Characterization of Microbial Growth Potential in Antibody Drug IV Admixtures by Microbial Challenge

Abstract

Monoclonal antibody (mAb) drug products (DP) for IV administration are commonly diluted in a diluent such 0.9% sodium chloride (saline) or 5% dextrose (D5W) injection yielding IV admixtures before infusion or injection. During dose preparation, storage, and administration, the sterility of IV admixtures must be maintained to ensure patient safety. However, the introduction of adventitious microorganisms may occur during dose preparation, and microbial proliferation may take place during IV admixture storage. Sterility testing of IV admixtures prior to administration is not feasible in clinic due to its destructive nature. Instead, microbial growth potential assessment could be performed to ensure patient safety. To assess microbial growth potential of IV admixtures, microbial challenge studies, which evaluate the ability of IV admixtures supporting or not supporting microorganism proliferation, are often recommended. Since the initial introduction of microbial challenge studies 2009, there has been very limited data published on microbial challenge studies for IV admixtures. In this publication, data from independent microbial challenge studies for IV admixtures prepared from 10 monoclonal antibodies (mAb) were generated, pooled, and analyzed together for microbial growth trends. The results indicated that major factors impacting the microbial growth in mAb IV admixtures include temperature and time as well as protein and excipient concentration. No microbial growth was observed for IV admixtures stored at 2–8 °C for up to 14 days. At room temperature, no microbial growth was observed for 12 h in IV admixture with protein concentration ≤32 mg/mL. Growth of E. coli, P. aeruginosa, and K. pneumoniae are commonly observed in IV admixtures stored for 16–48 h at room temperature. The study results provided input for designing effective challenge studies to maximize IV admixtures in-use time as well as for potential regulatory guidance development to facilitate the drug development while ensuring patient safety.