FDA原料药检查六个系统的内容.doc

APPENDIX A: Description of Each System and Areas of Coverage 附件A：系统的描述与包含的内容QUALITY SYSTEM 质量系统：Assessment of the Quality System has two phases. The first phase is to evaluate whether the Quality Unit has fulfilled the responsibility to review and approve all procedures related to production, quality control, and quality assurance and assure the procedures are adequate for their intended use. This also includes the associated recordkeeping systems. The second phase is to assess the data collected to identify quality problems and may link to other major systems for inspectional coverage. 质量系统的评价有两个方面。第一个方面是评价质量部门是否已经履行职责，审核批准所有与生产，质量控制和质量保证有关的程序，并确保有足够的程序来保证运行。这也包括相关的记录保存系统。第二个方面是评价收集到的数据资料来确定质量问题，可能相关的其他主要系统也在检查范围内。For each of the following bulleted items, the firm should have written and approved procedures and documentation resulting therefrom. The firms adherence to written procedures should be verified through observation whenever possible. These areas are not limited to the final APIs, but may also include starting materials and intermediates. These areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. All areas under this system should be covered; however the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings. 对下面所列的条款，公司应该有书面的经过批准的程序和文件记录。公司是否遵循书面程序应该通过观察来证明。这些内容不局限于API，也适用于起始物料和中间体。这些内容阐明的不仅仅是本系统的不足，也说明了其他系统存在的缺陷，这就需要扩大检查内容。本系统的所有方面都应该包括在内，但实际包含的范围可能与计划中的检查内容有所改变。 Adequacy of staffing to ensure fulfillment of quality unit duties 有足够的人员来确保履行质量部门的职责。 Periodic quality reviews as described in ICH Q7A Section 2.5, Product Quality Review; inspection audit coverage should include API types that are representative of manufacturing at this site; inspection audit should also examine some batch and data records associated with each API quality review to verify that firms review was sufficiently complete; and, audit should confirm that firm has identified any trends and has corrected or mitigated sources of unacceptable variation. 如ICH Q7A 2.5节产品质量审核 所述，进行周期性质量审核；检查审计内容应该包括生产中具有代表性的API，检查审计也应该包括检查每个API批记录和数据记录来核实公司的审核是完善的；审计应该确定公司已经针对不可接受的变更进行改进。 Complaint reviews (quality and medical): documented; evaluated; investigated in a timely manner; includes corrective action where appropriate. Determine whether pattern of complaints and records of internal rejection or reprocessing/reworking of API batches warrant expanding the inspection. 投诉审核（质量和药性）：文件记录；评价；及时进行调查；包括适当的改进措施。确定是否投诉和拒收记录或API批的返工/重加工记录也在检查范围内。 Discrepancy and failure investigations related to manufacturing and testing: documented; evaluated; critical deviations investigated in a timely manner and expanded to include any related APIs and material; includes corrective action where appropriate. 关于生产和试验的不符合和失败的调查：文件记录；评价；及时调查关键偏差，和对所有相关的API和物料展开调查；包括适当的改进措施。 Change Control (including “process improvements”): documented; evaluated; approved; need for revalidation assessed. 变更控制（包括“工艺改进”）：文件记录；评价；批准；重复验证评估的必要性。 Returns/Salvages: assessment; investigation expanded where warranted; final disposition. 退货/残料：评价；批准展开调查；最后的处置。 Rejects: investigation expanded where warranted; corrective action where appropriate. 拒收：批准展开调查；适当改进措施。 System to release raw materials. 原始物料放行系统。 Batches manufactured since last inspection to evaluate any rejections or conversions (i.e., from drug to non-drug use) due to processing problems. 对上次检查以后生产的批进行评价是否有不合格品或是由于工艺问题而发生的转变（亦即，从药物向非药物使用的转变）。 Reprocessing and/or reworking events are properly approved and evaluated for impact on material quality. 返工或再加工必须得到批准，并对物料质量的影响进行评价。 Recalls (including any attempt to recover distributed API not meeting its specifications or purported quality), determine cause and corrective actions taken. 召回（包括准备回收的已分发的不符和质量标准或预期要求的API），确定原因和采取的措施。 Stability Failures: investigation expanded where warranted; disposition. Determine if stability data supports API retest or expiry dates and storage conditions. 稳定性不符合：批准开展调查；处置。确定稳定性数据是否支持API复验或有效期和贮存条件。 Validation: Status of validation/revalidation activities (e.g., computer, manufacturing process, laboratory methods), such as reviews and approvals of validation protocols and reports. 