REMEDIUMREMEDIUM1561-59362658-3534Joint-Stock Company Chicot90710.21518/1561-5936-2021-3-56-68Original ArticleBiosimilars: evolution of approaches to the development, regulation, life cycle control and interchangeability managementNiyazovRavil R.-DranitsynaMargarita A.-VasilievAndrey N.-GavrishinaElena V.-Center of Scientific Advice151220213566818032022Copyright © 2021,2021The legal framework for biosimilar medicinal product was first established in 2004 in the European Union and later in the USA. Since then, based on the scientific and regulatory experience with biosimilarity assessment, regulatory approaches have evolved considerably. A clear understanding of the capabilities of each development stage in assessing comparability in terms of power to identify differences and assess their relevance to the final clinical outcome gradually accumulated. In addition to the commitment to the biosimilarity approach, it is important to comply with the general requirements applicable to any drugs produced at an industrial scale. Experience showed that the demonstration of biosimilarity based on a range of analytical and functional tests and mainly clinical pharmacological studies is universal and allows extrapolating therapeutic indications. The establishment of biosimilar interchangeability, since the active substance by definition is a version of the active substance of the corresponding reference biological product, can introduce additional difficulties. A single approach to the establishment of biosimilar interchangeability has not yet been developed.biosimilarbiotechnologyvariabilityqualityimmunogenicitycomparabilityбиоаналогбиосимилярбиотехнологиявариабельностькачествоиммуногенностьсопоставимость1.European Parliament, Council. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. EUR-Lex.. 31 March 2004.. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:32004L0027.2.European Medicenes Agency. Guideline on similar biological medicinal products — First version. Official Website of European Medicenes Agency.. 30 October 2005.. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guidelinesimilar-biological-medicinal-products-first-version_en.pdf.3.U.S. Congress. U.S. Code, Title 42, Section 262. Regulation of biological products. Legal Information Institute, Cornell Law School.. 23 March 2010.. Available at: https://www.law.cornell.edu/uscode/text/42/262.4.U.S. Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; Guidance for Industry. Official Website of the U.S. Food and Drug Administration.. 28 April 2015.. Available at: https://www.fda.gov/media/82647/download.5.Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, Guidance for Industry. Official Website of the U.S. Food and Drug Administration.2015.. Available at: https://www.fda.gov/media/135612/download.6.European Medicenes Agency. Omnitrope : European Public Assessment Report - Scientific Discussion. Official Website of European Medicenes Agency.. 2006.. Available at: https://www.ema.europa.eu/en/documents/scientific-discussion/omnitrope-eparscientific-discussion_en.pdf.7.Zarsio: European Public Assessment Report – Scientific Discussion. Official Website of European Medicenes Agency.. 2009.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/zarzio-epar-public-assessment-report_en.pdf.8.U.S. Food and Drug Administration. Drugs@FDA: Approval Package for Zarxio (filgrastim-sndz) – Chemistry Review(s). Official Website of the U.S. Food and Drug Administration.. 6 March 2015.. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000ChemR.pdf.9.Drugs@FDA: Approval Package for Zarxio (filgrastim-sndz) — Pharmacology Review(s). Official Website of the U.S. Food and Drug Administration.. 6 2015.. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000PharmR.pdf.10.Drugs@FDA: Approval Package for Zarxio (filgrastim-sndz) — Clinical Pharmacology and Biopharmaceutics Review(s). Official Website of the U.S. Food and Drug Administration.6 March 2015.. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000ClinPharmR.pdf.11.European Medicenes Agency. Inflectra : European Public Assessment Report — Scientific Discussion. Official Website of European Medicenes Agency.4 October 2013.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/inflectra-epar-public-assessment-report_en.pdf.12.U.S. Food and Drug Administration. Drugs@FDA: Approval Package for Inflectra (infliximab-dyyb) - Chemistry Review(s). Official Website of the U.S. Food and Drug Administration.5 April 2016.. