Drug-Device Combination in US Part 1

【审评规范】FDA药-械组合产品桥接指导原则介绍萧惠来国家药品监督管理局药品审评中心，北京100022摘要：美国食品药品管理局（F D A)的“供企业用药-械和生物制品-器械组合产品的桥接指导原则（草案）”详细描述 了药-械组合产品注册申请人，利用另外的开发方案产生的信息，作为拟开发产品的注册资料（即桥接），替代试验研究资 料的方法，支持拟申报产品的批准；推荐渐进式5步骤法，确定桥接策略和信息需求并列举了3个示例予以解读。

详细介绍 该指导原则的内容，期望为中国药-械组合产品研发和监管开辟新思路，建议在合适的条件下可考虑利用“桥接”方法减少 试验研究，加速研宄进程，缩短研宄周期，节省研宄经费，促进药-械组合产品的开发。

关键词：美国食品药品管理局：药-械组合产品：桥接：指导原则中图分类号：R951 文献标志码： A 文章编号：1674-6376 (2021) 03-0461-07DOI ：10.7501/j.issn. 1674-6376.2021.03.001Introduction to FDA's bridging for drug-device combination products guidanceXIAO HuilaiCenter for Drug Evaluation, National Medical Products Administration, Beijing 100022, ChinaAbstract: The FDA's Bridging for Drug-Device and Biologic-Device Combination Products Guidance for Industry (Draft) described in detail that the applicant for registration of drug-device combination products can use the information developed by another development program as the registration information of the product to be developed (i. e. bridging) and replace the experimental research data to support the approval of the product to be applied for. That is to say, the stepwise five step approach is recommended to determine the bridging strategy and information requirements are determined, and three examples are given to interpret. This paper introduces the guidance in detail, hoping to open up new ideas for the research and development as well as supervision of drug-device combination products in China. In suitable conditions, it can be considered to use "bridging" method to reduce experimental research, speed up the research process, shorten the research cycle, save research funds, and promote the development of drug-device combination products.Key words: FDA; drug-device combination product; bridging; guidance美国食品药品管理局（FDA)于2019年12月发 布了“供企业用药-械和生物制品-器械组合产品的 桥接指导原则（草案）”[1]。

以医疗器械作用为主的药械组合产品注册审查指导原则英语Guidance Principles for the Registration Review of Medical Device-Drug Combination Products1. IntroductionMedical device-drug combination products are a category of products that combine a medical device and a drug component to achieve the intended use. The registration review of such products requires a comprehensive assessment of both the device and drug components, as well as the interaction between them. This guidance outlines the key principles and considerations for the registration review of medical device-drug combination products.2. ScopeThis guidance applies to medical device-drug combination products where the device component is the primary mode of action. The principles and considerations outlined in this guidance may also be applicable to other types of combination products, such as those where the drug component is the primary mode of action.3. Regulatory FrameworkThe registration of medical device-drug combination products is subject to the regulatory requirements for both medical devices and drugs. Applicants should ensure compliance with the relevant regulations and guidelines for each component, as well as the specific requirements for combination products.4. Product Identification and ClassificationMedical device-drug combination products should be clearly identified and classified based on the primary mode of action and the intended use. Applicants should provide a detailed description of the product, including the device and drug components, their respective functions, and the intended use of the combination product.5. Quality ConsiderationsThe quality of both the device and drug components should be thoroughly evaluated. This includes the design, manufacturing, and control of the individual components, as well as the compatibility and interactions between them. Applicants should provide comprehensive information on thequality attributes, specifications, and control strategies for the combination product.6. Nonclinical EvaluationNonclinical studies should be conducted to assess the safety and performance of the combination product. This may include studies on the device-drug interaction, the local and systemic effects of the combination, and the potential for any adverse interactions or reactions.7. Clinical EvaluationClinical studies are essential to evaluate the safety and efficacy of the combination product. Applicants should design and conduct clinical trials that assess the overall performance of the combination product, including the device and drug components, and the interaction between them.8. Risk ManagementApplicants should implement a comprehensive risk management plan to identify, assess, and mitigate the potential risks associated with the combination product. This includes the risks related to the device and drugcomponents, as well as the risks arising from the interaction between them.9. Labeling and PackagingThe labeling and packaging of the combination product should provide clear and comprehensive information to healthcare professionals and patients. This includes the instructions for use, any special handling or storage requirements, and any warnings or precautions related to the combination product.10. Postmarket SurveillanceApplicants should establish a robust postmarket surveillance system to monitor the performance and safety of the combination product after it is approved for use. This includes the collection and analysis of adverse event reports, as well as the implementation of any necessary corrective or preventive actions.中文版本:医疗器械作用为主的药械组合产品注册审查指导原则1. 引言医疗器械-药物组合产品是一类将医疗器械和药物组合在一起以实现预期用途的产品。

固定剂量复方制剂注册指导原则缩写98绪论 991.适用范围 1002.总体考虑 1003.定义 1104.注册分类 1135.衡量衡量固定剂量复合剂型的优缺点 1136.固定剂量复方制剂上市许可所需要的数据 1167.固定剂量复方制剂产品信息或说明书 1358.上市后研究和上市后的变动变更136参考文献 138 附件1 组合包装的固定剂量复方制剂指导原则 139 附件2 判断科学文献数据是否可以被接受的原则 140附件3 药品研发（或处方前研究） 142 附件4 优效性、等效性和非劣效性临床试验 144缩写AIHW Australian Institute of Health and Welfare (澳大利亚卫生与福利研究所)API Active pharmaceutical ingredient (活性药物成分)BCS Biopharmaceutics Classification Scheme (生物药学分类系统)BCS #1 Biopharmaceutics class number 1(the most favourable) (生物药学分类系统第一类)（受欢迎最有利的一类）CHMP Committee for Medicinal Products for Human Use; see also CPMP (人用医疗产品委员会)（参见CPMP）CPMP Committee for Medicinal Products for Human Use (CHMP), formerly the Committee for Proprietary Medicinal Products (人用医疗产品委员会(CHMP), 前身为专利药品委员会)CPP Certificate of pharmaceutical product (药品证书)EMEA European Medicines Agency, formerly the European Medicines Evaluation Agency (欧洲药品局, 前身为欧洲药品评审局)EU European Union (欧盟)FDA Food and Drug Administration of the USA (美国食品药品管理局)FDC Fixed-dose combination (固定剂量复方治疗)(见词汇表)FDC-FPP Fixed-dose combination finished pharmaceutical product (固定剂量复方药品)(见词汇表)GCP Good clinical practice (药物临床试验管理规范)GLP Good laboratory practice (药物非临床研究质量管理规范)GMP Good manufacturing practice (药品生产质量管理规范)GTDP Good trade and distribution practice (药品贸易和分销管理规范)GSP Good storage practice (药品贮存管理规范)ICH International Conference on Harmonisation (人用药品注册技术要求国际协调会议)IUTLD International Union of Tuberculosis and Lung Disease (国际抗结核病和肺病联盟)MIC Minimum inhibitory concentration (最低抑菌浓度)PP Per-protocol (a form of clinical trial design and analysis) 符合方案集符合方案集（临床试验设计和分析的一种形式）SPC Summary of product characteristics (产品特点总结药品说明书)(见词汇表)TGA Therapeutic Good Administration (澳大利亚药品管理局)WHO World Health Organization (世界卫生组织)绪论随着固定剂量复方治疗（fixed-dose combinations, FDCs）的发展，它们在保护公众健康方面发挥了日益重要的作用。

51文章编号：1671-7104(2020)01-0051-05汤康丽，周俊蕾，李勇，瞿敏明，王钰婕，罗健上海微创医疗器械（集团）有限公司，上海市，201203药械组合产品作为药物和医疗器械的组合体，有效降低了传统医疗器械带来的并发症等风险，在临床应用尤其是植入式治疗领域取得巨大成功。

该研究团队首先阐述了各个国家对药械组合产品的定义和要求，其次对几类常见的药械组合产品的市场应用及其研究进展进行总结分析，对药械组合产品目前存在的技术问题及未来发展趋势进行了分析展望。

药械组合产品；研究和应用 R95；R197.39Adoi: 10.3969/j.issn.1671-7104.2020.01.011TANG Kangli, ZHOU Junlei, LI Yong, QU Minming, WANG Yujie, LUO JianShanghai MicroPort Medical (Group) Co., Ltd., Shanghai, 201203Drug-device combination product, which comprises at least a drug and a medical device, has beenproved to effectively reduce the risk of complications accompanied with conventional medical devices implantation, and has a great clinical success especially in implantable therapeutics. Herein, we firstly elaborated the definitions and requirements of drug-device combination product in different countries, then summarized the market application and research development of typical drug-device combination products. Technical problems and the trend of future development had also been analyzed.drug-device combination products, research and application药械组合产品研究及应用进展【作 者】【摘 要】【关 键 词】【中图分类号】【文献标志码】【 Writers 】【 Abstract 】【Key words 】Progress in Research and Application of Drug-DeviceCombination Product基金项目：上海市科技创新行动计划标准项目（19DZ2202100）通信作者：周俊蕾，E-mail: jlzhou@0 引言药械组合产品通常是指药品和医疗器械共同组成的产品，药械组合产品可以是药物增强型医疗器械，如药物洗脱支架、抗菌导管等，也可以是以器械作为辅助给药手段，如各种透皮贴剂技术等。

专利名称：Drug delivery device发明人：Irina Lanin,Bernhard Forys,AlastairClarke,Matthew Ekman,KirstenGoode,Michael Heald,John Hiles,Chris Smith申请号：US13202440申请日：20100304公开号：US08702659B2公开日：20140422专利内容由知识产权出版社提供专利附图：摘要：Drug delivery device, comprising a body unit having a first opening and a second opening, a plunger arranged such that its distal end is positioned inside the body unit,wherein the plunger is moveable in the distal direction with respect to the body unit, a needle assembly, with a proximal end and a distal end comprising a needle, wherein the proximal end of the needle assembly and the distal end of the plunger are configured such that they can get into an adhesion connection.申请人：Irina Lanin,Bernhard Forys,Alastair Clarke,Matthew Ekman,KirstenGoode,Michael Heald,John Hiles,Chris Smith地址：Frankfurt am Main DE,Frankfurt am Main DE,Nantwich GB,Macclesfield GB,Frankfurt am Main DE,Crewe GB,South Wirral GB,Holmes Chapel GB 国籍：DE,DE,GB,GB,DE,GB,GB,GB代理机构：McDonnell Boehnen Hulbert & Berghoff LLP更多信息请下载全文后查看。

