EU-GMP第六章節(jié)質(zhì)量控制--quality-control-翻譯.doc

Chapter 6: Quality Control第1部分第6章：質(zhì)量控制Legal basis for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.出版詳細指南的法律依據(jù)：指令2001/83/EC第47條關(guān)于人藥統(tǒng)一編碼和2001/82/EC第51條關(guān)于獸藥統(tǒng)一編碼規(guī)定。本文對指令2003/94/EC中人藥和91/412/EEC中獸藥的藥品GMP原則和指南解釋提供指南。Status of the document: Revision文件狀態(tài)：修訂Reasons for changes: 變更理由Inclusion of a new section on technical transfer of testing methods and other items such as Out Of Specification results.包括檢驗方法的技術(shù)轉(zhuǎn)移作為新章節(jié)，包括其它項目例如OOT結(jié)果。Deadline for coming into operation: 1 October 2014生效日期：2014年10月1日Principle 原則This chapter should be read in conjunction with all relevant sections of the GMP guide Quality Control is concerned with sampling, specifications and testing as well as the organisation, documentation and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control.本章應(yīng)與GMP指南中所有相關(guān)章節(jié)一起解讀。質(zhì)量控制主要關(guān)注取樣、質(zhì)量標(biāo)準(zhǔn)和檢測，同時也與組織機構(gòu)、文件記錄和放行程序相關(guān)，這些程序保證了必要和相關(guān)的測試。只有當(dāng)產(chǎn)品和物料的質(zhì)量被判定為可以接受時，物料才可以放行使用，產(chǎn)品才可以放行銷售。質(zhì)量控制不僅局限于化驗室操作，還必須包括所有可能與產(chǎn)品質(zhì)量相關(guān)的其它決定。質(zhì)量控制獨立于生產(chǎn)被認為是質(zhì)量控制可以令人滿意地操作的基礎(chǔ)。General 通則6.1 Each holder of a manufacturing authorisation should have a Quality Control Department. This department should be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. Adequate resources must be available to ensure that all the Quality Control arrangements are effectively and reliably carried out.每一個生產(chǎn)許可持有人均應(yīng)具有一個質(zhì)量控制部門。該部門應(yīng)獨立于其它部門，由一個具有相應(yīng)資質(zhì)和經(jīng)驗的人管理，他/她可以管理一個或幾個化驗室?；炇覒?yīng)具有充分的資源，以保證所有檢測要求能有效可靠地實施。6.2 The principal duties of the head of Quality Control are summarised in Chapter 2. The Quality Control Department as a whole will also have other duties, such as to establish, validate and implement all quality control procedures, oversee the control of the reference and/or retention samples of materials and products when applicable, ensure the correct labelling of containers of materials and products, ensure the monitoring of the stability of the products, participate in the investigation of complaints related to the quality of the product, etc. All these operations should be carried out in accordance with written procedures and, where necessary, recorded.質(zhì)量控制負責(zé)人基本職責(zé)在第2章里進行了概括。質(zhì)量控制部門作為一個整體，還具有其它職責(zé)，例如建立、驗證和實施所有質(zhì)量控制程序，監(jiān)督物料和產(chǎn)品的對照和/或留樣，保證物料和產(chǎn)品容器上標(biāo)簽正確，保證對產(chǎn)品穩(wěn)定性進行監(jiān)控，參與和產(chǎn)品質(zhì)量相關(guān)的客訴的調(diào)查等等。所有這些操作均應(yīng)根據(jù)書面程序進行，必要時，應(yīng)進行記錄。6.3 Finished product assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with Finished Product Specification and examination of the final finished pack.成品的評估應(yīng)綜合所有相關(guān)的因素，包括生產(chǎn)條件、中控檢測結(jié)果、生產(chǎn)（包括包裝）文件審核、成品符合質(zhì)量標(biāo)準(zhǔn)和最終包裝檢查。6.4 Quality Control personnel should have access to production areas for sampling and investigation as appropriate.質(zhì)量控制人員應(yīng)有權(quán)限進入生產(chǎn)區(qū)域進行取樣，及適當(dāng)?shù)恼{(diào)查。Good Quality Control Laboratory Practice 優(yōu)良質(zhì)量控制化驗室規(guī)范6.5 Control laboratory premises and equipment should meet the general and specific requirements for Quality Control areas given in Chapter 3. Laboratory equipment should not be routinely moved between high risk areas to avoid accidental cross-contamination. In particular, the microbiological laboratory should be arranged so as to minimize risk of cross-contamination.