Pioneering application of biological process engineering in innovative bio-pharmaceutical development——bioreactors

doi:10.16085/j.issn.1000-6613.2016.04.001

Abstract

Abstract: In recent years, the proportion of innovative biomedical in the biotechnology industry has been increasing gradually, which is mainly due to the improvement of upstream technology such as target screening and molecule construction and brings tremendous economic benefit. With the increasing applications of cell culture technology in biomedical industry, demand for its innovation has been increasing. And so it is with the equipment bioreactors. This review introduced the categories, development trend and driving force of bioreactors in biomedical industry. The achievements of novel bioreactors including the applications of novel bioreactor technology and process analytical technology are also summarized. Finally, we discussed the development status and problems of bioreactor industry in China and pointed out that increasing the product quality rather than production is the goal of bioreactor development. This review also expounded the key role of modern bioreactor technology and the "Quality by Design" principles of, as well as the developmenet status and trend of bioreactor technology.

Key words: bioreactor, biological process engineering, quality by design, PAT, innovative bio-pharmaceutical, biological engineering, microreactor

摘要： 近年创新生物医药在生物产业中的比重逐渐增大,也给生物产业带来了巨大的经济效益,靶点筛选及分子构建等上游技术的进步是促进生物医药进步的主要原因.随着目前细胞培养技术在生物医药生产中的广泛应用,对细胞培养技术的要求也不断提高,同时细胞培养技术的实现载体——生物反应器的技术改进和创新也越发凸显其重要性.本文介绍了生物反应器在创新生物医药产业中的应用种类、发展趋势及发展驱动力,回顾了全球范围内新型生物反应器的发展成果,包括新型反应器技术及过程分析技术在生物医药中的应用,最后,分析了中国生物反应器的发展现状与问题,指出了生物反应器的发展与进步应以提高生物培养过程的稳定性最终提高产品的质量而不是以提高产量为主要目标.本文详细阐述现代生物反应器技术及基于"质量源于设计"的质量控制理念在其中所起到的关键作用,以及生物反应器的技术发展的现状和未来走向.

关键词: 生物反应器, 生物过程工程, 质量源于设计, 过程分析技术, 创新生物医药, 生物工程, 微反应器

CLC Number:

Q815

SUN Yang, NIE Jianqi, LIU Xiuxia, YANG Yankun, DAI Xiaofeng, BAI Zhonghu. Pioneering application of biological process engineering in innovative bio-pharmaceutical development——bioreactors[J]. Chemical Industry and Engineering Progree, 2016, 35(04): 971-980.

孙杨, 聂简琪, 刘秀霞, 杨艳坤, 戴晓峰, 白仲虎. 生物过程工程研究在创新生物医药开发中应用的驱动力——生物反应器[J]. 化工进展, 2016, 35(04): 971-980.

