药学学报, 2019, 54(11): 2126-2134
引用本文:
刘伯宁, 徐刚领, 罗建辉. 关于我国单抗药物上市阶段药学评价的思考[J]. 药学学报, 2019, 54(11): 2126-2134.
LIU Bo-ning, XU Gang-ling, LUO Jian-hui. Chemistry, manufacturing and controls regulatory considerations for marketing authorization application of therapeutic antibody in China[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 2126-2134.

关于我国单抗药物上市阶段药学评价的思考
刘伯宁, 徐刚领, 罗建辉
国家药品监督管理局药品审评中心, 北京 100022
摘要:
申报注册上市是药物生命周期的重要节点,标志着具有临床价值“候选物”成为可以上市销售的“药品”。目前,我国自主研发的抗体药物上市产品仅12个。注册生产阶段的单抗药物研发与评价,对于工业界和监管界而言均缺乏经验。与此同时,近年来单抗生物类似药产品已开始集中报产,国外单抗进口注册进程不断加快,未来单抗药物上市阶段的药学评价将为我国生物制品注册上市审评的重要工作。本文结合笔者从事单抗药物研发与评价的实践经验,重点对单抗药物注册生产阶段的药学研究内容、评价要点及现存问题展开讨论,以期促进工业界规范开展药学研究,加速此类产品注册上市进程。
关键词:    抗体药物      上市申请      药学评价      生产现场检查      单克隆性      质量源于设计      工艺变更     
Chemistry, manufacturing and controls regulatory considerations for marketing authorization application of therapeutic antibody in China
LIU Bo-ning, XU Gang-ling, LUO Jian-hui
Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
Abstract:
The marketing authorization application is a milestone of drug life cycle, which indicates a candidate has potential to become a commercial drug. As of now, there are only 12 domestic therapeutic antibodies approved in China. The chemistry, manufacturing and controls (CMC) development and evaluation of monoclonal antibody were more challenging for both industry and authority agency. As the result of domestic biopharmaceutical industry development and implement of priority review system, the marketing authorization application of domestic antibody biosimilar and imported antibodies had dramatic increased in recent years. Thus, the CMC evaluation of monoclonal antibody become the important task of biological product's marketing authorization registration management. In the article, the CMC regulatory considerations for marketing authorization application based on author's review experience was proposed, in order to accelerate development and registration of commercial antibody in China.
Key words:    monoclonal antibody    marketing authorization application    chemistry, manufacturing and controls review    pre license inspection    clonality    quality by design    manufacturing process change   
收稿日期: 2019-07-08
DOI: 10.16438/j.0513-4870.2019-0534
基金项目: 国家“重大新药创新”资助项目(2015ZX09501008).
相关功能
PDF(388KB) Free
打印本文
0
作者相关文章
刘伯宁  在本刊中的所有文章
徐刚领  在本刊中的所有文章
罗建辉  在本刊中的所有文章

参考文献:
[1] Liu BN. The technology progress of antibody-producing cell line development[J]. China Biotechnol (中国生物工程杂志), 2013, 33: 111-116.
[2] Liu BN. The lasted development of large scale cell culture technology for commercial antibody manufacture[J]. China Biotechnol (中国生物工程杂志), 2013, 33: 103-111.
[3] Liu BN. The progress of therapeutic antibody drug and the industrial key-technology of antibody production[J]. J Chin Biotechnol (中国生物工程杂志), 2013, 33: 132-138.
[4] Kan HJ, Liu BN, Bai Y, et al. Analysis of monoclonal antibody drug registration in China[J]. Chin J New Drug (中国新药杂志), 2019, 28: 1-9.
[5] Kaplon H, Reichert JM. Antibodies to watch in 2019[J]. MAbs, 2019, 11: 219-238.
[6] Liu B, Guo H, Xu J, et al. Elimination of tumor by CD47/PD-L1 dual-targeting fusion protein that engages innate and adaptive immune responses[J]. MAbs, 2018, 10: 315-324.
[7] Gao L, Di YR, Huang QZ. Development of drug priority review system in China and relevant consideration[J]. Chin J New Drug (中国新药杂志), 2017, 26: 2656-2663.
