The Hidden Challenges Of Peptide Development: Bridging Discovery, Developability, and Commercial Reality

The peptide therapeutics market is expanding rapidly, driven by the success of molecules applied to metabolic disease, obesity, endocrinology, and oncology. What used to be a niche, difficult-to-handle modality is now a strategic focus for the industry. Companies are designing increasingly complex, heavily modified peptide sequences and are eager to move these assets into the clinic quickly.

There is just one major issue: Successful peptide products require more than optimized molecular design. Following initial formulation selection, drug product development is often a critical determinant of peptides’ clinical and commercial success. Additionally, as peptides become increasingly potent and complex, the importance of establishing an understanding of the molecule’s stability and an occupational safety plan early in development is amplified. Ultimately, the burden is on the developer to understand their molecule’s unique developability risks and then work in-house or with a CDMO partner to create individualized scientific assessment and formulation strategies that mitigate those risks throughout development.

Peptides Require More Than A Small Molecule Mindset

Peptides fill a critical gap between small molecules and protein therapies by combining attributes found in both. Like small molecules, peptides have the potential for high potency, giving them great versatility to address unmet medical needs or to improve upon existing treatments. Then, molecular engineering techniques, such as exchanging natural for non-natural amino acids and linking other functional components to the peptide (e.g. lipidation), have enabled peptides to exhibit some attributes shared by biologics — such as extended half-life, good receptor selectivity, and flexible dosing regimens — while also offering greater stability than proteins.

Peptides exhibit a much greater dependence on primary sequence than traditional small molecules, making their structure-property relationships more similar to those of biologics. Every modification intended to improve biological performance has the potential to introduce a new development liability. However, New Chemical Entity (NCE) groups often underestimate the impact of such peptide modifications on all program elements, from formulation robustness and analytical characterization to manufacturability and occupational safety. Sequence modifications may improve efficacy while increasing aggregation propensity. Lipidation may improve half-life while reducing solubility. Potency enhancements may lead to more restrictive occupational exposure requirements.

Further, since peptides are not built around common frameworks (e.g., antibodies or viral vectors), platform formulation approaches are less applicable. Peptides require molecule-specific development strategies to address challenges stemming from limited or variable solubility, sequence-dependent aggregation and fibrillation, multifaceted degradation pathways, and potency.

Devising and executing a strategy capable of identifying and overcoming these challenges requires developers to support collaboration across key teams within the organization, including toxicology, discovery, and development. Fostering this collaboration not only reduces technical and operational risk, it also enables each team to provide market insights early in development, such as whether a particular dosage or delivery device is likely be accepted by a given patient population.

The Discovery-Development Disconnect

Early collaboration between toxicology, discovery, and development is vital toward understanding a peptide’s critical quality attributes (CQAs) and degradation pathways, which enables development of robust analytical methods and stability-indicating assays. Some know-how can be translated from biologics development, but peptides’ inherent challenges require experience across different molecules to build the necessary expertise.

Peptide development is often challenged by both well-recognized scientific risks and unexpected issues that emerge after selection of the final candidate. One way to reduce these risks is to incorporate developability considerations early in discovery. In silico assessments can identify potential liabilities, such as chemical instability, aggregation propensity, fibrillation risk, or solubility limitations, helping teams to prioritize candidates that are more likely to succeed from both clinical and manufacturing perspectives. Subsequent analytical characterization can then confirm these findings and inform drug product (DP) development.

However, many organizations still defer developability assessment until later stages of development. As a result, opportunities to identify and mitigate risks before entering the laboratory are missed, creating one of the first critical disconnects between discovery and development.

The second is misalignment over peptide stability. Therapeutic peptides commonly range from approximately 1 kDa to 10 kDa, and experience both chemical degradation, such as oxidation and hydrolysis, and physical degradation, including aggregation and adsorption. Their stability profiles therefore share characteristics with both traditional small molecules and larger biologics. As a result, forced degradation studies are an important tool for characterizing peptide-specific degradation mechanisms and for developing stability-indicating analytical methods. Together with targeted pH-stability experiments, these studies help establish how degradation pathways vary across pH conditions and how they can best be mitigated.

