WHO GMP補充指南：驗證(中英對照)講述

1、Annex 4 附件 4Supplementary guidelines on good manufacturing practices: validation 藥品生產(chǎn)質量管理規(guī)范補充指南：驗證1 Introduction 簡介2 Scope 范圍 3 Glossary 術語4 Relationship between validation and qualication 驗證和確認之間的聯(lián)系5. Validation 5.1. Approaches to validation 驗證方法5.2. Scope of validation 驗證范圍5 Qualication 確認 6 Calib

2、ration and verication 校準和核實7 Validation master plan 驗證主計劃8 Qualication and validation protocols 確認和驗證方案9 Qualication and validation reports 確認和驗證報告10 Qualication stages 確認程序11 Change control 變更控制12 Personnel 人員References參考文獻 Appendix 1 附錄1Validation of heating, ventilation and air-conditioning syste

3、ms 采暖、通風和空氣凈化系統(tǒng)的驗證Appendix 2 附錄2Validation of water systems for pharmaceutical use 制藥用水系統(tǒng)的驗證Appendix 3 附錄3Cleaning validation 清潔驗證Appendix 4 附錄4Analytical method validation 分析方法驗證Appendix 5 附錄5Validation of computerized systems 計算機系統(tǒng)的驗證Appendix 6 附錄6Qualication of systems and equipment 系統(tǒng)和設備的確認Appen

4、dix 7 附錄7Non-sterile process validation 非滅菌工藝的驗證1. Introduction 簡介Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an element of the quality assurance programme associated with a particular product or process. The basic principles of quality assurance have as

5、their goal the production of products that are t for their intended use. These principles are as follows: 驗證是藥品生產(chǎn)管理規(guī)范（GMP）的一個重要組成部分；也正因如此，所以它同時也是產(chǎn)品或工藝的質量保證計劃的一個不可或缺的要素。質量保證的基本原則以生產(chǎn)出符合設計用途的產(chǎn)品為目的，它的主要內容為：Quality, safety and efcacy must be designed and built into the product. 要事先設計質量、安全和效力，并使之在產(chǎn)品中實現(xiàn)。Qu

6、ality cannot be inspected or tested into the product. 不能僅僅只考察和檢驗成品的質量。Each critical step of the manufacturing process must be validated. Other steps in the process must be under control to maximize the probability that the nished product consistently and predictably meets all quality and design spec

7、ications. 生產(chǎn)工藝的每一關鍵步驟都必須經(jīng)過驗證，非關鍵步驟也必須得到控制，從而實現(xiàn)在最大程度上生產(chǎn)出符合全部質量和既定標準的產(chǎn)品的目的。 Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish condence that the manufactured products will consistently meet their product speci c

8、ations. 工藝和系統(tǒng)的驗證是實現(xiàn)上述目標的基礎之一。通過對生產(chǎn)的設計和驗證，可使生產(chǎn)出的產(chǎn)品持續(xù)符合標準，并建立一定的置信區(qū)間。Documentation associated with validation includes: 與驗證有關的文件如下： standard operating procedures (SOPs) 標準操作規(guī)程（SOP） speci cations 合格標準 validation master plan (VMP) 驗證主計劃（VMP） qualication protocols and reports 確認方案和確認報告 validation protoco

9、ls and reports. The implementation of validation work requires considerable resources such as: 驗證方案和驗證報告。執(zhí)行驗證工作時，需要的資源有：Time: generally validation work is subject to rigorous time schedules. 時間：通常，驗證工作必須嚴格按照時間表的安排開展。Financial: validation often requires the time of specialized personnel and expensive

10、 technology. 資金：驗證工作的執(zhí)行常常需要專業(yè)人員和昂貴的技術支持。Human: validation requires the collaboration of experts from various dis-ciplines (e.g. a multidisciplinary team, comprising quality assurance, en-gineering, manufacturing and other disciplines, depending on the product and process to be validated). 人員：驗證工作的開展

11、要求有不同領域的專家的合作（如一支由來自多個領域的專家組成的驗證團隊，根據(jù)待驗證的產(chǎn)品和工藝的要求，包括質量保證、工程、生產(chǎn)和其它領域）。These guidelines aim to give guidance to inspectors of pharmaceutical manu-facturing facilities and manufacturers of pharmaceutical products on the requirements for validation. The main part covers the general principles of validat

