美国FDA原料药生产质量管理规范(中部分 中英文)

日期:2018-02-11 / 人气: / 来源:http://www.rzfanyi.com/ 作者:译声翻译公司

美国FDA原料药生产质量管理规范(中部分 中英文)

 4.4 Containment 4.4 限制

  4.40 Dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosprins.

  4.40 在高致敏性物质,如青霉素或头孢菌素类的生产中,应当使用专用的生产区,包括设施、空气处理设备和/或工艺设备。

  4.41 The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

  4.41 当涉及具有感染性、高药理活性或毒性的物料时(如,激素类或抗肿瘤类),也应当考虑专用的生产区,除非已建立并维持一套经验证的灭活和/或清洗程序。

  4.42 Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another. 4.42 应当建立并实施相应的措施,防止由于在各专用区域间流动的人员和物料而造成的交叉污染。

  4.43 Any production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials, such as herbicides and pesticides, should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic nonpharmaceutical materials should be separate from APIs.

  4.43 剧毒的非药用物质,如除草剂、杀虫剂的任何生产活动(包括称重、研磨或包装)都不应当使用生产原料药所使用的厂房和/或设备。这类剧毒非药用物质的处理和储存都应当与原料药分开。

  4.5 Lighting 4.5 照明

  4.50 Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.

  4.50 所有区域都应当提供充足的照明,以便于清洗、保养或其它操作。

  4.6 Sewage and Refuse 4.6 排污和垃圾

  4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.

  4.60 进入和流出厂房及邻近区域的污水、垃圾和其它废物(如生产中的固态、液态或气态的副产物),应当安全、及时、卫生的处理。废物的容器和/或管道应当显著地标明。

  4.7 Sanitation and Maintenance 4.7 卫生和保养

  4.70 Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.

  4.70 生产中间体和原料药的厂房应当适当地保养、维修并保持清洁。

  4.71 Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.

  4.71 应当制定书面程序来分配卫生工作的职责,并描述用于清洁厂房和设施的清洁的计划、方法、设备和材料。

  4.72 When necessary, written procedures should be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labeling materials, intermediates, and APIs.

  .72 必要时,还应当对合适的灭鼠药、杀虫剂、杀真菌剂、烟熏剂和清洁消毒剂的使用制定书面程序,以避免对设备、原料、包装/标签、中间体和原料药的污染。


  5.1 Design and Construction 5.1 设计和结构

  5.10 Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation (where appropriate), and maintenance.

  5.10 中间体和原料药生产中使用的设备应当有合理的设计和足够的尺寸,并且放置在适宜于其使用、清洁、消毒(根据情况而定)和保养的地方。

  5.11 Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.

  5.11 设备的构造中与原料、中间体或原料药接触的表面不会改变中间体和原料药的质量而使其不符合法定的或其他已规定的质量标准。

  5.12 Production equipment should only be used within its qualified operating range.

  5.12 生产设备应该只在其确认的操作范围内运行。

  5.13 Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.

  5.13 中间体或原料药生产过程中使用的主要设备(如反应釜、贮存容器)和永久性安装的工艺管道,应当作适当的识别标志。

  5.14 Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter the quality of APIs or intermediates beyond the official or other established specifications. Any deviations from this practice should be evaluated to ensure that there are no detrimental effects on the material’s fitness for use. Wherever possible, food grade lubricants and oils should be used.

  5.14 设备运转所需的任何物质,如润滑剂、加热液或冷却剂,不应当与中间体或原料药接触,以免影响其质量,导致无法达到法定的或其它已规定的质量标准。任何违背该规定的情况都应当进行评估,以确保对该物质效果的适用性没有有害的影响。可能的话,应当使用食用级的润滑剂和油类。

  5.15 Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.

  5.15 应当尽量使用关闭的或封闭的设备。若使用开放设备或设备被打开时,应当采取适当的预防措施,将污染的风险降至最小。

  5.16 A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems).

  5.16 应当保存一套现在的设备和关键装置的图纸(如测试设备和公用系统)。

  5.2 Equipment Maintenance and Cleaning 5.2 设备保养和清洁

  5.20 Schedules and procedures (including assignment of responsibility) should be established for the preventative maintenance of equipment.

  5.20 应当制订设备预防性保养的计划和程序(包括职责的分配)。

  5.21 Written procedures should be established for cleaning equipment release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:

  5.21 应当制订设备清洗及允许用于中间体和原料药生产的书面程序。清洁程序应当尽量详细,使操作者能对各类设备进行可重复的、有效 的清洗。这些程序应当包括:

  5.22 Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.

