GOODCHROMOTOGRAPHYPRACTICES優(yōu)良色譜規(guī)范

1、WHO 工作文件 QAS/19.791GOOD CHROMOTOGRAPHY PRACTICES優(yōu)良色譜規(guī)范(February2019)DRAFT FOR COMMENTS征求意見稿Description of Activity 活動描述Date 日期Following a recommendation by the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) byDr Andr Van Zyl, a member of the ECSPP, the WHO Secretariat

2、 was rec ommended to develop a new guidance ongood chromatograp hy practices.October 2018WHO 制劑標準專家委員會(ECSPP)建議，ECSPP成員 Dr Andr Van Zyl 建議 WHO 秘書處起草優(yōu)良色譜規(guī)范指南2018 年 10月Preparation of first draft working document.December 2018 -February2019第一份工作文件草案起草2018年12月-2019 年2月Mailing of working document to theE

3、xpert Advisory Panelo n the International Pharmacopoeiaand Pharmaceutical Preparations (EAP) inviting comments and posting of the working docu ment on the WHO website for public consultation.February May 2019將文件草案發(fā)給國際藥典和藥品專家顧問團(EAP)征求意見，在WHO 官網(wǎng)上發(fā) 布征求公眾意見2019 年 2-5 月Consolidation of comments received

4、and review of feedbacks.Pre paration of working document for discussion.June2019整合收到的意見和反饋審核。起草工作供討論。2019 年 6 月Discussion of working document and feedbacks received duri ngthe informal Consultation on Good Practices for Health Pr oducts Manufacture and Inspection.July2019討論工作文件和優(yōu)良藥品生產(chǎn)與檢查規(guī)范非正式咨詢期間收到的

5、反饋2019 年 7 月Revision of the working document based on comments receive d during the informal Consultation on Good Practices for Health Products Manufacture and Inspection.End ofJuly2019根據(jù)優(yōu)良藥品生產(chǎn)與檢查規(guī)范非正式咨詢期間收到的建議修訂工作文件2019 年7 月底Mailing of revised working documentto the EAP inviting com ments and posti

6、ng the working documenton the WHO website for public consultation.August September 201 9將修訂后的工作文件發(fā)給EAP征求意見，在WHO 官網(wǎng)上發(fā)布工作文件征求公2019 年 8-9 月眾意見Consolidation of comments receivedand review of feedbacks.Pre paration of working document for discussion.End of September 2019整合所收到的建議，審核反饋意見。起草工作文件供討論2019 年 9

7、月Presentation to the Fifty-fourth meeting of the ECSPP.14 -18 October2019提交第54 次 ECSPP會議2019 年 10 月 14-18Any other follow-up action as required.其它所需后續(xù)措施INTRODUCTION AND SCOPE 介紹與范圍The use of chromatography methods (such as High Pressure Liquid Chromatography (HPLC) andGas Chromatography (GC) in qual

8、ity control laboratoryanalysis has increased significantly inrecent years.近年來色譜方法(如高壓液相色譜( HPLC )和氣相色譜( GC )的使用在 QC 實驗室分析中已有顯著增加。HPLC and GC methods are used in, for example, the identification of materials and products, for determination of assay and related substances in materials and products, as

9、 well as in validation such as process validation and cleaning validation.HPLC 和 GC 方法被用于，例如，物料和產(chǎn)品鑒別、物料和產(chǎn)品中含量和有關(guān)物質(zhì)檢測，以及驗證如工藝驗證 和清潔驗證。Due to the criticality of the results obtained through chromatography, manufacturers should ensure that the data acquired is accurate and reliable. Results should meet

10、 ALCOA+ principles (i.e. attributable, legible, contemporaneous, original and accurate).由于通過色譜獲得的結(jié)果非常關(guān)鍵，生產(chǎn)商應(yīng)確保所獲取的數(shù)據(jù)的準確性和可靠性。結(jié)果應(yīng)符合 ALCOA+ 原 則(即可追溯、清晰、同步、原始和準確)。This guideline provides information on good practices to be considered in the analysis of samples when chromatographic systems are used. The

11、 principles should be applied in the analysis of, for example, raw materials, starting materials, intermediates, in-process materials and finished products.本指南提供了在使用色譜系統(tǒng)進行樣品分析時需要考慮的優(yōu)良規(guī)范。在分析如原料、起始物料、中間體、中 控物料和成品中應(yīng)使用這些原則。s,The principles contained in this guideline are applicable to all types of chrom