验证：验证/再验证活动的情况（例如，计算机，生产工艺，实验方法），比如验证方案和验证报告的审核和批准。 Training/qualification of employees in quality control unit functions. QC部门人员的资格/培训。ICH Q7A references for Quality System: ICH Q7A参考： Section 2, Quality Management 第2节：质量管理 Section 13, Change Control 第13节：变更控制 Section 14, Rejection and Reuse of Materials 第14节：拒收和物料的再利用 Section 15, Complaints and Recalls 第15节：投诉和召回 Section 16, Contract Manufacturers (including laboratories). 第16节：协议生产商（包括实验室）FACILITIES AND EQUIPMENT SYSTEM 设施和设备系统： For each of the following, the firm should have written and approved procedures and documentation resulting therefrom. The firms adherence to written procedures should be verified through observation whenever possible. These areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. When this system is selected for coverage in addition to the Quality System, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings. 对下面所列的条款，公司应该有书面的经过批准的程序和文件记录。公司是否遵循书面程序应该通过观察来证明。这些内容阐明的不仅仅是本系统的不足，也说明了其他系统存在的缺陷，这就需要扩大检查内容。除质量系统外，当本系统也包括在检查范围时，下列所有内容必须包括在内；但实际包含的范围可能与计划中的检查内容有所改变。1. Facilities 设施 Cleaning and maintenance. 清洁和维护。 Facility layout, flow of materials and personnel for prevention of cross-contamination, including from processing of non-drug materials. 设施布置，为避免交叉污染人流与物流的流动，包括非药品物质的工艺加工。 Dedicated areas or containment controls for highly sensitizing materials (e.g., penicillin, beta-lactams, steroids, hormones, and cytotoxics). 高致敏物料的专用区域或容器控制（例如，盘尼西林，类固醇，激素和细胞毒素）。 Utilities such as steam, gas, compressed air, heating, ventilation, and air conditioning should be qualified and appropriately monitored (note: this system includes only those utilities whose output is not intended to be incorporated into the API, such as water used in cooling/heating jacketed vessels). 公用系统如蒸汽，气体，压缩空气，热水，通风和空调应该符合质量规格，并进行适当的监控（注意：本系统包括那些只输出而不混合进入API的系统，比如用于冷却/加热夹套的水）。 Lighting, sewage and refuse disposal, washing and toilet facilities. 照明设备，污水和废物处理，清洗设施和卫生设施。 Control system for implementing changes in the building. 厂房实施变更的控制系统。 Sanitation of the building including use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents. 厂房卫生包括灭鼠剂，杀真菌剂，杀虫剂和清洁剂的使用。 Training and qualification of personnel. 相关人员资格和培训。2. Process Equipment 工艺设备 Equipment installation, operational, performance qualification where appropriate. 设备安装，操作，运行确认。 Appropriate design, adequate size and suitably located for its intended use. 根据用途进行合理设计，合理的尺寸大小，适当放置。 Equipment surfaces should not be reactive, additive, or absorptive of materials under process so as to alter their quality. 设备表面应该不具有反应活性，加和性或吸附性，不会影响加工过程中物料的质量。 Equipment (e.g., reactors, storage containers) and permanently installed processing lines should be appropriately identified. 设备（如反应釜，储存容器）和永久性工艺生产线应该经过确认。 Substances associated with the operation of equipment (e.g., lubricants, heating fluids or coolants) should not come into contact with starting materials, intermediates, final APIs, and containers. 与设备操作相关的物质（如润滑剂，加热液体或冷却剂）不能与起始物料，中间体，最后API和容器有接触。 Cleaning procedures and cleaning validation and sanitization studies should be reviewed to verify that residues, microbial, and, when appropriate, endotoxin contamination are removed to below scientifically appropriate levels. 清洁程序，清洁验证和卫生研究应该经过审核，确认残留物，微生物，内毒素（若需要）污染应该在标准下。 Calibrations using standards traceable to certified standards, preferably NIST, USP, or counterpart recognized national government standard-setting authority. 使用有证明的标准进行校验，最好是NIST，USP或本国政府标准设立机构认可的副本。 Equipment qualification, calibration and maintenance, including computer qualification/validation and security. 设备确认，校验和维护，包括计算机确认/验证和安全性。 Control system for implementing changes in the equipment. 设备实施变更的控制系统。 Documentation of any discrepancy (a critical discrepancy investigation is covered under the Quality System). 所有不符合项的文件记录（主要的不符合调查包括在质量系统中）。 Training and qualification of personnel. 相关人员的资格和培训。