21CFR111简介膳食补充剂.doc

INTRODUCTION to 21CFR111: DIETARY SUPPLEMENTS 21CFR111简介：膳食补充剂I appreciate the opportunity to speak to your group today.我很高兴有机会向在座的各位发言。I want to start by briefly talking about three laws passed by the U.S. Congress which have established the legal framework within which FDA operates. The first of these laws is the Federal Food, Drug, and Cosmetic Act (FD&C Act). Two other laws are the Dietary Supplement Health and Education Act (or DSHEA) and the Dietary Supplement and Nonprescription Drug Consumer Act both of which amended the FD&C Act. FDA develops regulations based on the laws set forth in the FD&C Act and other laws under which FDA operates.我想首先简要地谈论一下在美国国会通过的三部法律，FDA正是这些法律建立的法律框架内进行运作的。第一部法律是联邦食品，药品和化妆品法（FD&C Act）。另外两部法律是膳食补充品健康教育法（DSHEA）和膳食补充剂和非处方药消费者保护法, 两个法律都补充了食品，药品和化妆品法。 在上述FDA赖以运作的三部法律基础上，FDA制定了相关规章。 It is one of these regulations which I am going to discuss this afternoon. That is Title 21 Part 111 of the Code of Federal Regulations which is entitled “Current Good Manufacturing, Packing, Labeling, or Holding Operations for Dietary Supplements” or as this regulation is also known “the Dietary Supplement GMPs”. Before I talk about the Dietary Supplement GMPs, I need to first talk about the Dietary Supplement Health and Education Act.我今天下午要讨论的正是这些规章之一。这是标题21部的联邦规例,标题是“膳食补充剂现行优良制造，包装，标签，或控股经营”,亦称为“膳食补充的GMP”。在我谈论的膳食补充剂GMP之前，我有必要先讲一下膳食补充剂健康教育法。In October 1994, the Dietary Supplement Health and Education Act (DSHEA) was signed into law by President Clinton. Under DSHEA, a dietary supplement is defined as a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. The “dietary ingredients” in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. They can also be in other forms, such as a bar, but if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet. Whatever their form, DSHEA places dietary supplements in a special category under the general umbrella of “foods,” not drugs. DSHEA also requires that every supplement be specifically labeled as a dietary supplement.1994年10月，总统克林顿将膳食补充剂健康教育法（DSHEA）签署成为法律。根据DSHEA，膳食补充剂的定义是:一个含有“饮食成分”,由口摄取的饮食补充产品。在这些产品可包括：维生素，矿物质，草药或其他植物，氨基酸，以及诸如酶物质，器官组织，代谢产物。膳食补充剂也可以提取浓缩物，并可能有许多形式，如发片剂，胶囊，软胶囊，液体或粉末。它们也可以以其他形式出现，如条状食品（？）.但如果是这样，他们的标签信息不能代表作为传统的食品或者是单纯的肉或食物。无论何种形式，DSHEA都是把膳食补充剂作为一种特殊的类别的“食品”，而不是药品。 DSHEA还要求每种膳食补充剂必须在标签上特别标注。I have mentioned the term “dietary ingredient”. Now I want to introduce another term and that is “new dietary ingredient”. A “new dietary ingredient” is one that meets the definition for a “dietary ingredient” but was not sold in the U.S. in a dietary supplement before October 15, 1994 when DSHEA was signed into law.我已经说过“膳食补充剂成分”这个术语。现在我要介绍另一个词就是“新膳食补充剂成分”。 “新膳食补充剂成分”，是一个符合 “膳食补充剂成分”的定义，但这种成分在1994年10月15日DSHEA被签署成法律之前没有在美国出售。Now lets talk about FDAs role in regulating dietary supplements versus the manufacturers responsibility for marketing them.现在让我们谈谈美国FDA在膳食补充剂监管方面的角色，以及制造商的营销责任.Before DSHEA was signed into law in October 1994, dietary supplements were subject to the same regulatory requirements as were other foods. However after DSHEA was signed into law, it created a new regulatory framework for the safety and labeling of dietary supplements. Under DSHEA, a firm is responsible for determining that the dietary supplements it manufactures or distributes are safe and that any representations or claims made about them are substantiated by adequate evidence to show that they are not false and misleading. This means that dietary supplements do not need approval from FDA before they are marketed. Except in the case of a “new dietary ingredient” where the manufacturer and distributor must demonstrate to FDA why the ingredient is reasonably expected to be safe for use in a dietary supplement, unless it has been recognized as a food substance and is present in the food supply. This notification must be sent to FDA at least 75 days prior to marketing the product. Failure of the manufacturer or distributor to file this notification may make the dietary supplement containing the new dietary ingredient adulterated under the FD&C Act.在1994年10月DSHEA被签署成为法律之前，膳食补充剂的监管要求与普通食品是一样的。但是，当DSHEA被签署成为法律后，它为膳食补充剂的安全和标签创造了一个新的监管架构。根据DSHEA，企业负责确定其所生产和销售的膳食补充剂是安全的，并且任何关于它们的陈述或声称要想成立，都需要基于充足的证据显示他们没有造假或误导。这意味着，膳食补充剂上市前不需要FDA的批准。除了“新膳食补充剂成分”，制造商和分销商必须向FDA证明为什么该成分有理由认为是安全的，直到它已被确认为食品物质，并且当作食品供应。