Discover our rigorous nitrosamine approach.
N-Nitroso compounds are well described in a range of literature demonstrating their adverse effects on human health.
The unexpected finding in 2018 of nitrosamine impurities – which are a probable human carcinogen – in drugs, made clear the need to devise a risk assessment strategy for potential nitrosamine content in any at-risk pharmaceutical product.
Based on its comprehensive risk assessment, Roquette has been able to demonstrate that the risk of nitrosamine presence in its active pharmaceutical ingredients (APIs) and starch-based excipients can be considered as negligible.
On September 19, 2019, the European Medicines agency (EMA) published a document with seismic implications for drug manufacturers across the continent. Based on more than a year of investigation and report gathering, the paper laid out the EMA’s intent “to evaluate the risk of the presence of nitrosamine impurities in human medicinal products containing chemically synthesized active pharmaceutical ingredients”. This essentially obligated all marketing authorization holders of pharmaceutical drugs sold in the European Union (EU) to conduct an in-depth assessment of their product portfolios and prove their solutions were safe from nitrosamine contamination.
This article is a comprehensive summary of Roquette’s response to the serious issue of nitrosamine presence in pharmaceuticals, and our tireless efforts to go above and beyond for our customers and patients alike – committing ourselves to the highest standards of testing and reporting for complete safety from the first stages of pharmaceutical development.
Nitrosamine contamination and nitrosating agents: What’s the issue?
N-Nitroso compounds or nitrosamines are a group of chemical compounds classified as ‘probable human carcinogens’ based on extensive animal tests, though their effects on human health are also well-recognized. The 2018 discovery of N-nitrosodimethylamine (NMDA) in a class of blood pressure medications known a ‘sartans’ triggered the need for a comprehensive assessment on the presence of nitrosamine impurities in pharmaceutical products. The EMA, however, asserts the probability of patients being exposed to carcinogenic effects through contaminated drugs remains very low.
Time for action: Assessing the Roquette API portfolio
While we are best known for our extensive range of pharmaceutical excipients, Roquette also produces a wide variety of active ingredients, including:
- LYCADEX® PF
- NEOSORB® PF
- PEARLITOL® PF
- KLEPTOSE® HP and HPB Parenteral grades: HP, HPB, HPB-LB
- Sodium Gluconate Pharma
Upon receiving the recommendations regarding nitrosamine contamination from the EMA, we immediately began a risk assessment of our entire API offering. Our aim? To ensure we were primed to offer effective support to our customers as they began their own evaluation exercises.
Utilizing the standardized methodology set out by the EMA, we meticulously examined every step of our API production process, with particular attention on the use of nitrites or nitrosating agents. Through this, we were able to confirm that no sodium nitrite (NaNO2) or nitrosating agents are used in any step of the manufacturing process. This includes the preparation of raw materials, intermediates, reagents, catalysts or processing aids, nor were any known to be generated or added deliberately at any stage from production start to shipping.
This assessment demonstrates that the risk of nitrosamine presence in all active ingredients produced by Roquette can be considered negligible.
A step further: Evaluating the Roquette excipients portfolio
The evaluation exercise described above could have been the end of Roquette’s investigation into nitrosamine content. Since excipients – our principle offering in the pharmaceuticals space – were exempt from the scope of the EMA’s note, an additional risk assessment for these products was not considered mandatory.
Based on additional research from international authorities and the concerns of our customers, however, we were determined to investigate the potential for nitrosamine contamination to arise through interactions between APIs and specific trace compounds found within excipients too. As such, we began a deeper inspection of our excipient product range.
Defining and redefining: Our quest for testing excellence
Our decision to evaluate our excipients portfolio presented a challenge; given the EMA guidelines only dealt with the detection of nitrosamines in APIs, how should we define the risk of contamination in excipients specifically? Extrapolating the expectations apparent in the current advice on APIs, we determined that the presence of trace nitrites within excipient products should be considered as a risk factor for potential further nitrosamine formation in the final drug.
So, how to go about testing our products according to this standard?
We recognized that two of the key metrics for measuring nitrite content within a substance – the Limit of Detection and the Limit of Quantification – may vary significantly depending on the product. At this point, we could have prioritized speed, and proceeded with the existing analytical methods – but we chose to take the longer, more responsible route of developing a more reliable testing protocol, specially designed for the testing of pharmaceutical excipients.
A new approach: Devising a unique testing strategy
The development and validation of a new analytical method would be the key success factor in our goal of carrying out a complete risk assessment of our excipients portfolio – but this was not without its challenges.
We recognized the Limit of Detection and Limit of Quantification of nitrites within an excipient may vary depending on the product, due to possible interferences or the complexity of the excipient matrix during the extraction. We therefore began with the assessment of solid matrices, such as starch and their modified derivatives (sugars and polyols), combining various methods of high-performance liquid chromatography (HPLC) to overcome the quantification limit imposed on the matrix extraction by the dilution factor. With these parameters in place, we developed a highly reliable analytical method , capable of achieving the perfect compromise between managing the limit of quantification and ensuring accuracy of the end results.
Based on our analytical development and excipient testing program, we achieved a tailored risk assessment and succeeded in determining the nitrite content in all starch based Roquette excipients.
Based on our analytical development and excipient testing program, we achieved a tailored risk assessment and succeeded in determining the nitrite content in all starch based Roquette excipients.
“Formulators, researchers, marketers; every player at every point of the pharmaceutical supply chain has a fundamental responsibility to uphold the quality, safety and efficacy of medicines – for the benefit of patients everywhere.
What’s next for Roquette and nitrosamines?
Being the provider of an extensive pharmaceutical solutions portfolio comes with great responsibility; to our customers, their patients and the wider scientific community. We feel this duty so keenly, we weren’t content with only implementing the steps set out by the EMA. We’re going one step further, developing a whole new approach to nitrosamine assessment, specially designed for excipients. With the evaluation of our starch-based portfolio acting as proof of concept, we’re harnessing the learnings to begin a whole new testing project covering the rest of our leading excipients portfolio.
In the near future, we aim to be able to offer drug producers comprehensive solutions with peace of mind regarding the presence of nitrosating agents across our product portfolio. What more would you expect from Roquette?
Questions, concerns or just want to learn more? Speak to one of our experts for further support and to learn what our approach to nitrosamine content means for your drug development project.