近日，WHO發(fā)布了Working document QAS/20.865 《研發(fā)設施GxP規(guī)范》，現(xiàn)將翻譯版發(fā)給大家，如下：
Workingdocument QAS/20.865
November2020
Good practices for research and development facilities
研發(fā)設施GxP規(guī)范
1. Introductionand background
介紹和背景
2. Scope
范圍
3. Qualitymanagement
質量管理
4. Qualityrisk management
質量風險管理
5. Sanitationand hygiene
清潔衛(wèi)生
6. Qualificationand validation
確認與驗證
7. Outsourcedactivities
外包活動
8. Self-inspectionand quality audits
自檢和質量審計
9. Personnel
人員
10. Training
培訓
11. Premises
廠房
12. Equipmentand instruments
設備和儀器
13. Materials
物料
14. Documentation
文件記錄
15. Processingand process validation
工藝和工藝驗證
16. Qualitycontrol
質量控制
17. Stabilitystudies
穩(wěn)定性研究
18. Analyticalprocedure development
分析方法開發(fā)
19. Transferof technology
技術轉移
20. Lifecycle approach
生命周期方法
21. Cleaningprocedure development and cleaning validation
清潔程序開發(fā)和清潔驗證
Glossary
術語
Abbreviations
縮寫
References
參考文獻
Further reading
拓展閱讀
1. Background
背景
In view of the recent need for the unprecedentedfast development of health products for the treatment of COVID-19 therapies,the World Health Organization (WHO) Prequalification Inspection Services Team(PQT INS) raised the urgency for the development of good manufacturing practice(GMP) text to address the manufacturing of developmental batches, pilot batchesand the sequential stability data that is submitted in product applications(dossiers) for marketing authorization and the prequalification of medicalproducts.
鑒于最近醫(yī)藥產品治療COVID-19的前所未有的快速發(fā)展的需要，世界衛(wèi)生組織(WHO)預確認檢查服務團隊(PQT INS)提出了發(fā)展的緊迫性良好生產規(guī)范(GMP)文本解決發(fā)展的生產批次,為上市批準和醫(yī)藥產品預確認而提交的產品申請(檔案)中的中試批次和序列穩(wěn)定性數(shù)據(jù)。
There are currently no regulatory guidelines whichaddress this matter, although the data collected from these batches influencethe following aspects of the product:
目前還沒有針對這一問題的監(jiān)管指南，盡管從這些批次收集的數(shù)據(jù)影響了產品的以下方面:
stability
穩(wěn)定性
processvalidation; and
工藝驗證
analyticalmethod development and validation
分析方法開發(fā)和驗證
2. Introduction
介紹
2.1. The modern era of the pharmaceutical industry, inparticular focusing on chemicalsynthesis,began in the 19th century. The use of computerized systems inproduction and control is increasing rapidly. The ongoing evolution andadvancement in the pharmaceutical industry is fundamental in the control andelimination of disease around the world.
現(xiàn)代制藥業(yè)開始于19世紀，尤其是化學合成。計算機化系統(tǒng)在生產和控制方面的使用正在迅速增加。制藥工業(yè)的不斷發(fā)展和進步是全世界控制和消除疾病的基礎。
2.2. With an ever increasing awareness of the risks inpharmaceutical production and control, and the life cycle approaches beingfollowed, more and more emphasis is being placed on ensuring that the researchand development of products are appropriately controlled and documented.
隨著人們對藥品生產和控制的風險的認識不斷增強，以及對生命周期方法的遵循，人們越來越重視確保產品的研究和開發(fā)得到適當?shù)目刂坪陀涗洝?/span>
2.3. Furthermore,as regulators request and review data and information such as the developmentdata of products and processes, design of experiments, validation and stabilityresults, it has become necessary to ensure that the facilities, qualitysystems, data and information meet the appropriate standards and goodpractices.
此外，由于監(jiān)管機構要求并審查數(shù)據(jù)和信息，如產品和工藝的開發(fā)數(shù)據(jù)、實驗設計、驗證和穩(wěn)定性結果，因此有必要確保設施、質量體系、數(shù)據(jù)和信息符合適當?shù)臉藴屎土己靡?guī)范。
2.4. Thisdocument intends to provide guidance on GMP to research and developmentfacilities. It further aims to ensure that the correct systems are followed,ensuring appropriateness, reliability and the quality of products, processes,procedures and data. It further helps to help ensure that products meet therequirements for safety, efficacy and quality that they purport to possess.
本文件旨在為研發(fā)機構提供GMP方面的指導。它的進一步目標是確保遵循正確的系統(tǒng)，確保產品、工藝、程序和數(shù)據(jù)的適當性、可靠性和質量。它還有助于確保產品符合其聲稱擁有的安全、功效和質量要求。
2.5. In additionto product development, other activities including the production ofinvestigational products and pilot scale batches; process validation; cleaningprocedure development; cleaning validation studies; as well as stabilitystudies, are often undertaken in such facilities.
除產品開發(fā)外，其他活動包括試驗產品和中試批的生產；工藝驗證；清潔程序開發(fā)；清潔驗證研究；以及穩(wěn)定性研究，通常也在這些設施中進行。
2.6. The WHOdocument titled Good manufacturingpractices for investigational pharmaceutical products for clinical trials in humans (1) specifically addressesthe requirements and recommendationsfor products used in clinical trials. Other WHO guidelines address specificrequirements and recommendations including but not limited to stabilitytesting, analytical method validation, cleaning validation and the transfer oftechnology (TOT). (See the Referencesand Further Reading sections).
WHO題為《人用臨床試驗用藥良好生產規(guī)范》的文件(1)專門闡述了用于臨床試驗的產品的要求和建議。WHO的其他指南提供了，包括但不限于穩(wěn)定性測試、分析方法驗證、清潔驗證和技術轉移的具體要求和建議（參見參考文獻和拓展閱讀)。
2.7. Thisdocument should be read in conjunction with other WHO GMP guidelines, asreferenced in the document (2-9). Other documents of interest are also listedunder the section “Further reading”.
