As folding occurs, the tertiary structure of a protein changes as hydrophobic residues are buried within the 3D structure. The folding protein assumes transient intermediate structures of increasing stability and reaches a thermodynamic global minimum at the native conformation, sometimes guided by molecular chaperone proteins. During manufacture and storage, proteins are exposed to non-native conditions, such as non-physiological pH, ionic strength, extremes of temperature, interactions with impurities, hydrophobic interactions at interfaces with synthetic surfaces or air, which may induce partial unfolding or misfolding and can lead to noncovalent aggregation (Figure ). The change in structure may expose hydrophobic residues, which form patches on the surface of the protein. The energy landscape changes; it becomes more favourable to bury the hydrophobic patches by interacting with hydrophobic surfaces, such as similar patches on other protein molecules.