  5.22 设备和用具应当清洁、存放,必要时还应进行消毒或灭菌,以防止污染或夹带物质影响中间体或原料药的质量导致其不符合法定的或其它已规定的质量标准。

  5.23 Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g., degradants or objectionable levels of microorganisms).

  5.23 若设备指定用于同一中间体或原料药的连续生产,或连续批号的集中生产,应当在适宜是时间间隔对设备进行清洗,以防污染物(如降解物或达到有害程度的微生物)的累积和夹带。

  5.24 Nondedicated equipment should be cleaned between production of different materials to prevent cross-contamination.

  5.24 非专用设备应当在生产不同物料之间作清洁,以防止交叉污染。

  5.25 Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.

  5.25 对残留物的可接受限量、清洗程序和清洁剂的选择应当规定并说明理由。

  5.26 Equipment should be identified as to its contents and its cleanliness status by appropriate means.

  5.26 设备内容物及其清洁状况应当用合适的方法标明。

  5.3 Calibration 5.3 校验

  5.30 Control, weighing, measuring, monitoring, and testing equipment critical for ensuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.

  5.30 用于保证中间体或原料药质量的控制、称量、测量、监测和测试设备应当按照书面程序和规定的计划周期进行校验。

  5.31 Equipment calibrations should be performed using standards traceable to certified standards, if they exist.

  5.31 如果有的话,应当用可追溯到已检定的标准的标准来进行设备校验。

  5.32 Records of these calibrations should be maintained. 5.32 校验记录应当加以保存。

  5.33 The current calibration status of critical equipment should be known and verifiable.

  5.33 应当知道并可证实关键设备的当前校验状态。

  5.34 Instruments that do not meet calibration criteria should not be used.

  5.34 不应当使用不符合校验标准的仪器。

  5.35 Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an effect on the quality of the intermediates(s) or API(s) manufactured using this equipment since the last successful calibration.

  5.35 应当调查关键仪器相对于合格校验标准的偏差,以便确定这些偏差对自上次成功校验以来,用该设备生产的中间体或原料药的质量是否有影响。

  5.4 Computerized Systems 5.4 计算机控制系统

  5.40 GMP-related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity, and criticality of the computerized application.

  5.40 与GMP相关的计算机化系统应当验证。验证的深度和广度取决于计算机应用的差异性、复杂性和关键性。

  5.41 Appropriate installation and operational qualifications should demonstrate the suitability of computer hardware and software to perform assigned tasks.

  5.41 适当的安装确认和操作确认应当能证明计算机硬件和软件适合于执行指定的任务。

  5.42 Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.

  5.42 经证明合格的商用软件不需要进行系统水平的检验。如果现行系统在安装时没有进行验证,有合适的文件证明时可进行回顾性验证。

  5.43 Computerized system should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g., system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made.

  5.43 计算机化系统应当有足够的控制,以防止未经许可存取或改动数据。应当有防止数据丢失(如系统关闭而数据未捕获)的控制。任何数据的变更、上一次输入、谁作的变更和什么时候变更都应当有记录。

  5.44 Written procedures should be available for the operation and maintenance of computerized system.

  5.44 应当有计算机化系统操作和维护的书面程序。

  5.45 Where critical data are being entered manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself.

  5.45 手工输入关键性数据时,应当另外检查输入的准确性。这可由第二位操作人员或系统本身来进行。

  5.46 Incidents related to computerized system that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.

  5.46 应当加以记录可能影响中间体或原料药质量、或者记录或测试结果可靠性的与计算机化系统有关的偶发事件,并作调查。

  5.47 Changes to computerized system should be made according to a change procedure and should be formally authorized, documented, and tested. Records should be kept of all changes, including modifications and enhancements made to the hardware, software, and any other critical component of the system. These records should demonstrate that the system is maintained in a validated state.

