药学学报, 2021, 56(8): 2308-2314
引用本文:
崔靖, 宋丽娜*. 创新单抗药物申报临床试验病毒安全性相关监管指南调研与技术考量[J]. 药学学报, 2021, 56(8): 2308-2314.
CUI Jing, SONG Li-na*. Guidelines investigation and technical considerations of virus safety during investigational new drug application of innovative monoclonal antibody products[J]. Acta Pharmaceutica Sinica, 2021, 56(8): 2308-2314.

创新单抗药物申报临床试验病毒安全性相关监管指南调研与技术考量
崔靖, 宋丽娜*
国家药品监督管理局药品审评中心, 北京 100022
摘要:
随着我国生物制药自主创新能力的不断提高,越来越多的创新型单抗药物申报注册临床试验,同时国外已上市和/或国外开展临床试验的单克隆抗体药物在国内申报注册临床的数量也不断增加。2018年国家药品监督管理局对外发布了《新药Ⅰ期临床试验申请技术指南》(2018年第16号),该指南对创新药申报临床试验阶段药学研究及申报资料提出了相关要求,极大提高了生物创新药的申报质量。但相比美国药品监管机构和欧盟药品监管机构,我国针对创新药申报临床阶段细化的技术指南尚不完善,如生物技术产品申报临床阶段的病毒安全性评价。本文调研了2018~2020年申请人针对创新单抗药物申报临床阶段的一般性技术问题,发现申请人聚焦的问题包括生产终末细胞和/或细胞收获液检定以及病毒去除或灭活验证。同时,审评中也发现由于申请人对国内外技术指南阶段性要求理解的差异,导致申报资料也存在一定差异。结合我国和美国、欧盟药品监管机构病毒安全性相关技术指南的调研并基于技术考量,本文对生产过程中外源病毒因子检测和病毒去除或灭活验证提出个人建议,旨在确保创新单抗药物在申报临床试验阶段的病毒安全性。
关键词:    创新单抗药物      申报临床试验      病毒安全性      生产终末细胞和/或细胞收获液      病毒去除或灭活验证      技术考量     
Guidelines investigation and technical considerations of virus safety during investigational new drug application of innovative monoclonal antibody products
CUI Jing, SONG Li-na*
Center for Drug Evaluation, National Medical Products Administration (CDE, NMPA), Beijing 100022, China
Abstract:
With the development of antibody manufacturing technology and improvement of new drug research in domestic industry, more innovative monoclonal antibody products submitted investigational new drug (IND) application. At the same time, monoclonal antibody products from abroad which have been approved marketing authorization and/or conducted clinical trials submitted IND applications in China. The National Medical Products Administration (NMPA) issued the "Guideline of Investigational New Drug Application" (No. 16, 2018) which emphasized the chemical, manufacturing, and control (CMC) regulatory, and dossier requirements in IND application, greatly promoted the application quality of innovative biological products. However, compared to the Food and Drug Administration (FDA) and European Medicines Agency (EMA), our particular guidelines are insufficient, such as guideline on virus safety evaluation of biotechnological investigational medicinal products. This review investigated the questions raised by sponsors from 2018 to 2020, including the end of production cell (EOPC) and/or unprocessed bulk (UPB) testing and virus removal or inactivation validation. Meanwhile, sponsors submitted different dossiers due to differences in understanding of stage requirements of guidelines from domestic and abroad. Based on the guidelines of virus safety from NMPA, FDA, and EMA, and the technical considerations, this review puts forward personal suggestions on the adventitious agents testing and virus removal or inactivation validation in manufacturing process, aim to ensure virus safety of innovative monoclonal antibody products in clinical trials.
Key words:    innovative monoclonal antibody product    investigational new drug application    virus safety    end of production cell and/or unprocessed bulk    virus removal or inactivation validation    technical consideration   
收稿日期: 2021-02-05
DOI: 10.16438/j.0513-4870.2021-0195
通讯作者: 宋丽娜,Tel:86-10-85243036,E-mail:songln@cde.org.cn
Email: songln@cde.org.cn
相关功能
PDF(330KB) Free
打印本文
0
作者相关文章
崔靖  在本刊中的所有文章
宋丽娜*  在本刊中的所有文章

参考文献:
[1] Kan HJ, Liu BN, Bai Y, et al. Analysis of monoclonal antibody drug registration in China[J]. Chin J New Drugs (中国新药杂志), 2019, 28:1941-1946.
