How GLP-1 Drugs Are Analyzed: Chromatography & Mass Spectrometry Explained

🎤Kelly Broster McMahon (Senior Manager of Market Development and Collaborations at Thermo Fisher Scientific). 

Kelly has over 15 years of experience in LC-MS and protein mass spectrometry. Her work focuses on translating complex analytical challenges into scalable, compliant workflows for the biopharmaceutical industry.

In this episode of Concentrating on Chromatography, we sit down with Kelly Broster McMahon to explore the analytical science behind one of the most important pharmaceutical trends today: GLP-1 therapeutics.

Drugs like Semaglutide have transformed the treatment of diabetes and obesity—but ensuring their safety, efficacy, and quality requires cutting-edge analytical workflows.

In this conversation, we break down how chromatography and high-resolution mass spectrometry (LC-MS) work together to characterize complex peptide therapeutics, detect trace-level impurities, and support drug development from early research through regulated manufacturing.

What You’ll Learn

• Why GLP-1 drugs are uniquely challenging to analyze
• How LC-MS enables detailed peptide characterization
• The importance of detecting low-level impurities for patient safety
• How analytical workflows scale from R&D to manufacturing
• The role of software and data platforms in modern labs
• Where chromatography and mass spectrometry are heading next

Key Takeaways

• GLP-1 therapeutics are a “proof point” for the future of analytical chemistry—where success depends not on measuring more, but on measuring the right things earlier, with confidence.
• As molecules become more complex, integrated workflows combining chromatography, high-resolution mass spectrometry, and advanced informatics are becoming essential to ensure data integrity, regulatory compliance, and ultimately, patient safety.

Video Transcription

In this episode, Kelly, Senior Manager of Market Development and Collaborations at Thermo Fisher Scientific, discusses the analytical challenges associated with GLP-1 peptide therapeutics and explains how modern chromatography, high-resolution mass spectrometry, software, and data platforms are shaping the future of biopharmaceutical development. Drawing on more than 15 years of experience in LC-MS and protein mass spectrometry, she shares insights into peptide characterization, impurity profiling, workflow continuity, and the growing role of AI in analytical science.

Kelly's Background in Biopharmaceutical Analysis

Kelly currently focuses on biopharmaceutical development at Thermo Fisher Scientific, working closely with industry partners to transform complex analytical challenges into scalable and compliant workflows. Her scientific background includes cancer biology, quantitative proteomics, biomarker assays, systems oncology, and mass spectrometry-based drug discovery. Throughout her academic and industrial career, she has applied mass spectrometry to support patient stratification, treatment monitoring, and therapeutic development.

Why GLP-1 Therapeutics Are So Important Right Now

GLP-1 drugs have become one of the most discussed therapeutic classes because they occupy a unique space between traditional small molecules and large biologics. Their structural complexity, sensitivity to degradation, and global manufacturing scale make them an ideal example of how analytical science must evolve.

According to Kelly, these molecules require greater analytical sensitivity, deeper structural characterization, and seamless workflows that support everything from discovery through manufacturing and regulatory submission.

Analytical Challenges of Peptide Therapeutics

Unlike conventional small molecules, peptide drugs such as semaglutide are larger, conformationally dynamic, and often chemically modified to improve stability, half-life, and absorption.

These therapeutics may contain:

• Sequence variants
• Oxidation products
• Deamidation products
• Aggregates
• Trace-level impurities

Many of these species are difficult to separate chromatographically and challenging to identify confidently. As a result, peptide characterization requires both highly selective chromatography and high-resolution accurate-mass spectrometry.

What GLP-1 Drugs Teach Us About the Future of Analytical Science

Kelly emphasized that the future of analytical science is not necessarily about generating more data but about measuring the right attributes earlier and with greater confidence.

GLP-1 developers increasingly require integrated analytical workflows that generate actionable insights during discovery while remaining robust enough to support late-stage development, manufacturing, and global regulatory filings. This trend highlights the growing importance of scalable and harmonized analytical ecosystems.

Why Small Molecular Changes Matter

Even a single amino acid substitution or post-translational modification can dramatically alter a peptide's biological behavior.

Minor structural changes may affect:

• Receptor binding
• Potency
• Stability
• Immunogenicity

Because these changes can directly influence safety and efficacy, regulatory agencies require precise structural characterization and control throughout development and manufacturing.

The Power of Combining Chromatography and Mass Spectrometry

For complex peptide therapeutics, chromatography and mass spectrometry work together to provide comprehensive characterization.

Chromatography separates complex mixtures and resolves closely related species, while high-resolution mass spectrometry provides molecular specificity and structural confirmation. Together, advanced UHPLC and HRAM MS deliver the selectivity, sensitivity, and confidence required for modern peptide analysis.

