Principle
This Annex describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products. It is a GMP requirement that manufacturer’s control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed. Computerised systems used for the manufacture of medicinal products should be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8,Q10 and Q11 should also be taken into account.
原则
这个附录描述了用于药品生产的厂房、设备、设施和工艺的确认和验证的原则。GMP要求在产品和工艺的生命周期中，生产者通过确认和验证来控制他们独特操作的关键内容。任何可能影响厂房、设备、设施和工艺的有计划的变更，都要有正式的文件记录，并且要评估队验证的状态或控制策略的影响。根据附录11的要求，用于医药产品生产的计算机系统也要验证。这个附录也考虑了ICH Q8、Q9、Q10的理念和指南。
General
A quality risk management approach should be applied throughout the lifecycle of a medicinal product. As part of a quality risk management system, decisions on the scope and extent of validation and qualification should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes. The principles in ICH Q8, Q9, Q10 and Q11 or other systems guaranteeing at least the same level of product quality and security should be used to support validation and qualification activities.
Data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own validation programme may be used provided that this approach has been justified and that there is adequate assurance that controls were in place throughout the acquisition of such data.
通则
质量风险管理方法应该用于医药产品的整个生命周期中。作为质量风险管理系统的一部分，验证和确认的范围和程度应该建立在对厂房、设备、设施和工艺的合理的文件化的风险评估的基础上。应该使用至少保证同一水平的质量和安全的ICH Q8, Q9, Q10 and Q11或其它系统的原则，来支持验证和确认行动。
从别的拥有自己验证项目的生产商那得到的支持确认和/或验证研究的数据可以用来说明这种方法已经被证明合理并且能够足够确保这类数据的获取是受控的。
1. ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION
1.1 All qualification and validation activities should be planned and take the life cycle of equipment, process and product into consideration.
1.2 Validation activities should only be performed by suitably trained personnel whofollow approved validation procedures.
1.3 Validation personnel should report as defined in the pharmaceutical quality system although this may not necessarily be to a quality management or a quality assurance function, however there should be appropriate oversight over the whole validation life cycle.
1.确认和验证的组织与计划
1.1所有的确认和验证都要计划进行，并且要考虑设备、工艺和产品的整个生命
周期。
1.2验证活动只能由合适的经过培训的人按照批准的验证程序进行。
1.3验证人员要按照质量系统规定要求进行报告。
1.4 The key elements of the site validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document.
1.5 The VMP should be a summary document which is brief, concise, clear and contain data on at least the following:
a) Validation policy.
b) The organisational structure for validation activities.
c) Summary of the facilities, systems, equipment, processes on site and the current validation status.
d) Template formats to be used for protocols and reports.
e) Planning and scheduling.
f) Change control and deviation management for validation.
g) Handling of acceptance criteria
h) References to existing documents.
i) An assessment of the resources required.
j) The ongoing validation strategy, including revalidation and / requalification, where applicable.
k) Confirmation that the materials used for validation are of the required quality and suppliers are qualified to the appropriate level.
1.4厂地验证项目的关键元素要在验证主计划或类似文件中明确确定。
1.5VMP应是一份简洁、准确、清楚的概述文件，至少包括以下数据：
a)验证方针。
b)验证活动组织机构。
c)场地厂房、系统、设备工艺的概述和当前验证状态。
d)用于方案和报告的模板
e)计划和日程安排
f)验证的变更控制和偏差管理
g)可接受标准
h)参考文献
i)所需资源的评估
j)持续的验证策略，包括再验证/再确认
k)确认验证所需的材料符合质量要求并且供应商是符合适当的级别
1.6 For large and complex projects, planning takes on added importance and it may be necessary to create a separate VMP.
1.7 A quality risk management approach should be used for validation activities withrisk assessments repeated, as required, in light of increased knowledge and understanding from any changes during the project phase or during commercial production. The way in which risk assessments are used to support validation activity should be clearly documented.
1.6对于大的复杂的项目，更要注意计划，可能有必要制定单独的VMP。
1.7 验证活动应该使用质量风险管理方法，而且根据项目阶段或者商业生产过程的变化的新增加的知识和理解来重复风险评估。风险评估用来支持验证活动的方法要明确的文件说明。
2. DOCUMENTATION INCLUDING VMP
2.1 Good documentation practices are important to support knowledge management throughout the validation lifecycle.
2.2 All documents generated during validation should be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system.
2.3 The relationship between documents in complex validation projects should be clearly defined and any inter-relationships documented.
2.4 A written validation protocol should be prepared which defines the critical systems, attributes and parameters which are important and the acceptance criteria for each.
2.5 Where validation protocols are supplied by a third party, the manufacturer should confirm suitability and compliance with company procedures before approval.
