12.验证
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12. VALIDATION 12.验证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 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process parameters have been identified 2.Appropriate in-process acceptance criteriaand controls have been established3.There have not been significantprocess/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability4.Impurity profiles have been establishedfor the existing API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。