The Value of High-Resolution Accurate-Mass Spectrometry

Kelly described high-resolution accurate-mass (HRAM) mass spectrometry as an indispensable technology for drug development.

Compared with older analytical approaches, HRAM provides:

• Exact mass measurements
• Isotopic resolution
• Structural confirmation
• Trace impurity detection
• Identification of sequence variants
• Characterization of post-translational modifications

These capabilities enable confident data generation that can withstand regulatory scrutiny, audits, and global submissions.

Why Sensitivity Is Critical

The distinction between a safe and unsafe therapeutic can exist at extremely low concentration levels.

Detecting impurities at parts-per-billion levels allows developers to identify risks early in development and address them before manufacturing scale-up. Analytical sensitivity therefore supports both regulatory confidence and patient safety.

Resolving Co-Eluting Impurities

One of the greatest challenges in peptide analysis is distinguishing nearly identical molecular species.

By combining ultra-high-resolution mass spectrometry with optimized chromatographic separations, scientists can accurately differentiate closely related compounds and remove uncertainty from impurity profiling. This capability is essential for both regulatory submissions and therapeutic safety assessments.

Workflow Continuity Across Drug Development

Kelly stressed that analytical methods should not be reinvented at every stage of development.

Instead, workflows should transition smoothly from:

• Research and discovery
• Development
• Quality control
• Manufacturing

Maintaining continuity improves reproducibility, preserves data integrity, and enables scalable development without disrupting analytical performance.

The Evolution of Instruments, Software, and Data Platforms

Modern analytical ecosystems extend beyond LC-MS instrumentation alone.

Today's workflows integrate:

• Consumables
• Chromatography systems
• Mass spectrometers
• Informatics platforms

Instrumentation continues to become faster, more sensitive, and capable of higher throughput, while advanced software transforms complex datasets into actionable insights. These integrated platforms support compliance, traceability, and harmonized global operations.

Data Integrity and Regulatory Compliance

As drug development becomes increasingly global, maintaining data integrity is more important than ever.

Validated software systems, secure data management tools, and comprehensive audit trails help organizations harmonize workflows across multiple sites while ensuring that generated data can withstand regulatory review worldwide.

Lessons for Next-Generation Biologics

Although GLP-1 therapeutics are currently in the spotlight, Kelly believes the broader lesson is that molecular complexity is increasing across all therapeutic classes.

This includes:

• Peptides
• Monoclonal antibodies
• Fusion proteins
• Advanced biologics

Across all these modalities, the need for deeper molecular understanding, early risk detection, and scalable analytical control continues to grow.

Biosimilars, Generics, and Equivalence Testing

As GLP-1 patents expire, analytical science will play a crucial role in establishing biosimilarity and equivalence.

Developers must demonstrate rigorous structural and functional comparability between original products and follow-on versions. High-resolution analytical platforms provide the depth of characterization required to prove equivalence while protecting patient safety and therapeutic efficacy.

Future Opportunities in Chromatography and Mass Spectrometry

Looking ahead, Kelly sees significant innovation opportunities in:

• Greater integration of analytical platforms
• Faster chromatographic separations
• Enhanced multiplexing
• Smarter data analytics
• Increased automation
• Real-time process monitoring
• Process analytical technologies (PAT)

These developments will bring analytical insights closer to manufacturing environments and improve efficiency across the drug development lifecycle.

The Next 5–10 Years

Over the next decade, Kelly expects analytical workflows to become:

• More predictive
• More automated
• More interconnected
• Increasingly supported by AI-driven interpretation

However, she emphasized that these advances must remain grounded in high-quality analytical data generated by ultra-high-resolution instrumentation.

Final Thoughts

Kelly concluded by highlighting the critical role analytical scientists play in enabling patient access to safe and effective medicines. By identifying hidden risks, characterizing complex molecules, and supporting innovation without compromising scientific rigor, analytical science remains a cornerstone of modern drug development and aligns directly with Thermo Fisher Scientific's mission of making the world healthier, cleaner, and safer.

This text has been automatically transcribed from a video presentation using AI technology. It may contain inaccuracies and is not guaranteed to be 100% correct.

Concentrating on Chromatography Podcast

Dive into the frontiers of chromatography, mass spectrometry, and sample preparation with host David Oliva. Each episode features candid conversations with leading researchers, industry innovators, and passionate scientists who are shaping the future of analytical chemistry. From decoding PFAS detection challenges to exploring the latest in AI-assisted liquid chromatography, this show uncovers practical workflows, sustainability breakthroughs, and the real-world impact of separation science. Whether you’re a chromatographer, lab professional, or researcher you'll discover inspiring content!

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