Membrane technology for sterilization and virus elimination of biopharmaceuticals: Fouling matters

Membrane-based sterilization and virus removal have become an essential approach for Quality Control and Quality Assurance in biopharmaceutical manufacturing, offering significant advantages over traditional thermal and chemical methods. This green technology preserves drug integrity without chemical additives. However, the complex interactions between biomolecules and membrane surfaces often lead to membrane fouling and potential microbial breakthrough. This review first comprehensively interprets the physiochemical properties differences among four biopharmaceuticals (protein, nucleic acid, glycoconjugate vaccine and virus), and then, analyzed the major challenges facing in four biopharmaceuticals sterilization and virus removal. The separation mechanisms of sterilization and virus removal are discussed focusing on both physical (size exclusion) and chemical (electrostatic interactions, hydrophobic adsorption) properties. Particular attention is given to membrane fouling mechanisms and advanced mitigation strategies at the membrane-biomolecule interface. By integrating fundamental scientific principles with practical engineering considerations, this review offers valuable insights for optimizing downstream bioprocessing and advancing membrane technology in the biopharmaceutical industry.