PICGMP附件15确认和验证

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1、ANNEX 15 附件 15QUALIFICATION AND VALIDATION确认及验证PRINCIPLE 原则1. This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of t

2、he critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation.1. 本附则是说明适用于药品制造之确认与

3、验证的原则。药厂辨别其 所需要的验证作业，以证明其特别操作之关键层面的管制，是药品优 良制造准则的要求。对于会影响产品质量的设施、设备及制程之重大 变更，应进 验证。风险评估方法应加以使用，以确定其验证的范围 与程度。PLANNING FOR VALIDATION验证之规化2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VM

4、P) or equivalent documents.2. 一切验证活动均应加以规划。验证计划的关键因素应在验证主计 划书或在相当/等同的文件中清楚界定并文件化。3. The VMP should be a summary document which is brief, concise and clear.3. 验证主计划书，应是一个简短、简明且清楚的摘要文件。4. The VMP should contain data on at least the following:4. 验证主计划书应包含至少下列资料：a) validation policy;a) 验证策略；b) organisat

5、ional structure of validation activities;b) 验证活动的组织结构；c) summary of facilities, systems, equipment and processes to be validated;c) 所要验证的设施、系统、设备与制程的摘要；d) documentation format: the format to be used for protocols and reports;d) 文件格式：计划书及报告要使用的格式；e) planning and scheduling;e) 企划及时程安排；f) change contro

6、l;f) 变更控制；g) reference to existing documents.g) 参照现有文件.5. In case of large projects, it may be necessary to create separate validation master plans.5. 如为大型计划，可能需要建立个别的验证主计划书。 DOCUMENTATION 文件6. A written protocol should be established that specifies how qualification and validation will be conducted

7、. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria.6. 应建立一份书面计划书，载明将如何确认及验证。该计划书应经 审查及核准，并载明其关键步骤及允收标准。7. A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained,

8、commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification.7. 应制作交互参照确认及/或验证计划书之报告，摘述取得的结果、 评论观察到之任何偏差、以及研拟必要的结论

9、，包含为改正缺失所需 之变更的建议。对计划书中界定之计划的任何变更，应备有其正当理 由予以文件化。8. After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation.8. 在完成一个满意之确认后，应以书面授权做成一个正式放行，以 供下一步骤之确认及验证。QUALIFICATION 确认Design qualification设计确认9. Th

10、e first element of the validation of new facilities, systems or equipment could be design qualification (DQ).9. 新厂房设施、系统或设备之验证的第一要件可能是设计确认。10. The compliance of the design with GMP should be demonstrated and documented.10. 设计与药品优良制造准则之相符性应予证明并文件化。Installation qualification 安装确认11. Installation quali

11、fication (IQ) should be performed on new or modified facilities, systems and equipment.11. 对新的或修改过之厂房设施、系统及设备应为执行安装确认。12. IQ should include, but not be limited to the following:12. 安装确认应包括，但 限于下列各项：a) installation of equipment, piping, services and instrumentation checked 丫 /* to current engineering

12、 drawings and specifications;a) 将设备、管路、辅助装置及仪器装置之安装与现行工程图及标准 核对；b) collection and collation of supplier operating and working instructions and maintenance requirements;b) 供货商之操作及工作说明书，以及维护保养要求的收集与校对；c) calibration requirements;c) 校正要求；d) verification of materials of construction.d) 建造材料的确认。Operation

13、al qualification 操作确认13. Operational qualification (OQ) should follow Installation qualification.13. 操作确认应接在安装确认之后。14. OQ should include, but not be limited to the following:14. 操作确认应包括，但不限于下列各项a) tests that have been developed from knowledge of processes, systems and equipment;a) 从对工艺、系统及设备的了解所开发出的

14、试验。b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions.b) 包括操作上下限的一个条件或是一组条件的试验，有时候其称之 为“最差条件”；15. The completion of a successful Operational qualification should allow the finalisation of calibration,

