歐盟GMP附錄15確認和驗證中英文新版

1、歐盟GMP付錄15確認和驗證歐盟GMP寸錄15確認和驗證ANNEX 15 附件 15Qualification and Validation確認和驗證Table of Contents 目錄1. Qualification and Validatio n確認和驗證2. Pla nning for Validatio n驗證計劃3. Docume ntati on 文件4. Qualificatio n確認5. Process Validati on 工藝驗證6. Clea ning Validatio n清潔驗證7. Cha nge Co ntrol變更控制8. Revalidation 再驗

2、證9. Glossary 術(shù)語表Qualification and Validati on確認和驗證Pri nciple原理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 o

3、fthe critical aspects of their particular operations.Significantchanges to thefacilities, the equipment and the processes, which may affect the quality ofthe product, should be validated. A risk assessme nt approach should be used to determ ine the scope and exte nt of validati on.1. 本附件描述了確認和驗證的原理，

4、適用于醫(yī)藥產(chǎn)品的生產(chǎn)者。這是GM指導生產(chǎn)者明確他們整個操作中哪些是需要對其進行控制的關(guān)鍵方面。在設施、設備和工藝等，對產(chǎn)品質(zhì)量會產(chǎn)生重大影響的改變需要進行驗證。風險評估用來進行驗證的未來預測。PLANNING FOR VALIDATIO驗證計劃2. All validation activities should be planned. The key elements of a validation program should be clearly defined and documented in a validation master plan(VMP) or equivale nt

5、docume nts.所有驗證活動都要進行規(guī)劃。驗證計劃的關(guān)鍵組成部分應該明確定義并在驗證主計劃(VMP或類似文件中寫明。3. The VMP should be a summary document which is brief, concise and clear.VMP是一個簡短、簡明而清晰的綜述性文件。4. The VMP should contain data on at least the following:VMP應該至少包括以下資料：(a) Validation policy;驗證方針(b) Organizational structure of validation acti

6、vities;驗證組織機構(gòu)(c) Summary of facilities, systems, equipment and processes to be validated; 需要驗證的設備、系統(tǒng)、儀器、工藝的匯總(d) Documentation format: the format to be used for protocols and reports; 文件模版：制定草案和報告的模版(e) Planning and scheduling;計劃和時間表(f) Change control;變更控制(g) Reference to existing documents.引用已有文件5.

7、 In case of large projects, it may be necessary to create separate validation master plans.如果項目龐大，則需要制定分開的驗證主計劃。DOCUMENTATION6. A written protocol should be established that specifies how qualificationand validation will be conducted. The protocol should be reviewed and approved. The protocol should

8、 specify critical steps and acceptance criteria.應該制定一份書面草案來指導確認和驗證工作的實施。該方案要進行審核和批準。該 方案要寫明關(guān)鍵步驟和可接受標準。7. A report that cross-references the qualification and/or validation protocol should be prepared, summarizing the results obtained, commenting on anydeviations observed, and drawing the necessary c

9、onclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification. 制定確認和 /或驗證方案的交叉引用對照報告，來對所得結(jié)果進行總結(jié)、對任何觀察到的偏差進行評論、以便得出必要的結(jié)論，包括推薦進行必要變更以改正缺陷。在該計 劃中定義的任何變更都應該有書面記錄，并應有合理的解釋。8. After compl

10、etion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorization.當確認完成后，要對其驗證和確認的書面版本進行正式的發(fā)放。QUALIFICATION確認Design qualification 設計確認9. The first element of the validation of new facilities, systems or equipment could

11、 be design qualification (DQ).一臺新儀器、新系統(tǒng)或者新設備的第一個驗證步驟應該是設計確認(DQ)。10. The compliance of the design with GMPshould be demonstrated and documented. 設計與GMF要求是否符合要進行實例證明并編寫成文件形式。Installation qualification安裝確認11.Installation qualification (IQ) should be performed on new or modified facilities, systems and

12、equipment.安裝確認(IQ)用于新的或者改造后的設施、系統(tǒng)和設備。12.IQ should include, but not be limited to the following:IQ 應該包括以下內(nèi)容，但不局限于此。(a) Installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications;設備、管道、設施和儀器的安裝要符合其圖紙和標準要求。(b) Collection and collation of s