本文件應與參考文獻(2-9)中的其他WHO GMP指南一起閱讀。其他相關的文件也列在“拓展閱讀”一節(jié)中。
3. Scope
范圍
3.1. Thisguideline is applicable to research and development facilities of productsmanufactured by chemical synthesis, extraction, cell culture or fermentation,by recovery from natural sources, or by any combination of these processes. Itfurther covers development of procedures and processes intended for transferand use in marketing authorization applications, process validation, TOT (10)-relatedactivities, validation (7), quality control laboratory activities (11), such asstability testing and development, and validation of cleaning procedures (see Figure 1 and section 4 below).
本指南適用于通過化學合成、提取、細胞培養(yǎng)或發(fā)酵、從自然資源中回收或通過這些工藝的任何組合生產的產品的研究和開發(fā)設施。包括用于轉移的程序和工藝的開發(fā)，以及用于上市許可申請、工藝驗證、TOT（技術轉移）(10)相關活動、驗證(7)、質量控制實驗室活動(11)（如穩(wěn)定性測試和開發(fā)），以及清潔程序驗證的程序和工藝的開發(fā)(見圖1和下面的第4節(jié))。
3.2. This guideexcludes all vaccines, whole cells, whole blood and plasma, blood and plasmaderivatives (plasma fractionation), medical gases, commercial products,radiopharmaceuticals and gene therapy products.
本指南不包括所有疫苗、全細胞、全血和血漿、血液和血漿衍生物(血漿分離物)、醫(yī)用氣體、商業(yè)產品、放射性藥物和基因治療產品。
3.3. The goodpractices outlined below are to be considered general guides and they may beadapted to meet individual needs. The equivalence of alternative approaches,however, should be proven.
以下概述的良好做法將被視為一般指南，并可加以修改以滿足個別需要。但是，替代方法的等效性應以證明。
3.4. In thisguide, the term “should” indicates recommendations that are expected to applyunless shown to be inapplicable or replaced by an alternative demonstrated toprovide an acceptable level of control.
在本指南中，“應”一詞表示除非被證明不適用或被證明能提供可接受控制水平的替代方案所取代，否則應適用的建議。
3.5. This guide,as a whole, does not cover safety aspects for the personnel engaged in theresearch and development nor the aspects of protection of the environment. Thesecontrols are inherent responsibilities of the manufacturer and are governed bynational laws
總體上，本指南不包括從事研發(fā)的人員的安全方面，也不包括環(huán)境保護方面。這些控制是制造商固有的責任，受國家法律管轄。
3.6. This guideis not intended to define registration requirements or modify pharmacopoeialrequirements or other guideline recommendations. For details on processdevelopment, it is recommended that other guidelines, such as those publishedby The International Council for Harmonisation of Technical Requirements forPharmaceuticals for Human Use (ICH), be read in conjunction with this document.
本指南無意規(guī)定注冊要求或修改藥典要求或其他指南建議。關于工藝開發(fā)的細節(jié)，建議其他指南，如ICH指南，與本文件一起閱讀。
3.7. This guidedoes not affect the ability of the responsible regulatory agency to establishspecific registration or filing requirements. All commitments in registrationand filing documents must be met. This document provides information toconsider for a risk- and science-based approach in the research and developmentof medical products.
本指南不會影響負責監(jiān)管機構制定具體注冊或備案要求的能力。必須遵守注冊備案文件中的各項承諾。本文件就在醫(yī)藥產品研究和開發(fā)中采用基于風險和科學的方法提供考量信息。
3.8. The mainfocus of the document is on pharmaceutical formulation and development. Theprinciples described in this document may however be applied in facilitieswhere other products such as vaccines, veterinary products andbiopharmaceutical products are developed. The principles may also beconsidered, where appropriate, in facilities where medical devices aremanufactured.
本文件主要關注藥物制劑和開發(fā)。然而，本文件中描述的原則可能適用于其他產品(如疫苗、獸藥產品和生物制藥產品)開發(fā)的設施。在適當?shù)那闆r下，生產醫(yī)療器械的設施也可以考慮這些原則。
3.9. Due to thenature of research work, and an increasing expectation for compliance withstandards in manufacture, the guidance in this document would normally be appliedbased on risk assessment, in an increasing manner, from research to commercialbatch manufacturing. The stringency of GMP in research and development shouldincrease as the process proceeds from early research work to the final steps ofdevelopment and formulation, stability testing, process validation and cleaningvalidation.
由于研究工作的性質，以及對生產合規(guī)的期望越來越高，本文件中的指南通?；陲L險評估進行應用，以越來越多的方式，從研發(fā)到商業(yè)生產。從前期研究工作到開發(fā)、制劑、穩(wěn)定性測試、工藝驗證、清潔驗證等最后階段，研發(fā)過程中GMP的嚴格程度不斷提高。
Figure 1.Application of this guide
圖1. 本指南應用
*The principles described in this guideline areapplied, based on risk management principles, in an increased manner from earlyresearch to development to registration batches
*本指南中所描述的原則基于風險管理原則，從前期研究到開發(fā)再到注冊批次，應用方式不斷增加
4. Quality management
質量管理
4.1. Thereshould be a quality management system encompassing adequate resources, awritten organizational structure and procedures to follow.
應有一個包含足夠資源的質量管理體系，一個書面的組織結構和可遵循的程序。
4.2. The necessary resources should include, for example:
需要的資源應包括，例如：
a) asufficient number of appropriately qualified, trained personnel;
足夠數(shù)量的經適當確認、培訓的人員
b) adequatepremises and space;
足夠的廠房和空間
c) suitableequipment and services;
合適的設備和服務
d) appropriatematerials, containers and labels; and
適當?shù)奈锪?、容器和標?/span>
e) suitablestorage and transport.
適當?shù)膬Υ婧瓦\輸
4.3. Roles, responsibilities and authorities should be defined,communicated and implemented.
角色、職責和權限應明確、溝通和實施
4.4. The qualitysystem should facilitate innovation and continual improvement and strengthenthe link between pharmaceutical development and manufacturing activities.
質量體系應促進創(chuàng)新和持續(xù)改進，并加強制藥開發(fā)和生產活動之間的聯(lián)系。
4.5. All partsof the quality system should be adequately resourced and maintained, includingwith sufficient competent personnel, suitable premises, equipment andfacilities.
