美国FDA原料药生产质量管理规范翻译模板(下部分 中英文）

　　10. STORAGE AND DISTRIBUTION 10.储存和分发

　　10.1 Warehousing Procedures 10.1 入库程序

　　10.10 Facilities should be available for the storage of all materials under appropriate conditions (e.g., controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.

　　10.10 应当提供在适当条件下(需要时控制温度和湿度)贮存所有物料的设施。应当记录对保持物料特性至关重要的贮存条件。

　　10.11 Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.

　　10.11 除非另有其它系统可以防止待验的、不合格的退回或召回的物料的误用或未经许可擅自使用，应当为其临时存放指定单独的存放区域，直至其今后用途确定为止。

　　10.2 Distribution Procedures 10.2 分发程序

　　10.20 APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place.

　　10.20 原料药和中间体经质量部门放行后才能分发给第三方。经质量部门授权，而且如果有合适的控制并有文件证明，可允许待验的原料药和中间体在公司的控制范围下，转移到另一部门。

　　10.21 APIs and intermediates should be transported in a manner that does not adversely affect their quality.

　　10.21 原料药和中间体应当以对其质量不产生负面影响的方式运输。

　　10.22 Special transport or storage conditions for an API or intermediate should be stated on the label.

　　10.22 原料药或中间体的特殊运输或贮存条件应当在标签上注明。

　　10.23 The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.

　　10.23 生产商应当确保运输原料药或中间体的合同接受方(订约人)了解并遵从相关的运输和贮存条件。

　　10.24 A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.

　　10.24 应当建立一个系统，可用它来对每批中间体和/或原料药的分发随时决定召回。

　　11. LABORATORY CONTROLS 11.实验室控制

　　11.1 General Controls 11.1 控制通则

　　11.10 The independent quality unit(s) should have at its disposal adequate laboratory facilities.

　　11.10 独立的质量部门应当有受其支配的、足够的实验室设施。

　　11.11 There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.

　　11.11 应当备有阐述物料取样、测试、物料批准或拒收，和实验室的记录及保存的书面程序。实验室记录应当按照6.6节中所述要求保存。

　　11.12 All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).

　　11.12 所有的质量标准，取样方案和测试程序都应当科学合理并适当，以确保原料、中间体、原料药，标签和包装材料能达到规定的质量和/或纯度标准。质量标准和测试方法应当与注册/申报中的一致。可以有注册/申报以外的附加的质量标准。质量标准、取样方案和测试程序，包括相应的变更，应当由相关的组织机构起草，并由质量部门审核、批准。

　　11.13 Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g., organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.

　　11.13 应当根据已接受的标准和与生产工艺的一致性来制订合适的原料药质量标准。质量标准应当包括对杂质的控制(如有机杂质、无机杂质，和残留溶剂)。如果原料药有微生物纯度的质量规格，应当制订并达到合适的总菌落数和致病菌的处置限度。如果原料药有内毒素的质量规格，应当制订并达到合适的内毒素的处置限度。

　　11.14 Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.

　　11.14 应当遵守实验室控制，并边操作边记录。对上述程序的任何偏离都应当有记录并作解释。

　　11.15 Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.

　　11.15 得到的任何不符合质量标准的结果都应当按照程序进行调查，并备案。该程序应当要求对数据进行分析，评价是否有值得注意的问题存在，分配整改措施的任务和结论。发现不符合质量标准的结果后，任何重新取样和/或重新测试都应当按照成文的程序进行。

　　11.16 Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.

　　11.16 应当按照书面程序来配制试剂和标准溶液以及贴标签。分析试剂或标准溶液应当酌情采用用至日期。

　　11.17 Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

　　11.17 原料药生产时应当酌情获得合适的基本参考标准品。每一个基本参考标准品的来源要备案。应根据标准品供应商的要求进行标准品的储存和使用，并进行相应记录同时保存记录。对于从官方认可的渠道获得的基本参考标准品，在按照供应商的建议的保存条件进行保存的情况下，通常无需检验就可以使用。

　　11.18 Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.

