Introduction
The Growing Demand for GLP-1 Therapies
Current Manufacturing Challenges
The Future of GLP-1 Manufacturing
Conclusions
With the rising global obesity epidemic and the increasing demand for effective weight-loss treatments, the biopharma industry faces mounting pressure to revolutionize GLP-1 manufacturing to meet growing needs efficiently.
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Introduction
The World Health Organization (WHO) estimates that one in every eight people throughout the world are obese, which equates to about 890 million adults living with obesity. The presence of obesity increases the risk of numerous noncommunicable diseases (NCDs), some of which include cardiovascular disease, diabetes, cancer, neurological disorders, chronic respiratory diseases, and digestive disorders.1
Sustained weight loss of 5-10% has been shown to significantly reduce the risk of developing obesity-related comorbidities, with the risk of developing diabetes reduced by up to 60% in overweight and obese adults who sustained weight loss for at least two years. The wide range of health benefits associated with weight loss among obese individuals has led researchers to investigate different mechanisms and identify pharmacological targets to treat obesity.
Glucagon-like peptide 1 (GLP-1), for example, is a peptide secreted by the gastrointestinal tract in response to food intake, which leads to the secretion of insulin and inhibition of glucagon release, both of which facilitate glucose homeostasis.2
GLP-1 release also slows gastric emptying, reduces appetite, and decreases food intake, thus making this peptide an attractive target for obesity pharmacologics.
GLP-1 receptor agonists (GLP-1RAs) like liraglutide and semaglutide, as well as the dual GLP-1 and gastric inhibitory polypeptide (GIP) agonist tirzerpatide are a class of medications that were historically designed to treat type 2 diabetes.3
During these trials, which investigated the utility of these drugs for glycemic control, GLP-1RAs showed a secondary benefit of weight reduction, which has led to their recent approval for weight management in several countries worldwide.2
What's Next for Semaglutide? Beyond Diabetes and Weight Loss
The Growing Demand for GLP-1 Therapies
In 2023, over 174,000 people in the United States were prescribed GLP-1RAs, a rise of over 700% from 2019, when about 21,000 individuals were prescribed this medication.4 Although GLP-1RAs are expensive medications, they are considered more affordable than surgical weight loss interventions, which typically range between $15,000 and $25,000 USD.
Thus, the affordability, accessibility, and efficacy of these drugs have led financial analysts to predict that the GLP-1RA market will exceed $100 billion by 2030. In fact, about 30 million people in the U.S. are projected to use GLP-1RAs by 2030, which equates to about 9% of its population.5
The recent rise in the demand for GLP-1RAs has led to unexpected drug shortages that have prevented patients who typically use these medications for glycemic management, weight loss, and/or cardiovascular risk reduction from experiencing new challenges in their access to GLP-1RAs.
The reduced availability of these medications, combined with their high cost, has led many patients to seek alternative ways to obtain them, including compounded medications that may not offer the same potency or safety profile as approved drugs. Thus, there remains an urgent need to address these drug shortages through several different strategies.
Current Manufacturing Challenges
The production of GLP-1RAs like semaglutide begins with the culturing of Saccharomyces cerevisiae yeast cells engineered to produce GLP-1. After the yeast cells are fermented, culture broth is harvested and split for further processing, which is followed by the recovery and purification of GLP-1RA precursor molecules from the broth.
Thereafter, the semaglutide precursor undergoes a synthetic modification that transforms the isolated molecule into an active substance that can be subjected to purification.6
Importantly, this method is associated with numerous limitations, including variability between batches, time-consuming requirements, and difficulties in ensuring consistent quality when applied to commercial production settings.
Furthermore, GLP-1RAs produced through biological manufacturing techniques must abide by stringent regulatory standards, including the Good Manufacturing Practices, which are strictly enforced, which further increases the complexity and cost of these production processes as continuous monitoring, documentation, and validation of the processes are required.
The solid-phase peptide synthesis (SPS) method involves fixing the first amino acid of GLP-1 on a polymer and covering the N-terminal with a protecting agent to prevent self-reactions.
Thereafter, the protective group is removed when the subsequent amino acid is added to the sequence, along with a coupling reagent that forms an amide bond between the two newly added amino acids. This process is repeated until all amino acids that comprise GLP-1 are joined together, following which the peptide is purified through high-performance liquid chromatography.7
Despite the utility of this approach, SPS utilizes several organic solvents, including N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, and dichloromethane, all of which are associated with toxic effects following exposure to humans and animals.7
Several efforts have been made to overcome the limitations of current synthesis processes used to prepare semagltuide and other GLP-1RAs. For example, researchers have investigated the potential utility of combining both conventional biological fermentation processes with solid-phase peptide synthesis; however, this approach is not suitable for large-scale production processes.
Continuous vs. Batch Manufacturing: What's the Difference?
The Future of GLP-1 Manufacturing
Several industries have announced novel approaches to address GLP-1RA shortages through novel manufacturing processes. For example, CordenPharma announced a collaboration with PeptiSystems in 2022 that involved a continuous manufacturing synthesis approach for GLP-1RAs that reduces solvent consumption and corresponding waste production by 40%.8
Simultaneously, this technology provides greater synthesis control to the user and creates a more efficient manufacturing process that can support large-scale production needs in a timely manner.
Various industry trends in the biologics field will likely be applied to the production of GLP-1RAs as these technologies advance. For example, artificial intelligence (AI) is expected to accelerate the time-to-market for drug development, including orally bioavailable GLP-1RAs, as compared to current GLP-1RAs that are administered through weekly subcutaneous injections.
The combination of both AI and machine learning may also accelerate protein engineering by providing molecule-level innovations that can improve molecular functions and drug properties for superior therapeutic effects.
Conclusions
Obesity is a global public health issue that can be effectively mitigated through the development of effective medications like GLP-1RAs that are affordable and easily accessible to all.
The widespread prevalence of obesity necessitates production strategies that can meet the growing demand for anti-obesity medications without increasing the carbon footprint of these processes.
Thus, although notable advancements have been made in scaling current production processes, industrial investments into novel biopharmaceutical strategies are urgently needed.
References
- “Obesity and overweight” [Online]. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
- Burcelin, R., & Gourdy, P. (2016). Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obesity Reviews. doi:10.1111/obr.12465.
- Guo, H., Yang, J., Huang, J., et al. (2025). Comparative efficacy and safety of GLP-1 receptor agonists for weight reduction: A model-based meta-analysis of placebo-controlled trials. Obesity Pillars 13. doi:10.1016/j.obpill.2025.100162.
- Mahase, E. (2024). GLP-1 agonists: US sees 700% increase over four years in number of patients without diabetes starting treatment. BMJ. doi:10.1136/bmj.q1645.
- “The increase in appetite for obesity drugs” [Online]. Available from: https://www.jpmorgan.com/insights/global-research/current-events/obesity-drugs.
- “Ozempic” [Online]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/ozempic-epar-public-assessment-report_en.pdf.
- “What making weight-loss drugs means for the environment” [Online]. Available from: https://cen.acs.org/pharmaceuticals/pharmaceutical-chemicals/making-weight-loss-drugs-mean/102/i13.
- “CordenPharma Collaborates on Continuous Peptide Manufacturing & Green Chemistry” [Online]. Available from: https://cen.acs.org/pharmaceuticals/pharmaceutical-chemicals/making-weight-loss-drugs-mean/102/i13.
Further Reading