質量體系的所有部分都應有充足的資源和維護，包括有足夠能力的人員、適當?shù)膱鏊⒃O備和設施。
4.6. Initialresearch, as well as development activities, should be defined and documented.The detail should be in accordance with risk assessment and the increasingscale of GMP requirements from early to final stages of development.
最初的研究，以及開發(fā)活動，應予以定義和記錄。其詳細程度應與風險評估和從開發(fā)早期到最后階段不斷增長的GMP要求相一致。
4.7. The qualitysystem should ensure, as applicable and according to the stage of research anddevelopment, that:
質量體系應根據(jù)研發(fā)的階段，在適用時確保:
a) managerialresponsibilities are clearly specified in job descriptions;
在工作說明書中明確規(guī)定管理職責;
b) instructionsand procedures are written in clear and unambiguous language;
說明和程序以清晰和明確的語言編寫;
c) proceduresare correctly carried out;
程序得到正確地執(zhí)行
d) records aremade (manually and/or by recording instruments) during production and qualitycontrol;
在生產和質量控制過程中進行記錄(人工和/或使用記錄儀器);
e) anysignificant deviations are recorded, investigated and the appropriate actiontaken;
任何重大偏差均得到記錄、調查，并采取適當行動;
f) records aremaintained;
記錄得到保存
g) there is asystem for quality risk management (QRM);
具備質量風險管理的體系
h) arrangementsare made for the manufacture, supply and use of the correct starting andpackaging materials;
對正確的起始材料和包裝材料的制造、供應和使用作出安排;
i) allnecessary controls on starting materials, intermediate products, bulk productsand other in-process controls are carried out;
對起始物料、中間產品、待包裝產品和其他工藝控制進行了所有必要的控制;
j) calibrationsand validations are carried out where appropriate;
進行了適當?shù)男屎万炞C;
k) the productand process knowledge is managed;
產品和工藝知識得到管理
l) productsare designed and developed in accordance with applicable good practices (GxP);
產品根據(jù)適當?shù)牧己靡?guī)范（GxP）進行設計和開發(fā)；
m) production and control operationsare clearly specified in written form;
生產和控制操作以書面的形式進行了明確的規(guī)定
n) continualimprovement is facilitated through the implementation of quality improvementsappropriate to the current level of process and product knowledge;
推行與現(xiàn)行工藝及產品知識水平相適應的質量改善，以促進持續(xù)改善;
o) productrealization is achieved;
產品得到實現(xiàn)
p) cleaningprocedures are developed and validated;
清潔程序得到開發(fā)并驗證
q) stabilitytesting is done following written procedures and protocols; and
根據(jù)書面的程序和方案進行了穩(wěn)定性測試
r) data meetALCOA+ requirements.
數(shù)據(jù)符合ALCOA+要求
4.8. There should be periodic management reviewwith the involvement of senior management.
應定期進行管理評審，并由高級管理人員參與。
5. Quality risk management
質量風險管理
5.1. A system ofquality risk management (QRM) should be implemented. The system should ensurethat risks are identified based on scientific knowledge and experience. Theappropriate controls should be identified and implemented to mitigate risks.
應實施質量風險管理體系(QRM)。系統(tǒng)應確保風險根據(jù)科學知識和經驗得到識別。應建立并實施適當?shù)目刂?，以減輕風險。
5.2. The levelof effort, formality and documentation of the QRM process is commensurate withthe level of risk and the stage from research to development, to commercialbatch manufacturing and control (seeFigure 1).
質量風險管理過程的努力程度、正式程度和文件化程度應與風險的水平以及自研究到開發(fā)、商業(yè)生產和控制的所在階段相適應(見圖1)。
5.3. Systemsshould be in place to manage and minimize the risks inherent in research anddevelopment in order to ensure the ultimate quality, safety and efficacy ofproducts; and the reliability of data.
應有系統(tǒng)來管理和減少研發(fā)過程的固有風險，以確保產品的最終質量、安全性和有效性;以及數(shù)據(jù)的可靠性。
5.4. Riskassessments should be periodically reviewed in light of improvements, currenttechnology, scientific knowledge and experience.
風險評估應根據(jù)改進的情況、當前技術、科學知識和經驗定期審查。
6. Sanitation and hygiene
清潔衛(wèi)生
6.1. Proceduresshould be implemented to maintain sanitation and hygiene. The scope ofsanitation and hygiene covers personnel, premises, equipment and apparatus,production materials and containers, and products for cleaning anddisinfection.
應執(zhí)行程序以保持環(huán)境衛(wèi)生和個人衛(wèi)生。清潔衛(wèi)生的范圍包括人員、廠房、設備和儀器、生產物料和容器以及用于清潔消毒的產品。
6.2. Potential sources of contamination should beeliminated.
應消除潛在的污染源。
7. Qualification and validation
確認與驗證
7.1. Qualificationand validation required should be identified based on risk assessment and, inaddition, should be appropriate to the stage of research and development.
所需的確認和驗證應基于風險評估確定，此外，還應與所處的研發(fā)階段相適應。
7.2. Thequalification and validation policy and approach should be defined anddocumented, for example, in a validation master plan.
應定義和記錄確認和驗證的方正和方法，例如，在驗證主計劃中。
7.3. Wherequalification and validation is carried out, the responsibility of performingvalidation should be clearly defined.
在進行確認和驗證時，應明確定義執(zhí)行驗證的責任。
7.4. Qualificationand validation should provide documentary evidence that specifications andother requirements are met. Protocols and reports should be made available,when required.
確認和驗證應提供符合標準和其他要求的書面證據(jù)。需要時，應能提供方案和報告。
7.5. Whereprocess validation, cleaning validation and analytical procedure validation isdone as a part of development, procedures and protocols should be followed.Reports should be available and retained.
當工藝驗證、清潔驗證和分析方法驗證作為開發(fā)的一部分時，應遵循程序和方案。應有報告并保存。
8. Outsourced activities
外包活動
8.1. Outsourcedactivities should be correctly defined, agreed and controlled through a writtenagreement.
外包活動應通過書面協(xié)議正確定義、協(xié)定和控制。
8.2. Allresponsibilities and arrangements for activities, such as quality controltesting and technology transfer, should be clearly described.