2.包括VMP的文件
2.1在整个生命周期中，良好的文件规范对支持知识管理很重要。
2.2验证过程中产生的文件都应该按照质量系统规定的由合适的人员批准和授
权。
2.3复杂的验证项目的文件的关系应该明确清楚并交叉引用。
2.4验证方案要确定重要的关键系统、属性和参数，还有每个的接受标准。
2.5当验证方案由第三方提供，在批准之前生产商要确认符合公司的程序。
2.6 Any changes to the approved protocol during execution should be documented as
a deviation and be scientifically justified.
2.7 Results which fail to meet the pre-defined acceptance criteria should be recorded as a deviation, be fully investigated and any implications for the validation discussed in the report.
2.8 The conclusions of the validation should be reported and the results obtained summarised against the acceptance criteria. Any subsequent changes to acceptance criteria should be scientifically justified and a final recommendation made as to the outcome of the validation.
2.9 A formal release for the next step in the validation process should be authorised by the relevant responsible personnel either as part of the validation report approval or as a separate summary document. Conditional approval to proceed to the next stage can be given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment that there is no significant impact on the next activity.
2.6已批准方案的任何变化都应该用文件的形式作为偏差处理并科学的说明。
2.7没有满足既定接受标准的结果要被记录成偏差，全面调查，涉及到的内容要
在报告中讨论。
2.8要报告验证的结论，并且要针对接受标准总结得到的结果。对接受标准进行
任何变更应该进行科学的说明，作为验证的结果要给出一个最终的建议。2.9验证过程中进入下一个阶段的批准应由相关负责人员，或作为验证报告批准
的一部分货作为一个单独的概述文件。当一定的接受标准未完全达到或偏差未完全处理，可以有条件的批准进入下一个阶段，要有一个书面的评估证明对下一阶段的活动无显著影响。
3. QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES AND UTILITIES
3.1 Validation and qualification activities should consider all stages from initial development of the user requirements specification or initial process development through to the end of use of the equipment, facility or process. The main stages and some suggested criteria (although this depends on individual project circumstances and may be different) which could be included in each stage are indicated below: User requirements specification (URS)
3.2 The specification for new facilities, systems or equipment should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks minimised. The URS should be a point of reference throughout the validation life cycle.
3. 设备、厂房和设施的确认步骤
3.1 从最初制定URS或最初工艺开发到设备、厂房或工艺用到最后，验证和确认活动应考虑到每一个阶段。主要的确认阶段和每个阶段可以总结的一些建议标准（尽管这取决于单个项目并可能不一样）如下文所示：
URS
3.2 可以在URS和/或一个功能性说明中确定新的厂房、系统或设备的要求。在这个阶段要建立质量的基本要素并降低任何GMP风险。整个验证生命周期URS都是一个参考点。
Design qualification (DQ)
3.3 The next element in the validation of new facilities, systems or equipment is DQ where the compliance of the design with GMP should be demonstrated and documented.
The requirements of the user requirements specification should also be verified during the design qualification.
DQ
3.3 新厂房、系统或设备的验证的另一个元素是DQ，在DQ阶段需要文件化证明设计符合GMP要求。
Factory acceptance testing (FAT) /Site acceptance testing (SAT)
3.4 Equipment, especially if incorporating novel or complex technology, should be evaluated at the vendor prior to delivery.
3.5 Prior to installation, equipment should be confirmed to comply with the URS/ functional specification at the vendor site unless otherwise justified.
3.6 Where appropriate and justified, documentation review and some tests could be performed at the FAT stage without the need to repeat on site if it can be shown thatthe functionality is not affected by the transport and installation.
3.7 FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site.
FAT/SAT
3.4 设备，尤其是包含新的或复杂技术的，在制作商发货之前就要评估。
3.5 除非另有合理性说明，在安装之前，要确认设备符合URS/功能性说明。3.6 在合适且合理时，如果可以证明运输和安装不会影响设备得功能，那么文件审核和一些测试在SAT阶段进行了之后就没有必要再SAT阶段重复。
3.7 FAT是在生产商接收设备后对SAT执行的补充。
Installation qualification (IQ)
3.8 IQ should be performed on new or modified facilities, systems and equipment.
3.9 IQ could include, but is not be limited to the following:
a) Installation of equipment, pipe work, services and instrumentation as detailed in the design and confirmation of current engineering regarding drawings and specifications.
b) Verification of the correct installation against pre-defined criteria.
c) Collection and collation of supplier operating and working instructions and maintenance requirements.
d) Calibration of instrumentation.
e) Verification of the materials of construction.
安装确认IQ
3.8 新的或更改的厂房、系统和设备需要进行IQ。
3.9 IQ要包括但不局限于以下内容：
a）设备、管道、设施和仪表按照设计的内容安装，并依照图纸和说标准确认现行的工程系统。
b) 按照预定的标准确认正确的安装。
c) 收集整理供应商提供的操作指南和维护保养要求。
d) 仪表校验
e) 建筑材料的确认
Operational qualification (OQ)
3.10 OQ normally follows IQ but depending on the complexity of the equipment it may
be performed as a combined Installation/Operation Qualification (IOQ).