  5.47 对计算机化系统所作的变更应当按照变更程序进行,并应当经过正式批准、记录成文并作测试。所有变更记录都应当保存,包括对系统的硬件、软件和任何其它关键组件的修改和升级。这些记录应当证明该系统维持在验证过的状态。

  5.48 If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized system.

  5.48 如果计算机的故障或失效会导致记录的永久丢失,则应当提供备份系统。所有计算机化的系统都应当有数据保护措施。

  5.49 Data can be recorded by a second means in addition to the computer system.

  5.49 除计算机系统之外,数据可以用第二种方式记录。


  6.1 Documentation System and Specifications 6.1 文件系统和质量标准

  6.10 All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures. Such documents can be in paper or electronic form.

  6.10 与中间体或原料药生产有关的所有文件都应当按照书面程序进行拟定、审核、批准和分发。这些文件可以是纸张或电子形式。

  6.11 The issuance, revision, superseding, and withdrawal of all documents should be controlled by maintaining revision histories.

  6.11 所有文件的发放、修订、替换和收回应当通过保存修订历史来控制。

  6.12 A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

  6.12 应当制订一个保存所有适用文件(如开发历程报告、扩产报告、技术转移报告、工艺验证报告、培训记录、生产记录、控制记录和分发记录)的程序。应当规定这些文件的保存期。

  6.13 All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.

  6.13 所有生产、控制、销售记录都应保留至该批的有效期后至少一年。对于有复验期的原料药,记录应当保留至该批全部发出后三年。

  6.14 When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still legible.

  6.14 做记录时,应当在刚做操作活动后就在所提供的空白处以不易擦掉的方式填写,并标明填写者。修改记录时应当注明日期、签名并保持原来的记录仍可识读。

  6.15 During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

  6.15 在保存期间,记录的原件或副本都应保留在记录中描述的活动发生的地方。能以电子或其它方式从另一地点即时恢复的记录也可以接受。

  6.16 Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

  6.16 质量标准、指令、规程和记录保存方式可以是原件,或者真实的副本如影印本、缩微胶卷、缩微平片,或其它原始记录的准确复制件。在使用压缩技术如缩微胶卷或电子记录时,应当有适当的制备纸张副本的恢复设备和方法。

  6.17 Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically affect quality. Acceptance criteria should be established and documented for in-process controls.

  6.17 应当制订原料、中间体(必要时)、原料药和标签及包装材料的质量标准。此外,应当为工艺助剂、垫圈,或中间体或原料药生产中使用的能决定性地影响质量的物料制订质量标准。中间控制应当制定可接受的标准,并成文备查。

  6.18 If electronic signatures are used on documents, they should be authenticated and secure.6.18如果文件采用电子签名,它们应当经过证实,并且确保其安全可靠。

  6.2 Equipment cleaning and Use Record 6.2 设备的清洁和使用记录

  6.20 Records of major equipment use, cleaning, sanitation, and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment and the person who performed the cleaning and maintenance.

  6.20 主要设备的使用、清洁、消毒和/或灭菌和保养记录应当记有日期、时间(如有必要的话)、产品、设备中加工的每批批号以及进行清洁和保养的人。

  6.21 If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of intermediate or API follow in traceable sequence. In case where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.

  6.21 如果设备专门用于一种中间体或原料药的生产,而且该中间体或原料药的批号有可追溯性的顺序,那就不需要有单独的设备记录。专门设备的清洁、保养及使用记录可以作为批记录的一部分或单独保存。

  6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials

  6.3 原料、中间体、原料药的标签和包装材料的记录

  6.30 Records should be maintained including:The name of the manufacturer, identity, and quantity of each shipment of each batch of raw materials, intermediates, or labeling and packaging materials for API’s; the name of the supplier; the supplier’s control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt

  6.30 需保存的记录应当包括: 每次到货的每批原料、中间体、原料药标签和包装材料的生产商的名称,标识和数量;供应商的名称、供应商的管理编号,或其它识别号码;物料接收编号和接收日期;

  6.31 Master (approved) labels should be maintained for comparison to issued labels.

  6.31 标准标签(已批准的)应当保留,用来与发放的标签作比较。

  6.4 Master Production Instructions (Master Production and Control Records)

  6.4 生产工艺规程(主生产和控制记录)

  6.40 To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).

  6.40 为确保批与批的一致性,每种中间体和原料药的生产工艺规程应当由一人拟定、注明日期并签名,并由质量部门的另一人独立进行检查、填写日期和签名。

  6.5 Batch Production Records (Batch Production and Control Records)

  6.5 批生产记录(批生产和控制记录)

  6.50 Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

  6.50 应当为每种中间体和原料药准备批生产记录,内容应当包括与各批生产和控制有关的完整资料。批记录发放之前,应当检查版本是否正确,是否是相应生产规程的准确明了的再现。如果批生产记录是按主文件的另一独立部分制定的,该文件应当包括对现行的生产工艺规程的参考。

  6.51 These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the production code together with the date and time can serve as the unique identifier until the final number is allocated.