化驗室設(shè)施和設(shè)備應(yīng)符合第3章里給出的QC區(qū)域通用和特殊要求。為避免交叉污染事故，化驗室設(shè)備一般不應(yīng)該設(shè)計為需要常常在高風(fēng)險區(qū)域之間移來移去。特別是微生物化驗室的布置，應(yīng)盡可能將交叉污染的風(fēng)險降至最低。6.6 The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles detailed in Chapter 7, Contract Analysis, can be accepted for particular reasons, but this should be stated in the Quality Control records.化驗室的人員、設(shè)施、設(shè)備應(yīng)與其檢驗任務(wù)和生產(chǎn)規(guī)模相當(dāng)。在有特殊原因情況下，可以使用外部分化驗室，但應(yīng)符合第7章“外包分析”中的原則，并要在質(zhì)量控制記錄上說明。Documentation 文件6.7 Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department:化驗室文件應(yīng)符合第4章中給定的原則。這部分文件一個重要部分與質(zhì)量控制相關(guān)，質(zhì)量控制部門應(yīng)很容易獲得以下詳細信息i. Specifications;質(zhì)量標(biāo)準(zhǔn)ii. Procedures describing sampling, testing, records (including test worksheets and/or laboratory notebooks), recording and verifying;描述取樣、檢測、記錄（包括檢測原始記錄表和/或化驗室筆記本）、記錄和確認情況iii. Procedures for and records of the calibration/qualification of instruments and maintenance of equipment;儀器校正/確認，設(shè)備維保程序和記錄iv. A procedure for the investigation of Out of Specification and Out Of Trend results;OOS和OOT結(jié)果調(diào)查程序v. Testing reports and/or certificates of analysis;檢測報告和/或分析報告vi. Data from environmental (air, water and other utilities) monitoring, where required;環(huán)境（空氣、水和其它設(shè)施）監(jiān)控數(shù)據(jù)，必要時vii. Validation records of test methods, where applicable.檢驗方法的驗證記錄，必要時6.8 Any Quality Control documentation relating to a batch record should be retained following the principles given in chapter 4 on retention of batch documentation.所有與批記錄相關(guān)的質(zhì)量控制文件均應(yīng)按第4章中關(guān)于批文件保留要求的原則留存。6.9 Some kinds of data (e.g. tests results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any out of trend or out of specification data should be addressed and subject to investigation.一些類別的數(shù)據(jù)（例如檢測結(jié)果、收率、環(huán)境控制）記錄方式應(yīng)可以進行趨勢評估。所有OOT或OOS數(shù)據(jù)均應(yīng)說明，進行調(diào)查。6.10 In addition to the information which is part of the batch documentation, other raw data such as laboratory notebooks and/or records should be retained and readily available除了批記錄部分的信息外，其它原始數(shù)據(jù)例如化驗室記錄本和/或記錄均應(yīng)保留備查。Sampling 取樣6.11 The sample taking should be done and recorded in accordance with approved written procedures that describe:取樣應(yīng)根據(jù)書面程序進行并記錄，書面程序應(yīng)描述i. The method of sampling;取樣方法ii. The equipment to be used;取樣工具iii. The amount of the sample to be taken;取樣量iv. Instructions for any required sub-division of the sample;分樣方法v. The type and condition of the sample container to be used;要使用的樣品容器類型和條件 vi. The identification of containers sampled;所取樣的容器標(biāo)識vii. Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;觀察到的特殊預(yù)警情況，尤其是無菌或有毒的物料取樣時viii. The storage conditions;存貯條件ix. Instructions for the cleaning and storage of sampling equipment.取樣器具清潔和存貯方法6.12 Samples should be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process (e.g. beginning or end of a process). The sampling plan used should be appropriately justified and based on a risk management approach.樣品應(yīng)能代表所取批次的物料或產(chǎn)品。也可以取其它樣品以監(jiān)控工藝中最極端的情況（例如在工藝的開始或結(jié)束時）。所采用的取樣計劃應(yīng)基于風(fēng)險管理方法進行適當(dāng)論證。