FDA官员原料药检查指南(中).doc

EDIT: Made available by ORA/OE/DCIQA 01/29/03 - undated MS Word file received from CDER & table format revisedFood and Drug AdministrationCompliance Program Guidance Manual PROGRAM 7356.002FCHAPTER 56 - DRUG QUALITY ASSURANCE第56章药物质量保证SUBJECT: 主题IMPLEMENTATION DATE *ACTIVE PHARMACEUTICAL INGREDIENTS (APIs)* 活性药物成分Upon Receipt COMPLETION DATE Continuing DATA REPORTING PRODUCT CODES PRODUCT/ASSIGNMENT CODES Industry Codes: 54 and 56See Below 56002F- Active Pharmaceutical Ingredient Process Inspections (Drug Quality Assurance)56008A- Drug Product Surveillance, CDER Initiated56008H- Drug Product Surveillance, Imported Drugs, CDER and District Initiated surveys56R806- Foreign Routine Drug Surveillance Inspections*FIELD REPORTING REQUIREMENTSOAI ALERTSWhen the district becomes aware of any significant adverse inspectional, analytical, or other information that could or should affect the agencys new product approval decisions with respect to an *active pharmaceutical ingredient manufacturer referenced in an application, *the district should immediately notify HFC-240, Medical Products Quality Assurance Staff, via EMS or FAX. HFC-240 will then convey the information by FAX or equivalent expeditious means to the *Division of Manufacturing and Product Quality (HFD-320) in CDERs Office of Compliance.*When the district becomes aware of any significant adverse inspectional, analytical, or other information that could or should affect the agencys new product approval decisions with respect to an *active pharmaceutical ingredient manufacturer referenced in an application, *the district should immediately notify HFC-240, Medical Products Quality Assurance Staff, via EMS or FAX. HFC-240 will then convey the information by FAX or equivalent expeditious means to the *Division of Manufacturing and Product Quality (HFD-320) in CDERs Office of Compliance.*PROCESS PROFILE REPORTING*In December 1995, at the request of CDER, the Medical Products Quality Assurance Staff (HFC-240) added profile classes CSN (Non Sterile API by Chemical Synthesis) and CSS (Sterile API by Chemical Synthesis) to the drug profile classification system. This change was requested because separate profile classes existed for nonsterile and sterile active pharmaceutical ingredients produced by fermentation processes, but the same did not hold true for active pharmaceutical ingredients produced by chemical synthesis processes. In implementing the change, however, MPQAS did not eliminate the profile class CCS because deleting the latter would have caused a loss of history in the GWQAP profiling system.历程状态报告1995年十二月, 在药物疗效与审评中心(以下简称CDER)的要求下，药品质量保证属（HFC-240） 将CSN（由化学合成的非无菌原料药）以及CSS（由化学合成的无菌原料药）加入到了药品分类系统中。如此分类的必要性是因为通过发酵过程得到的活性药物成分就有无菌和非无菌之分，而化学合成的活性药物成分并没有这样的分类。然而在这一改变生效的过程中，MPQAS并没有去除“CCS”这一分类，因为如果去除了这一分类将会导致GWQAP分类系统部分历史的丢失。Therefore, effective with this program circular, discontinue using Profile class CCS (Chemical Synthesis Crude Drug) and use only the following seven bulk profile classes to report the processes covered during API inspections:*FULL DESCRIPTION PROFILE CLASSNon Sterile API by Chemical Synthesis CSNSterile API by Chemical Synthesis CSSNon Sterile API by Fermentation CFNSterile API by Fermentation CFSPlant/Animal Extraction API CEXBiotechnology API CBICrude Bulk Not Elsewhere Classified (i.e., producers CRU* of bulk intermediates, and contract micronizers of APIs)因此，为了让这一系统能有效运转，不再采用原来的CCS（化学合成原料药Chemical Synthesis Crude