4.4 Containment 4.4 限制

　　4.40 Dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosprins.

　　4.40 在高致敏性物質(zhì)，如青霉素或頭孢菌素類的生產(chǎn)中，應(yīng)當(dāng)使用專用的生產(chǎn)區(qū)，包括設(shè)施、空氣處理設(shè)備和/或工藝設(shè)備。

　　4.41 The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

　　4.41 當(dāng)涉及具有感染性、高藥理活性或毒性的物料時(shí)(如，激素類或抗腫瘤類)，也應(yīng)當(dāng)考慮專用的生產(chǎn)區(qū)，除非已建立并維持一套經(jīng)驗(yàn)證的滅活和/或清洗程序。

　　4.42 Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another. 4.42 應(yīng)當(dāng)建立并實(shí)施相應(yīng)的措施，防止由于在各專用區(qū)域間流動(dòng)的人員和物料而造成的交叉污染。

　　4.43 Any production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials, such as herbicides and pesticides, should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic nonpharmaceutical materials should be separate from APIs.

　　4.43 劇毒的非藥用物質(zhì)，如除草劑、殺蟲劑的任何生產(chǎn)活動(dòng)(包括稱重、研磨或包裝)都不應(yīng)當(dāng)使用生產(chǎn)原料藥所使用的廠房和/或設(shè)備。這類劇毒非藥用物質(zhì)的處理和儲(chǔ)存都應(yīng)當(dāng)與原料藥分開(kāi)。

　　4.5 Lighting 4.5 照明

　　4.50 Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.

　　4.50 所有區(qū)域都應(yīng)當(dāng)提供充足的照明，以便于清洗、保養(yǎng)或其它操作。

　　4.6 Sewage and Refuse 4.6 排污和垃圾

　　4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.

　　4.60 進(jìn)入和流出廠房及鄰近區(qū)域的污水、垃圾和其它廢物(如生產(chǎn)中的固態(tài)、液態(tài)或氣態(tài)的副產(chǎn)物)，應(yīng)當(dāng)安全、及時(shí)、衛(wèi)生的處理。廢物的容器和/或管道應(yīng)當(dāng)顯著地標(biāo)明。

　　4.7 Sanitation and Maintenance 4.7 衛(wèi)生和保養(yǎng)

　　4.70 Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.

　　4.70 生產(chǎn)中間體和原料藥的廠房應(yīng)當(dāng)適當(dāng)?shù)乇ｐB(yǎng)、維修并保持清潔。

　　4.71 Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.

　　4.71 應(yīng)當(dāng)制定書面程序來(lái)分配衛(wèi)生工作的職責(zé)，并描述用于清潔廠房和設(shè)施的清潔的計(jì)劃、方法、設(shè)備和材料。

　　4.72 When necessary, written procedures should be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labeling materials, intermediates, and APIs.

　　.72 必要時(shí)，還應(yīng)當(dāng)對(duì)合適的滅鼠藥、殺蟲劑、殺真菌劑、煙熏劑和清潔消毒劑的使用制定書面程序，以避免對(duì)設(shè)備、原料、包裝/標(biāo)簽、中間體和原料藥的污染。

　　5. PROCESS EQUIPMENT 5. 工藝設(shè)備

　　5.1 Design and Construction 5.1 設(shè)計(jì)和結(jié)構(gòu)

　　5.10 Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation (where appropriate), and maintenance.

　　5.10 中間體和原料藥生產(chǎn)中使用的設(shè)備應(yīng)當(dāng)有合理的設(shè)計(jì)和足夠的尺寸，并且放置在適宜于其使用、清潔、消毒(根據(jù)情況而定)和保養(yǎng)的地方。

　　5.11 Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.

　　5.11 設(shè)備的構(gòu)造中與原料、中間體或原料藥接觸的表面不會(huì)改變中間體和原料藥的質(zhì)量而使其不符合法定的或其他已規(guī)定的質(zhì)量標(biāo)準(zhǔn)。

　　5.12 Production equipment should only be used within its qualified operating range.

　　5.12 生產(chǎn)設(shè)備應(yīng)該只在其確認(rèn)的操作范圍內(nèi)運(yùn)行。

　　5.13 Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.

　　5.13 中間體或原料藥生產(chǎn)過(guò)程中使用的主要設(shè)備(如反應(yīng)釜、貯存容器)和永久性安裝的工藝管道，應(yīng)當(dāng)作適當(dāng)?shù)淖R(shí)別標(biāo)志。

　　5.14 Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter the quality of APIs or intermediates beyond the official or other established specifications. Any deviations from this practice should be evaluated to ensure that there are no detrimental effects on the material’s fitness for use. Wherever possible, food grade lubricants and oils should be used.

　　5.14 設(shè)備運(yùn)轉(zhuǎn)所需的任何物質(zhì)，如潤(rùn)滑劑、加熱液或冷卻劑，不應(yīng)當(dāng)與中間體或原料藥接觸，以免影響其質(zhì)量，導(dǎo)致無(wú)法達(dá)到法定的或其它已規(guī)定的質(zhì)量標(biāo)準(zhǔn)。任何違背該規(guī)定的情況都應(yīng)當(dāng)進(jìn)行評(píng)估，以確保對(duì)該物質(zhì)效果的適用性沒(méi)有有害的影響。可能的話，應(yīng)當(dāng)使用食用級(jí)的潤(rùn)滑劑和油類。

　　5.15 Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.

　　5.15 應(yīng)當(dāng)盡量使用關(guān)閉的或封閉的設(shè)備。若使用開(kāi)放設(shè)備或設(shè)備被打開(kāi)時(shí)，應(yīng)當(dāng)采取適當(dāng)?shù)念A(yù)防措施，將污染的風(fēng)險(xiǎn)降至最小。

　　5.16 A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems).

　　5.16 應(yīng)當(dāng)保存一套現(xiàn)在的設(shè)備和關(guān)鍵裝置的圖紙(如測(cè)試設(shè)備和公用系統(tǒng))。

　　5.2 Equipment Maintenance and Cleaning 5.2 設(shè)備保養(yǎng)和清潔

　　5.20 Schedules and procedures (including assignment of responsibility) should be established for the preventative maintenance of equipment.