OQ could include but is not be limited to the following:
a) Tests that have been developed from the knowledge of processes, systems and equipment.
b) Tests to confirm upper and lower operating limits, and /or “worst case” conditions.
3.11 The completion of a successful OQ should allow the finalisation of maintenance plans, standard operating and cleaning procedures, operator training and preventative maintenance requirements.
运行确认（OQ）
3.10 OQ通常在IQ之后，但根据设备的复杂性，可能将I/OQ结合起来。OQ包括但不限于以下方面：a) 根据生产工艺、系统和设备的知识进行测试。
b) 测试要确定操作上下限，和/或最差条件。
3.11 一份成功的OQ完成包括维护计划、标准清洁程序、操作人员培训和预防性维护要求的完成。
Performance qualification (PQ)
3.12 PQ should follow the successful completion of IQ and OQ.
3.13 Although PQ is described as a separate activity, it may in some cases be appropriate
to perform it in conjunction with OQ or Process Validation.
3.14 PQ could include, but is not be limited to the following:
a) Tests, using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with
worst case batch sizes. The frequency of sampling used to confirm process
control should be justified.
b) Tests should cover the operating range of the intended process, unless documented evidence from the development phases which confirm the
operational ranges are available.
性能确认（PQ）
3.12 PQ应该在IQ和OQ成功完成之后。
3.13 尽管PQ被描述成的行为，但有时可能与OQ或工艺验证结合更合适。
3.14 PQ应包括但不局限于以下方面：
a) 在最差条件的批量下，用生产物料、证明具有同样性质的合格的替代物或模拟产品来进行测试。要合理说明用于确认工艺控制的取样频次。
b) 测试要包括预定工艺的操作范围，除非有书面证据证明开发阶段已经确定的操作范围可用。
4. PROCESS VALIDATION
General
4.1 The requirements and principles outlined in this section are applicable to the manufacture of all pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes, site transfers and ongoing process verification.
4.2 This section should be used in conjunction with the current EMA guideline on Process Validation. Note: It should be taken into account that the guideline on Process Validation is intended to provide guidance on the information and data to be provided in the regulatory submission and GMP requirements extend beyond this. It should also be noted that a lifecycle approach is applied linking product and process development,validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.
4.3 Medicinal products may be developed using a traditional approach or a continuous verification approach however irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market. Manufacturing processes should undergo a prospective validation programme wherever possible prior to marketing of the product.
4.0 工艺验证
通则
4.1 这部分强调的要求和原则适用于所有药物制剂的生产。验证包括新工艺的初始验证、修改工艺的随后验证、场地转移和持续工艺确认。
4.2 这部分要与EMA关于工艺验证的指南一起应用。备注：要注意工艺验证指南是为了对用于提交法规资料的数据和信息进行指导，而GMP要求更高。也要注意，生命周期方法是在常规商业生产中在控制状态下将产品和工艺开发、商业生产工艺验证和工艺维护连接。
4.3 医药产品可以使用传统方法或连续确认的方法来开发，然而不论使用哪种方法，工艺必须被证实有效且在产品进入市场前能够保证一致的产品质量。生产工艺应尽可能采用在进入市场之前的前验证。
4.4 Process validation for new products should cover all intended marketed strengths and sites of manufacture, however for products which are transferred from one site to another or within the same site, and where there is existing product knowledge, including the content of the previous validation, the number of validation batches could be reduced by the use of a bracketing approach. This approach could be acceptable for different strengths, batch sizes and pack sizes/ container types if justified.
4.5 For the site transfer of legacy products, the manufacturing process and controls should comply with the Marketing Authorisation and meet current expected licensing standards for that product type. If necessary, variations to the Marketing Authorisation should be submitted.
4.6 Process validation should establish whether all quality attributes and process parameters which are considered important for ensuring the validated state and acceptable product quality can be consistently met by the process. The basis by which process parameters and quality attributes were identified as being critical or
non-critical
should be clearly documented, taking into account the results of any risk assessment activities.
4.4 新产品的工艺验证要包括所有预期的市场规格和生产场地，但是对于从一个场地转移到另一个或者再同一个场地的情况，而且已经有产品知识，包括之前验证的内容，那么可以通过使用支架法来减少验证的数目。如果证明合适，这种方法可以适用于不同规格、批量和包装量/容器类型。
4.5 对于老产品的场地转移，生产工艺和控制要符合市场许可要求并要满足此类产品现行的预期的批准标准。如有必要，需要进行市场销售许可的变更。
4.6 工艺验证的目的是为了确认那些能够确保验证了的状态和可接受的产品质量的所有质量属性和工艺参数能够一直实现。根据风险评估的结果，要文件明确说明将工艺参数和质量属性分为重要和不重要类别的原因。
4. 7 Normally batches manufactured for process validation should be the same size as the intended commercial scale batches and the use of any other batch sizes should be justified. e.g. for a continuous manufacturing process.
