【欧盟GMP基础知识系列】（中英文） Process Validation 工艺验证

酷哥

General 总则

4.1 The requirements and principles outlined in thissection are applicable to the manufacture o f all pharmaceutical dosage forms.They cover the in itia l validation o f new processes, subsequent validation of modified processes, site transfers and ongoing process verification. 本章所概述的要求与原则适用于所有药品剂型生产。其涵盖了新工艺的最初验证、后续改良工艺验证、现场转移与进行中的工艺确证。

4.2 Thissection should be used in conjunction w ith the current EM A guideline onProcess Validation. Note: It should be taken into account that the guideline onProcess Validation is intended to provide guidance on the information and datato be provided in the regulatory submission and G M P requirements extendbeyond this. It should also be noted that a lifecycle approach is appliedlinking product and process development, validation o f the commercialmanufacturing process and maintenance o f the process in a state o f controlduring routine commercial production. 本章应与现行欧洲药品管理局（E M A )的工艺验证指南一同使用。注：应考虑到欧洲药品管理局的 工艺验证指南旨在为药品递交文件和G M P所需的信息与数据提供指导，这些信息和数据己远远超出了本节范围。同样需要注意的是，在日常商业生产中，生命周期的方法被应用于产品与工艺开发、 商业生产工艺验证以及处于控制状态的工艺维持。

4.3 Medicinal products may be developed using atraditional approach or a continuous verification approach however irrespectiveo f the approach used, processes must be shown to be robust and ensureconsistent product quality before any product is released to the market.Manufacturing processes should undergo a prospective validation programmewherever possible prior to marketing o f the product.

药品可能是用传统方式或连续确证的方式开发，然而，不论使用的方法如何，工艺必须耐用并保证 产品投放到市场前质量始终如一。产品上市前，生产工艺应尽可能经过一个前验证程序。

4.4Process validation for new products should coverall intended marketed strengths and sites o f manufacture, however for productswhich are transferred from one site to another or w ithin the same site, andwhere there is existing product knowledge, including the content o f theprevious validation, the number o f validation batches could be reduced by theuse o f a bracketing approach. This approach could be acceptable for differentstrengths, batch sizes and pack sizes/ container types if justified. 新产品的工艺验证应包括其所有上市的规格与生产现场，然而对于从一个现场转移到另一个现场的或在同一现场内的产品，现有产品的知识，包括以前验证的内容、验证批次数量可以通过归类方法 减少。对于不同规格、批量与包装大小/容器类型，如果通过了论证，该方式是可接受的。

4.5For the site transfer o f legacy products, themanufacturing process and controls should comply w ith the MarketingAuthorisation and meet current expected licensing standards for that producttype. I f necessary, variations to the Marketing Authorisation should besubmitted. 对于老产品现场转移，生产工艺与控制应符合上市授权，并符合现在对该产品类型所期望的许可标准 。如果需要的话，应提交上市授权变更。

4.6Process validation should establish whether a llquality attributes and process parameters which are considered im - portant forensuring the validated state and acceptable product quality can be consistentlymet by the process. The basis by which process parameters and qualityattributes were identified as being critical or non-critical should be clearlydocumented, taking into account the results o f any risk assessment activities.工艺验证应确立所有产品质量属性和工艺参数都始终如一地符合工艺要求。在确保验证状态和可接受的生产质量时，这些质量属性和工艺参数被认为是重要的。应清楚地记录用以辨识工艺参数与质 量属性是否为关键性或非关键性的基础，同时考虑任何风险评估活动结果。

4.7Norm ally batches manufactured for processvalidation should be the same size as the intended commercial scale batches andthe use o f any other batch sizes should be justified, e.g. for a continuousmanufacturing process. 通常工艺验证所生产批次应与预期商业化规模生产批量一致，任何其他批量应经过论证。例如，对 于一个连续生产工艺。

4.8Facilities, systems, utilities and equipment usedfor process validation should be qualified and test methods should bevalidated. 用于工艺验证的设施、系统、公用工程与设备应经过确认，并且分析方法应经过验证。

4.9For all products irrespective o f the approachused, process knowledge from development studies should be accessible to themanufacturing site, unless otherwise justified, and be the basis for validationactivities. 对于所有产品来说，不管采用什么方法，来自开发研究的工艺知识应可在制造现场查阅，若经过论证 ，可作为验证活动的基础。

4.10For process validation batches, production,development, or other site transfer personnel may be involved. Batches shouldonly be manufactured by trained personnel in accordance w ith GMP usingapproved documentation. It is expected that production personnel are involvedin the manufacture o f validation batches to facilitate product understandingwhen commercial manufacture starts. 对于工艺验证批次，可能涉及生产、开发或其他现场转移人员。批次应仅由经过培训的人员按照药 品生产质量管理规范要求使用经过批准的文件来生产。在验证批次生产中最好涉及生产人员，以便当商业化生产开始时促进对产品的理解。

