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Peptide Manufacturing Scale-Up Challenges

Making a peptide in a lab is chemistry. Making a million doses of it is engineering, economics, and logistics — and the peptide industry is struggling with all three.

Making a peptide in a lab is chemistry. Making a million doses of it is engineering, economics, and logistics — and the peptide industry is struggling with all three. The explosive demand for GLP-1 agonists like semaglutide and tirzepatide has exposed manufacturing bottlenecks that existed quietly for decades. Solid-phase peptide synthesis (SPPS) generates roughly 13,000 kg of waste per kilogram of peptide produced. Purification can triple overall production time. Raw materials account for 60-70% of costs. And the capital expenditures required to build a single production facility can exceed $500 million.

The result is a market where demand has outpaced supply capacity, driving the largest capital investments in pharmaceutical manufacturing history and forcing the industry to rethink how peptides are made.

Table of Contents

The Scale of the Problem

The global peptide synthesis market was valued at $667 million in 2024 and is projected to reach $1.93 billion by 2033, growing at 12.5% annually. Meanwhile, the broader peptide therapeutics market is expected to roughly double from $46 billion in 2024 to $100 billion by 2034.

Those growth numbers sound promising until you realize what they demand from manufacturing. Unlike small-molecule drugs that can be synthesized in standard chemical reactors with established processes, peptides require specialized equipment, exotic reagents, and purification steps that don't scale linearly. A sequence that works at milligram quantities in a university lab may behave unpredictably at kilogram scale — different aggregation patterns, different impurity profiles, different yields.

The metabolic diseases segment alone captures more than 60% of the peptide therapeutics market in 2025, driven almost entirely by GLP-1 receptor agonists for obesity and diabetes. This concentration of demand in a single drug class has created a manufacturing bottleneck that the industry is scrambling to resolve.

SPPS: The Workhorse That Struggles at Scale

Solid-phase peptide synthesis, developed by Bruce Merrifield in the 1960s (earning him the 1984 Nobel Prize), remains the dominant manufacturing method for therapeutic peptides. The basic process is elegant: amino acids are added one at a time to a growing peptide chain anchored to a solid resin, with each coupling step followed by washing and deprotection.

At laboratory scale, it works beautifully. At manufacturing scale, the problems multiply.

The Waste Problem

SPPS is extraordinarily solvent-intensive. The process relies on solvents at nearly every step — activating coupling reactions, rinsing away byproducts, and cleaving the completed peptide from the resin. According to industry analyses reported by Syngene International, SPPS generates roughly 13,000 kg of waste per kilogram of peptide produced. For comparison, small-molecule API synthesis generates 168-308 kg of waste per kilogram of product.

That's not a typo. Making one kilogram of a therapeutic peptide generates approximately 13 metric tons of solvent waste. This inflates disposal costs, creates environmental compliance challenges, and requires massive solvent storage and handling infrastructure.

The Length Problem

Scale-up headaches intensify beyond 30 amino acids. Semaglutide contains 31 amino acids. Tirzepatide contains 39. As chain length increases, incomplete couplings and deletion sequences — where an amino acid fails to attach and the chain continues without it — become increasingly common.

These deletion sequences are structurally similar enough to the target peptide that they're difficult to remove during purification but different enough to compromise therapeutic efficacy and safety. At production scale, even a 99% coupling efficiency per step translates to significant impurity levels over 30+ steps: 0.99^30 = 0.74, meaning only 74% of chains are the correct full-length sequence.

The Predictability Problem

A sequence that performs well at tens of micromoles may behave unpredictably at multi-gram or kilogram scale. Aggregation behavior changes. Heat dissipation differs. Mixing dynamics shift. The large-scale manufacture of complex synthetic peptides is challenging due to manufacturing risk — including failed product specifications — as well as processes that are often low in both yield and overall purity.

Eli Lilly's published process for kilogram-scale tirzepatide manufacturing addressed some of these challenges through a hybrid SPPS/LPPS (liquid-phase peptide synthesis) approach combined with continuous manufacturing techniques. But developing such processes takes years of optimization and represents proprietary know-how that isn't easily transferred between manufacturers.

Purification Bottlenecks

If synthesis is the heart of peptide manufacturing, purification is the bottleneck. After SPPS produces a crude peptide mixture — containing the target sequence along with deletion sequences, truncated products, and other impurities — preparative high-performance liquid chromatography (HPLC) must separate the desired product to pharmaceutical purity (typically >98%).

