Léa Guerassimoff, Julien Nicolas
The production of pharmaceutical materials (i.e., drug substances, excipients and drug products) frequently involves the use of organic solvents to dissolve the active pharmaceutical ingredient (API), to enable the formulation of drug delivery systems and/or to facilitate manufacturing processes. In this context, a major underestimated challenge is the presence of residual solvents in the final product. Residual solvents, if not properly removed, can pose significant risks to patient health due to their potential toxicity especially when they exceed the levels recommended by the International Council for Harmonization (ICH). Therefore, ensuring negligible toxicity requires a careful choice of solvents, robust quantification methods and a rigorous evaluation of drug properties in the presence of residual solvents. In this review, we aim to highlight the critical importance of addressing residual solvents in pharmaceutical development. First, we will focus on ICH regulation and detail recent cases of solvent-related toxicity in approved pharmaceutical materials. Then, a wide range of solvent quantification techniques will be described with the aim of determining the amount of residual solvents after formulation. Particular attention will be paid on the impact of residual solvents on the final drug properties and their influence on biological activity through in vitro, ex vivo and in vivo examples. Finally, less-toxic and solvent-free alternatives for the production of pharmaceutical materials will be proposed as relevant avenues for greener and safer development.