Pegylation and formulation strategy of Anti-Microbial Peptide (AMP) according to the quality by design approach

Antimicrobial resistance is one of the main global threats according to the World Health Organization's (WHO) report (World Health Organization 2014), therefore there is a need for the development of other agents, such as antimicrobial peptides (AMPs). Although AMPs are considered as major candidates for next-generation antibiotics, several challenges including low bioavailability, high manufacturing cost and toxicity are still to be solved for their practical use in therapeutic applications. Novel chemical modification approaches as well as strategies for their delivery offer several opportunities to overcome these barriers and develop more stable and cost-effective synthetic peptides with efficient delivery to the target site. The integration of the Quality by Design (QbD) approach in the early pharmaceutical developments supports researchers in optimizing the targeted product by a risk based manner. Peptide modifications and formulation of peptide delivery systems are challenging tasks and hide several risks. Understanding and evaluating the cause - effect relations within the initial Risk Assessment (RA) step in case of all attributes give the basis for the experimental design as the next step, and aids the formulation development in order to get the final product in the targeted quality range. This study presents a Quality by Design based antimicrobial peptide modification and formulation design. Analyses the potential risks in the AMP PEGylation process through the example of PGLa. The QbD based initial RA screened and evaluated the risk factors in this AMP modification procedure. The critical quality and process related factors were defined and their ranking was performed due to their estimated critical effect on the PEGylated AMP. This pre-formulation design study highlights the critical risk factors as decision points for the further steps.