The multi-factorial interplay between particle engineering, particle properties, their downstream processability and aerodynamic performance contributes to the overall dry powder inhaler (DPI) performance. Inhalable particles of salbutamol sulphate were prepared by jet-milling and spray drying, characterized, and blended with lactose at low and high drug loads. These were filled into capsules using different process parameters and tested for their in vitro aerosolization performance. Differences were found in the particle interactions of jet-milled and spray dried powders, affecting their downstream processability. Blends of the spray dried particles revealed to be more prone to detachment during processing, resulting in a poorer aerodynamic in vitro performance. A higher drug load further affected the drug interaction with the excipient resulting in weaker carrier attachment and a higher in vitro fine particle fraction. The mean fill weight and blend homogeneity of the filled capsules showed distinct effects in relation to the type of mixture being processed, resulting into variable aerosolization performance results depending on the compression ratio used. By investigating the impact of distinct API properties and drug loadings on all the downstream processability chain, critical parameters needed to be considered in product quality and performance of jet-milled and spray dried drug particles were derived.