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000ChemR.pdf.13.Cilia M., Ruiz S., Richardson P., Salmonson T., Serracino-Inglott A., Wirth F., Borg J. Quality Issues Identified During the Evaluation of Biosimilars by the European Medicines Agency’s Committee for Medicinal Products for Human Use. AAPS PharmSciTech. 2017 г. https://doi.org/10.1208/s12249-017-0892-0.14.European Medicenes Agency. Guideline on similar biological medicinal products (Rev.1). Official Website of European Medicenes Agency.23 October 2014.. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf.15.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005). Official Website of European Medicenes Agency.22 February 2006.. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-1.pdf.16.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). Official Website of European Medicenes Agency.22 May 2014.. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-productscontaining-biotechnology-derived-proteins-active_en-0.pdf.17.Mielke J., Innerbichler F., Schiestl M., Ballarini N., Jones B. The Assessment of Quality Attributes for Biosimilars: a Statistical Perspective on Current Practice and a Proposal. The AAPS Journal. 2019;21. https://doi.org/10.1208/s12248-018-0275-9.18.European Medicenes Agency. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues — Revision 1. Official Website of European Medicenes Agency.26 February 2015.. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-clinical-development-similarbiological-medicinal-products-containing_en-0.pdf.19.U.S. Food and Drug Administration. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product: Guidance Document. Official Website of the U.S. Food and Drug Administration.29 December 2016.. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-pharmacology-data-support-demonstration-biosimilarityreference-product.20.Li J., Florian J., Campbell E., Schrieber S et al. Advancing Biosimilar Development Using Pharmacodynamic Biomarkers in Clinical Pharmacology Studies. Clinical Pharmacology and Therapeutics. 2019. https://doi.org/10.1002/cpt.1653.21.European Medicines Agency. Draft guideline on similar biological medicinal products containing recombinant granulocyte-colony stimulating factor (rG-CSF) — Revision 1. Official website of European Medicines Agency.15 August 2018.. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draftguideline-similar-biological-medicinal-products-containing-recombinantgranulocyte-colony_en.pdf.22.European Medicenes Agency. Zibarev: European Public Assessment Report — Scientific Discussion. Official Website of European Medicenes Agency.16 April 2019.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/zirabevepar-public-assessment-report_en.pdf.23.Gokemeijer J., Jawa V., i Mitra-Kaushik S. How Close Are We to Profiling Immunogenicity Risk Using In Silico Algorithms and In Vitro Methods?: an Industry Perspective. The AAPS Journal. 2017. https://doi.org/10.1208/s12248-017-0143-z.24.Groell F., Jordan O., Borchard G. In vitro models for immunogenicity prediction of therapeutic proteins. European Journal of Pharmaceutics and Biopharmaceutics. 2018. https://doi.org/10.1016/j.ejpb.2018.06.008.25.Yogurtcu O., Sauna Z., McGill J., Tegenge M., Hong Yang H. TCPro: an In Silico Risk Assessment Tool for Biotherapeutic Protein Immunogenicity. The AAPS Journal. 2019;96. https://doi.org/10.1208/s12248-019-0368-0.26.Barbier L., Ebbers H., Declerck P., Simoen S.,,. Vulto A., Huys I. The Efficacy, Safety, and Immunogenicity of Switching Between Reference Biopharmaceuticals and Biosimilars: A Systematic Review. Clinical Pharmacology and Therapeutics. 2020. https://doi.org/10.1002/cpt.1836.27.U.S. Food and Drug Administration. Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products; Guidance for Industry. Official Website of the U.S. Food and Drug Administration.25 November 2019.. Available at: https://www.fda.gov/media/133014/download.28.Immunogenicity Assessment for Therapeutic Protein Products; Guidance for Industry. Official Website of the U.S. Food and Drug Administration.14 August 2014.. Available at: https://www.fda.gov/media/85017/download.29.International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Pharmaceutical Development, Q8(R2). Official Website of the ICH.1 August 2009.. Available at:https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf.30.Development and manufacture of drug substances (chemical entities and biotechnological/biological entities), Q11. Official Website of the ICH.1 May 2012.. Available at: https://database.ich.org/sites/default/files/Q11_Guideline.pdf.31.Zhang E., Xie L., Qin P., Lu L., Xu Y., Gao W., Wang L., Xie M., Jiang W., Liu S. Quality by Design-Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira. The AAPS Journal. 