6.13 Sample containers should bear a label indicating the contents, with the batch number, the date of sampling and the containers from which samples have been drawn. They should be managed in a manner to minimize the risk of mix-up and to protect the samples from adverse storage conditions.樣品容器應(yīng)進行標(biāo)識，指明內(nèi)容物、批號、取樣日期、從哪個包裝取樣。標(biāo)簽應(yīng)能最大程度降低混淆風(fēng)險，保護樣品不會被存貯在有負面影響的條件下。6.14 Further guidance on reference and retention on reference and retention samples is given in Annex 19.更多關(guān)于對照品及存貯和留樣的指南在附錄19中給出。Testing 測試6.15 Testing methods should be validated. A laboratory that is using a testing method and which did not perform the original validation, should verify the appropriateness of the testing method. All testing operations described in the marketing authorisation or technical dossier should be carried out according to the approved methods.檢驗方法應(yīng)進行驗證。如果一個化驗室正在使用某一個檢測方法，但沒有做過初始的驗證，則應(yīng)該確認該方法的適用性。所有在上市批準(zhǔn)或技術(shù)文件中描述的檢測操作均應(yīng)根據(jù)所批準(zhǔn)的方法進行。6.16 The results obtained should be recorded. Results of parameters identified as quality attribute or as critical should be trended and checked to make sure that they are consistent with each other. Any calculations should be critically examined.檢查所得結(jié)果應(yīng)記錄。如果是關(guān)鍵質(zhì)量參數(shù)或質(zhì)量特性則應(yīng)進行趨勢分析，并檢查這些項目間是否具有一致性。所有計算均應(yīng)進行重點檢查。6.17 The tests performed should be recorded and the records should include at least the following data:所進行的檢測均應(yīng)記錄，記錄應(yīng)至少包括以下數(shù)據(jù)i. Name of the material or product and, where applicable, dosage form;物料名稱或產(chǎn)品名稱，以及劑型（適用時）ii. Batch number and, where appropriate, the manufacturer and/or supplier;批號，生產(chǎn)商和/或供應(yīng)商名稱（適用時）iii. References to the relevant specifications and testing procedures;所參照的相關(guān)質(zhì)量標(biāo)準(zhǔn)和檢驗方法iv. Test results, including observations and calculations, and reference to any certificates of analysis;檢測結(jié)果，包括觀察現(xiàn)象和計算，所參照的檢驗報告v. Dates of testing;檢測日期vi. Initials of the persons who performed the testing;測試人的姓名首字母vii. Initials of the persons who verified the testing and the calculations, where appropriate;對檢測和計算進行復(fù)核的人員的姓名首字母（適用時）viii. A clear statement of approval or rejection (or other status decision) and the dated signature of the designated responsible person;對結(jié)果批準(zhǔn)或拒絕的清楚結(jié)論（或其它狀態(tài)決定），受任命的責(zé)任人的簽名和日期ix. Reference to the equipment used.設(shè)備所用的對照品6.18 All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by Quality Control and the results recorded.所有中控檢測，包括在生產(chǎn)場所由生產(chǎn)人員所實施的檢測均應(yīng)按照質(zhì)量控制部門批準(zhǔn)的檢測方法進行，結(jié)果應(yīng)記錄。 6.19 Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.要特別注意化驗室試劑、溶液、玻璃器皿、對照品和培養(yǎng)基的質(zhì)量。這些物品應(yīng)根據(jù)書面程序進行準(zhǔn)備和控制，控制水平應(yīng)與其用途及穩(wěn)定性數(shù)據(jù)相當(dāng)。6.20 Reference standards should be established as suitable for their intended use. Their qualification and certification as such should be clearly stated and documented. Whenever compendial reference standards from an officially recognised source exist, these should preferably be used as primary reference standards unless fully justified (the use of secondary standards is permitted once their traceability to primary standards has been demonstrated and is documented). These compendial materials should be used for the purpose described in the appropriate monograph unless otherwise authorised by the National Competent Authority.