Formulation Strategies for Next-Generation Multiagonists

As GLP-1 therapies evolve from single-agonist peptides toward dual and triple agonists, formulation and CMC teams face a more demanding set of stability, delivery, and supply-chain decisions. PharmTech recently connected with Ishani Maharaj, application development specialist for pharmaceutical ingredients at Ingredients + Specialties from Univar Solutions, to discuss the degradation pathways that become harder to control, how developers weigh high-concentration liquids against sustained-release formats, and how low oral bioavailability affects API demand and cost of goods. Maharaj also addresses the regulatory data package for novel excipients and permeation enhancers, supplier qualification, and ingredient choices that can derail tech transfer. For PharmTech readers in formulation, process development, quality, and sourcing, her answers show how decisions made early in development can determine whether a multi-agonist peptide reaches commercial scale with a stable, manufacturable, and reliably supplied formulation.

PharmTech: As you move from monoagonists to dual and triple agonists, which degradation pathways become harder to control, and what works best to manage them?

IM:From a formulation-development perspective, the transition from GLP-1 monoagonists (eg, semaglutide, liraglutide) to dual agonists (eg, tirzepatide) and emerging triple agonists (GLP-1/GIP/glucagon) generally increases molecular complexity, hydrophobicity, and the number of chemically vulnerable residues. As a result, the stability challenge shifts from primarily controlling one or 2 degradation pathways to managing several competing pathways simultaneously.^1,2 The most challenging degradation pathways become oxidation, deamidation, and aggregation, which are often interrelated, as chemical degradation can trigger physical instability and particle formation.³

To manage these risks, formulators have found that maintaining a mildly acidic pH, selecting stabilizing buffer systems such as acetate or citrate, minimizing dissolved oxygen through nitrogen headspace control, and tightly controlling fill-finish conditions are the most effective levers for improving stability and extending shelf life.^3,4 Additionally, reducing agitation, limiting air-liquid interfaces, controlling temperature, and preventing exposure to light and trace metals help preserve peptide integrity and maintain potency in next-generation incretin therapies. GLP-1/GIP/glucagon triagonists are expected to require increasingly sophisticated formulation design to achieve commercial shelf life while maintaining very high drug concentrations for convenient injection volumes.^3,4

High-concentration and sustained-release formats are often at odds with viscosity, syringeability, and aggregation. How are teams deciding between those formats?

From a development perspective, the decision should be made as early as possible using a combination of biophysical characterization, rheological assessment, and stress-stability studies. Critical data sets include concentration-dependent viscosity profiles, injection force measurements, dynamic light scattering, size-exclusion chromatography, analytical ultracentrifugation, and subvisible particle analysis to quantify self-association and aggregation propensity.³ Forced degradation studies evaluating oxidation, deamidation, and hydrolysis under accelerated conditions are equally important because chemical degradation can act as a precursor to aggregation.³

Understanding the relationship between concentration, molecular interactions, and degradation pathways provides an early indication of whether a molecule can realistically support a high-concentration presentation. A high-concentration liquid should remain the lead when viscosity, injection force, aggregation, and shelf-life requirements can be controlled within realistic device and manufacturing limits. Sustained release or alternative delivery technology becomes more compelling when the required concentration creates an unacceptable developability barrier that justifies the additional CMC, release-control, and scale-up complexity.^4,5

For oral multiagonists, bioavailability is often in the low single digits. How do developers account for that in API demand and cost of goods?

Developers typically use the “cost per exposure-adjusted patient-year” metric when deciding if an oral multiagonist peptide can compete economically with an injectable. This measures how much it costs to deliver 1 year of clinically effective drug exposure to one patient, and unlike a simple “cost per pill” or “cost per patient,” this allows for the comparison of delivery routes on an equivalent pharmacologic basis.⁶ For example, if an injectable has 80% bioavailability and the oral formulation has 1%, the theoretical dose multiplier is approximately 80-fold before accounting for absorption variability, food effects, safety margins, and formulation losses.^6,7

The cumulative cost of absorption enhancers, tablet manufacture, packaging, stability overage, quality control, yield loss, and rejected batches is compared with the injector, sterile fill-finish, cold-chain, and device-assembly costs to evaluate its cost-effectiveness.^6,7 For dual and triple agonists, which are larger, more structurally complex molecules than the single GLP-1 agonist, it is more expensive to synthesize and purify these peptides. Furthermore, with higher pharmacokinetic variability and lower bioavailability, this will drive excessive API consumption, resulting in a significant rise in the cost of goods. If a weekly or monthly injectable delivers comparable or better efficacy with lower API demand, more predictable exposure, and similar patient convenience, the oral formulation must demonstrate a clear adherence or market-access advantage to remain viable.^6,7 Ultimately, an oral dosage becomes impractical when the commercial value of convenience no longer compensates for the API multiplier, manufacturing scale, variability, formulation burden, and potential loss of efficacy relative to the injectable.^6,7

When a novel excipient or permeation enhancer doesn’t have a precedent in an approved product, what does the regulatory and safety data package typically require?