4.8 Facilities, systems, utilities and equipment used for process validation should be qualified and test methods should be validated.
4.9 For all products irrespective of the approach used, process knowledge fromdevelopment studies should be accessible to the manufacturing site, unless otherwise justified, and be the basis for validation activities.
4.10 For process validation batches, production, development, or other site transfer personnel may be involved. Batches should only be manufactured by trained personnel in accordance with GMP using approved documentation. It is expected that production personnel are involved in the manufacture of validation batches to facilitate product understanding when commercial manufacture starts.
4.7 通常，工艺验证的批量应与预期的商业生产批量相同，如果使用其它批量应给予合理说明。
4.8 用于工艺验证的厂房、设备、设施、系统应确认合格，并且检验方法要经过验证。
4.9 对于所有产品不论使用了什么方法，除非有另外的合理说明，生产方要了解开发研究时获得的工艺知识，并且这些知识是验证的基础。
4.10 对于工艺验证批次、生产、开发或场地转移，人员都被涉及。批次的生产只能由受训的人员、使用批准的文件、在符合GMP的情况下进行生产。当商业皮生产时，参加过验证批生产的人员对产品的理解更容易。
4.11 The suppliers of critical starting and packaging materials should be qualified prior to
the manufacture of validation batches; otherwise a justification based on the application
of quality risk management principles should be documented.
4.12 It is especially important that the underlying process knowledge for the design space
justification (if used), and for development of any mathematical models used to confirm
a state of control should be available.
4.13 Where validation batches are released to the market this should be pre-defined. The conditions under which they are produced should fully comply with GMP, with the validation acceptance criteria, with any continuous process verification criteria (if used) and with the Marketing Authorisation.
4.11 验证批生产之前要确认关键起始物料和包材的供应商合格；否则要用质量风险管理的方法进行合理说明。
4.12 要有关于设计空间合理性（如果使用设计空间）和用于确认控制状态的任何数学模型的根本的工艺知识，这很重要。
4.13 验证批是否进入市场要提前确定。生产条件要完全符合GMP，符合验证接受标准、符合连续的工艺确认标准（如果使用）、符合注册要求。Concurrent validation
4.14 In exceptional circumstances where there is a strong risk – benefit to the patient, it may be acceptable not to complete a validation programme before routine production starts and concurrent validation could be used. However, the decision to carry out
concurrent validation must be justified, documented in the VMP and approved by authorised personnel.
4.15 Where a concurrent validation approach has been adopted, there should besufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. The results and conclusion should be formally documented and available to the Qualified Person prior to certification of the batch. 同步验证
4.14 在特殊情况下，当对病人的风险利益很高的时候，在常规生产之前，可以不完成验证项目，可以使用同步确认。但是，进行同步确认要有合理说明，要在VMP文件中体现并被授权的人批准。
4.15 当采用同步验证的时候，要有足够的数据证明任何验证批产品质量是一致的并满足既定的可接受标准。结果和结论要形成正式的文件，并在批合格放行之前提供给QP。
Traditional approach to validation
4.16 In the traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility.
4.17 The number of batches manufactured and the number of samples taken should be based on quality risk management principles, allow the normal range of variation and trends to be established and provide sufficient data for evaluation. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.
4.18 Without prejudice to 4.17, it is generally considered acceptable that a minimum of three consecutive batches would constitute a validation of the process although an alternative number of batches may be justified taking into account whether standard methods of manufacture are used and whether similar products or processes are already used at the site. An initial validation exercise with three batches may need to be supplemented with further data obtained from subsequent batches as part of an
on-going process verification exercise.
4.19 A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge.
4.20 Validation protocols should include, but are not be limited to the following:
a) A short description of the process.
b) Summary of the CQA’s to be investigated
c) Summary of CPP’s and their associated limits.
d) Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion.
e) List of the equipment/facilities to be used (including measuring/
f) monitoring/recording equipment) together with the calibration status.
g) List of analytical methods and method validation, as appropriate.
h) Proposed in-process controls with acceptance criteria and the reason(s) which each in-process control is selected.
i) Additional testing to be carried out, with acceptance criteria.
j) Sampling plan and the rationale behind it.k) Methods for recording and evaluating results.
l) Process for release and certification of batches (if applicable).
m) Functions and responsibilities.
n) Proposed timetable.
Continuous process verification
4.21 For products developed by a quality by design approach, where it has been scientifically established that routine process control provides a high degree of assurance of product quality, then continuous process verification can be used as an alternative to traditional process validation.
4.22 The process verification system should be defined and there should be a science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realisation. This should also include regular evaluation of the control strategy. Process Analytical Technology and multivariate statistic al process control may be used as tools. Each manufacturer must
determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.
