The bio/pharmaceutical industry is experiencing a paradigm shift—not only for therapies, but for the entire support infrastructure. The process streams and surrounding cleanroom and facility infrastructures for recombinant proteins are drastically different from those for small-molecule processes. Advances in cell and gene therapies and continuous bioprocessing require a shift as well. In these cases, the scale of the processes can range from small, per-patient batches to multiple, 2000-L fluid volume streams. These different applications require in-depth review so that that the best processing and cleanroom infrastructure platform may be chosen. Decisions can no longer be based on a single parameter, such as initial cost. Rather, a matrix of different factors must be evaluated. This article addresses the different decision points behind this approach, to guide determination of the best cleanroom and technology choice.