15、 operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal release of the facilities, systems and equipment.15. 一个成功之操作确认的完成应容许校正、作业及清洁程序、作业 人员训练，以及预防保养要求的定案。这应容许厂房设施、系统及设 备之正式“放行”。Performance qualification 性能确认16. Performance qualifica

16、tion (PQ) should follow successful completion of Installation qualification and Operational qualification.16. 性能确认应接在成功的安装确认及操作确认之后。17. PQ should include, but not be limited to the following:17. 性能确认应包括，但不限于下列各项：a) tests, using production materials, qualified substitutes or simulated product, that h

17、ave been developed from knowledge of the process and the facilities, systems or equipment;a) 从对工艺与设施、系统或设备的了解，使用生产原料、合格替代 品或是仿真产品所开发出来的试验；b) tests to include a condition or set of conditions encompassing upper and lower operating limits.b) 包括涵盖操作上下限的一个条件或是一套条件的试验。18. Although PQ is described as a se

18、parate activity, it may in some cases be appropriate to perform it in conjunction with OQ.18. 虽然性能确认(PQ)被描述为一个个别的作业活动，但是在某些情 况，这可能适合与操作确认(OQ)起为之。Qualification of established (in-use) facilities, systems and equipment 既有(使用中)厂房设施、系统及设备的确认19. Evidence should be available to support and verify the oper

19、ating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.19. 应有证据支持及证实操作设备之操作参数与重要变数的极限。另 外，校正、清洁、预防保养、操作程序及操作者训练程序以及记录，

20、 应予文件化。PROCESS VALIDATION 工艺验证General 通则20. The requirements and principles outlined in this chapter are applicable to the manufacture of pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and re-validation.20. 本章中所概述之要求与原则适用于

21、药品剂型的制造。这涵盖新制 程的初始验证、修改工艺之后续验证及再验证。21. Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (

22、concurrent validation). Processes in use for some time should also be validated (retrospective validation).21. 工艺验证通常应在药品运销与贩卖前完成(先期性验证)。在例外 情形，先期性验证不可行时，必需在例行的制造中验证工艺(并行性 验证)。制程在使用一段时间后也应予验证(回溯性验证)。22. Facilities, systems and equipment to be used should have been qualified and analytical testing me

23、thods should be validated. Staff taking part in the validation work should have been appropriately trained.22. 要使用之厂房设施、系统及设备应完成确认，且分析试验的方法 应经验证。 与该验证工作的员工应已完成适当的训。23. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid man

24、ner.23. 厂房设施、系统、设备及制程应定期评估，以确证其尚在一有效 方式中运转。Prospective validation 先期性验证24. Prospective validation should include, but not be limited to the following:24. 先期性验证应包括，但限于下各项：(a) short description of the process;(a) 制程的简要描述；(b) summary of the critical processing steps to be investigated;(b) 要调查之关键性制程步骤的摘

25、要；(c) list of the equipment/facilities to be used (including measuring / monitoring / recording equipment) together with its calibration status(c) 要使用之设备/设施(包括测/监测/记录设备)及其校正状态的清 单；(d) finished product specifications for release;(d) 供放用之最终产品的标准；(e) list of analytical methods, as appropriate;(e) 视情况，分

26、析方法的清单；(f) proposed in-process controls with acceptance criteria;(f) 建议之制程中管制及其允收标准；(g) additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate;(g) 视情况，要从事之追加试验，同其允收标准及分析验证；(h) sampling plan;(h) 抽样计划；(i) methods for recording and evaluating results(i)

27、 记录及评估结果的方法；(j) functions and responsibilities;(j) 功能及职责；(k) proposed timetable.(k) 建议的时程表。25. Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. In theory the number of process runs carried out and observati

28、ons made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the proce

29、ss.25. 使用本界定的制程(包括特定的组成物/组件)者，一系之最终产 品的批次可在条件下生产。理论上，制程的操作次数及所做之 观察，应足以提供变与趋势之正常程的建，并提供足够的数据， 以供评估。三个连续批次/操作在最终同意的参数内，构成该制程的 验证，通常被认为是可接受的。26. Batches made for process validation should be the same size as theintended industrial scale batches.26. 为供制程验证而制造的批次，应与预定之工业产规模批次的批 相同。27. If it is intended