ICH Q7A references for Facilities and Equipment ICH Q7A参考： Section 4, Buildings and Facilities 第4节：建筑和设备 Section 5, Process Equipment 第5节：工艺设备 Section 6, Documentation and Records 第6节：文件和记录MATERIALS SYSTEM 物料系统：For each of the following, the firm should have written and approved procedures and documentation resulting therefrom. The firms adherence to written procedures should be verified through observation whenever possible. These areas are not limited to the final API, but may also incorporate starting materials and intermediates. These areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. When this system is selected for coverage in addition to the Quality System, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings. 对下面所列的条款，公司应该有书面的经过批准的程序和文件记录。公司是否遵循书面程序应该通过观察来证明。这些内容不局限于API，也适用于起始物料和中间体。这些内容阐明的不仅仅是本系统的不足，也说明了其他系统存在的缺陷，这就需要扩大检查内容。除质量系统外，当本系统也包括在检查范围时，下列所有内容必须包括在内；但实际包含的范围可能与计划中的检查内容有所改变。 Training/qualification of personnel. 相关人员的资格和培训。 Identification of starting materials, containers. 起始物料，容器的确认。 Storage conditions. 储存条件。 Holding of all material and APIs, including reprocessed material, under quarantine until tested or examined and released. 保留所有物料和API，包括返工物料，待验物料必须经过检验后才能放行。 Representative samples are collected, tested or examined using appropriate means and against appropriate specifications. 收集代表性的样品，使用适当的方法和质量标准进行检测。 A system for evaluating the suppliers of critical materials. 关键物料的供应商的评价系统。 Rejection of any starting material, intermediate, or container not meeting acceptance requirement. 拒收不符合要求的起始物料，中间体或容器。 Appropriate retesting/reexamination of starting materials, intermediates, or containers. 起始物料，中间体或容器进行适当的复验/复检。 First-in / first-out use of materials and containers. 物料和容器遵循“先进先出”原则。 Quarantine and timely disposition of rejected materials.拒收物料的待验和及时处理。 Suitability of process water used in the manufacture of API, including as appropriate the water system design, maintenance, validation and operation.生产API的工艺用水的适用性，包括适当的水系统设计，维护，验证和操作。 Suitability of process gas used in the manufacture of API (e.g., gas use to sparge a reactor), including as appropriate the gas system design, maintenance, validation and operation. 生产API的工艺用气体的适用性（比如，反应釜中用于喷舞的气体），包括适当的水系统设计，维护，验证和操作。 Containers and closures should not be additive, reactive, or absorptive. 容器不应该具有加和性，反应活性或吸附性。 Control system for implementing changes. 实施变更的控制系统。 Qualification/validation and security of computerized or automated process. 计算机控制系统或自动工艺的确认/验证和安全性。 Finished API distribution records by batch. API的批发放记录。 Documentation of any discrepancy (a critical discrepancy investigation is covered under the Quality System). 所有不符合项的文件记录（主要的不符和调查包括在质量系统中）。ICH Q7A references for Materials System: ICH Q7A参考： Section 7, Materials Management 第7节：物料管理 Section 10, Storage and Distribution 第10节：储存和发放 Section 4.3, Water 第4.3节：水 Section 6, Documentation and Records 第6节：文件和记录PRODUCTION SYSTEM 生产系统：For each of the following, the firm should have written and approved procedures and documentation resulting therefrom. The firms adherence to written procedures should be verified through observation whenever possible. These areas are not limited to the final API, but may also incorporate starting materials and intermediates. These areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. When this system is selected for coverage in addition to the Quality System, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings. 对下面所列的条款，公司应该有书面的经过批准的程序和文件记录。公司是否遵循书面程序应该通过观察来证明。这些内容不局限于API，也适用于起始物料和中间体。这些内容阐明的不仅仅是本系统的不足，也说明了其他系统存在的缺陷，这就需要扩大检查内容。除质量系统外，当本系统也包括在检查范围时，下列所有内容必须包括在内；但实际包含的范围可能与计划中的检查内容有所改变。 Training/qualification of personnel. 相关人员的资格和培训。 Establishment, adherence, and documented performance of approved manufacturing procedures. 建立审批生产程序，坚持和文件记录。 Control system for implementing changes to process. 工艺实施变更的控制系统。 Controls over critical activities and operations. 关键活动和操作的控制。 Documentation and investigation of critical deviations. 关键偏差的文件记录和调查。 Actual yields compared with expected yields at designated steps. 实际生产产量与设计步骤中预期产量进行对比。 Where appropriate established time limits for completion of phases of production. 若需要建立完成生产阶段的时间限制。 Appropriate identification of major equipment used in production of intermediates and API.用于生产中间体和API的主要设备的适当确认。 Justification and consistency of intermediate specifications and API specification. 中间体质量规格和API质量规格的证明和一致性。 