FDA and other global regulators recommend that manufacturers of APIs and drug products detect and prevent unacceptable levels of genotoxic and carcinogenic nitrosamine impurities in pharmaceutical products such as angiotensin II receptor blockers (ARBs)/sartans, ranitidine, nizatidine, and metformin. The acceptable intake associated with nitrosamines requires the application of sensitive analytical procedures. The USFDA released a GC/MS analytical method, followed by an HRMS method to detect NDMA. USP -PF 46(5) has published 4 test procedures (i) HPLC-HRMS (ii) GC-MS (iii) HPLC-MS/MS (iv) GC-MS/MS (triple quad).
Sannova’s cutting edge instrumentation and experience in method development, validation and transfer are available to navigate the evolving regulatory topic with excellence. For assistance with detection strategies for nitrosamines or any other impurity profiling in drug substance, contact us at info@sannova.net or 732.412.3821.
In anticipating our sponsor’s needs, Sannova has been studying the problem almost from its inception.
Beginning with the discovery of an N-nitrosodimethylamine (NDMA) in lots of valsartan in July of 2018 , increasing attention has been paid to the possible contamination of drug substances and drug products with potentially genotoxic and carcinogenic N-nitrosoamines. Initially attention was limited to the popular “sartan” type drugs containing the carboxylic acid isostere tetrazolic functional group, which is widely utilized to improve bioavailability in drug design. “Sartans” including this element of drug design included candesartan, losartan, olmesartan, irbesartan, and fimasartan. The fact that the tetrazole ring is often generated synthetically by the addition of azides, generated via nitrite salts, to nitriles, generated concern, since many potential N-nitrosoamines can be generated in the presence of nitrites.
As a result of these concerns, the USFDA and other agencies initiated a number of recalls and issued advisories. Initially, the USFDA released a GC/MS analytical method to detect NDMA. In order to detect the very low acceptable intake levels of nitrosamines, USP-PF 46(5) has proposed 4 analytical methods:
(i) HPLC-HRMS
(ii) GC-MS
(iii) HPLC-MS/MS
(iv) GC-MS/MS (triple quad)
The recent unexpected finding of nitrosamine impurities, which are probable human carcinogens, in drugs such as angiotensin II receptor blockers (ARBs),4 ranitidine,5 nizatidine,6 and metformin,7 has made clear the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence. Shortly thereafter, as the concern broadened to drugs beyond the “Sartan” class
Sannova closely monitored the situation, keeping pace with new accurate and sensitive methods. This was because the problem of N-nitrosoamines extended further than previously recognized, extending to a wide array of drugs featuring nitrogen containing functional groups and/or those processed in nitrogenous solvents, for example, DMF and even water! Other potential sources for introduction of nitrosamine impurities are excipients, drug substances, manufacturing process, drug product (stability) and closures. This has led to additional recalls, and even, in the case of the popular OTC and prescription formulations containing ranitidine, removal from the market. Indeed, it is now understood that there are multiple pathways and mechanisms for the formation of N-nitrosoamines and the needs of our sponsors in this area are sure to grow. Sannova, with its team of committed scientists utilizing the most modern analytical tools, fully intends keep pace with developments as the situation evolves.
1. Sörgel et al., Journal of Pharmaceutical and Biomedical Analysis 172 (2019) 395–405.
2. Sörgel et al., Journal of Pharmaceutical and Biomedical Analysis 172 (2019) 278–284.
3. Ashworth et al., Org. Process Res. Dev. 2020, 24, 1629−1646.
4. Burns et al., Org. Process Res. Dev. 2020, 24, 1558−1585.
Photo credit: Khaja Moinuddin Shaik, Bhaskar Sarmah, Gaurav Suresh Wadekar & Pramod Kumar (2020) Regulatory Updates and Analytical Methodologies for Nitrosamine Impurities Detection in Sartans, Ranitidine, Nizatidine, and Metformin along with Sample Preparation Techniques, Critical Reviews in Analytical Chemistry, DOI: 10.1080/10408347.2020.1788375