Said,
I assume you are trying to understand a response surface (RSM is a methodology) describing two dependent variables. There are many approaches to doing this. I am biased to the sequential approach taught to me by Dr. G.E.P. Box. This is a scientific method approach, where you start with hypotheses (represented by factors in the experiment) and use data to provide insight to those hypotheses. There is no "right" way to do this and the most efficient and effective way is situation dependent. This approach typically starts with fractional 2-level designs for screening a large number of variables (based on the principles of Scarcity and Hierarchy of effects). Then moving the space in the direction of improvement and reducing the number of variables. As your work iterates, you start adding higher order terms to the model. These higher order effects may be factorial (interactions) or polynomial (curvature). The sequential work is quite helpful in understanding the surface. This type of work is best managed by the scientist or engineer that understands the mechanisms (e.g., physical, chemical) and can interpret the results of a statistical study. It is the scientist/engineer that should explain (hypotheses) and predict the possible effects of factors (and whether the effect is linear in the space being investigated), interactions and extremely important, the NOISE. Perhaps you should start by understanding the first order model and the impact of noise prior to investigating non-linear relationships, but this is a function of what you do and do not know. My advice based on your limited discussion of your situation, is to spend some time identifying what the noise might be and then developing a strategy to handle that noise. I also think blocking (or: repeats, split-plots, covariates, etc.) is a better strategy than randomizing. Why, because you want to understand the impact of the noise, preferably assign it, not just get a numerical estimate of the size of it. While randomizing will, hopefully, give you an un-biased estimate of the noise, it can compromise the precision of the design.
"Block what you can randomize what you cannot", G.E.P. Box
I'm not saying don't use definitive screening designs (Brad Jones has done an excellent job bringing this design strategy to the community), you just need to weigh what information you need to get at this point in time with the resources to get that information.
Good luck on your journey.
"All models are wrong, some are useful" G.E.P. Box