12、ion and qualication. In addition to the main part, appendices on vali-dation and qualication (e.g. cleaning, computer and computerized systems, equipment, utilities and systems, and analytical methods) are included. 這些指導方針能給藥品生產(chǎn)設施的檢查員及藥品生產(chǎn)商提供關于驗證要求的指導。正文部分的內容主要是關于驗證和確認，附錄中另有其它方面的內容（如清潔、計算機和計算機化系統(tǒng)、設備

13、、公用工程和公用系統(tǒng)、分析方法等）。2. Scope 范圍2.1 These guidelines focus mainly on the overall concept of validation and are intended as a basic guide for use by GMP inspectors and manufacturers. It is not the intention to be prescriptive in specic validation require-ments. This document serves as general guidance o

14、nly, and the principles may be considered useful in its application in the manufacture and control of active pharmaceutical ingredients (APIs) and nished pharmaceutical products. Validation of specic processes and products, for example in ster-ile product manufacture, requires much more consideratio

15、n and a detailed approach that is beyond the scope of this document. 這里給出的指導方針主要涵蓋了關于驗證的所有方面，可供GMP檢查員和生產(chǎn)商作為基本指南使用，但不可將本文視作驗證要求的專門說明文章；而應當僅將本文視為一般的指南。在遞交關于活性藥物成分（API）和藥物成品的生產(chǎn)和控制資料時，本文列出的基本原則也可作為參考。特定工藝和產(chǎn)品的驗證，如滅菌生產(chǎn)，通常需要考慮更多的方面以及詳細的方法，本文的內容不足以滿足它們的需要。2.2 There are many factors affecting the different t

16、ypes of validation and it is, therefore, not intended to dene and address all aspects related to one particular type of validation here. 驗證的類型雖然繁多，但卻有許多共同的因素能對之形成影響；因此，本文不會列舉和闡述某種特定類型的驗證的所有方面。2.3 Manufacturers should plan validation in a manner that will ensure regulatory compliance and ensuring tha

17、t product quality, safety and consis-tency are not compromised. 設計驗證時，生產(chǎn)商應當要保證驗證程序符合法規(guī)的要求，并能保證該程序能驗證產(chǎn)品的質量、安全和工藝的持續(xù)性。2.4 The general text in the main part of these guidelines may be appli-cable to validation and qualication of premises, equipment, utilities and systems, and processes and procedures.

18、More specic principles of quali-cation and validation are addressed in the appendices. Semi-automatic or fully automatic clean-in-place (CIP) systems and other special cases should be treated separately. 這里列出的指導方適用于平面布局、設備、公用工程和工用系統(tǒng)、工藝和規(guī)程的驗證和確認，更多的關于驗證和確認的專屬方法可參見附錄；半自動或全自動在線清潔（CIP）系統(tǒng)和其它特殊系統(tǒng)應當單獨對待。3.

19、 Glossary 術語The denitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. 以下是指導方針中使用的術語的定義；需注意，它們在其他文獻中出現(xiàn)時，可能有不同的含義。calibration 校準The set of operations that establish, under specied conditions, the relation-ship between values indicated by

20、 an instrument or system for measuring (for example, weight, temperature and pH), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. 在規(guī)定的條件下，

21、用來建立測量用（例如測量重量、溫度和pH值）、記錄用、控制用儀器或系統(tǒng)、及物料測量儀器測得的值與已知參照標準的相應值之間的關系的粗操作；在該項操作中，還應建立測量結果的合格限。 computer validation計算機驗證 Documented evidence which provides a high degree of assurance that a computerized system analyses, controls and records data correctly and that data processing complies with predetermine

22、d speci cations. 用以保證計算機化系統(tǒng)可提供正確的分析、控制和記錄數(shù)據(jù)及保證數(shù)據(jù)處理符合既定標準的文件證明。Commissioning試運行 The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specied in the user requirement speci-cation, and capacities as specied by the designer or developer. Commis