References

[1] 陳美恩,刘恩廷,陈鹏.全球生物产业发展主要模式及对我国的启示[J].未来与发展,2015(1):27-029.
[2] 杨宝盈.全球生物产业的发展模式及对加快我国生物产业集聚的启示[J].经济师,2013(4):60-61.
[3] SAVAGE P,MAHMOUD S. Development and economic trends in cancer therapeutic drugs:a 5-year update 2010—2014[J]. Br. J. Cancer,2015,112(6):1037-1041.
[4] WALTHER J,GODAWAT R,HWANG C,et al. The business impact of an integrated continuous biomanufacturing platform for recombinant protein production[J]. J. Biotechnol.,2015,213:3-12.
[5] TREE J A,RICHARDSON C,FOOKS A R,et al. Comparison of large-scale mammalian cell culture systems with egg culture for the production of influenza virus A vaccine strains[J]. Vaccine,2001,19(25-26):3444-3450.
[6] LANGER E S. Trends in capacity utilization for therapeutic monoclonal antibody production[J]. MAbs,2009,1(2):151-156.
[7] LEBRUN P,GIACOLETTI K,SCHERDER T,et al. A quality by design approach for longitudinal quality attributes[J]. J. Biopharm. Stat.,2015,25(2):247-259.
[8] RATHORE A S,PATHAK M,GODARA A. Process development in the QbD paradigm:role of process integration in process optimization for production of biotherapeutics[J]. Biotechnol. Prog.,2015,10.1002/btpr.2209.
[9] YU L X. Pharmaceutical quality by design:product and process development,understanding,and control[J]. Pharmaceutical Research,2008,25(4):781-791.
[10] YU L X,BAKER J,BERLAM S C,et al. Advancing product quality:a summary of the Inaugural FDA/PQRI Conference[J]. AAPS J.,2015,17(4):1011-1018.
[11] CLINCKE M F,MOLLERYD C,ZHANG Y,et al. Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor. Part I. Effect of the cell density on the process[J]. Biotechnology Progress,2013,29(3):754-767.
[12] SARANTOS K,CLEO K. Analysis of the landscape of biologically-derived pharmaceuticals in Europe:dominant production systems,molecule types on the rise and approval trends[J]. European Journal of Pharmaceutical Sciences,2013,48(3):428-441.
[13] LOFFELHOLZ C,KAISER S C,KRAUME M,et al. Dynamic single-use bioreactors used in modern liter-and m(3)-scale biotechnological processes:engineering characteristics and scaling up[J]. Disposable Bioreactors Ii,2014,138:1-44.
[14] EIBL R,KAISER S,LOMBRISER R,et al. Disposable bioreactors:the current state-of-the-art and recommended applications in biotechnology[J]. Applied Microbiology and Biotechnology,2010,86(1):41-49.
[15] EIBL R,LöFFELHOLZ C,EIBL D. Disposable bioreactors for inoculum production and protein expression[J].Methods Mol. Biol.,2014,1104:265-284.
[16] ENBLAD G,KARLSSON H,LOSKOG A S. CAR T-cell therapy:the role of physical barriers and immunosuppression in lymphoma[J]. Hum. Gene Ther.,2015,26(8):498-505.
[17] DAVENPORT A J,JENKINS M R,RITCHIE D S,et al. CAR-T cells are serial killers[J]. Oncoimmunology,2015,4(12):e1053684.
[18] BARBAROUX M,GERIGHAUSEN S,HACKEL H. An approach to quality and security of supply for single-use bioreactors[J]. Adv. Biochem. Eng. Biotechnol.,2014,138:239-272.
[19] LONG Q,LIU X X,YANG Y K,et al. The development and application of high throughput cultivation technology in bioprocess development[J]. Journal of Biotechnology,2014,192:323-238.
[20] BAREITHER R,BARGH N,OAKESHOTT R,et al. Automated disposable small scale reactor for high throughput bioprocess development:a proof of concept study[J]. Biotechnol. Bioeng.,2013,110(12):3126-3138.
[21] AMANULLAH A,OTERO J M,MIKOLA M,et al. Novel micro-bioreactor high throughput technology for cell culture process development:reproducibility and scalability assessment of fed-batch CHO cultures[J]. Biotechnology and Bioengineering,2010,106(1):57-67.
[22] HORTSCH R,STRATMANN A,WEUSTER-BOTZ D. New milliliter-scale stirred tank bioreactors for the cultivation of mycelium forming microorganisms[J]. Biotechnology and Bioengineering,2010,106(3):443-451.
