Pharmaceutical manufacturers should ensure that the analytical tests they are using are “fit for purpose” to ensure that the right test is measuring the right impurity in testing their drugs for nitrosamines, says Jason Rodriguez, director of the division of complex drug analysis at the US Food and Drug Administration’s (FDA’s) Office of Testing and Research in St. Louis. Manufacturers should also use orthogonal, or additional methods, to double-check results.
Rodriguez was giving an update on testing for nitrosamines at a 27 October Pharmaceutical Quality Symposium webinar sponsored by the Center for Drug Evaluation and Research’s (CDER) Small Business and Industry Assistance (SBIA). He also discussed some best practices for assessing the presence of nitrosamines and sources of nitrosamine contamination.
The nitrosamine impurity issue has been the focus of worldwide regulatory attention ever since elevated levels of N-nitrosodimethylamine (NDMA) were found in active pharmaceutical ingredients (APIs) for certain blood pressure medicines in June 2018. Subsequently, other types of nitrosamines have been discovered in other medicines, such as ranitidine and metformin, prompting a number of high-profile drug recalls.
Regulators learned a lot
Rodriguez said that, regulators and industry have “learned a lot” over the past three years about “what factors lead to the risk of nitrosamine impurities in pharmaceuticals.”
Nitrosamine impurities can be introduced in three ways, with contamination occurring during the manufacturing process or via the supply chain; impurities may also develop because of problems with the drug’s stability.
Process-related causes can be related to the physicochemical properties of the starting materials, intermediates or the drug substance; specific process conditions; or reactions with raw materials.
Supply chain risks can arise from using recovered or recycled materials or other intermediates contaminated with nitrosamines, or result from cross-contamination in multi-purpose facilities.
Alternatively, various impurities can form in the drug over its shelf life. “Sometimes the inherent chemistry of the drug or the expected shelf-life may cause nitrosamines to form as the product ages,” Rodriguez explained.
The agency issued a guidance in September 2020 to help manufacturers detect and prevent nitrosamines in products. The guidance was subsequently revised in February 2021 to give manufacturers more time to conduct nitrosamine risk assessments to ensure that these impurities do not exceed certain thresholds. Manufacturers had to conduct such assessments by the end of March.
Cross-checking
In conducting the required risk assessments, manufacturers must ensure they are using fit for purpose analytical techniques to measure impurities. Rodriguez gave several examples from case studies showing why fit for purpose tests are important in demonstrating FDA’s methods for conducting analytical studies on drugs suspected of having high nitrosamine impurity levels.
The first case study was in June 2020 after reports that a private lab tested various lots of ranitidine and found samples had levels of N-nitrosodimethylamine (NDMA) that were “very alarming.”
Rodriguez did not name the lab; however, in September 2020, testing laboratory Valisure filed a citizen petition with FDA indicating that ranitidine lots tested by Valisure had high levels of NDMA and requesting that FDA recall lots of Zantac and other ranitidine products.
FDA subsequently tested the samples to see if their findings correlated with the lab’s results. The agency “bought whatever acidic blockers we could find, and we ran the method in our lab,” said Rodriguez. The lab used the same testing method as Valisure had, using gas chromatography/mass spectrometry (GC/MS) to gauge nitrosamine impurity levels in samples.
After testing the samples, FDA staff discovered black material in the sample head space that proved to be the “charred remains” of the tested tablets. “This was not something that we usually see for head space, so we began to think, ‘What is going on here?’” said Rodriguez. “Is ranitidine undergoing some thermal degradations to form NDMA?”
This did prove to be the case. The learning from the case study, added Rodriguez, is that using GC/MS to detect NDMA does not work because the method causes a thermal degradation and “heating the sample promotes the formation of NDMA.”
The agency then ran the samples through an orthogonal method, liquid chromatography-high resolution mass-spectrometry (LC-HRMS). When running the samples on this method, “we saw that the levels while present are still much lower and not nearly at the level of those that were cited by a private lab,” said Rodriguez.
He added, “I cannot emphasize how important it is to have orthogonal methods because you always want to have a built-in check to make sure that your final results are cross-checked by completely independent testing.”
Fit for purpose
The second case Rodriguez reviewed also involved an unnamed “private testing lab” that wanted FDA to recall certain lots of metformin because of high amounts of NDMA in the drugs. In March 2020, Valisure filed a citizen petition reporting that its testing found that 16 batches of metformin from 11 companies had NDMA levels that exceeded the 96 ng daily acceptable intake limit.
FDA subsequently tested the same number of products and found a much smaller amount of these impurities. FDA’s results showed that eight of the 38 samples from five companies had NDMA amounts above the acceptable limit.
The agency concluded that the lab relied on mass spectrometry analyses to test the samples, a method that was not specific enough to distinguish the NDMA signal from that of another impurity, N,N-dimethylformamide (DMF). These findings were published in July 2020 in The AAPS Journal, in an article co-authored by Rodriguez.
This case study also demonstrates the importance of using fit for purpose analytical techniques.
“The results of the study described here indicate that care must be taken to ensure analytical procedure specificity in the presence of potential interfering substances in the development and validation of analytical tests for drugs like metformin,” according to the paper’s authors.
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