Spray-drying is expected to be a cost-efficient way to produce probiotic powders. Indeed, a novel simplified process was recently reported, using concentrated sweet whey (30 wt %) as a sole medium for both growth and spray drying of probiotics. The feasibility of scaling up this process was validated in the present work with a semi industrial pilot scale spray dryer. A multi-stage mild-conditions drying process, coupling spray-drying with belt drying and fluid-bed drying, was also applied in this work, in which the final probiotic survival was improved to approximately 100% (>109 CFU g−1). The change of probiotic viability in the powders was monitored during a 6-month storage, which indicated that storage temperature and moisture content of powders play crucial roles in the stability of probiotic powders. Moreover, spray-drying afforded a strain-dependent enhancement of bacterial tolerance in simulated intestinal fluid, in comparison with fresh cultures. •Concentrated sweet whey was used for both probiotic growth and spray-drying.•Drying was conducted at semi industrial pilot scale (500 L level).•Multi-stage drying coupled spray-drying, belt drying and fluid-bed drying.•High probiotic survival (∼100%) was obtained in multi-stage drying process.•Enhanced storage stability and protection towards digestion was observed.