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BioDrugs

, Volume 27, Issue 4, pp 305–316 | Cite as

Managing Unexpected Events in the Manufacturing of Biologic Medicines

  • Gustavo Grampp
  • Sundar Ramanan
Review Article

Abstract

The manufacturing of biologic medicines (biologics) requires robust process and facility design, rigorous regulatory compliance, and a well-trained workforce. Because of the complex attributes of biologics and their sensitivity to production and handling conditions, manufacturing of these medicines also requires a high-reliability manufacturing organization. As required by regulators, such an organization must monitor the state-of-control for the manufacturing process. A high-reliability organization also invests in an experienced and fully engaged technical support staff and fosters a management culture that rewards in-depth analysis of unexpected results, robust risk assessments, and timely and effective implementation of mitigation measures. Such a combination of infrastructure, technology, human capital, management, and a science-based operations culture does not occur without a strong organizational and financial commitment. These attributes of a high-reliability biologics manufacturer are difficult to achieve and may be differentiating factors as the supply of biologics diversifies in future years.

Keywords

Recombinant Human Erythropoietin Consent Decree Industry Peer Warning Letter Quality Target Product Profile 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Gustavo Grampp and Sundar Ramanan are employees of Amgen Inc. and own stock in Amgen Inc. Gustavo Grampp devised the concept for this paper; Gustavo Grampp and Sundar Ramanan wrote the paper; Amgen Inc. approved the manuscript for submission. Kathryn Boorer PhD of Amgen Inc. provided editorial assistance.

References

  1. 1.
    Gatesman ML, Smith TJ. The shortage of essential chemotherapy drugs in the United States. N Engl J Med. 2011;365(18):1653–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Kaakeh R, Sweet BV, Reilly C, Bush C, DeLoach S, Higgins B, et al. Impact of drug shortages on U.S. health systems. Am J Health Syst Pharm. 2011;68(19):1811–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. P T. 2011;36(11):740–57.PubMedGoogle Scholar
  4. 4.
    US Food and Drug Administration. Current drug shortages. http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm. Accessed 13 Nov 2012.
  5. 5.
    Woodcock J, Wosinska M. Economic and technological drivers of generic sterile injectable drug shortages. Clin Pharmacol Ther. 2013;93(2):170–6.PubMedGoogle Scholar
  6. 6.
    Weick KE, Sutcliffe KM. Managing the unexpected: resilient performance in an age of uncertainty. 2nd ed. San Francisco: Wiley; 2007.Google Scholar
  7. 7.
    Sasaki H, Bothner B, Dell A, Fukuda M. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem. 1987;262(25):12059–76.PubMedGoogle Scholar
  8. 8.
    Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer. 2001;84(Suppl 1):3–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Hokke CH, Bergwerff AA, van Dedem GW, van Oostrum J, Kamerling JP, Vliegenthart JF. Sialylated carbohydrate chains of recombinant human glycoproteins expressed in Chinese hamster ovary cells contain traces of N-glycolylneuraminic acid. FEBS Lett. 1990;275(1–2):9–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Ghaderi D, Taylor RE, Padler-Karavani V, Diaz S, Varki A. Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nat Biotechnol. 2010;28(8):863–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Prigge ST, Kolhekar AS, Eipper BA, Mains RE, Amzel LM. Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase. Science. 1997;278(5341):1300–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Boven K, Stryker S, Knight J, Thomas A, van Regenmortel M, Kemeny DM, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int. 2005;67(6):2346–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Haag-Weber M, Eckardt KU, Horl WH, Roger SD, Vetter A, Roth K. Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-alpha (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study. Clin Nephrol. 2012;77(1):8–17.PubMedGoogle Scholar
  14. 14.
    Seidl A, Hainzl O, Richter M, Fischer R, Bohm S, Deutel B, et al. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm Res. 2012;29(6):1454–67.PubMedCrossRefGoogle Scholar
  15. 15.
    Joubert MK, Hokom M, Eakin C, Zhou L, Deshpande M, Baker MP, et al. Highly aggregated antibody therapeutics can enhance the in vitro innate and late-stage T-cell immune responses. J Biol Chem. 2012;287(30):25266–79.PubMedCrossRefGoogle Scholar
  16. 16.
    Sauerborn M, Brinks V, Jiskoot W, Schellekens H. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci. 2010;31(2):53–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Jiang Y, Nashed-Samuel Y, Li C, Liu W, Pollastrini J, Mallard D, et al. Tungsten-induced protein aggregation: solution behavior. J Pharm Sci. 2009;98(12):4695–710.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang B, Towers EW, Poppe L, Cockrill SL. Analytical characterization of a novel degradation product in a PEGylated recombinant protein. J Pharm Sci. 2011;100(11):4607–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Vinther A. A novel bacterial contamination in cell culture manufacturing Leptospira licerasiae. PDA WCC Meeting July 19, 2012. http://www.wccpda.org/Pages/Archives/Anders%20Vinther%20Leptospira%20PDA%20WCC%2019%20Jul%202012.ppt. Accessed 30 Nov 2012.
  20. 20.
    US Food and Drug Administration. Quality systems. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm278584.htm. Accessed 13 Nov 2012.
  21. 21.
    US Food and Drug Administration. FDA Form 483 frequently asked questions. http://www.fda.gov/ICECI/EnforcementActions/ucm256377.htm. Accessed 30 Nov 2012.
  22. 22.
    Pritchett T. A 483 primer: learning from the mistakes of others. Bioprocess Int. 2011;9:12–6.Google Scholar
  23. 23.
    US Food and Drug Administration. Regulatory procedures manual, Chapter 4: advisory actions. http://www.fda.gov/downloads/ICECI/ComplianceManuals/RegulatoryProceduresManual/UCM074330.pdf. Accessed 20 Feb 2013.
  24. 24.
    US Food and Drug Administration. About Warning and Close-Out Letters. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm278624.htm. Accessed 30 Nov 2012.
  25. 25.
    US Food and Drug Administration. Inspections, compliance, enforcement, and criminal investigations. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm. Accessed 30 Nov 2012.
  26. 26.
    US Food and Drug Administration. News & events. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289224.htm. Accessed 30 Nov 2012.
  27. 27.
    US Food and Drug Administration. Regulatory procedures manual, Chapter 5: administrative actions. http://www.fda.gov/downloads/ICECI/ComplianceManuals/RegulatoryProceduresManual/UCM074324.pdf. Accessed 20 Feb 2013.
  28. 28.
    Genazzani AA, Biggio G, Caputi AP, Del Tacca M, Drago F, Fantozzi R, et al. Biosimilar drugs: concerns and opportunities. Biodrugs. 2007;21(6):351–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Prugnaud JL. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework. Br J Clin Pharmacol. 2008;65(4):619–20.PubMedCrossRefGoogle Scholar
  30. 30.
    Roger SD. Biosimilars: how similar or dissimilar are they? Nephrology (Carlton). 2006;11(4):341–6.CrossRefGoogle Scholar
  31. 31.
    Gottlieb S. Biosimilars: policy, clinical, and regulatory considerations. Am J Health Syst Pharm. 2008;65(14 Suppl 6):S2–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Amgen Inc.LongmontUSA
  2. 2.Amgen Inc.Thousand OaksUSA

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