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
美国FDA原料药生产质量管理规范（ 中英文）