　　5.20 應(yīng)當(dāng)制訂設(shè)備預(yù)防性保養(yǎng)的計(jì)劃和程序(包括職責(zé)的分配)。

　　5.21 Written procedures should be established for cleaning equipment release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:

　　5.21 應(yīng)當(dāng)制訂設(shè)備清洗及允許用于中間體和原料藥生產(chǎn)的書面程序。清潔程序應(yīng)當(dāng)盡量詳細(xì)，使操作者能對(duì)各類設(shè)備進(jìn)行可重復(fù)的、有效 的清洗。這些程序應(yīng)當(dāng)包括：

　　5.22 Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.

　　5.22 設(shè)備和用具應(yīng)當(dāng)清潔、存放，必要時(shí)還應(yīng)進(jìn)行消毒或滅菌，以防止污染或夾帶物質(zhì)影響中間體或原料藥的質(zhì)量導(dǎo)致其不符合法定的或其它已規(guī)定的質(zhì)量標(biāo)準(zhǔn)。

　　5.23 Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g., degradants or objectionable levels of microorganisms).

　　5.23 若設(shè)備指定用于同一中間體或原料藥的連續(xù)生產(chǎn)，或連續(xù)批號(hào)的集中生產(chǎn)，應(yīng)當(dāng)在適宜是時(shí)間間隔對(duì)設(shè)備進(jìn)行清洗，以防污染物(如降解物或達(dá)到有害程度的微生物)的累積和夾帶。

　　5.24 Nondedicated equipment should be cleaned between production of different materials to prevent cross-contamination.

　　5.24 非專用設(shè)備應(yīng)當(dāng)在生產(chǎn)不同物料之間作清潔，以防止交叉污染。

　　5.25 Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.

　　5.25 對(duì)殘留物的可接受限量、清洗程序和清潔劑的選擇應(yīng)當(dāng)規(guī)定并說(shuō)明理由。

　　5.26 Equipment should be identified as to its contents and its cleanliness status by appropriate means.

　　5.26 設(shè)備內(nèi)容物及其清潔狀況應(yīng)當(dāng)用合適的方法標(biāo)明。

　　5.3 Calibration 5.3 校驗(yàn)

　　5.30 Control, weighing, measuring, monitoring, and testing equipment critical for ensuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.

　　5.30 用于保證中間體或原料藥質(zhì)量的控制、稱量、測(cè)量、監(jiān)測(cè)和測(cè)試設(shè)備應(yīng)當(dāng)按照書面程序和規(guī)定的計(jì)劃周期進(jìn)行校驗(yàn)。

　　5.31 Equipment calibrations should be performed using standards traceable to certified standards, if they exist.

　　5.31 如果有的話，應(yīng)當(dāng)用可追溯到已檢定的標(biāo)準(zhǔn)的標(biāo)準(zhǔn)來(lái)進(jìn)行設(shè)備校驗(yàn)。

　　5.32 Records of these calibrations should be maintained. 5.32 校驗(yàn)記錄應(yīng)當(dāng)加以保存。

　　5.33 The current calibration status of critical equipment should be known and verifiable.

　　5.33 應(yīng)當(dāng)知道并可證實(shí)關(guān)鍵設(shè)備的當(dāng)前校驗(yàn)狀態(tài)。

　　5.34 Instruments that do not meet calibration criteria should not be used.

　　5.34 不應(yīng)當(dāng)使用不符合校驗(yàn)標(biāo)準(zhǔn)的儀器。

　　5.35 Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an effect on the quality of the intermediates(s) or API(s) manufactured using this equipment since the last successful calibration.

　　5.35 應(yīng)當(dāng)調(diào)查關(guān)鍵儀器相對(duì)于合格校驗(yàn)標(biāo)準(zhǔn)的偏差，以便確定這些偏差對(duì)自上次成功校驗(yàn)以來(lái)，用該設(shè)備生產(chǎn)的中間體或原料藥的質(zhì)量是否有影響。

　　5.4 Computerized Systems 5.4 計(jì)算機(jī)控制系統(tǒng)

　　5.40 GMP-related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity, and criticality of the computerized application.

　　5.40 與GMP相關(guān)的計(jì)算機(jī)化系統(tǒng)應(yīng)當(dāng)驗(yàn)證。驗(yàn)證的深度和廣度取決于計(jì)算機(jī)應(yīng)用的差異性、復(fù)雜性和關(guān)鍵性。

　　5.41 Appropriate installation and operational qualifications should demonstrate the suitability of computer hardware and software to perform assigned tasks.

　　5.41 適當(dāng)?shù)陌惭b確認(rèn)和操作確認(rèn)應(yīng)當(dāng)能證明計(jì)算機(jī)硬件和軟件適合于執(zhí)行指定的任務(wù)。

　　5.42 Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.

　　5.42 經(jīng)證明合格的商用軟件不需要進(jìn)行系統(tǒng)水平的檢驗(yàn)。如果現(xiàn)行系統(tǒng)在安裝時(shí)沒(méi)有進(jìn)行驗(yàn)證，有合適的文件證明時(shí)可進(jìn)行回顧性驗(yàn)證。

　　5.43 Computerized system should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g., system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made.

　　5.43 計(jì)算機(jī)化系統(tǒng)應(yīng)當(dāng)有足夠的控制，以防止未經(jīng)許可存取或改動(dòng)數(shù)據(jù)。應(yīng)當(dāng)有防止數(shù)據(jù)丟失(如系統(tǒng)關(guān)閉而數(shù)據(jù)未捕獲)的控制。任何數(shù)據(jù)的變更、上一次輸入、誰(shuí)作的變更和什么時(shí)候變更都應(yīng)當(dāng)有記錄。

　　5.44 Written procedures should be available for the operation and maintenance of computerized system.

　　5.44 應(yīng)當(dāng)有計(jì)算機(jī)化系統(tǒng)操作和維護(hù)的書面程序。

　　5.45 Where critical data are being entered manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself.

　　5.45 手工輸入關(guān)鍵性數(shù)據(jù)時(shí)，應(yīng)當(dāng)另外檢查輸入的準(zhǔn)確性。這可由第二位操作人員或系統(tǒng)本身來(lái)進(jìn)行。

　　5.46 Incidents related to computerized system that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.

　　5.46 應(yīng)當(dāng)加以記錄可能影響中間體或原料藥質(zhì)量、或者記錄或測(cè)試結(jié)果可靠性的與計(jì)算機(jī)化系統(tǒng)有關(guān)的偶發(fā)事件，并作調(diào)查。

　　5.47 Changes to computerized system should be made according to a change procedure and should be formally authorized, documented, and tested. Records should be kept of all changes, including modifications and enhancements made to the hardware, software, and any other critical component of the system. These records should demonstrate that the system is maintained in a validated state.

