Abstract A process for the reduction of residual solvents in spray-dried poly(lactide-co-glycolide) (PLGA)–darbepoetin alfa microparticles was developed using carbon dioxide (CO 2) as an extraction solvent. CO 2 was investigated in two phase states, liquid and gas. Detrimental effects on encapsulated protein integrity and microparticle morphology were observed with liquid CO 2 exposure. Extraction with CO 2 gas at <100 psig reduced residual solvent concentration and particle agglomeration was limited. Extraction rates and particle agglomeration increased with higher CO 2 gas pressures. The CO 2 pressures below which particles of polylactide (PLA) and PLGA microparticles significantly agglomerated were determined and the data used to develop extraction cycles. Extraction cycles were developed in which CO 2 gas pressure was increased as residual solvent concentration decreased in order to keep extraction rates high throughout the cycle. Spray dried darbepoetin alfa–PLGA microparticles were extracted with CO 2 gas and characterized for residual solvent concentration, process yield, particle size distribution, morphology, and protein integrity. The results indicated CO 2 gas may be used to reduce residual solvent to ∼200 ppm with no significant detrimental effects on protein integrity or microparticle morphology.