　　11.18 从官方认可的货源处无法得到基本参考标准品时，应该制备一个内部基本标准品。应当做合适的测试来全面制订该基本参考标准品的鉴别和纯度。该测试的相关证明文件应当保留。

　　11.19 Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.

　　11.19 二级参考标准品应当用合适的方法来制备，鉴别，测试，批准和储存。每一批二级参考标准品在第一次使用前，应当与基本参考标准品进行比较，来确定其适用性。每一批二级参考标准品应当根据书面方案，定期进行重新确认。

　　11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的测试

　　11.20 For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.

　　11.20 每一批中间体和原料药都应当进行适当的实验室测试，以确定是否符合质量标准。

　　11.21 An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.

　　11.21 每一种原料药都应当有杂质概况，描述用一特别控制的生产工艺生产出的典型批号中存在的已确定和未确定的杂质。杂质概况应当包括观测到的每一个杂质的鉴别或某个定量分析的标志(如保留时间)、范围，以及已确定杂质的类别(如有机的、无机的、溶剂)。杂质概况一般与原料药的生产工艺和起源有关。从植物或动物组织中得到的原料药通常不一定要有杂质概况。ICH指南Q6B讲述了对生物技术的考虑。

　　11.22 The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

　　11.22 每隔一端时间应当将杂质概况与药政申报中的杂质概况，或与以往的数据比较，以查明原材料、设备操作参数和生产工艺的修改所造成的原料药的变化。

　　11.23 Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.

　　11.23 在规定微生物质量时，应当对每一批中间体和原料药作适当的微生物测试。

　　11.3 Validation of Analytical Procedures 11.3 分析方法的验证

　　See Section 12. 见第12章

　　11.4 Certificates of Analysis 11.4 分析报告单

　　11.40 Authentic certificates of analysis should be issued for each batch of intermediate or API on request.

　　11.40 有要求时应当为每一批中间体或原料药出具可信的分析报告单。

　　11.41 Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided 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.

　　11.41 分析报告单应当提供中间体或原料药的名称，必要时包括其等级、批号和放行日期。有有效期的中间体或原料药，应当在标签和分析报告单上提供失效期。有复验期的中间体或原料药，应当在标签和/或分析报告单上提供复验期。

　　11.42 The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).

　　11.42 报告单应当列明按药典或客户要求所做的各项测试，包括可接受的限度，和得到的数值结果(如果测试结果是数值)。

　　11.43 Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original manufacturer.

　　11.43 报告单应当由指定的质量部门人员写明日期并签名，而且应当注明原生产商的名称、地址和电话。如果测试是由重新包装者或重新加工者做的，则分析报告单应当注明重新包装者/重新加工者的名称、地址和电话，并附注原生产商的名称。

　　11.44 If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address, and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.

　　11.44 如果由重新包装者/重新加工者、代理人，中间人或由其代表出具新的报告单，这些报告单上应当注明做分析的实验室的名称、地址和电话。还应当附注原生产商的名称和地址，并附上原始检验报告单复印件。

　　11.5 Stability Monitoring of APIs 11.5 原料药的稳定性监测

　　11.50 A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.

　　11.50 应当建立一个文件化的、持续监测的规程，以监测原料药的稳定性特征，而其结果应当用于确定适当的贮存条件和复验日期或有效期。

　　11.51 The test procedures used in stability testing should be validated and be stability indicating.

　　11.51 用于稳定性测试的测试规程应当经过验证，并能显示稳定性。

　　11.52 Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.

　　11.52 稳定性样品应当存放在与销售容器相仿的容器中。例如，如果原料药是装在纤维桶内的袋子里销售的，稳定性样品可以包装在同样材料的袋中，放入相似或相同与销售容器的材料的材料较小的桶中。

　　11.53 Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.

　　11.53 通常头三个销售批号应当放入稳定性监测计划，以证实复验期或有效期。然而，如果以前的研究数据表明原料药至少在两年内可望保持稳定，则所用的批号可少于三批。

　　11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.