　　5.47 對(duì)計(jì)算機(jī)化系統(tǒng)所作的變更應(yīng)當(dāng)按照變更程序進(jìn)行，并應(yīng)當(dāng)經(jīng)過(guò)正式批準(zhǔn)、記錄成文并作測(cè)試。所有變更記錄都應(yīng)當(dāng)保存，包括對(duì)系統(tǒng)的硬件、軟件和任何其它關(guān)鍵組件的修改和升級(jí)。這些記錄應(yīng)當(dāng)證明該系統(tǒng)維持在驗(yàn)證過(guò)的狀態(tài)。

　　5.48 If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized system.

　　5.48 如果計(jì)算機(jī)的故障或失效會(huì)導(dǎo)致記錄的永久丟失，則應(yīng)當(dāng)提供備份系統(tǒng)。所有計(jì)算機(jī)化的系統(tǒng)都應(yīng)當(dāng)有數(shù)據(jù)保護(hù)措施。

　　5.49 Data can be recorded by a second means in addition to the computer system.

　　5.49 除計(jì)算機(jī)系統(tǒng)之外，數(shù)據(jù)可以用第二種方式記錄。

　　6. DOCUMENTATION AND RECORDS 6. 文件和記錄

　　6.1 Documentation System and Specifications 6.1 文件系統(tǒng)和質(zhì)量標(biāo)準(zhǔn)

　　6.10 All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures. Such documents can be in paper or electronic form.

　　6.10 與中間體或原料藥生產(chǎn)有關(guān)的所有文件都應(yīng)當(dāng)按照書面程序進(jìn)行擬定、審核、批準(zhǔn)和分發(fā)。這些文件可以是紙張或電子形式。

　　6.11 The issuance, revision, superseding, and withdrawal of all documents should be controlled by maintaining revision histories.

　　6.11 所有文件的發(fā)放、修訂、替換和收回應(yīng)當(dāng)通過(guò)保存修訂歷史來(lái)控制。

　　6.12 A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

　　6.12 應(yīng)當(dāng)制訂一個(gè)保存所有適用文件(如開(kāi)發(fā)歷程報(bào)告、擴(kuò)產(chǎn)報(bào)告、技術(shù)轉(zhuǎn)移報(bào)告、工藝驗(yàn)證報(bào)告、培訓(xùn)記錄、生產(chǎn)記錄、控制記錄和分發(fā)記錄)的程序。應(yīng)當(dāng)規(guī)定這些文件的保存期。

　　6.13 All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.

　　6.13 所有生產(chǎn)、控制、銷售記錄都應(yīng)保留至該批的有效期后至少一年。對(duì)于有復(fù)驗(yàn)期的原料藥，記錄應(yīng)當(dāng)保留至該批全部發(fā)出后三年。

　　6.14 When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still legible.

　　6.14 做記錄時(shí)，應(yīng)當(dāng)在剛做操作活動(dòng)后就在所提供的空白處以不易擦掉的方式填寫，并標(biāo)明填寫者。修改記錄時(shí)應(yīng)當(dāng)注明日期、簽名并保持原來(lái)的記錄仍可識(shí)讀。

　　6.15 During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

　　6.15 在保存期間，記錄的原件或副本都應(yīng)保留在記錄中描述的活動(dòng)發(fā)生的地方。能以電子或其它方式從另一地點(diǎn)即時(shí)恢復(fù)的記錄也可以接受。

　　6.16 Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

　　6.16 質(zhì)量標(biāo)準(zhǔn)、指令、規(guī)程和記錄保存方式可以是原件，或者真實(shí)的副本如影印本、縮微膠卷、縮微平片，或其它原始記錄的準(zhǔn)確復(fù)制件。在使用壓縮技術(shù)如縮微膠卷或電子記錄時(shí)，應(yīng)當(dāng)有適當(dāng)?shù)闹苽浼垙埜北镜幕謴?fù)設(shè)備和方法。

　　6.17 Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically affect quality. Acceptance criteria should be established and documented for in-process controls.

　　6.17 應(yīng)當(dāng)制訂原料、中間體(必要時(shí))、原料藥和標(biāo)簽及包裝材料的質(zhì)量標(biāo)準(zhǔn)。此外，應(yīng)當(dāng)為工藝助劑、墊圈，或中間體或原料藥生產(chǎn)中使用的能決定性地影響質(zhì)量的物料制訂質(zhì)量標(biāo)準(zhǔn)。中間控制應(yīng)當(dāng)制定可接受的標(biāo)準(zhǔn)，并成文備查。

　　6.18 If electronic signatures are used on documents, they should be authenticated and secure.6.18如果文件采用電子簽名，它們應(yīng)當(dāng)經(jīng)過(guò)證實(shí)，并且確保其安全可靠。

　　6.2 Equipment cleaning and Use Record 6.2 設(shè)備的清潔和使用記錄

　　6.20 Records of major equipment use, cleaning, sanitation, and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment and the person who performed the cleaning and maintenance.

　　6.20 主要設(shè)備的使用、清潔、消毒和/或滅菌和保養(yǎng)記錄應(yīng)當(dāng)記有日期、時(shí)間(如有必要的話)、產(chǎn)品、設(shè)備中加工的每批批號(hào)以及進(jìn)行清潔和保養(yǎng)的人。

　　6.21 If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of intermediate or API follow in traceable sequence. In case where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.

