Leachables evaluation for bulk drug substance

This study describes a comprehensive analytical approach for evaluating potential leachables from product-contacting material surfaces in the manufacture of bulk drug substance (BDS) for use in parenteral products. A qualitative step-by-step evaluation of the process stream for the production, purification, and storage of the BDS was performed. The product-contact equipment surfaces were then grouped based on their materials of construction and prioritized according to the potential risk of contributing leachables to the BDS. Based on this evaluation, 13 potential leachable species were identified and classified either as volatile organic compounds (VOCs), semi-volatile organic compounds (SVOCs), anions, cations, or trace metals. The BDS was first screened for the presence of VOCs, SVOCs, anions, cations, and trace metals using analytical methods that were qualified for their application with the BDS. Thirteen potential leachables were then spiked in the BDS and in the water for injection for spike-recovery studies. The analysis of the BDS for potential leachables showed that the potential impurities were not present in the BDS except for a trace amount of silicon, and that the residual solvent concentrations were lower than the recommended limits established by the International Committee on Harmonisation. The spike-recovery studies confirmed that the analytical methods could effectively determine the leachable compounds in the BDS. Moreover, the 13 contaminants did not form a complex with the protein in the BDS and did not represent a potential risk to the BDS's safety and stability.