the FDA as a mitigation strategy. One study found that ascorbic acid and alpha-tocopherol demonstrated greater than 80% inhibition when spiked at 1% in solid oral dosage forms. The authors also showed the potential of amino acids as inhibitors of nitrosamine formation. By blocking the formation of toxic nitrosamine impurities, both antioxidants keep nitrosamine levels below the acceptable intake limits, making drug products safe for human use. Ascorbic acid and alpha-tocopherol, therefore, offer developers reliable opportunities to redesign their pharmaceuticals or innovate new drugs without the risk of nitrosamine formation. In addition, basification of the formulation will ensure that the micro-pH environment within the dosage form will be alkaline, preventing the formation of the key nitrosating agent, nitrous acid – which is formed from nitrites under acidic conditions.
5. What key factors do developers need to consider when reformulating their products, including drug metabolism? At what stage does the drug metabolism need to be taken into account in a reformulation process?
The risk of nitrosamine formation needs to be addressed during any reformulation exercise because impurities can be generated at any stage – from the manufacturing phase to the storage period of a drug product. Here, the use of nitrosamine inhibitors together with basifying excipients can help to mitigate the risk of nitrosamines forming – as mentioned above. The issue of nitrosamine formation via drug metabolism is particularly interesting though, as its greatly linked to the overall risk-benefit assessment of the drug, which is determined by pre-clinical and clinical safety trials. Nitrosamine formation only really becomes an issue when the risk-benefit of the drug comes under question.
For example, ranitidine and nizatidine – which are prescribed for treating conditions caused by too much acid being produced in the stomach – were better and safer alternatives, like proton pump inhibitors (PPIs). Therefore, when the presence of nitrosamines in the API and the risk of formation in the API and drug product during storage became apparent, the recall of these drug products from the market was seriously considered. Whereas, with valsartan and other sartans, global agencies consistently indicated that the ‘theoretical risk of cancer was very low and based on a worst-case scenario, and that patients should continue to take the medication.’ As part of the overall risk-benefit determination, agencies reminded patients that nitrosamines are a common by-product of food processing and are frequently found in the environment and drinking water.
6. Against this backdrop, how do you see the future of innovation in three dimensions: the science of treatment, the science of technology and the science of the expectant patient?
In the interim, regulators need to continue reassuring patients that the medications they’ve been prescribed are still safe against the backdrop of this emerging and rapidly evolving crisis. Interestingly though, the response from clinical regulators regarding the perceived safety risks to patients has been in stark contrast to the much more inflexible view taken by Chemistry, Manufacturing and Controls (CMC) regulators, who were not prepared to endorse even minimal risk – that is the acceptable daily intakes for nitrosamines. As such, the acceptable intake of NDEA is 26.5 ng/day is not endorsed in the EU. The control limit is just one-tenth of this, at 2.65 ng/day. Moreover, if both NDEA and NDMA were present, the trigger concentration would be the sum of the two nitrosamine impurities. Thus, it is evident that reliable quantification of N-nitrosamine impurities at low-ppb or sub-ppb levels is needed to conform with EMA’s risk-assessment procedures. Because these levels are significantly lower than the previous test-limit target concentration of 30 ppb, measuring nitrosamine impurities now represents an extremely difficult analytical challenge. It has already become evident that applying the extremely sensitive methodology, like GC-MS(n) or HPLC-MS(n), is ‘fraught with uncertainty’ and could lead to the recall of safe and acceptable products, further undermining the public’s confidence in the health system.7 The other major concern is that there are limited global laboratories and support staff who can routinely operate this type of methodology and produce reliable data.
This will be hard to comply with and not notably improve patient safety because people are exposed to the same molecules in drinking water and foodstuffs. It would be logical if agencies addressed public health emergencies like this one by aligning the message to patients – that is, to keep taking their medications because the risk is low – with that sent to MAHs – which is to drive nitrosamine levels to below existing safety-based limits.
Reflecting on patients’ responses to the crisis, many have criticized the lack of clear and explicit guidance from regulatory agencies and healthcare professionals on specific medications. One study showed that heightened non-compliance following the valsartan recalls led to proportionately higher hospital admissions. Therefore, it is clear that more information about the risks – or lack thereof – of nitrosamines in pharmaceuticals is required for peace of mind, plus details about how the industry is tackling the situation to remove that risk.
References
- FDA, 2021, Control of Nitrosamine Impurities in Human Drugs − Guidance for Industry R1, FDA CDER CGMP. https://www.fda.gov/media/141720/download.
- FDA. Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products. 18 November 2021. https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities.
- EMA, Nitrosamine impurities. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities.
- Oruganti S.A viewpoint on the presence of N-nitrosodimethylamine (NDMA) impurity in certain generic samples of Valsartan, Drils Perspectives; Dr. Reddy’s Institute of Life Sciences, 2018.
- EMA release. Assessment report. EMA/CHMP/217823/2019. https://www.ema.europa.eu/en/documents/variation-report/angiotensin-ii-receptor-antagonists-sartans-article-31-referral-chmp-assessment-report_en.pdf
- FDA. Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products. https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities.
- Elder DP, Johnson GE, Snodin DJ. Tolerability of risk: A commentary on the nitrosamine contamination issue. J Pharm Sci. 2021; 110(6): 2311-2328.
- European Medicines Regulatory Network. European Medicines Regulatory Network approach for the implementation of the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 for nitrosamine impurities in human medicines. https://www.ema.europa.eu/en/documents/referral/european-medicines-regulatory-network-approach-implementation-chmp-opinion-pursuant-article-53/2004-nitrosamine-impurities-human-medicines_en.pdf.
- Nanda et al. Inhibition of N-nitrosamine formation in drug products: a model study. J Pharm Sci., vol. 110, no. 12, pg. 3773-3775, 2021.
- Elder et al. Tolerability of risk: a commentary on the nitrosamine contamination issue. J Pharm Sci., vol. 110, no. 6, pg. 2311-2328, 2021.