(224g) Systematic Review of Impurity Formation Mitigation Methods for Lyophilization Scale-up

Upon production scale-up of a novel drug-linker, an impurity that had been previously encountered in small quantities (<4% liquid chromatography area percent) in the final product, was found in significantly higher quantities (up to 38% liquid chromatography area percent) post-lyophilization. This impurity, TFA ester, was only found in the drug-linker after the final isolation step, lyophilization. Though the impurity was readily hydrolyzed, it was imperative to adjust the production process to ensure batch to batch reproducibility. Here, a systematic review of impurity formation mitigation techniques is presented, that ultimately resulted in reducing TFA ester formation <1% area percent through the methods described during a scale-up >300g GMP campaign.