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BioDrugs

, Volume 28, Issue 4, pp 363–372 | Cite as

Drift, Evolution, and Divergence in Biologics and Biosimilars Manufacturing

  • Sundar Ramanan
  • Gustavo Grampp
Review Article

Abstract

Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.

Keywords

Quality Attribute Quality System Reference Product Darbepoetin Alfa Originator Product 
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

This study was funded by Amgen Inc. Kerri Hebard-Massey and Micah Robinson (Amgen Inc.) provided medical writing support. Sundar Ramanan and Gustavo Grampp are employees of and stockholders in Amgen Inc.

Conflict of interest

None.

References

  1. 1.
    US Food and Drug Administration. What is a biological product? http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194516.htm. Accessed 20 Sept 2013.
  2. 2.
    Genazzani AA, Biggio G, Caputi AP, Del Tacca M, Drago F, Fantozzi R, Canonico PL. Biosimilar drugs: concerns and opportunities. BioDrugs. 2007;21(6):351–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Wiggins JM, Skutnik J, Shimek-Cox J, Schwarzwalder N. The ideal pharmacopeia: a model for the future. Pharm Technol. 2008;32(11):122–5.Google Scholar
  4. 4.
    Crommelin DJ, Storm G, Verrijk R, de Leede L, Jiskoot W, Hennink WE. Shifting paradigms: biopharmaceuticals versus low molecular weight drugs. Int J Pharm. 2003;266(1–2):3–16.CrossRefPubMedGoogle Scholar
  5. 5.
    Chirino AJ, Mire-Sluis A. Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol. 2004;22(11):1383–91. doi: 10.1038/nbt1030.CrossRefPubMedGoogle Scholar
  6. 6.
    Berkowitz SA, Engen JR, Mazzeo JR, Jones GB. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat Rev Drug Discov. 2012;11(7):527–40. doi: 10.1038/nrd3746.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Glodek M, Liebowitz S, McCarthy R, McNally G, Oksanen C, Schultz T, Sundararajan M, Vorkapich R, Vukovinsky K, Watts C, Millili G. Process robustness—a PQRI white paper. Pharm Eng. 2006;26(6):1–11.Google Scholar
  8. 8.
    European Medicines Agency. Concept paper on the revision of the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/02/WC500102285.pdf. Accessed 20 Sept 2013.
  9. 9.
    The Patient Protection and Affordable Care Act. 2010. http://www.gpo.gov/fdsys/pkg/BILLS-111hr3590enr/pdf/BILLS-111hr3590enr.pdf. Accessed 27 Jan 2014.
  10. 10.
  11. 11.
    US Department of Health and Human Services. Guidance for industry quality systems approach to pharmaceutical CGMP regulations. 2006. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070337.pdf. Accessed 20 Sept 2013.
  12. 12.
    International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical quality system: Q10. ICH harmonized tripartite guideline. 2008. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf. Accessed 20 Sept 2013.
  13. 13.
    Szymczak MM, Friedman RL, Uppoor R, Yacobi A. Detection, measurement, and control in pharma manufacturing. Pharm Technol. 2011;70–76.Google Scholar
  14. 14.
    US Food and Drug Administration. Guidance for industry: changes to an approved application for specified biotechnology and specified synthetic biological products. 1997. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124805.pdf. Accessed 20 Sept 2013.
  15. 15.
    US Food and Drug Administration. Guidance for industry: comparability protocols—chemistry, manufacturing, and controls information. 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070545.pdf. Accessed 20 Sept 2013.
  16. 16.
    European Medicines Agency. Comparability of biotechnological/biological products subject to changes in their manufacturing process. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002805.pdf. Accessed 22 Oct 2013.
  17. 17.
    Fundamentals of US regulatory affairs, seventh edition. Regulatory Affairs Professionals Society. Maryland: Rockville; 2011.Google Scholar
  18. 18.
    Lee JF, Litten JB, Grampp G. Comparability and biosimilarity: considerations for the healthcare provider. Curr Med Res Opin. 2012;28(6):1053–8. doi: 10.1185/03007995.2012.686902.CrossRefPubMedGoogle Scholar
  19. 19.
    Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013;72(3):315–8. doi: 10.1136/annrheumdis-2012-202941.CrossRefPubMedGoogle Scholar
  20. 20.
  21. 21.
    Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310–2. doi: 10.1038/nbt.1839.CrossRefPubMedGoogle Scholar
  22. 22.
  23. 23.
    European Medicines Agency. Summary of opinion (post authorization): Erbitux. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000558/WC500117820.pdf. Accessed 20 Sept 2013.
  24. 24.
    Erbitux US prescribers information, Updated 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125084s153lbl.pdf. Accessed 16 Sept 2013.
  25. 25.
    Cohen MH, Chen H, Shord S, Fuchs C, He K, Zhao H, Sickafuse S, Keegan P, Pazdur R. Approval summary: cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Oncologist. 2013;18(4):460–6. doi: 10.1634/theoncologist.2012-0458.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469–75. doi: 10.1056/NEJMoa011931.CrossRefPubMedGoogle Scholar
  27. 27.
    Locatelli F, Del Vecchio L, Pozzoni P. Pure red-cell aplasia “epidemic”—mystery completely revealed? Perit Dial Int. 2007;27(Suppl 2):S303–7.PubMedGoogle Scholar
  28. 28.
    US Food and Drug Administration. Guidance for industry: good pharmacovigilance practices and pharmacoepidemiologic assessment. 2005. http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf. Accessed 20 Sept 2013.
  29. 29.
    Wieser C, Rosenkranz AR. Pure red cell aplasia after treatment of renal anaemia with epoetin theta. Clin Kidney J. 2013;6:539–42.CrossRefGoogle Scholar
  30. 30.
    Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation’s biosimilars program. N Engl J Med. 2011;365(5):385–8. doi: 10.1056/NEJMp1107285.CrossRefPubMedGoogle Scholar
  31. 31.
    Casadevall N, Edwards IR, Felix T, Graze PR, Litten JB, Strober BE, Warnock DG. Pharmacovigilance and biosimilars: considerations, needs and challenges. Expert Opin Biol Ther. 2013;13(7):1039–47. doi: 10.1517/14712598.2013.783560.CrossRefPubMedGoogle Scholar
  32. 32.
    Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, directive 2001/83/EC on the Community code relating to medicinal products for human use. Off J Eur Union. 2010;348:74–99.Google Scholar
  33. 33.
    US Food and Drug Administration. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed 22 Oct 2013.
  34. 34.
    Biologics Price Competition and Innovation Act of 2009; 2010.Google Scholar
  35. 35.
    Abood RR. Pharmacy practice and the law. 7th ed. Burlington, MA. 2012.Google Scholar
  36. 36.
    McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3):405–17. doi: 10.1038/clpt.2011.343.CrossRefPubMedGoogle Scholar
  37. 37.
    Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, Gravanis I, Heim HK, Heinonen E, Ho K, Moreau A, Narayanan G, Kruse NA, Reichmann G, Thorpe R, van Aerts L, Vleminckx C, Wadhwa M, Schneider CK. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111–7. doi: 10.1182/blood-2012-04-425744.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

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

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