药学英语- 1 -Table of ContentsLesson 1 Pharmacy in China …………………………………………………Lesson 2 Vitamins ………………………………………………………………Lesson 3 Foods That Fight Cancer …………………………………………Lesson 4 Good Drugs Dangerous DosesA growing threat to public and personal health …………………………Lesson 5 Green Pharmacy Herbal Medicine …………………………………Lesson 6 Traditional Chinese Herbal Medicine …………………………….. Lesson 7 Natural Products ……………………………………………………- 2 -LESSON ONETEXTPharmacy in ChinaThe educational system was perhaps the first shock I encountered in China. The schools of pharmacy in the People’s Republic of China (PRC) are operated by two different governmental agencies. The State Pharmaceutical Administration, an agency of the central government, operates two pharmaceutical universities that have 4000 and 4500 students respectively. These two schools, in Shenyang in Northeast China and in Nanjing in East China, exist to prepare industrial pharmacists for positions within the pharmaceutical industry.In addition, another approximately 50 colleges of pharmacy throughout the various provinces of the PRC are operated by the Ministry of Public Health. There, colleges of pharmacy are almost equally divided between western medicine oriented schools1and those which teach future pharmacists the art and skills of Chinese herbal medicine. Most of the western medicine oriented schools are departments within large medical faculties where the traditional Chinese Medicine schools are sometimes found at medical faculties.SIMILAR TO THE U.S.The next surprise was that the curricula at the colleges of pharmacy in China were not so different from those encountered by pharmacy students in the U. S. In fact, the American student would probably be pleased to learn that the state board examination2prevalent here does not exist in China; rather, graduation and successful completion of studies enable one to become a fully qualified and registered pharmacy practitioner. Furthermore, recent graduates have more options in seeking employment than those who were usually assigned to an employment site based on existing needs of state-run pharmaceutical enterprises. The guided search for employment upon graduation is one of the major changes in China’s higher education, embraced by most college graduates.Virtually all of the graduates of the two pharmaceutical universities operated by the State Pharmaceutical Administration are employed within the- 3 -pharmaceutical industry.Graduates of the other schools of pharmacy generally find employment in hospitals and clinics.You are probably asking: “What about community pharmacy3?”Well, the answer is that people usually receive medical care in clinics at their place of employment, within various neighborhood health centers, or as outpatients at large hospitals. All of these sites employ pharmacists who dispense drugs. Therefore, it is not often that a patient needs to go to a community pharmacy shop to obtain medications.EAST AND WESTMost of the community pharmacies have two departments or two areas, and this is also the case in hospitals and clinics. On one side of the pharmacy we find something which very much resembles any pharmacy that we would see in the U. S. or in Western Europe; but on the other side of the room, or in the next room, is a strange sight - drawers and drawers of herbs and items such as dried portions of small animals, antlers, roots, and pieces of various other dried objects. These are compounded by specialists in traditional Chinese medicine; powders are made, for swallowing by patients.It is easy for us to laugh at this latter type of therapy, but it retains its faithful followers and is considered to be equal in importance to the western drugs and western medicine practiced in China.If one chooses to purchase a drug and does not feel the need to visit the physician at a clinic, one can go to the several community pharmacies which are located on the main shopping streets in downtown areas and ask for drugs. Virtually all drugs except narcotics and other scheduled substances4are legally available without a prescription. The patient may walk into the pharmacy and ask for ampicillin by name and be sold a small bottle containing 12, 16 or 24 capsules.Or he may ask the pharmacist to recommend an antibiotic for a child with an infection, sore throat, etc.While this is rather unusual in our American orientation, it was not a complete surprise to me, as I have seen Rx drugs5 being sold over-the-counter in many parts of the world. I admit, though, that I was curious about the potential for- 4 -abuse. I was assured by numerous individuals that the Chinese population had better things to spend their money on than taking needless drugs, and that there was a minimal if not almost non-existent chemical dependency problem6.SCOPE OF SPASomething ought to be said about the State Pharmaceutical Administration (SPA) which was mentioned earlier. It is a combination of the Food and Drug Administration, the entire pharmaceutical industry, research laboratories, pilot factories7 and educational institutions-all rolled into one.The Beijing-based SPA is a huge unit within the central government. SPA operates thousands of pharmaceutical factories and dictates production schedules8. It arranges contracts for raw materials and intermediate products9and also negotiates for the sale of finished dosage forms to the pharmacies and for export.Other divisions maintain quality control and quality assurance while yet other divisions oversee SPA’s two massive pharmaceutical universities as well as their on campus pilot plants used for training and for the production of drugs for clinical trials.The SPA also has a technology branch which conducts research into improving production techniques and evaluating new technology.During the three-week visit, I gave about a dozen lectures. At many of them, questions about American pharmacy practice were asked. Perhaps the most difficult concept for my Chinese colleagues to grasp was that of Americans deciding individually to move to another part of the country - to quit their jobs, return to school, accept employment elsewhere, or whatever the reason might be. When I mentioned anything of this nature, I was deluged with questions which basically asked what would hap pen if one’s supervisor refused to grant permission to leave one’s job. This says something about the employment situation in the PRC. My audiences were stunned when I indicated that one need only give some notice if there is not a formal contract, as a courtesy, and to select freely another place of employment.SPARTAN, BUT SIMILARDespite the rather spartan conditions found at most pharmacy operations in hospitals and clinics, the work was similar to what we do in that nearly all of the- 5 -products were prefabricated at the factory, including most of the traditional remedies. The pharmacists generally dispensed already manufactured capsules, tablets or powders. Powders were seen more frequently than they are here, but the bulk of the medication was, as it is here, in tablet dosage forms.Most of my Chinese colleagues were professionally well informed, reasonably happy with their jobs, and optimistic about the future.Nearly all of the persons I encountered were enthusiastic and positive about their profession and its future.There is a Chinese Pharmaceutical Association which has its headquarters in Beijing and branches in most other cities and provinces. These groups get together, discuss professional matters, and often publish journals and newsletters.The Association receives a subsidy or support from the national government.Interest was shown in social pharmacy, clinical pharmacy and pharmacy management, as these subjects are not presently taught at the colleges of pharmacy within the PRC. It was my impression, however, that pharmaceutics, biopharmaceutics, medicinal chemistry and pharmacology are similar to what is taught and known in this country.MONTHLY W AGE: $ 70In the 1980s, pharmacist earns about $ 70 per month, an amount that enables one to live reasonably comfortably. Rents are minimal; only a few dollars per month pays for a typical small apartment. Nearly all of the urban population resides in that type of housing.Transportation on buses costs only about a dime a ride, but most people appear to use bicycles as their principal means of conveyance. A sight I found interesting was a parking lot with bicycles arranged in neat rows for as far as the eye could see-similar to the huge automobile parking lots in the U. S. It costs about two pennies to park a bicycle for a day. Most of the other needs are relatively inexpensive, although the cost of food is increasing.The Chinese pharmacists I met appeared well dressed and there is an ever increasing variety of clothing styles, colors and designs. Health care is considered good and the status of the pharmacist is at least equal to that accords to pharmacists in this country.The possibility exists for greater interprofessional relationships. Reason: so - 6 -much of pharmacy is practiced in institutional settings where other health care practitioners function in close coordination with the pharmacist.A large number of the people I met in pharmacy circles had been to the U. S. at one time or another for postgraduate studies, short training classes or professional visits.I was convinced that the warm reception I received was due in part to the fond memories that many of these people had about their kind reception by American families and pharmacists while they visited the U. S.The trip was indeed fascinating and an eye opener.I recommend that my colleagues take such a voyage after they have passed a test in the use of chopsticks, as knives and forks are unavailable at many places.In reflecting about the visit after coming home, I once again came to the conclusion that we are very fortunate with the resources, appliances and status that we have as a profession in the U.S.WORDS AND EXPRESSIONSpharmacy [ ♐❍☜♦♓] n.药学；药店pharmaceutical[ ♐❍☜♦◆♦♓☜●] adj.制药(学)上的药学的；药用的pharmacist [ ♐❍☜♦✋♦♦] n.药剂师，药商；a ~’s药房oriented[ ❒♓♏⏹♦♓♎☜☺] adj. 导向的；以…目的的；重视…的herbal[ ♒☜♌☜●] adj.草的；草药的curriculum[ ☜❒♓◆●☜❍] n.学校的全部课程，（一门）课程prevalent [ ☐❒♏❖☜●☜⏹♦] adj.普遍的；流行的option [ ☐☞☜⏹] n.选择权enterprise [ ♏⏹♦☜☐❒♋♓]n.企业；公司embrace [♓❍♌❒♏♓♦] vi. 拥抱n.拥抱拥抱，接受outpatient [♋◆♦☐♏♓☞☜⏹♦] n. 门诊病人an ~ clinic 门诊所dispense [♎♓♦☐♏⏹♦] vt.分发, 分配；(尤指按处方)配（药）、发（药）medication[ ❍♏♎♓♏♓☞☜⏹] n.药物；药物治疗antler [ ✌⏹♦●☜] n.鹿角, 茸角鹿角therapy [ ♏❒☜☐♓] n.治疗，- 7 -疗法retain [❒♓♦♏♓⏹] vt.保持, 保留narcotic [⏹♦♓] n. 麻醉剂；催眠药prescription[☐❒♓♦❒♓☐☞☜⏹] n.药方，处方ampicillin [ ✌❍☐♓♦♓●♓⏹] n. 氨苄青霉素orientation[ ☎✆❒♓♏⏹♦♏♓☞☜⏹] n.定向位，方向位，熟悉，适应minimal [ ❍♓⏹♓❍☜●] adj.最低限度的，最小的dictate [♎♓♦♏♓♦] v.命令，支配intermediate[ ♓⏹♦☜❍♓♎☜♦] adj.中间的negotiate [⏹♓♈☜◆☞♓♏♓♦] v. 谈判；解决dosage [ ♎☜◆♦♓♎✞] n.剂量,用量assurance [☜☞◆☜❒☜⏹♦] n.保证；自信oversee [ ☜◆❖☜♦♓] v. 监督/视；检查massive [ ❍✌♦♓❖] adj.规模巨大的；大剂量的on-campus [ ✌❍☐☜♦] adj.校园内的clinical [ ●♓⏹♓☜●] adj.临床的deluge [ ♎♏●◆♎✞] v.淹没；泛滥supervisor[ ♦◆☐☜❖♋♓☜] n. 主管人stun [♦♦✈⏹] vt. 使大吃一惊；不知所措courtesy[ ☜♦♓♦♓ ] n.礼貌；好意Spartan [ ♦☐♦☜⏹] adj.简朴的prefabricate[ ☐❒♓♐✌♌❒♓♏♓♦] v.预制；预先构想remedy [ ❒♏❍♓♎♓] n.治疗(法),药物capsule [ ✌☐♦◆●] n.胶囊tablet [ ♦✌♌●♓♦] n.药片powder [ ☐♋◆♎☜] n.药粉，粉剂bulk [♌✈●] n.大批（量）；大部分newsletter[ ⏹✞●♏♦☜☎❒✆] n.业务通讯subsidy [ ♦✈♌♦♓♎♓] n. 津贴pharmaceutics[ ♐❍☜♦◆♦♓♦] n.制药学，药剂学biopharmaceutics[ ♌♋♓☜◆♐❍☜♦✞8♦♓♦] [复] n.生物制药学，生物药剂学pharmacology[ ♐❍☜●☜♎✞♓]n.药理学，药物学reside [❒♓♋♓♎] vi.居住dime [♎♋♓❍] n.一角；很少的钱conveyance [ ☜⏹❖♏♓☜⏹♦] n.交通工具accord [☜♎] vt.给予，使一致interprofessional[ ♓⏹♦♏☐❒☜ ♐♏☞☜⏹●] adj.专业之间的；职业之间的institutional[ ♓⏹♦♦♓♦◆☞☜⏹☜●] adj.公共机构的setting [ ♦♏♦♓☠] n. 环境coordination[ ☜◆♎♓⏹♏♓☞☜⏹] n.协作；配合postgraduate[ ☐☜◆♦♦♈❒✌♎◆♓♦☐☜◆♦♦♈❒✌♎✞◆♓♦] adj.研究生的fascinating [ ♐✌♦♓⏹♏♓♦♓☠] adj.迷人的；吸引人的chopsticks [ ♦☞☐♦♦♓♦] n.筷子NOTES1.western medicine oriented schools: schools with western medicine as themain course2.the state board examination: the examination organized by the state board ofpharmacy in each statemunity pharmacy: public drug store on the street4.scheduled substances: Drugs with severe side effects have been classified bythe U.S. Government as the scheduled drugs, hence controlled by law.5.Rx drugs: drugs which must be prescribed by the doctor6....that the Chinese population had better things to spend their money onthan taking needless drugs, and that there was a minimal if not almost non-existent chemical dependency problems: ... that the Chinese people would spend their money on other things rather than on unnecessary drugs, and that the number of the persons addicted to drugs was quite limited, if there did exist such things7.pilot factories: factories in which drugs are produced for clinical trials8.production schedules: contents of drugs to be produced99.intermediate products: half-finished drugsEXERCISESI. Questions:1.Why was the author puzzled about the educational system in China?2.What’s the same characteristic of about 50 colleges of pharmacy throughoutChina?3.What kind of job will students get when they graduate from thepharmaceutical universities? And what about the graduates of other colleges of pharmacy?4.What’s the function of the SPA?5.What questions were often asked at the lectures given by the author?6.Why did the author think that the Chinese pharmacists were well-informed?7.According to the author, the Chinese colleagues were friendly to him. Why?8.The author was much impressed by what he had seen in China. Find the proofin the text.9.What’s the author’s attitude towards traditional Chinese medicine?10.Can you tell, according to the text, something about pharmacy in the USA?II. Translation1.人首次与医生打交道也许是在他出生时。

