A Primer for Pharmaceutical Process Development Chemists and Analysts in Relation to Impurities Perceived to Be Mutagenic or “Genotoxic”

Abstract

Regulatory guidance on impurities is becoming increasingly comprehensive and complex. The advent of ICH M7(R1) on mutagenic impurities has introduced a significant and sophisticated toxicological component that can easily be underestimated by the unwary. The term "genotoxic impurity" was used in guidelines that predated the current guidance but is now outdated, although it is still often (mis)used in publications on impurities. ICH M7(R1) applies only to mutagenic impurities, which are defined as compounds that are DNA-reactive and test positive in a bacterial reverse mutation assay or are predicted to do so using appropriate in silico structure−activity software. A tentative indication of mutagenic activity is provided by so-called structural alerts, which are certain electrophilic moieties within a chemical structure. It is now well-established that many conventional alerts are associated with a significant number of false-positive predictions of mutagenic potential. Consequently, caution is required when an alert is used to tag a particular impurity as "genotoxic" with no further checks. Such an approach might lead to the development of unnecessarily sensitive impurity assays, which may or may not be a deliberate choice, and possibly to wasted additional process development costs. This review is intended to provide pragmatic guidance on the evaluation of the mutagenicity status of impurities, on the basis of which it is possible to determine appropriate limits. In addition, a series of published examples are reviewed where analytical method development has been compromised by mistakes concerning mutagenicity status and where incorrect mechanistic assumptions have been made regarding the potential for the formation of particular impurities.

Utilization of Quality by Design, Kinetic Modeling, and Computational Fluid Dynamics for Process Optimization and Scale-Up

“…It is known that for the acetalization reaction, an aprotic organic solvent such as methylene dichloride, acetonitrile, 1,4-dioxane, chloroform, dimethyl formamide, toluene, and heptane is required, along with an additional acid catalyst such as perchloric acid (HClO 4 ), − phosphoric acid (H 3 PO 4 ), , sulfuric acid (H 2 SO 4 ), and sulfonic acids (p-TSA, BSA), − which requires tedious quenching and multiple work-up processes, leading to increased cycle time and production cost. Sulfonic acids may generate traces of sulfonate ester impurities, which are potentially genotoxic. − In some cases, large quantities of toxic solvents are required. On the other hand, it is noteworthy to mention that aqueous mineral acids such as hydrofluoric acid (HF), hydrochloric acid (HCl), HBr, and hydroiodic acid (HI) can offer an advantage by playing dual roles, both as a solvent and as an acid catalyst. − However, among these mineral acids, HF and HI are highly corrosive, light sensitive, expensive, and not eco-friendly .…”

Strategy of Choosing Templates in Molecular Imprinting to Expand the Recognition Width for Family-Selectivity

“…They are usually found in trace amounts in drugs, which can easily cause the genotoxicity in human. Thus, it is an important problem in quality control of drugs. − …”