Abstract
A crucial aspect of pharmaceutical development is the demonstration of long-term stability of the drug product. Biopharmaceuticals, such as proteins or peptides in liquid formulation, are typically administered via parental routes and should be stable over the shelf life, which generally includes a storing period (e.g., two years at 5 °C) and optionally an in-use period (e.g., 28 days at 30 °C). Herein, we present a case study where chemical degradation of SAR441255, a therapeutic peptide, in different formulations in combination with primary packaging materials was analyzed under accelerated conditions to derive long-term stability predictions for the recommended storing conditions (two years at 5 °C plus 28 days at 30 °C) using advanced kinetic modeling. These predictions served as a crucial decision parameter for the entry into clinical development. Comparison with analytical data measured under long-term conditions during the subsequent development phase demonstrated a high prediction accuracy. These predictions provided stability insights within weeks that would otherwise take years using measurements under long-term stability conditions only. To our knowledge, such in silico studies on stability predictions of a therapeutic peptide using accelerated chemical degradation data and advanced kinetic modeling with comparisons to subsequently measured real-life long-term stability data have not been described in literature before.
Highlights
Biopharmaceuticals, such as peptide or antibody drugs, are often provided to patients as an aqueous solution that is applied intravenously, or subcutaneously using an injection device
Such modeling approaches are not yet required for New Drug Submission according to official guidelines, many regulatory agencies are appreciative of their value in dossier submissions
In this genuinely prospective and predictive study that included the measurement of long-term stability data, we demonstrated the scope and usefulness of kinetic modeling for long-term stability predictions on SAR441255
Summary
Biopharmaceuticals, such as peptide or antibody drugs, are often provided to patients as an aqueous solution that is applied intravenously, or subcutaneously using an injection device. Instability of a drug product can result in undesired change in performance, adverse side effects and even cause product failures [1,2] Due to this critical aspect, physical and chemical stability have been recognized as crucial screening and optimization parameters already in early discovery projects by the pharmaceutical industry [3,4,5,6]. Due to their inherent conformational flexibility, therapeutic peptides are generally susceptible to chemical degradation in solution, for example, hydrolysis, oxidation, isomerization or deamidation. Covalent crosslinks between peptides or proteins might result in the formation of covalent dimers and high molecular
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