　　6.21 如果設(shè)備專門用于一種中間體或原料藥的生產(chǎn)，而且該中間體或原料藥的批號(hào)有可追溯性的順序，那就不需要有單獨(dú)的設(shè)備記錄。專門設(shè)備的清潔、保養(yǎng)及使用記錄可以作為批記錄的一部分或單獨(dú)保存。

　　6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials

　　6.3 原料、中間體、原料藥的標(biāo)簽和包裝材料的記錄

　　6.30 Records should be maintained including:The name of the manufacturer, identity, and quantity of each shipment of each batch of raw materials, intermediates, or labeling and packaging materials for API’s; the name of the supplier; the supplier’s control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt

　　6.30 需保存的記錄應(yīng)當(dāng)包括： 每次到貨的每批原料、中間體、原料藥標(biāo)簽和包裝材料的生產(chǎn)商的名稱，標(biāo)識(shí)和數(shù)量;供應(yīng)商的名稱、供應(yīng)商的管理編號(hào)，或其它識(shí)別號(hào)碼;物料接收編號(hào)和接收日期;

　　6.31 Master (approved) labels should be maintained for comparison to issued labels.

　　6.31 標(biāo)準(zhǔn)標(biāo)簽(已批準(zhǔn)的)應(yīng)當(dāng)保留，用來(lái)與發(fā)放的標(biāo)簽作比較。

　　6.4 Master Production Instructions (Master Production and Control Records)

　　6.4 生產(chǎn)工藝規(guī)程(主生產(chǎn)和控制記錄)

　　6.40 To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).

　　6.40 為確保批與批的一致性，每種中間體和原料藥的生產(chǎn)工藝規(guī)程應(yīng)當(dāng)由一人擬定、注明日期并簽名，并由質(zhì)量部門的另一人獨(dú)立進(jìn)行檢查、填寫日期和簽名。

　　6.5 Batch Production Records (Batch Production and Control Records)

　　6.5 批生產(chǎn)記錄(批生產(chǎn)和控制記錄)

　　6.50 Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

　　6.50 應(yīng)當(dāng)為每種中間體和原料藥準(zhǔn)備批生產(chǎn)記錄，內(nèi)容應(yīng)當(dāng)包括與各批生產(chǎn)和控制有關(guān)的完整資料。批記錄發(fā)放之前，應(yīng)當(dāng)檢查版本是否正確，是否是相應(yīng)生產(chǎn)規(guī)程的準(zhǔn)確明了的再現(xiàn)。如果批生產(chǎn)記錄是按主文件的另一獨(dú)立部分制定的，該文件應(yīng)當(dāng)包括對(duì)現(xiàn)行的生產(chǎn)工藝規(guī)程的參考。

　　6.51 These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the production code together with the date and time can serve as the unique identifier until the final number is allocated.

　　6.51 批記錄在發(fā)放時(shí)應(yīng)當(dāng)有一個(gè)唯一的批號(hào)或標(biāo)識(shí)號(hào)，有日期和簽名。連續(xù)生產(chǎn)時(shí)，在最終批號(hào)確定前，可以將產(chǎn)品代碼、日期和時(shí)間結(jié)合起來(lái)作為唯一的識(shí)別符。

　　6.53 Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation. 6.53 應(yīng)當(dāng)建立并執(zhí)行一種書面程序，對(duì)在符合規(guī)格上有重大偏差或不合格的一批中間體或原料藥進(jìn)行調(diào)查。調(diào)查還應(yīng)當(dāng)延伸到與這批失誤或偏差有關(guān)的其它批號(hào)。

　　6.6 Laboratory Control Records 6.6 實(shí)驗(yàn)室控制記錄

　　6.60 Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:

　　A description of samples received for testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing

　　A statement of or reference to each test method used

　　A statement of the weight or measure of sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions

　　A complete record of all raw data generated during each test, in addition to graphs, charts and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested

　　A record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors

　　A statement of the test results and how they compare with established acceptance criteria

　　The signature of the person who performed each test and the date(s) the tests were performed

　　The date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards 6.60 實(shí)驗(yàn)室控制記錄應(yīng)當(dāng)包括從為了確保符合規(guī)定的規(guī)格和標(biāo)準(zhǔn)所做的所有測(cè)試中得到的下列完整的數(shù)據(jù)，包括下列檢驗(yàn)和測(cè)定：

　　所收到檢測(cè)樣品的描述，包括物料名稱和來(lái)源、批號(hào)或其它編號(hào)、取樣日期，某些情況下記錄收到樣品的量和時(shí)間;

　　每個(gè)所用檢測(cè)方法的陳述或參引;

　　按方法描述的所用樣品重量或計(jì)量;標(biāo)準(zhǔn)品、試劑和標(biāo)準(zhǔn)溶液的配制和測(cè)試的數(shù)據(jù)或相互參考;

　　除了正確地標(biāo)明所測(cè)試的特定物料和批號(hào)的實(shí)驗(yàn)室儀器的圖譜、圖表和光譜外，還有一套從每次測(cè)試得到的所有原始數(shù)據(jù)的完整記錄;

　　與測(cè)試有關(guān)的所有計(jì)算記錄，包括測(cè)量單位、轉(zhuǎn)換因子以及等量因子等;

　　檢測(cè)結(jié)果的陳述以及與規(guī)定的認(rèn)可標(biāo)準(zhǔn)的比較;

　　每項(xiàng)測(cè)試的操作者的簽名以及測(cè)試的日期;

　　日期和第二個(gè)人的簽名，表明對(duì)原記錄的準(zhǔn)確性、完整性和規(guī)定的標(biāo)準(zhǔn)的符合性已復(fù)核過(guò)。

　　6.7 Batch Production Record Review 6.7批生產(chǎn)記錄審核

　　6.70 Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labeling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.

　　6.70 應(yīng)當(dāng)制定并執(zhí)行審核和批準(zhǔn)批生產(chǎn)記錄和實(shí)驗(yàn)室控制記錄，包括包裝和貼簽的書面程序，以便放行或分發(fā)前確定中間體或原料藥是否符合規(guī)定標(biāo)準(zhǔn)。

　　6.71 Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of noncritical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).

　　6.71 在一批原料藥放行或分發(fā)之前，關(guān)鍵工序的批生產(chǎn)記錄和實(shí)驗(yàn)室控制記錄應(yīng)當(dāng)由質(zhì)量部門審核和批準(zhǔn)。非關(guān)鍵性工序的生產(chǎn)和實(shí)驗(yàn)室控制記錄可按照經(jīng)質(zhì)量部門批準(zhǔn)的程序，由有資格的生產(chǎn)人員或其它部門審核。

　　6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.

　　6.72 在批放行前，所有偏差，調(diào)查和不合格報(bào)告都應(yīng)當(dāng)作為批記錄的一部分進(jìn)行審核。

　　6.73 The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

　　6.73 質(zhì)量部門可將發(fā)放中間體的職責(zé)和權(quán)力委派給生產(chǎn)部門，運(yùn)往生產(chǎn)商控制范圍以外的中間體除外。

　　7. MATERIALS MANAGEMENT 7. 物料管理

　　7.1 General Controls 7.1 控制通則

　　7.10 There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

　　7.10 應(yīng)當(dāng)有書面程序闡明物料的接收、鑒別、待驗(yàn)、貯存、搬運(yùn)、取樣、測(cè)試和批準(zhǔn)或拒收。

　　7.11 Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.