无源医疗器械技术文件和设计文档指南Whereas the term “Technical File“ is used for Medical Devices of class I, class IIa and class IIb, the term “Design Dossier“ is used for the class III products.标题中的“技术文件”适用于I类，IIa类,IIb类医疗器械，“设计文档”适用于III类医疗器械。

Technical Files are retained in the premises of the manufacturer or the Authorized Representative for potential review of Competent Authorities and Notified Body.Part B of the Technical File may be available at the manufacturer only.技术文件是保留在制造商或授权代表单位的主管部门和认证机构。

部分技术文件B部分只保留在制造商处。

Whereas Design Dossiers have to be submitted to the Notified Body for review prior to CE-Marking of the product (use form Application for CE Conformity Assessment (Product)MED_F_03.03). We will assign a project manager who will entrust one or more further experts with the review of particular modules. All experts are at your disposal directly or indirectly through the project manager. After successful review, the Notified Body issues a design examination certificate according to Annex II.4 of the Council Directive certifying compliance with the relevant provisions of Annex I of the MDD.设计档案材料已被提交到公告机构用于需要CE认证前的产品审查（用CE合格评定（产品）MED_F_03.03规定的格式）。

美国医疗器械促进协会---AAMI（.au/）ProfileAAMI: Leading insurer. Pacesetter in customer benefits and service.AAMI is a leading car, home, compulsory third party (CTP) and small business insurer. We deal directly with our customers and we use innovative business and marketing strategies to provide them with high quality products and excellent customer service. You've already found we're easy to contact.Insurance benefits such as no fault, no penalty; lifetime repair guarantee; lifetime rating one/maximum no claim bonus; valet service; progressive no claim discount on home insurance and the first general insurance customer charter were all introduced by AAMI.Established in 1970, AAMI today has more than 2.5 million policyholders and millions of incoming telephone calls annually.historyIncorporated in Victoria in September 1969, AAMI commenced business on 1 January 1970 as a motor vehicle insurer, offering a major independent alternative to government-owned and motor club-owned insurers. However, it was back in 1934, on 7 January, that the first policy was granted, but not by AAMI as it is known today. The risk was underwritten by a company called Club Motor Insurance Agency (Club Motor).Club Motor was established in 1933 as a highly specialised company to provide motor vehicle insurance for members of the RACV in Victoria, the RACQ in Queensland and the RACT in Tasmania. The Club Motor arrangement continued until 31 December 1969, when the RACV decided to become an insurer in its own right. The RACQ quickly followed suit so that only the RACT remained in the fold. But what was the end of a long liaison, was the beginning for AAMI as it is known today. After the split, and to avoid customer confusion, Club Motor's consortium of shareholders, which read like the who's who of the insurance industry, was no longer able to use the Club Motor name, so they decided on the name Australian Associated Motor Insurers Limited, known as AAMI.In 1978, AAMI branched out into South Australia and then into New South Wales in 1983. The RACT broke away from AAMI in 1985. However AAMI was able to retain 80% of that business. In 1989 came AAMI's decision to diversify. After nearly 20 years of operating solely in car insurance, AAMI launched into the home insurance market. This move was the result of a detailed analysis of the benefits of applying AAMI's strengths, experience and infrastructure to other endeavours without diluting its motoring expertise. The year 1989 also saw the deregulation of the CTP market in New South Wales, with AAMI being granted a licence to operate. In 1993, AAMI entered the Queensland CTP market.AAMI's business has continued to grow and develop so that, today, home insurance and CTP insurance are major components, making increasingly important contributions to the company'sresults.WuXi AppTec 副总裁兼总经理受邀加入美国医疗仪器促进协会(AAMI) 标准委员会在中美两国均有运营实体，全球领先的医药、生物制药以及医疗器械研发外包服务企业药明康德(NYSE: WX)，今日荣幸宣布其位于美国的子公司之一WuXi AppTec 亚特兰大运营分部的副总裁兼总经理Trabue D. Bryans 女士受邀加入美国医疗仪器促进协会(AAMI) 标准委员会，任期三年。

(Order No. 15 of SDA)The Provisions for Medical Device Classification were passed by the State Drug Administration at the administration affairs meeting on February 17 of 2000, are hereby promulgated and shall go into effect as of April 10, 2000.Zheng XiaoyuDirector- General of State Drug AdministrationApril 5, 2000Provisions for Medical Device ClassificationArticle1 The Provisions are stipulated in accordance with the Regulation on Supervision and Administration of Medical Device to standardize the classification of medical devices.Article2 "Medical devices" refer to those instruments, equipment, tools, materials and other objects, including the software attached to them, that are designed to be used either independently or in combination on human body. These devices are used for:1.Prevention, diagnosis, treatment, monitoring or remission of diseases;2. Diagnosis, treatment, monitoring, remission or compensation of injury or physical disability;3.Research, replacement or adjustment of anatomical or physiological process;4. Control of pregnancy.Basically, the effect of these devices on human body is not achieved through means of pharmacology, immunology or metabolism; though they might be resorted to in order to bring about certain supplementary effect.Article3 The Provisions are meant to direct the formulation of The Category of Medical Device Classification as well as to determine the classes of newly registered products.Article 4 The classification of medical devices should be determined by a combined judgement on three respects: its structural characteristics, form of operation as well as conditions for use.Specifically, their classification can be based on Criteria for Medical Device Classification (see appendix).Article 5 Guidelines for Medical Device Classification1. The structural characteristics of medical devicesAccording to their respective structural characteristics, medical devices are divided into active and passive devices.2. The forms of operation of medical devicesMedical devices are designated into different forms of operation in accordance with their intended purposes.1) Passive devices in terms of their form of operation can be classified as device used for transportation and storage of pharmaceutical liquid, device for alteration of blood, body fluids, medical dressing, surgical instruments;reusable surgical instruments, disposable aseptic device, implantable device, device for contraception and birth control, device for sterilization and cleaning, patient care device, in vitro diagnostic reagent, as well as other passive contacting device or passive supplementary device.2) Active devices in terms of their form of operation can be classified as device for treatment through energy, diagnostic monitoring, body fluids transportation and ionized radiation, laboratory instruments and medical sterilizer; as well as other active contacting device or active supplementary device.3. The conditions for use of medical devices:Medical devices may be divided into contacting or inserted devices and non-contacting devices based on their conditions for use, which include the possible injuries they might entail as well as their impact on the medical treatment.1) Contacting or inserted devicesa. Term of use: temporary use, short - term use, long-term use;b. Particular parts of the human body being contacted:skin, cavity and tract; trauma or body tissue; blood circulation system or central nervous system;c. The degree of injuries caused by malfunction of active devices:minor injuries, injuries, serious injuries.2) Non-contacting DevicesThe impact these devices have on treatment ranges from: basically no impact, indirect impact, substantial impact.Article 6 Principles for Medical Device Classification1. The classification of medical devices should be conducted in accordance with The Criteria for Medical Device Classification.2. The criteria for medical device classification are based on the intended purpose and the function of a medical device. To the same product, if the intended purpose or form of operation be different, its class shall be determined respectively.3. For the medical device to be used in combination with another, the classification of each should then be dealt with separately. Accessories to medical devices should be classified independently from the master device respecting its own conditions.4. For the medical device to be used on several parts of the human body, the classification should be determined on the basis of the risks involved in its intendedpurposes and form of operation.5. Software that controls the functions of the medical device should be designated to the same class of its associated medical device.6. If one medical device pertains to two classes at the same time, the higher one is adopted.7. Those products that are designed to monitor or affect the major functions of a medical device should be designated to the same class of the device being monitored or affected.8. The State Drug Administration shall readjust as it sees fit the classification of certain medical devices that call for special administration.Article 7 The State Drug Administration is competent authority take charge of the classification of medical devices. In case a medical device fails to be designated according to The Category of Medical Device Classification, its classification then should be based on The Regulation for Medical Device Classification at the discretion of the provincial drug administration, the result of which should be submitted to the State Drug Administration for approval.Article 8 The terms used in the provisions are defined as follows:1. Intended purpose: the desired effect of a medical device that is illustrated in its product specification, label or materials for publicity.2. Risk: the possible injuries that may be caused by the medical device and the seriousness of the injury.3.Term of use:1) Temporary Use: the intended term for consecutive use of the device is within 24 hours;2) Short-term Use: the intended term for consecutive use of the device ranges from 24 hours to 30 days;3) Long-term Use: the intended term for consecutive use of the device is more than 30 days.4) Term for consecutive use: the actual working time of a device without any stop in accordance with its intended purpose.4. Parts being operated upon and the device:1) Non-contacting devices: devices that do not directly or indirectly contact the body of a patient;2) Surface contacting devices: including devices contacting the following parts of the human body:a. skin: devices that only contact the surface of the unwounded skin;b. mucous membrane: devices that contact the mucous membrane;c. wounded surface: devices that contact the wounded area or the surface of other injured areas.3) Devices for surgical insertion: devices that are entirely or partly inserted into the body through the surface of body by surgery contacting the following parts of the human body:a. blood vessel: inserted devices contacting a point on a blood vessel or as a channel to the blood vessel system.b. tissue/bone/dentinum: devices and materials that are inserted into the tissue, bones as well as endodontium/dentinum system.c. blood circulation: devices that contact the blood circulation system.5.Implantables: devices that are entirely or partly inserted into the cavity or tract of the human body by surgery. These devices either remain in the body over a long period of time, or partly remain in the body for at least 30 days.6. Active device: any medical device that operates on electric power or other forms of energy excluding those directly generated by human body or gravity.7. Reusable surgical instruments: devices that are used to conduct such procedures during a surgery as excision, boring, sawing, clutching, scraping, clipping, drawing and clamping without having to resort to any active device and that can be reused after certain treatment.8.Central Circulation System: referring to a number of vessels of the blood circulation system including pulmonary artery, aorta, coronary artery, carotid artery, cerebral artery, cardiac vena, upper cavity vena, and lower cavity vena.9. Central Nervous System: referring to cerebrum, meninx and medulla spinalis.Article 9 The State Drug Administration is responsible for interpretation of the provisions.Article 10 The Provisions shall go into effect as of April 10, 2000.Criteria for Medical Devices Classification download。

