Insufficient physical stability remains a major challenge regarding the development of liquid therapeutics as aggregation and degradation of the drug substance can lead to patient safety concerns through increased immunogenicity or reduced potency. During its lifetime, a drug product (DP) containing for example a therapeutically active peptide can be exposed to various types of physical stress. Here, several methods to induce diverse forms of physical stress on liquid solutions were developed using a buffer solution and implemented by testing different therapeutically active peptides in a tool formulation. Methods to investigate the influence of stress induction during stirring, different kinds of shaking, pumping, and freezing and thawing of the peptide solutions were investigated. The establishment with buffer solution allowed fine-tuning of the parameters to not damage materials like glass vials and tubing themselves. Repeated peristaltic pumping at 110 rpm for 2 h led to time-dependent formation of subvisible particles (SVPs) in each peptide-containing sample. More peptide-specific results were achieved with stirring experiments at 600 rpm over three days. Shaking in glass vials on an orbital shaker at 420 rpm for 10 days did in most cases not introduce enough stress to trigger any response. When switching to a shaking motion induced by a microplate shaker at 1200 rpm, the distinguishability of samples could be increased over the same period due to increased interfacial stress. Freezing and thawing in glass vials at - 50°C led to the formation of SVPs already in peptide-free solutions, possibly due to glass delamination. Subsequent evaluation of visual appearance, absorbance at 620 nm, peptide concentration and covalently bound multimers revealed further insights into stress-induced particle formation of peptide drugs in solution.
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