  6.51 批记录在发放时应当有一个唯一的批号或标识号,有日期和签名。连续生产时,在最终批号确定前,可以将产品代码、日期和时间结合起来作为唯一的识别符。

  6.53 Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation. 6.53 应当建立并执行一种书面程序,对在符合规格上有重大偏差或不合格的一批中间体或原料药进行调查。调查还应当延伸到与这批失误或偏差有关的其它批号。

  6.6 Laboratory Control Records 6.6 实验室控制记录

  6.60 Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:

  A description of samples received for testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing

  A statement of or reference to each test method used

  A statement of the weight or measure of sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions

  A complete record of all raw data generated during each test, in addition to graphs, charts and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested

  A record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors

  A statement of the test results and how they compare with established acceptance criteria

  The signature of the person who performed each test and the date(s) the tests were performed

  The date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards 6.60 实验室控制记录应当包括从为了确保符合规定的规格和标准所做的所有测试中得到的下列完整的数据,包括下列检验和测定:









  6.7 Batch Production Record Review 6.7批生产记录审核

  6.70 Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labeling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.

  6.70 应当制定并执行审核和批准批生产记录和实验室控制记录,包括包装和贴签的书面程序,以便放行或分发前确定中间体或原料药是否符合规定标准。

  6.71 Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of noncritical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).

  6.71 在一批原料药放行或分发之前,关键工序的批生产记录和实验室控制记录应当由质量部门审核和批准。非关键性工序的生产和实验室控制记录可按照经质量部门批准的程序,由有资格的生产人员或其它部门审核。

  6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.

  6.72 在批放行前,所有偏差,调查和不合格报告都应当作为批记录的一部分进行审核。

  6.73 The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

  6.73 质量部门可将发放中间体的职责和权力委派给生产部门,运往生产商控制范围以外的中间体除外。


  7.1 General Controls 7.1 控制通则

  7.10 There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

  7.10 应当有书面程序阐明物料的接收、鉴别、待验、贮存、搬运、取样、测试和批准或拒收。

  7.11 Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.

  7.11 原料药和/或中间体生产商应当有对关键原料供应商的评估系统。

  7.12 Materials should be purchased against an agreed specification, from a supplier, or suppliers, approved by the quality unit(s).

  7.12 应当根据已确定的规格从经过质量部门核准的一个或多个供应商处购买物料。

  7.13 If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.7.13 如果关键物料的供应商不是该物料的生产商,原料药或中间体的生产商应当获知该物料生产商的名称和地址。

  7.14 Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.

  7.14 关键原料的供应商的变更应当参照第13章“变更控制”进行。

  7.2 Receipt and Quarantine 7.2接收和待验

  7.20 Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labeling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined, or tested, as appropriate, and released for use.

  7.20 一旦收到物料而尚未验收,应当目测检查物料每个或每组包装容器的标签是否正确(包括如果供应商所用名称与内部使用的名称不一致,应当检查其相互关系)、容器是否损坏、密封处和开启证据有无破裂或污染。物料应当存放的待验区,直至它们被取样、检查或酌情测试,并放行使用。

  7.21 Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.

  7.21 在进厂的物料与现有的库存(如储仓中的溶剂或货物)混合之前,应当确认货是否对、必要时进行测试并放行。应当有程序来防止把来料错放到现有的库存中。

  7.22 If bulk deliveries are made in nondedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following:


  7.23 Large storage containers and their attendant manifolds, filling, and discharge lines should be appropriately identified.

  7.23 大的储存容器及其随附的管路、填充和排放管都应当适当标明。

  7.24 Each container or grouping of containers (batches) of materials should be assigned and identified with a distinctive code, batch, or receipt number. This number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch.

  7.24 每个或每组物料容器(几批)的物料都应当指定并标上编号、批号或接收号。此号码应当用于记录每批的处置情况。应当有一个识别每批状态的系统。

  7.3 Sampling and Testing of Incoming Production Materials 7.3 进厂物料的取样与测试

  7.30 At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below. A supplier’s certificate of analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers.