4.11The suppliers o f critical starting andpackaging materials should be qualified prior to the manufacture o f validationbatches; otherwise a justification based on the application o f quality riskmanagement principles should be documented. 对关键原料与包装材料供应企业，应在进行验证批次生产前就进行资质确认；否则应进行基于质量 风险管理原则的论证并记录。

4.12It is especially important that the underlyingprocess knowledge for the design space justification ( if used)，and fordevelopment o f any mathematical models used to confirm a state o f controlshould be available. 作 为 设计 空间论证 的基础工艺 知 识（如果使用）特别重要，并应有用以确认控制状态的数字模型 开发。

4.13Where validation batches are released to themarket this should be pre-defined. The conditions under which they are producedshould fu lly comply w ith GMP, w ith the validation acceptance criteria, withany continuous process verification criteria ( if used) and w ith the MarketingAuthorisation. 应预先规定是否将验证批次放行销售。这种情况下，生产的产品应完全符合药品生产质量管理规范、符合验证验收标准、符合连续工艺确证标准（如果使用），并符合上市授权。

Concurrent Validation 同步验证

4.14In exceptional circumstances where there is astrong risk-benefit to the patient, it may be acceptable not to complete avalidation programme before routine production starts and concurrent validationcould be used. However, the decision to carry out concurrent validation must bejustified, documented in the VMP and approved by authorised personnel. 在对患者利益无显著风险的情况下，可能允许在日常生产开始前没有完成验证程序，并且可使用同步验证。然而，实施同步验证的决定必须进行论证，在验证总计划中进行记录，并由授权人员批准。

4.15Where a concurrent validation approach has beenadopted, there should be sufficient data to support a conclusion that any givenbatch o f product is uniform and meets the defined acceptance criteria. Theresults and conclusion should be form ally documented and available to theQualified Person prior to certification o f the batch. 当已经采用同步验证的方式，应有足够的数据来支持任何一个给定的批次产品都是均一的并且符合规定的可接受标准的结论。结果与结论应正式记录，质量受权人应在认证该批次前收到该文件。

Traditional Approach to Validation 验证的传统方法

4.16In the traditional approach, a number o fbatches o f the finished product are manufactured under routine conditions toconfirm reproducibility. 在传统方法中，日常条件下生产的若干批次的成品可用来确认其重现性。

4.17The number o f batches manufactured and thenumber o f samples taken should be based on quality risk management principles,allow the normal range o f variation and trends to be established and providesufficient data for evaluation. Each manufacturer must determine and justifythe number o f batches necessary to demonstrate a high level o f assurance thatthe process is capable o f consistently delivering quality product. 生产的批次数目与取样的数量应根据质量风险管理的原则，建立允许的正常变化范围与趋势，并提供足够的数据进行评估。每个生产企业必须确定并进行论证高保证水平所需要的批次数目，在该水 平下，应能始终如一地交付优质产品。

4.18W ithout prejudice to 4.17，it isgenerally considered acceptable that a minimum o f three consecutive batcheswould constitute a validation o f the process although an alternative number of batches may be justified taking into account whether standard methods o fmanufacture are used and whether sim ilar products or processes are alreadyused at the site. An initial validation exercise w ith three batches may needto be supplemented w ith further data obtained from subsequent batches as parto f an on-going process verification exercise. 在不违反第4.17条的情况下，虽然批次数量可进行论证来考量是否使用标准方法生产，及类似产品或工艺是否已经在现场使用，但至少三个连续批次将构成对一个工艺的验证，这通常被认为是可以 接受。三个批次的初始验证实践可能需要后续批次获得的数据类来补充，这些后续批次将作为一个持续工艺确证活动的一部分。

4.19A process validation protocol should be preparedwhich defines the critical process parameters (CPP), critical qualityattributes (CQA) and the associated acceptance criteria which should be basedon development data or documented process knowledge. 应编写工艺验证方案，以规定关键工艺参数（C P P )、关 键 质 量 属 性 （C Q A ) 与相关可接受标准，这些应基于开发数据或记录的工艺知识。