《可吸收医疗器械生物学评价 第1部分：可吸收植入物指南》标准编制说明一、工作简况1.任务来源根据食药监办械管〔2019〕23号文《国家药监局综合司关于印发2019年医疗器械行业标准制修订项目计划的通知》的安排，由全国医疗器械生物学评价标准化技术委员会（SAC/TC 248）负责归口制定《可吸收医疗器械生物学评价 第1部分：可吸收植入物指南》方法标准（项目编号：N2019069-JN ）。

2. 标准体系鉴于目前该标准主要参考ISO/TS 37137-1起草，该TS 的名称为Biological evaluation of medical devices — Part 1: Guidance for absorbable implants ，即医疗器械生物学评价 第1部分：可吸收植入物指南，其总标题与GB/T16886系列一样，因此YY/T XXXX.1的总标题在此基础上增加了“可吸收”，以区别GB/T16886系列，即：可吸收医疗器械生物学评价 第1部分 可吸收植入物指南。

该部分为可吸收植入物生物学评价的通用指南。

ISO/TS 37137-2计划的第2部分为镁合金植入物指南，因此YY/T XXXX 《可吸收医疗器械生物学评价》的第2部分同样拟设定为“镁合金植入物指南”，为镁合金植入物生物学评价的专用指南。

本标准的前言关于标准体系的描述如下：YY/T XXXX 《可吸收医疗器械生物学评价》拟分为以下几个部分： ——第1部分：可吸收植入物指南； ——第2部分：镁合金植入物指南； …… 本部分为YY/T XXXX 的第1部分。

3. 工作过程 接到任务后，SAC/TC 248秘书处及时组建工作组（见表1），并于2019年1月9日制定了该标准的工作计划并发放给各成员单位，并及时组建工作组微信群。

根据工作计划安排以及前期工作情况，在秘书处的组织下于2019年6月3日在山东中心视频室召开了该标准的首次工作组视频会议，工作组成员单位均派代表参加了会议，其中山东中心生物室和标准室相关人员也出席了会议。

