MICHAEL W. PENNINGTON, DENISE KAROUNOS, CHRIS BAI
AmbioPharm Inc., North Augusta, USA

Abstract

Peptide production has evolved over the past 50 years into a mature industry of both contract development and pharmaceutical manufacturers. Key to this evolution were improvements to the solid-phase production methods which utilized Fmoc-tBu protection strategies. Inherent to peptide synthesis are principal issues which result in a large impact on the green and sustainability factors for this industry. Some of these include: regular use of both transient and semi-permanent protecting groups which diminish the atom efficiency, generation of large amounts of hazardous chemical waste, and energy inefficient processes such as lyophilization. This short review describes some of the initiatives in our industry such as “greener” solvents, recycling key solvents, and alternatives to lyophilization such as precipitation, crystallization or spray drying.

INTRODUCTION

Peptide pharmaceuticals represent a unique group of products which are larger than small molecule drugs yet smaller than most biological drugs. With exquisite selectivity, lower off-target effects and ease of production, peptides are a very attractive modality for development. Peptides were rarely developed by large pharmaceutical companies in the 20^th century. Now, they represent worldwide sales of >(dollar)20 billion and green chemistry initiatives are needed to ensure the long-term sustainability of these products (1). With more than 70 approved peptide drugs and several hundred in clinical development (2), commercial peptide sales are projected to surpass $60 billion by 2026.

The first synthetic peptide drug, oxytocin, entered the clinic in 1962. The original oxytocin process was a liquid-phase assembly (LPPS) which was both time-consuming and cumbersome for the nine-residue peptide (3). Solid-phase peptide synthesis (SPPS) developed by Merrifield in 1963 (4) and its subsequent refinement throughout the following five decades has been essential for the growth and success of peptide therapeutics. The s ...