  7.30 除了7.32中指出的物料,对于每批物料至少要做一个鉴别试验。在生产商对供应商有一套审计体系的前提下,供应商的分析报告可以用来替代其他项目的测试。

  7.31 Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Complete analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis. Reliability of certificates of analysis should be checked at regular intervals.

  7.31 对供应商的核准应当包括一次评估,提供足够的证据(如过去的质量记录)证明该生产商始终都能提供符合质量标准的物料。在减少内部测试之前至少应当对三批物料作全检。然而,最低限度每隔一定时间应当进行一次全检,并与分析报告进行比较。分析报告的可靠性应当定期进行检查。

  7.32 Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s certificate of analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.

  7.32 工艺助剂、有害或剧毒的原料、其它特殊物料、或转移到公司控制范围内的另一个部门的物料不用测试,前提是能取得生产商的分析报告,证明这些原料符合规定的质量标准。对容器、标签和批号记录进行目测检查应当有助于鉴别这些原料。对这些物料不作现场测试应当说明理由,并用文件证明。

  7.33 Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quality needed for analysis.

  7.33 取样应当能代表被取的那批物料。取样方法应当规定:取样的容器数,取样部位,每个容器的取样量。取样容器数和取样量应当根据取样方案来决定。取样方案的制定要综合考虑物料的重要程度、变异性、供应商过去的质量情况,以及分析需用量。

  7.34 Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

  7.34 应当在规定的地点,用规定的方法取样,以避免取样的物料被污染,或污染其它物料。

  7.35 Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

  7.35 被取样的容器应当小心开启,随后重新密封。这些容器应当做标记表明样品已抽取。

  7.4 Storage 7.4储存

  7.40 Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

  7.40 物料的搬运和贮存应当防止降解、污染和交叉污染。

  7.41 Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.

  7.41 纤维板桶、袋子或盒装物料应当离地贮存,并根据情况留出适当空间便于清洁和检查。

  7.42 Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.

  7.42 物料应当在对其质量没有不良影响的条件下和时限内贮存,而且通常应当加以控制,做到先进先出。

  7.43 Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

  7.43 某些装在适当容器中的物料可以存放在室外,只要识别标签保持清晰,而且容器在开启和使用前进行适当清洁。

  7.44 Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorized use in manufacturing.

  7.44 不合格物料应当做标识,并用隔离系统控制,已防止未经许可而用于生产。

  7.5 Re-evaluation 7.5重新评估

  7.50 Materials should be re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

  7.50 应当根据情况对物料进行重新评估以便确定其使用的适合性(例如长期存放或暴露于热或潮湿的环境中)。


  8.1 Production Operations 8.1 生产操作

  8.10 Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.

  8.10 用于生产中间体和原料药的原料应当在适宜的条件下称重或测量,以便不影响其使用的适合性。称重和测量装置应当有适合于其用途的精度。

  8.11 If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:

  8.11 如果某物料分出一部分留待以后的生产操作中使用,应当用适合的容器来盛装该物料,并应当标明下列信息:

  8.12 Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.

  8.12 关键的称重、测量或分装操作应当有人作证或接受相应的控制。使用前,生产人员应当确认该物料是要生产的中间体或原料药的批记录中指定的。

  8.13 Other critical activities should be witnessed or subjected to an equivalent control.

  8.13 其它关键活动应当有人作证或接受相应的控制。

  8.14 Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

  8.14 在生产过程中的指定步骤,实际收率应当与预计的收率作比较。具有合适范围的预计收率应当根据以前的实验室、中试规模或生产的数据来确定。应当调查与关键工艺步骤有关的收率偏差,以确定其对相关批号最终质量的影响或潜在影响。

  8.15 Any deviation should be documented and explained. Any critical deviation should be investigated.

  8.15 任何偏差都应当记录,并作解释。任何关键的偏差应当作调查。

  8.16 The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

  8.16 应当标明主要设备的生产状态,可以标在每个设备上,或者用文件、计算机控制系统或其它替代的方法。

  8.17 Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

  8.17 对需要进行返工或重新加工的物料应当适当地加以控制,防止未经许可就使用。

  8.2 Time Limits 8.2 时限

  8.20 If time limits are specified in the master production instruction (see 6.40), these time limits should be met to ensure the quality of intermediates or APIs. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.

