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Biotherapeutic Drug Product Manufacturing and Process Development

  • Daniel Dixon
  • Anthony Gudinas
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 38)

Abstract

This chapter describes a typical biologics drug product manufacturing process and typical work to support that process. Unit operations addressed include dilution strategies and mixing, sterile filtration, filling, capping, and inspection, with a separate discussion on hold time monitoring. As each unit operation is discussed, manufacturing considerations and typical laboratory study designs are also introduced. A knowledge-based process design feeds into a robust risk management program, which in turn supports the Quality by Design paradigm. As a program progresses to later stages, the focus of the Quality by Design paradigm becomes demonstrating control of the process (through the control strategy) and proving consistency (through Process Performance Qualification).

Keywords

Drug substance dilution Sterile filtration Filling Hold times Quality by Design 

References

  1. 1.
    Antonsen H, Awafo V, Bender J, Carter J, Conway R, Egli S, et al. Sterilizing filtration of liquids. Technical Report 26. PDA J Sci Technol. 2008;62(S-5):2–60.Google Scholar
  2. 2.
    Brukl L, Hahn R, Sergi M, Scheler S. A systematic evaluation of mechanisms, material effects, and protein-dependent differences on friction-related protein particle formation in formulation and filling steps. Int J Pharm. 2016:931–45.Google Scholar
  3. 3.
    Chang D, Chang R-K. Review of current issues in pharmaceutical excipients. Pharm Technol. 2007 (May):56-66.Google Scholar
  4. 4.
    European Commission. Volume 4, Annex 1—manufacture of sterile medicinal products. Brussels; 2008.Google Scholar
  5. 5.
    FDA. Guidance for industry—process validation: general principles and practices. Rockville, MD; 2011.Google Scholar
  6. 6.
    FDA. Guidance for industry: sterile drug products producted by aseptic manufacturing current good manufacturing practice. Rockville, MD; 2004.Google Scholar
  7. 7.
    International Conference on Harmonization. Q10: pharmaceutical quality system. 2008.Google Scholar
  8. 8.
    International Conference on Harmonization. Q7: good manufacturing practice guide for active pharmaceutical ingredients. 2000.Google Scholar
  9. 9.
    International Conference on Harmonization. Q8(R2): pharmaceutical development. 2009.Google Scholar
  10. 10.
    International Conference on Harmonization. Q9: quality risk management. 2005.Google Scholar
  11. 11.
    Ishikawa T, Kobayashi N, Osawa C, Sawa E, Wakamatsu K. Prevention of stirring-induced microparticle formation in monoclonal antibody solutions. Biol Pharm Bull. 2010;33(6):1043–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Kerwin B, Remmele R Jr. Protect from light: photodegradation and protein biologics. J Pharm Sci. 2007;96(6):1468–79.CrossRefPubMedGoogle Scholar
  13. 13.
    Kishore R, Kiese S, Fischer S, Pappenberger A, Grauschopf U, et al. The degradation of polysorbates 20 and 80 and its potential impact on the stability of biotherapeutics. Pharm Res. 2011:1194–210.CrossRefPubMedGoogle Scholar
  14. 14.
    Nayak A, Colandene J, Bradford V, Perkins M. Characterization of subvisible particle formation during the filling pump operation of a monoclonal antibody solution. J Pharm Sci. 2011;100(10):4198–204.CrossRefPubMedGoogle Scholar
  15. 15.
    Patro S, Freund E, Chang B. Protein formulation and fill-finish operations. Biotechnol Ann Rev. 2002:55–84.Google Scholar
  16. 16.
    Paul E, Atiemo-Obeng V, Kesta S, editors. Handbook of industrial mixing: science and practices. Wiley; 2004.Google Scholar
  17. 17.
    Qi P, Volkin D, Zhao H, Nedved M, Hughes R, Bass R, et al. Characterization of the photodegradation of a human IgG1 monocloncal antibody formulated as a high-concentration liquid dosage form. J Pharm Sci. 2009;98(9):3117–30.CrossRefPubMedGoogle Scholar
  18. 18.
    Rathore N, Rajan R. Current perspectives on stability of protein drug products during formulation, fill and finish operations. Biotechnol Prog. 2008;24(3):504–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Sreedhara A, Yin J, Joyce M, Lau K, Wecksler A, Deperalta G, et al. Effect of ambient light on IgG1 monoclonal antibodies during drug product processing and development. Eur J Pharm Biopharm. 2016;100:38–46.CrossRefPubMedGoogle Scholar
  20. 20.
    Steele A, Arias J. Accounting for the Donnan effect in diafiltration optimization for high-concentration UFDF applications. BioProcess Int. 2014:50–4.Google Scholar
  21. 21.
    Tyagi A, Randolph T, Dong A, Maloney K, Hitscherich C, Carpenter J. IgG particle formation during filling pump operation: a case study of heterogeneous nucleation on stainless steel nanoparticles. J Pharm Sci. 2009;98(1):94–104.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang L, Yadav S, Demeule B, Wang YJ, Mozziconacci O, Schoeneich C. Degradation mechanisms of polysorbate 20 differentiated by 18O-labeling and mass spectrometry. Pharm Res. 2017:84–100.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.BioTherapeutics Pharmaceutical Sciences, Pharmaceutical R&DAndoverUSA

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