所有的職責和活動安排，例如質量控制測試和技術轉移，都應明確加以說明。
Thecontract giver
委托方
8.3. The contractgiver is responsible for assessing the suitability and competence of thecontract acceptor to successfully carry out the work or tests required and forapproval of the contract activities.
委托方負責評估受托方成功完成所需的工作或測試的適用性和能力，并對委托活動進行批準。
8.4. The contractgiver should provide the contract acceptor with all the information necessaryto carry out the contracted operations correctly.
委托方應向受托方提供正確實施合同操作所需的所有信息。
8.5. Thecontract giver should ensure that the contract acceptor is fully aware of anyhazards associated with the product, work or tests.
委托方應確保受托方完全清楚任何與產品、工作或測試相關的風險。
8.6. Thecontract giver should review and assess the records and results related to theoutsourced activities.
委托方應審查和評估與外包活動相關的記錄和結果。
8.7. Thecontract giver is responsible for ensuring that the contract accepterunderstands that his or her activities may be subject to inspection by thecompetent authorities.
委托方有責任確保受托方明白其活動可能受到主管當局的檢查。
The contract accepter
受托方
8.8. Thecontract accepter must have adequate premises, equipment, knowledge, experienceand competent personnel to satisfactorily carry out the work ordered by thecontract giver.
受托方必須具備足夠的廠房、設備、知識、經驗和足夠能力的人員，以圓滿完成委托方委托的工作。
8.9. Thecontract accepter should not pass to a third party any of the work entrustedunder the contract without the contract giver’s prior evaluation and approvalof the arrangements.
未經委托方事先評估和批準，受托方不得將合同項下委托的任何工作轉交給第三方。
The agreement
協(xié)議
8.10. The technical aspects of the agreement should be drawn up bycompetent persons suitably knowledgeable in the field of research, developmentand GMP.協(xié)議的技術方面應由在研發(fā)和GMP領域有適當知識的有足夠能力的人員起草。
8.11. The agreement should describe the handling of materials, such assamples and products, if they are out of specification or rejected
協(xié)議應描述物料（如樣品和產品）在出現(xiàn)OOS或不合格時的處理，。
8.12. The agreement should permit the contract giver to audit thefacilities and activities of the contract acceptor.
該協(xié)議應允許委托方對受托方的設施和活動進行審計。
9. Self-inspection and quality audits
自檢和質量審計
9.1. There should be a written self-inspection programme.
應有書面的自檢程序。
9.2. Self-inspectionsshould be performed routinely and may be, in addition, performed on specialoccasions.
自檢應定期進行，并可在特殊情況下額外進行。
9.3. The teamresponsible for self-inspection should consist of personnel with theappropriate knowledge and experience, free from bias.
負責自檢的團隊應由具有適當知識和經驗的人員組成，不存在偏見。
9.4. Self-inspectionsshould cover at least the following items:
自檢至少應包括下列各項:
a) personnel;
人員
b) premisesincluding personnel facilities;
設施，包括個人設施
c) maintenanceof buildings and equipment;
廠房和設備的維護
d) storage of startingmaterials and finished products;
起始物料和成品的儲存
e) equipment;
設備
f) productionand in-process controls;
生產和過程控制
g) qualitycontrol;
質量控制
h) documentation;
文件記錄
i) sanitationand hygiene;
清潔衛(wèi)生
j) qualificationand validation;
確認與驗證
k) calibrationof instruments or measurement systems;
儀器或測試系統(tǒng)的校準
l) control oflabels; and
標簽的控制
m) results of previousself-inspections and any corrective steps taken.
前次自檢的結果以及所采取的任何整改措施
9.5. The outcomeof the self-inspection should be documented. Corrective actions and preventiveactions should be identified and implemented. There should be an effectivefollow-up programme.
自檢的結果應記錄在案。應確定和執(zhí)行糾正措施和預防措施。應有一個有效的跟蹤程序。
9.6. Self-inspectionsmay be supplemented by quality audits.
自檢應可以由質量審計補充。
10.Personnel
人員
10.1. Individual responsibilities should be clearlydefined and understood by the persons concerned and recorded as writtendescriptions.
應明確定義人員的職責，并應被相關人員理解，并以書面形式記錄。
10.2. All personnel should be aware of theprinciples of this guideline and other applicable GxPs.
所有人員應了解本指南的原則和其他適用的GxPs。
10.3. Steps should be taken to prevent unauthorizedpeople from entering storage, production and quality control areas.
應采取措施防止未經授權的人員進入儲存、生產和質量控制區(qū)域。
10.4. The headsof production and quality unit should be independent of each other.
生產和質量部門的負責人應該彼此獨立。
10.5. Smoking, eating, drinking, chewing and keepingplants, food, drink, smoking material and personal medicines should not bepermitted in any area where they might adversely influence product quality.
在任何可能對產品質量產生不利影響的區(qū)域，都不允許吸煙、吃、喝、嚼和保存植物、食品、飲料、吸煙材料和個人藥品。
11.Training
培訓
11.1. Training should be provided in accordance witha written programme that covers topics such as the theory and practice of GMPand the duties assigned to them.
培訓應根據(jù)書面計劃提供，涵蓋諸如GMP理論和實踐以及所分配工作職責等主題。
11.2. The effectiveness of training should beassessed.
應評估培訓的效果。
11.3. Training and assessment records should bekept.
應保存培訓和評估記錄。
11.4. Where appropriate, specific training should begiven on the handling of highly active, toxic, infectious or sensitizingmaterials.
適當時，應就如何處理高活性、毒性、傳染性或致敏性物料進行專門培訓。
12.Premises
廠房
12.1. Premises should be located, designed, constructed,adapted and maintained to suit the operations to be carried out.
房地的選址、設計、建造、改造和維護應適合所進行的操作。
12.2. The layout and design should aim to minimizethe risk of errors and permit effective cleaning and maintenance in order toavoid cross-contamination, build-up of dust or dirt and, in general, anyadverse effect on the products and activities.
