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Biosimilars pp 221-258 | Cite as

Drug Product Considerations for Biosimilars

  • Satish K. SinghEmail author
  • Susanne Jörg
  • Hanns-Christian Mahler
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 34)

Abstract

Biosimilars are increasingly important for the expansion of access to life-saving biologics and to reduce the cost of prescription medicine. The design of the drug product for a biosimilar is of utmost importance, as it directly relates to patient efficacy, safety and product quality, even as it defines the similarity of the product to the reference innovator product. There are various components of a drug product: the formulation, the container closure system and/or device, and the drug product manufacturing process that must be considered during any biologic parenteral drug product development. The biosimilar drug product development strategy has to take additional multiple factors into consideration including matching the reference product presentation, intellectual property and the current state of the art in science and technology. This chapter reviews these factors in detail using case-studies from currently approved biosimilars.

Keywords

Product Composition Formulation Dosage form Device Manufacturing process Container closure 

References

  1. Abdul-Fattah AM, Oeschger R, Roehl H, Bauer Dauphin I, Worgull M, Kallmeyer G, Mahler HC. Investigating factors leading to fogging of glass vials in lyophilized drug products. Eur J Pharm Biopharm. 2013;85(2):314–26.PubMedGoogle Scholar
  2. Agalloco J. Open letter in reponse to MHRA blog on Vapour Hydrogen Peroxide fragility. 2018. https://www.linkedin.com/pulse/open-letter-response-mhra-blog-vapour-hydrogen-jim-agalloco/. Accessed June 2018.
  3. Bahal SM, Romansky JM. Sorption of parabens by fluoropolymer or fluoropolymer laminated flexible tubing. PDA J Pharm Sci Technol. 2001a;55(6):417–21.PubMedGoogle Scholar
  4. Bahal SM, Romansky JM. Sorption of parabens by flexible tubings. Pharm Dev Technol. 2001b;6(3):431–40.PubMedGoogle Scholar
  5. Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJ, Middaugh CR, Winter G, Fan YX, Kirshner S, Verthelyi D, Kozlowski S, Clouse KA, Swann PG, Rosenberg A, Cherney B. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J Pharm Sci. 2009;98(4):1201–5.PubMedPubMedCentralGoogle Scholar
  6. Celltrion. CT-P13 (infliximab biosimilar). Briefing Document for the Arthritis Advisory Committee. 2016. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm484860.pdf. Accessed June 2018.
  7. Chen L, Sloey C, Zhang Z, Bondarenko PV, Kim H, Ren D, Kanapuram S. Chemical modifications of therapeutic proteins induced by residual ethylene oxide. J Pharm Sci. 2015;104(2):731–9.PubMedGoogle Scholar
  8. Cheng W, Zheng X, Yang M. Hydrogen peroxide induced protein oxidation during storage and lyophilization process. J Pharm Sci. 2016;105(6):1837–42.PubMedGoogle Scholar
  9. Dimitrova MN, Bee JS, Lu L, Fernandez JF. Development of prefilled syringe combination products for biologics. In: Warne NW, Mahler H-C, editors. Challenges in protein product development. AAPS/Springer; 2018. p. 203–24.Google Scholar
  10. Ditter D, Mahler HC, Gohlke L, Nieto A, Roehl H, Huwyler J, Wahl M, Allmendinger A. Impact of vial washing and depyrogenation on surface properties and delamination risk of glass vials. Pharm Res. 2018a;35(7):146.PubMedGoogle Scholar
  11. Ditter D, Nieto A, Mahler HC, Roehl H, Wahl M, Huwyler J, Allmendinger A. Evaluation of glass delamination risk in pharmaceutical 10 mL/10R vials. J Pharm Sci. 2018b;107(2):624–37.PubMedGoogle Scholar
