Effective Impurity Management Personal Reflection by Andy Teasdale

Every time I look to prepare for the  Effective Impurity Management Course, I reflect on what has changed since previous events. This time as indeed virtually every time in the last 6 years, thoughts centre on N-Nitrosamines.  Since the initial observation of the presence of the potent carcinogen Nitroso dimethylamine (NDMA) in Valsartan there has been a virtually non-stop stream of news relating to Nitrosamines; whether this is new guidance or publication of new scientific data the issue has continued to evolve.

So, what will I be discussing in the course? Well key to understanding the current and the future you need to understand the past.

In the case of Nitrosamines, I will explain how we have learnt from the Valsartan contamination incident and how this now shapes awareness and ultimately avoidance of similar issues in the future.  Can we avoid another Valsartan? Absolutely, how, and why this occurred is now well understood and most importantly preventative and corrective actions can be taken to eliminate future risk. We have a far greater appreciation of the risk factors associated with formation of Nitrosamines during drug substance synthesis; indeed, we found a rich source of data including mechanistic understanding and the ability to model kinetically from data derived in the 1970s[i].  Even more remarkably we found that much of the work was carried out by the late Professor Lynn Williams, someone I knew from my time at Durham University.  What better proof of the old adage about a day in the library.

So, have we solved the issue? No doubt most it not all reading this know the answer to this! As we started to dig deeper into the risk to drug substance and drug product as mandated by EMA guidance, the potential for Nitrosamines to form in the drug product.  But these were different, not the small low molecular weight Nitrosamines like NDMA, but instead Nitrosamine Drug substance related impurities (NDSRIs).  These were found to form through reaction between the drug itself and part per million levels of nitrite in excipients. To compound this, such Nitrosamines have no relevant safety data upon which to base limits.  To steal a line from the 1960’s film Zulu, “there’s thousands of them”. In fact, huge swathes of existing drugs, across virtually all therapeutic areas, were placed at threat [ii].  So, what are appropriate limits? To begin with limits for NDSRIs were simply based on limits analogous to NDMA and Nitrosamine Diethylamine (NDEA), i.e., 96ng and 26.6ng/day respectively.

It soon became apparent that control to such limits was impractical, triggering another crisis with the very real threat of loss of access to vital medicines.  This prompted the development of a framework to establish limits present in the structure of the Nitrosamine.  While this averted an immediate crisis it has not resolved the issue.

So, what is needed? It’s vital that the issue of Nitrosamines is assessed and managed using the full armoury.  Control through management of both DS/DP manufacturing is vital to effective control long term. We have at our disposal the ability to mode formation and understand how to at least potentially, manipulate based on factors such as pka of amine in question, pH, moisture levels, nitrite levels in key excipients and others.  We also have the possible use of scavengers but let’s not pretend this is an exact science. Even if a successful scavenger is found this may bring with it other issues, discolouration is one that has been observed primarily associated with the use of ascorbic acid but also seen with other scavengers as well.

Critically we must recognise that chemical process and formulation cannot address all issues.  This particularly true if the drug is a secondary amine and has a low CPCA categorisation.  In such scenarios it becomes necessary to look to the potential to address through a pre-clinical approach.  Put simply, change the limits.  As part of the course I will look to examine how this might be achieved.  Ponting et al[iii] argued that the CPCA is a de minimis approach, based simply on the structure of the NDSRI. Consequently, this argues that other approaches can and should be considered.  Options include rea- across but this is challenging given the lack of quality data, certainly carcinogenicity, for NDSRIs.  Recently we have seen a slew of publications relating to safety testing for N-Nitrosamines.  Arguably the most important relates to the Enhanced AMES test (EAT)[iv], this been shown to be robust in the assessment of Nitrosamines. However, even a negative AMES is considered insufficient by the FDA to support 1500ng/day (1.5ug/day), let alone Q3A/Q3B which is the ICH M7 position.

So, if an EAT will make little difference, what else is possible?  Several papers recently have discussed other, novel in vitro assays, based on Mammalian cells; these look interesting / promising but have very limited datasets and are not subject to any formal agreed validation protocols.  How are we to use such data? Is it required to even produce it? And which assays? All tricky questions that I will touch during the course, however the reality is that it may take years and ICH to resolve.  We have also seen publications relating to in vivo studies, both transgenic and most excitingly next generation sequencing supporting higher limits than the CPCA, but again these are not yet supported by a clear standard such as OECD.

In addition, a recent publication supports the application of less than lifetime (LTL) limits for Nitrosamines, consistent with other mutagenic carcinogens and of course a central tenant of ICH M7[v].  Will the ICH M7 Nitrosamines Expert working group support this? Is another vital question.

We have also seen modelling of Nitrosamines in vivo in terms of endogenous formation.  How will such models be used? Again, will there be an anticipation that such models are required? And what if they indicate a substantive risk?  So many topics to discuss to discuss during the course!

As you can see from this there are lots of uncertainties and unknowns surrounding Nitrosamines  but I will seek to provide a strong commentary on both the current and future position around this complex and challenging topic. And remember this is only one of the impurity topics I will cover as I look to provide a holistic overview of effective impurity management.

If you are interested in attending the upcoming  Practical Management of Impurities and Development of Effective and Comprehensive Control Strategies course follow the link for further information and booking details.

[i] Williams D. L. H. Nitrosation, Cambridge University Press, Cambridge, 1988

[ii] Schlingemann et al. J Pharm Sci. 2023 May;112(5):1287-1304.

[iii] Ponting et al. Regulatory Toxicology and Pharmacology 156 (2025) 105762.

[iv] Puglisi et al. Regulatory Toxicology and Pharmacology 161 (2025) 105835

[v] Bercu et al. https://doi.org/10.1016/j.yrtph.2021.104926