Maurizio Sartorato of Olon reviews the options for manufacturing peptides at scale
Peptide therapeutics : Challenges & opportunities
Maurizio Sartorato of Olon reviews the options for manufacturing peptides at scale
Currently , around 80 peptides have been approved for human use , with over 150 others in clinical development and many more in the preclinical stages . Every year , new therapeutic peptides gain approval from the FDA and other regulatory agencies globally .
Peptide therapeutics offer unique advantages compared to small molecules : they tend to be more potent , more specific and capable of interacting with target receptors in ways that small molecules cannot . Furthermore , they can target a broader range of receptors and , due to their inherent properties , they are generally less harmful to the human body .
As the need for peptide-based therapies rises , the pharmaceutical industry faces the challenge of scaling up production to meet global demand while maintaining sustainability and cost-effectiveness .
Choosing the ideal production method for a therapeutic peptide requires careful consideration , as no single solution fits all needs . Several techniques are available , each offering distinct advantages and challenges . These include chemical synthesis ( solid- and solution-phase ), chemoenzymatic synthesis and recombinant DNA technology . Despite significant advances in these methods , large-scale peptide production , particularly for APIs , continues to present numerous obstacles .
The synthesis of peptides involves intricate chemistry . Although forming amide bonds to create the peptide backbone may seem simple , it often leads to unexpected difficulties . Peptides possess unique chemical and physical properties — such as secondary structure formation , low solubility and unusual reactivity — that complicate the process .
Solid-phase peptide synthesis ( SPPS ) is widely used to overcome these challenges , due to its well-established protocol , efficiency , scalability and ability to incorporate non-natural amino acids . A similar approach , liquidphase peptide synthesis ( LPPS ), is performed in solution .
Both SPPS and LPPS have their limitations , including the use of hazardous solvents and the high costs associated with longer sequences ( more than 20-25 amino acids ). As sequences grow longer ( up to 40-50 amino acids ), traditional methods become increasingly expensive and less viable .
This is where recombinant DNA technology is gaining traction ; especially for complex and longer peptides , chemical synthesis becomes both more challenging and costly , making recombinant methods a more feasible alternative ( Figure 1 ).
In the selection of the best production method for a therapeutic peptide , the required production scale is another critical factor . For largescale manufacturing , recombinant methods offer greater scalability , costeffectiveness and sustainability
Recombinant peptide & protein production
Recombinant peptides and proteins are produced using various expression systems , each tailored to specific protein characteristics , such as structure , post-translational modifications and desired product location ( intracellular or secreted ). The efficiency of these systems significantly impacts process costs and sustainability , with higher productivity leading to less consumption of water , energy and raw materials .
Escherichia coli is the most commonly used system for recombinant protein production , due to its high growth rate , low energy consumption and simple genetic manipulation . However , high plasmid copy numbers , which are essential for protein production , can strain bacterial growth , potentially leading to plasmid loss . To prevent this , vectors are equipped with selection markers , such as antibiotic resistance or metabolic markers .
E . coli expression systems also use strong inducible promoters , like the T7 promoter , to control protein production and optimise yields . Protein tags , such as His-tags , are added to aid protein purification and protect against proteolysis . However , challenges remain in protein refolding , post-translational modifications ( e . g . glycosylation ), and endotoxin contamination , which require additional purification steps .
Yeast expression systems , such as Saccharomyces cerevisiae and Pichia pastoris , are preferred when protein secretion is needed , as they have natural pathways for protein folding and secretion . Yeast can perform post-translational modifications like glycosylation .
Among yeast systems , P . pastoris stands out due to its high cell density and efficient protein expression , especially when using the methanol-
36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981