The levels, types, and sizes of aggregates in therapeutic protein products are important quality attributes that have received considerable attention from the biotechnology industry and regulatory agencies. 1 Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1080) Google Scholar , 2 Cordoba‐Rodriguez R. Aggregates in MAbs and recombinant therapeutic proteins: A regulatory perspective. BioPharm Int. 2008; 21: 44-53 Google Scholar In the context of therapeutic proteins, the term “aggregates” typically refers to assemblies of protein molecules that are considered degradation products and can include a range of sizes (from dimers to visible particles) and types (e.g., covalently crosslinked or noncovalent). Aggregation can occur at all steps in the manufacturing process, during product shipping and storage and even during administration to the patient (e.g., due to interactions with intravenous tubing). 3 Chi E.Y. Krishnan S. Randolph T.W. Carpenter J.F. Physical stability of proteins in aqueous solution: Mechanism and driving forces in nonnative protein aggregation. Pharm Res. 2003; 20: 1325-1336 Crossref PubMed Scopus (1098) Google Scholar , 4 Cromwell M.E. Hilario E. Jacobson F. Protein aggregation and bioprocessing. AAPS J. 2006; 8: E572-E579 Crossref PubMed Scopus (615) Google Scholar Moreover, aggregates of therapeutic proteins may cause adverse effects in patients such as injection site reactions, anaphylaxis, and immunogenicity, with consequences ranging from patient discomfort to permanent harm and potentially death. 5 Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (174) Google Scholar , 6 Hooks W.K. Urgent inhibitor issues: Targets for expanded research. Haemophilia. 2006; 12: 107-113 PubMed Google Scholar , 7 Reipert B.M. van den Helden P.M. Schwartz H.‐.P. Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with cogenital haemophilia A and factor VIII inhibitors. Br J Haemophilia. 2007; 136: 12-25 Crossref PubMed Scopus (82) Google Scholar , 8 Hermeling S. Crommelin D.J. Schellekens H. Jiskoot W. Structure‐immunogenicity relationships of therapeutic proteins. Pharm Res. 2004; 21: 897-903 Crossref PubMed Scopus (498) Google Scholar Importantly, the amount, type, size and other characteristics (e.g., the conformation of protein molecules within the aggregate) of aggregates needed to induce adverse effects cannot be predicted for a given product. It is thought, however, that even trace amounts (e.g., <1% by mass) of certain aggregates might be responsible for adverse effects in patients, and that larger‐sized aggregates are more prone to induce immunogenicity than smaller oligomers. 1 Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1080) Google Scholar , 9 Fradkin A.H. Carpenter J.F. Randolph T.W. Immunogenicity of aggregates of recombinant human growth hormone in mouse models. J Pharm Sci. 2009; 98: 3247-3264 Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Therefore, tremendous effort is put into minimizing protein aggregation during manufacturing steps and in the final formulation/dosage form.