此通知必须在该产品上市前至少75天前送交美国FDA。制造商或分销商未能提交此通知可能使膳食补充剂含有新的膳食成分违反食品，药品和化妆品法。There is no authoritative list of dietary ingredients that were marketed before October 15, 1994. Therefore manufacturers and distributors are responsible for determining if a dietary ingredient is “new” and if it is not, for documenting that the dietary supplements it sells, containing the dietary ingredient, were marketed before October 15, 1994.我们并没有在1994年10月15日之前就在被销售的膳食补充剂成分列表。因此，由制造商和分销商来负责决定饮食成分是不是“新” 的.如果它不是，他们还需负责记录他们所销售的膳食补充剂包含成分是1994年10月15日前销售的。The second law which I want to talk about is the Dietary Supplement and Nonprescription Drug Consumer Protection Act which was signed by President Bush in December 2006. The requirements of this law became effective in December 2007. This law requires firms to have a record keeping system in place for maintaining records of adverse event reports. It requires reporting serious adverse events to FDA. FDA has published two guidance documents which help dietary supplement firms understand their obligations under this law.第二，我想谈的是美国总统布什在2006年12月签署的关于膳食补充剂和非处方药消费者保护法。这项法律的规定在2007年12月生效。该法要求企业有一个记录不良反应事件报告的系统。它要求报告严重不良反应事件给FDA。 FDA已公布两份指导文件，帮助企业了解本法规定的义务。Be aware that there are certain specific label requirements for dietary supplements; however, due to the limited time I have, I am not going to discuss them during this presentation.请注意，膳食补充剂标签有一定的具体要求，但是，由于时间有限，我不打算在此讨论他们。 And lastly I wanted to mention that manufacturers of foods and feeds need to register their firms with FDA pursuant to the Public Health Security and Bioterrorism Preparedness and Response Act, commonly known as The Bioterrorism Act of 2002, before manufacturing and selling their products in the U.S.而最后我想提及的是，依据公众健康安全和生物恐怖主义防备和反应法,食品和饲料生产商必须在FDA登记他们的公司后，才能在美国制造和销售他们的产品.Now I would like to turn to a discussion on the Dietary Supplement GMPs in Part 111 of the regulations.现在我想谈谈规章111部分的膳食补充剂GMP。Compliance with this regulation is based on the number of employees for a firm as follows: For a firm employing 500 or more persons this regulation took effect on June 25, 2008 For a firm employing fewer than 500 but more than 20 persons this regulation took effect June 25, 2009 For firms employing fewer than 20 persons this regulation will take effect on June 25, 2010这个条例对有不同数量员工的公司有不同的要求： 对于雇用500人以上的公司,本规例已于2008年6月25日起生效 对于雇用500人以下20人以上的公司,本规例已于2009年6月25日起生效 对于雇用20人以下的公司,本规例于2010年6月25日起生效In preparing my talk today, I tried to determine what might be the best way to present this material and what would be most beneficial to you. I finally decided that I would try to identify the areas FDA will focus on when we perform dietary supplement GMP inspections.我在准备今天的演讲时，一直在努力寻找最好的演绎方式，以便给你们提供最有用的信息。我最后决定：我会尝试找出当我们执行膳食补充剂GMP检查时FDA重点关注的地方。There is a guidance document which FDA has issued for Investigators to follow when conducting these inspections. This guidance document is located on the FDA web site and I would encourage you to look at this document when you have the opportunity.美国FDA已发出进行这些检查时应遵循的一个指导文件。本指导文件位于美国食品药品管理局网站，我鼓励你们看看这个文件。This document is called Compliance Program 7321.008 entitled “Dietary Supplements Import and Domestic” and it has an implementation date of March 26, 2010. FDA Investigators will follow this compliance program when conducting inspections of both domestic and foreign dietary supplement firms.这份文件称为合规计划7321.008题为“膳食补充剂 - 进口和国产”，它有一个2010年3月26日的实施日期。 FDA的检查人员将遵循这一合规计划来进行国内和国外膳食补充剂企业的检查。I am going to go through step by step and describe the highlights of what your firm should have in terms of procedures and records and what we as Investigators will look for when conducting these inspections. Keep in mind that most but not all of the sections I am going to discuss may apply depending on your firms operations.我将一步一步地进行介绍，描述你们公司应有的程序和记录概要，以及我们作为检察官在检查时主要关注什么。请记住，我要讨论的大部分的章节可能和您公司的业务有关系。Subpart B Personnel You must have written procedures for preventing microbial contamination and hygienic practices for employees. (111.8) You must have training documentation for employee(s) that includes the date of training and the type of training they received. (111.14) You must identify who is responsible for quality control operations and their qualifications. (111.12(b)部分B - 人员 您必须有防止微生物污染和员工的卫生规范的书面程序。 （111.8） 您必须有员工培训的文档，包括培训日期和培训类型。 （111.14） 您必须确定是谁负责质量控制以及他们的资质。 （111.12（b）项）Subpart C Physical Plant and Grounds You must have written procedures for cleaning the physical plant and for pest control. (111.16) If water is a component of the dietary supplement, you must review water records to make certain that the water complies with applicable national, Federal, State, and local standards. (111.15(e) You must assign one or more employee to supervise overall plant sanitation. (111.15(k) You must keep records required under this subpart which includes the cleaning of the physical plant and for pest control, and records to document that water if used as a component of the dietary supplement meets the required standards. (111.23)C小节 实际厂房及场地 您必须有实际厂房清洁和害虫控制的书面程序。 （111.16） 如果水是膳食补充剂组分，您必须审核水记录，要确保水符合适用的国家，联邦，州和地方标准。 （111.15（e） 您必须指定一个或更多的员工，以监督整个工厂的卫生条件。 （111.15（k） 您必须保持本节法规要求的记录，其中包括厂房清洗和病虫害控制，以及水的文件记录，即作为膳食补充剂组分的水符合规定的标准。 （111.23）Subpart D Equipment and Utensils You must have written procedures for calibrating instruments and controls that you use in manufacturing or testing a component or dietary supplement; for calibrating, inspecting, and checking automated, mechanical and electronic equipment; and maintaining, cleaning, and sanitizing, as necessary, all equipment, utensils, and other contact surfaces. (111.25) If your firm uses freezers, refrigerators, or other cold storage compartments to store components or finished batches of dietary supplements, you must have a thermometer or temperature-recording device to allow for recording the temperature. You must have an automated device for regulating temperature or an automated alarm if you are using a manual system. (111.27(a) If you use wet processing, you must clean and sanitize all contact surfaces, before use, and after any interruption during which the contact surface may have become contaminated. (111.27(d) You must determine if automated, mechanical, or electronic equipment used in manufacturing, packaging, etc., is capable of operating satisfactorily within the operating limits required by the process. (111.30(b) You must establish appropriate controls for equipment (including software on a computer controlled process) and ensure that changes are approved by QC personnel and instituted only by authorized personnel. (111.30(d) You must establish appropriate controls to ensure the equipment functions in accordance with its intended use. 111.30(e) You must document the date of use, maintenance, cleaning, and sanitization of equipment. (111.35(b)(2)子部分 - 设备及用具 您必须有书面程序对测试组分或膳食补充剂使用到的仪器和控制进行校准;也要有书面程序对自动化，机械和电子设备进行校准，审计，检查；如有必要，对所有设备，器具，以及其他接触的表面进行维护，清洗，消毒也需要有书面程序。 （111.25） 如果你的公司采用冷冻机，冰箱，或其他冷藏装置来存储组分或成品膳食补充剂，你必须有一个温度计或温度记录装置，以便记录温度。你必须有一个自动温度控制仪器，或者如果您使用的是人工系统，必须有自动报警装置。 （111.27（a）条） 如果您使用湿处理，在每次使用前，或者在可能引入污染的中断以后，你都必须对所有接触的表面进行清洁和消毒.（111.27（d）项） 您必须确定生产或包装中用到的自动化、机械或电子设备能够在其工艺要求允许范围内良好地运作。 （111.30（b）项） 您必须建立适当的对设备的控制（包括计算机控制工艺所用的软件），并保证如有变化必须得到QC人员的批准，并只能由被授权的人员制定。 （111.30（d）项） 您必须建立适当的控制，以确保设备的功能符合其既定的用途。 111.30（e）段） 您必须对设备的使用、维修、清洗、消毒的日期进行书面记录。 （111.35（二）（2）Subpart E Requirements to Establish a Production and Process Control System You must establish a specification for components, in-process materials, labels, packaging components, and finished products where control is necessary to ensure the quality of the dietary supplement. (111.70) You must establish in-process specification and finished product specifications and determine whether those specifications demonstrate that the product has the appropriate identity, purity, strength, and composition. (111.75) You must qualify the suppliers of components and maintain documentation on how you qualified the suppliers. (111.75(a) You must conduct at least one appropriate test or examination on each dietary ingredient to verify its identity or you may submit a petition to FDA for exemption from this testing requirement. (111.75(a)(1) You must conduct and document appropriate tests or examinations to ensure the finished batch product specifications are met in the manufacture of the product (111.75(b) and(c) You must collect representative samples of components, packaging, labels, in-process materials, finished product, or at other locations as necessary to ensure specifications are met. (111.80) You must collect and retain reserve samples of each lot of packaged dietary supplements which is distributed. These samples must be retained for one year past the shelf life date (if shelf life dating is used) or for two years from the date of distribution of the last batch of dietary supplements associated with the reserve sample. (111.83)子部分E - 建立生产和工艺控制系统的要求 您必须为组分，中间物料，标签，包装材料和成品建立规格，实施必要的控制以确保膳食补充剂的质量。 （111.70） 您必须建立中间物料规格和成品规格，并确定这些规格是否证明该产品具有适当的特性，纯度，剂量和组成。 （111.75） 您必须对零部件供应商进行资格确认，并保留如何确认的文档记录。 （111.75（a）条） 您必须对每个膳食成分至少进行一项鉴别测试或检查;或者您可以提交豁免申请给美国FDA免除这一测试要求。 （111.75（1）（1） 您必须进行适当的测试或检查以确保产品生产可以符合成品规格，并存档（制造符合111.75（b）和（c）项） 您必须采集必要的组分、包装、标签、中间物料、成品或在他处生产的代表性样品，以确保符合规格。 （111.80） 您必须对分销的每批包装的膳食补充剂采集留样。如果使用货架期，则留样需保存至货架期结束后1年；或者保存至与这些记录相关的最后一批膳食补充剂产品分销日期后的两年。（111.83）Subpart F Quality Control You must establish and follow written procedures for the responsibility of the quality control operations, including written procedures for conducting a material review and making a disposition decision, and for approving or rejecting any reprocessing. (111.103) QC personnel must review and approve the documentation setting forth supplier qualification. (111.105(b) QC personnel must review and approve the documentation setting forth the basis for in-process specifications in order that the identity, purity, strength, and composition of the dietary supplements are met. (111.105(c) QC personnel must review and approve the documentation setting forth the basis for why the results of appropriate tests and examination for each product specification ensure that the finished batch of the dietary supplement meets product specifications. (111.105(d) QC personnel must determine that all manufacturing specifications are met. (111.105(h) QC personnel must review and approve all laboratory control processes associated with the production and process control system. (111.110(a) QC personnel must ensure that all tests and examination are conducted and they must approve all results of this testing and examinations. (111.110(b) and (c) QC personnel must conduct a material review and make a disposition decision when product specifications are not met. (111.113) QC personnel must review and approve all processes for calibrating instruments and controls and periodically review calibration records and inspections /checks of automated, mechanical, or electronic equipment. (111.117) QC personnel must determine whether all components, packaging, and labels conform to established specifications, and make required disposition decisions. (111.120) QC personnel must approve any treatment and in-process adjustments of components, packaging, or labels to make them suitable for use. (111.120(d) QC personnel must approve and release from quarantine, all components, packaging, and labels before they are used. (111.120(e) QC personnel must review and approve all ma-ster manufacturing records and all modifications to the ma-ster manufacturing records. (111.123(a)(2) QC personnel must review all monitoring for the production and process control system. (111.123(a)(3) QC personnel must determine whether all in-process specifications which are established are met. (111.123(a)(6) QC personnel must determine whether each finished batch conforms to the established product specifications. (111.123(a)(7) QC personnel must approve and release or reject each finished batch for distribution, including any reprocessed finished batches. (111.123(a)(8) QC personnel must review and approve all records for packaging and labeling operations. (112.127(c) QC personnel must determine whether finished packaged and labeled dietary supplements conform to established specifications, and are approve for release or are rejected. (111.127(d) QC personnel must conduct a required material review and make a required disposition decision for returned dietary supplements. (111.130(a) QC personnel must approve or reject any salvage and the redistribution of any returned dietary supplements. (111.130(b) QC personnel must review and approve any decision about whether reprocessed dietary supplements meet product specifications and either approve for release, or reject, any returned dietary supplement that was reprocessed. (111.130(d) QC personnel must review and approve decisions about whether to investigate a product complaint and review and approve the findings and follow-up action of any complaint i