Aggregation presents a significant challenge in the production and purification of active pharmaceutical ingredients (APIs) – particularly GLP-analogous peptides.^1,2 Uncontrolled aggregation can lead to batch failures and substantial economic losses.³ Additionally, the presence of aggregates in the final drug product can reduce its biological activity⁴ and – in the worst case – pose a potential risk of immunogenicity⁵. With the growing global demand for these peptides, regulatory agencies and contract development and manufacturing organizations (CDMOs) have intensified their focus on controlling aggregation. In response, quality control departments have developed and adapted a diverse array of analytical techniques to detect, monitor, and mitigate aggregation.

Here, we will provide an overview of key methodologies used in the industry, with a particular emphasis on distinguishing between two critical aggregate types: reversible, soluble aggregates and irreversible, insoluble aggregates. We will illustrate these approaches through stylized case studies, highlighting practical applications and insights gained from real-world scenarios.

[1]   K. L. Zapadka, F. J. Becher, A. L. Gomes dos Santos and S. E. Jackson, Interface Focus, 2017, 7, 20170030.
[2]   L. Wang, N. Wang, W. Zhang et al., Sig Transduct Target Ther, 2022, 7, 48
[3]   C. J. Roberts, Curr Opin Biotechnol., 2014, 30, 211-217
[4]   J. D. Downey, A. M. Crean, K. B. Ryan, Eur J Pharm Sci., 2025, 209, 107071
[5]       A. S. Rosenberg, AAPS J, 2006, 8, 59.