FDA原料藥檢查六個系統(tǒng)的內(nèi)容

1、appendix a: description of each system and areas of coverage附件a：系統(tǒng)的描述與包含的內(nèi)容quality system 質(zhì)量系統(tǒng)：assessment of the quality system has two phases. the first phase is to evaluate whether the quality unit has fulfilled the responsibility to review and approve all procedures related to production, quality

2、 control, and quality assurance and assure the procedures are adequate for their intended use. this also includes the associated recordkeeping systems. the second phase is to assess the data collected to identify quality problems and may link to other major systems for inspectional coverage.質(zhì)量系統(tǒng)的評價有

3、兩個方面。第一個方面是評價質(zhì)量部門是否已經(jīng)履行職責(zé)，審核批準(zhǔn) 所有與生產(chǎn)，質(zhì)量控制和質(zhì)量保證有關(guān)的程序，并確保有足夠的程序來保證運(yùn)行。這也包括 相關(guān)的記錄保存系統(tǒng)。第二個方面是評價收集到的數(shù)據(jù)資料來確定質(zhì)量問題，可能相關(guān)的其 他主要系統(tǒng)也在檢查范圍內(nèi)。for each of the following bulleted items, the firm should have written and approved procedures and documentation resulting therefrom. the firm，s adherence to written procedur

4、es should be verified through observation whenever possible. these areas are not limited to the final apfs, but may also include starting materials and intermediates. these areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. all

5、 areas under this system should be covered; however the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings.對下面所列的條款，公司應(yīng)該有書面的經(jīng)過批準(zhǔn)的程序和文件記錄。公司是否遵循書面 程序應(yīng)該通過觀察來證明。這些內(nèi)容不局限于api,也適用于起始物料和中間體。這些內(nèi)容 闡明的不僅僅是本系統(tǒng)的不足，也說明了其他系統(tǒng)存在的缺陷，這就需要擴(kuò)大檢查內(nèi)容。木 系統(tǒng)的所有方面都應(yīng)該包括在內(nèi)

6、，但實(shí)際包含的范圍可能與計劃屮的檢查內(nèi)容有所改變。 adequacy of staffing to ensure fulfillment of quality unit duties有足夠的人員來確保履行質(zhì)量部門的職責(zé)。 periodic quality reviews as described in ich q7a section 2.5, product quality review; inspection audit coverage should include api types that are representative of manufacturing at this sit

7、e; inspection audit should also examine some batch and data records associated with each api quality review to verify that firings review was sufficiently complete; and, audit should confirm that firm has identified any trends and has coitected or mitigated sources of unacceptable variation如ich q7a2

8、.5節(jié)產(chǎn)品質(zhì)量審核所述，進(jìn)行周期性質(zhì)量審核；檢查審計內(nèi)容應(yīng)該包括生產(chǎn)中 具有代表性的api,檢查審計也應(yīng)該包括檢查每個api批記錄和數(shù)據(jù)記錄來核實(shí)公司的審核 是完善的；審計應(yīng)該確定公司已經(jīng)針對不可接受的變更進(jìn)行改進(jìn)。 complaint reviews (quality and medical): documented; evaluated; investigated in a timely manner; includes coitective action where appropriate. determine whether pattern of complaints and reco

9、rds of internal rejection or reprocessing/reworking of api batches warrant expanding the inspection.投訴審核（質(zhì)量和藥性）：文件記錄；評價；及時進(jìn)行調(diào)查；包括適當(dāng)?shù)母倪M(jìn)措施。確定是 否投訴和拒收記錄或api批的返工/重加工記錄也在檢查范圍內(nèi)。 discrepancy and failure investigations related to manufacturing and testing: documented; evaluated; critical deviations investig

10、ated in a timely manner and expanded to include any related apis and material; includes corrective action where appropriate.關(guān)于生產(chǎn)和試驗的不符合和失敗的調(diào)查：文件記錄；評價；及時調(diào)查關(guān)鍵偏差，和對所有相 關(guān)的api和物料展開調(diào)查；包括適當(dāng)?shù)母倪M(jìn)措施。 change control （including "process improvements）: documented; evaluated; approved; need for revalidation a

