who驗證指南2016年版.docx

1. INTRODUCTION 簡介1.1 Validation is an essential part of good practices including good manufacturing practices (GMP) (4) and good clinical practices (GCP). It is therefore an element of the pharmaceutical quality system. Validation, as a concept, incorporates qualification and should be applied over the life cycle of, e.g. the applicable product, process, system, equipment or utility. 驗證是包括GMP和GCP在內(nèi)的良好規(guī)范的必要部分。因此是制藥質(zhì)量體系的組成部分。驗證這個概念包括確認并且應該在產(chǎn)品、工藝、系統(tǒng)、設備或設施的整個生命周期中被使用。1.2 These guidelines cover the general principles of validation and qualification. In addition to the main part, appendices on validation and qualification (e.g. cleaning, computer and computerized systems, equipment, utilities and systems, and analytical methods) are included.這個指南包括驗證和確認的一般原則。除了主體部分外，還包括確認和驗證附件（如清潔、計算機和計算機化系統(tǒng)、設備、設施和系統(tǒng)以及分析方法）。1.3 The following principles apply: 適用的原則如下: the execution of validation should be in compliance with regulatory expectations; 驗證的執(zhí)行應該符合監(jiān)管預期 quality, safety and efcacy must be designed and built into the product; 質(zhì)量、安全和效力應該被設計和構建到產(chǎn)品中 quality cannot be inspected or tested into the product; 質(zhì)量不能通過檢查或測試賦予產(chǎn)品 quality risk management principles should be applied in determining the need, scope and extent of validation; 應該應用質(zhì)量風險管理規(guī)則來決定驗證的需求、范圍和程度 ongoing review should take place to ensure that the validated state is maintained and opportunities for continuing improvement are identified.應該進行持續(xù)的回顧來確保維持驗證狀態(tài)并識別持續(xù)改進的機會1.4 The implementation of validation work requires considerable resources such as: 驗證工作的完成需要大量資源，例如 time: generally validation work is subject to rigorous time schedules; 時間：一般驗證工作需要有一個嚴密的時間表 financial: validation often requires the time of specialized personnel and expensive technology. 資金：驗證經(jīng)常需要專業(yè)人員和昂貴的技術 human: validation requires the collaboration of experts from various disciplines (e.g. a multidisciplinary team, comprising quality assurance, engineering, information technology, manufacturing and other disciplines, as appropriate.).人員：驗證需要不同學科專家的協(xié)作（例如一個多學科小組，視情況可能包括QA、工程、信息技術、生產(chǎn)以及其他學科人員）2. SCOPE 范圍2.1 These guidelines focus mainly on the overall concept of validation and are not intended to be prescriptive in specific validation requirements. This document serves as general guidance only and the principles may be considered useful in its application in the manufacture and control of starting materials and finished pharmaceutical products (FPPs), as well as other areas. Validation of specific processes and systems, for example, in sterile product manufacture, requires much more consideration and a detailed approach that is beyond the scope of this document. 這些指南主要關注驗證的整體概念，無意規(guī)定具體的驗證要求。用作GMP檢查官和生產(chǎn)商的基本指南， 本文件僅作為一個一般指南，其原則在其應用于起始物料及制劑的生產(chǎn)和控制時會比較有用，也應用于其他領域。特定工藝和產(chǎn)品的驗證，例如無菌產(chǎn)品生產(chǎn)，需要考慮更多內(nèi)容，和更詳細的方法，不在本文件范圍之內(nèi)。2.2 There are many factors affecting the different types of validation and it is, therefore, not intended to define and address all aspects related to one particular type of validation here.有很多因素會對不同類型的驗證產(chǎn)生影響，因此，這里不會對某個特定類型的驗證相關的所有方面進行定義和說明。2.3 The general text in the main part of these guidelines may be applicable to validation and qualification of premises, equipment, utilities, systems, processes and procedures.這些指南的主體部分的一般內(nèi)容可能適用于設施、設備、公用設施和系統(tǒng)、工藝和程序的驗證和確認。3. GLOSSARY 術語The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.本指南使用的術語定義如下。它們在其它環(huán)境中可能有不同的含義calibration. The set of operations that establish, under specified conditions, the relationship between values indicated by 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.校準：change control (including change management). A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state (reference working document QAS/15.639/Rev.1 - unpublished).變更控制（包括變更管理）cleaning validation. Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.清潔驗證commissioning. The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation.試車computer validation (including computerized system validation). Confirmation by examination and provision of objective documented evidence that computerized system specifications conform to user needs and intended uses, and that all requirements can be consistently fulfilled.計算機驗證（包括計算機化系統(tǒng)驗證）concurrent validation. Validation carried out during routine production of products intended for sale.同步驗證design qualification. Documented verification that the proposed design of facilities, systems and equipment is suitable for the intended purpose.設計確認good engineering practices. Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions.良好工程規(guī)范installation qualification. Documented verification that the installations (such as machines, computer system components, measuring devices, utilities and manufacturing areas) used in a processor system are appropriately selected and correctly installed in accordance with established specifications.安裝確認operational qualification. Documented verification that the system or subsystem operates as intended over all anticipated operating ranges.運行確認performance qualification. Documented verification that the equipment or system performs consistently and reproducibly within defined specifications and parameters in its normal operating environment (i.e. in the production environment). (In the context of systems, the term “process validation” may also be used.)性能確認process validation. The collection and evaluation of data, throughout the product life cycle, which provides documented scientific evidence that a process is capable of consistently delivering quality products.工藝驗證prospective validation. 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 the basis of past experience to determine whether they may lead to critical situations.前驗證qualification. Documented evidence that premises, systems or equipment are able to achieve the predetermined specifications properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation.確認revalidation. Repeated validation of a previously validated system (or a part thereof) to ensure continued compliance with established requirements.再驗證：對先前已驗證的系統(tǒng)（或它的一部分）的重復驗證來確保持續(xù)符合既定標準。standard operating procedure. An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain standard operating procedures may be used to supplement product-specific master batch production documentation.標準操作規(guī)程validation. Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results.驗證validation master plan. The validation master plan is a high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturers overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturers validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan.驗證主計劃validation protocol. A document describing the activities to be performed during a validation, including the acceptance criteria for the approval of a process or system or a part thereof for intended use.驗證方案validation report. A document in which the records, results and evaluation of validation are assembled and summarized. It may also contain proposals for the improvement of processes and/or systems and/or equipment.驗證報告verification. The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with established requirements and specifications.核實worst case. 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 conditions. Such conditions do not necessarily include product or process failure.最差條件4. RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATION 驗證與確認的關系4.1 Qualification and validation are essentially the same. The term qualication is normally used for equipment and utilities, and validation for systems and processes. In this sense, qualication can be seen as part of validation. 確認和驗證本質(zhì)上是一樣的。確認通常用于設備和設施，而驗證則用于系統(tǒng)和工藝。在這層意義上，確認可以被看做是驗證的一部分。