PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME藥品檢驗公約藥品檢驗合作計劃GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS PART I藥用產品良好生產規范指南第一部分目錄第一章 質量管理2第二章人員11第三章 廠房設施17第四章 文件25第五章 生產41第六章質量控制53第七章 委托生產與委托檢驗62第八章 產品投訴和召回66第九章 自檢69CHAPTER 1 第一章 質量管理QUALITY MANAGEMENTPRINCIPLE 原則The holder of a manufacturing authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the companys suppliers and by the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance Incorporating Good Manufacturing Practice, and thus Quality Control and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the manufacturing authorisation and for the authorised person(s). 生產許可證持有人必須生產藥品，從而確保藥品適合預期用途、符合相應的上市許可證或臨床試驗許 可證要求，不因為安全性問題、質量問題或有效性問題而把患者置于風險之中。實現上述質量目標是公司高級管理人員的職責，并要求公司的供應商、銷售商，公司內所有各級員工與許多不同部門的員工共同參與、一起努力。要可靠地實現這一質量目標，必須綜 合設計一個整合藥品生產質量管理規范（GMP）和質量控制、質量風險管理的制藥質量保證體系并正確實施。質量體系應當全面文件化，并監察其有效性。整個制藥質量體 系應當配備充足的具有資質的人員，以及充分并適用的建筑物、設備和設施。生產許可證持有人以及質量受權人有額外的法律責任。The basic concepts of Quality Assurance, Good Manufacturing Practice, Quality Control and Quality Risk Management are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products.質量保證、藥品生產質量管理規范、質量控制以及質量風險管理的基本概念是相互關聯的。在這里對其進行描述是為了強調它們之間的聯系以及其對藥品生產和控制的重要性。QUALITY ASSURANCE質量保證1.1 Quality Assurance is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide.質量保證是一個寬泛的概念，涵蓋所有因素，這些因素單獨或共同影響產品質量。質量保證是為了保證藥品質量符合預期用途，而進行的有組織的安排的總和。因此，質量保證中包含著藥品生產質量管理規范以及本指南的范圍內的其他因素。The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that: 一個適當的質量保證體系應當確保：i. medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice ;藥品的設計和開發應考慮藥品生產質量管理規范的要求；ii. production and control operations are clearly specified and Good Manufacturing Practice adopted;對生產和控制操作進行明確規定，并符合藥品生產質量管理規范的要求；iii. managerial responsibilities are clearly specified;明確規定管理職責；iv. arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; 對下述活動均有協議約束：生產、供應、使用正確的起始物料與包裝材料。v. all necessary controls on intermediate products, and any other inprocess controls and validations are carried out;對中間產品以及其他任何中間過程控制與驗證實施所有必要的控制；vi. the finished product is correctly processed and checked, according to the defined procedures;成品根據確定的程序進行正確生產和檢測；vii. medicinal products are not sold or supplied before an authorised person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorisation and any other regulations relevant to the production, control and release of medicinal products;質量受權人需簽發證明以確認每一批次藥品的生產和控制均符合上市許可要求以及與藥品生產 、控制和放行相關的任何其他法規要求，未經質量受權人簽發證明的藥品不得銷售或供貨；viii. satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life;藥品貯存 、發運和后續處理確保有滿意的管理規程，從而盡量保證藥品貨架期內的質量ix. there is a procedure for self-inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the quality assurance system.有自檢和 / 或質量審計規程，以定期評價質量保證體系的有效性與適用性。GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (GMP)藥品生產質量管理規范1.2 Good Manufacturing Practice is that part of Quality Assurance which ensures that Medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:藥品生產質量管理規范是質量管理體系的一部分，保證按適合預期用途的質量標準及上市許可、臨床試驗許可或產品質量標準要求始終如一地生產及控制產品。藥品生產質量管理規范涉及生產和質量控制。藥品生產質量管理規范的基本要求是：i. all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;所有生產工藝得到明確規定、按照經驗經過系統的審核，并經過證明表明有能力始終如一地生產具有所需質量且符合質量標準的藥品ii. critical steps of manufacturing processes and significant changes to the process are validated;生產工藝的關鍵步驟以及重大的工藝變更已經驗證；iii. all necessary facilities for GMP are provided including:提供了 GM P需要的所有設施，包 括 ：a. appropriately qualified and trained personnel; 有適當資質并經過培訓的員工；b. adequate premises and space; 充足的廠房與空間 ；c. suitable equipment and services; 適 當 的 設 備 及 保 養 ；d. correct materials, containers and labels; 恰當的材料、容 器 和 標 簽 ；e. approved procedures and