12、atographic analysis used in, for example, assay determination, testing for related substances and impuritie process validation, cleaning validation, cleaning verification and stability testing.本指南中人原則適用于如含量檢測、有關(guān)物質(zhì)和雜質(zhì)檢測、工藝驗證、清潔驗證、清潔確認和穩(wěn)定性測試中 所用的所有類型色譜分析。GLOSSARY 術(shù)語解釋ALCOAA commonly usedacronym for“at

13、tributable, legible, contemporaneous, original and accurate”.常用術(shù)語，代表“可追溯、清晰、同步、原始和準確”。ALCOA+A commonly used acronym for“attributable, legible, contemporaneous, original and accurate”which puts additional emphasis on the attributes of being complete, consistent, enduring and available implicit basic

14、ALCOA principles.常用術(shù)語，代表“可追溯、清晰、同步、原始和準確”，以及在其上增加 ALCOA 基本原則的更多屬性，即 完整、一致、持久和可及性。Backup 備份A backup means a copy of one or more electronic files created as an alternative in case the original data or system are lost or become unusable (for example, in the event of a system crash or corruption of a di

15、sk). It is important to note that backup differs from archival in that backup copies of electronic records are typically only temporarily stored for the purposes of disaster recovery and may be periodically overwritten. Such temporary backup copies should not be relied upon as an archival mechanism.

16、備份指創(chuàng)建一份或多份電子文件，在原始數(shù)據(jù)或系統(tǒng)丟失或不可使用時(如系統(tǒng)崩潰或磁盤損壞)作為替代 用途。注意備份與歸檔是不一樣的，電子記錄備份一般只是臨時存貯用于災(zāi)難恢復(fù)，可能會定期覆蓋。不應(yīng) 依賴此種臨時備份件作為歸檔用途。Calibration 校正The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), re

17、cording and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.在指定條件下建立儀器或系統(tǒng)測量指示值(尤其是稱重值)、記錄和控制，或物料測量代表值，與對應(yīng)的一 個標準物質(zhì)已知值之間的關(guān)系的一系列操作。應(yīng)建立測量結(jié)果的可接受限度。Chromatograp

18、hic column 色譜柱A tube commonlyfilled with a stationary phase over which a sample and mobile phase move, used in chromatographic analysis.一支通常用固定相填充，樣品和流動相在其中移動，用于色譜分析的柱子。Data 數(shù)據(jù)All original records and true copies of original records, including source data and metadata and all subsequent transformati

19、ons and reports of these data, which are generated or recorded at the time of the GMP activity and allow full and complete reconstruction and evaluation of the GMP activity. Data should be accurately recorded by permanent means at the time of the activity. Data may be contained in paper records (suc

20、h as worksheets and logbooks), electronic records and audit trails, photographs, microfilm or microfiche, audio- or video-files, or any other media whereby information related to GMP activities is recorded.所有原始記錄和原始記錄的真實副本，包括源數(shù)據(jù)和元數(shù)據(jù)以及這些 數(shù)據(jù)的所有后續(xù)轉(zhuǎn)移及報告。這些數(shù)據(jù) 是在 GMP 活動時生成或記錄，可全面完整重構(gòu)及評估該 GMP 活動。數(shù)據(jù)應(yīng)在活動發(fā)生時采

21、用永久方法準確 記錄。數(shù)據(jù)可保存在紙質(zhì)記錄上(例如工作記錄和日志)、電子記錄上和審計追蹤上、圖片上、微縮膠卷上、 影音文件或任何其它記錄與 GMP 活動有關(guān)信息的媒介上。Exponential skim 指數(shù)撇除The creation of a curvature in the skim line in an attempt to approximate the underlying baseline of the parent peak.在撇去線上創(chuàng)建一個曲率以使其接近母峰的下基線。Exponential curve fitting 指數(shù)曲線設(shè)置The drawing of acurve

22、using an exponential equation through the start and end of the child peak. The curve passes under each child peak that follows the parent peak; the area under the skim curve is subtracted from the child peaks and added to the parent peak.使用指數(shù)方程畫一條通過子峰起點和結(jié)點的曲線。該曲線通過母峰后的所有子峰，將撇去曲線下的面積從子 峰面積中扣除，加和到母峰面積

23、上。Front peak skim 前伸峰撇去The process of integrating child peaks on the front (upslope) of a peak subjectto specified criteria.根據(jù)指定標準對一個峰的前沿部分(上斜部分)上的子峰進行積分的過程Integration 積分The process of applying specified parameters for chromatographic peaks (determination of height, area and retention time).采用指定參數(shù)對色

24、譜峰進行處理(確定峰高、峰面積和保留時間)Metadata 元數(shù)據(jù)Metadata is data about data that provides the contextual information required to understand those data. These include structural and descriptive metadata. Such data describe the structure, data elements, interrelationships and other characteristics of data. They also

