CFD Supported Investigation of Shear Induced by Bottom-Mounted Magnetic Stirrer in Monoclonal Antibody Formulation.

PURPOSE: Biological pharmaceutical unit operations like homogenization or pooling of liquids are often performed in stirred vessels. Bottom-mounted magnetic stirrers are usually the system of choice in drug product manufacturing, because bottom-mounted magnetic stirrers are considered to be gentle mixing systems. Nevertheless, magnetic stirrers can cause shear stress and, thus, lead to protein damage. METHODS: This study uses computational fluid dynamics (CFD), because flow and shear rates cannot easily be measured at the spot of interest. The investigation utilizes CFD models, which were checked for plausibility by comparing experimental results and model outcome. The investigators first modeled macroscopic flow across a range of vessel volume capacities. Subsequently, detailed models focusing on two locations (bearing gap (2 mm - 3.5 mm) and spigot gap (40 µm - 80 µm)) were developed. RESULTS: The macroscopic flow modeling showed that the direction of flow varies based on the vessel volume capacity. The detailed CFD model estimated significant flow through the bearing gap. However, the calculated shear rates in the bearing gap were always lower than the shear rates which occur directly next to the impeller tip. The CFD model calculated significantly higher shear rates in the spigot gap and flow in the lower microliter range. CONCLUSIONS: Shear rates at the impeller tip are typically used as parameter to characterize stirred mixing systems. Although higher shear rates were found in the spigot gap, these higher shear rates can most likely be neglected for most applications due to non-significant flow through the spigot gap.

Factors Governing the Precision of Subvisible Particle Measurement Methods - A Case Study with a Low-Concentration Therapeutic Protein Product in a Prefilled Syringe.

PURPOSE: The current study was performed to assess the precision of the principal subvisible particle measurement methods available today. Special attention was given to identifying the sources of error and the factors governing analytical performance. METHODS: The performance of individual techniques was evaluated using a commercial biologic drug product in a prefilled syringe container. In control experiments, latex spheres were used as standards and instrument calibration suspensions. RESULTS: The results reported in this manuscript clearly demonstrated that the particle measurement techniques operating in the submicrometer range have much lower precision than the micrometer size-range methods. It was established that the main factor governing the relatively poor precision of submicrometer methods in general and inherently, is their low sampling volume and the corresponding large extrapolation factors for calculating final results. CONCLUSIONS: The variety of new methods for submicrometer particle analysis may in the future support product characterization; however, the performance of the existing methods does not yet allow for their use in routine practice and quality control.