布局和設計應盡量減少差錯風險，并允許有效的清潔和維護，以避免交叉污染，灰塵或污垢的積聚，以及對產品和活動的任何不利影響。
12.3. Where product dust is generated, measuresshould be taken to avoid cross-contamination and to facilitate cleaning.
對于易產塵的產品，應采取措施避免交叉污染并便于清洗。
12.4. Premises should be cleaned according todetailed written procedures. Records should be maintained.
廠房應按照詳細的書面程序進行清潔。記錄應保存。
12.5. Electricalsupply, lighting, temperature, humidity and ventilation should be appropriate.
電氣供應、照明、溫度、濕度和通風應適當。
12.6. Toilets,rest and refreshment rooms should be separate from production and controlareas.
廁所、休息和茶點室應與生產和控制區(qū)域分開。
12.7. Animal houses should be well isolated fromother areas, with a separate entrance (animal access) and air-handlingfacilities.
動物房應與其他區(qū)域良好隔離，有單獨的入口(動物通道)和空氣處理設施。
12.8. Storage areas should be of sufficient capacitywith proper separation and segregation between materials, based on riskassessment.
儲存區(qū)域應足夠使用，并根據(jù)風險評估，在物料之間進行適當?shù)拈g隔和隔離。
12.9. Storage areas should be clean and dry,designed or adapted to ensure the required storage conditions are maintained.Conditions should be controlled, monitored and recorded where appropriate.
儲存區(qū)域應潔凈干燥，設計或適合確保維持所需的儲存條件。適當時，應控制、監(jiān)測和記錄儲存條件。
12.10.Segregation should be provided for the storage of quarantined, released andrejected materials and products.
對已檢驗、已放行和不合格的物料和產品的存放應實行隔離。
12.11.Certain materials, such as highly active, radioactive materials and narcotics,should be stored in safe and secure areas.
某些物質，如高活性、放射性物料和麻醉品，應存放在安全的地方。
12.12.Materials identified for testing should be sampled in accordance with writtenprocedures and analysed for compliance with their specifications.
確定用于測試的物料應按照書面程序取樣，并進行分析，以確保符合其標準。
12.13. Thestages in production, including weighing, compounding, and packaging, should bedone in a manner to prevent contamination, cross-contamination and mix-ups.
在生產過程中，包括稱量、配料和包裝，應以防止污染、交叉污染和混淆的方式進行。
12.14.Quality control (QC) laboratories should be separated from production areas.They should be designed to suit the operations to be carried out in them. Thereshould be sufficient space, instruments, equipment and the appropriatereference materials, solvents and reagents.
質量控制(QC)實驗室應與生產區(qū)域分開。它們的設計應該適合所進行的操作。應有足夠的空間、儀器、設備和適當?shù)膶φ瘴锪?、溶劑和試劑?/span>
13.Equipment and instruments
設備和儀器
13.1. Equipment and instruments should be located,designed, constructed, adapted and maintained to suit the operations to becarried out. They should allow for effective cleaning and maintenance in orderto avoid cross-contamination and a build-up of dust or dirt.
設備和儀器的安裝、設計、制造、改造和維護應適合所進行的操作。它們應該允許有效的清潔和維護，以避免交叉污染和灰塵或污垢的堆積。
13.2. Pipework,instruments and devices should be adequately marked.
管道、儀器和裝置應適當標識。
13.3. Balancesand other measuring equipment of an appropriate range and precision should beavailable for production and control operations and should be calibrated on ascheduled basis.
生產和控制操作應備有量程和精度合適的天平和其他測量設備，并應定期校準。
13.4. Equipmentand instruments should be thoroughly cleaned on a scheduled basis.
設備和儀器應定期進行徹底清潔。
13.5. Defective equipment and instruments should beremoved from operational areas or be clearly labelled as defective in order toprevent use.
有缺陷的設備和儀器應移出操作區(qū)域，或清楚地標明有缺陷，以防止使用。
14.Materials
物料
14.1. Materials should be purchased from approvedsuppliers.
材料應從認可的供應商處購買。
14.2. Materials, identified through risk assessment,should be quarantined immediately after receipt, sampled and tested inaccordance with specifications.
物料，通過風險評估確定，應在收到后立即隔離，并按照規(guī)程取樣和檢驗。
14.3. Materialsreleased by the quality department and within their shelf life should be used.
應使用質量部發(fā)放的材料，并在其保質期內使用。
14.4. Materials identified through risk assessmentshould be stored under the appropriate conditions as specified on their labelsand in an orderly fashion to permit segregation, stock rotation and afirst-expire, first-use rule.
通過風險評估確定的物料應按照標簽上規(guī)定的適當條件儲存，以允許隔離、庫存輪換和近效期先使用的原則。
14.5. The dispensing of materials for the productionof a batch should be done according to a written procedure. Materials should beaccurately weighed or measured into clean and properly labelled containers.
用于生產批次的物料的分發(fā)應按照書面程序進行。物料應準確稱量或計量，裝入干凈并貼有適當標簽的容器中。
14.6. No materials used for operations, such ascleaning, the lubrication of equipment and pest control, should come intodirect contact with the product. Where possible, such materials should be of asuitable grade (e.g. food grade) to minimize health risks.
清潔、設備潤滑、蟲害控制等操作中使用的物料不得與產品直接接觸。如有可能，這些物料應有適當?shù)牡燃?/span>(例如食品級)以降低健康風險。
14.7. Water used shouldbe suitable for its intended use.
使用的水應該適合其預期用途。
14.8. Packaging materials should be stored in secureconditions so as to exclude the possibility of unauthorized access.
包裝材料應儲存在安全的條件下，以避免未經授權的進入。
14.9. Intermediateand bulk products should be kept under appropriate conditions.
中間體和待包裝產品應儲存在適當?shù)臈l件下。
14.10. Finished products should be stored undersuitable conditions.
成品應儲存在適當條件下。
14.11.Rejected materials and products should be clearly marked as such and storedseparately in restricted areas. They should be handled in an appropriate andtimely manner. Whatever action is taken should be approved by authorized personneland recorded.