Drug）分类而只采用以下的七大分类来说明API检查所包含的生产过程：完整的分类描述：由化学合成的非无菌原料药（CSN）由化学合成的无菌原料药（CSS）由发酵得来的非无菌原料药（CFN）由发酵得来的无菌原料药（CFS）由动/植物中提取得来的原料药（CEX）生物制品的原料药（CBI）别处未有分类的粗制过程（ie., producers of bulk intermediates, and contract micronizers of APIs）（CRU）*REPORTING TO FORENSIC CHEMISTRY CENTER (FCC):*In order to assure that foreign firms supply the requested profile samples and documentation (See Page12, Items 1 & 2), the Forensic Chemistry Center (FCC) should receive a copy of the coversheet for all inspections of foreign active pharmaceutical ingredient manufacturers. The coversheet endorsement should include a phone and fax number of the contact person at the firm. If a sample is not collected by the investigator during the inspection, the coversheet should also state that the manufacturer was instructed to collect and ship a sample and applicable records directly to FCC as per Appendix B. This will permit proper follow-up by FCC and also serve to identify the investigator who will receive a copy of the annotated collection report prepared by FCC. On a quarterly basis, FCC will send a summary of sample testing results to the Foreign Inspection Team (FIT), HFD-322.The container/closure and product information obtained from Appendix B will be included in the Active Pharmaceutical Ingredient Databases and made available to District Import Offices to help prevent counterfeit APIs from entering the United States market.*当前更改*法医化学中心（FCC）的报告* 为了确保国外的厂家提供的是所要求的样品及文件（见12页，12项），法医化学中心（FCC）应该收到海外活性药物成分制造商检查coversheet复印件。 该coversheet背书里应该包括厂家的联系人的电话及传真。 如果样品不是由检查官在检查时收集得到的， 则coversheet里应该声明厂家被通知收集并运输一份样品以及相关记录连带附件B直接寄到FCC。 这就使得FCC得以允许继续并且能够确认将收到由FCC出具的带注解的整理报告检查官。FCC将会在每一季度寄出一份样品检测结果小结给海外检查组（FIT）， HFD-322。从附件B获得的容器/包装及生产信息应该也包括在活性药物成分数据库中并且可被地区进口部可用，以帮助制止假冒伪劣的API产品进入美国市场*REPORTING TO CDER_S DIVISION OF MANUFACTURING AREPORTING TO CDER_S DIVISION OF MANUFACTURING AND PRODUCT QUALITY:For domestic inspections of active pharmaceutical ingredient manufacturers, submit a copy of the EIR coversheet, FD-483, and District issued copy of Warning Letters (after CDER review and concurrence) to CDERs Division of Manufacturing and Product Quality, HFD-320, for review and trend analysis.给CDER 制造和生产质量部的报告对于国内活性药物成分制造商的检查，提交一份EIR coversheet的复印件，FD-483，并且地区管理部门要发布警告信的复印件（CDER 讨论并且同时发布后）给CDER的制造和生产质量部， HFD-320， 用于讨论和进行趋势分析。PART I - BACKGROUND*Since the late 1980s, the U.S. Food and Drug Administration has intensified its inspectional coverage of active pharmaceutical ingredient (API) manufacturers. This is due, in part, to an increased awareness that API quality plays a potentially significant role in the quality, efficacy, and safety of finished dosage form pharmaceuticals. For example, physical properties of APIs formulated into solid oral dosage forms, suspensions, and topicals may adversely affect drug product dissolution/bioavailability. In addition, extremely small quantities of unidentified or uncharacterized impurities in drugs may cause serious patient side effects.第一部分-背景*从上世纪80年代末以来，美国食品药品监督管理局已经加强了它对活性药物成分生产厂家的检查覆盖范围。 由于认识到原料药的质量对于药物终产品的质量，效果以及安全性起到很重要的显著影响，例如，原料药的物理性质会带进固体口服制剂的形态，悬浮性以及分布性，这些都会导致药品的溶解度以及生物利用度产生相反的效果。另外，存在于药品中的那些特别少量的未确定或未定性的杂质将会导致严重的副作用。这些认识的不断提高是导致上述结果出现的部分原因.FDA has long recognized that CGMP concepts, embodied in the good manufacturing practice regulations for finished pharmaceuticals (21 CFR 210 and 211), are valid and can be applied to API processes. These concepts include, among others, building quality into the product, employing appropriately qualified and trained personnel, establishing adequate written procedures and controls, establishing a system of inprocess and end product tests, process validation, and ensuring stability of APIs for the intended period ofuse.