FDA October 2025 Draft Guidance Sparks Industry Biosimilars Buzz 

The FDA’s October 29, 2025 draft guidance has generated significant attention due to the implications for both developers and patients.  By allowing developers to bypass comparative efficacy studies (CES) when advanced analytics are successful substitutes, the draft guidance avoids one of the most expensive steps, estimated to account for 70% of the total biosimilar development costs (1, 2). This change can cut years from timelines and expand patient access. Additionally, interchangeability studies may rely on analytics as well, signaling an even greater opportunity for broader patient access (3). For developers though, the burden doesn’t disappear; it shifts directly from clinical trials to analytical testing. 

How Large is the Biosimilars Market? 

Extracting insights from Global Data (4), a database that aggregates companies, therapies, and stages shows the massive scale of this market: 

• 415+ parent companies actively developing biosimilars 
• 575 biosimilars marketed globally 
• ~250 companies marketed (released) biosimilars 

Monoclonal antibodies (mAbs) and proteins dominate with blockbuster drugs like trastuzumab, with 40+ marketed biosimilars (4). Because one innovator often spans many biosimilars, the total number of marketed mAbs and biosimilars are nearly equal, but the count of unique therapies is very different.  

Analytical Characterization to Address Regulatory Expectations for Biosimilars Comparability Studies 

The development of a biosimilar is as complicated as the therapy itself. Unlike small-molecule generics, the goal isn’t chemical identity but, instead, demonstrating “highly similar” characteristics to the Reference Biologic (RB) through a comprehensive analytical package. 

Regulators demand scientifically sound, reproducible methods to assess critical quality attributes (CQAs) (1). Minor differences in modifications of the protein backbone and the higher order structure affect immunogenicity and biological activity.

Guidance also emphasizes “Methods that use different physicochemical or biological principles to assess the same attribute are especially valuable” (1).

For example, pairing size-exclusion with UV absorbance detection (SEC-UV) with multi-angle light scattering (MALS) provides an efficient way to meet these expectations.  

The Role of Robust Method Development in Biosimilar QC and Release 

Success in biosimilar development hinges on developing fit-for-purpose methods that can withstand the scrutiny of regulatory review. Key considerations include: 

1. High resolution and mass accuracy: comprehensive comparative analytical studies. Guidance specifically outlines evaluating physicochemical properties–a combination of analytical (e.g., liquid chromatography (LC) and biophysical (e.g., MALS). 
2. Reproducibility: Guidance emphasizes evaluating multiple lots, sites, which can lead into the case for #3 being an enterprise solution. 
3. Streamlined compliance: Integrating analytics with compliance-ready software. 

LC-MS for Biosimilar Intact Mass, Peptide Mapping, and Glycan Analysis 

It is estimated that more than 90% of biosimilar FDA filings include LC and LC-MS data (5). The combination of chromatographic separation and mass accuracy provides the confidence  developers need to assess molecular similarity and accelerate development timelines. Specifically, LC-MS solutions like the BioAccord System support intact analysis and the ACQUITY QDa II Mass Detector helps ensure simpler peptide mapping. These solutions are ideal for:

• Intact and subunit analysis: Confirming mass with high confidence. 
• Peptide mapping: Detailed sequence coverage and unambiguous ID of PTMs. 
• Glycan analysis: Comprehensive profiling to ensure glycan pattern similarity. 

By standardizing and simplifying these complex characterization assays into robust, compliant-ready workflows, development teams gain confidence in their foundational data, starting with the chemistry prep like RapiZyme Kits. 

Biosimilar HOS, Stability, and Particle Analysis Using DSC, MALS, and BMI 

Biosimilarity proof requires robust analysis of the protein’s three-dimensional shape (higher-order structure, or HOS) and stability. MALS, dynamic light scattering (DLS), and differential scanning calorimetry (DSC)— all instruments in the Waters portfolio— support more than 50% of FDA biosimilar filings (5). Critical technology solutions include: 

• Hydrogen deuterium exchange mass spectrometry (HDX-MS) for confirmation of structural similarity 
• Light scattering, DAWN MALS Photometer: Quantify molecular weight, size, and aggregation
• Calorimetry and light scattering, DSC and DynaPro Plate Reader 4 DLS: Assess thermal stability and conformational integrity
• Particle analysis, Aura Backgrounded Membrane Imaging (BMI) System: Characterize and quantify sub-visible particles for safety and regulatory compliance. 

By integrating data from these diverse analytical platforms—from high-resolution mass spectrometry (HRMS) to thermal analysis and particle sizing— developers gain the complete analytical picture required to confidently submit a biosimilar. 

PAT for Biosimilar and Innovator Consistency Under FDA Guidance 

Consistency between a biosimilar and its reference product – and consistency from batch to batch- is essential to avoid triggering regulatory concerns. This requires a tightly controlled and monitored process, enabled by process analytical technology (PAT) for real-time monitoring of CQAs. With tools like PATROL System in place, comparability assays become easier and reduce pressure on final release testing because the product quality is directly measured at the point of manufacture.  

Streamlining Biosimilar Data for Faster Regulatory Submission with Empower CDS 

Empower Chromatography Data System (CDS) integrates and simplifies data acquisition, analysis, and reporting— accelerating regulatory submissions while enhancing traceability, reproducibility, and operational efficiency. LC, simple mass detection, and MALS are all supported by this globally accepted GMP-ready software solution. Investing in integrated analytical systems results in faster submissions due to streamlined data acquisition on the growing number of instruments supported by Empower CDS.  

Advancing Biosimilars with Confident, Analytics-Driven Decisions 

As regulatory expectations evolve, biosimilar developers face increasing pressure to deliver deeper analytical proof faster. Waters technologies enable teams to generate confident, high-quality analytical data across every stage of biosimilar development, from structural confirmation to comparability to QC release. Together, these integrated platforms help developers reduce uncertainty and bring safe, effective biosimilars to patients sooner. 

Visit the Waters Biosimilar page for technical details, methods, case studies and webinars for biosimilar characterization and release. 

Resources

1. FDA Draft Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies, Draft Guidance for Industry, October 29, 2025. Available from FDA. 
2. McKinsey Consulting Company. An inflection point for biosimilars. Editorial. June 7, 2021 | Article Link 
3. FDA Guidance “Considerations for Demonstrating Interchangeability with a Reference Product: Update”. June 2024. Available from FDA.  
4. Global Data. Data extracted October 2025. All molecules indicated as a biosimilar. 
5. Estimates are a combination of multiple references. AI was used to parse 40+ FDA filings and then manually reviewed. The percentage is an estimate from what was extracted from these documents.  

Additional reading: “Handbook of Analytical Techniques in Biopharmaceutical Development” USP, FDA Briefing Documents, Analytical Procedures and Methods Validation for Drugs and Biologics (2015).