　　7.11 原料藥和/或中間體生產(chǎn)商應(yīng)當(dāng)有對(duì)關(guān)鍵原料供應(yīng)商的評(píng)估系統(tǒng)。

　　7.12 Materials should be purchased against an agreed specification, from a supplier, or suppliers, approved by the quality unit(s).

　　7.12 應(yīng)當(dāng)根據(jù)已確定的規(guī)格從經(jīng)過(guò)質(zhì)量部門核準(zhǔn)的一個(gè)或多個(gè)供應(yīng)商處購(gòu)買物料。

　　7.13 If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.7.13 如果關(guān)鍵物料的供應(yīng)商不是該物料的生產(chǎn)商，原料藥或中間體的生產(chǎn)商應(yīng)當(dāng)獲知該物料生產(chǎn)商的名稱和地址。

　　7.14 Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.

　　7.14 關(guān)鍵原料的供應(yīng)商的變更應(yīng)當(dāng)參照第13章變更控制進(jìn)行。

　　7.2 Receipt and Quarantine 7.2接收和待驗(yàn)

　　7.20 Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labeling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined, or tested, as appropriate, and released for use.

　　7.20 一旦收到物料而尚未驗(yàn)收，應(yīng)當(dāng)目測(cè)檢查物料每個(gè)或每組包裝容器的標(biāo)簽是否正確(包括如果供應(yīng)商所用名稱與內(nèi)部使用的名稱不一致，應(yīng)當(dāng)檢查其相互關(guān)系)、容器是否損壞、密封處和開(kāi)啟證據(jù)有無(wú)破裂或污染。物料應(yīng)當(dāng)存放的待驗(yàn)區(qū)，直至它們被取樣、檢查或酌情測(cè)試，并放行使用。

　　7.21 Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.

　　7.21 在進(jìn)廠的物料與現(xiàn)有的庫(kù)存(如儲(chǔ)倉(cāng)中的溶劑或貨物)混合之前，應(yīng)當(dāng)確認(rèn)貨是否對(duì)、必要時(shí)進(jìn)行測(cè)試并放行。應(yīng)當(dāng)有程序來(lái)防止把來(lái)料錯(cuò)放到現(xiàn)有的庫(kù)存中。

　　7.22 If bulk deliveries are made in nondedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following:

　　對(duì)于非專用槽車運(yùn)送的大宗物料，應(yīng)當(dāng)確保沒(méi)有來(lái)自槽車的交叉污染?？捎靡韵碌囊环N或幾種方法來(lái)提供這種保證：

　　7.23 Large storage containers and their attendant manifolds, filling, and discharge lines should be appropriately identified.

　　7.23 大的儲(chǔ)存容器及其隨附的管路、填充和排放管都應(yīng)當(dāng)適當(dāng)標(biāo)明。

　　7.24 Each container or grouping of containers (batches) of materials should be assigned and identified with a distinctive code, batch, or receipt number. This number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch.

　　7.24 每個(gè)或每組物料容器(幾批)的物料都應(yīng)當(dāng)指定并標(biāo)上編號(hào)、批號(hào)或接收號(hào)。此號(hào)碼應(yīng)當(dāng)用于記錄每批的處置情況。應(yīng)當(dāng)有一個(gè)識(shí)別每批狀態(tài)的系統(tǒng)。

　　7.3 Sampling and Testing of Incoming Production Materials 7.3 進(jìn)廠物料的取樣與測(cè)試

　　7.30 At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below. A supplier’s certificate of analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers.

　　7.30 除了7.32中指出的物料，對(duì)于每批物料至少要做一個(gè)鑒別試驗(yàn)。在生產(chǎn)商對(duì)供應(yīng)商有一套審計(jì)體系的前提下，供應(yīng)商的分析報(bào)告可以用來(lái)替代其他項(xiàng)目的測(cè)試。

　　7.31 Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Complete analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis. Reliability of certificates of analysis should be checked at regular intervals.

　　7.31 對(duì)供應(yīng)商的核準(zhǔn)應(yīng)當(dāng)包括一次評(píng)估，提供足夠的證據(jù)(如過(guò)去的質(zhì)量記錄)證明該生產(chǎn)商始終都能提供符合質(zhì)量標(biāo)準(zhǔn)的物料。在減少內(nèi)部測(cè)試之前至少應(yīng)當(dāng)對(duì)三批物料作全檢。然而，最低限度每隔一定時(shí)間應(yīng)當(dāng)進(jìn)行一次全檢，并與分析報(bào)告進(jìn)行比較。分析報(bào)告的可靠性應(yīng)當(dāng)定期進(jìn)行檢查。

　　7.32 Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s certificate of analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.

　　7.32 工藝助劑、有害或劇毒的原料、其它特殊物料、或轉(zhuǎn)移到公司控制范圍內(nèi)的另一個(gè)部門的物料不用測(cè)試，前提是能取得生產(chǎn)商的分析報(bào)告，證明這些原料符合規(guī)定的質(zhì)量標(biāo)準(zhǔn)。對(duì)容器、標(biāo)簽和批號(hào)記錄進(jìn)行目測(cè)檢查應(yīng)當(dāng)有助于鑒別這些原料。對(duì)這些物料不作現(xiàn)場(chǎng)測(cè)試應(yīng)當(dāng)說(shuō)明理由，并用文件證明。

　　7.33 Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quality needed for analysis.

　　7.33 取樣應(yīng)當(dāng)能代表被取的那批物料。取樣方法應(yīng)當(dāng)規(guī)定：取樣的容器數(shù)，取樣部位，每個(gè)容器的取樣量。取樣容器數(shù)和取樣量應(yīng)當(dāng)根據(jù)取樣方案來(lái)決定。取樣方案的制定要綜合考慮物料的重要程度、變異性、供應(yīng)商過(guò)去的質(zhì)量情況，以及分析需用量。

　　7.34 Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

　　7.34 應(yīng)當(dāng)在規(guī)定的地點(diǎn)，用規(guī)定的方法取樣，以避免取樣的物料被污染，或污染其它物料。

　　7.35 Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

　　7.35 被取樣的容器應(yīng)當(dāng)小心開(kāi)啟，隨后重新密封。這些容器應(yīng)當(dāng)做標(biāo)記表明樣品已抽取。

　　7.4 Storage 7.4儲(chǔ)存

　　7.40 Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

　　7.40 物料的搬運(yùn)和貯存應(yīng)當(dāng)防止降解、污染和交叉污染。

　　7.41 Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.