　　11.54 以后每年至少应当加一批生产的原料药到稳定性监测计划(除非当年不生产)，并且至少每年测试，以证实其稳定性。

　　11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.

　　11.55 对于储存期较短的原料药，应当更频繁的测试。例如，储存期不超过一年的生物工程/生物制品或其它原料药，应当有稳定性样品，头三个月内应当每月测试，随后每三个月测试一次。如果有数据表明原料药的稳定性不会受影响，可以考取消特定的测试间隔(如9个月的测试)。

　　11.56 Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.

　　11.56 根据情况，稳定性储存条件应当与ICH的稳定性指南一致。

　　11.6 Expiry and Retest Dating 11.6 有效期和复验期

　　11.60 When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).

　　11.60 当一个中间体要运送到生产商物料管理系统控制范围以外，并已制定了有效期或复验期时，那就应当有支持的稳定性信息(如发表的数据、测试结果)。

　　11.61 An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.

　　11.61 一种原料药的有效期或复验期应当基于稳定性研究所得数据的评估。通常会用复验期，而不用有效期。

　　11.62 Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and (2) the quality of the API represents the material to be made on a commercial scale.

　　11.62 如果(1)中试批号采用的生产方法和规程是模拟用于商业生产规模的最终工艺，而且(2)原料药的质量代表了商业生产规模的物料，则原料药的初步有效期或复验期可基于中试规模的批号。

　　11.63 A representative sample should be taken for the purpose of performing a retest.

　　11.63 应当取一个具有代表性的样品进行复验。

　　11.7 Reserve/Retention Samples 11.7 留样

　　11.70 The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.

　　11.70 留样的包装和储存是为了今后可能会对原料药批号的质量进行评价，而不是以将来的稳定性测试为目的的。

　　11.71 Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.

　　11.71 适当标识的每一批原料药的留样应当保留到由生产商规定的该批号的有效期满后一年，或该批产品销售后三年，以较长时间为准。对于有复验期的原料药，相似的留样应当保留到生产商全部销售完该批号后三年。

　　11.72 The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.

　　11.72 留样应当储存在原料药储存的同样的包装系统中，或者与销售包装相同，或更具保护性。应当留足够的量来至少做两次法定的全检，或者没有药典专论时，两次质量标准的全检。

　　12. VALIDATION 12.验证

　　12.1 Validation Policy 12.1 验证方针

　　12.10 The company’s overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.

　　12.10 公司的总体验证原则、目的和方法，包括生产工艺、清洁规程、分析方法、过程控制测试规程以及计算机系统的验证和负责设计、审核、批准和为各个验证阶段提供证明文件的人员都应当明文规定。

　　12.11 The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include:

　　Defining the API in terms of its critical product attributes

　　Identifying process parameters that could affect the critical quality attributes of the API

　　Determining the range for each critical process parameter expected to be used during routine manufacturing and process control

　　12.11 关键的工艺参数/属性通常应当在开发阶段或从以往的数据中加以确定，并应当规定工艺可重复性操作所必需的范围。包括：

　　定义原料药生产的关键产品属性;

　　确认可能对原料药关键质量属性有影响的工艺参数;

　　确定在日常生产和工艺控制中会用到的每个关键工艺参数的范围。

　　12.12 Validation should extend to those operations determined to be critical to the quality and purity of the API.

　　12.12 验证还应当涉及到那些对原料药质量和纯度至关重要的操作。

　　12.2 Validation Documentation 12.2 验证文件

　　12.20 A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.

　　12.20 应当有书面的验证方案，阐明如何进行某个工艺的验证。验证方案应当由质量部门和其他指定的部门审核并批准。

　　12.21 The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs.

　　12.21 验证方案应当明确规定验证的关键工序和认可标准，所要进行的验证类型(回顾性验证、预验证、同步验证)和工序运转的次数。

　　12.22 A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

　　12.22 应当拟定一份能交叉引用验证方案的验证报告，概括得到的结果，说明发现的任何偏差，并作出必要的结论，包括为整改而必须做的变更。

　　12.23 Any variations from the validation protocol should be documented with appropriate justification.

　　12.23 任何对验证方案的偏离都应当归档备案，并作适当说明。

　　12.3 Qualification 12.3 确认

　　12.30 Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:

　　Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose

　　Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements

　　Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges

　　Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications

　　12.30 在开始工艺验证活动前，应当完成适当的关键设备和辅助系统的确认。确认一般是通过单独或联合进行以下活动来实行的：

　　设计确认(DQ)：是对提议的设施、设备或系统适用于预期的目的的一种成文的确认;

　　安装确认(IQ)：对安装好的和调整过的设备或系统符合已批准的设计、制造商建议的和/或用户的要求的成文的确认;

　　运行确认(OQ)：对安装好的和调整过的设备或系统能在整个预期的操作范围内按要求运行的成文的确认;

　　性能确认(PQ)：是对设备或其辅助系统在相互连接后，能根据已获准工艺方法和质量标准有效的、重现的进行运转的成文的确认。

　　12.4 Approaches to Process Validation 12.4 工艺验证的方法

　　12.40 Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

　　12.40 工艺验证(PV)是证明在预定的工艺参数范围内运行的工艺能持续有效地生产出符合预定的质量标准和质量属性的中间体或原料药的证明文件。

　　12.41 There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.

　　12.41 验证方法有三种，预验证是首选的方法，但在其它方法可采用的情况下也有例外。这些方法及其适用性见下文。

　　12.42 Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation for an API process should be completed before the commercial distribution of the final drug product manufactured from that API.

　　12.42 12.1中所述的所有原料药生产工艺一般来说都应当进行预验证。对原料药工艺所作的预验证的结果，必须在用该原料药制成的制剂产品销售前完成。

　　12.43 Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches. 12.43 有时由于原料药生产批号有限，原料药批号不是经常生产，或原料药是用验证过的，但已变更的工艺生产的，无法从连续生产中得到数据，可进行同步验证。同步验证完成之前，只要对原料药批号进行了充分的监控和测试，这些批号可以放行并用于最终制剂药的商业销售。

　　12.44 An exception can be made for retrospective validation well-established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:

　　1. Critical quality attributes and critical process parameters have been identified

　　2. Appropriate in-process acceptance criteria and controls have been established

　　3. There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability

　　4. Impurity profiles have been established for the existing API

　　12.44 某些工艺已确立了很久，而且原料、设备、系统、设施或生产工艺的变化对原料药的质量没有明显的影响，此时就可以例外地进行回顾性验证。这一验证方法适合于下列情况：

　　1. 关键质量属性和关键工艺参数均已确定;

　　2. 已确立了合适的过程控制和认可标准;

　　3. 从来没有因为除了操作人员失误或设备故障这些与设备适应性无关的因素之外的原因而造成值得注意的工艺/产品的不合格;

　　4. 现有原料药的杂质概况已确定。

　　12.45 Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.

　　12.45 回顾性验证选用的批号应当能够代表审核时段中的所有批号，包括任何不合格的批号，而且应当有足够的批数来证明工艺的稳定。可用测试留样来获取回顾性工艺验证数据。

　　12.5 Process Validation Program 12.5 工艺验证的程序

　　12.50 The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

　　12.50 验证时生产工艺的运行次数，应当由工艺的复杂性或要考虑的工艺变更的大小来决定。作为一个指南，预验证和同步验证应当采用三个连续的、成功的批号，但可能在某些情况下需要更多的批号来保证工艺的一致性(例如，复杂的原料药生产工艺，或原料药工艺耗时很长)。回顾性验证一般应当审查从10到30个连续批号得到的数据来评估工艺的一致性，但是，如果有理由，审查的批数可以少些。

　　12.51 Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

　　12.51 在工艺验证研究时应当控制并监测关键的工艺参数。与质量无关的参数，例如为了将能量消耗或所用设备减到最低而控制的变量，无需包括在工艺验证中。

　　12.52 Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

　　12.52 工艺验证应当确认每一个原料药的杂质概况都在规定的限度内。杂质概况应当与以往的数据相似或更好，如果可能，应当与工艺开发阶段确定的杂质概况，或用于关键的临床和毒理研究的批号的数据相似或更好。

　　12.6 Periodic Review of Validated Systems 12.6验证系统的定期审核

　　12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.