11、ssessed.變更控制（包括“工藝改進(jìn)”）：文件記錄；評價；批準(zhǔn)；重復(fù)驗證評估的必要性。 returns/salvages: assessment; investigation expanded where warranted; final disposition.退貨/殘料：評價；批準(zhǔn)展開調(diào)查；最后的處置。 rejects: investigation expanded where warranted; corrective action where appropriate.拒收：批準(zhǔn)展開調(diào)查；適當(dāng)改進(jìn)措施。 system to release raw materials.原始物料放行系統(tǒng)

12、。 batches manufactured since last inspection to evaluate any rejections or conversions （i.e., from drug to non-drug use） due to processing problems.對上次檢查以后生產(chǎn)的批進(jìn)行評價是否有不合格品或是由于工藝問題而發(fā)生的轉(zhuǎn)變（亦即， 從藥物向非藥物使用的轉(zhuǎn)變）。 reprocessing and/or reworking events are properly approved and evaluated for impact on material

13、quality.返工或再加工必須得到批準(zhǔn)，并對物料質(zhì)量的影響進(jìn)行評價。 recalls （including any attempt to recover distributed api not meeting its specifications or purported quality）, determine cause and corrective actions taken. 召冋（包括準(zhǔn)備冋收的已分發(fā)的不符和質(zhì)量標(biāo)準(zhǔn)或預(yù)期要求的api）,確定原因和采取的措 施。 stability failures: investigation expanded where waitanted; d

14、isposition. determine 訐 stability data supports api retest or expiry dates and storage conditions.穩(wěn)定性不符合：批準(zhǔn)開展調(diào)查；處置。確定穩(wěn)定性數(shù)據(jù)是否支持api復(fù)驗或有效期和貯存條 件。 validation: status of validation/revalidation activities （e.g., computer, manufacturing process, laboratory methods）, such as reviews and approvals of valida

15、tion protocols and reports.驗證：驗證/再驗證活動的情況（例如，計算機(jī)，生產(chǎn)工藝，實(shí)驗方法），比如驗證方案和 驗證報告的審核和批準(zhǔn)。 training/qualification of employees in quality control unit functions.qc部門人員的資格/培訓(xùn)。ich q7a references for quality system:ich q7a參考: section 2, quality management 笫2節(jié)：質(zhì)量管理 section 13, change control第 13節(jié)：變更控制 section 14,

16、rejection and reuse of materials第 14節(jié)：拒收和物料的再利用 section 15, complaints and recalls 第 15節(jié)：投訴和召回 section 16, contract manufacturers (including laboratories).第16節(jié)：協(xié)議生產(chǎn)商(包括實(shí)驗室)facilities and equipment system 設(shè)施和設(shè)備系統(tǒng)：for each of the following, the firm should have written and approved procedures and docu

17、mentation resulting therefrom. the firm?s adherence to written procedures should be verified through observation whenever possible. these areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. when this system is selected for cover

18、age in addition to the quality system, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings.對下面所列的條款，公司應(yīng)該有書面的經(jīng)過批準(zhǔn)的程序和文件記錄。公司是否遵循書面程序 應(yīng)該通過觀察來證明。這些內(nèi)容闡明的不僅僅是本系統(tǒng)的不足，也說明了其他系統(tǒng)存在的缺 陷，這就需要擴(kuò)大檢查內(nèi)容。除質(zhì)量

19、系統(tǒng)外，當(dāng)本系統(tǒng)也包括在檢查范圍時，下列所有內(nèi)容 必須包插在內(nèi)；但實(shí)際包含的范圍可能與計劃中的檢查內(nèi)容有所改變。1. facilities 設(shè)施 cleaning and maintenance.清潔和維護(hù)。 facility layout, flow of materials and personnel for prevention of cross-contamination, including from processing of non-drug materials.設(shè)施布置，為避免交叉污染人流與物流的流動，包括非藥品物質(zhì)的工藝加工。 dedicated areas or conta

