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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.

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

11.6 Expiry and Retest Dating

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).

11.61 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.

11.62 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.

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

11.7 Reserve/Retention Samples

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.

11.71 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.

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 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 有效期和复验期

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 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 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 应当取一个具有代表性的样品进行复验。

11.7 留样

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 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。

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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.

12. VALIDATION 12.1 Validation Policy

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.

12.11 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

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

12.2 Validation Documentation

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.

12.21 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

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.验证

12.1 验证方针

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 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 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 验证文件

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 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。

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number of process runs.

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.

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

12.3 Qualification

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

12.4 Approaches to Process Validation

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.

12.41 There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches

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 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 确认

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 工艺验证的方法 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 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。

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can be used. These approaches and their applicability are discussed here.

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.

12.43 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.

12.44 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

12.45 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.

12.5 Process Validation Program

12.50 The number of process runs for validation should depend on the complexity of the process or

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 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 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 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 工艺验证的程序

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

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