First, sponsors should not treat a novel permeation enhancer as a formulation component, but rather a development program of its own. Once an excipient lacks regulatory precedent, agencies typically expect a safety package approaching that of a new molecular entity.^1,8,9 The specific package depends on the route of administration, duration of use, patient population, and expected exposure, but sponsors should expect to generate a comprehensive nonclinical safety package, including basic characterization of the novel excipient, its pharmacokinetics (ADME) and toxicokinetic, general toxicology that supports the intended clinical exposure per ICH principles, genotoxicity, reproductivity and carcinogenicity assessments, and local tolerance studies.⁹

For oral peptides and multiagonist metabolic medicines, regulators frequently focus on long-term gastrointestinal safety because repeated barrier modulation may occur for years using these novel excipients aimed at increasing absorption.^10-12 Reviewers will want evidence that the excipient does not damage epithelial barriers, cause chronic inflammation, disrupt tight junctions irreversibly and increase infection susceptibility.^10-12 As a result, the use of novel excipients can add 12-36 months to development if qualification activities are not initiated early vs using excipients already supported in the FDA Inactive Ingredient Database.¹

What should CMC teams look for when qualifying suppliers of specialty ingredients?

CMC teams should focus less on whether a supplier can meet today’s specification and more on whether they can reliably deliver the same material at commercial scale for the next decade. The highest risks typically arise from molecular variability, inadequate change control, single-sourced raw material supply chain, and limited manufacturing capacity. A supplier should provide multiyear batch history demonstrating trends in critical quality attributes of the ingredient and its process controls, not just compliance with release specifications, as evidence of tight lot-to-lot variation.^13,14

Strong suppliers understand which process variables drive molecular weight, impurity formation, morphology, particle size and release characteristics, and they evaluate process reproducibility, critical process parameters, process validation status and change control procedures when assessing their manufacturing robustness.¹⁴ Novel and specialty excipients often require significant regulatory justification so the supplier should provide GMP documentation, detailed specifications, stability data, and excipient safety assessments.^13,15 It is also important assess quality systems by requesting regulatory inspection history, CAPA effectiveness, deviation trends, complaint management, change control management and data integrity controls.¹⁴

A key supply-chain challenge associated with novel excipients is the lack of qualified alternative suppliers. As these materials are often proprietary, recently developed, or produced using specialized manufacturing processes, supply is frequently concentrated within a single manufacturer or a very limited supplier base. Unlike established excipients, where multiple qualified suppliers may exist, replacing a novel excipient supplier can require extensive comparability, regulatory, and stability assessments.^1,2

CMC teams should evaluate business continuity measures, and the availability of secondary sourcing options early in development to avoid creating a long-term supply bottleneck. Ideally, an alternative supplier should offer geographic diversification to minimize supply risk associated with natural disasters or geopolitical disruptions.^5,14 CMC teams should also employ strategic inventory management and accurate forecasting models to maintain supply continuity where long lead-times can disrupt production schedules.

Additionally, a supplier that can support clinical development may not necessarily be capable of supplying the metric-ton quantities required after launch. Scale-up limitations may create insufficient supply for phase III trials or commercial launch when suppliers are only capable of small-batch production, making early commercial readiness audits critical.² Capacity constraints may lead to allocation shortages during periods of rapid market growth, particularly when adjacent markets compete for the same materials, making long-term supply agreements and capacity reservations important safeguards. CMC teams should evaluate a suppliers current production capacity, expansion potential, commercial campaign size, and capacity utilization, while also confirming that clinical batches are representative of commercial manufacturing and that larger-scale engineering runs have been successfully completed. Given the potential for significant demand growth, suppliers should demonstrate a clear ability to increase capacity by 5-10 times within commercially relevant timelines.^2,5

Which ingredient choices made in early formulation work most often cause problems later in tech transfer or commercial manufacturing?

One of the most common root causes of tech-transfer delays is that a formulation is optimized for proof-of-concept performance rather than manufacturability at scale. Materials that behave well in small laboratory batches may exhibit entirely different processing, stability, and supply-chain characteristics when scaled from grams to kilograms or metric tons. The ingredient choices that create the most downstream CMC challenges are typically those that maximize stability or bioavailability but reduce manufacturability, scalability, or supply robustness. These include peptide stabilizers, novel excipients, complex polymers, and buffer systems optimized at a narrow pH range. Developers can test for these risks and make more informed choices to support commercial success.^2,4

