Drug delivery systems with reduced hold-up volumes are provided. The drug delivery systems include a cartridge configured to hold a liquid drug. A cartridge stopper is positioned in a first portion of the cartridge. A needle guide component is positioned within the cartridge stopper. A needle is positioned within a central opening of the needle guide. A plunger is positioned in a second portion of the cartridge. The plunger includes a fluid path pocket facing and aligned with the central opening of the needle guide component. The plunger is driven toward the cartridge stopper to expel the liquid drug from the cartridge through the needle. An end of the needle can be positioned within the fluid path pocket when the plunger is pushed against the cartridge stopper, ensuring that only a small volume of the liquid drug remains in the cartridge when delivery of the liquid drug is completed.