Skip to main content
SpringerLink
Log in

Chapter 12: Strategies in the Development of Formulations for Antibody-Based Therapeutics

  • Chapter
  • First Online:
Development of Biopharmaceutical Drug-Device Products

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 35))

  • 2845 Accesses

Abstract

Rapid innovation of antibody-based modalities to treat different diseases, such as oncology, immuno-oncology, and chronic inflammation, and the speed with which these modalities are progressing through discovery is requiring the acceleration of product development to clinical studies and launch. Development of a stable formulation is critical for initiating and progressing through clinical trials. In this chapter, we provide guidance on leveraging phase-appropriate platform approaches to shorten development cycle time and strategies to arrive at optimal conditions for the final drug product composition and primary container configuration that can maintain the efficacy and safety of the drug as it is processed through various unit operations of manufacturing and administration to the patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Cleland JL, Powell MF, Shire SJ. The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Crit Rev Ther Drug Carrier Syst. 1993;10(4):307–77.

    CAS  PubMed  Google Scholar 

  2. Kamerzell TJ, Esfandiary R, Joshi SB, Middaugh CR, Volkin DB. Protein-excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev. 2011;63(13):1118–59.

    Article  CAS  PubMed  Google Scholar 

  3. Lai MC, Topp EM. Solid-state chemical stability of proteins and peptides. J Pharm Sci. 1999;88(5):489–500.

    Article  CAS  PubMed  Google Scholar 

  4. Ohtake S, Kita Y, Arakawa T. Interactions of formulation excipients with proteins in solution and in the dried state. Adv Drug Deliv Rev. 2011;63(13):1053–73.

    Article  CAS  PubMed  Google Scholar 

  5. Siedler M, Kumar V, Chari R, Saluja S, Fraunhofer W. Development of drug product formulations: molecular design and early candidates screening. In: Jameel F, Hershenson S, Khan MA, Martin-Moe S, editors. Quality by design for biopharmaceutical drug product development. New York: Springer New York; 2015. p. 61–85.

    Chapter  Google Scholar 

  6. Perez-Ramírez B, Guziewicz N, Simler R, Sreedhara A. Approaches for early developability assessment of proteins to guide quality by design of liquid formulations. In: Jameel F, Hershenson S, Khan MA, Martin-Moe S, editors. Quality by design for biopharmaceutical drug product development. New York: Springer New York; 2015. p. 87–114.

    Chapter  Google Scholar 

  7. Jarasch A, Koll H, Regula JT, Bader M, Papadimitriou A, Kettenberger H. Developability assessment during the selection of novel therapeutic antibodies. J Pharm Sci. 2015;104(6):1885–98.

    Article  CAS  PubMed  Google Scholar 

  8. Morar-Mitrica S, Adams ML, Crotts G, Wurth C, Ihnat PM, Tabish T, Antochshuk V, DiLuzio W, Dix DB, Fernandez JE, Gupta K, Fleming MS, He B, Kranz JK, Liu D, Narasimhan C, Routhier E, Taylor KD, Truong N, Stokes ESE. An intercompany perspective on biopharmaceutical drug product robustness studies. J Pharm Sci. 2018;107(2):529–42.

    Article  CAS  PubMed  Google Scholar 

  9. Correia IR. Stability of IgG isotypes in serum. MAbs. 2010;2(3):221–32.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Niedziela-Majka A, Kan E, Weissburg P, Mehra U, Sellers S, Sakowicz R. High-throughput screening of formulations to optimize the thermal stability of a therapeutic monoclonal antibody. J Biomol Screen. 2015;20(4):552–9.

    Article  CAS  PubMed  Google Scholar 

  11. Bam NB, Cleland JL, Yang J, Manning MC, Carpenter JF, Kelley RF, Randolph TW. Tween protects recombinant human growth hormone against agitation-induced damage via hydrophobic interactions. J Pharm Sci. 1998;87(12):1554–9.

    Article  CAS  PubMed  Google Scholar 

  12. Beckley NS, Lazzareschi KP, Chih HW, Sharma VK, Flores HL. Investigation into temperature-induced aggregation of an antibody drug conjugate. Bioconjug Chem. 2013;24(10):1674–83.

    Article  CAS  PubMed  Google Scholar 

  13. Pan LY, Salas-Solano O, Valliere-Douglass JF. Conformation and dynamics of interchain cysteine-linked antibody-drug conjugates as revealed by hydrogen/deuterium exchange mass spectrometry. Anal Chem. 2014;86(5):2657–64.

    Article  CAS  PubMed  Google Scholar 

  14. Hedberg SH, Heng JY, Williams DR, Liddell JM. Micro scale self-interaction chromatography of proteins: a mAb case-study. J Chromatogr A. 2016;1434:57–63.

    Article  CAS  PubMed  Google Scholar 

  15. Liu Y, Caffry I, Wu J, Geng SB, Jain T, Sun T, Reid F, Cao Y, Estep P, Yu Y, Vasquez M, Tessier PM, Xu Y. High-throughput screening for developability during early-stage antibody discovery using self-interaction nanoparticle spectroscopy. MAbs. 2014;6(2):483–92.