Time and Solvent Consumption

Purification can triple overall production time. Preparative HPLC cycles consume large volumes of organic solvents (primarily acetonitrile), running columns that may be several feet in diameter for production-scale batches. Each purification run takes hours, and complex peptides may require multiple passes to achieve target purity.

According to a 2024 report on peptide therapeutics manufacturing, companies must invest heavily in advanced purification systems to meet stringent regulatory requirements. The equipment alone costs millions, and the operating costs — primarily solvents and column media — are substantial.

Emerging Purification Technologies

Multicolumn gradient chromatography technologies promise to cut solvent consumption by roughly 50%, but adoption remains limited. Continuous chromatography, which enables constant downstream processing rather than batch-by-batch purification, could transform throughput. Though not yet widespread among GLP-1 manufacturers, continuous purification represents the clearest path to solving the downstream bottleneck.

GLP-1 Manufacturing Demand: An Unprecedented Surge

The GLP-1 revolution created a manufacturing demand unlike anything the peptide industry had seen. Before semaglutide's weight-loss approval, the largest peptide manufacturing campaigns served relatively small patient populations — growth hormone deficiency, neuroendocrine tumors, HIV lipodystrophy.

Then tens of millions of people wanted a weight-loss injection.

The GLP-1 peptide synthesis CDMO (contract development and manufacturing organization) market has become one of the fastest-growing segments in pharmaceutical outsourcing. Manufacturers that had been running at comfortable utilization rates suddenly couldn't keep up. Novo Nordisk, the maker of Ozempic and Wegovy, reported persistent supply constraints. Eli Lilly, maker of Mounjaro and Zepbound, invested $5.3 billion in a single Indiana manufacturing plant in 2024.

The demand spike was compounded by the clinical expansion of GLP-1 agonists beyond diabetes and obesity. The SELECT trial led to semaglutide's cardiovascular risk reduction approval in March 2024. Tirzepatide received historic FDA approval in December 2024 for obstructive sleep apnea. Each new indication expanded the eligible patient population, putting additional pressure on manufacturing capacity.

The Cost Drivers

Peptide manufacturing costs are driven by several factors that interact in ways not typical of conventional pharmaceuticals.

Raw Materials (60-70% of COGS)

Raw materials account for 60-70% of cost of goods sold for synthetic peptides. This includes protected amino acids (which are themselves expensive to manufacture), coupling reagents, resins, solvents, and cleavage cocktails. Specialized amino acids — such as the non-natural amino acids used in semaglutide's modification — can be orders of magnitude more expensive than standard building blocks.

Supply chain concentration amplifies the risk. Several key amino acid suppliers operate at near-capacity, meaning any disruption — a factory issue, a shipping delay, a quality failure — ripples through the entire peptide manufacturing ecosystem.

Capital Expenditure

Building a dedicated peptide manufacturing facility is a massive capital investment. CordenPharma's new Swiss greenfield facility cost over 500 million euros. The company's total peptide platform investment exceeds 1 billion euros across facilities in Colorado, Frankfurt, and Switzerland.

For smaller CDMOs, the economics are punishing. Capital expenditures for dedicated kilogram-scale labs often exceed $50 million, stretching break-even timelines that can make investors nervous.

Regulatory Compliance

Peptide manufacturing must meet current Good Manufacturing Practice (cGMP) standards, which require validated processes, documented procedures, environmental controls, and quality testing at every stage. The regulatory burden is proportionally heavier for peptides than for small molecules because of the greater analytical complexity — confirming that a 31-amino-acid chain is correct at every position requires sophisticated analytical methods including mass spectrometry, HPLC, and amino acid analysis.

The FDA approved four novel peptide therapeutics in 2024, maintaining its fast-track pathways for complex peptides. But the regulatory review process itself adds time and cost to the manufacturing equation.

Capacity Constraints and Capital Response

The industry's response to the manufacturing crisis has been unprecedented investment. Here are the major expansion programs underway:

CordenPharma: The German CDMO announced a record 900 million euro investment in July 2024, later expanded to over 1 billion euros. The program includes:

  • A new greenfield facility near Basel, Switzerland (>500 million euros) with SPPS reactor capacity exceeding 5,000 liters
  • Colorado (US) expansion adding 25,000 liters of SPPS capacity, bringing total reactor capacity to over 42,000 liters by 2028
  • Multi-year contracts totaling 3 billion euros with additional upside

Bachem: The Swiss CDMO is advancing a major expansion at its Bubendorf site, with test batches from new capacity expected from Q2 2025. A second site at Sisslerfeld provides up to 155,000 square meters for long-term expansion. Bachem acquired additional land in 2024 and plans to submit construction applications in 2025.

