Validation of Gel Clot Endotoxin Testing for Pharmaceutical Injectables with Undefined Limits: A Regulatory and Analytical Framework
Keywords:
bacterial endotoxin, gel clot validation, undefined limits, Omeprazole injection, endotoxin harmonization, MVD, LAL assay.Abstract
The current study validates the gel clot assay for bacterial endotoxin in pharmaceutical injectables with no defined bacterial endotoxin limit. 8.75 EU/mg on a dose basis was calculated for the model solubility-limited formulation as Omeprazole 40 mg IV injection. It verified the maximum allowable dilution (MAD) up to 1:1152 using Limulus Amebocyte Lysate (LAL) reagent of sensitivity limit of 0.03 EU/mL. Results in three production batches demonstrated the reproducibility, sensitivity and absence of inhibition/enhancement. At MVD/16 the assay has been demonstrated to function equally well throughout, demonstrating no interference even in water insoluble matrices. This study addresses a significant oversight in the regulations by providing an evidence-based validation pathway for unlimited formulations. AI-guided risk analysis and streamlined processes across USP, EP, JP and IP can additionally automate international compliance.
