(719a) CMC Sampling Considerations for Applying Enabling Technologies to Pharmaceutical Development and Manufacturing: Challenges and Opportunities

CMC sampling is an essential aspect for Chemistry, Manufacturing, and Control (CMC). CFR §211.110 explicitly stated that “sampling and testing of in-process materials and drug products, as part of production and process controls”.

When applying enabling technologies such as Process Analytical technology (PAT) tools to pharmaceutical development and manufacturing, in lieu of traditional physical sampling, various PAT sensors can provide information of the material stream during process or product at release in real time via on-line/in-line/at-line PAT sensor, i.e., indirect sampling. Under such circumstances, it is of critical importance to understand the similarity and difference between physical sampling and indirect virtual sampling, measurement principles of PAT sensors, how process dynamics impacts sampling accuracy and representativeness, and how representative PAT data can be acquired and effectively used for intended purpose such as process understanding, routine commercial manufacturing process monitoring, and feedforward and feedback control loop in advanced manufacturing.

Based on case studies on crystallization monitoring and control, blend uniformity and batch uniformity control, certain fundamental and practical CMC considerations are discussed to ensure virtual sampling representativeness, manufacturing process robustness, and batch variability control.