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Best Practices for Submission of NMR Data to Support Higher Order Structure Assessment of Generic Peptide Drugs

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References

  1. Muttenthaler M, King GF, Adams DJ, Alewood PF. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021;20(4):309–25.

    Article  CAS  PubMed  Google Scholar 

  2. de la Torre BG, Albericio F. Peptide Therapeutics 2.0. Molecules (Basel, Switzerland). 2020;25(10):2293.

  3. The “Deemed To Be a License” provision of the BPCI Act Questions and Answers Guidance for Industry. Health and Human Services. 2020. https://www.fda.gov/media/135838/download. Accessed 11 Jan 2023.

  4. Patil SM, Keire DA, Chen K. Comparison of NMR and dynamic light scattering for measuring diffusion coefficients of formulated insulin: implications for particle size distribution measurements in drug products. AAPS J. 2017;19(6):1760–6.

    Article  CAS  PubMed  Google Scholar 

  5. Wang D, Zhuo Y, Karfunkle M, Patil SM, Smith CJ, Keire DA, et al. NMR spectroscopy for protein higher order structure similarity assessment in formulated drug products. Molecules (Basel, Switzerland). 2021;26(14):4251.

  6. Lee SL, Yu LX, Cai B, Johnsons GR, Rosenberg AS, Cherney BW, et al. Scientific considerations for generic synthetic salmon calcitonin nasal spray products. AAPS J. 2011;13(1):14–9.

    Article  CAS  PubMed  Google Scholar 

  7. Motta A, Pastore A, Goud NA, Castiglione Morelli MA. Solution conformation of salmon calcitonin in sodium dodecyl sulfate micelles as determined by two-dimensional NMR and distance geometry calculations. Biochemistry. 1991;30(43):10444–50.

    Article  CAS  PubMed  Google Scholar 

  8. Wagman ME, Dobson CM, Karplus M. Proton NMR studies of the association and folding of glucagon in solution. FEBS Lett. 1980;119(2):265–70.

    Article  CAS  PubMed  Google Scholar 

  9. Sasaki K, Dockerill S, Adamiak DA, Tickle IJ, Blundell T. X-ray analysis of glucagon and its relationship to receptor binding. Nature. 1975;257(5529):751–7.

    Article  CAS  PubMed  Google Scholar 

  10. Gelenter MD, Smith KJ, Liao S-Y, Mandala VS, Dregni AJ, Lamm MS, et al. The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations. Nat Struct Mol Biol. 2019;26(7):592–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zapadka KL, Becher FJ, Gomes dos Santos AL, Jackson SE. Factors affecting the physical stability (aggregation) of peptide therapeutics. Interface Focus. 2017;7(6):20170030.

  12. Aubin Y, Hodgson DJ, Thach WB, Gingras G, Sauvé S. Monitoring effects of excipients, formulation parameters and mutations on the high order structure of filgrastim by NMR. Pharm Res. 2015;32(10):3365–75.

    Article  CAS  PubMed  Google Scholar 

  13. Moussa EM, Panchal JP, Moorthy BS, Blum JS, Joubert MK, Narhi LO, et al. Immunogenicity of therapeutic protein aggregates. J Pharm Sci. 2016;105(2):417–30.

    Article  CAS  PubMed  Google Scholar 

  14. Lundahl MLE, Fogli S, Colavita PE, Scanlan EM. Aggregation of protein therapeutics enhances their immunogenicity: causes and mitigation strategies. RSC Chem Biol. 2021;2(4):1004–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of rDNA origin guidance for industry. Health and Human Services. 2021. https://www.fda.gov/media/107622/download. Accessed 11 Jan. 2023.

  16. Chang R-K, Raw A, Lionberger R, Yu L. Generic development of topical dermatologic products: formulation development, process development, and testing of topical dermatologic products. AAPS J. 2013;15(1):41–52.

