Abstract
In 2018 N-nitrosodimethylamine (NDMA) was detected in a batch of valsartan at levels exceeding ICH acceptable intake limits for mutagenic impurities. Since then, the analysis of nitrosamines has become an intense focus point for the pharmaceutical industry. The identification and low-level determination of nitrosamines in potentially affected materials is challenging and requires the application of highly sensitive analytical techniques. This white paper reviews the evolution of the regulatory landscape and discusses the development of analytical methods for the determination of nitrosamine impurities referenced by regulatory authorities. The development of a separation of these compounds from the active pharmaceutical ingredient (API) is discussed, together with application of mass spectrometry (MS) to ensure that the required detection limits can be reached. Additionally, the potential for interference, notably from N,N- dimethylformamide (DMF), is considered, along with strategies for mitigating the risks of inaccurate quantification that arises.
Introduction
In July 2018, the pharmaceutical landscape for the manufacture of small molecules changed with the detection of a small mutagenic compound in a batch of valsartan. Valsartan, is a prescription only selective angiotensin II receptor blocker (ARB) drug, used to treat high blood pressure and heart failure. During routine analysis, QC chemists identified the presence of a nitrosamine, N-nitrosodimethylamine (NDMA), and subsequently reported an average level of 66.5 parts per million in affected batches1, which is high enough to have a detrimental impact on patient safety.2 Mutagenic compounds damage the genetic information within a cell, causing mutations which may result in cancer. The damage to the cell is caused by interactions with the DNA sequence and the DNA structure. DNA alteration may also result in permanent heritable changes to the somatic cells of the organism or germ cells which can then be passed on to future generations. It is vital that mutagenic compounds such as nitrosamines are detected and their production avoided wherever possible.
Nitrosamines are a class of compound containing a nitroso group bonded to an amine (Figure 1) and were first reported by Barnes and Magee, who found that NDMA produced liver tumours in rats. Subsequent studies showed that of over 300 nitrosamines tested, nearly 90% were carcinogenic to a wide variety of animals.3 Nitrosamines have since been reported in numerous sources, including environmental samples, drinking water and processed food products. Their potential formation in pharmaceutical drug products was established in the 1970’s with the detection of NDMA in aminophenazone. In this case, NDMA was believed to form as an API degradation product, via hydrolysis of the API to release dimethylamine, followed by nitrosation in the presence of nitrosating agents.4 Subsequently, it has been reported that nitrosamines can potentially form during the synthesis of several other APIs, including aminopyrimidine, amitriptyline, chloramphenicol, oxytetracycline, promazine, propoxyphene, chlorpromazine, diphenhydramine, doxylamine, trimipramine, tetracycline, erythromycin, imipramine and methapyrilene.4,5 The detection of high-levels of NDMA in batches of valsartan drug product in 2018 prompted renewed focus on this class of potentially mutagenic impurities.
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