不合格的物料和產品必須有明確的標識，并單獨存放在受限區(qū)域內。應妥善、及時地處理。無論采取什么措施，都應得到授權人員的批準并加以記錄。
14.12.Toxic substances and flammable materials should be stored in suitably designed,separate, enclosed containers and, as required, by national legislation. Allwaste materials should be stored in a safe manner and disposed of at regularintervals to avoid accumulation.
有毒物質和易燃材料應儲存在設計適當、隔離、封閉的容器中，并按國家法律的要求儲存。所有廢棄物應以安全的方式儲存，并定期處置，以避免堆積。
15.Documentation
文件記錄
15.1. Documentation includes specifications andprocedures for materials and methods of production and control. The design anduse of documents depend upon the research and development facility. The scopeand extent should be established based on risk assessment and the stage ofresearch and development (see Figure 1).
文件包括物料的標準和程序以及生產和控制的方法。文件的設計和使用取決于研發(fā)機構。其范圍和程度應根據(jù)風險評估和研發(fā)階段來確定(見圖1)。
15.2. Documents should be designed, prepared,reviewed and authorized for use.
文件應設計、準備、審核和批準以供使用。
15.3. Documents should be reviewed periodically andkept up-to-date. Superseded documents should be retained for a defined periodof time.
文件應定期審查并保持更新。被取代的文件應在規(guī)定的時間內保存。
15.4. Entries ofdata and information should be clear and legible.
數(shù)據(jù)和信息的輸入應清晰易讀。
15.5. Data (and records for storage) may be recordedby electronic data-processing systems or by photographic or other reliable means.Batch production and control records should be protected throughout the definedperiod of retention.
數(shù)據(jù)(和存儲記錄)可由電子數(shù)據(jù)處理系統(tǒng)或攝影或其他可靠的方法記錄。批生產和控制記錄應在規(guī)定的保存期內得到保護。
15.6. Labelsshould be clear, unambiguous and in the company’s agreed format.
標簽應清晰、明確，并采用公司所規(guī)定的格式。
15.7. There should be appropriately authorized anddated specifications, including tests on identity, purity and quality, forstarting materials and for finished products.
應有適當?shù)呐鷾屎蜕掌诘墓潭ǎ▽ζ鹗嘉锪虾统善返蔫b別、純度和質量的測試。
15.8. Pharmacopoeias, reference standards, referencespectra and other reference materials should be available in the QC laboratory.
QC實驗室應有藥典、對照標準品、對照光譜和其他對照物質。
15.9. Specifications should contain appropriateinformation such as the designated name; internal code reference; andqualitative and quantitative requirements with acceptance limits. Other datamay be added to the specification.
質量標準應包含適當?shù)男畔?，如指定的名稱；內部編號；以及帶有接受標準的定性和定量要求。可以將其他數(shù)據(jù)添加到標準中。
15.10. The packaging material should be examined forcompliance with the specification.
應檢查包裝材料以符合標準。
15.11.Specifications for intermediate and bulk products should be available where theneed has been identified.
必要時，應提供中間產品和待包裝產品的標準。
15.12. Specifications for finished products shouldbe available and include the required information.
應有成品的標準，并包含所要求的信息。
15.13. Amaster formula, containing the relevant information, should be available forthe product and batch size to be manufactured.
應有包含適用于所生產產品和批量大小相關信息的主配方。
15.14. Packaging instructions should exist for theproducts to be packed.待包裝的產品應有包裝說明。
15.15. Abatch processing record should be kept for each batch processed. It should bebased on the relevant parts of the current specifications on record.
應保存每一加工批次的批加工記錄。應基于現(xiàn)行規(guī)程的相關部分進行記錄。
15.16. Duringprocessing, detailed information should be recorded at the time each action istaken and, after completion, the record should be dated and signed by theperson responsible for the processing operations.
在加工過程中，應詳細記錄每項操作的執(zhí)行情況，并在完成后由負責加工操作的人員填寫日期和簽名。
15.17. A batch packaging record should be kept foreach batch or part batch processed.
應保存所處理的每個批次或分批的批包裝記錄。
15.18.Standard operating procedures (SOP) and corresponding records, where required,should be available. These include, but are not limited to, for example:
必要時，應提供標準操作規(guī)程(SOP)和相應的記錄。包括但不限于，例如:
a) equipmentassembly and cleaning;
設備組裝和清潔
b) personneltraining, clothing and hygiene;
人員培訓、更衣和衛(wèi)生
c) maintenance;
維護
d) sampling;
取樣
e) analyticalapparatus and instrument calibration;
分析儀器校準
f) testing;
檢驗
g) release andrejection; and
放行和拒簽
h) pestcontrol.
蟲害控制
15.19.Cross-contamination should be avoided by taking the appropriate technical ororganizational measures.
應采取適當?shù)募夹g或組織措施避免交叉污染。
15.20.Before any processing operation is started, steps should be taken to ensurethat the work area and equipment are clean and free from any startingmaterials, products, product residues, labels or documents not required for thecurrent operation.
在任何加工操作開始前，應采取步驟確保工作區(qū)域和設備是清潔的，沒有當前操作不需要的起始物料、產品、產品殘留物、標簽或文件。
15.21. Toprevent cross-contamination and mix-ups, different products should not bepackaged in close proximity.
為了防止交叉污染和混淆，不同的產品不應近距離包裝。
16.Processing and process validation
工藝和工藝驗證
Note: Fordetails on process validation, see WHO Technical Report Series, No. 1019, Annex3, Appendix 7, 2019.
注:有關工藝驗證的詳情，見WHO技術報告第1019號，附錄3，附件7，2019年。
Processing
工藝
Note: For more details on specific aspects relatingto process development, see ICH Q 11.
注：有關工藝開發(fā)的具體方面的更多詳情，請參閱ICH Q11。
16.1. The selection of the starting materials andmanufacturing process should be carefully considered in order to ensure thatthe intended product will meet the intended standards of safety, efficacy andquality in a consistent manner.
起始物料和生產工藝的選擇應予以謹慎考慮，以確保預期產品以一致的方式滿足預期的安全性、有效性和質量標準。
16.2. Knowledge management and risk assessmentprinciples should be applied. Quality attributes, critical quality attributes,process parameters and critical process parameters should be defined anddocumented.