    Article  CAS  PubMed  Google Scholar 

  17. Kessler H, Gehrke M, Griesinger C. Two-dimensional NMR spectroscopy: background and overview of the experiments [New Analytical Methods (36)]. Angew Chem Int Ed Engl. 1988;27(4):490–536.

    Article  Google Scholar 

  18. Piotto M, Saudek V, Sklenář V. Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions. J Biomol NMR. 1992;2(6):661–5.

    Article  CAS  PubMed  Google Scholar 

  19. Sklenar V, Piotto M, Leppik R, Saudek V. Gradient-tailored water suppression for 1H–15N HSQC experiments optimized to retain full sensitivity. J Magn Reson Ser A. 1993;102(2):241–5.

    Article  CAS  Google Scholar 

  20. Chen K, Long DS, Lute SC, Levy MJ, Brorson KA, Keire DA. Simple NMR methods for evaluating higher order structures of monoclonal antibody therapeutics with quinary structure. J Pharm Biomed Anal. 2016;128:398–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen K, Park J, Li F, Patil SM, Keire DA. Chemometric methods to quantify 1D and 2D NMR spectral differences among similar protein therapeutics. AAPS PharmSciTech. 2018;19(3):1011–9.

    Article  CAS  PubMed  Google Scholar 

  22. Ghasriani H, Hodgson DJ, Brinson RG, McEwen I, Buhse LF, Kozlowski S, et al. Precision and robustness of 2D-NMR for structure assessment of filgrastim biosimilars. Nat Biotechnol. 2016;34:139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xie T, Fang H, Ouyang W, Angart P, Chiang M-J, Bhirde AA, et al. The ELISA detectability and potency of pegfilgrastim decrease in physiological conditions: key roles for aggregation and individual variability. Sci Rep. 2020;10(1):2476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li M, Falk BT, Lu X, Schroder R, McCoy M, Xu W, et al. Molecular mechanism of antimicrobial excipient-induced aggregation in parenteral formulations of peptide therapeutics. Mol Pharm. 2022;19(9):3267–78.

    Article  CAS  PubMed  Google Scholar 

  25. Wang, K., Chen, K. Direct Assessment of Oligomerization of Chemically Modified Peptides and Proteins in Formulations using DLS and DOSY-NMR. Pharm Res. 2023. https://doi.org/10.1007/s11095-022-03468-8.

  26. Wang D, Park J, Patil SM, Smith CJ, Leazer JL Jr, Keire DA, et al. An NMR-based similarity metric for higher order structure quality assessment among U.S. marketed insulin therapeutics. J Pharm Sci. 2020;109(4):1519–28.

  27. Brereton RG. The Mahalanobis distance and its relationship to principal component scores. J Chemom. 2015;29(3):143–5.

    Article  CAS  Google Scholar 

  28. Jolliffe IT, Cadima J. Principal component analysis: a review and recent developments. Philos Trans Royal Soc A Math Phys Eng Sci. 2016;374(2065):20150202.

    Article  Google Scholar 

  29. Wu LC, Chen F, Lee SL, Raw A, Yu LX. Building parity between brand and generic peptide products: regulatory and scientific considerations for quality of synthetic peptides. Int J Pharm. 2017;518(1):320–34.

    Article  CAS  PubMed  Google Scholar 

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Funding

Support for this work from the US FDA CDER Critical Path Award is gratefully acknowledged.

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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

    Kang Chen

  2. Division of Liquid-Based Products I, Office of Lifecycle Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Cameron J. Smith

Authors
  1. Kang Chen
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  2. Cameron J. Smith
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K.C. and C.J.S. wrote the paper.

Corresponding author

Correspondence to Kang Chen.

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The authors declare no competing interests.

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Chen, K., Smith, C.J. Best Practices for Submission of NMR Data to Support Higher Order Structure Assessment of Generic Peptide Drugs. AAPS J 25, 17 (2023). https://doi.org/10.1208/s12248-023-00782-w

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  • DOI: https://doi.org/10.1208/s12248-023-00782-w

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