Although both the Inherent Safety Principles (ISPs) and the Safe-by-Design (SbD) approach revolve around the central value of safety, they have a slightly different focus in terms of developing add-on features or considering initial design choices. This paper examines the differences between these approaches and analyses which approach is more suitable for a specific type of research—fundamental or applied. By applying the ISPs and SbD to a case study focusing on miniaturized processes using Hydrogen Cyanide, we find that both approaches encounter internal value-conflicts and suffer from external barriers, or lock-ins, which hinder implementation of safety measures. By applying the Technology Readiness Levels (TRLs), we gain insight in the matureness of a technology (thereby distinguishing fundamental and applied research) and the extent of lock-ins being present. We conclude that the ISPs are better able to deal with lock-ins, which are more common in applied research stages, as this approach provides guidelines for add-on safety measures. Fundamental research is not subject to lock-ins yet, and therefore SbD would be a more suitable approach. Lastly, application of either approach should not be associated with a specific field of interest, but instead with associated known or uncertain risks.