2020;69(22). https://doi.org/10.1208/s12248-020-00454-z.32.Visser J., Feuerstein I., Stangler T., Schmiederer T., Fritsch C., Schiestl M. Physicochemical and Functional Comparability Between the Proposed Biosimilar Rituximab GP2013 and Originator Rituxima. BioDrugs. 2013;5(27). https://doi.org/10.1007/s40259-013-0036-3.33.Nie L., Gao D., Jiang H., Gou J., Li L., Hu F., Guo T., Wang H., Qu H. Development and Qualification of a Scale-Down Mammalian Cell Culture Model and Application in Design Space Development by Definitive Screening Design. AAPS PharmSciTech. 2019;246(20). https://doi.org/10.1208/s12249-019-1451-7.34.European Medicenes Agency. Semglee : European Public Assessment Report - Scientific Discussion. Official Website of European Medicenes Agency.4 June 2018.. Available at: https:// www.ema.europa.eu/en/documents/assessment-report/semglee-eparpublic-assessment-report_en.pdf.35.Insulin lispro Sanofi: European Public Assessment Report - Scientific Discussion. Official Website of European Medicenes Agency.18 May 2017.. Available at: https://www.ema. europa.eu/en/documents/assessment-report/insulin-lispro-sanofi-eparpublic-assessment-report_en.pdf.36.Майоров А.Ю., Федотов И.А., Драй Р.В., Авдеева О.И., Макаренко И.Е. Результаты оценки биоподобия препаратов РинЛиз® (ООО «ГЕРОФАРМ», Россия) и Хумалог® («Лилли Франс», Франция) с использованием метода гиперинсулинемического эугликемического клэмпа на здоровых добровольцах. Разработка и регистрация лекарственных средств. 2020;2(9). https://doi.org/10.33380/2305-2066-2020-9-1-13-17.37.European Medicenes Agency. Idacio : European Public Assessment Report - Scientific Discussion. Official Website of European Medicenes Agency.17 April 2019.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/idacio-epar-public-assessment-report_en.pdf.38.Cegfila (previously Pegfilgrastim Mundipharma): European Public Assessment Report — Scientific Discussion. Official Website of European Medicenes Agency.12 Februay 2020.. Available at: https://www.ema.europa.eu/en/documents/assessmentreport/pegfilgrastim-mundipharma-epar-public-assessment-report_en.pdf.39.Udenyc: European Public Assessment Report – Scientific Discussion. Official Website of European Medicenes Agency.23 October 2018.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/udenyca-epar-public-assessmentreport_.pdf.40.Ritemvia: European Public Assessment Report – Scientific Discussion. Official Website of European Medicenes Agency.15 August 2017.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/ritemvia-epar-public-assessmentreport_en.pdf.41.Amsparity: European Public Assessment Report – Scientific Discussion. Official Website of European Medicenes Agency.14 February 2020.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/amsparity-epar-publicassessment-report_en.pdf.42.Ruxience: European Public Assessment Report – Scientific Discussion. Official Website of European Medicenes Agency.7 April 2020.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/ruxience-epar-public-assessment-report_en.pdf.43.Idacio: European Public Assessment Report – Scientific Discussion. Official Website of European Medicenes Agency.17 April 2019.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/idacio-epar-public-assessment-report_en.pdf.44.Kanjinti: European Public Assessment Report — Scientific Discussion. Official Website of European Medicenes Agency.30 May 2018.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/kanjinti-epar-public-assessmentreport_en.pdf.45.Kang J., Kim S., Vallejo D., Hageman T et al. Multifaceted assessment of rituximab biosimilarity: The impact of glycan microheterogeneity on Fc function. European Journal of Pharmaceutics and Biopharmaceutics. 2019. https://doi.org/10.1016/j.ejpb.2019.12.003.46.WHO Expert Committee on Biological Standardization. Guidelines on evaluation of similar Biotherapeutic Products (SBPs), Annex 2, Technical Report Series No. 977, 2009. Official website of the World Health Organisation.2013.. Available at: https://www.who.int/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=1.47.Ниязов Р.Р., Драницына М.А., Васильев А.Н., Гавришина Е.В. Биоаналоги: воспроизведение клинического профиля с помощью современных биотехнологий. Ремедиум. 2021;(2):8–24. https://doi.org/10.21518/1561-5936-2021-2-8-24.48.Weise M., Kurki P., Wolff-Holz E., Bielsky M.C., Schneider C.K. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191–3196. https://doi.org/10.1182/blood-2014-06-583617.49.Arnold J.N., Wormald M.R., Sim R.B., Rudd P.M., Dwek R.A. