FDA原料藥檢查六個系統(tǒng)的內容

1、appendix a: description of each system and areas of coverage附件a：系統(tǒng)的描述與包含的內容quality system 質量系統(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.質量系統(tǒng)的評價有

3、兩個方面。第一個方面是評價質量部門是否已經履行職責，審核批準 所有與生產，質量控制和質量保證有關的程序，并確保有足夠的程序來保證運行。這也包括 相關的記錄保存系統(tǒng)。第二個方面是評價收集到的數(shù)據資料來確定質量問題，可能相關的其 他主要系統(tǒng)也在檢查范圍內。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，公司應該有書面的經過批準的程序和文件記錄。公司是否遵循書面 程序應該通過觀察來證明。這些內容不局限于api,也適用于起始物料和中間體。這些內容 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，這就需要擴大檢查內容。木 系統(tǒng)的所有方面都應該包括在內

6、，但實際包含的范圍可能與計劃屮的檢查內容有所改變。 adequacy of staffing to ensure fulfillment of quality unit duties有足夠的人員來確保履行質量部門的職責。 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)產品質量審核所述，進行周期性質量審核；檢查審計內容應該包括生產中 具有代表性的api,檢查審計也應該包括檢查每個api批記錄和數(shù)據記錄來核實公司的審核 是完善的；審計應該確定公司已經針對不可接受的變更進行改進。 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（質量和藥性）：文件記錄；評價；及時進行調查；包括適當?shù)母倪M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。 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.關于生產和試驗的不符合和失敗的調查：文件記錄；評價；及時調查關鍵偏差，和對所有相 關的api和物料展開調查；包括適當?shù)母倪M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”）：文件記錄；評價；批準；重復驗證評估的必要性。 returns/salvages: assessment; investigation expanded where warranted; final disposition.退貨/殘料：評價；批準展開調查；最后的處置。 rejects: investigation expanded where warranted; corrective action where appropriate.拒收：批準展開調查；適當改進措施。 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的批進行評價是否有不合格品或是由于工藝問題而發(fā)生的轉變（亦即， 從藥物向非藥物使用的轉變）。 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，并對物料質量的影響進行評價。 recalls （including any attempt to recover distributed api not meeting its specifications or purported quality）, determine cause and corrective actions taken. 召冋（包括準備冋收的已分發(fā)的不符和質量標準或預期要求的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：批準開展調查；處置。確定穩(wěn)定性數(shù)據是否支持api復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，生產工藝，實驗方法），比如驗證方案和 驗證報告的審核和批準。 training/qualification of employees in quality control unit functions.qc部門人員的資格/培訓。ich q7a references for quality system:ich q7a參考: section 2, quality management 笫2節(jié)：質量管理 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)議生產商(包括實驗室)facilities and equipment system 設施和設備系統(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，公司應該有書面的經過批準的程序和文件記錄。公司是否遵循書面程序 應該通過觀察來證明。這些內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，這就需要擴大檢查內容。除質量

19、系統(tǒng)外，當本系統(tǒng)也包括在檢查范圍時，下列所有內容 必須包插在內；但實際包含的范圍可能與計劃中的檢查內容有所改變。1. facilities 設施 cleaning and maintenance.清潔和維護。 facility layout, flow of materials and personnel for prevention of cross-contamination, including from processing of non-drug materials.設施布置，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，通風和空調應該符合質量規(guī)格，并進行適當?shù)?監(jiān)控(注意：本系統(tǒng)包括那些只輸出而不混合進入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.照明設備，污水和廢物處理，清洗設施和衛(wèi)生設施。 control system for implementing changes in the building. 廠房實施變更的控制系統(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. 相關人員資格和培訓。2

23、. process equipment 工藝設備 equipment installation, operational, performance qualification where appropriate. 設備安裝，操作，運行確認。 appropriate design, adequate size and suitably located for its intended use.根據用途進行合理設計，合理的尺寸大小，適當放置。 equipment surfaces should not be reactive, additive, or absorptive of material

24、s under process so as to alter their quality.設備表面應該不具有反應活性，加和性或吸附性，不會影響加工過程屮物料的質量。 equipment （e.g., reactors, storage containers） and permanently installed processing lines should be appropriately identified.設備（如反應釜，儲存容器）和永久性工藝生產線應該經過確認。 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.與設備操作相關的物質（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)生研究應該經過審核，確認殘留物，微生物，內毒素（若需要） 污染應該在標準下。 calibrations using standards traceable to certified standards, preferably nist, usp, or counterpart recognized national government standar

