Higher‐order structure and conformational change in biopharmaceuticals
2018
Orphanou, Charlotte | Gervais, David
The higher order structure (HOS) of protein biopharmaceuticals is critical for biological and pharmacological function. Slight changes in HOS can impact product efficacy and quality, and therefore must be characterised. The technology and techniques available for HOS characterisation has advanced in recent years. Although methods such as the low‐resolution technique circular dichroism (CD) and the labour‐intensive but high‐resolution technique X‐ray crystallography may still be routinely used to assess HOS, other techniques, such as mass spectrometry (MS) with hydrogen‐deuterium exchange (HDX) and small‐angle X‐ray scattering (SAXS) are becoming more commonplace. Post‐translational modifications (PTMs) may have a large impact on HOS, potentially resulting in undesirable biopharmaceutical variant formation, as well as aggregation. In addition to PTMs, factors such as pH, temperature, stabilising agents and polymers have the potential to induce alterations in protein HOS. A proposed HOS assessment strategy is presented in this review to ensure the robustness of biopharmaceuticals during full process development. Where changes in HOS do occur, there may be a risk of immunogenic response in patients, so regulatory authorities now require comprehensive characterisation, risk assessment and understanding of biopharmaceuticals during development, manufacture and storage. This enables quality controls to be put in place to mitigate or avoid conditions where conformational changes are known to occur, and ensures that the quality, safety and efficacy of biopharmaceutical proteins are not compromised. © 2018 Society of Chemical Industry
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