NADJA BERGER1*, MANOJ KUMAR MUTHYALA1, DOMINIK SARMA1,
KARIN RUSTLER2, THOMAS BRUCKDORFER2, ROBERT ZITTERBART1*
*Corresponding authors
1. Belyntic GmbH, Berlin, Germany
2. Iris Biotech GmbH, Marktredwitz, Germany

Abstract

With a remarkable amount of peptide therapeutics already on the market and many more to come, there is an ongoing need to improve manufacturing scale and efficiency for a sustainable, global supply. Especially the trend towards longer and modified peptides challenges manufacturers to meet quality specifications and scale requirements. For example, more orally available peptide drugs will enter the market requiring worldwide supply in ton-scale. Herein, we introduce an innovative route for the chemical synthesis combined with orthogonal Peptide Easy Clean (PEC)-purification of the blockbuster peptide drug liraglutide, a fatty acid-modified peptide. We demonstrate easy and seamless upscaling to gram-scale, rendering this manufacturing route an attractive way to produce complex peptides for R&D and potentially in multi-kg and ton scales. PEC-assisted manufacturing can significantly save downstream costs due to high productivity, high yield, and low solvent consumption.

INTRODUCTION
Peptides represent a powerful class of drugs due to their low toxicity, good tolerability, high selectivity, and high potency. The journey of peptide-based drugs started with the first use of the peptide insulin to treat diabetes in 1922 (1).
It took over three decades, until the next peptides entered the clinic, namely the synthetically produced hormones oxytocin and vasopressin in the 1950s (2, 3). The next milestones in the history of peptide manufacturing were set by the invention of the solid phase peptide synthesis (SPPS) (4, 5) by Merrifield in 1963 and almost one decade later the introduction of high-pressure liquid chromatography (HPLC) (6-7) for purification. In recent years, tremendous efforts in developing peptide-based new chemical entities (NCEs) resulted in a current total amount of about 80 peptide drugs on the global market (8). Nowadays, there are various ways to address peptide production at different scales to meet the demand along the value chain from milligram to gram and kilogram (9, 10).

However, the chromatographic purification of synthetic peptides remains a challenging task with the cu ...