30、that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and (where applicable) the marketing authorisation.27. 预定将验证批次销售或供应者，其生产条

31、件应完全符合优制造 准则的要求，包括验证操作的满意结果在内，以及视情况，符合上市 许可之要求。Concurrent validation 并性验证28. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts.28. 在外的情形，于生产开始前尚未完成验证计划，可以接受。29. The decision to carry out concurrent validation must be justified,

32、documented and approved by authorised personnel.29. 执并性验证的决定，应证明其合，并予以文件化，且要经 由被授权人员核准。30. Documentation requirements for concurrent validation are the same as specified for prospective validation.30. 并性验证的文件要求，与先期性验证的规定相同。Retrospective validation 回溯性验证31. Retrospective validation is only acceptable

33、 for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.31. 回溯性验证，只有对完善既定的制程才可以接受。在产品组成、 操作程序或设备上有新近变时，就适合采用回溯性验证。32. Validation of such processes should be based on historical data. The steps

34、 involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.32. 这些制程的验证应以历史数据为基础。涉及的验证步骤要求要有 特定的计划书之制备，以及导引出结论和建议之数据之审查结果的报 告。33. The source of data for this validation should include, but not be limited t

35、o batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results.33. 验证数据的来源，应包括，但局限于批次操作与分/包装记录、 制程管制图表、维修保养使用日志、人员换记录、制程能研究、 最终产品数据包含其趋势卡及储存安

36、定性的结果在内。34. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may

37、 be needed to obtain the necessary amount or type of data to retrospectively validate the process.34. 选供回溯性验证的批次，应为审查期间生产的所有批次的代表 品，包括未合规格之任何批次在内，且应有足够的批次数目，以证明 制程的一致性。必要时，可以储备样品（样品）来做追加测试，以取 得回溯性验证所需要数据的数或类型。35. For retrospective validation, generally data from ten to thirty consecutive batches sho

38、uld be examined to assess process consistency, but fewer batches may be examined if justified.35. 为回溯性验证，通常应检查取自10 至30个续批次的资，以 评估制程的一致性。有正当由者，亦可检查较少的批次。CLEANING VALIDATION清洁验证36. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for

39、selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.36. 为确认清洁程序的有效性，应执清洁验证。选定产品残物、 清洗剂及微生物污染之残转限的论依据，逻辑上应以涉及的物质 为基础。该限应为可达成且是可确证的。37. Validated analytical m

40、ethods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.37. 应使用对残物或污染物具灵敏之经验证的分析方法。每一种 分析方法之侦测极限，应足够灵敏，以侦测残物或污染物之已建 的允收标准。38.

41、Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.38.

42、通常，只对设备之产品接触表面的清洁程序才需要验证。对于与 产品没有接触的部份也应加以考虑。对于制造设备在使用与清洁间， 以及在清洁与再使用间之时间间隔应予验证。清洁的时间间隔与方法 应予确定。39. For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilisin

43、g a “worst case” approach can be carried out which takes account of the critical issues.39. 对于类似产品及制程的清洁程序，选择类似产品与制程之代表性 的范围是可接受的。用考虑到关键问题之“最差状况”做法，得执 单一验证试验。40. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that t

44、he method is validated.40. 典型上，应执该清洁程序之三次连续应用，并显示其成功，以 证明该方法是验证的。41. Test until clean is not considered an appropriate alternative to cleaning validation.41. “试验直到洁净”被认为是清洁验证之适当替代方法。42. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used i

45、nstead of the substances themselves, where such substances are either toxic or hazardous.42. 仿真要移除之物质的物化学性质之产品，得外地用来取代本 身为剧毒的或危险的物质。CHANGE CONTROL 变更控制43. Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, proc

46、ess equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will resu

47、lt in a product of the desired quality, consistent with the approved specifications.43. 对原料、产品成分/组件、制程设备、制程环境(或场所)、生产或 测试方法的变，或对任何其它可能影响产品质量或制程之再现性的 变提出建议时，应备有书载程序描述要采取的措施/动。变管 制程序应确保产生足够的支持数据，证明修正的制程会产生与核准规 格一致之预期质量的产品。44. All changes that may affect product quality or reproducibility of the proces