instructions; 經批準的規程與操作方法；f. suitable storage and transport; 合 適 的 貯 存 與 運 輸 ；iv. instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;操作方法與規程應當使用有指導意義的方式來書寫，并且條理清楚、用語明確 ，特別是要適用于相應的設施 ；v. operators are trained to carry out procedures correctly; 操作人員接受過正確執行規程的培訓；vi. records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated; 在生產過程中進行了記錄，可由手工和/ 或儀器記錄，以證明規程和操作要求的所有步驟切實得到了執行，以及產品的質量和數量達到預期要求；所有重大偏差得到了完整記錄、經過了調查vii. records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;生產記錄包括銷售記錄以易懂且可獲得的方式得到了保留，使整個批次的完整歷史可追溯；viii. the distribution (wholesaling) of the products minimises any risk to their quality;降低產品銷售過程中的質量風險；ix. a system is available to recall any batch of product, from sale or supply;有藥品召回系統，確保任何一批產品都能從銷售商或供應處收回；x. complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent re-occurrence.對產品投訴進行檢查，調查質量缺陷原因，對缺陷產品采取適當措施并防止再次發生。QUALITY CONTROL 質量控制1.3 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are that:質量 控 制 是 G M P 的一部分，涉及取樣、質量標準、檢驗，同樣也涉及組織機構、文件和放行規程，以保證切實執行了必要的相關檢驗，并且確保物料或產品被判定符合要求之前不被放行使用或銷售。質量控制的基本要求是：i. adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;有 充足 的設施設 備、經過培訓的人員及經過批準的規程用于起始物料、包 裝 材 料 、中間體、半成品與成品取樣和檢驗，以及 G M P 要 求 的 環 境 監 測ii. samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control;由經過批準的人員按經過批準的方法對起始物料、包裝材料、中間產品、半成品、成 品 取 樣 ；iii. test methods are validated; 檢 驗 方法 經過 驗 證 ；iv. records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated;由手工和/ 或儀器做了記錄，以證明所有要求的取樣、檢查和檢驗規程切實得到了執行。任何偏差得到了完整記錄和調查；v. the finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorisation, are of the purity required, and are enclosed within their proper containers and correctly labelled;成品中的活性成分符合上市許可或臨床試驗許可的定性和定量要求，及符合純度要求，并貯 存在適當的容器中、貼 上 正 確 的 標 簽 ；vi. records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;物料 、中間體、半成品及成品的檢查與檢驗結果有記錄，成品按質量標準做了正式評估。產品評估包括回顧與評估相關生產文件，以及評估對特定規程的偏差；vii. no batch of product is released for sale or supply prior to certification by an authorised person that it is in accordance with the requirements of the relevant authorisations;在質量受權人確認產品批次符合相應許可要求之前，任何批次不被放行銷售或供貨；viii. sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.留有足夠的起始物料和成品對照樣品， 以備將來有需要的時候對產品進行檢驗，樣品包裝方式與對應的產品最終包裝方式相同。PRODUCT QUALITY REVIEW產品質量回顧1.4 Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:應當對所有獲得批準的藥品，包括僅供出口的藥品，進行定期的或滾動式的質量回顧，質量回顧的目的是確認現有工藝的一致性、起始物料和成品現行質量標準的適宜性，強調任何趨勢并識別產品和工藝改進點。通常應當每年回顧并文件化，回顧中還應當考慮以前的回顧情況，并至少應當包括：i. A review of starting materials including packaging materials used in the product, especially those from new sources.回顧產品所用起始物料、包裝材料，特別是來自新供應商的起始物料和包裝材料，ii. A review of critical in-process controls and finished product results. 回顧關鍵中間過程控制與成品結果。iii. A review of all batches that failed to meet established specification(s) and their investigation.回顧未能符合既定質量標準的所有批次及其調查結果。iv. A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken.回顧所有重大偏差或不符合事件與相關調查，以及后續糾正與預防措施的有效性。v. A review of all changes carried out to the processes or analytical methods.回顧工藝或分析方法的所有變更。vi. A review of Marketing Authorisation variations submitted/granted/refused, including those for third country (export only) dossiers.回顧已遞交的、 已批準的或被拒絕的上市許可變更，包括已遞交的、 已批準的或被拒絕的第三 國 （ 僅供出口）上市許可變更資料。vii. A review of the results of the stability monitoring programme and any adverse trends.回顧穩定性監測程序的結果以及任何不良的趨勢。viii. A review of all quality-related returns, complaints and recalls and the investigations performed at the time.回顧與質量相關的所有退貨、投訴與召回，以及當時實施的調查。ix. A review of adequacy of any other previous product process or equipment corrective actions.回顧任何其他先前產品工藝或設備糾正措施的適宜性。x. For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments.對于新的上市許可和上市許可變更，回顧上市后承諾。