　　7.41 纖維板桶、袋子或盒裝物料應(yīng)當(dāng)離地貯存，并根據(jù)情況留出適當(dāng)空間便于清潔和檢查。

　　7.42 Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.

　　7.42 物料應(yīng)當(dāng)在對(duì)其質(zhì)量沒(méi)有不良影響的條件下和時(shí)限內(nèi)貯存，而且通常應(yīng)當(dāng)加以控制，做到先進(jìn)先出。

　　7.43 Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

　　7.43 某些裝在適當(dāng)容器中的物料可以存放在室外，只要識(shí)別標(biāo)簽保持清晰，而且容器在開(kāi)啟和使用前進(jìn)行適當(dāng)清潔。

　　7.44 Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorized use in manufacturing.

　　7.44 不合格物料應(yīng)當(dāng)做標(biāo)識(shí)，并用隔離系統(tǒng)控制，已防止未經(jīng)許可而用于生產(chǎn)。

　　7.5 Re-evaluation 7.5重新評(píng)估

　　7.50 Materials should be re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

　　7.50 應(yīng)當(dāng)根據(jù)情況對(duì)物料進(jìn)行重新評(píng)估以便確定其使用的適合性(例如長(zhǎng)期存放或暴露于熱或潮濕的環(huán)境中)。

　　8. PRODUCTION AND IN-PROCESS CONTROLS 8. 生產(chǎn)和過(guò)程控制

　　8.1 Production Operations 8.1 生產(chǎn)操作

　　8.10 Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.

　　8.10 用于生產(chǎn)中間體和原料藥的原料應(yīng)當(dāng)在適宜的條件下稱重或測(cè)量，以便不影響其使用的適合性。稱重和測(cè)量裝置應(yīng)當(dāng)有適合于其用途的精度。

　　8.11 If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:

　　8.11 如果某物料分出一部分留待以后的生產(chǎn)操作中使用，應(yīng)當(dāng)用適合的容器來(lái)盛裝該物料，并應(yīng)當(dāng)標(biāo)明下列信息：

　　8.12 Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.

　　8.12 關(guān)鍵的稱重、測(cè)量或分裝操作應(yīng)當(dāng)有人作證或接受相應(yīng)的控制。使用前，生產(chǎn)人員應(yīng)當(dāng)確認(rèn)該物料是要生產(chǎn)的中間體或原料藥的批記錄中指定的。

　　8.13 Other critical activities should be witnessed or subjected to an equivalent control.

　　8.13 其它關(guān)鍵活動(dòng)應(yīng)當(dāng)有人作證或接受相應(yīng)的控制。

　　8.14 Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

　　8.14 在生產(chǎn)過(guò)程中的指定步驟，實(shí)際收率應(yīng)當(dāng)與預(yù)計(jì)的收率作比較。具有合適范圍的預(yù)計(jì)收率應(yīng)當(dāng)根據(jù)以前的實(shí)驗(yàn)室、中試規(guī)?；蛏a(chǎn)的數(shù)據(jù)來(lái)確定。應(yīng)當(dāng)調(diào)查與關(guān)鍵工藝步驟有關(guān)的收率偏差，以確定其對(duì)相關(guān)批號(hào)最終質(zhì)量的影響或潛在影響。

　　8.15 Any deviation should be documented and explained. Any critical deviation should be investigated.

　　8.15 任何偏差都應(yīng)當(dāng)記錄，并作解釋。任何關(guān)鍵的偏差應(yīng)當(dāng)作調(diào)查。

　　8.16 The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

　　8.16 應(yīng)當(dāng)標(biāo)明主要設(shè)備的生產(chǎn)狀態(tài)，可以標(biāo)在每個(gè)設(shè)備上，或者用文件、計(jì)算機(jī)控制系統(tǒng)或其它替代的方法。

　　8.17 Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

　　8.17 對(duì)需要進(jìn)行返工或重新加工的物料應(yīng)當(dāng)適當(dāng)?shù)丶右钥刂疲乐刮唇?jīng)許可就使用。

　　8.2 Time Limits 8.2 時(shí)限

　　8.20 If time limits are specified in the master production instruction (see 6.40), these time limits should be met to ensure the quality of intermediates or APIs. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.

　　8.20 如果生產(chǎn)工藝規(guī)程(見(jiàn)6.40)中規(guī)定了時(shí)限，應(yīng)當(dāng)遵守這些時(shí)限，以保證中間體和原料藥的質(zhì)量。所有偏差都要有記錄并解釋原因。在加工到一個(gè)目標(biāo)值時(shí)(例如，調(diào)節(jié)pH、氫化、干燥到預(yù)定標(biāo)準(zhǔn))，時(shí)限可能就不合適了，因?yàn)榉磻?yīng)或加工步驟的完成是取決于過(guò)程中的取樣和測(cè)試的。

　　8.21 Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.

　　8.21 留作進(jìn)一步加工的中間體應(yīng)當(dāng)在適宜的條件下儲(chǔ)存，以保證其適宜于使用。

　　8.3 In-process Sampling and Controls 8.3 工序間的取樣和控制

　　8.30 Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the developmental stage or from historical data.

　　8.30 應(yīng)當(dāng)制定書面程序來(lái)監(jiān)測(cè)會(huì)造成中間體和原料藥質(zhì)量特性變異的工藝步驟的進(jìn)程，并控制其生產(chǎn)情況。工序間控制及其接受標(biāo)準(zhǔn)應(yīng)當(dāng)根據(jù)項(xiàng)目開(kāi)發(fā)階段或者以往的生產(chǎn)數(shù)據(jù)來(lái)確定。

　　8.31 The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).

　　8.31 綜合考慮所生產(chǎn)中間體和原料藥的特性，反應(yīng)類型，該工序?qū)Ξa(chǎn)品質(zhì)量影響的程度大小等因素來(lái)確定可接受的標(biāo)準(zhǔn)，檢測(cè)類型和范圍。前期生產(chǎn)的中間體控制標(biāo)準(zhǔn)可以松一些，越接近成品，中間控制的標(biāo)準(zhǔn)越嚴(yán)(如分離，純化)。

　　8.32 Critical in-process controls (and critical process monitoring), including control points and methods, should be stated in writing and approved by the quality unit(s).

