The Development of a Stable Peptide-Loaded Long-Acting Injection Formulation through a Comprehensive Understanding of Peptide Degradation Mechanisms: A QbD-Based Approach.

Abstract

Quality by design (QbD) serves as a systematic approach to pharmaceutical development, beginning with predefined objectives and emphasizing an understanding of the product based on sound science and risk management. The purpose of this study is to utilize the QbD concept to develop a stable peptide-loaded long-acting injection formulation. An in-depth comprehension of peptide degradation mechanisms was achieved through forced degradation investigations, elucidating (acid) hydrolysis and oxidation as the primary degradation pathways for the peptide ACTY116. The quality built into the product was focused on risk assessment, for which the critical material attributes (CMAs) and critical process parameters (CPPs) associated with the critical quality attributes (CQAs) of each formulation were identified, leading to the development of the corresponding control strategies. CQAs for three LAI (long-acting injectable) formulations were enhanced by taking the right control strategies. The LAI formulation exhibiting the highest stability for ACTY116 was chosen for subsequent pharmacokinetic investigations in rats. The objective of addressing peptide chemical instability and in vivo long-acting release was achieved. For other molecules with susceptible functionalities like amide bonds, amino groups, and hydroxyl groups, the utilization of PLGA-based in situ gel as an LAI formulation for stabilizing molecules provides valuable insights.