Implementation and documentation of process controls, testing, and examinations (e.g., pH, temperature, purity, actual yields, clarity). 工艺控制，试验和检查的实施和文件记录（如，pH，温度，纯度，实际产量，澄清度）。 In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material. 中间取样应该根据设计好的规程进行，以免对取样物料造成污染。 Recovery (e.g., from mother liquor or filtrates) of reactants; approved procedures and recovered materials meet specifications suitable for their intended use. 反应物回收（如，从母液或滤液中回收）；审批后的规程和回收的物料应该符合标准。 Solvents can be recovered and reused in the same processes or in different processes provided that solvents meet appropriate standards before reuse or commingling. 溶剂能够回收，并在相同工艺或不同工艺中再利用，如果溶剂符合质量标准。 API micronization on multi-use equipment and the precautions taken by the firm to prevent or minimize the potential for cross-contamination. API在多功能设备中微粉化应该采取预防措施来避免或降低交叉污染的可能性。 Process validation, including validation and security of computerized or automated process 工艺验证，包括计算机控制系统或自动工艺过程的验证和安全性。 Master batch production and control records. 主要批生产和控制记录。 Batch production and control records. 批生产和控制记录。 Documentation of any discrepancy (a critical discrepancy investigation is covered under the Quality System). 所有不符合项的文件记录（主要的不符和调查包括在质量系统中）。ICH Q7A references for Production System: ICH Q7A参考： Section 6, Documentation and Records 第6节：文件和记录 Section 8, Production and In-Process Controls 第8节：生产和中间控制 Section 12, Validation 第12节：验证 Section 18, Specific Guidance for APIs Manufactured by Cell Culture / Fermentation 第18节：采取细胞培养/发酵生产API的特殊指南See also 7356.0002M for additional inspection guidance on fermentation, extraction, and purification processes.也可以参考7356.0002关于发酵，提取和纯化工艺的附加检查指南。PACKAGING AND LABELING SYSTEM 包装和贴签系统：For each of the following, the firm should have written and approved procedures and documentation resulting therefrom. The firms adherence to written procedures should be verified through observation whenever possible. These areas are not limited to the final API, but may also incorporate starting materials and intermediates. These areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. When this system is selected for coverage in addition to the Quality System, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings. 对下面所列的条款，公司应该有书面的经过批准的程序和文件记录。公司是否遵循书面程序应该通过观察来证明。这些内容不局限于API，也适用于起始物料和中间体。这些内容阐明的不仅仅是本系统的不足，也说明了其他系统存在的缺陷，这就需要扩大检查内容。除质量系统外，当本系统也包括在检查范围时，下列所有内容必须包括在内；但实际包含的范围可能与计划中的检查内容有所改变。 Training/qualification of personnel. 相关人员的资格和培训。 Acceptance operations for packaging and labeling materials. 包装和贴标签物料的可接受操作。 Control system for implementing changes in packaging and labeling operations 实施包装和贴签操作变更的控制系统。 Adequate storage for labels and labeling, both approved and returned after issued. 标签的储存，包括已批准的标签和发行后退还的标签的储存。 Control of labels which are similar in size, shape, and color for different APIs.用于不同的API的，但尺寸，形状和颜色相近的标签的控制。 Adequate packaging records that will include specimens of all labels used. 足够的包装记录包括所有标签使用样本。 Control of issuance of labeling, examination of issued labels and reconciliation of used labels. 标签的发行控制，已有标签的检查和使用的标签的一致性。 Examination of the labeled finished APIs. API标签的检查。 Adequate inspection (proofing) of incoming labeling. 新来标签的检查（证明）。 Use of lot numbers, destruction of excess labeling bearing lot/control numbers. 批号使用，多余标签的销毁。 Adequate separation and controls when labeling more than one batch at a time. 在同一时间，多于一批贴标签时应有足够的分离和控制。 Adequate expiration or retest dates on the label. 标签的有效期或复验期。 Validation of packaging and labeling operations including validation and security of computerized process. 包装和贴签操作的验证，包括计算机控制系统的验证和安全性。 Documentation of any discrepancy (a critical discrepancy investigation is covered under the Quality System). 所有不符合项的文件记录（主要的不符和调查包括在质量系统中）。ICH Q7A references for Packaging and Labeling System: ICH Q7A参考： Section 9, Packaging and Identification Labeling of APIs and Intermediates第9节：API和中间体包装和标签确认 Section 17, Agents, Brokers, Traders, Distributors, Repackers, and Relabellers (applies to the handling of APIs after original site of manufacture and before receipt by the dosage manufacturer)LABORATORY CONTROL SYSTEM 实验室控制系统：For each of the following, the firm shou