4.23 The general principles in 4.1 – 4.15 above still apply.
4.24 A hybrid approach using the traditional approach and continuous process verification for different production steps can also be used. Where there is a substantial
amount of product and process knowledge and understanding which has been gained from manufacturing experience and historical batch data, continuous verification may also be used for any validation activities after changes or during ongoing process verification even though the product was initially validated using a traditional approach.
连续工艺验证
4.21对于通过QbD方法开发的产品，已经是科学的确立起来的，常规的工艺控制能够对产品质
量提供高的保证，那么连续的工艺确认可以来替代传统的工艺确认。
4.22应该确立工艺验证系统并且用科学的方法对到货的物料的要求属性、关键的质量属性和关
键的工艺参数建立控制策略。工艺分析技术和多元的数据工艺控制可用作分析工具。每个生产商必须决定和说明需要的批次数来证明能够很好的保证生产工艺能够持续的生产出符合质量要求的产品。
4.23上述通则4.1-4.15也适用。
4.24在不同生产步骤使用传统方法和连续工艺确认的混合方法也可以使用。当已生产了大量的
产品，从以往生产过程和历史数据中获得了大量的工艺知识和理解，即使产品最初采用传统方法验证的，那么在变更后的任何验证行为中或者在持续的工艺确认中也可以使用连续确认的工艺验证方法。
Ongoing Process Verification during Lifecycle
4.25 Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated.
4.26 The extent and frequency of ongoing process verification should be reviewedperiodically and modified if appropriate, considering the level of process understanding and process performance at any point in time in the product lifecycle.
4.27 On going process verification should be conducted under an approved protocol and a corresponding report should be prepared to document the results obtained. Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability of a given process and ensure a state of control.
4.28 On going process verification should be used to support the validated status of the product in the Product Quality Review, however, incremental changes over time should also be considered and the need for any additional actions (e.g. enhanced sampling) should be assessed.
4.29 On going process verification should be considered where any individual change or successive incremental changes during the product lifecycle could have an impact on the validated status of the process.
生命周期中的持续工艺确认
4.25生产商需要监控产品质量并评价相关工艺趋势以维持整个生命周期的控制状态。
4.26根据产品生命周期中对任何一点工艺理解和工艺性能的水平，持续工艺验证的程度和频率
应定期审核并适时修改。
4.27 持续工艺确认应依照批准的方案进行，并且要将对应的报告准备好来记录所得的结果。如果合适，可以使用数据分析工具来支持关于验证工艺的变化和能力的结论。
4.28持续工艺确认应用来支持产品年度审核中的产品的验证状态，但是，要考虑随着时间推移的增加的变化和评估是否需要额外的措施（例如加强取样）。
4.29在产品生命周期中任何单个变化或者后续增加的变化可能对工艺的验证状态有影响，需要考虑持续工艺验证。
5. VERIFICATION OF TRANSPORTATION
5.1 Finished medicinal products, investigational medicinal products, bulk product and samples should be transported in accordance with the conditions defined in the Marketing Authorisation, product specification file or by the manufacturer.
5.2 It is recognised that validation of transportation may be challenging due to the variable factors involved however transportation routes should be clearly defined. For transport across continents seasonal variations should also be considered.
5.3 A risk assessment should be performed to consider the impact of conditions other than temperature during transportation e.g. humidity, vibration, handling, delays during transportation, failure of data-loggers, topping up liquid Nitrogen, product susceptibility and any other relevant factors.
5.4 Due to the variable conditions expected during transport e.g. delays at airports, continuous monitoring of any critical environmental conditions to which the product may be subjected should be performed.
5.0 运输确认
5.1 要明确规定运输路线，由于存在可变因素应进行挑战性的运输验证。也要考虑到运输过程季节的变化。
5.2 风险评估中除了考虑温度还要考虑运输过程中的其它条件的影响，如湿度、震动、交接、耽搁、数据无法记录、产品敏感性和其它相关因素。
5.3 由于运输过程中可能出现的变化条件，例如在机场的耽搁，需要对产品可能面临的关键的环境条件进行持续监控。
6. VALIDATION OF PACKAGING
6.1 Variation in equipment processing parameters during primary packaging may have a significant impact of the integrity and correct functioning of the pack (e.g. blister strips, sachets and sterile components) therefore primary packaging processes should undergo validation.
6.2 Qualification of the machine settings for the types of pack above should be carried out at the minimum and maximum operating ranges defined for the critical components parameters such as temperature, machine speed and sealing pressure or for any other factors.
6. 包装验证
6.1 内包装时设备的工艺参数的变化可能严重影响包装的完整性和正确的功能（例如泡罩袋、药袋和无菌组件），因此内包装工艺需要验证。
6.2对于不同类型的包装，机器设置的确认应该包括关键参数的操作范围的最大值和最小值，如温度、机器运转速度、封口压力或其它因素。
7. VALIDATION OF UTILITIES
7.1 The quality of steam, water, air, other inert gases, coolants etc. should be confirmed following installation using the qualification steps described in section 3. 7.2 The period and extent of qualification should also reflect any seasonal variations, if applicable, and the intended use of the utility.