*FDA很久以来就已经认可cGMP的概念，具体体现在药品中的优良质量管理规范（21CFR 210及211），已经执行并且可应用到原料药生产过程中。除了别的一些观念以外，这些观念包括，将质量嵌入到产品中，招聘适当的合格的受过培训的人员，建立足够的书面形式的生产和控制程序，建立一套生产过程及终产品检测，工艺验证这样一套程序，并且保证原料药在以后的使用过程中的稳定性。*The *September 1991 FDA Guide to Inspections of Bulk Pharmaceutical Chemicals, reformatted in May 1994 with minor editorial changes, contains general guidance as to the extent and application of GMP/validation concepts to API production and agency expectations regarding tests for impurities and impurity profiles. This guide must be used for inspection of both foreign and domestic facilities to promote inspectional consistency and uniformity.*1991年九月出版的的FDA的化学原料药检查指南，在1994年5月进行了细小的改动， 这份指南基本包含了总的指南并且要API生产和代理商在关于杂质状况检测及杂质profile中要用到GMP/验证的概念。 这一指南必须应用到海外及国内厂家的检查中以提高检查的一致性与均匀性。*At present, FDA expects API manufacturers to apply CGMPs to all steps of an API process, beginning with the use of starting materials, and to validate critical process steps that impact the quality and purity of the final API. This approach recognizes that the control needed is highly dependent on the manufacturing process and that the level of control increases throughout the synthesis as the process proceeds from early intermediate steps to final isolation and purification steps. This approach also allows _appropriate_ levels of control, depending on the process itself (i.e., fermentation process vs. chemical synthesis) and the risk or criticalness associated with the specific process step being performed. * 目前，FDA希望API生产厂家能把cGMP应用到生产API的所有步骤中去，从原料的使用开始，一直到验证影响API终产品的质量及纯度的关键步骤。这个做法认为所需的控制是高度依赖于生产工艺的，而从早期的中间体合成步骤到到最终的分离及纯化步骤的控制水平的提高是贯穿于整个合成工艺的。这一做法还允许根据生产本身（如，发酵过程 VS 化学合成过程）以及与所采用的特殊的生产过程所产生的风险与紧急情况而采取相应的控制级别。This control all manufacturing steps, validate critical process steps approach is embodied in the draft FDA Guidance for Industry on the Manufacture, Processing or Holding of Active Pharmaceutical Ingredients, which was released for public discussion on September 20, 1996. The latter can be obtained from CDER_s Drug Information Branch, HFD-210, or can be downloaded from CDER_s Home Page at _/cder/api.htm._*这一“控制所有的生产步骤，验证关键步骤”的做法具体体现在“FDA对生产，制造及持有活性药物成分的厂家指南”中，这一指南于1996年9月20日公布。 可以从CDER的药品信息部，HFD-210获得该指南，或者从CDER的主页中下载。_/cder/api.htm._*PART II - IMPLEMENTATIONOBJECTIVEThe primary objective of this compliance program is to provide comprehensive CGMP inspectional coverage of the domestic and foreign active pharmaceutical ingredient (API) industry in all profile classes (processes).第二部分目的执行这一程序的主要目的是为了保证完整的cGMP检查能覆盖到所有profile类型（工艺）的国内及海外API生产厂家。PROGRAM MANAGEMENT INSTRUCTIONS*This program circular applies only to active pharmaceutical ingredients intended for use in drug products. An active pharmaceutical ingredient is defined as any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug. Although the agency has used the terms _bulk pharmaceutical chemicals_ and _bulk drug substances_ to describe these materials, FDA is aware that the term _active pharmaceutical ingredient_ has international recognition. In light of this and for addedclarity, the agency is adopting the term active pharmaceutical ingredient for use in this compliance program.*程序执行说明*这一程序只适用于用来生产药品的活性药物成分。 活性药物成分（API）的定义是指在药品中所使用到的任何物质以及当在药品制造，生产或者包装中使用并且最终变成这一药物的一个活性成分或一个剂型的任何物质。尽管当局曾采用过诸如“化学原料药”及“原料药”这些术语来描述这些物质， 但FDA知道“活性药物成分”是国际上认可的。