對照品應(yīng)適合其用途，應(yīng)該清楚說明和記錄其確認情況及證書。如果有官方認可的來源，則應(yīng)優(yōu)先采用作為基本對照品，否則應(yīng)有完整的證明（采用第二對照品也是可以的，只要證明其可追溯至基本對照品并有相關(guān)記錄）。除非經(jīng)過國家藥監(jiān)部門的批準(zhǔn)，這些藥典物質(zhì)只能用于其在相應(yīng)藥典各論中所指明的用途。6.21 Laboratory reagents, solutions, reference standards and culture media should be marked with the preparation and opening date and the signature of the person who prepared them. The expiry date of reagents and culture media should be indicated on the label, together with specific storage conditions. In addition, for volumetric solutions, the last date of standardisation and the last current factor should be indicated.化驗室試劑、溶劑、對照品和培養(yǎng)基均應(yīng)標(biāo)識制備和開瓶日期，以及制備人簽名。試劑和培養(yǎng)基有效期應(yīng)在標(biāo)簽上標(biāo)明，上次標(biāo)化日期和上次標(biāo)化所得濃度因子應(yīng)在標(biāo)簽上注明。6.22 Where necessary, the date of receipt of any substance used for testing operations (e.g. reagents, solutions and reference standards) should be indicated on the container. Instructions for use and storage should be followed. In certain cases it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use.必要時，用于檢測操作的所有物質(zhì)的接收日期（例如，試劑、溶液和對照品）應(yīng)在容器上標(biāo)識。要遵守使用和存貯規(guī)范。在某些情況下，可能需要在接受時，或使用前對試劑物料進行鑒別測試和/或其它測試。6.23 Culture media should be prepared in accordance with the media manufacturers requirements unless scientifically justified. The performance of all culture media should be verified prior to use.除非另有科學(xué)判定，否則培養(yǎng)基應(yīng)根據(jù)培養(yǎng)基生產(chǎn)廠家的要求進行制備。所有培養(yǎng)基的性能均應(yīng)在使用前進行確認。6.24 Used microbiological media and strains should be decontaminated according to a standard procedure and disposed of in a manner to prevent the cross-contamination and retention of residues. The in-use shelf life of microbiological media should be established, documented and scientifically justified.使用過的微生物培養(yǎng)基和菌種應(yīng)根據(jù)標(biāo)準(zhǔn)程序避免污染，其處理方式應(yīng)能防止交叉污染和殘留。應(yīng)建立、記錄并科學(xué)判定微生物培養(yǎng)基的使用壽命。6.25 Animals used for testing components, materials or products, should, where appropriate, be quarantined before use. They should be maintained and controlled in a manner that assures their suitability for the intended use. They should be identified, and adequate records should be maintained, showing the history of their use.用于測試成分、物料或產(chǎn)品的動物，適當(dāng)時，在使用前應(yīng)進行隔離。其維護和控制方式應(yīng)能保證適用于其用途。應(yīng)對其進行標(biāo)識，保留充分的記錄顯示其使用歷史。On-going stability programme 持續(xù)穩(wěn)定性試驗方案6.26 After marketing, the stability of the medicinal product should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package.上市后，藥品的穩(wěn)定性應(yīng)根據(jù)適當(dāng)?shù)某掷m(xù)方案進行監(jiān)控，這樣可以發(fā)現(xiàn)所有與上市包裝配方有關(guān)的穩(wěn)定性問題（例如，雜質(zhì)水平變化、溶出度概況變化）。6.27 The purpose of the on-going stability programme is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labelled storage conditions.持續(xù)穩(wěn)定性考察的目的是在貨架期內(nèi)對產(chǎn)品進行監(jiān)控，確認產(chǎn)品在標(biāo)識的存貯條件下能，或預(yù)期能符合質(zhì)量標(biāo)準(zhǔn)。6.28 This mainly applies to the medicinal product in the package in which it is sold, but consideration should also be given to the inclusion in the programme of bulk product. For example, when the bulk product is stored for a long period before being packaged and/or shipped from a manufacturing site to a packaging site, the impact on the stability of the packaged product should be evaluated and studied under ambient conditions. In addition, consideration should be given to intermediates that are stored and used over prolonged periods. Stability studies on reconstituted product are performed during product development and need not be monitored on an on-going basis. However, when relevant, the stability of reconstituted product can also be monitored.