Controlling a Cohort: Use of Mirabilis-Based Purge Calculations to Understand Nitrosamine-Related Risk and Control Strategy Options

Abstract

The recent discovery of nitrosamines within marketed drugs, such as Valsartan, has led to changes within the regulatory landscape. Most notably, the requirement for a risk evaluation of the presence of nitrosamines within the drug product has been extended from sartan-type tetrazole containing drugs to all marketed products. The largest inherent risks associated with a drug substance will generally arise from impurity formation and carryover in the synthetic manufacturing process. Despite the classification of nitrosamines within the cohort of concern, the understanding of their behavior based on physicochemical properties is unaffected by this status, and as such all control options laid out in ICH M7 should be considered acceptable. This communication aims to show how the use of purge calculations, utilizing the Mirabilis software, fully de-risked nitrosamine concerns related to the development of Candesartan cilexetil. Aligned to the principles of impurity control in the ICH M7 guideline, this provided a suitable strategy to determine, and subsequently demonstrate control of, the nitrosamine risk.

Regulatory Highlights

“…This examined how the use of purge calculations, utilizing the Mirabilis software, fully derisked nitrosamine concerns related to the development of Candesartan Cilexetil. Aligned to the principles of impurity control in the ICH M7 guideline, this provided a suitable strategy to determine, and subsequently demonstrate control of, the nitrosamine risk …”

Mass spectrometry based fragmentation patterns of nitrosamine compounds

“…Nitrosamines belong to a class of mutagenic substances that can display high carcinogenic potential and are grouped together in the ICH guideline M7 as a cohort of concern 9 . Nitrosamines are formed from a secondary or a tertiary amine reacting with a nitrosating agent in an acidic environment 10–14 .…”

“…Nitrosamines belong to a class of mutagenic substances that can display high carcinogenic potential and are grouped together in the ICH guideline M7 as a cohort of concern. 9 Nitrosamines are formed from a secondary or a tertiary amine reacting with a nitrosating agent in an acidic environment. [10][11][12][13][14] The high carcinogenic potency of these compounds results in very low acceptable daily intakes, as low as 18 ng, with no staging of the limit allowed for less than lifetime dosing.…”

Nitrosamine Reactivity: A Survey of Reactions and Purge Processes

“…It is the intent of the authors for this review to complement other recent reports of nitrosamine chemistry and control, namely publications by Burns et al, López-Rodríguez et al, Ashworth et al., and Beard and Swager. ,,, This review is a compilation of research from a variety of disciplines, e.g. traditional organic synthesis, water purification, physical organic chemistry, etc.…”

“…The nitroso group polarizes the N− N bond and makes it reactive to nucleophiles and electrophiles, including cleavage of the N−N bond under acidic conditions, which is a reversible transformation. Next, there are a variety of 5,6,10,11 This review is a compilation of research from a variety of disciplines, e.g. traditional organic synthesis, water purification, physical organic chemistry, etc.…”