根据这个并且为了增加其透明度，当局在这份执行程序中采用了这一术语。*Owners or operators of all domestic drug establishments, to include APIs, not exempt under section 510(g) of the Federal Food, Drug, and Cosmetic Act, as amended, or 21 CFR 207.10 are required to register and to submit a list of every drug in commercial distribution. Foreign drug manufacturers are not required to register, although they are required to list all drugs imported or offered for import into the United States. Refer to 21 CFR 207.40 for additional information on drug listing requirements for foreign drug establishments.* 所有国内药品生产厂家的所有者或经营者，包括API生产厂家，都要遵守“联邦食品，药品和化妆品法”中的510（g）部分，修改过后，则每一个在商业区里的药品的注册及提交列表或者按21 CFR 207.10要求来做。海外药品生产厂家并不要求被登记，尽管他们被要求提交所有进口或提供进口到美国的药品的列表。Although the current good manufacturing practice (CGMP) regulations, 21 CFR 210 and 211, do not apply to APIs, active pharmaceutical ingredients are subject to the broad requirement of Section 501(a)(2)(B) of the Act in that they must be prepared in conformance with current good manufacturing practice. 尽管现行优良质量管理规范（ cGMP）条例，21CFR210和211都没有应用于API生产厂家，但活性药物成分受法规中501(a)(2)(B)管辖，在此，他们必须按照现行良好质量管理规范来生产。*No distinction is made between APIs and finished pharmaceuticals in the Act, and failure of either to comply with CGMP constitutes a violation of the Act.* Therefore, in this document, the term CGMP refers to the latter, rather than 21 CFR 210 and 211 provisions.*法规对活性药物成分和药品成品的生产厂家并没有不同要求，不遵守cGMP则等同于违背了法规*因此，在这份文件里，cGMP这一术语则指的是后者，而不仅仅是21 CFR 210 and 211所规定的。EXCLUSION*This program circular does not apply to the sterilization and aseptic processing steps of sterile active pharmaceutical ingredients, which are covered by Compliance Program 7356.002A, Sterile Drug Process Inspections. The FDA has long maintained that sterile APIs are finished drug products subject to the CGMP regulation for finished pharmaceuticals (21 CFR 210 and 211) because these are repacked as finished dosage forms under aseptic conditions without further purification or processing.*EXCLUSION（排他）这一程序文件并不适用于无菌产品和无菌活性药物成分的无菌生产过程，而7356.002A的附属程序（无菌药物生产检查）则适用于这些生产过程。FDA 长久以来一直坚持认为无菌API产品就是等同于最终的药品，它的生产应该服从cGMP中药物成品生产的规定（21 CFR 210 and 211）因为它们没有进一步的纯化或生产过程而只是在无菌条件下重新包装成为药品成品。PART III - INSPECTIONAL*Inspections of active pharmaceutical ingredient manufacturers, whether foreign or domestic, should be conducted by experienced investigators with education and/or training in fermentation, chemical synthesis, recombinant DNA, and other biotechnology manufacturing methods. Use of chemists and/or microbiologists during API inspections is recommended, particularly for evaluating laboratory operations (e.g., analytical methods evaluation, analytical data, lab procedures and instrumentation), analytical review of methods used to establish impurity profiles, fermentation manufacturing processes, and complex multi-step chemical synthesis processes.*第三部分检查*对于活性药物成分生产厂家的检查，不管是国外的还是国内的厂家，都应该由受过发酵，化学合成，DNA重组以及别的生物技术生产方法的教育或/和培训的有经验的检查官来进行。在API检查中推荐使用化学家或/和微生物学家，特别是要评估实验操作（如分析方法评估，分析数据，实验操作和仪器使用等），杂质状况的方法分析审查，发酵生产过程以及复杂的多步化学合成过程。*Investigators conducting API inspections must understand the basic differences between the processes used for the production of APIs and those used for finished dosage forms. APIs are usually produced by chemical synthesis, recombinant DNA technology, fermentation, enzymatic reactions, recovery from natural materials, or combinations of these processes. The production of APIs typically involves significant changes of starting materials or intermediates by various chemical, physical, and biological processing steps. Purification is the ultimate objective.