13、upplier operating and working instructions and maintenance requirements;收集和整理供應商的操作說明書以及維護資料。(c) calibration requirements;校驗要求(d) Verification of materials of construction.材質(zhì)確認Operational qualification 運行確認 13.Operational qualification (OQ) should follow Installation qualification.運行確認(OQ在安裝確認之后進行。1

14、4.OQ should include, but not be limited to the following:0Q應該包括以下內(nèi)容，但不局限于此：(a) tests that have been developed from knowledge of processes, systems and equipment;從工藝、系統(tǒng)和設備常識中發(fā)展而來的檢查(b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referre

15、d to as“worst case ” conditions.檢查應包括條件要求或者一組圍繞操作限度上下限的條件，有時要包括“最差情況” 的條件。15. The completion of a successful Operational qualification should allow the finalization of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a form

16、al "release" of the facilities, systems and equipment. 一份完整的成功的運行確認應該包括結(jié)論性的校正、操作和清潔程序，操作者培訓和 預防性維護要求。此步驟的完成相當于允許設施、系統(tǒng)和設備正式“發(fā)放”。Performance qualification 性能確認16. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification.性能

17、確認(PQ應該在安裝確認和運行確認成功完成的基礎上進行。17. PQ should include, but not be limited to the following:PQ應該包括以下內(nèi)容，但不僅限于此：(a) tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment;使用生產(chǎn)材料，經(jīng)確認的代替品或者

18、模擬產(chǎn)品的、從工藝、系統(tǒng)和設備常識中發(fā)展而 來的檢查。(b) Tests to include a condition or set of conditions encompassing upper and lower operating limits.檢查應包括一個條件或者一組圍繞操作限度上下波動的條件。18. Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ.盡管PQ被描述為一個獨立的活動，但是在某

19、些情況下它會與0Q結(jié)合起來。Qualification of established (in-use) facilities, systems and equipment. 已建立(使用中)設施、系統(tǒng)和設備的確認。19. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preven

20、tative maintenance, operating procedures and operator training procedures and records should be documented. 必須有證據(jù)支持和證明操作設備關(guān)鍵變量的操作參數(shù)和限度。另外，校準、清潔、預 防性維護、操作程序和操作者培訓程序和記錄也要以文件形式記錄。PROCESS VALIDATIC工藝驗證General 概述20. The requirements and principles outlined in this chapter are applicable to the manufactur

21、e of pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and re-validation. 本章所列要求和原理適用于藥品劑型生產(chǎn)者。本章涵蓋了新工藝的最初驗證，改良工 藝的后續(xù)驗證和重新驗證。21. Process validation should normally be completed prior to the distributionand sale of the medicina

22、l product (prospective validation).In exceptionalcircumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation).Processes inuse for some time should also be validated (retrospective validation). 工藝驗證通常應該在醫(yī)藥產(chǎn)品分發(fā)銷售 (預驗證)前完成。如有例外情況

23、使工藝驗證不 能如期進行，則必須在日常生產(chǎn)過程中進行驗證 (同步驗證) 。使用中工藝有時也應該 進行驗證(回顧性驗證)。22. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated. Staff taking part in thevalidation work should have been appropriately trained. 所使用的設施、系統(tǒng)和設備應事先經(jīng)過確認，而且使用的分析測定方法也

24、要經(jīng)過驗 證。驗證工作中的相關(guān)人員都要進行過良好的培訓。23. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner. 設施、系統(tǒng)，設備和工藝應該定期進行評估檢測以確保其運行仍然在正常允許的狀態(tài) 下。Prospective validation 預驗證24. Prospective validation should include, but not be limited to

25、the following: 預驗證包括以下內(nèi)容，但不僅限于此：(a) short description of the process; 工藝簡短描述(b) Summary of the critical processing steps to be investigated; 所考察的關(guān)鍵工藝步驟的總結(jié)(c) List of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with its calibration status. 所使用的設備

26、/設施(包括測量、監(jiān)視、記錄儀器)，以及各自的校正情況的列表(d) finished product specifications for release;發(fā)放成品標準(e) list of analytical methods, as appropriate;適宜分析方法列表(f) Proposed in-process controls with acceptance criteria; 被提倡的過程中控制以及其可接受標準(g) Additional testing to be carried out, with acceptance criteria and analytical val

27、idation, as appropriate;適宜的必要的附加測試，包括可接受標準，分析驗證。(h) sampling plan; 取樣計劃(i) methods for recording and evaluating results記錄和評估結(jié)果的方法(j) functions and responsibilities; 功效和責任(k) Proposed timetable.提議的時間表25. Using this defined process (including specified components) a series of batches of the final prod