應應用知識管理和風險評估原則。應定義質量屬性、關鍵質量屬性、工藝參數(shù)和關鍵工藝參數(shù)并形成文件。
16.3. The designof experiments should cover identified variables.
實驗設計應包括已識別的變量。
Process validation
工藝驗證
16.4. Process validation is usually initiated by researchand development organizations. During this stage, the validation is also referredto as “process design”. (In a traditional or historical approach, this wasoften referred to as “prospective validation”).
工藝驗證通常由研發(fā)組織發(fā)起。在這個階段，驗證也被稱為“工藝設計”。(在傳統(tǒng)的或歷史的方法中，這通常被稱為“前瞻性驗證”)。
16.5. Product development activities provide key inputsto the process design stage. Laboratory or pilot-scale models designed to be representativeof the commercial process can be used to estimate variability.
產品開發(fā)活動為工藝設計階段提供關鍵的輸入?？梢允褂糜靡源砩虡I(yè)化工藝的實驗室或中試規(guī)模的模型來估計變異性。
16.6. Process design should normally cover thedesign of experiments, process development, the manufacture of products for usein clinical trials, pilot-scale batches and technology transfer.
工藝設計通常應包括實驗設計、工藝開發(fā)、臨床試驗產品生產、中試批量和技術轉移。
16.7. Process design should be verified duringproduct development. Process design should cover aspects for the selection ofmaterials; expected production variation; selection of production technology/processand qualification of the unitary processes that form the manufacturing processas a whole; selection of in-process controls; tests; inspection; and itssuitability for the control strategy.
工藝設計應在產品開發(fā)過程中進行確認。工藝設計應包括物料選擇的各個方面；預期的生產變異性；生產技術/工藝的選擇，對整個生產過程的單個工藝進行確認；過程控制的選擇；測試；檢查；以及其對控制策略的適用性。
16.8. As the validation data are intended to be usedin applications for marketing authorizations, all batch data, results andrelated information should be clear, detailed and in compliance with ALCOA+.
由于驗證數(shù)據(jù)將用于上市許可申請，所有批次數(shù)據(jù)、結果和相關信息都應清晰、詳細，并符合ALCOA+要求。
17.Quality control
質量控制
17.1. The QC unit should be independent fromproduction.
QC部門應獨立于生產。
17.2. There should be adequate resources availableto ensure that all the QC arrangements are effectively and reliably carriedout.
應該有足夠的資源來確保所有的QC工作均得到有效和可靠地執(zhí)行。
17.3. Activities and responsibilities of the QC unitinclude:
QC的活動和職責包括：
a) samplingand testing (e.g. starting materials, packaging materials, intermediateproducts, bulk products and finished products);
取樣和檢驗（例如，起始物料、包裝材料、中間產品、待包裝產品和成品）
b) performingthe necessary qualification and validation;
執(zhí)行必要的確認與驗證
c) evaluating,maintaining and storing reference standards for substances;
評估、維護和保存對照標準
d) ensuring thatstability programme and testing is done;
確保穩(wěn)定性計劃和測試得到執(zhí)行
e) participatingin environmental monitoring; and
參與環(huán)境監(jiān)測
f) participatingin QRM programmes.
參與質量風險管理程序
17.4. Appropriate records should be kept, demonstrating that all therequired activities were performed
應保存適當?shù)挠涗?，以證明所有必需的活動都已執(zhí)行。
17.5. Sufficient samples of materials and products should be retained fora defined period of time.
應保留足夠的物料和產品留樣在規(guī)定的時間內。
17.6. Appropriate reference standards should be used. Standards should bestored in an appropriate way.
應使用適當?shù)膶φ諛藴?。標準應以適當?shù)姆绞絻Υ妗?/span>
17.7. Wheneverofficial reference standards exist, these should preferably be used.只要有官方對照標準，就最好使用這些標準。
17.8. Where secondary and working standards are established and used,these should be tested at regular intervals to ensure that they are fit fortheir intended use.
在建立和使用二級標準和工作標準時，應定期對這些標準進行測試，以確保它們適合其預期用途。
17.9. Reference standards should be appropriately labelled with at leastthe following information:
對照標準應至少適當標明以下信息:
a) name of thematerial;
物料名稱
b) batch orlot number and control number;
批號和控制編號
c) date ofpreparation;
配制日期
d) shelf life;
有效期
e) potency;and
效價
f) storageconditions.
儲存條件
18.Stability studies
穩(wěn)定性研究
Note: See guideline on stabilitytesting of active pharmaceutical ingredients and finished pharmaceuticalproducts , WHO Technical Report Series, No. 1010, Annex 10, 2018.
注:參見WHO技術報告 第1010號附錄10《藥品活性成分和成品穩(wěn)定性試驗指南》，2018年。
18.1. Where stability determination is initiated by research and developmentorganizations, a written programme should be developed and implemented toinclude elements such as:
研發(fā)組織在確定穩(wěn)定性時，應制定和執(zhí)行一項書面方，其中應包括以下要素:
a) a completedescription of the medicine involved in the study;
所研究的藥物的完整描述;
b) thecomplete set of testing procedure, parameters and limits;
一套完整的測試程序、參數(shù)和限度;
c) attributessuch as potency or assay and physical characteristics;
屬性，如效價或含量和物理特性
d) evidencethat these tests indicate stability;
這些測試表明穩(wěn)定性的證據(jù);
e) the testingschedule for each medicine;
每種藥物的測試時間表;
f) provisionfor special storage conditions; and
特殊儲存條件的規(guī)定;和
g) provisionfor adequate sample retention.
足夠的留樣樣品的規(guī)定
18.2. Sampling should be done in accordance with written procedures.
取樣應按照書面程序進行。
18.3. Sample preparation and testing procedures should be detailed andfollowed. Any deviations from the procedures should be clearly documented.
樣品制備和檢測程序應詳細并遵循。任何與程序的偏差都應清楚記錄在案。
18.4. The results and data generated should be documentedand include the evaluation and the conclusions of the study.
產生的結果和數(shù)據(jù)應記錄在案，包括評價和試驗的結論
18.5. Where stability data are intended to be usedin applications for marketing authorizations, all batch data, results andrelated information should be clear, detailed and in compliance with ALCOA+.