    Article  PubMed  Google Scholar 

  16. Sun T, Reid F, Liu Y, Cao Y, Estep P, Nauman C, Xu Y. High throughput detection of antibody self-interaction by bio-layer interferometry. MAbs. 2013;5(6):838–41.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jacobs SA, Wu SJ, Feng Y, Bethea D, O’Neil KT. Cross-interaction chromatography: a rapid method to identify highly soluble monoclonal antibody candidates. Pharm Res. 2010;27(1):65–71.

    Article  CAS  PubMed  Google Scholar 

  18. Kohli N, Jain N, Geddie ML, Razlog M, Xu L, Lugovskoy AA. A novel screening method to assess developability of antibody-like molecules. MAbs. 2015;7(4):752–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors and analysis. J Pharm Sci. 2009;98(9):2909–34.

    Article  CAS  PubMed  Google Scholar 

  20. Boswell CA, Tesar DB, Mukhyala K, Theil FP, Fielder PJ, Khawli LA. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug Chem. 2010;21(12):2153–63.

    Article  CAS  PubMed  Google Scholar 

  21. Reusch D, Haberger M, Falck D, Peter B, Maier B, Gassner J, Hook M, Wagner K, Bonnington L, Bulau P, Wuhrer M. Comparison of methods for the analysis of therapeutic immunoglobulin G Fc-glycosylation profiles-Part 2: mass spectrometric methods. MAbs. 2015;7(4):732–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Song T, Ozcan S, Becker A, Lebrilla CB. In-depth method for the characterization of glycosylation in manufactured recombinant monoclonal antibody drugs. Anal Chem. 2014;86(12):5661–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen B, Bautista R, Yu K, Zapata GA, Mulkerrin MG, Chamow SM. Influence of histidine on the stability and physical properties of a fully human antibody in aqueous and solid forms. Pharm Res. 2003;20(12):1952–60.

    Article  CAS  PubMed  Google Scholar 

  24. Paborji M, Pochopin NL, Coppola WP, Bogardus JB. Chemical and physical stability of chimeric L6, a mouse-human monoclonal antibody. Pharm Res. 1994;11(5):764–71.

    Article  CAS  PubMed  Google Scholar 

  25. Yadav S, Liu J, Shire SJ, Kalonia DS. Specific interactions in high concentration antibody solutions resulting in high viscosity. J Pharm Sci. 2010;99(3):1152–68.

    Article  CAS  PubMed  Google Scholar 

  26. Zheng K, Bantog C, Bayer R. The impact of glycosylation on monoclonal antibody conformation and stability. MAbs. 2011;3(6):568–76.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Miller AK, Hambly DM, Kerwin BA, Treuheit MJ, Gadgil HS. Characterization of site-specific glycation during process development of a human therapeutic monoclonal antibody. J Pharm Sci. 2011;100(7):2543–50.

    Article  CAS  PubMed  Google Scholar 

  28. Hoogenboom HR. Selecting and screening recombinant antibody libraries. Nat Biotechnol. 2005;23:1105.

    Article  CAS  PubMed  Google Scholar 

  29. CMC Working Group. A-mAb: A case study in bioprocess development, V 2.1. 2009.

    Google Scholar 

  30. Sreedhara A, Wong RL, Lentz Y, Schoenhammer K, Stark C. Application of QbD principles to late-stage formulation development for biological liquid products. In: Jameel F, Hershenson S, Khan MA, Martin-Moe S, editors. Quality by design for biopharmaceutical drug product development. New York: Springer New York; 2015. p. 115–35.

    Chapter  Google Scholar 

  31. Timasheff SN. Protein-solvent preferential interactions, protein hydration, and the modulation of biochemical reactions by solvent components. Proc Natl Acad Sci. 2002;99(15):9721–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Thirumangalathu R, Krishnan S, Ricci MS, Brems DN, Randolph TW, Carpenter JF. Silicone oil- and agitation-induced aggregation of a monoclonal antibody in aqueous solution. J Pharm Sci. 2009;98(9):3167–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gervais A, Angiuoni G, O’Hara J, Juul Jensen K, Sewerin K, Rossi M, Nedved M, Dillon P, Uddin S, Cornen S, Schnaible V. Forced degradation studies for therapeutic proteins: European Biopharmaceutical Enterprises; 2015. Brussels.

    Google Scholar 

  34. Zheng JY, Janis LJ. Influence of pH, buffer species, and storage temperature on physicochemical stability of a humanized monoclonal antibody LA298. Int J Pharm. 2006;308(1–2):46–51.

    Article  CAS  PubMed  Google Scholar 

  35. Thompson RW Jr, Latypov RF, Wang Y, Lomakin A, Meyer JA, Vunnum S, Benedek GB. Evaluation of effects of pH and ionic strength on colloidal stability of IgG solutions by PEG-induced liquid-liquid phase separation. J Chem Phys. 2016;145(18):185101.