  12. European Agency for Safety and Health at Work. Directive 2010/32/EU - Prevention from sharp injuries in the hospital and healthcare sector. 2010. https://osha.europa.eu/en/legislation/directives/council-directive-2010-32-eu-prevention-from-sharp-injuries-in-the-hospital-and-healthcare-sector. Accessed June 2018.
  13. Hopkins A. VHP (vapour hydrogen peroxide) fragility. 2018. https://mhrainspectorate.blog.gov.uk/2018/04/20/vhp-vapour-hydrogen-peroxide-fragility/. Accessed June 2018.
  14. Jahn M. Leachables and extractables: from regulatory expectations to laboratory assessment. In: Warne NW, Mahler HC, editors. Challenges in protein product development. AAPS/Springer; 2018. p. 337–51.Google Scholar
  15. Kishore RS, Kiese S, Fischer S, Pappenberger A, Grauschopf U, Mahler HC. The degradation of polysorbates 20 and 80 and its potential impact on the stability of biotherapeutics. Pharm Res. 2011a;28(5):1194–210.PubMedGoogle Scholar
  16. Kishore RS, Pappenberger A, Dauphin IB, Ross A, Buergi B, Staempfli A, Mahler HC. Degradation of polysorbates 20 and 80: studies on thermal autoxidation and hydrolysis. J Pharm Sci. 2011b;100(2):721–31.PubMedGoogle Scholar
  17. Kolhe P, Goswami S. Bulk protein solution: freeze-thaw process, storage and shipping considerations. In: Warne NW, Mahler HC, editors. Challenges in protein product development. AAPS/Springer; 2018. p. 313–36.Google Scholar
  18. Lamanna WC, Holzmann J, Cohen HP, Guo X, Schweigler M, Stangler T, Seidl A, Schiestl M. Maintaining consistent quality and clinical performance of biopharmaceuticals. Expert Opin Biol Ther. 2018;18(4):369–79.PubMedGoogle Scholar
  19. Lambert P. Dispensing biopharmaceuticals with piston and peristaltic pumps. PharmTech; 2008.Google Scholar
  20. Liu W, Swift R, Torraca G, Nashed-Samuel Y, Wen ZQ, Jiang Y, Vance A, Mire-Sluis A, Freund E, Davis J, Narhi L. Root cause analysis of tungsten-induced protein aggregation in pre-filled syringes. PDA J Pharm Sci Technol. 2010;64(1):11–9.PubMedGoogle Scholar
  21. Lolas AG, Metcalfe JW. Evaluation of the microbial growth potential of pharmaceutical drug products and quality by design. PDA J Pharm Sci Technol. 2011;65(1):63–70.PubMedGoogle Scholar
  22. Manning MC, Chou DK, Murphy BM, Payne RW, Katayama DS. Stability of protein pharmaceuticals: an update. Pharm Res. 2010;27(4):544–75.PubMedGoogle Scholar
  23. Metcalfe JW. Microbiological quality of drug products after penetration of the container system for dose preparation prior to patient administration. Am Pharm Rev. 2009;12(1, Jan/Feb):84–9.Google Scholar
  24. 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.PubMedGoogle Scholar
  25. Piedmonte DM, Summers C, McAuley A, Karamujic L, Ratnaswamy G. Sorbitol crystallization can lead to protein aggregation in frozen protein formulations. Pharm Res. 2007;24(1):136–46.PubMedGoogle Scholar
  26. Piedmonte DM, Hair A, Baker P, Brych L, Nagapudi K, Lin H, Cao W, Hershenson S, Ratnaswamy G. Sorbitol crystallization-induced aggregation in frozen mAb formulations. J Pharm Sci. 2015;104(2):686–97.PubMedGoogle Scholar
  27. Ricci MS, Frazier M, Moore J, Cromwell M, Galush WJ, Patel AR, Adler M, Altenburger U, Grauschopf U, Goldbach P, Fast JL, Kramer I, Mahler HC. In-use physicochemical and microbiological stability of biological parenteral products. Am J Health Syst Pharm. 2015;72(5):396–407.PubMedGoogle Scholar
  28. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.PubMedPubMedCentralGoogle Scholar
  29. Rubic-Schneider T, Kuwana M, Christen B, Assenmacher M, Hainzl O, Zimmermann F, Fischer R, Koppenburg V, Chibout SD, Wright TM, Seidl A, Kammuller M. T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia. Blood Adv. 2017;1(6):367–79.PubMedPubMedCentralGoogle Scholar