4.20Validation protocols should include, but are notbe lim ited to the follow ing ： 验证方案应该包括，但不仅限于以下内容：

a) A short description o f the process. 对工艺的简短描述。

b) Summary of the CQA，s to be investigated. 即将调查的关键质量属性汇总。

c) Summary of CPP，s and their associated lim its. 关键工艺参数与相关限度汇总。

d) Summary o f other (non-critical) attributes andparameters which w ill be investigated or monitored during the validationactivity, and the reasons for their inclusion. 在验证工艺活动中即将调查或监测的其他（非关键）属性与参数，及调查或监测原因的汇总。

e) List o f the equipment/facilities to be used(including measuring/monitoring/recording equipment) together with thecalibration status. 即将使用的设备、设 施 （包括测量、监测、记录设备）及其验证状态的清单。

f) List o fanalytical methods and method validation, as appropriate. 分析方法与方法验证的清单（如适用）。

g) Proposedin-process controls w ith acceptance criteria and the reason (s) which eachin-process control is selected. 建议的中间工艺控制与验收标准，及选择每个中间工艺控制的原因。

h) Additional testing to be carried out, w ithacceptance criteria.即将实施的附加测试与接受标准。

i) Sampling plan and the rationale behind it. 取样计划与其原理。

j) Methodsfor recording and evaluating results. 结果记录与评估的方法。 k) Process for releaseand certification o f batches ( if applicable). 批次放行与认证的过程（如果适用）。

1) Functions and responsibilities. 职能与职责。

m) Proposed timetable. 建议的时间表。

Continuous Process Verification 连续工艺确证

4.21For products developed by a quality by designapproach, where it has been scientifically established that routine processcontrol provides a high degree o f assurance o f product quality, thencontinuous process verification can be 375 Annexes 附录 used asan alternative to traditional process validation. 对于用质量源于设计方式开发的产品，在已经科学建立了提供产品质量高度保证的日常工艺控制后，可以使用连续工艺确证作为传统工艺验证的替代方法。

4.22The process verification system should bedefined and there should be a science based control strategy for the requiredattributes for incoming materials, critical quality attributes and criticalprocess parameters to confirm product realisation. This should also includeregular evaluation o f the control strategy. Process Analytical Technology andmultivariate statistical process control may be used as tools. Eachmanufacturer must determine and justify the number o f batches necessary todemonstrate a high level o f assurance that the process is capable o fconsistently delivering quality product. 应规定工艺确证系统，并且对于接收物料所要求的属性、关键质量属性与关键工艺参数应有一个基 于科学的控制策略来确认产品实现。这还应包括控制策略定期评估。工艺分析技术与多变量统计工艺控制可作为工具使用。每个生产企业必须确定并进行论证来证明高保证水平所需要的批次数目， 在该水平下，工艺应能始终如一地交付优质产品。

4.23The general principles in 4.1-4.15 above stillapply. 上述第4.1条到第4.15条的总体原则仍然适用。

4.24A hybrid approach using the traditional approachand continuous process verification for different production steps can also beused. Where there is a substantial amount o f product and process knowledge andunderstanding which has been gained from manufacturing experience andhistorical batch data, continuous verification may also be used for anyvalidation activities after changes or during ongoing process verification eventhough the product was in itia lly validated using a traditional approach. 在不同的生产步骤可采用传统工艺验证方式与连续工艺确证混合方法。如果有从生产经验与历史数据中获得的大量产品与工艺的知识及理解，即使产品最初是使用传统方式进行验证的，进行中的工 艺确证也可用于任何变更后或在持续工艺确证活动期间的验证活动。

On Going Process Verification during Lifecycle 生命周期中进行中的工艺确证

4.25Manufacturers should monitor product quality toensure that a state o f control is maintained throughout the product lifecyclew ith the relevant process trends evaluated. 生产企业应监测产品质量，确保在整个产品生命周期中保持控制状态，并进行相关工艺趋势评价

4.26The extent and frequency o f ongoing processverification should be reviewed periodically and modified if appropriate,considering the level o f process understanding and process performance at anypoint in time in the product life - cycle. 考虑到产品生命周期在任何时间点对工艺的理解水平与工艺性能的变化，在适当的情况下，应对进 行中的工艺确证的范围和频率进行定期审查和修改

4.27On going process verification should beconducted under an approved protocol and a corresponding report should beprepared to document the results obtained. Statistical tools should be used,where appropriate, to support any conclusions w ith regard to the variabilityand capability o f a given process and ensure a state o f control. 进行中的工艺确证应按照已经批准的方案实施，编写相应报告并记录获得的结果。如恰当，应使用统计工具，来支持任何给定工艺可变性与能力的结论，确保系统处于控制状态。

4.28On going process verification should be used tosupport the validated status o f the product in the Product Quality Review,however, incremental changes over time should also be considered and the needfor any additional actions (e.g. enhanced sampling) should be assessed. 进行中的工艺确证应用于支持在产品质量审核中的产品验证状态，然而，随着时间的推移，评估还应考虑变更积累与任何额外措施的需求（例如，增强取样)。

4.29On going process verification should beconsidered where any individual change or successive incremental changes duringthe product lifecycle could have an impact on the validated status o f theprocess. 在产品生命周期中，在单次变更或连续积累变更可能会影响工艺的验证状态的情况下，应考虑使用进行中的工艺确证。

文章来源：欧盟GMP法规汇编

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