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A Real-Time NMR Method for Measurement of In Vitro Aggregation Kinetics Of Degarelix Drug Products

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Abstract

Degarelix is a gonadotropin-releasing hormone (GnRH) receptor antagonist. Upon contact with physiological fluid, degarelix undergoes quick gelation and forms a depot at the site of injection providing sustained release. The molecular gelling kinetics is a critical physiochemical quality attribute of degarelix products that may impact drug delivery. However, high-resolution and drug substance (DS)-specific analytical methods for characterizing gelling kinetics of degarelix are still lacking. Accordingly, the current study focused on developing NMR-based methods to characterize in vitro initial aggregation of degarelix in Firmagon® drug product (DP). The high-precision real-time NMR method was demonstrated to quickly differentiate lot to lot differences in degarelix aggregation kinetics, and to reveal the effects of degarelix concentration, pH, salt, and temperature on the kinetics. The results could be useful for quality assurance of degarelix products and facilitate complex generic drug development. The real-time NMR method developed here could also be adopted to other complex DPs that have varied aggregation and release properties.

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Abbreviations

EQ:

Equivalent

DP:

Drug product

DS:

Drug substance

CV:

coefficient of variation

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Acknowledgements

This project was supported, in part, by an appointment (S.M.P) to the Research Participation Program at the CDER administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. FDA.

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Authors and Affiliations

  1. Division of Complex Drug Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Sharadrao M. Patil & Kang Chen

  2. Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drug, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Bin Qin, Yan Wang & Xiaohui Jiang

  3. Division of Complex Drug Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, St. Louis, Missouri, 63110, USA

    Snober Ahmed & Huzeyfe Yilmaz

  4. Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, St. Louis, Missouri, 63110, USA

    David A. Keire

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  1. Sharadrao M. Patil
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  2. Bin Qin
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Correspondence to Kang Chen.

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Patil, S.M., Qin, B., Wang, Y. et al. A Real-Time NMR Method for Measurement of In Vitro Aggregation Kinetics Of Degarelix Drug Products. AAPS PharmSciTech 22, 73 (2021). https://doi.org/10.1208/s12249-021-01948-5

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