當穩(wěn)定性數(shù)據(jù)用于上市許可申請時，所有批次數(shù)據(jù)、結果和相關信息應清晰、詳細并符合ALCOA+要求。
18.6. Recordsshould be maintained for a defined period of time.
記錄應在規(guī)定時間內保存。
19.Analytical procedure development
分析方法開發(fā)
19.1. Analytical procedures developed by researchand development organizations should be appropriately recorded.
應適當記錄研發(fā)組織開發(fā)的分析程序。
19.2. As the procedures are usually intended to betransferred to quality control units in manufacturing facilities of commercialbatches, procedures and records should be sufficiently detailed to ensure thatTOT will be successful.
由于分析方法通常需要移交給商業(yè)批次生產工廠的QC部門，因此程序和記錄應足夠詳細，以確保TOT（技術轉移）的成功。
19.3. Analyticalprocedures should be appropriately validated.
分析方法應適當驗證。
Note: For details on analyticalprocedure validation, see WHO Technical Report Series, No. 1019, Annex 3,Appendix 4, 2019.
注:有關分析方法驗證的詳情，見WHO技術報告系列，第1019號，附錄3，附件4，2019年。
20.Transfer of technology
技術轉移
Note: For details on transfer oftechnology, see WHO Technical Report Series, No. 961, Annex 7, 2011 (update inprogress).
注:有關技術轉移的詳情，見WHO技術報告系列，第961號，附錄7，2011年(正在更新)。
20.1. Development work, including programmes,procedures, protocols, specifications and validation from research anddevelopment organizations, may be transferred to production and quality controlsites.
開發(fā)工作，包括研發(fā)組織的計劃、程序、方案、標準和驗證，可轉移到生產和質量控制工廠。
20.2. Data and information relating to equipment,instruments, manufacturing, and testing should be detailed, traceable andavailable.
與設備、儀器、生產和檢驗有關的數(shù)據(jù)和信息應詳細、可追溯和可用。
20.3. Authorized procedures should be followed whentransferring technology from research and development organizations toproduction and quality control facilities.
在將技術從研發(fā)機構轉移到生產和質量控制工廠時，應遵循經批準的程序。
21.Life cycle approach
生命周期方法
21.1. Industry should implement policies andprocedures that will encourage science-based and risk-based approaches inproduct research and development.
企業(yè)應實施政策和程序，鼓勵以科學和風險為基礎的方法進行產品研究和開發(fā)。
21.2. Continualimprovement should be encouraged across the entire product life cycle.
應鼓勵在整個產品生命周期內進行持續(xù)改進。
21.3. Knowledge gained from the commercial manufacturingof a product, as well as knowledge gained from other products, can be used tofurther improve process understanding and process performance.
從一個產品的商業(yè)制造中獲得的知識，以及從其他產品中獲得的知識，可以用于進一步提高對工藝的理解和提高工藝性能。
21.4. New technologies and the review and interpretationof statistical evaluation of results from validation and other processes, aswell as other applicable data and information, should be considered in order toencourage continual improvement during the process development stage of thelife cycle of the product.
應考慮新技術、驗證和其他工藝結果的統(tǒng)計評價的評審和解釋，以及其他適用的數(shù)據(jù)和信息，以支持在產品生命周期的工藝開發(fā)階段進行持續(xù)改進。
21.5. Where appropriate, these should be shared andtransferred to commercial manufacturing facilities.
適當時，應共享并轉移給商業(yè)生產設施。
22.Cleaning procedure development and cleaning validation
清潔程序開發(fā)和清潔驗證
Note: Fordetails on cleaning validation, see WHO Technical Report Series, No. 1019,Annex 3, Appendix 3, 2019 and the WHO Points to consider when including HBELsin cleaning validation, TRS XXX, Annex 2, 2021.
注:有關清潔驗證的詳細信息，請參閱WHO技術報告系列第1019號，附錄3，2019和WHO《清潔驗證中應用HBEL的考量》，TRS XXX，附錄2，2021。
22.1. Research and development facilities are ofteninvolved in the development and validation of cleaning procedures. QRMprinciples should be applied in cleaning procedure development and cleaningvalidation.
研發(fā)設施經常涉及到清潔程序的開發(fā)和驗證。應在清潔程序的制定和清潔驗證中應用QRM原則。
22.2. Thedevelopment of cleaning procedures should include cleanability.
清潔程序的開發(fā)應包括清潔能力。
22.3. Health Based Exposure Limits (HBELs) should beconsidered in the approach to cleaning validation.
在進行清潔驗證時，應考慮基于健康的暴露限。
22.4. The sampling of procedures should include swaband rinse samples. Maximum Safe Residue, Maximum Safe Surface Residue andVisible Residue Limits should be considered in the new cleaning validationapproach.
取樣程序應包括擦拭和淋洗樣品。在新的清潔驗證方法中，應考慮最大安全殘留、最大安全表面殘留和可見殘留限度。
22.5. The development of the analytical proceduresto be used in the testing for residues should be appropriately documented. Theprocedures should be validated.
用以檢測殘留物的分析方法的開發(fā)應有適當?shù)挠涗洝＿@些程序應該經過驗證。
22.6. Proceduresfor sampling and testing, and the results obtained, should meet ALCOA+principles.The dataand information should be retained over the life cycle of the product.
取樣和測試的程序，以及得到的結果，應符合ALCOA+原則。這些數(shù)據(jù)和信息應該在產品的生命周期中保存。
22.7. Procedures and protocols should be followedfor the TOT to commercial manufacturing sites.Records should be maintained.
應遵循TOT（技術轉移）到商業(yè)生產工廠的程序和方案。記錄應保存。
公眾號
GMP辦公室
專業(yè)的GMP合規(guī)性研究組織
國內外（FDA、EMA、MHRA、NMPA、WHO、PIC/S等）GMP法規(guī)解讀；
國內外制藥行業(yè)GMP監(jiān)管動態(tài)；
GMP技術指南（ISPE、PDA、ISO、ASTM等）分享