  8.20 如果生产工艺规程(见6.40)中规定了时限,应当遵守这些时限,以保证中间体和原料药的质量。所有偏差都要有记录并解释原因。在加工到一个目标值时(例如,调节pH、氢化、干燥到预定标准),时限可能就不合适了,因为反应或加工步骤的完成是取决于过程中的取样和测试的。

  8.21 Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.

  8.21 留作进一步加工的中间体应当在适宜的条件下储存,以保证其适宜于使用。

  8.3 In-process Sampling and Controls 8.3 工序间的取样和控制

  8.30 Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the developmental stage or from historical data.

  8.30 应当制定书面程序来监测会造成中间体和原料药质量特性变异的工艺步骤的进程,并控制其生产情况。工序间控制及其接受标准应当根据项目开发阶段或者以往的生产数据来确定。

  8.31 The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).

  8.31 综合考虑所生产中间体和原料药的特性,反应类型,该工序对产品质量影响的程度大小等因素来确定可接受的标准,检测类型和范围。前期生产的中间体控制标准可以松一些,越接近成品,中间控制的标准越严(如分离,纯化)。

  8.32 Critical in-process controls (and critical process monitoring), including control points and methods, should be stated in writing and approved by the quality unit(s).

  8.32 关键的中间控制(和工艺监测),包括控制点和方法,应当书面规定,并经质量部门批准。

  8.33 In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All test and results should be fully documented as part of the batch record.

  8.33 中间控制可以由合格的生产部门的人员来进行,而调节的工艺可以事先未经质量部门批准,只要该调节在由质量部门批准的预先规定的限度以内。所有测试及结果都应当作为批记录的一部分全部归档。

  8.34 Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.

  8.34 应当制定书面程序,说明中间物料、中间体和原料药的取样方法。取样方案和程序应当基于科学合理的取样实践。

  8.35 In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.

  8.35 工序间取样应当按能防止污染所取的样品、其它中间体或原料药的程序进行。应当制定保证样品收集后的完整性的程序。

  8.36 Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

  8.36 生产操作中的正常监控过程和工艺调节过程中出现的超出标准的偏差(OOS),通常情况不需要调查。

  8.4 Blending Batches of Intermediates or APIs 8.4 中间体或原料药的混批

  8.40 For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.

  8.40 根据本文件的目的,混合的定义是为了生产出均匀的中间体或原料药而将同一质量标准的物料混在一起的过程。同一批号几部分(例如,收集一个结晶批号出来的几次离心机装的料)的工艺间的混合,或者混合从几个批号来的部分作进一步加工,看作是生产工艺的一部分,而不是混合。

  8.41 Out-of-specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

  8.41 不合格的批号不能与其他批号混合在一起来达到符合质量标准的目的。混合的每一个批号都应该是用规定的生产工艺生产的,混合前应当单独检测,并符合相应的质量标准。

  8.43 Blending processes should be adequately controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate.


  8.44 The batch record of the blending process should allow traceability back to the individual batches that make up the blend.

  8.44 混合过程的批记录应当允许追溯到参与混合的每个单独批号。

  8.45 Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process.

  8.45 如果原料药的物理性质至关重要(例如,用于固体口服制剂或混悬剂的原料药),混合工艺应当验证,以显示混合后批号的均匀性。验证应当包括测试可能受混合过程影响的关键属性(例如,粒度分布,堆密度和振实密度)。

  8.46 If the blending could adversely affect stability, stability testing of the final blended batches should be performed.

  8.46 如果混合会对稳定性有不良影响,应当对最终混合批号进行稳定性测试。

  8.47 The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend.

  8.47 混合批号的有效期或复验期应当以混合中生产日期最早的尾料或批次的批号为基准。

  8.5 Contamination Control 8.5 污染控制

  8.50 Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.

  8.50 在得到充分控制的前提下,上一批号的同一中间体或原料药的剩余物可以带入下几个连续批号。例如,黏附在微粉机壁上的残留,离心出料后残留在离心机筒体内的潮湿的结晶,将物料转至下一步工序时无法从反应器中彻底放尽的物料。此类带入不应当导致因带入降解物或微生物的污染而对已经建立的原料药杂质概况有不良影响。

  8.51 Production operations should be conducted in a manner that prevents contamination of intermediates or APIs by other materials.

  8.51 生产操作应当防止中间体或原料药被其它物料污染。

  8.52 Precautions to avoid contamination should be taken when APIs are handled after purification. 8.52 处理精制后的原料药应当采取预防污染的措施。



  9.1 General 9.1 总则

  9.10 There should be written procedures describing the receipt, identification, quarantine, sampling, examination, and/or testing, release, and handling of packaging and labeling materials.