[2] FDA. Content and format of investigational new drug applications (INDs) for Phase I studies of drugs, including well charecterized, therapeutic, biotechnology-derived products[EB/OL]. Rockvill:FDA, 1995[2020-03-24]. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071597.pdf.
[3] ICH. Viral safety evaluation of biotechnology products derived from cell lines of human of animal origin[EB/OL]. Geneva:ICH, 1999[2020-03-24]. https://www.ich.org/page/quality-guidelines.
[4] National Pharmacopoeia Convention. Manufacture and Quality Control of Animal Cell Substrate for Biological Products (生物制品生产检定用动物细胞基质制备及质量控制) [M]. Beijing:NMPA, 2020:12-13.
[5] NMPA. General principles of evaluation of mammalian cell quality control technology for the production of recombinant biological products (重组制品生产用哺乳动物细胞质量控制技术评价一般原则) [EB/OL]. Beijing:NMPA, 2006[2020-03-24].http://www.cde.org.cn/zdyz.do?method=largePage&id=54482a65ad322f6a.
[6] NMPA. General principles of virus safety evaluation of biological tissue extraction and eukaryotic cell expression biological products (生物组织提取制品和真核细胞表达制品的病毒安全性评价技术审评一般原则) [EB/OL]. Beijing:NMPA, 2005[2020-03-24]. http://www.cde.org.cn/zdyz.do?method=largePage&id=71fc578fd703429e.
[7] FDA. Points to consider in the manufacture and testing of monoclonal antibody products for human use[EB/OL]. Rockvill:FDA, 1997[2020-03-24]. https://www.fda.gov/media/76798/download.
[8] EMA. Guideline on virus safety evaluation of biotechnological investigational products[EB/OL]. Amsterdam:EMA, 2008[2020-03-24]. https://www.ema.europa.eu/en/virus-safety-evaluation-biotechnological-investigational-medicinal-products.
[9] NMPA. Guideline on technology and validation of virus removal/inactivation of blood products (血液制品去除/灭活病毒技术方法及验证指导原则) [EB/OL]. Beijing:NMPA, 2002[2020-03-24]. http://www.cde.org.cn/search.do?method=searchTitle.
[10] FDA. Points to consider in the characterization of cell lines used to product biologicals[EB/OL]. Rockvill:FDA, 1997[1993-07-02]. https://www.fda.gov/media/76255/download.
[11] United States Pharmacopeial Convention. Viral safety evaluation of biotechnology products derived from cell lines of human of animal origin[EB/OL]. United States:United States Pharmacopeial Convention, 2013[2020-03-24]. https://online.uspnf.com/uspnf/document/1_GUID-72F7A1BD-306E-41EC-8C84-64FCB73248E1_1_en-US?source=Search%20Results&highlight=Viral%20safety%20evaluation%20of%20biotechnology%20products%20derived%20from%20cell%20lines%20of%20human%20of%20animal%20origin.
[12] United States Pharmacopeial Convention. Design, evaluation, and characterization of viral clearance procedures introduction[EB/OL]. United States:United States Pharmacopeial Convention, 2016[2020-03-24]. https://online.uspnf.com/uspnf/document/1_GUID-ADC8111F-7678-475A-AECF-30BEFBE31C07_1_en-US?source=Search%20Results&highlight=Design%2C%20evaluation%2C%20and%20characterization%20of%20viral%20clearance%20procedures%20introduction.
[13] EMA. Virus validation studies:the design, contribution and interpretation of studies validating the inactivation and removal of viruses[EB/OL]. Amsterdam:EMA, 1996[2020-03-24]. https://www.ema.europa.eu/en/virus-safety-evaluation-biotechnologicalinvestigational-medicinal-products.
[14] EMA. Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials[EB/OL]. Amsterdam:EMA, 2018[2020-03-24]. https://www.ema.europa.eu/en/requirements-quality-documentationconcerningbiological-investigational-medicinal-products-clinical.