7.3 A risk assessment should be carried out where there may be direct contact with the product e.g. HVAC systems or indirect contact such as through heat exchangers to mitigate any risks of failure.
7. 设施的确认
7.1 蒸汽、水、空气、其它惰性气体、冷却剂等的质量应按照部分3描述的确认步骤在安装后进行确认。
7.2确认的时间和程度，如有需要要反映季节因素，还要反应厂房设施的预期用途。
7.3 当可能存在直接接触产品的地方，如HVAC系统或者不直接接触的，例如通过换热器来降低失败的风险，需要进行风险评估。
8. VALIDATION OF TEST METHODS
8.1 All analytical test methods used in qualification, validation or cleaning exercises should be validated with an appropriate detection and quantification limit, where necessary, as described in Chapter 6 of the EU-GMP guide Part I.
8.2 Where microbial testing of product is carried out, the method should be validated to confirm that the test product does not influence the result.
8.3 Where microbial testing of surfaces in clean rooms is carried out, validation should be performed on the test method to confirm that sanitising agents do not influence the result.
8. 测试方法验证
8.1如有需要，所有用于确认、验证和清洁工作的分析测试方法都应经过检测限和定量限的
确认。
8.2如果测试产品的微生物，测试方法应经过验证，确认产品本身不影响测试结果。
8.3如果进行洁净厂房表面微生物测试，应验证测试方法，确认清洁剂不会影响测试结果。
9. CLEANING VALIDATION
9.1 Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. Where different equipment is grouped together a justification of the specific equipment selected for cleaning validation is expected.
9.2 A visual check for cleanliness may form an important part of the acceptance criteria for cleaning validation however, it is not acceptable for this criterion alone to be used. Repeated cleaning “until clean” is also not considered an acceptable approach.
9.3 It is recognised that a cleaning validation programme may take some time to complete and validation with ongoing verification after each batch may be required. The level of data from the verification to support a conclusion that the equipment is clean should be evaluated.
9.4 Validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities should be validated. Where a manual process is used, an assessment should be performed to determine the variable factors which influence cleaning effectiveness, e.g. operators, the level of detail in procedures such as rinsing times etc. For manual cleaning, if variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies.
9.5 Limits for the carry over of product residues should be based on a toxicological evaluation to determine the product specific permitted daily exposure (PDE) value. The justification for the selected PDE value should be documented in a risk assessment which includes all the supporting references. The removal of any cleaning agents used should also be confirmed.
Acceptance criteria should consider the potential cumulative effect of multiple equipment in the process equipment train.
9.6 The potential for microbial and, or if relevant, endotoxin contamination, should be assessed during validation. The influence of the storage time before cleaning and the time between cleaning and use taken into account to define (dirty and clean) hold times for the cleaning validation.
9.7 Where campaign manufacture is carried out, the impact on the ease of cleaning between batches should be considered and the maximum length of a campaign (in both
time and number of batches) should be the basis for cleaning validation exercises. 9.8 Where a worst case product approach is used as a cleaning validation model, the rationale for selection of the worst case product should be justified and the impact of new products to the site assessed. When there is no single worst case product when using multi-purpose equipment, the choice of worst cases should consider toxicity and PDE value as well as solubility. Worst case cleaning validation should be performed for each cleaning method used.
9.9 Cleaning validation protocols should detail the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.9.10 Sampling should be carried out by swabbing and/or rinsing at the last stage of cleaning or by other means depending on the sampling location. The swab material should not influence the result. If rinse methods are used, the sampling should be performed during the final rinse in the cleaning procedure. Recovery should be shown to be possible from all materials used in the equipment with all the sampling methods used.
9.11 Typically the cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.
9.12 For investigational medicinal products or products which are only manufactured infrequently, cleaning verification may be used instead of cleaning validation. If used, cleaning verification after each batch should be based on the principles in this section of the Annex
9.13 Where cleaning validation has shown to be ineffective or is not appropriate for some equipment, dedicated equipment should be used for each product.