  30. Saller V, Matilainen J, Grauschopf U, Bechtold-Peters K, Mahler HC, Friess W. Particle shedding from peristaltic pump tubing in biopharmaceutical drug product manufacturing. J Pharm Sci. 2015;104(4):1440–50.PubMedGoogle Scholar
  31. Saller V, Matilainen J, Rothkopf C, Serafin D, Bechtold-Peters K, Mahler HC, Friess W. Preservative loss from silicone tubing during filling processes. Eur J Pharm Biopharm. 2017;112:109–18.PubMedGoogle Scholar
  32. Sandoz. FDA Oncologic Drugs Advisory Committee Meeting. Zarxio (filgrastim). Advisory Committee Briefing Materials. 2015. https://wayback.archive-it.org/7993/20170405222933/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428782.pdf. Accessed June 2018.
  33. 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.PubMedGoogle Scholar
  34. Scott Morton F, Stern AD, Stern S. The impact of entry of biosimilars: evidence from Europe; Harvard Business School Working Paper. No. 16-141: June 2016. Revised April 2018. https://www.hbs.edu/faculty/Pages/item.aspx?num=51309. Accessed June 2018
  35. Seidl A, Hainzl O, Richter M, Fischer R, Bohm S, Deutel B, Hartinger M, Windisch J, Casadevall N, London GM, Macdougall I. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm Res. 2012;29(6):1454–67.PubMedGoogle Scholar
  36. Singh SK. Storage considerations as part of the formulation development program for biologics. Am Pharm Rev. 2007;10(2, Mar/Apr):26–33.Google Scholar
  37. Singh SK. Impact of product-related factors on immunogenicity of biotherapeutics. J Pharm Sci. 2011;100(2):354–87.PubMedGoogle Scholar
  38. Singh SK. Sucrose and trehalose in therapeutic protein formulations. In: Warne NW, Mahler HC, editors. Challenges in protein product development. AAPS/Springer; 2018. p. 63–95.Google Scholar
  39. Singh SK, Mahler H-C. Current trends in control and monitoring of subvisible particulate matter in biotherapeutics. BioPharma Asia. 2018;7(1, Jan/Feb):30–7.Google Scholar
  40. Singh SK, Nema S. Freezing and thawing of protein solutions. In: Jameel F, Hershenson S, editors. Formulation and process development strategies for manufacturing biopharmaceuticals. Hoboken: Wiley; 2010. p. 625–75.Google Scholar
  41. Singh SK, Afonina N, Awwad M, Bechtold-Peters K, Blue JT, Chou D, Cromwell M, Krause HJ, Mahler HC, Meyer BK, Narhi L, Nesta DP, Spitznagel T. An industry perspective on the monitoring of subvisible particles as a quality attribute for protein therapeutics. J Pharm Sci. 2010;99(8):3302–21.PubMedGoogle Scholar
  42. Thakrar K, Bodalia P, Grosso A. Assessing the efficacy and safety of omnitrope. Br J Clin Pharm. 2010;2:298–301.Google Scholar
  43. Tyagi AK, Randolph TW, Dong A, Maloney KM, Hitscherich C Jr, Carpenter JF. 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.PubMedGoogle Scholar
  44. U.S. Department of Labor. Occupational exposure to bloodborne pathogens: Needlestick and other sharps injuries. Final rule. OSHA Federal Register Final Rules 2011;66:5317--5325. https://www.osha.gov/SLTC/bloodbornepathogens/recognition.html. Accessed June 2018.
  45. U.S. FDA. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. BLA 125553. EP2006, a proposed biosimilar to Neupogen (filgrastim). Sandoz Inc.; 2015a. http://patentdocs.typepad.com/files/briefing-document.pdf. Accessed June 2018.
  46. U.S. FDA. Scientific Considerations in Demonstrating Biosimilarity to Reference Product. Guidance for Industry. 2015b. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed June 2018.
  47. U.S. FDA. CDER. Application Number 125533Orig1s000. Other Review(s). Zarxio (filgrastim-sndz). 2015c. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000OtherR.pdf. Accessed June 2018.
  48. U.S. FDA. BLA 761024. Approval Letter Amjevita (adalimumab-otto). 2016a. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761024Orig1s000ltr.pdf. Accessed June 2018.
