A Holistic Strategy for Cyanide Control and Safety for Pharmaceutical Manufacturing

Abstract

The manufacturing route toward gefapixant citrate generates a trace amount of cyanide as a byproduct of a reaction employing the reagent chloroacetonitrile. In the development of a cyanide control strategy, conventional process and analytical approaches fell short because of challenges and incompatibilities with the matrices of the process and waste streams. To overcome these, we identified and adapted specific procedures for cyanide control. Our strategy ensured safety for patients, operators, and waste management.

MSD’s Process Safety Scale-Up Methodology for Pilot Plant Scale and Beyond

“…In the commercial process of gefapixant citrate (Figure ), one of the steps uses chloroacetonitrile as a reagent. As disclosed in a recent publication, under strong alkaline conditions, a small quantity of cyanide (∼100 ppm) is found in an aqueous waste stream. At elevated pH, exposure of HCN would not be a significant IH concern.…”

Ecological and Economic Efforts in the Development of Molecular Sensors for the Optical Detection of Cyanide Ions

“…Thus, it is crucial to analyze toxic species such as cyanide (CN À ) since diverse cyanidecontaining compounds are used in the chemical, plastic, pharmaceutical, and metallurgic industries. [2,3] Moreover, some cyanogenic compounds naturally occur in apples, starch, cassava, and potatoes. [4] Then, it can be released into the air, soil, water, or food from many sources.…”

“…Sustainable research in chemistry and related areas is highly needed. Thus, it is crucial to analyze toxic species such as cyanide (CN − ) since diverse cyanide‐containing compounds are used in the chemical, plastic, pharmaceutical, and metallurgic industries [2,3] . Moreover, some cyanogenic compounds naturally occur in apples, starch, cassava, and potatoes [4] .…”

Selective Plate-Based Assay for Trace EDTA Analysis via Boron Trifluoride-methanol Derivatization UHPLC-QqQ-MS/MS Enabling Biologic and Vaccine Processes

“…Furthermore, in production involving catalytic processes, ng·mL –1 differences in small-molecule constituents are the kinetic levers that can dictate the ultimate fate of a large-scale manufacturing batch, the success or uncorrectable loss of hundreds of liters. As such, trace quantitation and monitoring of common small molecules in matrices that are unfavorable for otherwise routine traditional analytical methods become a recurring bottleneck in the development process and downstream investigational studies. ,− …”