20、inment controls for highly sensitizing materials (e.g., penicillin, beta-lactams, steroids, hormones, and cytotoxics).高致敏物料的專用區(qū)域或容器控制(例如，盤尼西林，類固醇，激素和細(xì)胞毒素)。 utilities such as steam, gas, compressed air, heating, ventilation, and air conditioning should be qualified and appropriately monitored (note:

21、this system includes only those utilities whose output is not intended to be incorporated into the api, such as water used in cooling/heating jacketed vessels).公用系統(tǒng)如蒸汽，氣體，壓縮空氣，熱水，通風(fēng)和空調(diào)應(yīng)該符合質(zhì)量規(guī)格，并進(jìn)行適當(dāng)?shù)?監(jiān)控(注意：本系統(tǒng)包括那些只輸出而不混合進(jìn)入api的系統(tǒng)，比如用于冷卻/加熱夾套的水)。 lighting, sewage and refuse disposal, washing and toile

22、t facilities.照明設(shè)備，污水和廢物處理，清洗設(shè)施和衛(wèi)生設(shè)施。 control system for implementing changes in the building. 廠房實(shí)施變更的控制系統(tǒng)。 sanitation of the building including use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents廠房衛(wèi)生包括滅鼠劑，殺真菌劑，殺蟲劑和清潔劑的使用。 training and qualification of personnel. 相關(guān)人員資格和培訓(xùn)。2

23、. process equipment 工藝設(shè)備 equipment installation, operational, performance qualification where appropriate. 設(shè)備安裝，操作，運(yùn)行確認(rèn)。 appropriate design, adequate size and suitably located for its intended use.根據(jù)用途進(jìn)行合理設(shè)計，合理的尺寸大小，適當(dāng)放置。 equipment surfaces should not be reactive, additive, or absorptive of material

24、s under process so as to alter their quality.設(shè)備表面應(yīng)該不具有反應(yīng)活性，加和性或吸附性，不會影響加工過程屮物料的質(zhì)量。 equipment （e.g., reactors, storage containers） and permanently installed processing lines should be appropriately identified.設(shè)備（如反應(yīng)釜，儲存容器）和永久性工藝生產(chǎn)線應(yīng)該經(jīng)過確認(rèn)。 substances associated with the operation of equipment （e.g., l

25、ubricants, heating fluids or coolants） should not come into contact with starting materials, intermediates, final apis, and containers.與設(shè)備操作相關(guān)的物質(zhì)（如潤滑劑，加熱液體或冷卻劑）不能與起始物料，中間體，最后 api和容器有接觸。 cleaning procedures and cleaning validation and sanitization studies should be reviewed to verify that residues, m

26、icrobial, and, when appropriate, endotoxin contamination are removed to below scientifically appropriate levels.清潔程序，清潔驗證和衛(wèi)生研究應(yīng)該經(jīng)過審核，確認(rèn)殘留物，微生物，內(nèi)毒素（若需要） 污染應(yīng)該在標(biāo)準(zhǔn)下。 calibrations using standards traceable to certified standards, preferably nist, usp, or counterpart recognized national government standar

27、d-setting authority.使用有證明的標(biāo)準(zhǔn)進(jìn)行校驗，最好是nist, usp或本國政府標(biāo)準(zhǔn)設(shè)立機(jī)構(gòu)認(rèn)可的副本。 equipment qualification, calibration and maintenance, including computer qualification/validation and security.設(shè)備確認(rèn)，校驗和維護(hù)，包括計算機(jī)確認(rèn)/驗證和安全性。 control system for implementing changes in the equipmen匸設(shè)備實(shí)施變更的控制系統(tǒng)。 documentation of any discrepan

28、cy （a critical discrepancy investigation is covered under the quality system）.所有不符合項的文件記錄（主要的不符合調(diào)查包括在質(zhì)量系統(tǒng)中）。 training and qualification of personnel. 相關(guān)人員的資格和培訓(xùn)。ich q7a references for facilities and equipmentich q7a參考: section 4, buildings and facilities笫4節(jié)：建筑和設(shè)備 section 5, process equipment第5節(jié):工藝設(shè)備

29、 section 6, documentation and records第6節(jié)：文件和記錄materials system 物料系統(tǒng)：for each of the following, the firm should have written and approved procedures and documentation resulting therefrom. the firm's adherence to written procedures should be verified through observation whenever possible. these ar