SK pharmteco: Invested $260 million in September 2024 for a new 135,800-square-foot facility in Sejong, South Korea.

PolyPeptide Laboratories: Announced a 100 million euro expansion in January 2025 to double SPPS capacity at its Malmo, Sweden manufacturing site.

Eli Lilly (in-house): Invested $5.3 billion in a new Indiana manufacturing plant to meet demand for Mounjaro and Zepbound.

Switzerland alone attracted CHF 2.7 billion in biotech investment in 2024, with CordenPharma and Bachem both establishing large-scale operations near Basel.

In February 2025, Granules India acquired Swiss peptide manufacturer Senn Chemicals AG, signaling that emerging market pharmaceutical companies see peptide manufacturing as a strategic growth area.

Emerging Solutions

The manufacturing challenges have spurred technical innovation across the production chain.

Hybrid Synthesis: SPPS + Enzymatic Ligation

The most promising near-term solution combines traditional SPPS for building short peptide fragments (10-15 amino acids each) with enzymatic ligation to stitch those fragments together. Enzymatic ligation offers near-perfect stereoselectivity under ambient conditions, producing fewer byproducts and easing downstream purification.

This modular strategy lets manufacturers leverage the reliability of SPPS for short sequences — where coupling efficiency is high — while avoiding the yield collapse that occurs when trying to synthesize long sequences in a single SPPS run. Hybrid chemo-enzymatic routes have already produced stable lasso peptides with improved oral bioavailability, according to a review of emerging peptide technologies.

Microwave-Assisted SPPS

Microwave-assisted synthesis has compressed reaction times from hours to minutes while lifting crude purities above 90%. The faster cycle times mean more batches per day from the same equipment, effectively increasing capacity without building new facilities. Several CDMOs have retrofitted existing production lines with microwave capabilities.

Continuous Manufacturing

The transition from batch to continuous manufacturing — already underway in small-molecule pharmaceuticals — is reaching peptide production. Continuous flow synthesis offers better heat management, more consistent mixing, and potentially higher yields at scale. Eli Lilly's published tirzepatide process incorporated continuous manufacturing elements, demonstrating feasibility for commercial-scale peptides.

Flow Chemistry

Related to continuous manufacturing, flow chemistry approaches run SPPS in continuous-flow reactors rather than traditional batch vessels. This provides better control over temperature, mixing, and reagent exposure — all variables that become harder to manage in large-batch SPPS.

Automated and AI-Assisted Process Development

Automation and machine learning approaches are being applied to process optimization. AI models can predict which synthesis conditions will maximize yield for a given sequence, reducing the trial-and-error cycles that traditionally extend process development timelines.

The Workforce Problem Nobody Talks About

Manufacturing capacity isn't just about reactors and buildings. It's about people.

Tight labor markets have doubled average recruitment lead times for senior chromatographers, according to industry reports. Salary inflation for experienced peptide synthesis chemists and purification specialists has exceeded broader pharmaceutical industry averages.

CordenPharma's Swiss expansion alone expects to generate over 300 new jobs — skilled positions that require specialized training in peptide synthesis, analytical chemistry, and cGMP operations. Across the industry, the simultaneous expansion of multiple major facilities is creating a talent competition that could become the binding constraint on manufacturing growth.

What This Means for Drug Prices and Access

Manufacturing costs directly affect drug prices, and peptide manufacturing is expensive. The cost structure — high raw material inputs, capital-intensive facilities, solvent-heavy processes, and complex purification — contributes to the high prices of drugs like Ozempic ($900+ per month at list price in the US before recent discount programs) and Mounjaro.

The capacity investments underway should improve the supply-demand balance by 2027-2028, potentially enabling more competitive pricing. Oral formulations like orforglipron — which is a small molecule rather than a peptide — could bypass some of these manufacturing challenges entirely, offering a different cost structure.

Generic peptide manufacturing (biosimilar peptides, technically) represents another potential cost relief mechanism, though the analytical complexity of proving peptide equivalence creates its own regulatory and manufacturing challenges.

For now, the manufacturing bottleneck is one reason why peptide therapeutics remain expensive — and why the industry is spending billions to solve it.

FAQ

Why can't peptide manufacturing just scale up like regular drugs?