xi. The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.回顧相關設備與公用系統的確認狀態，例如空氣凈化系統、制水系統、壓縮空氣系統等。xii. A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date.回顧第7 章規定的所有合同、協 議 ，以確保未過時。The manufacturer and marketing authorisation holder should evaluate the results of this review and an assessment made of whether corrective and preventative action or any revalidation should be undertaken. Reasons for such corrective actions should be documented. Agreed corrective and preventative actions should be completed in a timely and effective manner. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during selfinspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified. 生產企業，或是上市許可證持有人，如果生產企業不是上市許可證持有人的話，應當在制藥質量體系下評估產品質量回顧的結果，并評估是否應當釆取糾正與預防措施或是任何再驗證。對于現有管理活動及這些管理活動的回顧，應當有管理規程，并通過自檢確認這些規程的有效性。經過科學論證后 ，可以按產品類別進行質量回顧，例如固體劑型、液體劑型、無菌產品等。Where the marketing authorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The authorized person responsible for final batch certification together with the marketing authorisation holder should ensure that the quality review is performed in a timely manner and is accurate.如果上市許可證持有人不是生產企業，各方之間應當簽訂技術協議，規定各自在產品貭量回顧中的責任。授權人和銷售許可持有人負責最后一批認證，應確保及時準確的的進行質量回顧。QUALITY RISK MANAGEMENT質量風險管理1.5 Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively. 質量風險管理是一個用于藥品質量風險評估、控 制 、交流與評審的系統過程?？梢圆捎们罢靶曰蚧仡櫺孕问健?.6 The quality risk management system should ensure that: 質量風險 管理的原 則是 ：- the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient;質量風險評估是以科學知識和對工藝的經驗為基礎，并最終與保護患者相關聯。- the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.質量風險管理過程的投入、正式程度與文件應當與風險水平相適應。Examples of the processes and applications of quality risk management can be found inter alia in Annex 20.在附錄20 中所述的質量風險管理的過程與應用實例。CHAPTER 2第二章人員PERSONNEL PRINCIPLE原則The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.符合要求的質量保證體系的建立和維護以及藥品的正確生產依賴于人。因此，必須有足夠的有資質的人員來完成與生產企業職責相應的所有工作。每個人應當清楚地理解自己的職責并記錄。所有人員都應當知曉與自己相關的藥品生產質量管理規范基本原則，并且接受培訓與繼續培訓，這些培訓包括與人員衛生相關的教育工作。GENERAL總則2.1. The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.生產企業應當配備足夠數量并具有適當資質及實際經驗的人員。為防止出現任何質量風險，每個人所承擔的職責不應當過多。2.2. The manufacturer must have an organisation chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.生產企業必須具有組織機構圖，針對各崗位員工應制定崗位職責說明書，對崗位職責進行書面描述并給員工充分的授權來履行職責。這些職責可以委派給其他人，但受托人必須具有相應的資質。在藥品生產質量管理規范實施過程中，員工職責之間應無縫銜接，并且沒有無故的重疊。KEY PERSONNEL關鍵人員2.3. Key Personnel includes the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the authorised person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organisations, it may be necessary to delegate some of the functions listed in 2.5., 2.6. and 2.7.關鍵管理人員包括生產負責人和質量負責人，如果這些人中未有至少一人承擔職責，則應當指定 適當數量的質量受權人（至少一名）來履行該職責。通常，關鍵崗位人員應當為全職人員。生產負責人和質量負責人必須相互獨立。構龐大的組織中，可能需要對第2.5 2.6 2.7條中所列的職責進行授權。2.4. .2.5. The head of the Production Department generally has the following responsibilities:生產負責人通常有以下職責：i. to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;確保產品按照造當的文件規定生產和貯存，從而達到質量要求 ；ii. to approve the instructions relating to production operations and to ensure their strict implementation;批準與生產操作相關的規程，并確保規程得到嚴格執行；iii. to ensure that the production records are evaluated and signed by an authorised person before they are sent to the Quality Control Department;在送到質量控制部門前，確保生產記錄經過授權人員評估和簽字；iv. to check the maintenance of his department, premises and equipment;檢查本部門廠房、設施和設備進行了維護；v. to ensure that the appropriate validations are done;確保實施了適當的驗證vi. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.確保對本部門人員進行了必要的入職培訓與持續培訓，培訓應符合實際需要。2.6. The head of the Quality Control Department generally has the following responsibilities:質量負責人通常有以下職責