[23] HORTSCH R,WEUSTER-BOTZ D. Milliliter-scale stirred tank reactors for the cultivation of vicroorganisms[J]. Advances in Applied Microbiology,2010,73:61-82.
[24] AGGARWAL K,JING F,MARANGA L,et al. Bioprocess optimization for cell culture based influenza vaccine production[J]. Vaccine,2011,29(17):3320-3328.
[25] PAILLET C,FORNO G,KRATJE R,et al. Suspension-Vero cell cultures as a platform for viral vaccine production[J]. Vaccine,2009,27(46):6464-6467.
[26] CHEN A,POH S L,DIETZSCH C,et al. Serum-free microcarrier based production of replication deficient Influenza vaccine candidate virus lacking NS1 using Vero cells[J]. Bmc. Biotechnology,2011,11:81.
[27] SHEN C F,LANTHIER S,JACOB D,et al. Process optimization and scale-up for production of rabies vaccine live adenovirus vector (AdRG1.3)[J]. Vaccine,2012,30(2):300-306.
[28] KNOWLES S,DRUGMAND J C,LENNAERTZ A,et al. Virus production with the ICELLIS (R) single-use bioreactor[J]. Human Gene Therapy,2014,25(11):A84-A.
[29] RAJENDRAN R,LINGALA R,VUPPU S K,et al. Assessment of packed bed bioreactor systems in the production of viral vaccines[J]. AMB Express,2014,4:25.
[30] VENTINI-MONTEIRO D,DUBOIS S,ASTRAY R M,et al. Insect cell entrapment,growth and recovering using a single-use fixed-bed bioreactor. Scaling up and recombinant protein production[J]. J. Biotechnol.,2015,216:110-115.
[31] LESCH H P,VALONEN P,HEIKKILA K M,et al. iCELLis (R) fixed-bed technology provides an efficient scalable system for viral vector production[J]. Human Gene Therapy,2015,26(10):A25.
[32] EIBL R,WERNER S,EIBL D. Bag bioreactor based on wave-induced motion:characteristics and applications[J]. Disposable Bioreactors,2009,115:55-87.
[33] CLINCKE M F,MOLLERYD C,ZHANG Y,et al. Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor. Part I. Effect of the cell density on the process[J]. Biotechnol. Prog.,2013,29(3):754-767.
[34] SWAIKA A,HAMMOND W A,JOSEPH R W. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy[J]. Mol. Immunol.,2015,67(2):4-17.
[35] LUSSIER D M,O'NEILL L,NIEVES L M,et al. Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions[J]. J. Immunother,2015,38(3):96-106.
[36] SHUKLA A A,GOTTSCHALK U. Single-use disposable technologies for biopharmaceutical manufacturing[J]. Trends Biotechnol.,2013,31(3):147-154.
[37] MINOW B,SEIDEMANN J,TSCHOEPE S,et al. Harmonization and characterization of different single-use bioreactors adopting a new sparger design[J]. Engineering in Life Sciences,2014,14(3):272-282.
[38] LEVINE L H. Vaccine manufacturing facilities of the future[R]. London:Vaccines Europe,2010.
[39] ANDERSSON H,VAN DEN BERG A. Microfluidic devices for cellomics:a review[J]. Sensors and Actuators B:Chemical,2003,92(3):315-325.
[40] LANGEMANN T,MAYR U B,MEITZ A,et al. Multi-parameter flow cytometry as a process analytical technology (PAT) approach for the assessment of bacterial ghost production[J]. Appl. Microbiol. Biotechnol.,2016,100(1):409-418.
[41] LOPES J A,COSTA P F,ALVES T P,et al. Chemometrics in bioprocess engineering:process analytical technology (PAT) applications[J]. Chemometrics and Intelligent Laboratory Systems,2004,74(2):269-275.
[42] AKSU B,DE BEER T,FOLESTAD S,et al. Strategic funding
priorities in the pharmaceutical sciences allied to quality by design (QbD) and process analytical technology (PAT)[J]. Eur. J. Pharm. Sci.,2012,47(2):402-405.
[43] SCHAEFER C,CLICQ D,LECOMTE C,et al. A process analytical technology (PAT) approach to control a new API manufacturing process:development,validation and implementation[J]. Talanta,2014,120:114-125.
[44] WHEELOCK A M,WHEELOCK C E. Trials and tribulations of 'omics data analysis:assessing quality of SIMCA-based multivariate models using examples from pulmonary medicine[J]. Mol. Biosyst.,2013,9(11):2589-2596.