30、eas are not limited to the final api, but may also incorporate starting materials and intermediates. these areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. when this system is selected for coverage in addition to the quality

31、system, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings.對下面所列的條款，公司應(yīng)該有書面的經(jīng)過批準(zhǔn)的程序和文件記錄。公司是否遵循書面程序 應(yīng)該通過觀察來證明。這些內(nèi)容不局限于api,也適用于起始物料和中間體。這些內(nèi)容闡明 的不僅僅是本系統(tǒng)的不足，也說明了其他系統(tǒng)存在的缺陷，這就需要擴(kuò)大檢查內(nèi)容。除質(zhì)量 系統(tǒng)外，當(dāng)

32、本系統(tǒng)也包括在檢查范圍時，下列所有內(nèi)容必須包括在內(nèi)；但實(shí)際包含的范圍可 能與計劃中的檢查內(nèi)容有所改變。 training/qualification of personnel.相關(guān)人員的資格和培訓(xùn)。 identification of starting materials, containers.起始物料，容器的確認(rèn)。 storage conditions.儲存條件。 holding of all material and apis, including reprocessed material, under quarantine until tested or examined and re

33、leased.保留所有物料和api,包括返工物料，待驗物料必須經(jīng)過檢驗后才能放行。 representative samples are collected, tested or examined using appropriate means and against appropriate specifications.收集代表性的樣品，使用適當(dāng)?shù)姆椒ê唾|(zhì)量標(biāo)準(zhǔn)進(jìn)行檢測。 a system for evaluating the suppliers of critical materials.關(guān)鍵物料的供應(yīng)商的評價系統(tǒng)。 rejection of any starting material,

34、intermediate, or container not meeting acceptance requirement.拒收不符合要求的起始物料，中i、可體或容器。 appropriate retesting/reexamination of starting materials, intermediates, or containers. 起始物料，中間體或容器進(jìn)行適當(dāng)?shù)膹?fù)驗/復(fù)檢。 first-in / first-out use of materials and containers.物料和容器遵循“先進(jìn)先出”原則。 quarantine and timely disposition

35、 of rejected materials.拒收物料的待驗和及時處理。 suitability of process water used in the manufacture of api, including as appropriate the water system design, maintenance, validation and operation.生產(chǎn)api的工藝用水的適用性，包括適當(dāng)?shù)乃到y(tǒng)設(shè)計，維護(hù)，驗證和操作。 suitability of process gas used in the manufacture of api (e.g., gas use to sp

36、arge a reactor), including as appropriate the gas system design, maintenance° validation and operation.生產(chǎn)api的工藝用氣體的適用性（比如，反應(yīng)釜中用于噴舞的氣體），包括適當(dāng)?shù)乃到y(tǒng) 設(shè)計，維護(hù)，驗證和操作。 containers and closures should not be additive, reactive, or absorptive.容器不應(yīng)該具有加和性，反應(yīng)活性或吸附性。 control system for implementing changes.實(shí)施變更的

37、控制系統(tǒng)。 qualification/validation and security of computerized or automated process- 計算機(jī)控制系統(tǒng)或自動工藝的確認(rèn)/驗證和安全性。 finished api distribution records by batch.api的批發(fā)放記錄。 documentation of any discrepancy （a critical discrepancy investigation is covered under the quality system）.所有不符合項的文件記錄（主要的不符和調(diào)查包括在質(zhì)量系統(tǒng)中）。ic

38、h q7a references for materials system:ich q7a參考： section 7, materials management第7節(jié)：物料管理 section 10, storage and distribution 第 10節(jié)：儲存和發(fā)放 section 4.3, water第4.3節(jié)：水 section 6, documentation and records笫6節(jié)：文件和記錄production system 生產(chǎn)系統(tǒng)：for each of the following, the firm should have written and approved

39、 procedures and documentation resulting therefrom. the firm，s adherence to written procedures should be verified through observation whenever possible. these areas are not limited to the final api, but may also incorporate starting materials and intermediates. these areas may indicate deficiencies n

