The Future Looks Bright
The cost of manufacturing peptides has come down mainly because of reductions in the cost of raw materials, according to Jane Salik, Ph.D., CEO of PPL. At the same time, advances in purification technology have improved scale-up capabilities.
"The issue for bulk peptide manufacturers is the availability of raw materials," says Rodney Lax, director of sales and marketing at PPL. In particular, the newer protected amino acids are often difficult to obtain in large quantities or are exceptionally expensive.
Activotec(www.activotec.com) leverages its IP position in chemical peptide modification to produce custom peptides for research and drug discovery applications with an emphasis on long, cyclic, and other difficult to synthesize peptides.
With about 250 peptide candidates in clinical development in the U.S., the future looks bright, according to Chris Littlewood, CEO of Activotec. The company holds patents for proprietary modifications of the peptide backbone and is able to carry out solid phase peptide synthesis in the N-terminal to C-terminal direction, enabling the preparation of peptide analogues with C-terminal modifications and peptide bond modification. This method yields no detectable racemization and is amenable to automation, according to the company.
Working under a two-year research grant from the British government, Activotec is developing a novel method for de novo synthesis of highly pure therapeutic proteins, using polyethylene glycol as a temporary solubilizing agent in the sequential chemical ligation of synthetic peptide fragments.
Littlewood highlights the company’s recent success developing stable, active analogues of glucagons-like peptide 1 (GLP-1).
In addition to the importance of pricing and quality, "speed is the essence of the business," says Dr. Barthelemy. "Due to the complexity and length of synthetic processes for peptides, the catch-22 is to supply material within a short timeline and still develop the process in such a way that the chemistry is cost-efficient and robust for scale-up in the long term."
Most APIs are manufactured using traditional solution-phase synthesis. However, there is a move toward hybridsequential solid and solution phase synthesisstrategies, as costs of solid-phase peptide chemistry continue to decline. Expect this trend to continue, as demand for long peptides steadily increases. With hybrid synthesis, small peptide fragments produced with solid-phase synthesis are then joined in solution to form longer peptides.
The choice of synthesis strategy is primarily driven by economics and feasibility issues related to a particular peptide project.
"The future is likely to be a landscape where all three possibilities coexist," says Dr. Barthelemy. Peptisyntha recently completed construction and validation of two additional GMP suites at its Torrance, CA, facility, dedicated to solid-phase synthesis. It has budgeted funds to add medium-size capacity for solution-phase synthesis at its Brussels, Belgium site.
An emerging trend in the peptide API arena is the FDA’s apparent tightening of purification specifications, with expectations approaching those in place for small organic molecules. "Impurities will be a hot topic," with the need to keep levels low, even as production quantities increase, says Hagopian of NeoMPS. Whereas accepted levels of impurities had been >0.5%, the trend has been toward the need to identify impurities that exceed 0.1%.
"We need guidelines from the FDA for peptides," says Hagopian. We are seeing this same kind of shift in Japan and Europe, he adds, and the consensus appears to be moving toward 0.1%.
Whether for research-grade or GMP peptides, product purity and quality will remain front-burner issues. Unfortunately they recently garnered front-page attention as well, with charges of mail fraud and false statements filed in May against SynPep, accused of falsifying data supporting the purity of peptides supplied by the company between 1999 and 2004.