Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows the online monitoring of critical process parameters to ensure acceptable product quality attributes. This chapter provides a systematic review of latest PAT tools for freeze-drying, with emphasis on suitability for large-scale manufacturing process. Common process monitoring devices such as product temperature sensors (including wireless sensors), Pirani gauge, manometric temperature measurement (MTM), tunable diode laser adsorption spectroscopy (TDLAS), plasma emission spectroscopy (Lyotrack), near-infrared (NIR), and Raman et al. are reviewed in terms of the operation mechanism, major applications, and limitations. These PAT tools are then compared based on their capabilities, practical advantages, and scalability to a large-scale freeze dryer. The criteria of an “ideal” future PAT tool for freeze-drying are then proposed in order to be compliant with the QbD requirements. Finally, the current status of PAT implementation in both development scale and manufacturing scale lyophilizer is discussed, and future implementation of promising PAT tools is proposed.