MedDRA概述、编码规则及使用时的考虑Anna Zhao-Wong, MD, PhD (Anna.zhao-wong@)Deputy Director, MedDRA MSSOICH药物警戒相关指南研讨会Beijing, China. 17 March 2018Agenda•Basic of MedDRA use(MedDRA使用的基本信息)–When, where, and how MedDRA is used•Getting started with MedDRA (准备引入/使用MedDRA)–Stakeholders in MedDRA community (MedDRA社会成员)–MSSO’s roles (MSSO的职责)–Implementing MedDRA (引入MedDRA)–MedDRA data sharing (MedDRA数据共享)2Agenda (cont)•MedDRA terminology and MedDRA user Guides (MedDRA 术语和用户指南)–Fundamentals of MedDRA terminology (MedDRA术语基本点)–MedDRA maintenance (MedDRA维护)–Download MedDRA (如何下载MedDRA)–ICH Points to Consider (PTC) documents (ICH考虑要点文档)–Condensed PTC documents in Chinese (ICH考虑要点文档精要版-中文版)•MSSO Services (MSSO服务范围)–Help Desk (服务台)–Training (培训)–Tools (软件工具)– website (MedDRA官方网站)3Basics of MedDRA Use (MedDRA使用的基本信息)–When, Where, and How MedDRA Is UsedWhat is MedDRA?Med= MedicalD= Dictionary forR= RegulatoryA= Activities《监管活动医学词典》5 000024MedDRA’s Purpose•Facilitate the exchange of clinical information through standardization (通过标准化促进临床信息交流)•Important tool for product evaluation (评估), monitoring (监测),communication (交流), electronic records exchange (交流), andoversight (监督管理)•Supports coding (编码) (data entry) and retrieval (检索) and analysis (分析) of clinical information about human medical products including pharmaceuticals (化学药), biologics (生物制品), vaccines (疫苗), and drug-device combination products (药物－器械综合产品)6 000024When to use MedDRAMedDRA Definition •MedDRA is a clinically-validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry (药监部门和制药业). The terminology is used through the entire regulatory process (整个监管过程中), from pre-marketing to post-marketing, and for data entry (数据输入), retrieval (检索), evaluation (评估),and presentation (展示).7Where MedDRA is Used8000024Individual Case Safety Reports (ICSR) (个例安全报告) and Safety SummariesClinical Study Reports (临床研究报告)Investigators’ Brochures (临床研究者手册)Core Company Safety InformationMarketing Applications (上市申请)PublicationsPrescribing Information (处方信息)Advertising Regulatory Authority and Industry DatabasesMedDRA’s Scope •Information included in MedDRA–Medical conditions–Indications (适应症)–Investigations (tests 检查, results 检查结果)–Medical and surgical procedures (手术及医疗操作)–Medical, social, family history (病史，家史，社会史)–Medication errors (用药错误)–Product quality issues (产品质量问题)–Drug-device combination product issues–Pharmacogenetic (药物基因学) terms–Toxicologic (毒理) issues–Standardised MedDRA Queries (标准MedDRA 分析查询)9How MedDRA Is Used•ICH E2B (R3) –Individual Case Safety Report (个例安全报告)10Regulatory Database监管部门数据库Getting Started with MedDRA (准备引入/使用MedDRA)Stakeholders in MedDRACommunity (MedDRA社区成员)•MedDRA communityManagement Committee12ICH MedDRA ManagementCommittee Members(MedDRA管理委员会成员)13 000056MSSO’s Roles (MSSO的职责)•Distribute (颁发)MedDRA: deliver MedDRA tosubscribers worldwide•Maintain (维护)MedDRA: process users’ changerequests•Develop (开发)MedDRA: further developMedDRA to keep up with the changes inmedicine and meet the regulatory needs•Provide (提供)user support–Free Help Desk service–Free training: face-to-face, webinar, videocast–Free user group meetings held in US, Europe, andChina, and more…14ISO Certification (ISO证书)•MSSO certified as ISO 9001:2015compliant–ISO 9001:2015 standard is aninternationally recognized qualitymanagement system standard–Developed by the InternationalStandards Organization (ISO)•MSSO has held ISO certificationscontinuously since 2003•Involves:–Inspection of SoPs–Inspection of records to supportthe use of SoPs–Interviews with MSSO staff toensure understanding ofprocesses15Implementing MedDRA (引入MedDRA)•Establish an implantation team–Set goals and objectives•Have an implementation plan to consider–Define roles and responsibilities•Who is responsible for getting a MedDRA subscription?•Who is responsible for IT?•Who is in charge of communication?•Who is responsible for data conversion (if applicable)?–Identify impacts to your organization’s standardoperating procedures–Plan for staff training: who, when, and what–Include IT considerations: database, system, and tools–Set implementation timeline16Obtaining MedDRA Subscription (订阅MedDRA)• A valid MedDRA subscription is required for anyperson/organization to use MedDRA•Step by step instruction on how to apply forMedDRA subscription and pay for MedDRAinvoice (commercial organizations) are availablein Chinese at: https:///chinese-subscription-rates–如何订阅MedDRA–如何递交公司年销售额:only for commercialorganizations–如何支付MedDRA 的invoice: only for commercialorganizations17MedDRA Subscription Rates(MedDRA订阅费)•Enterprise wide subscription (以公司为单位)•Free subscription (免费订户)–Nonprofit organizations (⾮盈利机构)–Regulatory authorities (监管机构)•Paid subscription (付费订户)–Software developers (软件开发公司)–Commercial organizations (盈利机构), such aspharma companies, CROs•Sliding scale subscription fee based on annual revenue•Example, A company with annual revenue (年销售额) less than$1 million (630万人民币) pays $162 (1020人民币) per year.182018 MedDRA 订阅费•Commercial 0-2 subscription rates reduced in 2018•Reduction (减价) is a reflection of the continued success of MedDRA as a global standard in public health•Costs of maintaining and developing MedDRA are distributed over a wider base–While still providing the same high standard of tools and services to MedDRA users–In fact, expanding services to include more translation and more software tools192018 MedDRA 订阅费表2076% of all MedDRAusers pay no fee or$688 (or less )IT Considerations (软件系统)•Many software tools available to support the use of MedDRA–Several provided free with the MedDRA subscription •Two browsers (Desktop 桌面浏览器and Web-Based网页浏览器)•MedDRA Version Analysis Tool (MVAT) 版本分析工具–Need for software tools should be driven by thevolume of data to be supported (软件类别取决于数据量)•With small amounts of data users can use simplesoftware tools (e.g., free MSSO browsers,spreadsheets)•Larger implementations should consider commercialdata management software products•List of third-party software tools on MedDRA website21IT Considerations(cont)•At 22IT Considerations (cont)•Build robust MedDRA safety database based on theknowledge of–Structure and relations of MedDRA tables–Versioning impact–Data retrieval needs•Reference document –MedDRA发布文件格式文档(MedDRA Distribution File Format Document)–Describe the relationships among MedDRA tables.23MedDRA Data Sharing (MedDRA数据共享)•MSSO Statement on MedDRA Data Sharing is posted at (MSSO关于MedDRA数据共享的声明)https:///subscription/process•According to MedDRA Subscription Agreement (MedDRA订阅规定)24MedDRA Users Profile (用户概况)25•As of Dec 2017–5,000 Subscribing organizations (MSSO+JMO)–115 Countries•Graph shows types of subscribing organizationsMedDRA Users by Region and Top 20 Countries26Country Count United States 1439Germany331United Kingdom 322France 244Italy220China 中国146Spain 143Canada 116Australia 88South Korea 84Poland 83Switzerland 77Netherlands 77Sweden 74India 70Belgium 68Greece 56Denmark 47Austria 47Portugal42MedDRA Terminology and MedDRA User Guides (MedDRA术语和用户指南)Fundamentals of MedDRAterminology (MedDRA术语基本点) MedDRA Hierarchy (纵向结构)System Organ Class (SOC)系统器官分类(27)High Level Group Term (HLGT) 高位组语(337)High Level Term (HLT) 高位语(1,738)Preferred Term (PT) 首选语(22,499)Lowest Level Term (LLT) 低位语(77,248)MedDRA Version 20.028Fundamentals of MedDRA terminology (cont)29MedDRA System Organ Classes (系统器官分类)•血液及淋巴系统疾病•心脏器官疾病•各种先天性家族性遗传性疾病•耳及迷路类疾病•内分泌系统疾病•眼器官疾病•胃肠系统疾病•全身性疾病及给药部位各种反应•肝胆系统疾病•免疫系统疾病•感染及侵染类疾病•各类损伤、中毒及手术并发症•各类检查•代谢及营养类疾病•各种肌肉骨骼及结缔组织疾病•良性、恶性及性质不明的肿瘤（包括囊状和息肉状）•各类神经系统疾病•妊娠期、产褥期及围产期状况•产品问题•精神病类•肾脏及泌尿系统疾病•生殖系统及乳腺疾病•呼吸系统、胸及纵隔疾病•皮肤及皮下组织类疾病•社会环境•各种手术及医疗操作•血管与淋巴管类疾病MedDRA and Coded CasesUse MedDRA hierarchy to retrieve casesCase1Case4Case3Case2Case5SOC InfecSOC GastrSOC3SOC4HLGT Infec ‐pathogen unspec HLGT Exocrine pancreas condiHLGT3HLGT4HLT Abdo & gastr infec HLT A&C pancreatitis HLT3HLT4LLT1LLT2LLT3LLT4PT Pancreatic abscessPT PancreatitisacutePT3PT4Case6LLTA HLT Pancr condi NEC LLTB PT Pancreatic necrosisLLTCCase7Case10Case9Case8Case11Case12Case13Case14ICH MedDRA User Guides –PTC Documents (ICH考虑要点文档)•MedDRA Term Selection: Points to Consider (MedDRA术语选择:考虑要点)•MedDRA Data Retrieval and Presentation: Points toConsider (MedDRA数据检索和展示:考虑要点)31ICH MedDRA User Guides –PTCDocuments (cont)•Developed by an ICH working group–Regulators and industry representatives from ICH regions–WHO–MSSO and JMO•Updated twice yearly with each MedDRA release•Available on MedDRA and JMO websites–English and Japanese (只有英文版和日文版)–Word (“clean” and “redlined”), PDF, HTML formats–“Redlined” document identifies changes made from previous to current release of document32ICH M1 Points to ConsiderWorking Group (PtC WG)•Regulators andindustry from EU,US, and Japan•MFDS, Republic ofKorea•Health Canada,Canada•MSSO•JMOMeeting 13‐15 November 2017, Geneva, Switzerland33Condensed PTC Documents inChinese•Condensed (精要版) PTC documents are translated into all other MedDRA languages–Contain all PTC principles with fewer examples•Will be available to users in late half of 201834PTC Companion Document•New addition to PTC Document, focus on–Data quality–Medication errors•Will be available to users in late half of 201835Fundamentals of MedDRAterminology (cont)•MedDRA languages (MedDRA语言版本)36MedDRA维护•MedDRA是一个根据用户反馈信息进行更新的术语集–用户反馈信息–MSSO 积极维护和响应•用户可以提交修改申请，由MSSO 进行审核确认–MedDRA变更(英文)–MedDRA中文译文的修改–MSSOrequest@–Each organization: up to 100 CRs per month–For simple changes (简单更改要求) (PT and LLT levels),notification of final disposition within 7-10 working days–Complex changes (复杂更改要求) above PT level receivedall year round. Posted for users’ comments mid-year.37MedDRA维护（续）•每年进行2次正式更新–9月1日发布X.1 英文版（只有简单的变化）•9月15日－MedDRA的翻译版–3月1日发布X.0 英文版（复杂和简单的变化）•3月15日－MedDRA的翻译版38MedDRA Release Zipped Package (版本文件压缩包)•Release documents include:–MedDRA Introductory Guide* (MedDRA 入门指南)–SMQ Introductory Guide* (标准MedDRA 分析查询入门指南)–What’s New document*–Distribution File Format Document* (MedDRA发布文件格式文档)–Detail Change Request Report –SMQ Spreadsheet –Version Report* Translated in all MedDRA languages39What to do with theContents of the Zip File (压缩包)?40标准MedDRA分析查询入门指南SMQ 电子数据表版本报告新增内容MedDRA发布文件格式文档MedDRA入门指南Download MedDRA (如何下载MedDRA)Click onDownloads41 Download MedDRA (cont)•Enter Subscriber ID and password42Download MedDRA (cont)•Select the versionand language(s)–Password protectedzip file•Save the zip file toyour computer43 Extract the MedDRA Files•Zip file structureand contents–Select a file toextract–Enter Unzippassword fromWelcome letter44MedDRA Transition Date (版本转换日期) (ICSR个例安全报告)• A new release version of MedDRA should becomethe ICSR reporting version on the first Monday ofthe second month after it is released.•To synchronize this event over the ICH regions, theMSSO recommends midnight GMT, Sunday toMonday, for the switchover.45 MSSO Services (MSSO服务范围)Free Help Desk Service (免费服务台)•MSSO Help Desk: mssohelp@•Hours of operation: 5:00 –17:00 US EasternTime.•Users may ask a variety of questions–Subscription–Tools–Change request–Training–Meeting47Free Training (免费培训)•Formats–Face-to-face sessions (课堂培训), webinars (网上培训), videocasts(视频培训)•Languages–English, French, German, Spanish, Mandarin Chinese •Locations–Worldwide and “virtual”48Free Training (cont)Face-to-face sessions –Full Day (课堂培训)•Coding with MedDRA (MedDRA编码)•MedDRA: Safety Data Analysis and SMQs (MedDRA:安全性数据分析和SMQs)•Getting Started with MedDRA (per request)•自2010年，每年在中国办一次–今年九月在上海办培训，具体时间未定49Free Training (cont)Webinars –1 hour (网上培训)•Introduction module–MedDRA Overview–Getting Started with MedDRA•Coding module–MedDRA Coding Basics–Advanced MedDRA Coding•Data analysis module–Data Analysis and Query Building with MedDRA–Standardised MedDRA Queries (SMQs)•What’s New webinarYouTube Channel with recorded videocasts and webinars50Free Training (cont)•Free videocasts on MedDRA website (视频培训)–Short videocasts on a variety of MedDRA-related topics –Available in several different languages –Can be downloaded or viewed directly on website –Available to all51Free Training (cont)Videocasts (视频培训)52Videocast Language Chinese English French German SpanishVideocast TopicGetting Started with MedDRA +++++Introduction to the Points to Consider (PTC) Documents +++++MedDRA Structure and Scope +++++Standardised MedDRA Queries (SMQs)+++++MedDRA Version Updates +++++MedDRA Version Analysis Tool (MVAT)+Primary SOC Allocation in MedDRA +MedDRA Desktop Browser 4.0 Enhancements +MedDRA Web ‐Based Browser (WBB)+Self ‐Service Application (SSA) Features +The Top 12 Things to Know about the MedDRA Website +Summary of 2017 Training•63 face-to-face sessions (45 subscriber, 18regulator):–1,736 attendees–Central/South and North America, Europe,Asia/Eurasia, Scandinavia•27 webinars:–2,705 connections–Central/South and North America, Europe,Asia/Eurasia, Africa, Australia, Scandinavia53Free Tools (免费工具)•Desktop Browser (MDB) 桌面浏览器•Web-based Browser (WBB) 网页浏览器•MedDRA Version Analysis Tool (MVAT) 版本分析工具•Web-based Change Request Tool (WebCR)•Self Service Application (SSA) 自助服务工具54 Website•Online interface with MedDRA users•Source of information for–Subscribing to MedDRA: 订阅MedDRA–Renewing subscription: 续约MedDRA执照–Downloading MedDRA:下载MedDRA–News and Events: 新闻和活动通知•MedDRA activities, such as training, meetings–Access MSSO tools: MedDRA工具–Points to Consider documents:考虑要点文档–MSSO Best Practice documents: 最佳规范文档–MSSO training materials: 培训文档–Recorded webinars and videocasts: 录的网上培训课程和视频培训–Frequent asked questions (FAQs): 经常问的问题55Translations of MedDRA•Your MedDRA subscription includes the following languages –English, Chinese, Czech, Dutch, French, German, Hungarian,Italian, Portuguese, Spanish•MedDRA Japanese translation requires an additional fee.56Chinese MedDRA WeChat Group(MedDRA群)•Set up and run by users in China•Have a few hundred members•Provide platform to ask questions aboutMedDRA subscription, coding, data sharing,etc.•Free to participate•MSSO is a member of the group•Contact me if you are interested in joiningthe group: 若想加入，请与我联系57Paying Subscription by CreditCard 信用卡付订阅费•New feature coming later in 2018•For Level 0-2 commercial subscribers•Goal is to make paying MedDRA subscription easier for lower revenue users 方便用户58MSSO Contacts•Website–•Email–mssohelp@•Frequently Asked Questions–/faq59 Questions?。

