Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities

Abstract

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

A Cautionary Tale: Quantitative LC-HRMS Analytical Procedures for the Analysis of N-Nitrosodimethylamine in Metformin

“…NDMA and other nitrosamines are common contaminants in low amounts in foods, beverages, cosmetics, water, tobacco products, and consumer goods (1)(2)(3)(4). In 2018, observations of NDMA and NDEA in angiotensin receptor blocker drugs (ARBs) led to recalls of batches of products which had unacceptable amounts of nitrosamines (5,6). Since the ARB nitrosamine impurities were discovered, there have been additional drugs found to contain nitrosamines in the parts-per-million (ppm or ng/mg) to parts-per-billion (ppb or pg/mg) range (e.g., ranitidine in 2019, metformin in 2020 (7)) each with unique properties in terms of the route and source of their presence.…”

Pharmaceutical Quality, Team Science, and Education Themes: Observations and Commentary on a Remarkable AAPS PharmSciTech Theme Issue

“…Hence, we will discuss these in our commentary. The need to link the development of drug substances, their products, and their manufacturing process to patient safety (in the QbD paradigm) was a conclusion of the paper entitled "Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities" (14).…”

“…The AAPS PharmSciTech Theme Issue entitled "Team Science and Education for Pharmaceuticals -the NIPTE Model" curates nineteen papers (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) listed in Table I and written before and amidst the COVID-19 pandemic. Another manuscript, currently in the editorial process, is expected to be the final paper in the Theme Issue.…”

How to deal with the occurrence of rare drug-induced adverse events: the example of sprue-like enteropathy induced by olmesartan medoxomil and other angiotensin-receptor blockers

“…Moreover, together with valsartan, olmesartan medoxomil is the only ARB that fulfils ESC/ ESH guidelines recommending starting treatment of hypertension with a dual single pill combination as the first step and following with a triple single pill combination as second step in most hypertensive patients [9]. Coupled with the recent recall of valsartan [10], the unavailability of olmesartan would severely limit the ability of physicians to follow the ESC/ESH guidelines.…”