23、-sioning is carried out before qualication and validation. 根據(jù)用戶需求說明書所述及設計人員或研發(fā)人員的能力，用來保證設備或儀器的裝配、調整和測試符合要求，及保證設備或儀器滿足其設計和研發(fā)人員的要求的活動。試運行應先于確認和驗證執(zhí)行。concurrent validation 同步驗證Validation carried out during routine production of products intended for sale. 針對銷售產(chǎn)品的常規(guī)生產(chǎn)過程進行的驗證。cleaning validation清潔驗證 Docum

24、ented evidence to establish that cleaning procedures are remov-ing residues to predetermined levels of acceptability, taking into con-sideration factors such as batch size, dosing, toxicology and equipment size. 在考慮了批量、劑量、毒理學和設備大小因素的前提下，用以表明清潔方法去除殘余物的能力可滿足既定合格標準的文件證明。design qualication (DQ)設計確認（DQ）

25、Documented evidence that the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the re-quirements of GMP. 用以表明廠房建筑、支持系統(tǒng)、公用工程、設備和工藝的設計符合GMP要求的證明文件。good engineering practices (GEP) 工程設計規(guī)范（GEP）Established engineering methods and standards that are app

26、lied throughout the project life-cycle to deliver appropriate, cost-effective solutions. 對于項目的整個運作周期，建立了工程方法和技術標準來設計適當且又低本高效的解決方法。installation qualication (IQ) 安裝確認（IQ）The performance of tests to ensure that the installations (such as machines, measuring devices, utilities and manufacturing areas) u

27、sed in a manufactur-ing process are appropriately selected and correctly installed and operate in accordance with established speci cations. 為證明某一生產(chǎn)工藝中使用到的設備（如設備、測量儀器、公用工程和生產(chǎn)區(qū)域）的安裝地點的選擇、設備的安裝和運行達到設定的要求而進行的各種運行試驗。operational qualication (OQ)運行確認（OQ） Documented verication that the system or subsystem

28、performs as intended over all anticipated operating ranges. 為證明系統(tǒng)或系統(tǒng)的組成設備達到設定的運行要求而進行的文件化確認工作。 performance qualication (PQ) 性能確認（PQ）Documented verication that the equipment or system operates consistently and gives reproducibility within de ned specications and parameters for prolonged periods. (In

29、the context of systems, the term “process validation” may also be used.) 為證明設備或系統(tǒng)可長期實現(xiàn)設計性能的文件化確認工作，如正確運轉并表現(xiàn)出良好的再現(xiàn)性。（就系統(tǒng)而言，性能確認即“工藝驗證”。）process validation 工藝驗證Documented evidence which provides a high degree of assurance that a specic process will consistently result in a product that meets its prede

30、ter-mined specications and quality characteristics. 為證明某工藝可持續(xù)生產(chǎn)出符合既定標準且擁有規(guī)定的質量特性的產(chǎn)品的文件化工作。prospective validation 前驗證Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on t

31、he basis of past experience to determine whether they may lead to critical situations. 在生產(chǎn)工藝投入使用前的研發(fā)階段開展的驗證工作；它通常以風險分析為基礎，并被分解為單個步驟來驗證。根據(jù)過去的經(jīng)驗對前驗證進行評估，判斷該工藝是否會導致關鍵情況的出現(xiàn)。qualication 確認Action of proving and documenting that any premises, systems and equip-ment are properly installed, and/or work corre

32、ctly and lead to the expected results. Qualication is often a part (the initial stage) of validation, but the individual qualication steps alone do not constitute process validation. 為證明所有廠房建筑、系統(tǒng)和設備均正確安裝且/或正確運行，并能實現(xiàn)預期結果的文件化證明活動。確認常常是驗證的（起始階段的）一個部分，但單獨的確認步驟不是驗證。retrospective validation 回顧性驗證Involves

33、the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged. 在產(chǎn)品組成、操作規(guī)程和設備不發(fā)生改變的情況下，評估分析生產(chǎn)的歷史數(shù)據(jù)。revalidation 再驗證Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirement

34、s. 重復對獲準工藝（或工藝的某個部分）的驗證，以證實已驗證狀態(tài)沒有發(fā)生漂移、工藝依然符合既定要求。standard operating procedure (SOP) 標準操作規(guī)程（SOP）An authorized written procedure giving instructions for performing opera-tions not necessarily specic to a given product or material but of a more general nature (e.g. equipment operation, maintenance and

