This study evaluates a pilot-scale spray dryer against a laboratory-scale dryer to spray-dry multiple monoclonal antibodies (mAbs) from the perspective of scale-up, impact on mAb stability, and feasibility of a high-concentration preparation. The data demonstrated that there is no process limitation in solution viscosity when high-concentration mAb formulations are prepared from spray-dried powder reconstitution compared with concentration via the conventional ultrafiltration process. This study offers a commercially viable spray-drying process for biological bulk storage and a high-concentration mAb manufacturing option for subcutaneous administration. The outcomes of this study will benefit scientists and engineers who develop high-concentration mAb products by providing a viable manufacturing alternative.

Processing equipment involving grinding of two solid surfaces has been demonstrated to induce subvisible particle formation in monoclonal antibody drug product manufacturing processes. This study elucidated potential stress types associated with grinding action to identify the stress mechanism responsible for subvisible particle formation. Several potential stress types can be associated with the grinding action, including interfacial stresses (air-liquid and liquid-solid), hydraulic/mechanical shear stress, cavitation, nucleation of stressed protein molecules, and localized thermal stress. More than one stress type can synergically affect monoclonal antibody product quality, making it challenging to determine the primary mode of stress. Our strategy was to assess and rule out some stress types through platform knowledge, rational judgments, or via small-scale models, for example, rheometer/rotator-stator homogenizer for hydraulic/mechanical shear stress, sonicator for cavitation, etc. These models may not provide direct evidence but can offer rational correlations. Cavitation, as demonstrated by sonication, proved to be quite detrimental to monoclonal antibody molecules in forming not just subvisible particles but also soluble high-molecular-weight species as well as low-molecular-weight species. This outcome was not consistent with that of grinding monoclonal antibodies between the impeller and the drive unit of a bottom-mounted mixer or between the piston and the housing of a rotary piston pump, both of which formed only subvisible particles without obvious high-molecular-weight species and low-molecular-weight species. In addition, a -nitrophenol model suggested that cavitation in the bottom-mounted mixer is barely detectable. We attributed the grinding-induced, localized thermal effect to be the primary stress to subvisible particle formation based on a high-temperature, spray-drying model. The heat effect of spray drying also caused subvisible particles, in the absence of significant high-molecular-weight species and low-molecular-weight species, in spray-dried monoclonal antibody powders. This investigation provides a mechanistic understanding of the underlying stress mechanism leading to monoclonal antibody subvisible particle formation as the result of drug product processing involving grinding of solid surfaces. Subvisible particles present in therapeutic protein formulations could adversely affect drug product safety and efficacy. We previously illustrated that grinding action of the solid surfaces in some bottom-mounted mixers and piston pump is responsible for subvisible particle formation of monoclonal antibody formulations. In this study, we delved into mechanistic understanding of the stress types associated with solid surface grinding. The approach was to employ several scale-down stress models with known stress types. Protein formulations stressed in these models were analytically characterized for subvisible particles and other degradants. Some commonly known stress types-such as air-liquid int...

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 pr...

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