28、uct may be produced under routine conditions. In theory the number of process runs carried out and observations madeshould 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 thre

29、e consecutive batches/runs within the finally agreed parameters would constitute a validation of the process.在常規(guī)條件下，使用該已確定的工藝 (包括指定的成分)可能生產(chǎn)出一系列批次的最終 產(chǎn)品。理論上講，工藝運行執(zhí)行的次數(shù)和觀察到的結(jié)果，應該足以建立變化和趨勢的 普通范圍，并足以提供較為充足的評估數(shù)據(jù)。所以通常意義上接受三個連續(xù)的、最終 參數(shù)均合格的批次 /運行，可以作為對于工藝的驗證。26. Batches made for process validation should be

30、the same size as the intended industrial scale batches. 工藝驗證批次的生產(chǎn)規(guī)模應該與已定的工業(yè)生產(chǎn)批次相同。27.If it is intended 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 outcom

31、e of the validation exercise, and with the marketing authorization.如果該驗證批次要進行銷售或者供應，則其生產(chǎn)的條件要完全符合GM要求，并要包括令人滿意的驗證結(jié)果和銷售批準。Concurrent validation 同步驗證28.In exceptional circumstances it maybe acceptable not to complete a validation program before routine production starts.在特殊情況下可以接受在常規(guī)生產(chǎn)開始之前沒有完成驗證的情況。29.

32、 The decision to carry out concurrent validation must be justified, documented and approved by authorized personnel.關(guān)于進行同步驗證的決定，必須要有權(quán)威人士進行決策、文件性證明以及批準。30. Documentation requirements for concurrent validation are the same as specified for prospective validation.對于同步驗證的文件要求與預驗證相同。Retrospective validat

33、ion 回顧性驗證31. Retrospective validation is only acceptable for well-established processesand will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.回顧性驗證僅適用于已經(jīng)完善的工藝，對于近期在產(chǎn)品組成、操作程序或者設備方面 有過變更的情況是不適用的。32. Validation of such process

34、es should be based on historical data. The steps 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. 該工藝驗證應該以歷史數(shù)據(jù)為基礎。有關(guān)步驟要求制定詳細方案和數(shù)據(jù)回顧結(jié)果的報 告，以便得出結(jié)論和建議。33. The source of data for this validation sho

35、uld include, but not be limitedto 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. 該驗證的數(shù)據(jù)來源應該包括但是不局限于：批處理和包裝記錄，工藝工職流程 圖，維護保養(yǎng)記錄表，

36、人員變更記錄，加工能力研究，成品數(shù)據(jù)，包括趨勢卡片和耐 儲存性結(jié)果。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 testi

37、ng of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process. 用于回顧性驗證的批次，必須在所有回顧期間生產(chǎn)的批次中選擇具有代表性的批次， 包括任何沒有達到標準的批次，并且在數(shù)量上應該足以示范工藝過程的一致性。也許 需要進行保留樣品的額外測試，以得到必要數(shù)量或種類的數(shù)據(jù)來回對工藝進行回顧性 的驗證。35. For retrospective validation, generally data from ten

38、 to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified.對于回顧性驗證，通常要對10到 30個連續(xù)批次的數(shù)據(jù)進行檢查來評估工藝的一致性，如果可以證明正確性，那么也可以使用稍少的批次進行。CLEANING VALIDATION!潔驗證36. Cleaning validation should be performed in order to confirm the effectiveness of

39、 a cleaning procedure. The rationale for 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. 清潔驗證是為了確保清潔程序的有效性而進行的。對于產(chǎn)品殘留物清除、清潔劑和微 生物污染的限度選擇，理論上應該以相關(guān)原料為基礎。

40、這些限度應該是可以達到的并 且是可以被證實的。37. Validated analytical methods 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. 應該使用經(jīng)確認的、對于檢測殘留物或污染物

41、具有靈敏度的分析方法。每一種分析方 法的檢測限度應該足夠靈敏來檢測出符合可接受標準要求的殘留物或污染物。38. 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.

42、Cleaning intervals and methods should be determined. 一般情況下，僅僅對于和產(chǎn)品接觸的設備表面需要進行清潔驗證。也要考慮到非接觸 部分。要對使用清潔間隔以及清潔再使用間隔進行驗證。清潔間隔和方法應該是確定 的。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.