　　8.32 關(guān)鍵的中間控制(和工藝監(jiān)測(cè))，包括控制點(diǎn)和方法，應(yīng)當(dāng)書面規(guī)定，并經(jīng)質(zhì)量部門批準(zhǔn)。

　　8.33 In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All test and results should be fully documented as part of the batch record.

　　8.33 中間控制可以由合格的生產(chǎn)部門的人員來(lái)進(jìn)行，而調(diào)節(jié)的工藝可以事先未經(jīng)質(zhì)量部門批準(zhǔn)，只要該調(diào)節(jié)在由質(zhì)量部門批準(zhǔn)的預(yù)先規(guī)定的限度以內(nèi)。所有測(cè)試及結(jié)果都應(yīng)當(dāng)作為批記錄的一部分全部歸檔。

　　8.34 Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.

　　8.34 應(yīng)當(dāng)制定書面程序，說(shuō)明中間物料、中間體和原料藥的取樣方法。取樣方案和程序應(yīng)當(dāng)基于科學(xué)合理的取樣實(shí)踐。

　　8.35 In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.

　　8.35 工序間取樣應(yīng)當(dāng)按能防止污染所取的樣品、其它中間體或原料藥的程序進(jìn)行。應(yīng)當(dāng)制定保證樣品收集后的完整性的程序。

　　8.36 Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

　　8.36 生產(chǎn)操作中的正常監(jiān)控過(guò)程和工藝調(diào)節(jié)過(guò)程中出現(xiàn)的超出標(biāo)準(zhǔn)的偏差(OOS)，通常情況不需要調(diào)查。

　　8.4 Blending Batches of Intermediates or APIs 8.4 中間體或原料藥的混批

　　8.40 For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.

　　8.40 根據(jù)本文件的目的，混合的定義是為了生產(chǎn)出均勻的中間體或原料藥而將同一質(zhì)量標(biāo)準(zhǔn)的物料混在一起的過(guò)程。同一批號(hào)幾部分(例如，收集一個(gè)結(jié)晶批號(hào)出來(lái)的幾次離心機(jī)裝的料)的工藝間的混合，或者混合從幾個(gè)批號(hào)來(lái)的部分作進(jìn)一步加工，看作是生產(chǎn)工藝的一部分，而不是混合。

　　8.41 Out-of-specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

　　8.41 不合格的批號(hào)不能與其他批號(hào)混合在一起來(lái)達(dá)到符合質(zhì)量標(biāo)準(zhǔn)的目的。混合的每一個(gè)批號(hào)都應(yīng)該是用規(guī)定的生產(chǎn)工藝生產(chǎn)的，混合前應(yīng)當(dāng)單獨(dú)檢測(cè)，并符合相應(yīng)的質(zhì)量標(biāo)準(zhǔn)。

　　8.43 Blending processes should be adequately controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate.

　　混合過(guò)程應(yīng)當(dāng)充分控制并記錄，混合后的批號(hào)應(yīng)當(dāng)根據(jù)情況進(jìn)行測(cè)試，以確認(rèn)是否達(dá)到質(zhì)量標(biāo)準(zhǔn)。

　　8.44 The batch record of the blending process should allow traceability back to the individual batches that make up the blend.

　　8.44 混合過(guò)程的批記錄應(yīng)當(dāng)允許追溯到參與混合的每個(gè)單獨(dú)批號(hào)。

　　8.45 Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process.

　　8.45 如果原料藥的物理性質(zhì)至關(guān)重要(例如，用于固體口服制劑或混懸劑的原料藥)，混合工藝應(yīng)當(dāng)驗(yàn)證，以顯示混合后批號(hào)的均勻性。驗(yàn)證應(yīng)當(dāng)包括測(cè)試可能受混合過(guò)程影響的關(guān)鍵屬性(例如，粒度分布，堆密度和振實(shí)密度)。

　　8.46 If the blending could adversely affect stability, stability testing of the final blended batches should be performed.

　　8.46 如果混合會(huì)對(duì)穩(wěn)定性有不良影響，應(yīng)當(dāng)對(duì)最終混合批號(hào)進(jìn)行穩(wěn)定性測(cè)試。

　　8.47 The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend.

　　8.47 混合批號(hào)的有效期或復(fù)驗(yàn)期應(yīng)當(dāng)以混合中生產(chǎn)日期最早的尾料或批次的批號(hào)為基準(zhǔn)。

　　8.5 Contamination Control 8.5 污染控制

　　8.50 Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.

　　8.50 在得到充分控制的前提下，上一批號(hào)的同一中間體或原料藥的剩余物可以帶入下幾個(gè)連續(xù)批號(hào)。例如，黏附在微粉機(jī)壁上的殘留，離心出料后殘留在離心機(jī)筒體內(nèi)的潮濕的結(jié)晶，將物料轉(zhuǎn)至下一步工序時(shí)無(wú)法從反應(yīng)器中徹底放盡的物料。此類帶入不應(yīng)當(dāng)導(dǎo)致因帶入降解物或微生物的污染而對(duì)已經(jīng)建立的原料藥雜質(zhì)概況有不良影響。

　　8.51 Production operations should be conducted in a manner that prevents contamination of intermediates or APIs by other materials.

　　8.51 生產(chǎn)操作應(yīng)當(dāng)防止中間體或原料藥被其它物料污染。

　　8.52 Precautions to avoid contamination should be taken when APIs are handled after purification. 8.52 處理精制后的原料藥應(yīng)當(dāng)采取預(yù)防污染的措施。

　　9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES

　　原料藥和中間體的包裝和貼簽

　　9.1 General 9.1 總則

　　9.10 There should be written procedures describing the receipt, identification, quarantine, sampling, examination, and/or testing, release, and handling of packaging and labeling materials.

　　9.10 應(yīng)當(dāng)有書面程序描述包裝和貼簽用物料的接收、鑒別、待驗(yàn)、取樣、檢查和/或測(cè)試、放行和搬運(yùn)。

　　9.11 Packaging and labeling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.

　　9.11 包裝和貼簽用物料應(yīng)當(dāng)符合規(guī)定的質(zhì)量標(biāo)準(zhǔn)。不合格者要拒收，不得用于不適合于其的操作中。

　　9.12 Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

　　每次運(yùn)來(lái)的標(biāo)簽和包裝材料應(yīng)當(dāng)有接收、檢查或測(cè)試、以及合格還是拒收的記錄。

　　9.2 Packaging Materials 9.2 包裝材料

　　9.20 Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.