  49. U.S. FDA. BLA 125544. Approval Letter Inflectra (infliximab-dyyb). 2016b. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/125544Orig1s000ltr.pdf. Accessed June 2018.
  50. U.S. FDA. BLA 761042. Approval Letter Erelzi (etanercept-szzs). 2016c. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761042Orig1s000ltr.pdf. Accessed June 2018.
  51. U.S. FDA. CDER Application Number 761024Orig1s000. Chemistry Reviews ABP501 (adalimumab-otto). 2016d. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761024Orig1s000ChemR.pdf. Accessed June 2018.
  52. U.S. FDA. CDER Application Number 125544Orig1s000. Chemistry Reviews CT-P13 (infliximab-dyyb). 2016e. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000ChemR.pdf. Accessed June 2018.
  53. U.S. FDA. CDER. Application Number 761042Orig1s000. Other Reviews. Erelzi (etanercept-szzs). 2016f. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761042Orig1s000OtherR.pdf. Accessed June 2018.
  54. U.S. FDA. CDER. Application Number 761024Orig1s000. Other Reviews. ABP501 (adalimumab-otto). 2016g. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761024Orig1s000OtherR.pdf. Accessed June 2018.
  55. U.S. FDA. Considerations in demonstrating interchangeability with a reference product. Guidance for Industry. Draft Guidance. 2017a. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed June 2018.
  56. U.S. FDA. Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products. 2017b. https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm429304.pdf. Accessed June 2018.
  57. U.S. FDA. FDA briefing document. Oncologic Drugs Advisory Committee Meeting. BLA 761074. MYL-1401O, a proposed biosimilar to Herceptin (trastuzumab). Mylan Pharmaceuticals. 2017c. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566369.pdf. Accessed June 2018.
  58. U.S. FDA. FDA Briefing Document. Oncologics Drug Avisory Commitee Meeting. BLA 125545. “Epoein Hospira”, a proposed biosimilar to Epogen/Procrit (epoetin alfa). Hospira Inc.; 2017d. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM559967.pdf. Accessed June 2018.
  59. U.S. FDA. BLA 760158. Approval Letter Cyltezo (adalimumab-adbm). 2017e. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761058Orig1s000ltr.pdf. Accessed June 2018.
  60. U.S. FDA. BLA 761054. Approval Letter Renflixis (infliximab-abda). 2017f. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761054Orig1s000ltr.pdf. Accessed June 2018.
  61. U.S. FDA. BLA 761072. Approval Letter Ixifi (infliximab-qbtx). 2017g. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761072Orig1s000ltr.pdf. Accessed June 2018.
  62. U.S. FDA. Search orphan drug designations and approvals. 2018a. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/. Accessed June 2018.
  63. U.S. FDA. FDA withdraws draft guidance for industry: Statistical approaches to evaluate analytical similarity. 2018b. https://www.fda.gov/Drugs/DrugSafety/ucm611398.htm. Accessed July 2018.
  64. Vandekerckhove K, Seidl A, Gutka H, Kumar M, Gratzl G, Keire D, Coffey T, Kuehne H. Rational selection, criticality assessment, and tiering of quality attributes and test methods for analytical similarity evaluation of biosimilars. AAPS J. 2018;20(4):68.PubMedPubMedCentralGoogle Scholar
  65. Wang W, Cui TY, Wang YJ, Martin-Moe S. Oxidation of protein by vaporized sanitizing agents. PDA J Pharm Sci Technol. 2004;58(3):121–9.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Satish K. Singh
    • 1
    Email author
  • Susanne Jörg
    • 1
  • Hanns-Christian Mahler
    • 1
  1. 1.Lonza Pharma and Biotech, Drug Product ServicesBaselSwitzerland

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