Long Peptide or Protein?
As the length of therapeutic peptides increases, so too do the synthetic challenges, as described by Hazel Moncrieff, Ph.D., senior group leader, GMP peptides, Almac Sciences. Errors in amino acid addition to a growing peptide strand are compounded as the peptide lengthens and can greatly compromise the quality of the final product.
“The coupling efficiency at each synthesis step must be extremely high,” resulting from a robust and reproducible synthetic chemistry process, said Dr. Moncrieff. She described Almac’s expertise in producing long peptides and the company’s ability to synthesize peptides greater than 100 amino acids in length routinely. She also reported the successful production of peptides as large as 200 amino acids using solid-phase synthesis.
A key factor in producing long peptides is resin selection to optimize solubility of the forming peptide and minimize aggregation. Another important factor is post-synthesis product characterization and the need for high resolving analytical methods such as UPLC and LC/MS to differentiate full-length peptides from impurities, which are mainly shortened peptides that lack the full complement of amino acids, and which typically elute together with the full-length molecule on separation.
Almac is pursuing in-house research to develop purification technology that Dr. Moncrieff believes will enable production of even longer peptides using solid-phase synthesis. The company is currently testing these new LC-based techniques in small-scale development work, and Dr. Moncrieff reported preliminary findings that demonstrate their ability to increase product yield.
Commenting on industry trends in general, Dr. Moncrieff described an increase in project complexity, with customers requesting the production of both longer peptides and more multicomponent products, in which the API contains a mixture of multiple peptides.
“We are also seeing an increase in the breadth of projects,” she said, referring to growing interest in Almac’s rapidd™ service package that integrates chemical and process development and analytics for API synthesis, drug production, preclinical safety studies, and testing and documentation to support regulatory filings.