In any case, slowing degradation requires formulators to balance competing priorities, perhaps optimizing solubility at the expense of some aggregation stability. It is rare to solve all problems for a peptide, so the path forward typically lies in understanding how these factors are interconnected. This requires sufficient data to inform candidate selection, which is often heavily weighted toward clinical outcomes rather than the characteristics of a viable drug product.

The third key disconnect arises from the fact that discovery teams work with powders, which they assess to determine occupational exposure limits (OELs), and drug product (DP) teams work with a liquid formulation. In the absence of formulation-specific occupational exposure data, development teams may initially apply conservative assumptions when defining safe handling practices for liquid formulations and assume that the liquid is as potent as the powder. However, a growing number of next-generation peptide therapeutics are classified as highly potent compounds (HPCs) subject to increasingly stringent OELs, which stipulate enhanced containment strategies during development and manufacturing, creating additional complexity for process design, facility requirements, personnel protection and overall project economics.

Safe-handling requirements for highly potent compounds are sometimes recognized later in development than ideal, creating challenges during technology transfer and scale-up and reinforcing the need for coordination among the toxicology, discovery, and drug development teams to determine how the compound should be handled. Not every lab is equipped or trained for this, making it a significant issue in peptide development that will become increasingly relevant as peptides become more potent.

The Development Implications Of Higher Peptide Concentrations

Peptide concentrations have increased in large part due to market demand. For example, many patient groups want self-administration options and longer gaps between dosing, which requires delivering the intended dose in a smaller injection volume subcutaneously, driving the need for higher concentrations.

Notably, high concentration is not inherently problematic. Challenges are revealed as concentration increases and issues with the peptide that did not impact low-concentration formulations unveil. One potential issue is intermolecular interactions in the formulation, which can lead to increased viscosity, making it difficult to apply the drug product through a small needle. High-concentration formulations can also lead to or exacerbate manufacturing issues, raising important questions about process capabilities: Can the filling pumps handle a higher-viscosity peptide? Will the high-viscosity product lead to quicker filter fouling or problems during filtration processes? Are the CMO or processing site’s equipment and processes still capable of producing the formulation? Will the peptide tolerate the increased mechanical shear stress during mixing, pumping and filling?

Consider, too, that peptides can also be formulated as a multi-dose product requiring preservatives. Molecule-excipient interactions are critical factors due to the delays and costs associated with late formulation changes. For example, hydrophobic interactions between the preservative and the peptide, often enhanced by lipidation, might diminish preservative availability, leading to antimicrobial effectiveness test failures.

Clinical Promise Isn’t Enough

While industry attention is largely focused on the clinical success of peptide-based medicines, particularly in metabolic and obesity-related indications, long-term success depends also on a molecule’s developability, manufacturability, stability, and safety profile. An integrated DP development strategy built around peptides’ specific challenges can reduce risk, accelerate timelines, and improve the likelihood of clinical and commercial success.

Toward this end, it is important to seek a CDMO partner experienced in applying tailored analytical methods to test both chemical and physical degradation, is able to handle high potency compounds and brings in a commercial perspective to early development. Such a CDMO can help sponsors develop an end-to-end path to commercialization rooted in thorough characterization of the peptide, rather than depending on efficacy and clinical outcomes, which often results in drug products that do not meet the needs or preferences of patients or clinicians because market considerations were not adequately incorporated into formulation and development.

Coriolis can help fill those gaps, bringing a commercial perspective to the assessment of a molecule through early in development. While many providers offer broad development capabilities, fewer combine an end-to-end approach with demonstrated peptide experience and facilities equipped to work with high potency compounds. Learn more about Coriolis’s expertise in formulation and drug product development for peptides here.