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol. 2007;25:21–50. https://doi.org/10.1146/annurev.immunol.25.022106.141702.50.Aggarwal B.B., Gupta S.C., Kim J.H. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012;119. https://doi.org/10.1182/blood-2011-04-325225.51.U.S. Food and Drug Administration. Drugs@FDA: Approval Package for TRUXIMA (rituximab-abbs). Official Website of the U.S. Food and Drug Administration.28 November 2018.. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761088Orig1s000TOC.cfm.52.European Medicenes Agency. Riximyo: European Public Assessment Report — Scientific Discussion. Official Website of European Medicenes Agency.21 April 2017.. Available at: https://www.ema.europa.eu/en/documents/assessment-report/riximyoepar-public-assessment-report_en.pdf.53.International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7. Official Website of the ICH.10 November 2000.. Available at: https://database.ich.org/sites/default/files/Q7_Guideline.pdf.54.European Commission. Commission Directive (EU) 2017/1572 of 15 September 2017 supplementing Directive 2001/83/EC of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products for human use. EudraLex – EU Legislation: Official web portal of the European Commission.15 September 2017.. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1591803567186&uri=CELEX:32017L1572.55.Hamela H., Kangb H.-N. Quality changes to approved biotherapeutic product: Simulated case studies on reporting categories & supporting data requirements. Biologicals. 2019;62. https://doi.org/10.1016/j.biologicals.2019.10.008.56.European Medicenes Agency. Overview of comments received on ‘Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance (revision 1)’. Official Website of European Medicenes Agency.3 June 2014.. Available at: https://www.ema.europa.eu/en/documents/other/overview-comments-received-guideline-similar-biological-medicinal-productscontaining-biotechnology_en.pdf.57.International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Comparability of Biotechnological/ Biological Products Subject To Changes In Their Manufacturing Process (Q5E). Official Website of the ICH.18 November 2004.. Available at: https://database.ich.org/sites/default/files/Q5E%20Guideline.pdf.58.Clapp K., Castan A., Lindskog E. Chapter 24, Upstream Processing Equipment. Biopharmaceutical Processing: Development, Design, and Implementation of Manufacturing Processes. Amsterdam, Netherlands: Elsevier; 2018.59.Миронов А.Н., Васильев А.Н., Е.В. Гавришина Е.В., P.P. Ниязов Р.Р. Взаимозаменяемость лекарственных препаратов: зарубежный опыт, препятствия и условия становления концепции в России, роль научной экспертизы. Ремедиум. 2013;(10).60.WHO Expert Committee on Biological Standardization. WHO Questions and Answers: Similar Biotherapeutic Products: Complementary document to the WHO Guidelines on evaluation of similar biotherapeutic products (SBPs). Official website of the World Health Organisation.November 2018.. Available at: https://www.who.int/biologicals/expert_committee/QA_for_SBPs_ECBS_2018.pdf?ua=1.61.U.S. Food and Drug Administration. Considerations in Demonstrating Interchangeability With a Reference Product, Guidance for Industry. Official Website of the U.S. Food and Drug Administration.10 May 2019.. Available at: https://www.fda.gov/media/124907/download.62.Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. Official Website of the U.S. Food and Drug Administration.11 May 2020.. Available at: https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/purple-book-listslicensed-biological-products-reference-product-exclusivity-and-biosimilarity-or.63.U.S. Government Printing Office. Docket for public cooments for Considerations in Demonstrating Interchangeability With a Reference Product. Regulations.gov.U.S. Government Printing Office, 11 June 2020.. Available at: https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2017-D-0154.64.Mielke J., Woehling H., Jones B. Longitudinal assessment of the impact of multiple switches between a biosimilar and its reference product on efficacy parameters. Pharmaceutical Statistics. 2018;1. https://doi.org/10.1002/pst.1849.65.Vermeer N., Giezen T., Zastavnik S., Wolff-Holz E., Hidalgo-Simon A. Identifiability of Biologicals in Adverse Drug Reaction Reports Received From European Clinical Practice. Clin Pharmacol Ther. 2019;105(4):962–969. https://doi.org/10.1002/cpt.1310.66.Ниязов Р.Р., Драницына М.А., Васильев А.Н., Гавришина Е.В. Биоаналоги: разработка и изучение с помощью современных биотехнологий. Сахарный диабет. 2020;23(6):548–560. https://doi.org/10.14341/DM12576.