    Article  CAS  PubMed  Google Scholar 

  36. Scherer TM. Cosolute effects on the chemical potential and interactions of an IgG1 monoclonal antibody at high concentrations. J Phys Chem B. 2013;117(8):2254–66.

    Article  CAS  PubMed  Google Scholar 

  37. Inoue N, Takai E, Arakawa T, Shiraki K. Arginine and lysine reduce the high viscosity of serum albumin solutions for pharmaceutical injection. J Biosci Bioeng. 2014;117(5):539–43.

    Article  CAS  PubMed  Google Scholar 

  38. Inoue N, Takai E, Arakawa T, Shiraki K. Specific decrease in solution viscosity of antibodies by arginine for therapeutic formulations. Mol Pharm. 2014;11(6):1889–96.

    Article  CAS  PubMed  Google Scholar 

  39. Wang S, Zhang N, Hu T, Dai W, Feng X, Zhang X, Qian F. Viscosity-lowering effect of amino acids and salts on highly concentrated solutions of two IgG1 monoclonal antibodies. Mol Pharm. 2015;12(12):4478–87.

    Article  CAS  PubMed  Google Scholar 

  40. Hermeling S, Crommelin DJ, Schellekens H, Jiskoot W. Structure-immunogenicity relationships of therapeutic proteins. Pharm Res. 2004;21(6):897–903.

    Article  CAS  PubMed  Google Scholar 

  41. Liu D, Ren D, Huang H, Dankberg J, Rosenfeld R, Cocco MJ, Li L, Brems DN, Remmele RL Jr. Structure and stability changes of human IgG1 Fc as a consequence of methionine oxidation. Biochemistry. 2008;47(18):5088–100.

    Article  CAS  PubMed  Google Scholar 

  42. Houde D, Peng Y, Berkowitz SA, Engen JR. Post-translational modifications differentially affect IgG1 conformation and receptor binding. Mol Cell Proteomics. 2010;9(8):1716–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bertolotti-Ciarlet A, Wang W, Lownes R, Pristatsky P, Fang Y, McKelvey T, Li Y, Li Y, Drummond J, Prueksaritanont T, Vlasak J. Impact of methionine oxidation on the binding of human IgG1 to Fc Rn and Fc gamma receptors. Mol Immunol. 2009;46(8–9):1878–82.

    Article  CAS  PubMed  Google Scholar 

  44. Pan H, Chen K, Chu L, Kinderman F, Apostol I, Huang G. Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn. Protein Sci. 2009;18(2):424–33.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang A, Hu P, MacGregor P, Xue Y, Fan H, Suchecki P, Olszewski L, Liu A. Understanding the conformational impact of chemical modifications on monoclonal antibodies with diverse sequence variation using hydrogen/deuterium exchange mass spectrometry and structural modeling. Anal Chem. 2014;86(7):3468–75.

    Article  CAS  PubMed  Google Scholar 

  46. Wang W, Vlasak J, Li Y, Pristatsky P, Fang Y, Pittman T, Roman J, Wang Y, Prueksaritanont T, Ionescu R. Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies. Mol Immunol. 2011;48(6–7):860–6.

    Article  CAS  PubMed  Google Scholar 

  47. Martin-Moe S, Lim FJ, Wong RL, Sreedhara A, Sundaram J, Sane SU. A new roadmap for biopharmaceutical drug product development: integrating development, validation, and quality by design. J Pharm Sci. 2011;100(8):3031–43.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Formulation Development, New Biological Entities, AbbVie (United States), North Chicago, IL, USA

    Feroz Jameel, Ehab M. Moussa & Brittney J. Mills

  2. Biologics Preformulation and Drug Development, AbbVie Bioresearch Center, Worcester, MA, USA

    Peter M. Ihnat

Authors
  1. Feroz Jameel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ehab M. Moussa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brittney J. Mills
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter M. Ihnat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feroz Jameel .

Editor information

Editors and Affiliations

  1. Formulation Development New Biological Entities, AbbVie (United States), North Chicago, IL, USA

    Feroz Jameel

  2. Drug Product Development (Retired), AbbVie (United States), North Chicago, IL, USA

    John W. Skoug

  3. Combination Product Development, AbbVie, Inc., North Chicago, IL, USA

    Robert R. Nesbitt

Rights and permissions

Reprints and permissions

Copyright information

© 2020 American Association of Pharmaceutical Scientists

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Jameel, F., Moussa, E.M., Mills, B.J., Ihnat, P.M. (2020). Chapter 12: Strategies in the Development of Formulations for Antibody-Based Therapeutics. In: Jameel, F., Skoug, J., Nesbitt, R. (eds) Development of Biopharmaceutical Drug-Device Products. AAPS Advances in the Pharmaceutical Sciences Series, vol 35. Springer, Cham. https://doi.org/10.1007/978-3-030-31415-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation