[19] A. Nikolay, A. Léon, K. Schwamborn, Y. Genzel, and U. Reichl, “Process in-

tensification of EB66® cell cultivations leads to high-yield yellow fever and Zika virus

production,” Appl. Microbiol. Biotechnol., vol. 102, no. 20, pp. 8725–8737, 2018.

[20] Y. Genzel et al., “High cell density cultivations by alternating tangential flow (ATF)

perfusion for influenza A virus production using suspension cells,” Vaccine, vol. 32,

no. 24, pp. 2770–2781, May 2014.

[21] K. Scharfenberg and R. Wagner, “A Reliable Strategy for The Achievement of Cell

Lines Growing in Protein-Free Medium,” in Animal Cell Technology: Developments

Towards the 21st Century, E. C. Beuvery, J. B. Griffiths, and W. P. Zeijlemaker, Eds.

Dordrecht: Springer Netherlands, 1995, pp. 619–623.

[22] V. Lohr, Y. Genzel, I. Behrendt, K. Scharfenberg, and U. Reichl, “A new MDCK

suspension line cultivated in a fully defined medium in stirred-tank and wave

bioreactor,” Vaccine, vol. 28, no. 38, pp. 6256–6264, Aug. 2010.

[23] A. L. Caron, R. T. Biaggio, and K. Swiech, “Strategies to suspension serum-free

adaptation of mammalian cell lines for recombinant glycoprotein production,” (in

eng), Methods. Mol. Biol., vol. 1674, pp. 75–85, 2018.

[24] J. A. Howe et al., “Matching complementing functions of transformed cells with

stable expression of selected viral genes for production of E1-deleted adenovirus

vectors,” (in eng), Virology, vol. 345, no. 1, pp. 220–230, Feb. 2006.

[25] C. Chu, V. Lugovtsev, H. Golding, M. Betenbaugh, and J. Shiloach, “Conversion of

MDCK cell line to suspension culture by transfecting with human siat7e gene and

its application for influenza virus production,” (in eng), Proc. Nat. Acad. Sci. United

States of America, vol. 106, no. 35, pp. 14802–14807, Sep. 2009.

[26] P. B. Capstick, R. C. Telling, W. G. Chapman, and D. L. Stewart, “Growth of a cloned

strain of Hamster kidney cells in suspended cultures and their susceptibility to the

virus of foot-and-mouth disease,” Nature, vol. 195, no. 4847, pp. 1163–1164, 1962.

[27] T. W. Pay, A. Boge, F. J. Menard, and P. J. Radlett, “Production of rabies vaccine

by an industrial scale BHK 21 suspension cell culture process,” (in eng), Dev. Biol.

Stand., vol. 60, pp. 171–174, 1985.

[28] A. Doroshenko and S. A. Halperin, “Trivalent MDCK cell culture-derived influenza

vaccine Optaflu (Novartis Vaccines),” (in eng), Expert Rev. Vaccines, vol. 8, no. 6,

pp. 679–688, Jun. 2009.

[29] EMA, “Flucelvax Tetra (influenza vaccine [surface antigen inactivated prepared in cell

cultures]),” vol. EMA/510023/2020, Amsterdam, NetherlandsEuropean Medicines

Agency, 2020.

[30] FDA, “Sequirus, Flucelvax, Supplement approval,” vol. BL 125408/366, U.S.

Department of Health and Human Services, Food and Drug Administration, Center

for Biologics Evaluation and Research, 2021.

[31] P. N. Barrett, W. Mundt, O. Kistner, and M. K. Howard, “Vero cell platform in

vaccine production: moving towards cell culture-based viral vaccines,” Expert Rev.

Vaccines, vol. 8, no. 5, pp. 607–618, 2009.

[32] J. J. Ramsden, S.-Y. Li, J. E. Prenosil, and E. Heinzle, “Kinetics of adhesion and

spreading of animal cells,” Biotechnol. Bioeng., vol. 43, no. 10, pp. 939–945,

1994.

[33] Cytiva. (2021). Microcarrier cell culture, principles and methods [Online]. Available:

https://cdn.cytivalifesciences.com/dmm3bwsv3/AssetStream.aspx?mediaformatid=

10061&destinationid=10016&assetid=11250

[34] F. Grinnell, “Cellular adhesiveness and extracellular substrata,” (in eng), Int. Rev.

Cytol., vol. 53, pp. 65–144, 1978.

[35] D. E. Martens et al., “Death rate in a small air-lift loop reactor of vero cells grown

on solid microcarriers and in macroporous microcarriers,” Cytotechnology, vol. 21,

no. 1, pp. 45–59, 1996.

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