Definition: Aggregation is when peptide or protein molecules stick to each other and form clumps. The clumps range from pairs of molecules far too small to see up to visible particles. Aggregated drug may work less well, and FDA notes that aggregates can trigger an immune response to the drug.
FDA guidance on protein drugs defines aggregates as "any self-associated protein species." They range from dimers (two molecules stuck together) to visible particles hundreds of micrometers across. FDA says aggregates have been known for over half a century to be able to trigger immune responses, and that particles of 0.1 to 10 microns have "a strong potential to be immunogenic" but are not precisely measured by current methods.
The guidance gives one real-world case: epoetin alfa stored the wrong way by unauthorized sellers was linked to high levels of aggregates and to an antibody-driven loss of red blood cell production.
A 2017 review of peptide drugs lists the factors that affect clumping: the peptide's sequence, its concentration, pH, net charge, other ingredients, chemical breakdown, surfaces, impurities, temperature, agitation (shaking) and freeze-drying (Zapadka 2017).
The Omnitrope label says not to use the mixed drug if it is cloudy or has particles, and that it must be clear and colorless after mixing. Visible particles are a warning sign. But the particles FDA worries about most are too small to see, so a clear vial does not prove the drug is free of aggregates.
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