As growth in the GMP peptides business continues, “customers are asking how we would implement increasing scales of manufacture,” says Alastair Hay, Ph.D., senior group leader at Almac. “The complexity of the design of peptide products is increasing,” whether due to the peptide’s longer length, or some sort of unnatural modification or linkage to another molecule to improve biological function or selectivity. This may require adapting the chemistry used in synthesizing the peptides, Dr. Hay notes.
He remarks on the continuous advances in peptide synthesis and downstream processing technology over the past several years, including new resins and purification media. While it is important to keep abreast of these developments and to assess their value, it is critical to do so in the context of a particular process and application.
“You need to understand whether a new development is an improvement for your process,” says Dr. Hay. “You do not want to make a change if, on the whole, it will not give you a benefit.” Additionally, something that is advantageous on a small scale might not be beneficial economically on a larger scale.
Even as the resins used in peptide synthesis are becoming more sophisticated, “research is still needed to determine what features are relevant for consistent high yield bearing,” says de Chastonay.
Improvements in analytical methodology are enabling manufacturers to measure more impurities and with greater accuracy, which becomes increasingly important with the production of longer peptides.
Yet new types of molecular species, unnatural modifications, and analytical techniques often mean breaking new ground from a regulatory perspective, and there is not always clear regulatory guidance to cover every circumstance, often requiring manufacturers to use their judgment.
“Scale does not present any particular challenges at present from a synthesis perspective,” says Lax. “Few peptides are being manufactured at a scale above 100 kilograms/year; many more are being produced within the 30–50 kilogram range, and that number is increasing.
“You can make 100s of kilograms cost efficiently using solid-phase peptide synthesis technology, but you need large-scale reactors and the capability to do large-scale cleavage and purification, all the way through spray drying, or more typically lyophilization,” says de Chastonay. And you need all of the infrastructure to go along with such a large-scale manufacturing operation, including, for example, solvent delivery, solvent handling, and waste-stream handling. At the same time, notes de Chastonay, companies are under pressure to meet increasingly strict emission and waste disposal standards.
As recently as five years ago, “the upper sequence length we would seriously look at for a GMP project without extensive preliminary investigation would have been about 40 amino acids,” explains Lax. “That number has now shifted to 60–70 amino acids, largely due to progress in analytical technology and improvements in preparative HPLC media.”
With the large columns available “we routinely make batches of many kilograms,” says de Chastonay. But there are important considerations, such as having that much money invested in a single batch of product. “And you have to consider issues related to scale-up, such as how long it takes to purify; will you get degradation?” Similarly, for large batches, is it important to invest in lyophilization equipment that is sized properly?
As peptide drugs are progressing through clinical development and successfully achieving commercialization, and both scale of production and a reliable supply chain become critical concerns, companies are increasingly seeking back-up manufacturers for their products. Lax describes this as “logical development” as the GMP peptide market matures. For peptide producers, it provides an additional revenue source, in addition to generic peptides and proprietary projects developed in-house.