Peptides are fundamentally different from small-molecule drugs. They're made by adding amino acids one at a time in a specific sequence, with each step requiring coupling reactions, washing, and deprotection. The process generates enormous amounts of solvent waste (roughly 13,000 kg per kg of product), coupling efficiency decreases with chain length, and the crude product requires extensive HPLC purification. These challenges don't exist in traditional pharmaceutical manufacturing.

How much does it cost to build a peptide manufacturing facility?

Major facilities cost hundreds of millions to billions of dollars. CordenPharma's Swiss greenfield site exceeds 500 million euros. Eli Lilly invested $5.3 billion in a single plant. Even smaller dedicated kilogram-scale labs typically exceed $50 million in capital expenditure. These costs reflect the specialized equipment (large-scale SPPS reactors, preparative HPLC systems), environmental controls, and cGMP compliance requirements.

Will the manufacturing bottleneck ease?

Industry projections suggest significant capacity additions by 2027-2028 as current expansion projects come online. CordenPharma's Swiss facility targets commercial operations in the first half of 2028. Bachem's expansions are progressing through 2025. However, if GLP-1 demand continues growing — with new indications, new markets, and new drugs — the race between demand and capacity may continue.

What makes GLP-1 agonists particularly difficult to manufacture?

GLP-1 agonists like semaglutide (31 amino acids) and tirzepatide (39 amino acids) are at the upper end of what SPPS handles well. They also incorporate non-natural modifications — fatty acid chains for albumin binding, amino acid substitutions for DPP-4 resistance — that require specialized raw materials and additional synthesis steps. The sheer volume of demand adds another layer: manufacturing capacity that was adequate for smaller patient populations is overwhelmed by the tens of millions of potential GLP-1 users.

Are there alternatives to SPPS for making peptides?

Yes, and they're gaining traction. Hybrid approaches combine SPPS for short fragments with enzymatic ligation for assembly. Recombinant expression in bacteria or yeast is used for some peptides, though it can't incorporate non-natural amino acids. Flow chemistry and continuous manufacturing improve on batch SPPS. And for the next generation of oral GLP-1 agonists like orforglipron, which are small molecules rather than peptides, traditional chemical synthesis applies — potentially a major cost advantage.

The Bottom Line

The peptide manufacturing industry is in the middle of its most dramatic transformation since Merrifield invented solid-phase synthesis. Demand from GLP-1 agonists has exposed every weakness in the existing production infrastructure — solvent-heavy processes, purification bottlenecks, high raw material costs, and insufficient global capacity.

The response has been massive. Over $10 billion in combined capital investment is flowing into new facilities, equipment upgrades, and workforce expansion across the US, Europe, and Asia. Technical solutions — hybrid synthesis, enzymatic ligation, continuous manufacturing, and microwave-assisted SPPS — are moving from academic proof-of-concept to commercial implementation.

The fundamental challenge remains: peptides are complex molecules that resist the economies of scale that make small-molecule drugs cheap. Every innovation that improves yield, reduces waste, or increases throughput matters — not just for pharmaceutical companies' margins, but for the millions of patients whose access to transformative therapies depends on whether the manufacturing can keep up with the science.

References

  1. CordenPharma. "CordenPharma Invests €900 Million in Transformational Peptide Platform Expansion." Press Release. July 2024. CordenPharma

  2. CordenPharma. "CordenPharma Expands Peptide Platform with >€500 Million Greenfield Facility Construction near Basel, Switzerland." Press Release. March 2025. CordenPharma

  3. Syngene International. "Peptide synthesis and the hidden complexities of scaling peptide therapeutics." 2024. Syngene

  4. Spare NJ, et al. "Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing." Organic Process Research & Development. 2021. ACS

  5. PharmaSource. "Peptide Therapeutics Manufacturing: A comprehensive guide." 2024. PharmaSource

  6. CRB Group. "The GLP-1 boom: Challenges, trends, and CapEx strategies for manufacturers." 2024. CRB

  7. Grand View Research. "Peptide Synthesis Market Size, Share & Trends Analysis Report." 2025. Grand View Research

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  9. GlobeNewsWire. "Peptide Synthesis Market Research Report 2026: Automated Technologies and CDMO Expansion Drive Growth." February 2026. GlobeNewsWire

  10. Zhang Y, et al. "From precision synthesis to cross-industry applications: The future of emerging peptide technologies." Pharmacological Research. 2025. ScienceDirect

  11. InsightAce Analytic. "GLP-1 Peptide Synthesis CDMO Market Size, Share and Scope to 2034." 2025. InsightAce