药学学报, 2021, 56(10): 2630-2641
引用本文:
耿颖, 杨泉, 张军, 王蕊, 周颖, 郑静, 宁保明, 魏宁漪. 经口吸入和鼻用药物制剂体外生物等效性统计学评价方法[J]. 药学学报, 2021, 56(10): 2630-2641.
GENG Ying, YANG Quan, ZHANG Jun, WANG Rui, ZHOU Ying, ZHENG Jing, NING Bao-ming, WEI Ning-yi. Statistical evaluation methods of in vitro studies for bioequivalence for orally inhaled and nasal drug products[J]. Acta Pharmaceutica Sinica, 2021, 56(10): 2630-2641.

经口吸入和鼻用药物制剂体外生物等效性统计学评价方法
耿颖1, 杨泉2, 张军3, 王蕊1, 周颖1, 郑静1, 宁保明1*, 魏宁漪1*
1. 中国食品药品检定研究院, 北京 102629;
2. 默克雪兰诺 (北京) 医药研发有限公司, 北京 100000;
3. 国家药典委员会, 北京 100061
摘要:
本文系统阐述了经口吸入和鼻用药物制剂(orally inhaled and nasal drug products,OINDPs)生物等效性(bioequivalence,BE)研究评估背景,综述了中国及国际上对该类制剂生物等效性的要求及体外等效性评价指导原则,详细阐述了美国食品药品管理局(FDA)体外生物等效性(in vitro bioequivalence,IVBE)评估的统计学方法和计算公式。采用FDA颁布的布地奈德吸入混悬液指导原则拟定稿中的实例,通过R语言编程途径计算群体生物等效性(population bioequivalence,PBE)统计学参数,并将结果与指导原则中的结果进行对比,提供计算程序的伪代码。本文为OINDPs的研发、质量控制及仿制制剂的开发提供了有益的思路与参考。
关键词:    经口吸入和鼻用药物      生物等效性      体外生物等效性      群体生物等效性      计算程序伪代码      布地奈德吸入混悬液     
Statistical evaluation methods of in vitro studies for bioequivalence for orally inhaled and nasal drug products
GENG Ying1, YANG Quan2, ZHANG Jun3, WANG Rui1, ZHOU Ying1, ZHENG Jing1, NING Bao-ming1*, WEI Ning-yi1*
1. National Institutes for Food and Drug Control, Beijing 102629, China;
2. Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100000, China;
3. Chinese Pharmacopoeia Commission, Beijing 100061, China
Abstract:
This article systematically reviews the background and regulatory requirements of bioequivalence of orally inhaled and nasal drug products (OINDPs), as well as the basic regulatory requirements for the assessment by the guidelines and guidance issued in China, the United States, and the European Union. Detailed statistical evaluation method considerations and calculations of the US FDA population bioequivalence (PBE) method were presented for the evaluation of in vitro bioequivalence (IVBE) for OINDPs. Using the example described in the FDA Draft Guidance for budesonide inhalation suspension, the PBE analysis statistical parameters were calculated via the R programming, and the results were compared with that in the guidelines. Moreover, pseudo-code for the PBE calculation program was provided. This paper aims to provide guidance and references for the research and development of new drug, as well as pharmaceutical quality control, and development of generic medicinal products for OINDPs.
Key words:    orally inhaled and nasal drug product    bioequivalence    in vitro bioequivalence    population bioequivalence    pseudo-code of calculation program    budesonide inhalation suspension   
收稿日期: 2021-04-27
DOI: 10.16438/j.0513-4870.2021-0640
基金项目: 国家食品药品监督管理局化学药品研究与评价重点实验室资助项目.
通讯作者: 宁保明,Tel/Fax:86-10-53851575,E-mail:ningbm@nifdc.org.cn;魏宁漪,Tel:86-10-53851604,E-mail:weiny@nifdc.org.cn
Email: ningbm@nifdc.org.cn;weiny@nifdc.org.cn
相关功能
PDF(493KB) Free
打印本文
0
作者相关文章
耿颖  在本刊中的所有文章
杨泉  在本刊中的所有文章
张军  在本刊中的所有文章
王蕊  在本刊中的所有文章
周颖  在本刊中的所有文章
郑静  在本刊中的所有文章
宁保明  在本刊中的所有文章
魏宁漪  在本刊中的所有文章

参考文献:
[1] Lu D, Lee SL, Lionberger RA, et al. International guidelines for bioequivalence of locally acting orally inhaled drug products:similarities and differences[J]. AAPS J, 2015, 17:546-557.