這主要適用于市售包裝的藥品，但也要考慮散裝產(chǎn)品。例如，如果散裝產(chǎn)品在包裝和/或從生產(chǎn)場所發(fā)運至包裝場所前存貯了相當(dāng)長時間，則包裝后產(chǎn)品穩(wěn)定性受到的影響需要進行評估，并在室溫條件下進行考察。另外，還要考慮存貯并在延長的時間內(nèi)使用的中間體。再生產(chǎn)品的穩(wěn)定性研究已經(jīng)在研發(fā)期間做過了，不需要持續(xù)考察。但如果需要，也應(yīng)該監(jiān)控再生產(chǎn)品的穩(wěn)定性。6.29 The on-going stability programme should be described in a written protocol following the general rules of Chapter 4 and results formalised as a report. The equipment used for the ongoing stability programme (stability chambers among others) should be qualified and maintained following the general rules of Chapter 3 and Annex 15.持續(xù)穩(wěn)定性試驗應(yīng)在一份書面方案中描述，應(yīng)符合第4章的一般規(guī)則，試驗結(jié)果應(yīng)匯總作為一份報告。持續(xù)穩(wěn)定性試驗所用設(shè)備（穩(wěn)定性考察箱）應(yīng)根據(jù)第3章和附錄15的一般要求進行確認和維護。6.30 The protocol for an on-going stability programme should extend to the end of the shelf life period and should include, but not be limited to, the following parameters:持續(xù)穩(wěn)定性計劃方案應(yīng)延長至產(chǎn)品的貨架期，方案應(yīng)包括，但不僅限于以下項目：i. Number of batch(es) per strength and different batch sizes, if applicable;適用時，每個劑量和不同批量的批數(shù)ii. Relevant physical, chemical, microbiological and biological test methods;相關(guān)物理、化學(xué)、微生物和生物檢測方法iii. Acceptance criteria;可接受標(biāo)準(zhǔn)iv. Reference to test methods;檢驗方法引用標(biāo)準(zhǔn)v. Description of the container closure system(s);容器密閉系統(tǒng)的描述vi. Testing intervals (time points);檢測間隔（時間點）vii. Description of the conditions of storage (standardised ICH/VICH conditions for long term testing, consistent with the product labelling, should be used);存貯條件的描述（ICH/VICH長期穩(wěn)定性標(biāo)準(zhǔn)條件，應(yīng)與產(chǎn)品標(biāo)簽一致）viii. Other applicable parameters specific to the medicinal product.藥品特定的其它適用參數(shù)6.31 The protocol for the on-going stability programme can be different from that of the initial longterm stability study as submitted in the marketing authorisation dossier provided that this is justified and documented in the protocol (for example the frequency of testing, or when updating to ICH/VICH recommendations).如果經(jīng)過證明，并記錄在方案中（例如，檢測頻次，或根據(jù)ICH/VICH建議更新），則在檢的穩(wěn)定性方案可以與初始提交申報上市許可的長期穩(wěn)定性試驗方案不同。6.32 The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none are produced during that year). For products where on-going stability monitoring would normally require testing using animals and no appropriate alternative, validated techniques are available, the frequency of testing may take account of a risk-benefit approach. The principle of bracketing and matrixing designs may be applied if scientifically justified in the protocol.批數(shù)和檢測頻次應(yīng)能提供足夠量的數(shù)據(jù)來進行趨勢分析。除非另有說明，在生產(chǎn)品種每個劑量、每個內(nèi)包形式，如果對穩(wěn)定性有影響的話，至少每年增加一批至穩(wěn)定性試驗中（除非該年度未生產(chǎn)該品種）。對于正常需要用動物進行檢測，且并沒有適當(dāng)?shù)目梢蕴娲?、?jīng)過驗證的技術(shù)的情況，其測試頻次可以采用風(fēng)險-利益權(quán)衡方法決定。如果在方案中經(jīng)過科學(xué)論證，也可以采用括號法和矩陣法設(shè)計原則。6.33 In certain situations, additional batches should be included in the on-going stability programme.在特定情形下，要增加批次到持續(xù)穩(wěn)定性試驗中。For example, an on-going stability study