USFDA Guidances: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment, Other Quality-Related Considerations & Classification Categories for Certain Supplements
- Sharan Murugan
- Sep 9
- 2 min read
In 08 September 2025, the U.S. Food and Drug Administration (FDA) issued two final guidances addressing critical aspects of biosimilar development and lifecycle management. The first focuses on comparative analytical assessments for therapeutic protein biosimilars, while the second introduces classification categories for supplements under BsUFA III.
Together, these documents enhance regulatory clarity and streamline review processes for biosimilar and interchangeable biosimilar products.
Guidance: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations
This guidance outlines FDA’s recommendations for the comparative analytical studies required to demonstrate that a proposed therapeutic protein is biosimilar to a licensed reference product under section 351(k) of the Public Health Service (PHS) Act.
Key Elements:
Analytical Foundation of Biosimilarity: Comparative physicochemical and biological testing forms the backbone of biosimilar evaluation, shaping subsequent nonclinical and clinical requirements.
Critical Quality Attributes: Sponsors must assess molecular structure (primary to quaternary), post-translational modifications, functional activities, impurities, and stability.
Reference and Comparator Products: Emphasis on characterizing both U.S.-licensed reference products and, when used, non-U.S.-licensed comparator products, with clear justification for bridging studies.
Manufacturing and Expression Systems: Guidance highlights the role of expression systems and process-related differences, recommending minimization of variability where possible.
Risk-Based Data Analysis: Sponsors are expected to integrate quantitative and qualitative analyses, with emphasis on orthogonal methods and sensitivity to clinically meaningful differences.
CMC Considerations: A robust Chemistry, Manufacturing, and Controls (CMC) package is essential, with validated analytical methods and comprehensive reference material qualification.
In summary, FDA reinforces that comparative analytical data provide the cornerstone for biosimilar development, influencing the scope of required clinical studies and enabling more efficient regulatory pathways.
This guidance introduces six supplement categories (A–F) under the Biosimilar User Fee Amendments of 2022 (BsUFA III), aligning review goals with the type of change proposed to an approved 351(k) Biologics License Application (BLA).
Supplement Categories:
Category A – Safety information updates consistent with reference product labeling.
Category B – Additional indications without new datasets (except analytical justifications).
Category C – Removal of previously approved indications.
Category D – Additional indications requiring new datasets or pediatric study plan updates.
Category E – Additional indications supported by efficacy datasets.
Category F – Determination of interchangeability.
Performance Goals:
Categories A–D: FDA aims to act within 3–6 months after submission.
Categories E–F: More complex reviews with 10-month timelines, reflecting the need for full clinical datasets or interchangeability demonstrations.
Procedural Highlights:
Applicants must clearly identify the supplement category in their Form FDA 356h and cover letter.
FDA may reclassify a submission if necessary, ensuring consistency across divisions.
Labeling updates must align with physician labeling rules and biosimilar labeling guidances.
By establishing clear supplement classifications and timelines, FDA provides predictability for industry while ensuring regulatory rigor for biosimilars.
Together, these guidances will support the growth of the U.S. biosimilar market, fostering competition, access, and innovation while safeguarding patient safety and treatment efficacy.
For more details, access the FDA guidances:
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