We presented ethanol fed-batch bioreactor operations (FBBOs) designed for enhanced recombinant human growth hormone (rhGH) production in Pichia pastoris constructed with novel hybrid-architectured ADH2 promoter, PADH2-Cat8-L2. The parameters in the fed-batch fermentation of ethanol were investigated, and the boundaries of the production domain in terms of the design parameters were determined. Two FBBO design methods were used, and a platform aiming to adjust cellular metabolism for the generation of constant specific growth rate (mu) and substrate concentration (C-EtOH) was established. The highest overall productivity (r(P),(ov)) was generated with model-based continuous feed-stream (CFS) design with mu(preD) = 0.035 h(-1) up to t(max) <= 9 h as r(P),(ov) = 3.0 mg L-1 h(-1) and C-rhGH = 34 mg L-1. The ethanol-stat FBBO at C-EtOH,(set) = 0.5 g L-1 allowed increased product titer with high productivity and the highest C-rhGH =90.1 mg L-1 at t(max) = 24 h. The effect of C-EtOH on specific rates for cell reactions was represented by the Haldane model in which the cell generation and rhGH production were simulated with low mean relative errors of 6.5 and 16%, respectively. The results indicate the need for an upgraded CFS design model with kinetic expressions involving substrate inhibition. We conclude that a two-step hybrid fed-batch design strategy to be started (i) with the initial-period of the model-based FBBO, in turn, proceeded (ii) with the controlled feeding with ethanol-stat FBBO enables a gradual approach to the hypothetical performance of FBBOs.