Global peptide pipelines are booming and key players in the market are under pressure to keep up with demand. As more programs enter the market, an increasing number of peptide sponsors are turning to contract development and manufacturing organizations (CDMOs) to help them establish a pathway to commercialization. 

Within that broader trend, CDMO Neuland Labs has observed peptide sponsors turn to outsourcing much earlier in the development process. Earlier this year, the company reported that Japanese-based sponsors of peptide programs are asking for assistance in preclinical or very early clinical stages, due to the complex development requirements of the programs.  

“One reason for this is that in-house capacities today for most of the companies are found to be insufficient to meet increased technical requirements,” said Sharadsrikar Kotturi, chief scientific officer at Neuland Labs. “The growing complexity of the nature of the molecule is resulting in sponsors having service providers fairly early on both in developing and optimizing processes and taking the process all the way to its validation and to commercialization.”

Kotturi observes the trend is not unique to Japan or any one specific location and more so reflects the state of global peptide development. 

“As the global pipeline of peptides seemingly is exploding every passing day, we see there are very many assets that are moving very fast into the drug development space,” he notes.

In response to this market behavior, Neuland has expanded both its peptide capabilities and manufacturing capacity. At the same time, Kotturi said sponsors increasingly view CDMOs as strategic development partners rather than simply manufacturing service providers.  

“The expectation today is no longer to just make it on scale; our partners expect us to help with the design of the process, optimize the process, create an impurity control strategy, along with a robust yet sensitive methods that have to be developed, and more importantly, have the regulatory ready documentation package at all times and in real time that needs to get updated,” he adds. 

The state of peptides 

The surge of Japanese sponsors looking to outsource peptide programs in earlier stages of development is happening against the backdrop of a rapidly expanding peptide market struggling to keep pace with expectations from the demand. 

The immense popularity of GLP-1 therapies, along with continued investment in novel and specialized peptide therapeutics, has accelerated peptide development faster than manufacturing capacity and technical expertise have been able to keep pace. 

“With these two events taking place in tandem, we see that there is suddenly a shortage of capacity and a shortage of technical expertise at a global level when it comes to making peptides,” Kotturi says. “This basically pushed pharma companies to contract to specialized partners such as Neuland very early on in the development of the lifecycle of the product.” 

Because of this phenomenon, Kotturi predicts sponsor companies of peptide programs continuing to turn to contract manufacturers for developmental and manufacturing support for the next few years. 

“More complexity, earlier outsourcing, and greater dependence on specialized execution partners would be the way peptide development will progress, at least in the foreseeable future of the next 18 to 24 months, before the market begins to stabilize with additional capacities that get added to by the service providers,” he contends. 

A recent report from Global Growth Insights found the pharmaceutical industry overall represents nearly 72% of total peptide CDMO demand, with more than 60% of clinical peptide candidates originating from outsourced manufacturing partnerships. 

Key challenges 

As sponsors look to move peptide programs forward more efficiently with the help of outsourcing partners, Kotturi identified three major technical challenges CDMOs are facing: analytical complexity, scale-up, and access to qualified raw materials. 

Analytical complexity is one of the earliest challenges to address in peptide programs, due in particular to the inherent batch variability of solid-phase peptide synthesis. Ultimately, Kotturi stressed the importance of developing robust analytical methods to more accurately identify impurities before they become larger manufacturing problems during scale-up.  

“Sensitive methods should be developed early on to ensure the robustness of the process and integrity of the process,” he said. “Analytical complexity perhaps is universally accepted as an early challenge for peptides, as peptides usually have closely related molecules — very similar to peptides themselves — that are impurities.” 

Beyond impurity mapping, Kotturi points out developers also need to understand aggregate formation, peptide solubility, stability, and degradation pathways early in development. Together, these factors influence how successfully a process can be scaled for commercial manufacturing.  

“Having this information developed early on can serve as signposts and guardrails as the program matures into commercial production,” he said. 

CDMOs that are involved from early development through commercial manufacturing can better identify risks of scale-up before production reaches commercial volumes, according to Kotturi.  

“Scale up is absolutely punishing, especially in practice, as a route that looks fine on a gram scale, especially in the laboratories, can behave in a totally different manner when we look at a kilogram or a commercial scale,” he observes. “Especially when we start looking at coupling efficiencies, aggregation, purification, glass transition temperatures, and also the other factors that adversely affect the output, both in terms of quality and quantity of the desired materials.” 

Raw materials play a vital role toward the scaling up of peptide programs, particularly when development timelines are compressed. Kotturi makes the case that material shortages or variability in amino acids and other key materials can lead to program delays. 

“Raw material access is another aspect of this battle that is purely situational but has the potential to break the schedule when time is of huge constraint,” he argues. “Especially when the need to get the material either into the clinic for a trial or to the market becomes very critical. So, in that context, the access to raw materials, amino acids, and other qualified vendors becomes extremely critical.”

Addressing these issues early is key to why sponsors are engaging CDMOs sooner in the process. Early involvement allows development teams to resolve analytical, manufacturing, and supply chain challenges before programs reach commercial production.  

“Early stage such projects often arrive at very difficult sequences, extremely tight analytical requirements, and raw material constraints,” Kotturi says, noting it’s a “unique challenge for us where we need to solve problems before the program settles into a mature mode.” 

Scaling long-chain peptides  

Exacerbating the challenges seen across the global peptide pipeline is an increased demand for high-purity and long-chain peptides. 

Global Growth Insights found that approximately 55% of complex peptide development is outsourced to CDMOs, reflecting increasing demand from pharma companies for high-purity and long-chain synthesis. Long-chain and high-purity peptides are continuing to present technical challenges with approximately 32% of CDMOs citing batch variability and production scalability as significant hurdles, according to the report.  

“The long chain, high purity peptides are hard to scale, primarily because every additional amino acid in the sequence multiplies and amplifies any small inefficiencies across the synthesis,” Kotturi notes. “Longer sequences usually require more coupling and deprotection cycles, so even a tiny stepwise loss compounds into a steep loss at an overall level. That means a route that looks workable in the development stage essentially becomes very fragile as it goes into the plant for a scale-up.”

He also points out that minute variations in moisture content, mixing parameters, or resin behaviors in a plant can significantly alter the outcome of the active pharmaceutical ingredient (API), which would be at variance with what has been observed in the lab. 

This is where having robust analytical methodologies in place is vital, according to Kotturi. 

“Analytical hurdles also begin to mount around the same time, as impurities have very similar mass and similar chromatographic behaviors, especially in columns,” he says. “In practice, this makes the need for developing highly sensitive methods, but very robust methods to first detect the impurity and then separate them from the peptide of interest.” 

Successfully identifying impurities is essential as peptide programs move toward commercial manufacturing, where things like reproducibility and quality become critical.  

“This directly has a role in impacting the reproducibility of the process. And this gets more exacerbated in the situation due to the heterogeneous behavior of the solid phase peptide synthesis,” Kotturi adds.