A previously validated constraint based model and possibilistic MFA have been used to design a simple estimator of protein production rate in Pichia pastoris cultures. A structured model of the yeast P. pastoris metabolism is used to predict the balance of key energetic equivalents such as ATP from available measurements, mainly substrate consumption, gases exchange rates and biomass specific growth. It has been shown that ATP flux can be related to biomass growth and protein productivity specific rates by linear regression. Cross-validation has been applied for robust parameter fitting on the basis of chemostat, steady-state experimental conditions. In this way, protein estimation can be integrated in the constraint-based model, and possibilistic protein productivity prediction can be given even if only a few extracellular rates are known. Complimentary estimation of biomass growth and intracellular rates are also shown in different lacking-data conditions, frequent in industrial environment. (C) 2012 Elsevier Ltd. All rights reserved.