25、 permitdata to beattributable to an individual. Metadata necessary to evaluate the meaning of data should be securely linked to the data and subject to adequate review. For example, in weighing, the number 8 is meaningless without metadata, such as, the unit, milligram, etc. Other examples of metada

26、ta include the time/date stamp of anactivity, the operator identification (ID) of the person who performed an activity, the instrument ID used, processing parameters, sequence files, audit trails and other data required to understand data and reconstruct activities.元數(shù)據(jù)是提供理解數(shù)據(jù)所需環(huán)境信息的數(shù)據(jù)。其中包括結(jié)構(gòu)性和描述性元數(shù)據(jù)

27、。此類數(shù)據(jù)描述結(jié)構(gòu)、數(shù)據(jù)元 素、相互關(guān)系和數(shù)據(jù)的其它特性。他們亦可讓數(shù)據(jù)追溯至個人。評估數(shù)據(jù)含義所需的元數(shù)據(jù)應(yīng)與數(shù)據(jù)安全鏈 接，并進行充分審核。例如，在稱重過程中，如果沒有元數(shù)據(jù)，如單位 mg 等，數(shù)字 8 是無意義的。元數(shù)據(jù) 的其它例子包括一個活動的時間 /日期戳，執(zhí)行活動的操作員身份( ID )、所用儀器 ID 、處理參數(shù)、序列文 件、審計追蹤和理解數(shù)據(jù)和重構(gòu)活動所需的其它數(shù)據(jù)。Peak valley ratio 峰谷比The peak to valley ratio is a measure of quality indicating how well the peak is separ

28、ated from other substance peaks.峰谷比是顯示一個峰與其它物質(zhì)峰分離程度的質(zhì)量指標Qualification 確認Documented evidence that premises, systems or equipment are able to achieve the predetermined specifications properly installed, and/or work correctly, and lead to the expected results.證明設(shè)施、系統(tǒng)或設(shè)備能夠達到預(yù)定標準、適當安裝，和/ 或正確運轉(zhuǎn)并獲得預(yù)期結(jié)果的文件化

29、證據(jù)。Rear peak skim 峰尾撇去The process of integrating child peaks on the tail (downslope) of a peak subject to specified criteria. 根據(jù)指定標準對一個峰的拖尾部分(下斜部分)上的子峰進行積分的過程Restoration 恢復(fù)The process of retrieving electronic data that had previously been backed-up and presented in areadable format.恢復(fù)之前已有備份的電子數(shù)據(jù)并以可讀

30、格式展現(xiàn)的過程。Source data 源數(shù)據(jù)Original data obtained as the first-capture of information, whether recorded on paper or electronically.在信息首次捕獲中獲取的紙質(zhì)或電子原始數(shù)據(jù)。Straight line skim直線撇去ht of the的一條切線The process ofdrawing a straight line through the start and end of a child peak. The heig start of the child peak is

31、 corrected for the parent peak slope. The area under the straight line is subtracted from the child peak and added to the parent peak.畫一條通過子峰起點和終點的處理方法。子峰的起點高度根據(jù)母峰斜率進行調(diào)整。直線下面的面積從子峰面 積中扣除，加到母峰面積上。Tangential skim 切線撇去The process of integrating a small peak located on the tailing edge of a larger peak.

32、 The baseline of the small peak becomes a tangent drawn from the valley of the larger peak to the tangent point on the chromatogram.對一個較大峰的尾部邊緣上一個小峰進行積分的過程。小峰的基線成為大峰峰谷至色譜圖切點Validation 驗證Action of proving and documenting that any process, procedure or method actually and consistently leads to the exp

33、ected results.提供和記錄所有工藝、程序或方法實際一致獲得預(yù)期結(jié)果的行動。Valley height ratio峰高比Valley height ratio is the ratio of the height of the child peak above the baseline to the height of the valley above the baseline. This ratio must be smaller than the specified value for the child peak to be skimmed.峰高比是高于基線的子峰峰高比高于基線

34、的谷高比值。該比率必須小于要撇去的子峰的指定值。CHROMATOGRAPHIC SYSTEMS 色譜系統(tǒng)Manufacturers should select, install and use chromatographic systems that are appropriate for the intended use.生產(chǎn)商應(yīng)選擇、安裝和使用適合其既定用途的色譜系統(tǒng)。Vendor qualification should ensure that hardware and software are suitable for their intended application and th