Whereas the term “Technical Documentation” or “Technical File“ is used for medical devices of class I, class IIa, andclass IIb, the term “Design Dossier“ is used for class III products.术语“技术文档”或“技术文件”用于医疗设备的I类，IIA类和IIB类，术语“设计档案”用于第三类产品。

Technical Documentation is retained in the premises of the manufacturer or the Authorized Representative for potential review of Competent Authorities and Notified Bodies.技术文件保留在制造商或授权代表处，以备主管部门和公告机构审查。

Part B of the Technical File may be available at the manufacturer only, whereas Design Dossiers have to be submitted to the Notified Body for review prior to CE marking of the product技术文件的B部分可能仅在制造商提供，然而在产品标识"CE"之前，设计档案材料必须提交给认证机构(use form MDD Application for CE Conformity Assessment MED_F_03.15; http://www.tuev-sued.de/industry-and-consumer- products/download-center/applications).（使用MDD应用程序MED_F_03.15进行CE合格评估）We will assign a project coordinator who will entrust one or more further experts with the review of particular modules.我们将指派一个项目协调员，他将委托一个或多个进一步的专家对特定的模块进行评审。

药物筛选器官芯片流程Drug screening is a crucial step in the drug discovery process. It involves the use of various methods to identify potential drug candidates that could effectively treat a specific disease. One of the most advanced and promising technologies for drug screening is the use of organ-on-a-chip platforms, also known as organ chips. 药物筛选是药物发现过程中的关键步骤。

它涉及使用各种方法来确定潜在的药物候选者，可以有效地治疗特定疾病。

器官芯片平台，也被称为器官芯片，是药物筛选的先进和有前途的技术之一。

Organ chips are microfluidic cell culture devices that simulate the activities, mechanics, and physiological response of entire organs. They are designed to replicate the functions of specific organs, such as the liver, lung, heart, and kidney, in a controlled environment. 器官芯片是微流体细胞培养装置，模拟整个器官的活动、机械和生理反应。

它们旨在在受控环境中复制特定器官的功能，例如肝脏、肺部、心脏和肾脏。

The use of organ chips in drug screening offers several advantages over traditional cell culture and animal models. Firstly, they provide a more accurate representation of human physiology, allowing forbetter predictions of drug responses and toxicities. Additionally, they enable the study of inter-organ interactions and disease mechanisms, which are crucial for understanding the overall effects of a drug on the human body. 器官芯片在药物筛选中的使用相对于传统的细胞培养和动物模型具有几个优点。

英语医学科研论文的格式和要求打开一本医学专业期刊，可以看到不同文体的文章。

除了综述(review)或述评（comments ）、编者按（editorials ）和个例报告（case reports ）外，大量的是医学科研论文，即原始报告（original articles ）。

医学科研论文有许多不同的类型，常见的有两大类：医学基础研究报告和临床研究报告。

医学基础研究报告和临床研究报告。

了解英语医学科研论文的结了解英语医学科研论文的结构特点和要求，逐步掌握其写作技巧，逐步掌握其写作技巧，是医学研究人员和临床医学工作者所必须是医学研究人员和临床医学工作者所必须具备的基本技能。

具备的基本技能。

为了写好医学论文的英文摘要，应对医学论文的格式和要求有所了解。

1．格式根据国际医学杂志编辑委员会根据国际医学杂志编辑委员会 (The (The International International International Committee Committee Committee of of of Medical Medical Medical Journal Journal Editors, ICMJE) 制定的《生物医学杂志投稿统一要求》（The Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 5th Ed., 1997），一篇生物医学科研论文（篇生物医学科研论文（ 以下简称“论文”以下简称“论文” ）应包括以下12个部分：个部分：1）标题（Title ） 7）致谢（Acknowledgements ） 2）摘要（Abstract ） 8）参考文献（References ）3）引言（Introduction ） 9）插图说明（Legends ）4）材料与方法（Materials and Methods ） 10）插图（Figures ）5）结果（Results ） 11）表格（Tables ）6）讨论（Discussion ） 12）照片和说明（Plates and Explanations ）以上除7）、9）、10）、11）、12）部分因实际情况不需要外，其他各部分是一篇论文必不可少的内容。

美国仿制药申报常见缺陷解读(一):组成和辅料部分发布者：国际药用辅料网发表时间：2014/9/15 13:27:24美国仿制药申报简称为ANDA申报。

对于意图进入美国医药市场的中国企业,这是一个相对方便快捷的途径。

Atoka Srinivasan 和Robert Iser发表了,介绍了美国仿制药申报的常见缺陷。

在得到原作者书面授权后,笔者进行了翻译和适当的解读。

美国ANDA审评中出现在描述、组成和辅料部分的案例1.制剂中成份和组成表不完整,请修订申请者的成份和组成表以包括制剂的每种规格的所有成份的百分比。

2.在处方中盐酸或氢氧化钠的功能已规定表示为缓冲剂。

请详加阐述,因为这两个试剂通常不作为缓冲剂。

必要时,提供更新的成份和组成表。

3.请通过论证参比药物(RLD)有相似或更高的过量投料来证实你们处方中的过量投料的合理性。

我们建议与多批RLD对比来证实所推荐的过量投料量。

4.我们注意到申请人所推荐的处方与RLD有明显差别,我们要求你们做进一步的解释,以说明为什么这些差异不会影响你们制剂标签所声明的性能和既定用途。

5.我们要指出辅料相容性研究的前提是确保原辅料间无不良的化学反应,因此,我们要求在你们以后的申请中,在药物开发中,要研究化学变化而不是仅研究物理变化。

6.请提供计算证明铁元素的量符合21CFR 73.1200中的推荐值,该值根据建议的产品最大日剂量来计算。

7.请证明你们的缓释制剂中释放控制(辅料名称)相关特性的功能合理性,比如:粘度范围。

请叙述范围的最低点和最高点对制剂的关键质量属性(如释放分布情况)有何影响。

8.由于原料药有羧基存在,可能与处方中甘油有潜在的相互作用。

请证实推荐采用的分析方法是适合于鉴别和定量任何可能形成的酯类产品。

9.有文献报道在制药生产工艺条件和产品有效期内乳糖与伯胺反应形成加合物“Amadori”(Maillard反应),既然你们的原料药是胺类且乳糖是主要辅料,而你们的药物开发报告并未对此进行研究。