  9.10 应当有书面程序描述包装和贴签用物料的接收、鉴别、待验、取样、检查和/或测试、放行和搬运。

  9.11 Packaging and labeling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.

  9.11 包装和贴签用物料应当符合规定的质量标准。不合格者要拒收,不得用于不适合于其的操作中。

  9.12 Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.


  9.2 Packaging Materials 9.2 包装材料

  9.20 Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.

  9.20 容器应当能够对中间体和原料药提供足够的保护,使其在运输和建议的贮存条件下不会变质或受到污染。

  9.21 Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.

  9.21 容器应当清洁,如果中间体或原料药有要求时,应当进行消毒,以确保适合于其预期的用途。这些容器应无反应活性、加和性或吸附性,一面改变中间体或原料药的质量使其超出质量标准的限度。

  9.22 If containers are reused, they should be cleaned in accordance with documented procedures, and all previous labels should be removed or defaced.

  9.22 容器被重新使用时,应当按照规定程序进行清洁,并出去或涂毁以前的所有标签。

  9.3 Label Issuance and Control 9.3 标签发放与控制

  9.30 Access to the label storage areas should be limited to authorized personnel.

  9.30 只有获准人员才能进入标签贮存区。

  9.31 Procedures should be established to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labeled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).

  9.31 应当建立规程来平衡发出的、使用的和退回的标签的数量,并评估已贴签的容器数和发出的标签数之间的偏差值。此种差异应当加以调查,调查应当由质量保证部门批准。

  9.32 All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.

  9.32 所有剩余的印有批号或与批有关内容的标签都应当销毁。收回的标签应当以防止混淆并提供适当标识的方式加以保留和贮存。

  9.33 Obsolete and out-dated labels should be destroyed.

  9.33 废弃的和过期的标签应当销毁。

  9.34 Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record.

  9.34 包装操作中用于印刷标签的印刷设备应当加以监控,以确保所有印刷内容符合批生产记录中的内容。

  9.35 Printed labels issued for a batch should be carefully examined for proper identity and conformity to specifications in the master production record. The results of this examination should be documented.

  9.35 应当仔细检查发放给某批的打印好的标签,其标识是否正确,并符合主生产记录的内容。检查结果应当记录在批生产记录中。

  9.36 A printed label representative of those used should be included in the batch production record. 9.36 批生产记录中应当附一张代表那些所用标签的印制好的标签。

  9.4 Packaging and Labeling Operations 9.4 包装和贴签操作

  9.40 There should be documented procedures designed to ensure that correct packaging materials and labels are used.

  9.40 应当有文件化的规程确保使用正确的包装材料和标签。

  9.41 Labeling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.

  9.41 帖签操作应当防止混淆。应当与涉及其它中间体或原料药的操作有物理的或空间的隔离。

  9.42 Labels used on containers of intermediates or APIs should indicate the name or identifying code, batch number, and storage conditions when such information is critical to ensure the quality of intermediate or API.

  9.42 用于中间体或原料药容器的标签应当注明:确保中间体或原料药质量的关键信息,如名称、识别代码、产品批号和储存条件。

  9.43 If the intermediate or API is intended to be transferred outside the control of the manufacturer’s material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be included on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.

  9.43 如果中间体或原料药要向生产商的物料管理系统控制范围以外运输,标签上还应当包括生产商的名称、地址,装量,特殊的运输要求,和其它特殊的法定要求。对于有失效期的中间体或原料药,标签和分析报告单上应当注明失效期。对于有复验期的中间体或原料药,标签和/或分析报告单上应当注明复验期。

  9.44 Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation system.

  9.44 包装和帖签设施应当在使用前进行检查,以确定下一次包装操作不需要的所有物料都已清除。该检查应当记录在批生产记录、设备使用记录或其它文件系统中。

  9.45 Packaged and labeled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label. This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control records.

  9.45 应当检查已包装和帖签的中间体或原料药,以确保该批的容器和包装的标签正确。该检查应当作为包装操作的一部分。检查结果应当记录在批生产或控制记录中。

  9.46 Intermediate or API containers that are transported outside of the manufacturer’s control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.



现在致电 158-9898-6870 OR 查看更多联系方式 →

Go To Top 回顶部
  • 扫一扫,微信在线