40、ot only in this system but also in other systems that would warrant expansion of coverage. when this system is selected for coverage in addition to the quality system, all areas listed below should be covered; however, the actual depth of coverage may vary from the planned inspection strategy depend

41、ing upon inspectional findings.對下面所列的條款，公司應(yīng)該有書面的經(jīng)過批準(zhǔn)的程序和文件記錄。公司是否遵循書面程序 應(yīng)該通過觀察來證明。這些內(nèi)容不局限于api,也適用于起始物料和中間體。這些內(nèi)容闡明 的不僅僅是本系統(tǒng)的不足，也說明了其他系統(tǒng)存在的缺陷，這就需要擴(kuò)大檢查內(nèi)容。除質(zhì)量 系統(tǒng)外，當(dāng)本系統(tǒng)也包括在檢查范圍時，下列所有內(nèi)容必須包括在內(nèi)；但實(shí)際包含的范圍對 能與計劃中的檢查內(nèi)容有所改變。 training/qualification of personnel.相關(guān)人員的資格和培訓(xùn)。 establishment, adherence, and documented

42、 performance of approved manufacturing procedures.建立審批生產(chǎn)程序，堅持和文件記錄。 control system for implementing changes to process.工藝實(shí)施變更的控制系統(tǒng)。 controls over critical activities and operations.關(guān)鍵活動和操作的控制。 documentation and investigation of critical deviations.關(guān)鍵偏差的文件記錄和調(diào)查。 actual yields compared with expected y

43、ields at designated steps.實(shí)際生產(chǎn)產(chǎn)量與設(shè)計步驟屮預(yù)期產(chǎn)量進(jìn)行對比。 where appropriate established time limits for completion of phases of production. 若需要建立完成生產(chǎn)階段的吋間限制。 appropriate identification of major equipment used in production of intermediates and api.用于生產(chǎn)屮間體和api的主要設(shè)備的適當(dāng)確認(rèn)。 justification and consistency of interm

44、ediate specifications and api specification.中i'可體質(zhì)量規(guī)格和api質(zhì)量規(guī)格的證明和一致性。 implementation and documentation of process controls, testing, and examinations (e.g., ph, temperature, purity, actual yields, clarity).工藝控制，試驗和檢查的實(shí)施和文件記錄(如，ph,溫度，純度，實(shí)際產(chǎn)量，澄清度)。 in-process sampling should be conducted using pro

45、cedures designed to prevent contamination of the sampled material.中間収樣應(yīng)該根據(jù)設(shè)計好的規(guī)程進(jìn)行，以免對収樣物料造成污染。 recovery (e.g., from mother liquor or filtrates) of reactants; approved procedures and recovered materials meet specifications suitable for their intended use.反應(yīng)物冋收(如，從母液或濾液中冋收)；審批后的規(guī)程和冋收的物料應(yīng)該符合標(biāo)準(zhǔn)。 solven

46、ts can be recovered and reused in the same processes or in different processes provided that solvents meet appropriate standards before reuse or commingling.溶劑能夠回收，并在相同工藝或不同工藝屮再利用，如果溶劑符合質(zhì)量標(biāo)準(zhǔn)。 api micronization on multi-use equipment and the precautions taken by the firm to prevent or minimize the po

47、tential for cross-contamination.api在多功能設(shè)備中微粉化應(yīng)該采収預(yù)防措施來避免或降低交叉污染的可能性。 process validation, including validation and security of computerized or automated process工藝驗證，包括計算機(jī)控制系統(tǒng)或白動工藝過程的驗證和安全性。 master batch production and control records.主要批生產(chǎn)和控制記錄。 batch production and control records.批生產(chǎn)和控制記錄。 document

48、ation of any discrepancy (a critical discrepancy investigation is covered under the quality system).所有不符合項的文件記錄(主要的不符和調(diào)查包括在質(zhì)量系統(tǒng)中)。ich q7a references for production system: ich q7a參考： section 6, documentation and records第6節(jié)：文件和記錄 section& production and in-process controls笫8節(jié)：生產(chǎn)和屮間控制 section 12,