4.2 Where the term “validation” is used in the document, the same principles may be applicable for “qualification在文件中使用術語“驗證”的規(guī)則同樣適用于“確認”5. VALIDATION驗證Approaches to validation驗證的方法5.1 Manufacturers should organize and plan validation in a manner that will ensure product quality, safety and efficacy throughout its life cycle. 生產(chǎn)商應該組織和計劃驗證以保證產(chǎn)品在其生命周期內(nèi)的質(zhì)量、安全和有效。5.2 The scope and extent of qualification and validation should be based on risk management principles. 確認和驗證的范圍和程度應該基于風險管理規(guī)則。5.3 Statistical calculations should be applied, where appropriate, and provide scientific evidence that the process, system or other related aspect is appropriately validated. 適當時，應該使用統(tǒng)計學計算并提供工藝、系統(tǒng)或其它相關方面有效的科學證據(jù)5.4 Qualification and validation should be done in accordance with predetermined protocols, and the results appropriately documented, e.g. in reports. 確認和驗證應該按照預定的方案執(zhí)行并且結果應被適當?shù)挠涗洠缭趫蟾嬷小?.5 There should be an appropriate and effective quality system ensuring the organization and management of validation. 應有適當?shù)暮陀行У馁|(zhì)量體系來保證驗證的組織和管理。5.6 Senior management should ensure that there are sufficient resources to perform validation in a timely manner. Management and persons responsible for quality assurance should be actively involved in the process and authorization of protocols and reports. 高級管理層應該確保充分的資源來及時地執(zhí)行驗證。管理層和質(zhì)量保證負責人應該積極參與方案和報告的批準活動中。5.7 Personnel with appropriate qualification and experience should be responsible for performing validation. 有適當資質(zhì)和經(jīng)驗的人員應該對驗證的執(zhí)行負責。5.8 There should be a specific programme or schedule to support planning and execution of validation activities. 應有專門的計劃或時間表來支持計劃和執(zhí)行驗證活動。5.9 Validation should be performed in a structured way according to the documented protocols and procedures. 驗證應該按照文件化的方案和規(guī)程以一種有組織的方式執(zhí)行。5.10 Qualification and validation should be performed: 確認和驗證應該被執(zhí)行： for new premises, equipment, utilities and systems, and processes and procedures; 新設施、設備、公用設施和系統(tǒng)，以及新的工藝和程序； when changes are made, depending on the outcome of risk assessment; 當發(fā)生變更時，根據(jù)風險評估的結果； where necessary or indicated based on the outcome of periodic review. 基于定期回顧的結果表明需要的5.11 A written report on the outcome of the validation should be prepared. 應該對驗證的結果準備一份書面報告。5.12 The scope and extent of validation should be based on knowledge and experience, and the outcome of quality risk management principles as described in the World Health Organization (WHO) guidelines on quality risk management. Where necessary worst-case situations or specific challenge tests should be considered for inclusion in the validation, for example, stress load and volume verification in computer system validation.驗證的范圍和程度應該基于知識和經(jīng)驗，以及描述于WHO質(zhì)量風險管理指南中的質(zhì)量風險管理管理規(guī)則的結果來決定。6. DOCUMENTATION 文件6.1 -Qualification and validation should be done according to written procedures. 確認和驗證應該按照書面程序執(zhí)行6.2 Documents associated with qualification and validation include: 與確認和驗證相關的文件包括： validation master plan (VMP); 驗證主計劃（VMP） standard operating procedures (SOPs); 標準操作規(guī)程（SOP） specifications;規(guī)范 protocols and reports;方案和報告 risk assessment outcomes; 風險管理結果 process flow charts; 工藝流程圖 operator manuals; 操作手冊 training records; 培訓記錄 calibration procedures and records; 校準規(guī)程和記錄 sampling plans; 取樣計劃 testing plans and methods; 測試計劃和方法 statistical methods and results; 統(tǒng)計學方法和結果 history of qualification or validation; 確認或驗證歷史 plan for ensuring review of validation status; 確保回顧驗證狀態(tài)的計劃 plan for ensuring maintaining a validated state.確保維持驗證狀態(tài)的計劃7. VALIDATION MASTER PLAN 驗證主計劃7.1 A manufacturer should have a VMP which reflects the key elements of validation. It should be concise and clear and contain at least the following: 生產(chǎn)商應有一份VMP反映驗證的關鍵要素。