Thanks to decades of regulatory oversight and pharmacovigilance, we tend to take for granted the quality and safety of our most used medicines. Sometimes, though, the challenges and complexities of ensuring this peace of mind are thrown into the spotlight. Recently, potentially carcinogenic nitrosamine impurities were found to be present in commercially available drug products. This discovery, and the measures taken to quickly mitigate any risks, highlight the role of advancing analytical technology in safeguarding consumer health.

In September 2019, the United States Food and Drug Administration (FDA) reported unacceptable levels of N-nitrosodimethylamine (NDMA), a probable human carcinogen, in several batches of the heartburn medication ranitidine (Zantac) [1], which prompted a large-scale product recall. Coming little over a year after similar findings triggered a recall of batches of the angiotensin II receptor blocker (ARB) valsartan [2], the ranitidine results meant an increased focus on this impurity, its risks and, in particular, its detection. One outcome has been the adoption of novel analytical methods developed using the latest high-resolution accurate mass (HRAM) mass spectrometry techniques, which are helping overcome some of the limitations of previous approaches to nitrosamine detection.

Nitrosamines in the manufacturing chain

Certain pharmaceutical manufacturing processes can result in the production of genotoxic impurities (GTIs), such as NDMA and other nitrosamines, many of which are potentially carcinogenic, even at low levels. Consequently, regulatory authorities closely monitor drug products for these compounds.

Documentation from the European Medicines Agency (EMA) highlights potential sources of nitrosamine formation and contamination in ARB drugs [3]. These include specific active pharmaceutical ingredient (API) processing conditions and materials, the use of sodium and other nitrites in the presence of secondary or tertiary amines, and the inclusion of contaminated raw materials in API production. Of note is the significant challenge posed by vendor-sourced raw and starting materials, particularly because an API manufacturer whose own process is incapable of producing nitrosamines may be unaware of the risk of such impurities being present.

NDMA and other nitrosamines can be difficult to detect in the standard laboratory tests that are reviewed during a routine surveillance inspection. Since the discovery of unacceptable levels of NDMA in valsartan, there has been global sharing of analytical methods, which continue to evolve as technology moves forward. With the more recent ranitidine findings, manufacturers are under intense pressure to carry out rigorous risk assessments and use highly robust analytical methods for the detection of NDMA and other nitrosamines in all drug products.

Advancing detection using LC-MS

As part of its function, the FDA maintains up-to-date official testing methodologies and has developed validated methods to detect and quantify NDMA and other nitrosamines in ARB medicines. Methods such as gas chromatography-mass spectrometry (GC-MS) headspace or liquid injection can all be used to evaluate both active drug substances and finished ARB products. A different approach is needed, however, when it comes to evaluating NDMA in ranitidine.

Ranitidine products are known to be susceptible to thermal degradation, which itself leads to NDMA formation, rendering unsuitable any NDMA detection methods that employ gas chromatography. Moreover, the low molecular weight of NDMA and structurally similar GTIs mean the analyses are prone to background interferences, making the development of methods robust to formulation interferences a complex analytic challenge. To address this, the FDA has developed a new liquid chromatography HRAM mass spectrometry (LC-MS) method that is validated to ICH Q2(R1) [4]. This method brings together the robust separation achievable using liquid chromatography and high-confidence HRAM detection technology. In doing so, it delivers the means to accurately detect and quantify NDMA in ranitidine APIs and drug products. Manufacturers can also be confident that they satisfy GMP compliance requirements by adding state-of-the-art chromatography data system software to streamline instrument control and data processing.

Development of this ranitidine method follows the FDA’s publication of a LC-MS method validated to ICH Q2(R1) for the determination of NDMA and five other nitrosamine impurities in various ARB drugs, including valsartan [5]. These impurities are separated from one another and from the drug product by reverse phase chromatography. Subsequent detection employs a high-resolution, high mass accuracy spectrometer.

Toward the safest future

With patient safety of paramount concern, it is critically important to detect pharmaceutical impurities before products reach the marketplace. Product recalls are not only logistically challenging and commercially disruptive, but also risk interrupting the availability of supplies to consumers.

The presence of NDMA and other nitrosamines in drugs, such as valsartan and ranitidine, which are in widespread use, has required manufacturers to review their processes and apply robust detection methodologies. Analytical methods based on the latest HRAM mass spectrometry technology, as published by the FDA, has given laboratories access to fast, accurate detection capabilities for these impurities.

The exceptional speed, sensitivity and resolving power of HRAM systems is making a significant contribution to detecting potentially harmful impurities throughout the pharmaceutical production lifecycle. Compliance-ready systems capable of quality testing in GMP environments deliver further support, helping drug companies to achieve the highest safety and quality standards.

References

1. FDA, Statement alerting patients and health care professionals of NDMA found in samples of ranitidine, September 2019. Available at https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine
2. FDA, FDA Statement on FDA’s ongoing investigation into valsartan impurities and recalls and an update on FDA’s current findings, August 2018. Available at https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-ongoing-investigation-valsartan-impurities-and-recalls-and-update-fdas-current
3. EMA. Information on nitrosamines for marketing authorisation holders.

   4.     FDA, Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product. Available at https://www.fda.gov/media/130801/download

   5.     FDA, Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of Six Nitrosamine Impurities in ARB Drugs. Available at https://www.fda.gov/media/125478/download