35、at after-sales services will be available.供應(yīng)商確認應(yīng)確保硬件和軟件適合其既定應(yīng)用程序，能提供售后服務(wù)。Valid agreements should specify the respective responsibilities between the purchaser and supplier.購買方和供應(yīng)商之前應(yīng)有有效協(xié)議說明雙方職責。Systems should meet regulatory requirements and expectations for Good Manufacturing Practices, including b

36、ut not limited to, ensuring that data are acquired, processed and stored in accordance with national legislation and ALCOA+ principles.系統(tǒng)應(yīng)符合法規(guī)要求和 GMP 要求，包括但不僅限于，確保數(shù)據(jù)采集、處理和存貯符合國家法律和 ALCOA+ 原則。QUALIFICATION AND VALIDATION確認與驗證The scope and the extent of validation and qualification of chromatographic

37、systems should be determined based on risk management principles.色譜系統(tǒng)驗證和確認的范圍和程度應(yīng)根據(jù)風險管理原則確定。The approach to, and execution of validationand qualification, should be described in an authorized document such as avalidation master plan.驗證和確認方法及其執(zhí)行應(yīng)在批準的文件如驗證主計劃中闡明。All stages of qualification should be c

38、onsidered and may include, for example, user requirement specifications (URS), design qualification (DQ), factory acceptance test (FAT), site acceptance test(SAT), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ).(See also the Guideline for Computeri

39、zed Systems).確認的所有階段均應(yīng)考慮包括如用戶需求手冊(URS )、設(shè)計確認( DQ )、工廠接收測試( FAT )、用戶接收測試( SAT )、安裝確認( IQ )、運行確認( OQ )和性能確認( PQ)。(亦請參見計算機化系統(tǒng)指南)Validation and qualification should be described in protocols and recorded in reports.Reports should contain documented evidence such as screen shots, printouts or other sourc

40、e data of tests executed as part of validation and qualification.驗證和確認應(yīng)在方案中進行說明，并記錄在報告中。報告中應(yīng)包括文件化證據(jù)，如截屏、打印條或其它作為 驗證和確認的一部分所執(zhí)行檢測的源數(shù)據(jù)。The data should provide evidence of the consistency of performance of the system, and reliable and accurate results.數(shù)據(jù)應(yīng)提供證據(jù)證明系統(tǒng)性能一致性，以及結(jié)果可靠準確。Parameters such as, but no

41、t limited to, password control, audit trail, access and privileges, should be described and verified during validation and qualification.參數(shù)(例如但不僅限于密碼控制、審計追蹤、訪問和權(quán)限) 應(yīng)在驗證和確認時說明并核對。Chromatographic systems should be calibrated at periodic intervals in accordance with written procedures. Records should b

42、e maintained.色譜系統(tǒng)應(yīng)根據(jù)書面程序定期進行校正。記錄應(yīng)保存。Root cause analysis, impact and risk assessment should be done when any calibrationparameter is found out of calibration or not meeting the predefined limits. Appropriate corrective and preventive action (CAPA) should be taken.如發(fā)現(xiàn)任何校正參數(shù)未校正或不符合既定限度，則應(yīng)進行根本原因分析、影響性分

43、析和風險評估。應(yīng)采取適 當?shù)?CAPA 。ACCESS AND PRIVILEGES 訪問與權(quán)限There should be a standard operating procedure (SOP) for the creation and deletion of user groups and users of the chromatographic system, indicating the relevant privileges allocated to each user. Records should be maintained.應(yīng)有標準操作程序( SOP )規(guī)定色譜系統(tǒng)用戶組和

44、用戶的創(chuàng)建與刪除，寫明配置給每個用戶的相關(guān)權(quán)限。記 錄應(yīng)保存。An up-to-date matrix of user groups and users should be maintained.應(yīng)維護一份用戶組和用戶最新清單。Users in each group should be appropriately qualified for the responsibility and privileges given.每個組內(nèi)的用戶應(yīng)有適當資質(zhì)可承擔指定的職責和權(quán)限。Manual records of user groups, users and their privileges shoul

45、d be concordant with electronic data.用戶組、用戶及其權(quán)限的手工記錄應(yīng)與電子數(shù)據(jù)相一致。Where required, justification should be provided for privileges granted to user groups or users.必要時，為用戶組或用戶授予的權(quán)限應(yīng)有理由支持。6.AUDIT TRAIL審計追蹤Chromatographic systems should have (an) audit trail(s).色譜系統(tǒng)應(yīng)有審計追蹤。Full audit trails should be enabled

