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 (H2O2) and characterize VPHP uptake mechanisms in the filling process. The acceptable H2O2 uptake level was determined to be 100 ng/mL for the antibody in the H2O2 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 H2O2, absorbs VPHP during different stages of the filling process and transmits H2O2 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 H2O2 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 H2O2 could be removed during tubing cleaning and sterilization in the subsequent isolator aeration phase, demonstrating that H2O2 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.LAY ABSTRACT: 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.

Three-dimensional assessment of impacted canines and root resorption using cone beam computed tomography.

OBJECTIVE: The objective of this study was to localize impacted canines in 3 dimensions and determine the most common location of impaction using cone beam computed tomography (CBCT). We also assessed root resorption of adjacent teeth. The cusp tip of each impacted canine was located and digitized using Dolphin 3D imaging, after viewing sagittal, coronal, and axial views. The position on the occlusal plane where the normally erupted canine cusp tip should be located was used as a control reference point. The degree of impaction was defined by the difference between the impacted canine cusp tip and reference cusp tip positions. MATERIALS AND METHODS: CBCT scans of 29 consecutive individuals with impacted canines undergoing orthodontic treatment at the UCSF Orthodontic Clinic were included in this study. RESULTS: The average degree of mesial impactions was 10.1 mm, of distal impactions was 4.2 mm, of facial impactions was 4.16 mm, of palatal impactions was 1.8 mm, and of gingival impactions was 10 mm; 40.4% had no root resorption, 35.7% showed slight root resorption, 14.2% showed moderate resorption, and 4% showed severe root resorption of the adjacent lateral incisor. CONCLUSION: We reliably assessed the position of impacted canines in 3 dimensions using CBCT, thereby improving accuracy of location and facilitating precise surgical and orthodontic management. In our study 40.4% had no root resorption, 35.7% showed slight root resorption, 14.2% showed moderate resorption, and 4% showed severe root resorption of the adjacent lateral incisor. The most frequent location of impacted canines was palatal, mesial, and gingival.