How do you troubleshoot and prevent protein aggregation throughout the manufacturing process?

Aggregation troubleshooting examines multiple process stages. Cell culture: temperature, osmolality, and shear stress optimization; media formulation (surfactants, chaperone co-expression). Harvest: minimize hold times, temperature control, avoid foaming. Purification: optimize chromatography conditions (pH, ionic strength), minimize high-concentration exposure, appropriate column velocities. Viral inactivation: low pH stress minimization through timing and formulation. Formulation: surfactants (polysorbate 20/80), optimal pH and ionic strength, lyoprotectants for lyophilization. Storage: appropriate temperature, freeze-thaw controls. Analytics: SEC, DLS, AUC, imaging-based particle counting across process stages. Process-specific aggregation propensity requires mechanistic understanding - interface adsorption, conformational instability, nucleation and growth. Structural insights guide rational formulation design.