Trends and Challenges in Nitrosamine Testing: Part Six – Live Roundtable

Part One: Scoping the Problem

“In the years after the discovery of NDMA, conferences at Valsartan Pittcon, ACS, and the American Society for Mass Spectrometry had a noticeable increase in the attention given to nitrosamines and the analytical challenges they pose.” – Kevin Parker 

“While standard methods exist for small molecule nitrosamines, testing for formation of NDSRIs can introduce additional analytical challenges, as NDSRIs are typically unique to each project’s chemistry. In other industries small molecule nitrosamines are typically the main area of concern; and in some cases they may not be regulated to as low of levels as they are in the pharmaceutical industry.” – Jessica Hoskins 

Part Two: Analytical Challenges 

“Isomeric structure can have an impact on nitrosamine analysis, especially if the API contains isomeric impurities. However, these isomeric impurities will have the same MRM transition as the nitrosamine under investigation and can therefore be identified and quantified should they be resolved from the main impurity.” – Alan Thompson 

“In the pharmaceutical industry, I’ve encountered quite a few challenges with sample preparation. As I previously mentioned, we often try to increase the sample concentration as much as is practical to reach the necessary LOQ for the nitrosamine. Since we want to ensure that the sample preparation step does not generate any additional nitrosamine, I usually try to avoid sonication or heating of the sample.” – Jessica Hoskins

Part Three: Building a Method

“Nitrosamines encompass a wide range of chemical structures, making the development of universal analytical methods challenging, particularly for nitrosamine drug substance-related impurities (NDSRIs), which often require unique detection and quantification methods.” – Naiffer Romero

“I’d start by firstly determining the method’s analytical target profile; i.e., figuring out the limit of quantitation (LOQ) based on the recommended acceptable intake limit of NDSRIs and the maximum daily dosage of the drug product – to ensure I understood the intended use of the method. Next, I’d focus on achieving LC separation of NDSRIs from the API or other major components, with reverse-phase chromatography and common mobile phases as my initial choices for separation.” – Yingyue Yang 

Part Four: The Regulatory Landscape 

“International regulatory agencies have actively collaborated to address nitrosamine impurities in pharmaceutical products since the issue first emerged. Various workshops and training sessions have been held by regulatory authorities to explain policies, as well as to gather insights and feedback from stakeholders. In a relatively short period, multiple agencies have released guidance documents.” – Yingyue Yang

“At this point in time, I’d sum up the regulatory environment as continually evolving. As the analytical experts in the lab, we must be familiar with the regulatory environment and work closely with other areas of the organization to make sure we are developing methods to appropriately assess the risk of nitrosamine formation.” – Jessica Hoskins 

Part Five: Pharma’s Future 

“I think future development will focus on the prevention of nitrosamine formation all together. Using scavengers that can remove the building blocks or inhibitors that stop the chemical reactions required for nitrosamine formation, the control strategies surrounding nitrosamines will become more robust.” – Kevin Parker 

“I hope to see advancements in LC-MS technology and methodology that enables the direct identification of any nitrosamine species in a sample without prior knowledge (a non-targeted analysis).” – Yingyue Yang 

Part Six: Live Roundtable
 

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