A wide variety of aggregates are encountered in biopharmaceutical samples ranging in size and characteristics (e.g., soluble or insoluble, covalent or noncovalent, reversible or irreversible). Protein aggregates span a broad size range, from small oligomers (nanometers) to insoluble micron-sized aggregates that can contain millions of monomer units.
Protein aggregation can occur at all steps in the manufacturing process (cell culture, purification and formulation), storage, distribution and handling of products. It results from various kinds of stress such as agitation and exposure to extremes of pH, temperature, ionic strength, or various interfaces (e.g., air–liquid interface). High protein concentrations (as in the case of some monoclonal antibody formulations) can further increase the likelihood of aggregation.
Therefore, aggregation needs to be carefully characterised and controlled during development, manufacture, and subsequent storage of a drug substance and formulated product. Similarly, by monitoring the state of aggregation, modification or optimisation of the production process can be achieved.