[8] Liu BN, Bai Y, Lou JH. Biosimilarity study regarding product quality of recombinant monoclonal antibodies as biosimilars[J]. Chin Pharm J (中国药学杂志), 2017, 52: 1194-1199.
[9] Liu BN, Luo JH. Research and development of innovative antibody-based drugs[J]. Acta Pharm Sin (药学学报), 2017, 52: 1811-1819.
[10] Li M, Guo XX, Liu BN. Discussion on general principle and key point of process validation for biologics[J]. Chin J Biologicals (中国生物制品学杂志), 2017, 30: 664-668.
[11] Dye E, Sturgess A, Maheshwari G, et al. Examining manufacturing readiness for breakthrough drug development[J]. AAPS PharmSciTech, 2016, 17: 529-538.
[12] Dye ES, Groskoph J, Kelly B, et al. CMC considerations when a drug developmnet project is assigned breakthrough therapy status[J]. Pharm Eng, 2015, 35: 1-11.
[13] Frye C, Deshpande R, Estes S, et al. Industry view on the relative importance of "clonality" of biopharmaceutical-producing cell lines[J]. Biologicals, 2016, 44: 117-122.
[14] Jia A. Regulatory Considerations in Establishing Clonality for Cell Lines Expressing Therapeutic Proteins[C]. Shanghai: 5th Annual Cell Line Development & Engineering Asia, 2016.
[15] Welch J. Tilting at clones: a reulatory perspective on the importance of clonality of mammlian cell banks[EB/OL].[2018-8-6]. https://www.topbiox.com/wp-content/uploads/2017/06/Joel-Welch.pdf-Amsterdam-April-2017.pdf.
[16] Rawat R. Regulatory Consideration for Biotechnology Products: Clonality of the Production Cell Bank[C]. Vienna: Informa Life Sciences Annual Cell Line Devellopment and Engineering Conference, 2016.
[17] Liu B, Guo H, Xu J, et al. Acid-induced aggregation propensity of nivolumab is dependent on the Fc[J]. MAbs, 2016, 8: 1107-1117.
[18] Lamanna WC, Mayer RE, Rupprechter A, et al. The structure-function relationship of disulfide bonds in etanercept[J]. Sci Rep, 2017, 7: 3951.
[19] Guo A, Han M, Martinez T, et al. Electrophoretic evidence for the presence of structural isoforms specific for the IgG2 isotype[J]. Electrophoresis, 2008, 29: 2550-2556.
[20] Yang X, Wang F, Zhang Y, et al. Comprehensive analysis of the therapeutic IgG4 antibody pembrolizumab: hinge modification blocks half molecule exchange in vitro and in vivo[J]. J Pharm Sci, 2015, 104: 4002-4014.
[21] Rogstad S, Faustino A, Ruth A, et al. A retrospective evaluation of the use of mass spectrometry in FDA biologics license applications[J]. J Am Soc Mass Spectrom, 2017, 28: 786-794.
[22] Liu B, Guo H, Zhang J, et al. In-depth characterization of a pro-antibody-drug conjugate by LC-MS[J]. Mol Pharm, 2016, 13: 2702-2710.
[23] Shahrokh Z, Salamat N, Thomas JJ. Biophysical Analyses Suitable for Chemistry, Manufacturing, and Control Sections of the Biologic License Application (BLA)[M]//Das TK. Biophysical Methods for Biotherapeutics: Discovery and Development Applications. New Jersey: John Wiley & Sons, Inc., 2014: 317-353.
[24] Ambrogelly A, Gozo S, Katiyar A, et al. Analytical comparability study of recombinant monoclonal antibody therapeutics[J]. MAbs, 2018, 10: 513-538.
[25] Xu Y, Wang D, Mason B, et al. Structure, heterogeneity and developability assessment of therapeutic antibodies[J]. MAbs, 2019, 11: 239-264.
[26] Khawli LA, Goswami S, Hutchinson R, et al. Charge variants in IgG1: isolation, characterization, in vitro binding properties and pharmacokinetics in rats[J]. MAbs, 2010, 2: 613-624.