43、 A single validation study utilizing a“worst case ” approach canbe carried out which takes account of the critical issues.對于相似產(chǎn)品和工藝的清潔程序，選擇相似產(chǎn)品和工藝具有代表性的范圍是可以接受 的。當考慮到關(guān)鍵結(jié)果時，可以利用“最壞情況”來進行單獨的驗證研究。40. Typically three consecutive applications of the cleaning procedure should be performed and shown to be

44、successful in order to prove that the method is validated.應該使用典型的連續(xù)三次清潔程序并保證結(jié)果成功，以證明該方法是經(jīng)過驗證的。41. "Test until clean" is not considered an appropriate alternative to cleaning validation.一直測試直到干凈為止這種作法在清潔驗證中是錯誤的。42. Products which simulate the physicochemical properties of the substances to

45、be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.當要被清除的物質(zhì)有毒或者存在危險性時，要使用產(chǎn)品而非該物質(zhì)本身，產(chǎn)品同該物 質(zhì)具有相似的物理化學特性。CHANGE CONTR變更控制43. Written procedures should be in place to describe the actions to be takenif a change is proposed to a

46、starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Changecontrol procedures should ensure that sufficient supporting data are generated to demon

47、strate that the revised process will result in a product of the desired quality, consistent with the approved specifications. 如果有原料、產(chǎn)品組成、工藝設備、加工環(huán)境 (或場地)、生產(chǎn)方法或檢測或任何其他 可能對產(chǎn)品質(zhì)量或者工藝重現(xiàn)性產(chǎn)生影響的變更時，已定要有相應的書面指導處理程 序。變更控制程序應該確保足夠的支持數(shù)據(jù)的一致性以顯示經(jīng)過修訂的工藝可以保證 生產(chǎn)出符合要求質(zhì)量的產(chǎn)品和規(guī)定標準的組成。44. All changes that may affect produ

48、ct quality or reproducibility of the process 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 sh

49、ould be determined. 所有可能對產(chǎn)品質(zhì)量或工藝重現(xiàn)性產(chǎn)生影響的變更應該正式進行提出、寫成文件并被 接受。應該對生產(chǎn)設施、系統(tǒng)和設備的變更中可能存在的沖突進行評估，包括風險分 析。對于重新確認和重新驗證范圍的要求應該事先確定。REVALIDATION再驗證45. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant chang

50、es have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. 設施、系統(tǒng)、設備和工藝，包括清潔，應該定期進行評估已確保其各自情況是符合標 準要求的。如果驗證方面沒有明顯的變更，設施、系統(tǒng)、設備和工藝達到了要求，則 對其進行審核后重新驗證就算完成了。GLOSSARY 語表Definitions

51、of terms relating to qualification and validation which are not given in the glossary of the current ECGuide to GMP,but which are used in this Annex, are given below.與確認和驗證有關(guān)的、在歐共體指導GM術(shù)語表中沒有列出，但是在附件中使用到的詞如下所示：Change Control 變更控制A formal system by which qualified representatives of appropriate discip

52、lines 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 that would ensure and document that the system is maintained in a validated state.一個正式系統(tǒng)Cleaning Validation 清潔驗證Cleaning valid

53、ation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products. 清潔驗證是用一套文件來證明用于藥品生產(chǎn)的設備已經(jīng)通過了清潔程序。Concurrent Validation 同步驗證Validation carried out during routine production of products intended for sale. 用于銷售的產(chǎn)品生產(chǎn)過程中進行的驗證。Des

54、ign qualification (DQ)設計確認(DQThe documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.本文件確認所提供的設施、系統(tǒng)和設備的設計是與預期要求一致的。Installation Qualification (IQ)安裝確認(IQ)The documented verification that the facilities, systems and equipment,

55、 as installed or modified, comply with the approved design and the manufacturer 's recommendations.本文件確認設施、系統(tǒng)和設備的安裝或改進是完全根據(jù)批準的設計和生產(chǎn)者的推薦所 進行的。Operational Qualification (OQ)操作確認(OQThe documented verification that the facilities, systems and equipment, as installed or modified, perform as intended

56、throughout the anticipated operating ranges.用文件確認安裝或改進的設施、系統(tǒng)和設備，表現(xiàn)失重按照預先規(guī)定的操作范圍進 行。Performanee Qualification (PQ)運行確認(PQ)The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.用文件確認安裝連接好的設施、系統(tǒng)和設備，在經(jīng)過批準的工