Peptides make up around 8% of all active pharmaceutical ingredients (APIs). Those molecules are short polymers formed from the linking of ≤100 amino acids. They comprise some of the most basic, yet key components of biological processes. Several peptides are significant commercial or pharmaceutical products, ranging from the sugar substitute aspartame to clinically relevant hormones, such as oxytocin and insulin. Today, the peptide market is valued at around $ 20 billion annually with a compound annual growth rate (CAGR) of 9.4%. However, the peptide manufacturing industry is in a state of change.

In recent years peptides — as new chemical entities (NCEs) — have raised the interest of the pharma industry due to their unique therapeutic properties: high target affinity, specificity and potency, low toxicity and reduced antigenicity. Thus, the number of peptide-based drugs entering clinical trials is rising each year, leading to an increasing demand of peptides as APIs. However, this growth is hampered by challenges in the available peptide manufacturing processes such as production costs (e. g. inefficient processes and high need for expensive raw materials), scalability issues and sustainability. As a result, there is an unmet need for cost-efficient scalable technologies specifically designed for peptide production.

Current State of Peptide Manufacturing
With a growing demand, the production of peptides at commercial scale has become a barrier to the industry because limited production capacity exists. Thus, there is a shortage of peptides in the market (as stated by the 2019 Peptide Therapeutics Opportunity Assessment) as a result of the limitations imposed by current peptide production processes, which fall into two types:
One is chemical synthesis, which is responsible for 85% of peptide production. It requires high amounts of expensive and partly toxic raw materials and is rather unaffordable for the production of peptides at large scale, especially for peptides over 30 amino acids in size.
The other are bioprocesses (recombinant production) as alternative methods for peptide production that use genetically modified microorganisms. However, they entail three major technological hurdles: peptide degradation by proteases; peptide aggregation; and toxic effects of the peptides on the production host. These factors can result in low production titers as well as lengthy and risky development, making this approach often inefficient and less pop­ular than chemical synthesis.

Bioprocesses are, however, very successfully applied for the production of larger molecules such as proteins. As proteins have a very complex folding pattern, their structure protects them against fast proteolytic degradation.
The major players in the contract manufacturing business of peptides, such as the Sweden-based PolyPeptide group or Bachem from Switzerland, have set their focus on chemical synthesis. The reason for that could be as simple as that truly overcoming named hurdles in recombinant production of peptides remains unsolved. Yet, according to a recent annual report of Bachem, recombinant production is a topic that the company keeps an eye on. For good reason: the industry is certainly facing some changes.

Bioproduction Breakthrough
In 2015, the German Ministry of Economic Affairs and Energy approved a grant called “EXIST Forschungstransfer” to a group of young scientists around Christian Schwarz of the Heinrich-Heine-University in Düsseldorf. The target of the funded project was to further develop a technology that can be regarded as a break­through for the bioproduction of peptides.
Schwarz could convince the jury, that the peptide-related technical challenges in production could potentially be solved based on discoveries he made during his doctoral thesis at the Institute of Biochemistry. He found a way to secrete specific molecules efficiently using gram-negative Escherichia coli bacteria. Secretion describes the transport of a molecule from the interior of a cell to its external environment. From there it can be harvested.
While this process is rather easy to achieve with gram-positive bacteria, it is challenging for gram-negative strains due to their complex cell membrane. As this transport is difficult for any molecule, meaning also unwanted impurities or proteases, the surrounding of E.  coli is very pure, free of proteases and therefore a “safe harbor” for peptides. What Schwarz did precisely is that he modified a type-1 secretion system of E. coli and added a tag to the peptide, which contains a transport signal. As a result, the tag including the peptide as a cargo is efficiently secreted. The fusion construct is subsequently cleaved, leaving the pure peptide ready for the downstream processing.

Apart from efficiency in regard to production titers, another crucial aspect is reliability of the system, especially when it comes to NCEs. Drug development projects face a tight schedule, moving from the discovery to pre-clinical and then to clinical phases. Even though a bioproduction of the API can have a major positive impact on the commercial stage business case, lengthy development times for setting up the manufacturing have to be avoided by all means. The technology now available has success rates that are comparable or even superior to those of chemical synthesis and development times are reduced from months or even years to weeks.
The university project has been a success and the technology could be scaled up and diversified delivering promising results in regard to a commercial use for peptide production. In 2017, the project spun out of the university, attracted prominent investors such as Evonik Venture Capital and is since then growing its peptide manufacturing business under the firm ­Numaferm.

Outlook
Apart from the manufacturing of generics or NCEs, there are other hot topics in pharma that further drive the demand for efficient, quick and reliable peptide production. One example are antimicrobial peptides, which play an important role in the development of new antibiotics. An­other example can be found in the field of immuno-oncology, where personalized peptide vaccines (PPV) are one major strategy. PPVs are cocktails of peptides that help stimulate the body’s immune system to attack tumor cells.
With growing demands and additional technologies emerging — like the recombinant approach of Numaferm, enzymatic ligation of shorter peptide fragments or synthetic biology — the peptide production industry is undergoing a major change. A complete substitution of one technology with the other may not be the case. The real opportunity lies in their combination.