Designation as a Pharmacy bulk package is limited to prepara-〈1〉 INJECTIONStions from Nomenclature categories 1, 2, or 3 as defined above.Pharmacy bulk packages, although containing more than one single dose, are exempt from the multiple-dose container volume limit of 30 mL and the requirement that they contain a substance or suitable mixture of substances to prevent the growth of microorganisms.Where a container is offered as a Pharmacy bulk package, the INTRODUCTIONlabel shall (a) state prominently “Pharmacy Bulk Package—Not for direct infusion,” (b) contain or refer to information on proper tech-Parenteral articles are preparations intended for injection through niques to help assure safe use of the product, and (c) bear a state-the skin or other external boundary tissue, rather than through the ment limiting the time frame in which the container may be used alimentary canal, so that the active substances they contain are ad-once it has been entered, provided it is held under the labeled stor-ministered, using gravity or force, directly into a blood vessel, or-age conditions.gan, tissue, or lesion. Parenteral articles are prepared scrupulously by methods designed to ensure that they meet Pharmacopeial re-quirements for sterility, pyrogens, particulate matter, and other con-LARGE - AND SMALL -VOLUME INJECTIONStaminants, and, where appropriate, contain inhibitors of the growth of microorganisms. An Injection is a preparation intended for par-Where used in this Pharmacopeia, the designation Large-volume enteral administration and/or for constituting or diluting a parenteral intravenous solution applies to a single-dose injection that is in-article prior to administration.tended for intravenous use and is packaged in containers labeled as containing more than 100 mL. The designation Small-volume Injec-tion applies to an Injection that is packaged in containers labeled as NOMENCLATURE AND DEFINITIONScontaining 100 mL or less.BIOLOGICSNomenclature *The following nomenclature pertains to five general types of The Pharmacopeial definitions for sterile preparations for paren-preparations, all of which are suitable for, and intended for, paren-teral use generally do not apply in the case of the biologics because teral administration. They may contain buffers, preservatives, or of their special nature and licensing requirements (see Biologics other added substances.〈1041〉).1.[DRUG] Injection—Liquid preparations that are drug sub-stances or solutions thereof.2.[DRUG] for Injection—Dry solids that, upon the addition ofINGREDIENTSsuitable vehicles, yield solutions conforming in all respects to the requirements for Injections.3.[DRUG] Injectable Emulsion—Liquid preparations of drugVehicles and Added Substancessubstances dissolved or dispersed in a suitable emulsion medium.Aqueous Vehicles—The vehicles for aqueous Injections meet 4.[DRUG] Injectable Suspension—Liquid preparations of sol-the requirements of the Pyrogen Test 〈151〉 or the Bacterial Endo-ids suspended in a suitable liquid medium.toxins Test 〈85〉, whichever is specified. Water for Injection gener-5.[DRUG] for Injectable Suspension—Dry solids that, upon theally is used as the vehicle, unless otherwise specified in the individ-addition of suitable vehicles, yield preparations conforming ual monograph. Sodium chloride may be added in amounts in all respects to the requirements for Injectable Suspensions.sufficient to render the resulting solution isotonic; and Sodium Chloride Injection, or Ringer’s Injection, may be used in whole or in part instead of Water for Injection, unless otherwise specified in Definitionsthe individual monograph. For conditions applying to other ad-juvants, see Added Substances in this chapter.Other Vehicles—Fixed oils used as vehicles for nonaqueous In-jections are of vegetable origin, are odorless or nearly so, and have PHARMACY BULK PACKAGEno odor suggesting rancidity. They meet the requirements of the test for Solid paraffin under Mineral Oil, the cooling bath being main-A Pharmacy bulk package is a container of a sterile preparation tained at 10°, have a Saponification Value between 185 and 200for parenteral use that contains many single doses. The contents are (see Fats and Fixed Oils 〈401〉), have an Iodine Value between 79intended for use in a pharmacy admixture program and are re-and 141 (see Fats and Fixed Oils 〈401〉), and meet the requirements stricted to the preparation of admixtures for infusion or, through a of the following tests.sterile transfer device, for the filling of empty sterile syringes.Unsaponifiable Matter—Reflux on a steam bath 10 mL of the oil The closure shall be penetrated only one time after constitution with 15 mL of sodium hydroxide solution (1 in 6) and 30 mL of with a suitable sterile transfer device or dispensing set which allows alcohol, with occasional shaking until the mixture becomes clear.measured dispensing of the contents. The Pharmacy bulk package Transfer the solution to a shallow dish, evaporate the alcohol on a is to be used only in a suitable work area such as a laminar flow steam bath, and mix the residue with 100 mL of water: a clear solu-hood (or an equivalent clean air compounding area).tion results.*This nomenclature has been adopted by the USP Drug Nomenclature Committee for Free Fatty Acids—The free fatty acids in 10g of oil require for implementation by supplemental revisions of USP 23-NF 18. For currently official neutralization not more than 2.0 mL of 0.020N sodium hydroxide monograph titles in the form Sterile [DRUG] that have not yet been revised, the following nomenclature continues in use in this Pharmacopeia:(1) medicaments or (see Fats and Fixed Oils 〈401〉).solutions or emulsions thereof suitable for injection, bearing titles of the form [DRUG]Synthetic mono- or diglycerides of fatty acids may be used as Injection; (2) dry solids or liquid concentrates containing no buffers, diluents, or other vehicles, provided they are liquid and remain clear when cooled to added substances, and which, upon the addition of suitable solvents, yield solutions conforming in all respects to the requirements for Injections, and which are 10° and have an Iodine Value of not more than 140 (see Fats and distinguished by titles of the form Sterile [DRUG]; (3) preparations the same as those Fixed Oils 〈401〉).described under (2) except that they contain one or more buffers, diluents, or other These and other nonaqueous vehicles may be used, provided they added substances, and which are distinguished by titles of the form [DRUG] for are safe, in the volume of Injection administered, and also provided Injection; (4) solids which are suspended in a suitable fluid medium and which are not to be injected intravenously or into the spinal canal, distinguished by titles of the form they do not interfere with the therapeutic efficacy of the preparation Sterile [DRUG] Suspension; and (5) dry solids which, upon the addition of suitable or with its response to prescribed assays and tests.vehicles, yield preparations conforming in all respects to the requirements for Sterile Added Substances—Suitable substances may be added to prepa-Suspensions, and which are distinguished by titles of the form Sterile [DRUG] for Suspension.rations intended for injection to increase stability or usefulness, un-less proscribed in the individual monograph, provided they are Containers for Injections that are intended for use as dialysis, harmless in the amounts administered and do not interfere with the hemofiltration, or irrigation solutions and that contain a volume of therapeutic efficacy or with the responses to the specified assays more than 1 L are labeled to indicate that the contents are not in-and tests. No coloring agent may be added, solely for the purpose of tended for use by intravenous infusion.coloring the finished preparation, to a solution intended for paren-Injections intended for veterinary use are labeled to that effect. teral administration (see also Added Substances under General No-The container is so labeled that a sufficient area of the container tices and Antimicrobial Effectiveness Testing 〈51〉).remains uncovered for its full length or circumference to permit in-spection of the contents.Observe special care in the choice and use of added substances inpreparations for injection that are administered in a volume exceed-ing 5 mL. The following maximum limits prevail unless otherwiseSTRENGTH AND TOTAL VOLUME FOR SINGLE- AND directed: for agents containing mercury and the cationic, surface-active compounds, 0.01%; for chlorobutanol, cresol, phenol, and MULTIPLE-DOSE INJECTABLE DRUG PRODUCTS similar types of substances, 0.5%; and for sulfur dioxide, or anequivalent amount of the sulfite, bisulfite, or metabisulfite of potas-For single-dose and multiple-dose injectable drug products, the sium or sodium, 0.2%.strength per total volume should be the primary and prominent ex-pression on the principal display panel of the label, followed in A suitable substance or mixture of substances to prevent theclose proximity by strength per mL enclosed by parentheses. For growth of microorganisms must be added to preparations intendedcontainers holding a volume of less than 1 mL, the strength per for injection that are packaged in multiple-dose containers, regard-fraction of a mL should be the only expression of strength. Strength less of the method of sterilization employed, unless one of the fol-per single mL should be expressed as mg/mL, not mg/1 mL. lowing conditions prevails: (1) there are different directions in theThe following formats are acceptable for contents of greater individual monograph; (2) the substance contains a radionuclidethan 1 mL:with a physical half-life of less than 24 hours; and (3) the activeTotal strength/total volume: 500 mg/10 mLingredients are themselves antimicrobial. Such substances are usedStrength/mL: 50 mg/mLin concentrations that will prevent the growth of or kill microorgan-orisms in the preparations for injection. Such substances also meet theTotal strength/total volume: 25,000 Units/5 mL requirements of Antimicrobial Effectiveness Testing 〈51〉 and Anti-Strength/mL: 5,000 Units/mLmicrobial Agents—Content 〈341〉. Sterilization processes are em-The following format is acceptable for contents of less than 1 ployed even though such substances are used (see also SterilizationmL: 12.5 mg/0.625 mLand Sterility Assurance of Compendial Articles 〈1211〉). The air inThere are, however, some exceptions to expressing strength per the container may be evacuated or be displaced by a chemically in-total volume. In certain cases, the primary and prominent expres-ert gas. Where specified in a monograph, information regardingsion of the total drug content per container would not be effective in sensitivity of the article to oxygen is to be provided in the labeling.preventing medication errors (e.g., insulin). An example is the useof lidocaine or other similar drugs used as a local anesthetic wherethe product is ordered and administered by percentage (e.g., 1%, LABELS AND LABELING2%) or a local anesthetic in combination with epinephrine that isexpressed as a ratio (e.g., 1:100,000). In such cases, the totalstrength should be expressed: for example, 1% (100 mg/10 mL).Dry solids, which need to be reconstituted, should follow the same Labeling format, with the exception that only the total strength of the drugshould be listed, not the strength/total volume or strength/mL. NOTE—See definitions of “label” and “labeling” in Labeling in(Official February 1, 2009) the section Preservation, Packaging, Storage, and Labeling of theGeneral Notices and Requirements.The label states the name of the preparation; in the case of a liq-Aluminum in Large-Volume Parenterals (LVPs), uid preparation, the percentage content of drug or amount of drug in Small-Volume Parenterals (SVPs), and Pharmacy a specified volume; in the case of a dry preparation, the amount ofBulk Packages (PBPs) Used in Total Parenteral active ingredient; the route of administration; a statement of storageconditions and an expiration date; the name and place of business of Nutrition (TPN) Therapythe manufacturer, packer, or distributor; and an identifying lot num-ber. The lot number is capable of yielding the complete manufactur-(a)The aluminum content of LVPs used in TPN therapy must ing history of the specific package, including all manufacturing,not exceed 25 µg per L (µg/L).filling, sterilizing, and labeling operations.(b)The package insert of LVPs used in TPN therapy must state Where the individual monograph permits varying concentrations that the drug product contains no more than 25 µg of alumi-of active ingredients in the large-volume parenteral, the concentra-num per L. This information must be contained in the “Pre-tion of each ingredient named in the official title is stated as if part cautions” section of the labeling of all LVPs used in TPN of the official title, e.g., Dextrose Injection 5%, or Dextrose (5%)therapy.and Sodium Chloride (0.2%) Injection.