Polfa Tarchomin SA

Rafał Łunio

Rafal Lunio is the Director of Research and Development (R&D) and Qualified Person (QP) at Tarchomiskie Zakłady Farmaceutyczne Polfa Tarchomin S.A., where he oversees R&D operations and ensures that medicinal products comply with European Union regulations. Holding both a Master’s and a PhD in Pharmaceutical Sciences from the Faculty of Pharmacy at the Medical University of Gdańsk, he began his career as an academic teacher in the Department of Applied Pharmacy at the same university, engaging in industry-collaborative research. Previously, Lunio served as the Head of the Global R&D Department and Acting Director of R&D at Polpharma S.A., leading new drug formulation research and partnerships with academic centers. As an Expert Member of the European Directorate for the Quality of Medicines & HealthCare (EDQM) at the Council of Europe, he plays a key role in shaping and implementing European quality standards for medicines

Kamil Szala, PhD candidate in the field of chemical sciences. He is a graduate of the Medical University of Warsaw with a degree in pharmacy. He currently works as an Analytical Scientist in the Research and Development Department at Tarchomiskie Zakłady Farmaceutyczne Polfa Tarchomin S.A., where he is involved in the development of analytical methods for new products and APIs. His main interests include chromatographic techniques coupled with mass spectrometry.

Through this article, Lunio and Szala discusses the critical issue of nitrosamines in pharmaceuticals, recognised as potent carcinogens that can arise from various active pharmaceutical ingredients and their degradation products. They highlight the health risks associated with nitrosamine exposure in drug products and the consequent need for developing sensitive analytical methods and stringent regulatory compliance to mitigate these risks.

Introduction to Nitrosamines

Nitrosamines are identified as potent carcinogens that can form easily via reaction of secondary, tertiary or quaternary amines with nitro sating agents. Due to the fact that various active pharmaceutical ingredients and their degradation products (e.g. sertraline, azithromycin, cyanocobalamin and metformin) are a potential source of nitrosamines, exposure to these contaminants in drug products poses a serious health risks to patients. Consequently, there has been a growing emphasis on the development of sensitive analytical methods and stringent regulatory guidelines to mitigate the risk of nitrosamine contamination in pharmaceuticals.

Current Challenges in Nitrosamine Analysis

Nitrosamine analysis poses numerous challenges due to their low concentrations in pharmaceutical products and the complexity of sample matrices, hence developed methods should be sensitive and specific enough to detect even trace levels of contaminants and to exclude any interferences from placebo or API-related impurities. Traditional analytical methods such as gas chromatography and highperformance liquid chromatography, require extensive sample preparation steps and long analysis times. Additionally, the detection limits of these methods may not always meet regulatory requirements, particularly in light of the stringent thresholds of acceptable intake up to eight ng per day for N-methyl-Nnitroso phenethylamine or N-nitrosonortriptyline set by regulatory agencies like the FDA and EMA.

Since recent studies and reports have highlighted the limitations of conventional analytical approaches in nitrosamine analysis automation of analytical procedures could be helpful in overcoming these challenges.

Overview of Automation Solutions

Automation has emerged as a promising solution to streamline and enhance nitrosamine analysis in pharmaceuticals. Various automation platforms and technologies have been developed to address the challenges associated with traditional manual methods.

One key area of automation is sample preparation, which is crucial for isolating and concentrating nitrosamines from complex matrices. Automated sample preparation systems, such as solid-phase extraction (SPE) and liquid-liquid extraction (LLE), offer several advantages over manual techniques, including improved reproducibility, reduced sample handling errors and increased sample throughput. Furthermore, innovative sample preparation techniques such as solid-phase microextraction (SPME) and microfluidic-based extraction, offer enhanced efficiency and throughput for nitrosamine analysis.

These systems automate the extraction and cleanup steps, allowing analysts to process multiple samples simultaneously with minimal intervention, reduced sample and reagent consumption and enhanced portability.

In addition to sample preparation, automation extends to the chromatographic analysis of nitrosamines. Mass spectrometry instrumentation, such as highresolution mass spectrometry (HRMS) and tandem mass spectrometry (MS/MS), enable improved sensitivity and selectivity for nitrosamine detection at ultra-trace levels. These systems are often equipped with automated sample injectors, column switching capabilities and data processing software enable high-throughput analysis.

It is worth mentioning that integration of artificial intelligence (AI) and machine learning (ML) algorithms have the potential to enhance data processing and interpretation, improving the accuracy and reliability of nitrosamine analysis results. AI algorithms can assist in identifying subtle patterns and trends in complex datasets, leading to more robust analytical insights and decision-making.

Furthermore, advancements in automation software allow for the integration of multiple analytical instruments into a single workflow, streamlining the entire analytical process from sample preparation to data analysis.

Conclusion

Automation emerges as a critical tool in addressing the challenges posed by nitrosamine analysis in pharmaceuticals. By streamlining sample preparation, enhancing reproducibility and improving throughput, automation significantly enhances the efficiency and reliability of nitrosamine detection workflows. Automated systems can handle multiple samples simultaneously, significantly reducing turnaround times compared to manual techniques and improving reproducibility by minimising human error and variability.

Automated sample preparation ensures consistency in extraction and cleanup procedures, leading to more reliable results across different batches or operators. The integration of advanced technologies such as AI, miniaturisation, and novel detection methods further enhances the analytical capabilities of automated systems. Moreover, automation aligns with regulatory requirements set forth by agencies like the FDA and EMA, ensuring compliance and facilitating quality assurance in pharmaceutical manufacturing.

As the pharmaceutical industry continues to prioritise product safety and regulatory compliance, the role of automation in nitrosamine analysis will undoubtedly expand. Future developments in automation hold promise for further advancements in sensitivity, speed and portability, ultimately contributing to improved public health outcomes by ensuring the integrity of pharmaceutical products.