Development and Implementation of a Mathematical Model As a Key Component of a Palladium Control Strategy for a Semi-Continuous Process to Produce a Small Molecule Drug Substance

The manufacture of a small molecule drug substance employs a coupling reaction catalyzed with soluble palladium in the final synthetic step of the sequence. The control strategy around palladium removal involves selective adsorption of the palladium onto a functionalized silica resin in a continuous fashion followed by a continuous deprotection reaction and the selective crystallization of the drug substance. During the registration stability campaign, at-line and off-line samples were collected. To minimize cost associated with the selective adsorbent, and to ensure a robust control strategy for palladium, a predictive model was developed to aid in the appropriate design, scaling and setup of the manufacturing equipment. Use of the model and the selected control strategy for palladium, alleviated the need for continuous sampling for palladium during processing and enabled a robust operation during validation with significant production cost reduction.