(c)If the maximum amount of aluminum in SVPs and PBPs is The labeling includes the following information if the complete25 µg per L (µg/L) or less, instead of stating the exact formula is not specified in the individual monograph: (1) In the case amount of aluminum that each contains, as in paragraph (d), of a liquid preparation, the percentage content of each ingredient or the immediate container label for SVPs and PBPs used in the the amount of each ingredient in a specified volume, except that preparation of TPN parenterals (with exceptions as noted be-ingredients added to adjust to a given pH or to make the solution low) may state: “Contains no more than 25 µg/L of alumi-isotonic may be declared by name and a statement of their effect;num”. If the SVP or PBP is a lyophilized powder, the im-and (2) in the case of a dry preparation or other preparation to mediate container label may state the following: “When which a diluent is intended to be added before use, the amount of reconstituted in accordance with the package insert instruc-each ingredient, the composition of recommended diluent(s) [the tions, the concentration of aluminum will be no more than 25 name(s) alone, if the formula is specified in the individual mono-µg/L”.graph], the amount to be used to attain a specific concentration of(d)The maximum level of aluminum at expiry must be stated on active ingredient and the final volume of solution so obtained, a the immediate container label of all SVPs and PBPs used in brief description of the physical appearance of the constituted solu-the preparation of TPN parenterals and injectable emulsions. tion, directions for proper storage of the constituted solution, and an The aluminum content must be stated as follows: “Contains expiration date limiting the period during which the constituted no more than __ µg/L of aluminum”. The immediate con-solution may be expected to have the required or labeled potency if tainer label of all SVPs and PBPs that are lyophilized powder it has been stored as ed in the preparation of TPN solutions must contain the fol-lowing statement: “When reconstituted in accordance with pul is prohibited, except for Potassium Chloride for Injection the package insert instructions, the concentration of alumi-Concentrate.num will be no more than __ µg/L.” This maximum amount of aluminum must be stated as the highest one of the follow-Neuromuscular Blocking and Paralyzing Agentsing three levels:(1)The highest level for the batches produced during the lastAll injectable preparations of neuromuscular blocking agents and three yearsparalyzing agents must be packaged in vials with a cautionary state-(2)The highest level for the latest five batchesment printed on the ferrules or cap overseals. Both the container cap (3)The maximum level in terms of historical levels, but only un-ferrule and the cap overseal must bear in black or white print til completion of production of the first five batches after July (whichever provides the greatest color contrast with the ferrule or 26, 2004.cap color) the words: “Warning: Paralyzing Agent” or “Paralyzing The package insert for all LVPs, SVPs, and PBPs used in the Agent” (depending on the size of the closure system). Alternatively,preparation of TPN products must contain a warning statement.the overseal may be transparent and without words, allowing for This warning must be contained in the “Warning” section of the visualization of the warning labeling on the closure ferrule.labeling and must state the following: “WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is Containers for Sterile Solidsimpaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium Containers, including the closures, for dry solids intended for and phosphate solutions that contain aluminum. Research indicates parenteral use do not interact physically or chemically with the that patients with impaired kidney function, including premature preparation in any manner to alter the strength, quality, or purity neonates, who receive parenteral levels of aluminum at greater than beyond the official requirements under the ordinary or customary 4 to 5 µg per kg per day accumulate aluminum at levels associated conditions of handling, shipment, storage, sale, and use.with central nervous system and bone toxicity. Tissue loading may A container for a sterile solid permits the addition of a suitable occur at even lower rates of administration of TPN products.”solvent and withdrawal of portions of the resulting solution or sus-pension in such manner that the sterility of the product is maintained.PACKAGING Where the Assay in a monograph provides a procedure for the Assay preparation, in which the total withdrawable contents are to be withdrawn from a single-dose container with a hypodermic nee-dle and syringe, the contents are to be withdrawn as completely as Containers for Injectionspossible into a dry hypodermic syringe of a rated capacity not ex-ceeding three times the volume to be withdrawn and fitted with a Containers, including the closures, for preparations for injections 21-gauge needle not less than 2.5 cm (1 inch) in length, with care do not interact physically or chemically with the preparations in any being taken to expel any air bubbles, and discharged into a con-manner to alter the strength, quality, or purity beyond the official tainer for dilution and assay.requirements under the ordinary or customary conditions of han-dling, shipment, storage, sale, and use. The container is made of material that permits inspection of the contents. The type of glass Volume in Containerpreferable for each parenteral preparation is usually stated in the individual monograph. Unless otherwise specified in the individual Each container of an injection is filled with sufficient excess of monograph, plastic containers may be used for packaging injections the labeled “size” or that volume which is to be withdrawn. See (see Containers—Plastics 〈661〉).Injections under Pharmaceutical Dosage Forms 〈1151〉.For definitions of single-dose and multiple-dose containers, see Containers in the General Notices and Requirements. Containers meet the requirements under Containers—Glass 〈660〉 and Con-DETERMINATION OF VOLUME OF INJECTION INtainers—Plastics 〈661〉.Containers are closed or sealed in such a manner as to prevent CONTAINERS contamination or loss of contents. Validation of container integrity must demonstrate no penetration of microbial contamination or Suspensions and emulsions must be shaken before withdrawal of chemical or physical impurities. In addition, the solutes and the ve-the contents and before the determination of the density. Oily and hicle must maintain their specified total and relative quantities or viscous preparations may be warmed according to the instructions concentrations when exposed to anticipated extreme conditions of on the label, if necessary, and thoroughly shaken immediately be-manufacturing and processing, and storage, shipment, and distribu-fore removing the contents. The contents are then cooled to tion. Closures for multiple-dose containers permit the withdrawal of 20°–25°C before measuring the volume.the contents without removal or destruction of the closure. The clo-Single-Dose Containers—Select 1 container if the volume of the sure permits penetration by a needle and, upon withdrawal of the container is 10 mL or more, 3 containers if the nominal volume is needle, closes at once, protecting the container against contamina-more than 3 mL and less than 10 mL, or 5 containers if the nominal tion. Validation of the multiple-dose container integrity must in-volume is 3 mL or less. Take up individually the total contents of clude verification that such a package prevents microbial contami-each container selected into a dry syringe of a capacity not exceed-nation or loss of product contents under anticipated conditions of ing three times the volume to be measured and fitted with a 21-multiple entry and use.gauge needle not less than 2.5 cm (1 inch) in length. Expel any air Piggyback containers are usually intravenous infusion containers bubbles from the syringe and needle, and then discharge the con-used to administer a second infusion through a connector of some tents of the syringe, without emptying the needle, into a standard-type or an injection port on the administration set of the first fluid,ized, dry cylinder (graduated to contain rather than to deliver the thereby avoiding the need for another injection site on the patient’s designated volumes) of such size that the volume to be measured body. Piggyback containers are also known as secondary infusion occupies at least 40% of its graduated volume. Alternatively, the containers.volume of the contents in mL may be calculated as the mass, in g,divided by the density. For containers with a nominal volume of 2mL or less, the contents of a sufficient number of containers may be Potassium Chloride for Injection Concentratepooled to obtain the volume required for the measurement, provided that a separate, dry syringe assembly is used for each container. The The use of a black closure system on a vial (e.g., a black flip-off contents of containers holding 10 mL or more may be determined button and a black ferrule to hold the elastomeric closure) or the use by means of opening them and emptying the contents directly into of a black band or series of bands above the constriction on an am-the graduated cylinder or tared beaker.The volume is not less than the nominal volume in the case of Injections packaged for intravascular use that may be used for containers examined individually or, in the case of containers with a intermittent, continuous, or bolus replacement fluid administration nominal volume of 2 mL or less, is not less than the sum of the during hemodialysis or other procedures, unless excepted above,nominal volumes of the containers taken collectively.must conform to the 1-L restriction.Multi-Dose Containers—For Injections in multiple-dose con-Injections labeled for veterinary use are exempt from packaging tainers labeled to yield a specific number of doses of a stated vol-and storage requirements concerning the limitation to single-dose ume, select 1 container, and proceed as directed for single-dose containers and the limitation on the volume of multiple-dose containers, using the same number of separate syringe assemblies as containers.the number of doses specified. The volume is such that each syringe delivers not less than the stated dose.Injections in Cartridges or Prefilled Syringes—Select 1 con-FOREIGN AND PARTICULATE MATTERtainer if the volume is 10 mL or more, 3 containers if the nominal volume is more than 3 mL and less than 10 mL, or 5 containers if All articles intended for parenteral administration shall be pre-the nominal volume is 3 mL or less. If necessary, fit the containers pared in a manner designed to exclude particulate matter as defined with the accessories required for their use (needle, piston, syringe)in Particulate Matter in Injections 〈788〉 and other foreign matter.and transfer the entire contents of each container without emptying Each final container of all parenteral preparations shall be inspected the needle into a dry tared beaker by slowly and constantly depress-to the extent possible for the presence of observable foreign and ing the piston. Determine the volume in mL, calculated as the mass,particulate matter (hereafter termed “visible particulates”) in its in g, divided by the density.contents. The inspection process shall be designed and qualified to The volume measured for each of the containers is not less than ensure that every lot of all parenteral preparations is essentially free the nominal volume.from visible particulates. Qualification of the inspection process Large-Volume Intravenous Solutions—For intravenous solu-shall be performed with reference to particulates in the visible range tions, select 1 container. Transfer the contents into a dry measuring of a type that might emanate from the manufacturing or filling pro-cylinder of such a capacity that the volume to be determined occu-cess. Every container whose contents shows evidence of visible par-pies at least 40% of the nominal volume of the cylinder. Measure ticulates shall be rejected. The inspection for visible particulates the volume transferred.may take place when inspecting for other critical defects, such as The volume is not less than the nominal volume.cracked or defective containers or seals, or when characterizing the appearance of a lyophilized product.Where the nature of the contents or the container-closure system permits only limited capability for the inspection of the total con-Labeling on Ferrules and Cap Oversealstents, the 100% inspection of a lot shall be supplemented with the inspection of constituted (e.g., dried) or withdrawn (e.g., dark am-Only cautionary statements are to appear on the top (circle) sur-ber container) contents of a sample of containers from the lot.face of the ferrule or cap overseal of a vial containing an injectable All large-volume Injections for single-dose infusion and small-product. A cautionary statement is one intended to prevent an immi-volume Injections are subject to the light obscuration or micro-nent life-threatening situation if the injectable drug is used inappro-scopic procedures and limits for subvisible particulate matter set priately. Examples of such statements include but are not limited to forth in Particulate Matter In Injections 〈788〉, unless otherwise the following: “Warning”, “Dilute Before Using”, “Paralyzing specified in the individual monograph. An article packaged as both Agent”, “I.M. Use Only”, and “Chemotherapy”.a large-volume and a small-volume Injection meets the require-The text must be in contrasting color and conspicuous under ordi-ments set forth for small-volume Injections where the container is nary conditions of use. The cautionary statement may appear solely labeled as containing 100 mL or less, if the individual monograph on the ferrule, provided the cap overseal is constructed so as to al-states a test for Particulate Matter 〈788〉; it meets the requirements low the cautionary statement beneath the cap to be readily legible.set forth for large-volume Injections for single-dose infusion where Identifying numbers or letters, such as code numbers, lot num-the container is labeled as containing more than 100 mL. Injections bers, etc., may appear on the side (skirt) surface of the ferrule on administered exclusively by the intramuscular or subcutaneous vials containing injectable products. The appearance of such identi-route or packaged and labeled for use as irrigating solutions are ex-fying data on the skirt surface of the ferrule, placed where it does empt from requirements for Particulate Matter 〈788〉.not detract from, or interfere with, the cautionary statement on the top surface, should be considered to be a beneficial attribute of the in-process quality control of a product throughout the manufactur-ing process. Any anticounterfeiting scheme must not detract from or STERILITYinterfere with the cautionary statements.Under no circumstances would advertising such as company Sterility Tests—Preparations for injection meet the requirements names, logos, or product names be permitted to appear on the top under Sterility Tests 〈71〉.(circle) surface of any ferrule or cap overseal.(Official February 1, 2009)CONSTITUTED SOLUTIONSPackaging and StorageDry solids from which constituted solutions are prepared for in-jection bear titles of the form [DRUG] for Injection. Because these The volume of injection in single-dose containers provides the dosage forms are constituted at the time of use by the health care amount specified for parenteral administration at one time and in no practitioner, tests and standards pertaining to the solution as consti-case is more than sufficient to permit the withdrawal and adminis-tuted for administration are not included in the individual mono-tration of 1 L.graphs on sterile dry solids or liquid concentrates. However, in the Preparations intended for intraspinal, intracisternal, or peridural interest of assuring the quality of injection preparations as they are administration are packaged only in single-dose containers.actually administered, the following nondestructive tests are pro-Unless otherwise specified in the individual monograph, a multi-vided for demonstrating the suitability of constituted solutions when ple-dose container contains a volume of Injection sufficient to per-they are prepared just prior to use.mit the withdrawal of not more than 30 mL.Completeness and Clarity of Solution—Constitute the solution The following injections are exempt from the 1-L restriction of as directed in the labeling supplied by the manufacturer for the ster-the foregoing requirements relating to packaging:ile dry dosage form.1.Injections packaged for extravascular use as irrigation solu-A:The solid dissolves completely, leaving no visible residue tions or peritoneal dialysis solutions as undissolved matter.2.Injections packaged for intravascular use as parenteral nutri-B:The constituted solution is not significantly less clear than tion or as replacement or substitution fluid to be administeredan equal volume of the diluent or of Purified Water contained in a continuously during hemofiltrationsimilar vessel and examined similarly.。