9.0清洁验证
清洁验证部分对标准和验证次数的规定有变化，以下为摘要：
9.1为确认所有产品相关设备清洁规程的效力，应进行清洁验证。设备清洁验证时，可以科
学的创建组，要合理说明选择某个设备的原因。
9.2目测检查是清洁验证可接受标准的重要组成部分，但不能作为唯一标准。不断清洁直至
清洁的方法是不合适的。
9.3完成清洁验证可能需要一段时间，可以使用每批产品后的持续确认进行验证。确认获得
的数据是用来支持设备已洁净的结论，这些数据需要经过评估。
9.4验证应考虑清洁工艺的自动化水平。对于自动化清洁工艺，应验证设施规定的正常操作
范围。对于手工清洁工艺，应通过风险评估确定影响清洁效果的因素，例如操作人员、操作规程的详细程度例如冲洗时间等。如果上述因素被确认，应使用最差条件作验证。
9.5产品残留标准应基于毒理评估，确定产品独特的PDE。PDE的确定的合理性应在风险评
估中记录，记录要包括所有参考资料。任何清洁剂的去除都应被确认。可接受标准应考虑工艺所用系列设备中的多个设备的潜在的累积效应。
9.6验证时，应评估潜在的微生物或内毒素污染（如果相关）。应考虑清洁前存放时间和清
洁与使用之间的间隔，定义清洁验证的保留时间。
9.7进行间歇生产时，应考虑批与批之间清洁的容易程度。间歇生产的最长时间（时间和批
量）都应作为验证的基础。
9.8当以最差条件作为清洁验证的模型时，应科学的评价选择最差条件的理论，并评估新产
品对其他产品的影响。当使用多功能设备时，没有单一的最差条件，最差条件的选择应考虑毒性、PDE值和溶解度。每种清洁方法都应进行最差条件验证。
9.9清洁验证方案中应明确取样点，选择该取样点的理由和可接受标准。
9.10应在清洁的最后阶段使用擦拭或冲淋的方法进行取样，也可根据取样点采取其他方法。
用于擦拭取样的物品不得影响测试结果。若采用冲淋取样，应在冲淋的最后进行取样。
要求证明用于设备及取样方法的所有原料可以被回收。
9.11为证明清洁方法是有效的，应根据风险评估确定合适的验证次数，而且满足可接受的标
准。
9.12对于研究用药品和极少生产的药品，可以使用清洁确认的方式代替清洁验证。
部分设备，若清洁验证结果是无效的或不合适的，应对每种产品使用专用设备。
10. RE-QUALIFICATION
10.1 Facilities, utilities, systems, equipment should be evaluated at an appropriate frequency to confirm that they remain in a state of control.
10.2 Where additionally re- qualification is necessary and performed at a specific time period, the period should be justified and, the criteria for evaluation defined. Furthermore
the possibility of incremental changes should be assessed.
10.3 Where manual processes are used, such as for cleaning of equipment, the continued
effectiveness of the process should be confirmed at a justified frequency.
10. 再确认
10.1 厂房、设施、系统、设备应以一定的频率进行评价来确认它们处于控制状态。
10.2 当需要额外的再确认并在特定时间执行时，要说明验证周期的合理性，要确定评价的标准。
10.3 当使用人工操作工艺时，例如清洁设备，需要以一个合理的频率来确定这个工艺持续有效。
11. CHANGE CONTROL
11.1 The change process is an important part of knowledge management and should be handled within the pharmaceutical quality system.
11.2 Written procedures should be in place to describe the actions to be taken if a planned change is proposed to a starting material, product component, process, equipment, premises, product range, method of production or testing, batch size, design space or any other change during the lifecycle that may affect product quality or reproducibility.
11. 变更控制
11.1 变更程序是知识管理中重要的一部分，应该在药学质量体系中进行管理。
11.2 在生命周期中，当计划对起始物料、产品组分、工艺、设备、常犯、系列产品、生产或检验方法、产品批量、设计空间或其它内容提出可能影响产品质量或重复性的变更时，需要有书面的程序描述应该采取的行动。
11.3 应用设计空间的，根据注册申报时注册的设计空间，考虑变更对设计空间的影响，并评估是否需要别的法规行为。
11.3 Where design space is used, the impact on changes to the design space should be considered against the registered design space within the Marketing Authorisation and the need for any regulatory actions assessed.
11.4 Quality risk management should be used to evaluate planned changes to determine the potential impact on product quality, pharmaceutical quality systems, documentation, validation, regulatory status, calibration, maintenance and on any other system to avoid unintended consequences and to plan for any necessary process verification or requalification efforts.
11.5 Changes should be authorised and approved by the responsible persons or relevant functional personnel in accordance with the pharmaceutical quality system. 11.4 应使用质量风险管理来评估计划的变更以确定变更对产品质量、质量系统、文件、验证、法规状态、校验、维护和其它系统的影响，以此避免未预期的后果，并且筹划必要的工艺确认或者再确认。
11.5 变更要根据药品质量体系要求由负责人员或相关职能人员进行授权和批准。
11.6 Supporting data should be generated to confirm that the impact of the change has been demonstrated prior to approval.
11.7 Following implementation, and where appropriate, an evaluation of the effectiveness of change should be carried out to confirm that the change has been successful.
11.6 在批准之前要有支持数据来确认变更的影响已被证实。
11.7 变更执行后，如果适合，要评估变更的效果来确认变更的成功。
术语：
Bracketing approach:
A validation scheme/protocol designed such that only batches on the extremes of certain predetermined and justified design factors, e.g., strength, batch size, pack size are tested during process validation. This approach assumes that validation of any intermediate levels is represented by the extremes validated. Where a range of strengths is to be validated, bracketing could be applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills
in the same container closure system.
