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A survey of FDA Approved Monoclonal Antibodies and Fc-fusion Proteins for Manufacturing Changes and Comparability Assessment

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Abstract

Objective

Manufacturing changes occur commonly throughout stages of biologics development and may result in product quality attribute changes. As changes in critical quality attributes have the potential to affect clinical safety and efficacy of products, it is imperative to ensure the quality and clinical performance before introducing the after-change products. Thus, we embarked on this project to understand what data have supported the manufacturing changes for licensed products with pre- and post-approval changes.

Methods

We surveyed the manufacturing changes of 85 monoclonal antibodies and 10 Fc fusion proteins approved by the Food and Drug Administration as of December 25, 2021. After collecting the type and timing of changes for these products, we investigated the approaches that provided supporting data for the changes. The source documents included reports submitted by applicants and FDA’s regulatory reviews.

Results

Analytical comparability was assessed to support all identified manufacturing changes. Supporting clinical data were available in 92% of these manufacturing changes; including data from pharmacokinetic comparability studies alone (3%), other studies on efficacy or safety (70%) and a combination of both (19%). Clinical pharmacokinetic comparability data contributed to supporting substantial changes, such as host cell type or master cell bank changes, concentration or formulation changes, and changes from pre-filled syringes to autoinjectors, especially when introduced after completing pivotal studies.

Conclusion

Our comprehensive retrospective analysis provides an understanding of the regulatory experience and industry practice, which could facilitate develo** appropriate comparability approaches to support manufacturing changes in the future.

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Data Availability

The data used to generate Fig. 1, Fig. 2, and Table III are available in Supplemental Table S2. The source data of Supplemental Table S2 and all the other figures and tables are composed in part of proprietary information in the regulatory submissions and in part of publicly available information in the following two sources:

• Purple Book Database of Licensed Biological Products (https://purplebooksearch.fda.gov/)

• Labels and reviews in the citation retrievable at Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/)

Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

AI:

Autoinjector

BE:

Bioequivalence

BLA:

Biological license application

CI:

Confidence interval

CMC:

Chemistry, Manufacturing, and Controls

CQA:

Critical quality attributes

DS:

Drug substance

DP:

Drug product

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

GMR:

Geometric mean ratios

ICH:

International Conference on Harmonisation

IV:

Intravenous

pI :

Isoelectric point

MCB:

Master cell bank

FcRn:

Neonatal Fc receptor

PK:

Pharmacokinetics

PD:

Pharmacodynamics

PFS:

Prefilled syringe

SC:

Subcutaneous

sBLA:

Supplemental BLA

WCB:

Working cell bank

WHO:

World Health Organization

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Funding

This project was supported, in part, by an appointment to the ORISE Research Fellowship Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

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Authors and Affiliations

  1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (OCP/CDER/FDA), 10903 New Hampshire Avenue, Silver Spring, MD, USA

    Zhe Li, **ulian Du & Yow-Ming C. Wang

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  1. Zhe Li
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  3. Yow-Ming C. Wang
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Contributions

YMW contributed substantially to the conception and design of the work. ZL collected and analyzed the data and drafted the manuscript. All authors contributed to the interpretation of the data and critical editing of the manuscript with important intellectual content.

Corresponding author

Correspondence to Zhe Li.

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Disclosure

This article has been reviewed by FDA and determined to reflect the views of the authors but not the Agency. It should not be construed to represent FDA’s views or policies. The authors report no conflict of interest. We acknowledge Drs. Leopold Kang, Haoheng Yan, for their valuable input to this project and Drs. Amy Hsu, Shiew-Mei Huang, and Sarah Ridge for their constructive feedback on the manuscript.

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Li, Z., Du, X. & Wang, YM.C. A survey of FDA Approved Monoclonal Antibodies and Fc-fusion Proteins for Manufacturing Changes and Comparability Assessment. Pharm Res 41, 13–27 (2024). https://doi.org/10.1007/s11095-023-03627-5

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  • DOI: https://doi.org/10.1007/s11095-023-03627-5

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