49、validation第 12節(jié)：驗證 section 1& specific guidance for apis manufactured by cell culture /fermentation第18節(jié)：采取細(xì)胞培養(yǎng)/發(fā)酵生產(chǎn)api的特殊指南see also 7356.0002m for additional inspection guidance on fermentation, extraction, and purification processes.也可以參考7356.0002關(guān)于發(fā)酵，提取和純化工藝的附加檢查指南。packaging and labeling syste

50、m 包裝和貼簽系統(tǒng)：for each of the following, the firm should have written and approved procedures and documentation resulting therefrom. the finrfs adherence to written procedures should be verified through observation whenever possible. these areas are not limited to the final api, but may also incorporate

51、 starting materials and intermediates. these areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. when this system is selected for coverage in addition to the quality system, all areas listed below should be covered; however, the

52、 actual depth of coverage may vary from the planned inspection strategy depending upon inspectional findings.對下面所列的條款，公司應(yīng)該有書面的經(jīng)過批準(zhǔn)的程序和文件記錄。公司是否遵循書面程序 應(yīng)該通過觀察來證明。這些內(nèi)容不局限于api,也適用于起始物料和中間體。這些內(nèi)容闡明 的不僅僅是本系統(tǒng)的不足，也說明了其他系統(tǒng)存在的缺陷，這就需要擴(kuò)大檢查內(nèi)容。除質(zhì)量 系統(tǒng)外，當(dāng)本系統(tǒng)也包括在檢查范圍時，下列所有內(nèi)容必須包括在內(nèi)；但實(shí)際包含的范圍可 能與計劃中的檢查內(nèi)容有所改變。 training/q

53、ualification of personnel.相關(guān)人員的資格和培訓(xùn)。 acceptance operations for packaging and labeling materials.包裝和貼標(biāo)簽物料的可接受操作。 control system for implementing changes in packaging and labeling operations 實(shí)施包裝和貼簽操作變更的控制系統(tǒng)。 adequate storage for labels and labeling, both approved and returned after issued 標(biāo)簽的儲存，包括已批

54、準(zhǔn)的標(biāo)簽和發(fā)行后退還的標(biāo)簽的儲存。 control of labels which are similar in size, shape, and color for different apis. 用于不同的api的，但尺寸，形狀和顏色相近的標(biāo)簽的控制。 adequate packaging records that will include specimens of all labels used. 足夠的包裝記錄包括所有標(biāo)簽使用樣本。 control of issuance of labeling, examination of issued labels and reconciliat

55、ion of used labels-標(biāo)簽的發(fā)行控制，已有標(biāo)簽的檢查和使用的標(biāo)簽的一致性。 examination of the labeled finished apis.api標(biāo)簽的檢查。 adequate inspection (proofing) of incoming labeling.新來標(biāo)簽的檢查(證明)。 use of lot numbers, destruction of excess labeling bearing lot/control numbers.批號使用，多余標(biāo)簽的銷毀。 adequate separation and controls when labelin

56、g more than one batch at a time. 在同一吋間，多于一批貼標(biāo)簽吋應(yīng)有足夠的分離和控制。 adequate expiration or retest dates on the label.標(biāo)簽的有效期或復(fù)驗期。 validation of packaging and labeling operations including validation and security of computerized process.包裝和貼簽操作的驗證，包括計算機(jī)控制系統(tǒng)的驗證和安全性。 documentation of any discrepancy (a critical

57、discrepancy investigation is covered under the quality system).所有不符合項的文件記錄(主要的不符和調(diào)查包扌舌在質(zhì)量系統(tǒng)屮)。ich q7a references for packaging and labeling system: ich q7a參考： section 9, packaging and identification labeling of apis and intermediates 第9節(jié)：api和中間體包裝和標(biāo)簽確認(rèn) section 17, agents, brokers, traders, distribut

58、ors, repackers, and relabellers (applies to the handling of apis after original site of manufacture and before receipt by the dosage manufacturer)laboratory control system 實(shí)驗室控制系統(tǒng)：for each of the following, the firm should have written and approved procedures and documentation resulting therefrom. the firm's adherence to written procedures should be verified through observation whenever pos