35、 cleaning; vali-dation; cleaning of premises and environmental control; sampling and in-spection). Certain SOPs may be used to supplement product-speci c master batch production documentation. 具有約束力的書面規(guī)程，它描述了如何進行操作。標準操作規(guī)程所針對的內容廣泛，其中包括但不限于給定的產(chǎn)品或物料（還可用來說明如設備的操作、維護和清潔；驗證；廠房建筑的清潔和環(huán)境控制；取樣和檢查等）。某些特定的SOP可視

36、為某些產(chǎn)品專屬的批生產(chǎn)主文件的補充部分。validation 驗證Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results. 為證明工藝、程序或方法在實際使用中能持續(xù)實現(xiàn)預期結果的文件化證明活動。validation protocol (or plan) (VP) 驗證方案（或計劃）（VP）A document describing the activities to be performed in

37、 a validation, in-cluding the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use. 一個闡述如何進行對常規(guī)生產(chǎn)工藝或生產(chǎn)工藝的一部分進行驗證并確定其驗證合格標準的文件。validation report (VR)驗證報告（VR） A document in which the records, results and evaluation of a completed validation programme are as

38、sembled and summarized. It may also contain proposals for the improvement of processes and/or equipment. 已完成的驗證方案的記錄、結果和評估文件。它常常包括工藝和/或設備的改進措施的內容。validation master plan (VMP) 驗證主計劃（VMP）The VMP is a high-level document that establishes an umbrella validation plan for the entire project and summarizes

39、 the manufacturers overall phi-losophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturers validation work programme and denes details of and timescales for the validation work to be performed, including a statement of the responsibilities of

40、those implementing the plan. VMP是整個項目工程的驗證計劃的概述文件，它總結了生產(chǎn)商采用的所有方法，可用來證明性能的完備能力。驗證主計劃里有關于生產(chǎn)商的驗證計劃的資料，待執(zhí)行的驗證工作的時間表，還包括執(zhí)行驗證計劃的人員的職責。verication核查The application of methods, procedures, tests and other evaluations, in ad-dition to monitoring, to determine compliance with the GMP principles. 為檢查GMP條例的落實力度，

41、而使用的除監(jiān)控之外的方法、程序、試驗和其它評估分析措施。worst case 最差狀況A condition or set of conditions encompassing the upper and lower processing limits for operating parameters and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared to ideal con-ditions. Such conditions do

42、not necessarily include product or process failure. 系指導致產(chǎn)品或工藝失敗的概率高于正常運行工藝的某個條件或一組條件（包括SOP中規(guī)定的運行參數(shù)和狀態(tài)的上限和下限），這些狀況不一定包括產(chǎn)品或工藝的失敗。4. Relationship between validation and quali cation 驗證和確認之間的聯(lián)系Validation and qualication are essentially components of the same concept. The term qualication is normally use

43、d for equipment, utilities and systems, and validation for processes. In this sense, qualication is part of validation. 驗證和確認系同一概念的基本組成部分，即是說它們是同義詞。“確認”這個詞往往用在設備、公用工程和系統(tǒng)以及工藝驗證中；在這層意義上，確認是驗證的一部分。5. Validation 驗證5.1 Approaches to validation 驗證方法5.1.1 There are two basic approaches to validation one ba

44、sed on evi-dence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retro-spective validation is no longer encouraged and is, in any case,

45、 not appli-cable to the manufacturing of sterile products. 驗證有兩種基本方法其一是以試驗（前驗證和同步驗證）獲取的證據(jù)為基礎，另一種則以積累的（歷史）數(shù)據(jù)（回顧性驗證）為基礎。驗證時，應當盡可能的使用前驗證，而不鼓勵執(zhí)行回顧性驗證；要特別指出的是，無論何時，回顧性驗證都不適用于無菌產(chǎn)品的生產(chǎn)。5.1.2 Both prospective and concurrent validation, may include: 前驗證和同步驗證可能包括的內容如下：l extensive product testing, which may inv