27、d-setting authority.使用有證明的標準進行校驗，最好是nist, usp或本國政府標準設立機構認可的副本。 equipment qualification, calibration and maintenance, including computer qualification/validation and security.設備確認，校驗和維護，包括計算機確認/驗證和安全性。 control system for implementing changes in the equipmen匸設備實施變更的控制系統(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（主要的不符合調查包括在質量系統(tǒng)中）。 training and qualification of personnel. 相關人員的資格和培訓。ich q7a references for facilities and equipmentich q7a參考: section 4, buildings and facilities笫4節(jié)：建筑和設備 section 5, process equipment第5節(jié):工藝設備

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，公司應該有書面的經過批準的程序和文件記錄。公司是否遵循書面程序 應該通過觀察來證明。這些內容不局限于api,也適用于起始物料和中間體。這些內容闡明 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，這就需要擴大檢查內容。除質量 系統(tǒng)外，當

32、本系統(tǒng)也包括在檢查范圍時，下列所有內容必須包括在內；但實際包含的范圍可 能與計劃中的檢查內容有所改變。 training/qualification of personnel.相關人員的資格和培訓。 identification of starting materials, containers.起始物料，容器的確認。 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?shù)姆椒ê唾|量標準進行檢測。 a system for evaluating the suppliers of critical materials.關鍵物料的供應商的評價系統(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，中間體或容器進行適當?shù)膹万?復檢。 first-in / first-out use of materials and containers.物料和容器遵循“先進先出”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api的工藝用水的適用性，包括適當?shù)乃到y(tǒng)設計，維護，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api的工藝用氣體的適用性（比如，反應釜中用于噴舞的氣體），包括適當?shù)乃到y(tǒng) 設計，維護，驗證和操作。 containers and closures should not be additive, reactive, or absorptive.容器不應該具有加和性，反應活性或吸附性。 control system for implementing changes.實施變更的

37、控制系統(tǒng)。 qualification/validation and security of computerized or automated process- 計算機控制系統(tǒng)或自動工藝的確認/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（主要的不符和調查包括在質量系統(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，公司應該有書面的經過批準的程序和文件記錄。公司是否遵循書面程序 應該通過觀察來證明。這些內容不局限于api,也適用于起始物料和中間體。這些內容闡明 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，這就需要擴大檢查內容。除質量 系統(tǒng)外，當本系統(tǒng)也包括在檢查范圍時，下列所有內容必須包括在內；但實際包含的范圍對 能與計劃中的檢查內容有所改變。 training/qualification of personnel.相關人員的資格和培訓。 establishment, adherence, and documented

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

43、ields at designated steps.實際生產產量與設計步驟屮預期產量進行對比。 where appropriate established time limits for completion of phases of production. 若需要建立完成生產階段的吋間限制。 appropriate identification of major equipment used in production of intermediates and api.用于生產屮間體和api的主要設備的適當確認。 justification and consistency of interm

44、ediate specifications and api specification.中i'可體質量規(guī)格和api質量規(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，試驗和檢查的實施和文件記錄(如，ph,溫度，純度，實際產量，澄清度)。 in-process sampling should be conducted using pro

45、cedures designed to prevent contamination of the sampled material.中間収樣應該根據設計好的規(guī)程進行，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)程和冋收的物料應該符合標準。 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，如果溶劑符合質量標準。 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在多功能設備中微粉化應該采収預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.主要批生產和控制記錄。 batch production and control records.批生產和控制記錄。 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(主要的不符和調查包括在質量系統(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)：采取細胞培養(yǎng)/發(fā)酵生產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，公司應該有書面的經過批準的程序和文件記錄。公司是否遵循書面程序 應該通過觀察來證明。這些內容不局限于api,也適用于起始物料和中間體。這些內容闡明 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，這就需要擴大檢查內容。除質量 系統(tǒng)外，當本系統(tǒng)也包括在檢查范圍時，下列所有內容必須包括在內；但實際包含的范圍可 能與計劃中的檢查內容有所改變。 training/q

53、ualification of personnel.相關人員的資格和培訓。 acceptance operations for packaging and labeling materials.包裝和貼標簽物料的可接受操作。 control system for implementing changes in packaging and labeling operations 實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 標簽的儲存，包括已批

54、準的標簽和發(fā)行后退還的標簽的儲存。 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簽使用樣本。 control of issuance of labeling, examination of issued labels and reconciliat

55、ion of used labels-標簽的發(fā)行控制，已有標簽的檢查和使用的標簽的一致性。 examination of the labeled finished apis.api標簽的檢查。 adequate inspection (proofing) of incoming labeling.新來標簽的檢查(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，多于一批貼標簽吋應有足夠的分離和控制。 adequate expiration or retest dates on the label.標簽的有效期或復驗期。 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(主要的不符和調查包扌舌在質量系統(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和中間體包裝和標簽確認 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