JEFFREY R. FERGUSON*, MICHAEL O. FREDERICK, MICHAEL E. KOPACH, KEVIN D. SEIBERT, MARK A. STREGE
*Corresponding author
Eli Lilly and Company, Indianapolis, IN, USA

Abstract

Commercial peptide production historically utilizes Solid Phase Peptide Synthesis, but in recent years, hybrid Solid Phase Peptide Synthesis / Liquid Phase Peptide Synthesis approaches have been developed and utilized. This manuscript reviews several case studies using alternate hybrid approaches and includes discussion of comparative benefits and limitations of linear and hybrid peptide synthesis approaches, as well as their resulting impact on manufacturing process, control and regulatory strategies. Further, analytical techniques are described that enable an enhanced development approach including characterization of starting materials, intermediates and final drug substances, leading to improved process understanding and the development of holistic control strategies.

INTRODUCTION

The development of novel synthetic peptides are increasing for pharmaceutical applications across many disease states. Pharmaceutical research and development teams are tasked with developing efficient synthetic processes and effective control strategies that enable the timely delivery of clinical trial and ultimately commercial supplies. The following sections provide a comparative review of synthetic peptide synthesis and development approaches along with their impact on the design of holistic control strategies and regulatory submission strategies.

SOLID PHASE PEPTIDE SYNTHESIS

Current commercial peptide synthesis predominately utilizes Solid Phase Peptide Synthesis (SPPS). Based on Merrifield’s pioneering work (1), SPPS rapidly replaced Liquid Phase Peptide Synthesis (LPPS) as the primary means for synthetically preparing peptides. SPPS attaches the first amino acid (AA) to resin and then the amine terminus is deprotected and subsequent amino acids are attached until the peptide of desired length is produced (Figure 1). A key benefit to SPPS is that excess reagents are washed away from the growing peptide affixed t ...