* 检查官在对API进行检查时必须了解API生产过程与药品成品生产过程的基本差异。API通常是通过化学合成，DNA重组技术，发酵，酶反应，天然产物提取或者结合这些方法来生产的，API的生产明显涉及到通过多种化学的，物理的以及生物的操作步骤来使得原材料或者中间体发生显著改变。纯化是最终目标。In contrast, finished drug products are formulated from bulk raw materials that are usually subjected to some degree of quality control by the users (dosage form manufacturers). Most important, the manufacturing processes for finished pharmaceuticals typically do not involve purification steps.相反地，药品成品的生产是从原料药形成的，它通常是由使用者（制剂生产厂家）进行不同等级的质量控制。最重要的是，药品成品的生产过程很显然地没有涉及到纯化过程。For these reasons, the manufacturing and quality controls employed in API production and their application throughout the process (i.e., stringency of controls, written instructions, in-process controls, sampling, testing, monitoring, and documentation employed in early processing steps vs. later isolation and purification steps) differ somewhat from those found in finished dosage form plants. These differences, however, are simply reflections of different manufacturing processes, not inherent differences in the importance of GMPs for the two types of production.*由于这些原因，API生产中的制备以及所采用的质量控制以及这些控制在整个生产中的应用（如控制的力度，书面指导，工序间控制，取样，检测，监控以及在早期步骤中所使用的文件与后面的分离纯化步骤所使用的文件的比较）都有些不同于在药品成品生产厂家中所发现的控制。然而，这些差异仅仅反映了生产过程的不同，对于这两种形式的生产过程中执行GMP的重要性并没有质的区别。*Since manufacturers of active pharmaceutical ingredients are often referenced in many drug applications, each inspection should cover as many API processes as is feasible. This strategy will maximize the use of agency resources and avoid repeated visits to the same manufacturing site to cover different API profile classes referenced in subsequent applications. Thus, effective with this CP revision, all inspections of API manufacturers, regardless of how these are initiated, will be GMP qualifying inspections. Inspections should cover the specific API profile classes referenced in the assignment and all other API profile classes not inspected in the last two years.由于活性药物成分生产厂家通常在许多药品申请中被提及到，因此每次检查都应该包括尽可能多的API生产过程。这一策略将会最大化地利用当局资源并且避免了到一个相同的生产厂进行重复检查，而这些生产厂可能涉及在随后的申请中所被提及的不同类的API生产。因此，有效地进行CP修正，所有的API厂家检查，不管是如何起源的都将会是“GMP保证的检查”。检查应该包括所有在分配中提到的明确的profile分类中的API以及所有别的在这两年没有检查过的其它类的API。For foreign API firms, investigators should only cover profile classes for APIs intended to be marketed or already marketed in the United States.APIs selected for coverage should include those referenced in drug applications，are therapeutically significant, are intended for use in parenteral drug products, are difficult to manufacture, or those on record as having past compliance problems. However, this does not preclude the selection of less therapeutically significant active pharmaceutical ingredients to evaluate specific API processes (profile classes) not previously given in-depth coverage at the facility.对于海外API生产厂家，检查官应该只检查涉及到那些将要或已经在美国上市的API。所选出来作为代表的API都应该包括在那些在药品申请中所涉及到的API，比如那些具有治疗重要性的API，将要用于制备非肠道给药药品的API，对于厂家难于生产的API或者那些过去有问题记录在案的API。 然而，这些并不排除选择那些缺少治疗重要性的活性药物成分来评估特定的但之前没有给予深入覆盖的API生产过程（profile classes的）。Investigators conducting API inspections should understand the general inspection strategy set forth in Part II of this program. Recognizing that API firms vary greatly in size, diversity of operations, and quality assurance systems, investigators should carefully plan their inspectional strategy at each firm. Of particular concern are API manufacturing operations located in developing countries. *Impurities and contaminants present in compo