支架方法
一种设计的验证计划/方案，只有预先确定的且合理的设计因素（例如规格、批量、包装量）的极限值在验证过程中才会被测试。这个方法假定对于极限值的验证可以代表任何中间值的验证。当要验证一系列规格时，如果这些规格在组成方面一样或者非常接近，那么可以使用支架法（例如，例如一系列由类似的基本颗粒制成的不同压片重量的片剂，或者一系列的胶囊是把相同的基本成分的不同装量装入不同大小的胶囊壳中）。支架法可以应用于不同大小的容器或者同一容器密封系统的不同装量。
Change Control
A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action to ensure and document that the system is maintained in a validated state.
变更控制
经过适当专业的有资历的代表对可能影响厂房、系统、设备或工艺的建议变更或实际变更进行评估。目的是确定需要采取的措施来保证系统处于验证状态。Cleaning Validation
Cleaning validation is documented evidence that an approved cleaning procedure will remove all traces of the previous product used in the equipment
清洁验证
清洁验证是文件化的证据能证明批准的清洁程序能够清除以前设备中使用的产品的所有痕迹。
Concurrent Validation
Validation carried out in exceptional circumstances, justified on the basis of significant patient benefit, where the validation protocol is executed concurrently with commercialisation of the validation batches.
同步验证
在特殊情况下，在维护病人的利益的基础上进行合理说明，验证与商业化验证批同步。
Continuous process verification
An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated.
持续工艺确认
工艺验证的一种可选择的方法，生产工艺的性能可以得到持续的监控和评价。Control Strategy:
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components,facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.(ICH Q10)
源自于对当前产品和工艺理解的一系列计划的控制措施，它保证了工艺性能和产品质量。控制可以包括与原料药及药物制剂材料和组分相关的参数和特性，设施和设备的运行条件、在线控制、成品标准、监控及控制的相关方法和频率。Critical process parameter (CPP)
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8)
关键工艺参数
指一种工艺参数，其变化能够对一种关键质量特性造成影响，从而应当受到监控仪保证工艺能够生产出预期质量的产品。
Critical quality attribute (CQA)
A physical, chemical, biological or microbiological property or characteristic that should be within an approved limit, range or distribution to ensure the desired product quality. (ICH Q8)
关键质量特性
指某种物理、化学、生物学或微生物学的特性，它应当处于适当限度、范围或分布以保证预期产品的质量。
Design qualification (DQ)
The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.
Design Space
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movementout of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8)
设计空间
指输入变量（如物料属性）和那些易正明对质量提供保障的工艺参数的度组合和相互作用。在设计空间之内运行不认为是一种变更。超出了设计空间则被认为是一种变更，通常需要启动批准后的变更申请程序。设计空间由申请人提出，由药品注册机构审查批准。
Knowledge management
A systematic approach to acquire, analyse, store and disseminate information
知识管理
获取、分析、存储和传播信息的系统方法。
Lifecycle
All phases in the life of a product, equipment or facility from initial development or use through to discontinuation of use.
生命周期
药品从研发、上市、直至终止所经历的的所有阶段。
Ongoing Process Verification (also known as continued process verification) Documented evidence that the process remains in a state of control during commercial manufacture.
连续工艺验证
文件化的证据能够证明商业化生产过程中工艺处在控制状态。
Prospective Validation
Validation carried out before routine production of products intended for sale.
前验证
在常规生产用于销售的产品前的验证。
Simulated Product
A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch.
模拟产品
验证时使用的一种物理性质、如果可行的话还有化学性质（例如粘度、粒径、pH 等）很接近产品。许多时候，这些性质可以通过安慰剂产品批来满足。
State of control
A condition in which the set of controls consistently provides assurance of continued process performance and product quality.
控制状态
一系列的控制能够一致的保证持续的工艺性能和产品质量。
Product realisation
Achievement of a product with the quality attributes to meet the needs of patients, health care professionals and regulatory authorities and internal customer requirements. (ICH Q10)
生产出质量可以满足患者、专业医护人员、监管当局和内部客户的要求的产品。Quality by design
A systematic approach that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management.
一种研发的系统化方法，它从预先确定的目标开始，强调基于坚实的科学和质量风险管理的产品和工艺理解和工艺控制。
Quality risk management
A systematic process for the assessment, control, communication and review of risks to quality across the lifecycle. (ICH Q9)
质量风险管理
在药品整个生命周期对质量产生的风险进行评估、控制、沟通和审核的过程。Traditional approach
A product development approach where set points and operating ranges for process parameters are defined to ensure reproducibility.
传统方法
一种产品开发方法通过为工艺参数设置数值和操作范围来保证重复性。
Worst Case
A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
最差条件
一种条件或者一系列条件，在标准操作规程范围内，他们包含着工艺限度或者环境的上下限，与理想条件相比，这样能够形成产品或工艺失败的最大挑战。这些条件不是必然能够引起产品或工艺失败的。下载本文
