Processing Impact on Monoclonal Antibody Drug Products: Protein Subvisible Particulate Formation Induced by Grinding Stress
| Autor: | Oliver B. Stauch, Robert Ovadia, Eric S. Day, Benson Gikanga, Yuh-Fun Maa, Devon Roshan Eisner |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Drug Compounding
Mixing (process engineering) Pharmaceutical Science 02 engineering and technology 030226 pharmacology & pharmacy Stress (mechanics) Immunoglobulin Fab Fragments Protein Aggregates 03 medical and health sciences Impeller 0302 clinical medicine Technology Pharmaceutical Chromatography High Pressure Liquid Piston pump Chromatography Fouling Chemistry Antibodies Monoclonal Equipment Design 021001 nanoscience & nanotechnology Grinding Pharmaceutical Preparations Cavitation Chromatography Gel Biophysics Particle Stress Mechanical 0210 nano-technology Ultracentrifugation |
| Zdroj: | PDA Journal of Pharmaceutical Science and Technology. 71:172-188 |
| ISSN: | 1948-2124 1079-7440 |
| DOI: | 10.5731/pdajpst.2016.006726 |
| Popis: | Subvisible particle formation in monoclonal antibody drug product resulting from mixing and filling operations represents a significant processing risk that can lead to filter fouling and thereby lead to process delays or failures. Several previous studies from our lab and others demonstrated the formation of subvisible particulates in mAb formulations resulting from mixing operations using some bottom-mounted mixers or stirrer bars. It was hypothesized that the stress (e.g., shear/cavitation) derived from tight clearance and/or close contact between the impeller and shaft was responsible for protein subvisible particulate generation. These studies, however, could not distinguish between the two surfaces without contact (tight clearance) or between two contacting surfaces (close contact). In the present study we expand on those findings and utilize small-scale mixing models that are able to, for the first time, distinguish between tight clearances and tight contact. In this study we evaluated different mixer types including a top-mounted mixer, several impeller-based bottom-mounted mixers, and a rotary piston pump. The impact of tight clearance/close contact on subvisible particle formation in at-scale mixing platforms was demonstrated in the gap between the impeller and drive unit as well as between the piston and the housing of the pump. Furthermore, small-scale mixing models based on different designs of magnetic stir bars that mimic the tight clearance/close contact of the manufacturing-scale mixers also induced subvisible particles in mAb formulations. Additional small-scale models that feature tight clearance but no close contact (grinding) suggested that it is the repeated grinding/contacting of the moving parts and not the presence of tight clearance in the processing equipment that is the root cause of protein subvisible particulate formation. When multiple mAbs, Fabs (fragment antigen binding), or non-antibody related proteins were mixed in the small-scale mixing model, for molecules investigated, it was observed that mAbs and Fabs appear to be more susceptible to particle formation than non-antibody-related proteins. In the grinding zone, mAb/Fab molecules aggregated into insoluble particles with neither detectable soluble aggregates nor fragmented species. This investigation represents a step closer to the understanding of the underlying stress mechanism leading to mAb subvisible particulate formation as the result of drug product processing. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|