[2] European Medicines Agency. Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents (CPMP/EWP/4151/00Rev.1)[EB/OL]. 2009[2021-07-12]. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-clinical-documentation-orally-inhaled-products-oip-including-requirements_en.pdf.
[3] Center for Drug Evaluation, National Medical Products Administration. Technical guideline on the investigation of human bioequivalence of chemical drug generic drugs with pharmacokinetic parameters as the end-point[EB/OL]. 2016[2021-07-12]. http://www.cde.org.cn/zdyz.do?method=largePage&id=353342c97683d4fb.
[4] Center for Drug Evaluation,National Medical Products Administration. Guideline on the study of bioequivalence for generic orally inhaled products (OIP)[EB/OL]. 2020[2021-07-12]. http://www.cde.org.cn/news.do?method=largeInfo&id=dd8b4c48fe04fedf.
[5] Zhou JY, Zhang L, Mao SR. Recent progress of dry powder inhalation of proteins and peptides[J]. Acta Pharm Sin (药学学报), 2015, 50:814-823.
[6] Tang Y, Zhu JB, Chen XJ. A novel pulmonary delivery system--dry powder inhalers[J]. Acta Pharm Sin (药学学报), 2009, 44:571-574.
[7] Forbes B, Bckman P, Christopher D, et al. In vitro testing for orally inhaled products:developments in science-based regulatory approaches[J]. AAPS J, 2015, 17:837-852.
[8] Lee SL, Saluja B, García-Arieta A, et al. Regulatory considerations for approval of generic inhalation drug products in the US, EU, Brazil, China, and India[J]. AAPS J, 2015, 17:1285-1304.
[9] Hochhaus G, Davis-Cutting C, Oliver M, et al. Current scientific and regulatory approaches for development of orally inhaled and nasal drug products:overview of the ipac-rs/university of florida orlando inhalation conference[J]. AAPS J, 2015, 17:1305-1311.
[10] US Food and Drug Administration. Draft guidance on budesonide[EB/OL]. 2012[2020-04-22]. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm319977.pdf.
[11] US Food and Drug Administration. Draft guidance on albuterol sulfate[EB/OL]. 2016[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Albuterol%20sulfate_metered%20inhalation%20aerosol_RLD%2020503;%2020983;%2021457_RV12-16.pdf.
[12] US Food and Drug Administration. Draft guidance on mometasone furoate[EB/OL]. 2016[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Mometasone%20furoate_Metered%20aerosol%20inhalation_RLD%20205641_RC04-16.pdf.
[13] US Food and Drug Administration. Draft guidance on fluticasone propionate and salmeterol xinafoate[EB/OL]. 2019[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_208799.pdf.
[14] US Food and Drug Administration. Draft guidance on formoterol fumarate[EB/OL]. 2015[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Formoterol%20fumarate_Inhalation%20powder_020831_RC09-15.pdf.
[15] US Food and Drug Administration. Draft guidance on ketorolac tromethamine[EB/OL]. 2020[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_022382.pdf.
[16] US Food and Drug Administration. Draft guidance on olopatadine hydrochloride[EB/OL]. 2016[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Olopatadine%20HCl_nasal%20metered%20spray_RLD%20021861_RC09-16.pdf.
[17] US Food and Drug Administration. Draft guidance on azelastine hydrochloride[EB/OL]. 2017[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Azelastine%20HCl_nasal%20metered%20spray_NDA%20022203_RC08-17.pdf.
[18] US Food and Drug Administration. Draft guidance on fluticasone propionate[EB/OL]. 2019[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Fluticasone%20propionate%20nasal%20spray%20NDA%20020121%20RV%2002-2019.pdf.
[19] US Food and Drug Administration. Draft guidance on ipratropium bromide[EB/OL]. 2021[2021-07-12]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_021527.pdf.
[20] Al-Numani D, Colucci P, Ducharme MP. Rethinking bioequivalence and equivalence requirements of orally inhaled drug products[J]. Asian J Pharm Sci, 2015, 10:461-471.
[21] Center for Drug Evaluation,National Medical Products Administration. Technical guideline on quality control of inhaled preparations[EB/OL]. 2007[2021-07-12]. http://www.cde.org.cn/zdyz.do?method=largePage&id=006e32f00b5598ea.
[22] US Food and Drug Administration. Guidance for industry. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action DRAFT GUIDANCE[EB/OL]. 2003[2021-07-12]. https://www.fda.gov/media/70867/download.