[27] Brorson K, Jia AY. Therapeutic monoclonal antibodies and consistent ends: terminal heterogeneity, detection, and impact on quality[J]. Curr Opin Biotechnol, 2014, 30: 140-146.
[28] Wong HE,Huang CJ, Zhang Z. Amino acid misincorporation in recombinant proteins[J]. Biotechnol Adv, 2018, 36: 168-181.
[29] Du Y, Walsh A, Ehrick R, et al. Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies[J]. MAbs, 2012, 4: 578-585.
[30] Kruse NA.Manufacturing Process Changes, Biologic Product Comparability and Post Approval Changes[C]. London: SME Workshop, 2015.
[31] Zhuang Y, Chen D, Sharma A, et al. Risk-based comparability assessment for monoclonal antibodies during drug development: a clinical pharmacology perspective[J]. AAPS J, 2018, 20: 109-123.
[32] Schenerman MA, Hope JN, Kletke C, et al. Comparability testing of a humanized monoclonal antibody (Synagis) to support cell line stability, process validation, and scale-up for manufacturing[J]. Biologicals, 1999, 27: 203-215.
[33] Chioato A, Noseda E, Colin L, et al. Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: a randomized study in healthy subjects[J]. Clin Drug Investig, 2013, 33: 801-808.
[34] Kelley B. Quality by design risk assessments supporting approved antibody products[J]. MAbs, 2016, 8: 1435-1436.
[35] Finkler C, Krummen L. Introduction to the application of QbD principles for the development of monoclonal antibodies[J]. Biologicals, 2016, 44: 282-290.
[36] Kelley B, Cromwell M, Jerkins J. Integration of QbD risk assessment tools and overall risk management[J]. Biologicals, 2016, 44: 341-351.
[37] Alt N, Zhang TY, Motchnik P, et al. Determination of critical quality attributes for monoclonal antibodies using quality by design principles[J]. Biologicals, 2016, 44: 291-305.
[38] Hakemeyer C, McKnight N, St John R, et al. Process characterization and design space definition[J]. Biologicals, 2016, 44: 306-318.
[39] Liu BN, Wang Y, Zhou XJ, et al. Large scale perfusion culture of CHO-C 28 cells in fixed bedreactor for production of hepaqtitis B surface antigen[J]. Chin J Biologicals (中国生物制品学杂志), 2014, 27: 954-958.
[40] Li F, Hashimura Y, Pendleton R, et al. A systematic approach for scale-down model development and characterization of commercial cell culture processes[J]. Biotechnol Prog, 2006, 22: 696-703.
[41] Nowak C, Cheung JK, Dellatore SM, et al. Forced degradation of recombinant monoclonal antibodies: a practical guide[J]. MAbs, 2017, 9: 1217-1230.
[42] Wang G: Overview of Biological Drug Inspections[R]. Beijing: IPEM, 2018.
[43] Broschard TH, Glowienke S, Bruen US, et al. Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics-current challenges and approaches[J]. Reg Toxicol Pharmacol, 2016, 81: 201-211.
[44] Pahl I, Dorey S, Barbaroux M, et al. Analysis and evaluation of single-use bag extractables for validation in biopharmaceutical applications[J]. PDA J Pharm Sci Technol, 2014, 68: 456-471.
[45] Vezer B, Buzas Z, Sebeszta M, et al. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents[J]. Curr Med Res Opin, 2016, 32: 829-834.
[46] Kelley BD, Kleinjans A, Lester P. Post-Licensure Purification Process Improvements for Therapeutic Antibodies: Current and Future States[M]//Gunter J, Eva L, Karol L, al et. Biopharmaceutical Processing Development,Design, andImplementation of Manufacturing Processes. Amsterdam: Elsevier, 2018: 1137-1149.
[47] Liu BN, Kan HJ, Bai Y, et al. The discussion on a proposed quality similarity assessment criteria of rituximab biosimilar[J]. Acta Pharm Sin (药学学报), 2019. DOI: 10.16438/j.0513-4870. 2019-0477.
[48] Melsheimer R, Calmann M, DeRitis A, et al. Ensuring product quality, consistency and patient supply over time for a large-volume biologic: experience with remicade?[J]. BioDrugs, 2018, 32: 405-414.