48、s should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, re-qualification and re-validation should be determined.44. 可能影响产品质量或制程再现性的一变应正式

49、申请/请求、文 件化并经核准。设施、系统及设备的变对产品之可能影响应加以评 估，包括风险分析。再确认及再验证的需求及程应予确定。REVALIDATION再验证45. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with

50、evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.45. 设施、系统、设备及制程，包括清洁，均应定期评估，以确认其 仍然有效。对于验证之态未为重大变者，以设施、系统、设备及 制程均符合规定要求之证据审核之，就已满足再验证要件。 GLOSSARY 术语Definitions of terms relating to qualification and validation which are no

51、t given in the glossary of the current PIC/S Guide to GMP, but which are used in this Annex, are given below. 与确认及验证有关之术语的定义，在对药品优制造准则之现 PIC/S GMP指引的术语汇编中没规定，而在本附则中使用者，规定如 下：Change Control 变更控制A formal system by which qualified representatives of appropriate disciplines review proposed or actual cha

52、nges that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state. 变管制是一个正式系统。在该系统下，由具有适当学科与经验之合 格代表人审核可能影响设施、系统、设备或工艺验证状态之建议的或 实际的变。其目的在于决定动需求，以

53、确保并文件化该系统是维 持在经验证的态。Cleaning Validation 清洁验证Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.清洁验证是经文件化的证据，证明核准的清洁程序将提供适合于制造 药品的设备。Concurrent Validation并行性验证Validation carried out during routine p

54、roduction of products intended for sale.在预定供贩卖之产品的行生产中执行的验证。Design qualification (DQ) 设计确认The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. 设施、系统及设备之建议的设计适合于预定目的之文件化的确证。Installation Qualification (IQ) 安装确认The documente

55、d verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturers recommendations.设施、系统及设备经安装或修改时，其符合核准的设计及制造厂的建 议之文件化的确证。Operational Qualification (OQ) 操作确认The documented verification that the facilities, systems and equipment

56、, as installed or modified, perform as intended throughout the anticipated operating ranges.设施、系统及设备经安装或修改时，在遍及预计的作业范围中，如所 预期执行之文件化的确证。Performance Qualification (PQ) 性能确认The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reprodu

57、cibly, based on the approved process method and product specification. 连结在一起的设施、系统及设备，在核准的制程方法及产品规格的基 础上，能有效且再现性地执之文件化的确证。Process Validation 工艺验证The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product m

58、eeting its predetermined specifications and quality attributes.制程在建之参数内作业时，能有效且再现性地生产符合其预定标准 及质量属性的药品之文件化的证据。Prospective Validation先期性验证Validation carried out before routine production of products intended for sale.在预定供贩卖之产品的生产前执的验证。Retrospective Validation 回溯性验证Validation of a process for a product

59、 which has been marketed based upon accumulated manufacturing, testing and control batch data. 为一个已上市的产品，以其积的制造、测试及管制之批次据为基 础的制程验证。Re-Validation再验证A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures

60、do not adversely affect process characteristics and product quality.再次为制程验证，用以确保依变管制程序导入之制程/设备的变 无地影响制程特性与产品质量。Risk analysis风险分析Method to assess and characterise the critical parameters in the functionality of an equipment or process.用以评估及描述一种设备或制程功能之关键之特性的方法。Simulated Product仿真产品A material that clo

61、sely 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. 一种与验证中产品之物的，以及视情形化学的特性(如黏、 子大小、pH等)非常接近的原料。在许多情形，这些特性可藉由空白 产品批

62、次满足之。System系统A group of equipment with a common purpose. 为一组具有共同目的之设备。Worst Case最差状况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. 一个或一套条件，包含在标准作业程序内之上限及下限作业极限及环 境，当其与想条件相比，这有最大之产品或制程的失败机会。然该 条件一定引起产品或工艺之失败。