[23] European Medicines Agency. Guideline on the pharmaceutical quality of inhalation and nasal products[EB/OL]. 2006[2021-07-12]. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-quality-inhalation-nasal-products_en.pdf.
[24] European Medicines Agency. Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98Rev.1/Corr)[EB/OL]. 2010[2021-07-12]. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf.
[25] General Requirements for Preparations <0111 Preparations for Inhalation> (Pharmacopoeia of the People's Republic of China 2020, Volume Ⅳ)[S]. Beijing:China Medical Science Press, 2020:12-16.
[26] General Requirements for Preparations <0106 Nasal Preparations> (Pharmacopoeia of the People's Republic of China 2020, Volume Ⅳ)[S]. Beijing:China Medical Science Press, 2020:8-9.
[27] Center for Drug Evaluation,National Medical Products Administration. Guideline on statistical approaches to investigating bioequivalence[EB/OL]. 2018[2021-07-12]. http://www.cde.org.cn/zdyz.do?method=largePage&id=b675758d481432f6.
[28] U.S. Pharmacopeia 43NF38. <5> Inhalation and Nasal Drug Products-General Information and Product Quality Tests[S]. Rockville:U.S. Pharmacopeia, 2020:6360-6367.
[29] U.S. Pharmacopeia 2021. <601> Inhalation and Nasal Drug Products:Aerosols, Sprays, and Powders-Performance Quality Tests[S]. Rockville:U.S. Pharmacopeia, 2020:1-25.
[30] US Food and Drug Administration. Code of federal regulations Title 21, PART 320 Bioavailability and bioequivalence requirements[EB/OL]. 2020[2021-07-12]. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=320.
[31] US Food and Drug Administration. Guidance for industry:statistical approaches to establishing bioequivalence[EB/OL]. 2001[2021-08-30]. https://www.fda.gov/media/70958/download.
[32] US Food and Drug Administration. Guidance for industry. Bioavailability and bioequivalence studies for orally administered drug products-general considerations DRAFT GUIDANCE[EB/OL]. 2002[2021-07-12]. https://www.fda.gov/files/drugs/published/Guidance-for-Industry-Bioavailability-and-Bioequivalence-Studies-for-Orally-Administered-Drug-Products——General-Considerations.PDF.
[33] US Food and Drug Administration. Metered dose inhaler (MDI) and dry powder inhaler (dpi) products-quality considerations guidance for industry DRAFT GUIDANCE[EB/OL]. 2018[2021-07-12]. https://www.fda.gov/media/70851/download.
[34] US Food and Drug Administration. Guidance for industry:nasal spray and inhalation solution, suspension, and spray drug products-chemistry, manufacturing and controls documentation[EB/OL]. 2002[2021-07-12]. https://www.fda.gov/media/70857/download.
[35] Council of Europe.European Pharmacopoeia 10.0. Preparations for Inhalation[S]. 2019:927-932.
[36] Council of Europe. European pharmacopoeia 10.0. Nasal Preparations[S]. 2019:918-920.
[37] Conference on the Future of Europe. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use[EB/OL].[2021-07-12]. https://eur-lex.europa.eu/legal-content/en/ALL/?uri=CELEX%3A02001L0083-20190726.
[38] Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies[M]. Third Ed. Taylor & Francis Group, 2009:455-459.
[39] US Food and Drug Administration. Statistical comparison of particle size distribution profiles[EB/OL]. 2004[2021-07-12]. http://pqri.org/commworking/minutes/pdfs/dptc/psdpcwg/Addl/DC01-475116-v2-Yi_Tsong_Statistical_Archive_PQRI_Profile_Comparisons.DOC.
[40] Adams WP, Christopher D, Lee DS, et al. Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 1:background for a statistical method[J]. AAPS PharmSciTech, 2007, 8:4.
[41] Christopher D, Adams WP, Lee DS, et al. Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols:part 2-evaluation of a method for determining equivalence[J]. AAPS PharmSciTech, 2007, 8:5.
[42] Christopher D, Adams W, Amann A, et al. Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3:final report on a statistical procedure for determining equivalence[J]. AAPS PharmSciTech, 2007, 8:E90.
[43] Grmaš J, Lužar-Stiffler V, Dreu R, et al. A novel simulation-based approach for comparing the population against average bioequivalence statistical test for the evaluation of nasal spray products on spray pattern and droplet size distribution parameters[J]. AAPS PharmSciTech, 2019, 20:38.