How to develop a safe process with hazardous chemistry

Introduction
Hazardous chemistry can be a key element in the development of commercial scale processes to manufacture APIs. We focus on managing the risks of hazardous chemistry for developing safe and efficient processes on commercial scale. Based on an established pharmaceutical product – Oteseconazole/VT-1161 – we walk you through the project phases from development to scale-up and commercial production, showcasing a process safety methodology and tests. This example will focus on azide chemistry, involving in-situ generated hydrazoic acid as reactive species to introduce a tetrazole moiety. We show that optimized and robust large-scale commercial processes can be developed even though hazardous chemistry is involved or even thanks to the involvement of hazardous chemistry. (1, 2, 3).

Main contents
Oteseconazole is the active pharmaceutical ingredient (API) of VivjoaTM introduced to the market by Mycovia Pharmaceuticals Inc. in April 2022. VivjoaTM is an azole antifungal indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVCC) in females with a history of RVCC. RVCC (also known as chronic yeast infection) is a debilitating, chronic infectious condition that affects 138 million women worldwide each year.

In our internal process development methodology we are following a process safety protocol to evaluate the potential risk of the species and reaction mixtures. This protocol starts with a first theoretical assessment based on known critical structure elements. Oteseconazole (called VT-1161 during development) contains a tetrazole group (4, 5). Tetrazole moieties belong to the group of hazardous structure elements (figure 1) that lead to safety investigations with respect to thermal and mechanical stability as well as explosive and self-decomposing properties according to transport regulations described in the UN manual of tests and criteria (6).