Vapor Phase Hydrogen Peroxide Decontamination or Sanitization of an Isolator for Aseptic Filling of Monoclonal Antibody Drug Product-Hydrogen Peroxide Uptake and Impact on Protein Quality.

A monoclonal antibody drug product manufacturing process was transferred to a different production site, where aseptic filling took place within an isolator that was decontaminated (sanitized) using vapor phase hydrogen peroxide (VPHP). A quality-by-design approach was applied for study design to understand the impact of VPHP uptake on drug product quality. Both small-scale and manufacturing-scale studies were performed to evaluate the sensitivity of the monoclonal antibody to hydrogen peroxide (HO) and characterize VPHP uptake mechanisms in the filling process. The acceptable HO uptake level was determined to be 100 ng/mL for the antibody in the HO spiking study; protein oxidation was observed above this threshold. The most prominent sources of VPHP uptake were identified to be the silicone tubing assembly (associated with the peristaltic pumps) and open, filled vials. Silicone tubing, an effective depot to HO, absorbs VPHP during different stages of the filling process and transmits HO into the drug product solution during filling interruptions. A small-scale isolator model, established to simulate manufacturing-scale conditions, was a useful tool in understanding HO uptake in relation to tubing dimensions and VPHP concentration in the isolator air (or atmosphere). Although the tubing assembly had absorbed a substantial amount of VPHP during the decontamination phase, the majority of HO could be removed during tubing cleaning and sterilization in the subsequent isolator aeration phase, demonstrating that HO in the final drug product solution is primarily taken up from residual VPHP in the isolator during filling. Picarro sensor monitoring demonstrated that the validated VPHP aeration process generates reproducible residual VPHP profiles in isolator air, allowing small-scale studies to provide relevant recommendations on tubing size and interruption time limits for commercial manufacturing. The recommended process parameters were demonstrated to be acceptable and rendered no product quality impact in six consecutive manufacturing batches in the process validation campaign. Overall, this case study provides process development scientists and engineers an in-depth understanding of the VPHP process and a science-based approach to mitigating drug product quality impact. While the use of vapor phase hydrogen peroxide as a sanitizing agent for isolator and cleanroom decontamination has gained popularity in recent years, its impact on product quality during aseptic manufacturing of biopharmaceutical drug products is yet to be fully understood. With this scope in mind, this case study offers a detailed account of defining process parameters and developing their operating ranges to ensure that the impact to product quality is minimized. Both small-scale and manufacturing-scale studies were performed to assess the sensitivity of a monoclonal antibody to hydrogen peroxide, to characterize hydrogen peroxide uptake sources and mechanisms, and to eventually define process parameters and their ranges critical for minimizing product quality impact. The approach and outcome of this study is expected to benefit scientists and engineers who develop biologic product manufacturing processes by providing a better understanding of drug product process challenges.