For peptide stabilizers, whether its buffers, surfactants, antioxidants, and chelators, performing stress-test formulations using accelerated aging, agitation studies, and long-term stability evaluation before selecting for the final option.^3,4 Also, if formulators optimize peptide stability using a very narrow pH range, pH deviations during scale-up can significantly accelerate degradation pathways, leading to batch failures, shortened shelf life, and increased out-of-specification investigations. To reduce this risk, a robust pH range should be established rather than relying on a single-point target by conducting pH robustness studies, accelerated stability testing across ±0.2 to 0.5 pH units, and buffer-strength sensitivity assessments. The broader the validated operating range, the smoother the technology transfer process.^4,5

Formulating with novel excipients present more difficult challenges during scale-up because it introduces additional uncertainty across manufacturing, regulatory, supply chain, and product performance dimensions simultaneously.^1,2 Similarly, using complex polymer systems, critical attributes can directly influence product performance, drug release profiles or bioavailability, so it important to establish detailed polymer fingerprinting methods, perform stress testing under commercial processing conditions, conduct release-performance testing, and evaluate multiple production lots early in development.^4,5 Qualification decisions should never be based on a single lot since understanding normal manufacturing variability is essential for long-term product consistency when using novel excipients and complex polymer systems.^2,14 Additionally, materials sensitive to supply variability, particularly natural and biologically derived ingredients, can introduce hidden commercialization risks. Variability in purity, molecular structure, moisture content, or impurity profiles may not be apparent during early development but can significantly affect manufacturing robustness at larger scales. Commercially, this can lead to inconsistent product quality, increased incoming quality control requirements, and reduced yields.

Ultimately, the most successful teams evaluate these risks early through manufacturability studies, multilot testing, scale-down models to identify potential failure points without risking a commercial batch, commercial-equipment simulations, stress testing under commercial processing conditions and supply-chain qualification activities before locking the formulation. This approach helps ensure the formulation is not only stable and efficacious, but also robust enough for global commercial manufacturing.^2,4,5

References

1. United States Pharmacopeia. Novel excipients knowledge hub. USP.org. Published 2026. Accessed Oct 14, 2026. https://www.usp.org/excipients/novel-excipients.

2. International Society for Pharmaceutical Engineering. Good Practice Guide: Technology Transfer. ISPE; 2022. https://ispe.org/publications/guidance-documents/good-practice-guide-technology-transfer-3rd-edition.

3. Zapadka KL, Becher FJ, Gomes Dos Santos AL, Jackson SE. Factors affecting the physical stability (aggregation) of peptide therapeutics. Interface Focus. 2017;7(6):20170030. doi:10.1098/rsfs.2017.0030

4. International Council for Harmonisation. ICH Q8(R2): pharmaceutical development. ICH.org. Published 2009. Accessed Oct 14, 2026. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf.

5. International Council for Harmonisation. ICH Q9(R1): quality risk management. ICH.org. Published 2023. Accessed Oct 14, 2026. https://database.ich.org/sites/default/files/ICH_Q9(R1)_Guideline_Step4_2025_0115.pdf.

6. Abramson A, Halperin F, Kim J, Traverso G. Quantifying the value of orally delivered biologic therapies: a cost-effectiveness analysis of oral semaglutide. J Pharm Sci. 2019;108(9):3138-3145. doi:10.1016/j.xphs.2019.04.022

7. Niazi SK. Oral delivery of peptides and proteins: pharmacokinetic boundaries, negative selection, and route triage. Front Drug Deliv. 2026;6:1776167. doi:10.3389/fddev.2026.1776167

8. Van Norman GA. Drugs, devices, and the FDA: part 1: an overview of approval processes for drugs. JACC Basic Transl Sci. 2019;4(2):170-179. doi:10.1016/j.jacbts.2018.10.005

9. International Council for Harmonisation. ICH M3(R2): nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. ICH.org. Published 2009. Accessed Oct 14, 2026. https://database.ich.org/sites/default/files/M3_R2__Guideline.pdf.

10. Bohley M, Leroux JC. Gastrointestinal permeation enhancers beyond sodium caprate and SNAC: what is coming next? Adv Sci (Weinh). 2024;11(33):e2400843. doi:10.1002/advs.202400843

11. Clinical translation of permeation enhancers. Nat Rev Mater. Published online 2026. doi:10.1038/s41578-026-00954-y

12. Kim JC, Park EJ, Na DH. Gastrointestinal permeation enhancers for the development of oral peptide pharmaceuticals. Pharmaceuticals (Basel). 2022;15(12):1585. doi:10.3390/ph15121585

13. International Pharmaceutical Excipients Council. IPEC Safety Guide for Pharmaceutical Excipients. IPEC Federation; 2021. https://ipec-federation.org/ipec-safety-guide/.

14. International Council for Harmonisation. ICH Q10: pharmaceutical quality system. ICH.org. Published 2008. Accessed Oct 14, 2026. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf.

15. Elder DP, Kuentz M, Holm R. Pharmaceutical excipients and the information paradox. Int J Pharm. 2016;495(2):114-115. doi:10.1016/j.ijpharm.2015.11.039