　　9.20 容器應(yīng)當(dāng)能夠?qū)χ虚g體和原料藥提供足夠的保護(hù)，使其在運(yùn)輸和建議的貯存條件下不會(huì)變質(zhì)或受到污染。

　　9.21 Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.

　　9.21 容器應(yīng)當(dāng)清潔，如果中間體或原料藥有要求時(shí)，應(yīng)當(dāng)進(jìn)行消毒，以確保適合于其預(yù)期的用途。這些容器應(yīng)無(wú)反應(yīng)活性、加和性或吸附性，一面改變中間體或原料藥的質(zhì)量使其超出質(zhì)量標(biāo)準(zhǔn)的限度。

　　9.22 If containers are reused, they should be cleaned in accordance with documented procedures, and all previous labels should be removed or defaced.

　　9.22 容器被重新使用時(shí)，應(yīng)當(dāng)按照規(guī)定程序進(jìn)行清潔，并出去或涂毀以前的所有標(biāo)簽。

　　9.3 Label Issuance and Control 9.3 標(biāo)簽發(fā)放與控制

　　9.30 Access to the label storage areas should be limited to authorized personnel.

　　9.30 只有獲準(zhǔn)人員才能進(jìn)入標(biāo)簽貯存區(qū)。

　　9.31 Procedures should be established to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labeled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).

　　9.31 應(yīng)當(dāng)建立規(guī)程來(lái)平衡發(fā)出的、使用的和退回的標(biāo)簽的數(shù)量，并評(píng)估已貼簽的容器數(shù)和發(fā)出的標(biāo)簽數(shù)之間的偏差值。此種差異應(yīng)當(dāng)加以調(diào)查，調(diào)查應(yīng)當(dāng)由質(zhì)量保證部門批準(zhǔn)。

　　9.32 All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.

　　9.32 所有剩余的印有批號(hào)或與批有關(guān)內(nèi)容的標(biāo)簽都應(yīng)當(dāng)銷毀。收回的標(biāo)簽應(yīng)當(dāng)以防止混淆并提供適當(dāng)標(biāo)識(shí)的方式加以保留和貯存。

　　9.33 Obsolete and out-dated labels should be destroyed.

　　9.33 廢棄的和過(guò)期的標(biāo)簽應(yīng)當(dāng)銷毀。

　　9.34 Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record.

　　9.34 包裝操作中用于印刷標(biāo)簽的印刷設(shè)備應(yīng)當(dāng)加以監(jiān)控，以確保所有印刷內(nèi)容符合批生產(chǎn)記錄中的內(nèi)容。

　　9.35 Printed labels issued for a batch should be carefully examined for proper identity and conformity to specifications in the master production record. The results of this examination should be documented.

　　9.35 應(yīng)當(dāng)仔細(xì)檢查發(fā)放給某批的打印好的標(biāo)簽，其標(biāo)識(shí)是否正確，并符合主生產(chǎn)記錄的內(nèi)容。檢查結(jié)果應(yīng)當(dāng)記錄在批生產(chǎn)記錄中。

　　9.36 A printed label representative of those used should be included in the batch production record. 9.36 批生產(chǎn)記錄中應(yīng)當(dāng)附一張代表那些所用標(biāo)簽的印制好的標(biāo)簽。

　　9.4 Packaging and Labeling Operations 9.4 包裝和貼簽操作

　　9.40 There should be documented procedures designed to ensure that correct packaging materials and labels are used.

　　9.40 應(yīng)當(dāng)有文件化的規(guī)程確保使用正確的包裝材料和標(biāo)簽。

　　9.41 Labeling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.

　　9.41 帖簽操作應(yīng)當(dāng)防止混淆。應(yīng)當(dāng)與涉及其它中間體或原料藥的操作有物理的或空間的隔離。

　　9.42 Labels used on containers of intermediates or APIs should indicate the name or identifying code, batch number, and storage conditions when such information is critical to ensure the quality of intermediate or API.

　　9.42 用于中間體或原料藥容器的標(biāo)簽應(yīng)當(dāng)注明：確保中間體或原料藥質(zhì)量的關(guān)鍵信息，如名稱、識(shí)別代碼、產(chǎn)品批號(hào)和儲(chǔ)存條件。

　　9.43 If the intermediate or API is intended to be transferred outside the control of the manufacturer’s material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be included on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.

　　9.43 如果中間體或原料藥要向生產(chǎn)商的物料管理系統(tǒng)控制范圍以外運(yùn)輸，標(biāo)簽上還應(yīng)當(dāng)包括生產(chǎn)商的名稱、地址，裝量，特殊的運(yùn)輸要求，和其它特殊的法定要求。對(duì)于有失效期的中間體或原料藥，標(biāo)簽和分析報(bào)告單上應(yīng)當(dāng)注明失效期。對(duì)于有復(fù)驗(yàn)期的中間體或原料藥，標(biāo)簽和/或分析報(bào)告單上應(yīng)當(dāng)注明復(fù)驗(yàn)期。

　　9.44 Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation system.

　　9.44 包裝和帖簽設(shè)施應(yīng)當(dāng)在使用前進(jìn)行檢查，以確定下一次包裝操作不需要的所有物料都已清除。該檢查應(yīng)當(dāng)記錄在批生產(chǎn)記錄、設(shè)備使用記錄或其它文件系統(tǒng)中。

　　9.45 Packaged and labeled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label. This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control records.

　　9.45 應(yīng)當(dāng)檢查已包裝和帖簽的中間體或原料藥，以確保該批的容器和包裝的標(biāo)簽正確。該檢查應(yīng)當(dāng)作為包裝操作的一部分。檢查結(jié)果應(yīng)當(dāng)記錄在批生產(chǎn)或控制記錄中。

　　9.46 Intermediate or API containers that are transported outside of the manufacturer’s control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.

　　9.46需向生產(chǎn)商的物料管理系統(tǒng)控制范圍以外運(yùn)輸?shù)闹虚g體或原料藥的容器應(yīng)當(dāng)用一種密封形式，以至于一旦密封破損或遺失，收貨者會(huì)留意到其內(nèi)容物有可能被動(dòng)過(guò)。