它應該簡潔清晰并至少包括： title page and authorization (approval signatures and dates); 書名頁和批準（批準簽名和日期） table of contents; 目錄 abbreviations and glossary; 縮寫和術語 validation policy; 驗證方針 philosophy, intention and approach to validation; 驗證的原理、目的和方法 roles and responsibilities of relevant personnel; 相關人員的角色和責任 resources to ensure validation is done; 確保驗證執(zhí)行的資源 outsourced services (selection, qualification, management through life cycle); 外包服務（選擇、確認和生命周期管理） deviation management in validation; 驗證偏差管理 change control in validation; 驗證變更控制 risk management principles in validation; 驗證風險管理規(guī)則 training; 培訓 scope of validation; 驗證的范圍 documentation required in qualification and validation such as procedures, certificates, protocols and reports; 確認和驗證所需的文件，如規(guī)程、證書、方案和報告 premises qualification; 設施確認 utilities qualification; 公用設施確認 equipment qualification; 設備確認 process validation;工藝驗證 cleaning validation; 清潔驗證 personnel qualification such as analyst qualification;人員確認例如分析人員確認 analytical method validation; 分析方法驗證 computerized system validation; 計算機化系統(tǒng)驗證 establishing acceptance criteria; 建立接受標準 life-cycle management including retirement policy; 生命周期管理包括退役的方針 requalification and revalidation; 再確認和再驗證 relationship with other quality management elements; 與其他質(zhì)量管理要素的關系 validation matrix; 驗證矩陣 references.參考文獻7.2 The VMP should be reviewed at regular intervals and kept up to date according to current GMP.VMP應該每隔一段時間回顧并保持持續(xù)符合現(xiàn)行GMP8. QUALIFICATION AND VALIDATION PROTOCOLS 確認和驗證方案8.1 There should be qualification and validation protocols describing the qualification and validation to be performed. 應有確認和驗證方案描述所要執(zhí)行的確認和驗證。8.2 As a minimum the protocols should include the following significant background information:方案應該至少包括下列重要的背景信息： the objectives; 目的 the site; 場所 the responsible personnel 負責的人員 description of the standard operating procedures (SOPs) to be followed; 所遵循的標準操作規(guī)程描述 equipment or instruments to be used; 所使用的設備或儀器 standards and criteria as appropriate; 適當?shù)臉藴?the stage of validation or qualification; 驗證或確認的階段 the processes and/or parameters; 工藝和/或參數(shù) sampling, testing and monitoring requirements; 取樣，測試和監(jiān)測需求 stress testing where appropriate; 壓力測試（如適用） calibration requirements; 校準需求 predetermined acceptance criteria for drawing conclusions; 預定的用于下定結論的接受標準 review and interpretation of results; 結果的審核和分析 change control, deviations; 變更控制、偏差 archiving and retention. 歸檔和保留8.3 There should be a description of the way in which the results will be analysed, including statistical analysis where appropriate. 應有一個結果分析方法，包括統(tǒng)計學分析（如使用）的描述8.4 The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change.方案應該在使用前被批準。方案的任何變更應在實施前被批準。9. QUALIFICATION AND VALIDATION REPORTS 確認和驗證報告9.1 There should be written reports on the qualification and validation performed. 應有所執(zhí)行的確認和驗證的書面報告9.2 Reports should reflect the protocols and procedures followed and include at least the title and objective of the study; make reference to the protocol; reference to the appropriate risk assessment; details of materials, equipment, programmes and cycles used; procedures and test methods with appropriate traceability. 報告應該反映所遵循的方案和規(guī)程并至少包括題目和目的；方案的參考；適當?shù)娘L險評估的參考；所使用的材料、設備、計劃和周期的描述；適當?shù)囊?guī)程和測試方法追溯9.3 Results should be recorded and be in compliance with good data and record management practices. 應該記錄結果并符合良好數(shù)據(jù)和記錄管理規(guī)范。9.4 Results should be reviewed, analysed and compared against the justified predetermined acceptance criteria, interpreted and statistically analysed where appropriate. 結果應該被回顧、分析并與預定的接受標準比較，解釋和統(tǒng)計學分析（如適用）9.5 Results should meet the acceptance criteria. Deviations, out-of- specification and out-of-limit results should be documented and investigated according to appropriate procedures. If these deviations are accepted, this should be justified. Where necessary, further studies should be performed. 結果應該符合接受標準。偏差、OOS和超限結果應該按照適當?shù)某绦蛴涗浐驼{(diào)查。如接受這些偏差，應有正當理由。必要時，應進行更進一步的研究。9.6 The conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful, and s