　　12.60 应当对系统和工艺进行周期性的评价，以确认它们仍然能有效地运作。如果系统或工艺并没有大的变动，而质量回顾证实系统和工艺在稳定地生产着符合其质量标准的物料，通常就不必验证了。

　　12.7 Cleaning Validation 12.7 清洗验证

　　12.70 Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. 12.70 通常应当验证清洗程序。一般来说，清洗验证应当针对那些如果受到污染或偶然带入异物就会对原料药的质量带来极大危险的情况或工序。例如，在生产的前期阶段，可能就无需验证设备的清洗程序，那里的残留物会被后面的纯化步骤除去。

　　12.71 Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.

　　12.71 清洗程序的验证应当反映实际的设备使用情况。如果多个原料药或中间体都在同一设备内生产，而该设备用同一个程序清洗，那么就要选择代表性的中间体或原料药来作清洗验证。应当根据溶解性，清洗难度，以及依据效价、毒性和稳定性计算出来的残留物的限量来作选择。

　　12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.

　　12.72 清洗验证方案应当描述要清洗的设备、程序、物料、可接受的清洗程度、要监测和控制的参数、以及分析方法。方案还应当指出要得到的样品的种类，和如何取样及标记。

　　12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).

　　12.73 取样应当包括擦拭法、冲洗法或可供选择的方法(如直接萃取)，如果合适的话，同时检测不溶性和可溶性的残留物。所用的取样方法应当能定量地检测出清洗之后留在设备表面的残留物质。当与产品接触的表面，由于设备的设计和/或工艺限制(如，软管的内表面，运输管道，反应釜的开口很小或装卸有毒物质，以及一些小的复杂的设备，如微粉粉碎机，流化床式微粉机)，很难触及时，擦拭取样就无法实施。

　　12.74 Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.

　　12.74 应当采用验证过的、具有检测残留物或污染物的灵敏度的分析方法。每一个分析方法的检测限度必须足够灵敏，来检测到残留物或污染物的规定的可接受水平。应当规定方法的可达到的回收率。残留物的限度切实可行的，可检测的，并由最有害的残留物来确定。可以根据原料药或其最有害的组分的已知最小药理、毒理或生理活性浓度来制定限度。

　　12.75 Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).

　　12.75 对于需要降低原料药中的总微生物数或内毒素的工艺，或担心此类污染的其它工艺(如，用于生产无菌产品的非无菌原料药)，设备清洗/消毒的研究应当对付微生物和内毒素污染。

　　12.76 Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

　　12.76 验证后，清洗程序应当在适当的时间间隔进行监测，以确保这些程序用在日常生产中是有效的。设备的清洁程度可以根据可行性通过测试或目测来监测。目测能检测到用取样和/或分析方法测不到的集中在小面积上的严重的污染。

　　12.8 Validation of Analytical Methods 12.8 分析方法的验证

　　12.80 Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented. 12.80 分析方法应当进行验证，除非采用的方法列在相关的药典或其它公认的参照标准中。然而，所有测试方法的适应性应当在实际使用条件下加以证实，并归档备查。

　　12.81 Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

　　12.81 方法验证应当包括ICH分析方法验证指南中的特征的考虑。方法验证进行的程度应当反映分析的目的和原料药生产工艺的步骤。

　　12.82 Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.

　　12.82 在开始分析方法验证前，应当考虑对分析设备的适当的确认。

　　12.83 Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method. 12.83已验证过的分析方法的任何修改都应当保存完整的记录。这类记录应当包括修改的理由和合适的数据，以证实该修改所产生的结果和规定的方法同样准确、可靠。