46、olve extensive sample testing (with the estimation of condence limits for individual results) and the demonstration of intra- and inter-batch homogeneity; 大量產(chǎn)品測試，包括大量的樣品測試（以及單個結果的置信限的評估）和批間及批內均一性的證明；l simulation process trials; 模擬生產(chǎn)試驗；l challenge/worst case tests, which determine the robustness of t

47、he process; and 挑戰(zhàn)性/最差狀況試驗，以證明工藝的耐用性；以及l(fā) control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process. 監(jiān)控正常運行的生產(chǎn)過程的工藝參數(shù)的控制措施，以獲取可證明該工藝的可靠性的資料。5.2 Scope of validation 驗證范圍5.2.1 There should be an appropriate and sufcien

48、t system including organizational structure and documentation infrastructure, sufcient personnel and nancial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved. 為了及時執(zhí)行驗證工作，應當建立一個適當且能滿足需要的系統(tǒng)，包括組織機構和文件管理的下層組織結構、充足的人力和財政

49、資源，同時還應指定質量保證的管理和責任人。5.2.2 Personnel with appropriate qualications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed. 執(zhí)行驗證工作的人員應當具備相應的資格和經(jīng)驗，并對驗證負責。根據(jù)待執(zhí)行的驗證工作的需要，決定由哪些部門的人員參與驗證工作的執(zhí)行。5.2.3 There

50、should be proper preparation and planning before validation is performed. There should be a specic programme for validation activities. 執(zhí)行驗證之前，應有充分的準備和計劃。應針對具體的驗證活動，制訂專門的計劃。5.2.4 Validation should be performed in a structured way according to the documented procedures and protocols. 應根據(jù)成文的程序和方案，以設計好

51、的方式執(zhí)行驗證工作。5.2.5 Validation should be performed: 驗證應： for new premises, equipment, utilities and systems, and processes and procedures; 在新的廠房建筑、設備、公用工程和系統(tǒng)、工藝和方法上執(zhí)行； at periodic intervals; and 定期執(zhí)行； when major changes have been made. 在發(fā)生了重大變更后執(zhí)行。(Periodic revalidation or periodic requalication may be

52、substituted, where appropriate, with periodic evaluation of data and information to establish whether requalication or revalidation is required.) （在適當?shù)那闆r下，可用數(shù)據(jù)和資料的定期評估代替定期再驗證或定期再確認，以確定是否需要進行再驗證或再確認。）5.2.6 Validation should be performed in accordance with written protocols. A written report on the ou

53、tcome of the validation should be produced. 應根據(jù)書面方案執(zhí)行驗證。驗證的結果應當以書面報告的形式給出。5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demon-strate consistency. Worst case situations should be considered. 驗證項目的執(zhí)行時間的設定應

54、能證明驗證對象的持續(xù)性。如驗證應當至少在三個連續(xù)批上開展（生產(chǎn)規(guī)模）。驗證時，要考慮最差狀況。5.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specications and methods devised during the develop-ment phase. Their objective is to

55、monitor the process continuously. 過程控制和驗證之間應有明顯的區(qū)別。為監(jiān)測工藝的連續(xù)性，應根據(jù)針對研發(fā)階段設計的技術標準和方法，開展每批產(chǎn)品生產(chǎn)的過程測試。5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The dened process, using the materials and equipment speci ed, shou

56、ld be shown to result in the consistent yield of a product of the required quality. 采用新的生產(chǎn)配方或方法時，應證明它們對常規(guī)工藝的適應性。驗證時，應使用規(guī)定的物料和設備，運行既定的工藝，持續(xù)得到的產(chǎn)品質量應符合要求。5.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled.

57、Signicant changes to the facilities or the equipment, and processes that 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 required. 生產(chǎn)商需明白為了證明他們的操作的關鍵問題得到了合理的控制，應采取哪些驗證工作。比如，對產(chǎn)品質量可能產(chǎn)生影響的廠房設施、設備和工藝的重大變更是需要驗證的。為確定需要開展的驗證的范圍和驗證的程度，可使用風險評估的方法。1 6. Qualication 確認6.1 Qualication should be completed before process validation is per-formed. The process of qualication should be a logical, systematic