46、 from the time of installation of software.從軟件安裝開始即應(yīng)全面激活審計追蹤。Audit trails should remain enabled throughout the life cycle of a chromatographic system.審計追蹤在色譜系統(tǒng)的生命周期中應(yīng)保持激活。Audit trails should be reviewed in accordance with an SOP. There should be evidence of the regular (each chromatographic analysis

47、) and periodic review (at random checks at specifiedintervals) of audit trails.審計追蹤應(yīng)根據(jù) SOP 進行審核。應(yīng)有證據(jù)證明對審計追蹤進行了日常(每次色譜分析)和定期審核(按指定 時間間隔隨機檢查)。Audit trails are part of metadata and should be stored as part of the data set for all chromatographic analysis.審計追蹤是元數(shù)據(jù)的一部分，應(yīng)作為所有色譜分析數(shù) 據(jù)系列的一部分存貯。DATE AND TIME

48、FUNCTIONS日期與時間功能Chromatographic systems should have date and time functions enabled.色譜系統(tǒng)應(yīng)激活日期與時間功能。The date and time function should be locked and access to change the date and time should be controlled.This includes time zones.日期和時間應(yīng)鎖定，修改日期和時間的權(quán)限應(yīng)受控。其中包括時區(qū)。All actions on chromatographic systems sho

49、uld be date and time -tracked. 色譜系統(tǒng)的所有動作均應(yīng)可追蹤到日期和時間。ELECTRONIC SYSTEMS 電子系統(tǒng)Note: This includes computerized systems注：其中包括計算機化系統(tǒng)。Electronic systems used in chromatographic systems should be suitable for their intended use.色譜系統(tǒng)所用電子系統(tǒng)應(yīng)適合其既定用途。Where possible, all chromatographic systems should be linked

50、 to a network.所有色譜系統(tǒng)應(yīng)盡可能連接到網(wǎng)絡(luò)。Stand-alone systems should be appropriately managed. Risk assessment should be done to ensure that sufficient controls are in place to eliminate the risks associated with stand- alonesystems. These include, but are not limited to, access, privileges, date and time funct

51、ion, audit trail, back-up and data management單機系統(tǒng)應(yīng)進行恰當管理。應(yīng)進行風險評估以確保有足夠的控制用以消除單機系統(tǒng)帶來的風險。其中包括但 不僅限于訪問、權(quán)限、日期和時間功能、審計追蹤、備份和數(shù)據(jù)管理。Electronic Data Management Systems (EDMS) should be considered for the appropriate management of data, including acquisition, processing and storage of data. EDMS should be app

52、ropriate for their intended use and ensure the accuracy and reliability of data obtained and processed.應(yīng)考慮使用電子數(shù)據(jù)管理系統(tǒng)( EDMS )對數(shù)據(jù)進行管理，包括數(shù)據(jù)采集、處理和存貯。 EDMS 應(yīng)適合其既 定用途，確保所獲取和處理的數(shù)據(jù)的準確性和可靠性。Appropriate procedures should be followed when a new electronic system is taken into use. Procedures should also be fol

53、lowed for the removal of a system from use. Records should be maintained.在開始使用新的電子系統(tǒng)時應(yīng)遵守適當?shù)某绦?。系統(tǒng)退出使用時亦應(yīng)遵守程序。記錄應(yīng)有保存。SOLVENTS, BUFFER SOLUTIONS AND MOBILE PHASES 溶劑、緩沖液和流動相Solvents, buffer solutions and mobile phases should be prepared, stored and used in accordance with authorized specifications, pro

54、cedures and pharmacopoeia. These should be used within their validated shelf life.溶劑、緩沖液和流動相制備、存貯和使用應(yīng)根據(jù)批準的質(zhì)量標準、程序和藥典。應(yīng)在其經(jīng)過驗證的貨架期內(nèi) 使用。Records for their preparation should be maintained.其配制記錄應(yīng)保存。Chemicals, reagents and other materials used should be of appropriate grade and quality.所用化學品、試劑和其它物料應(yīng)為適當級別

55、和質(zhì)量。Mobile phases should be filtered and degassed when required. 流動相應(yīng)過濾除氣（必要時）。COLUMN MANAGEMENT色譜柱管理Columns used in chromatography should be appropriate for their intended use. 色譜所用柱子應(yīng)適合其既定用途。Columns should be purchased from approved suppliers. 色譜柱應(yīng)從批準的供應(yīng)商處采購。Columns should be verified on receiptan

56、d checked for their suitability prior to use. 收到色譜柱時應(yīng)驗收，使用前應(yīng)檢查其是否適用性。Columns, tubing and fittings should beappropriate to ensure that the system performs as expected.色譜柱、管和配件應(yīng)適當，以確保系統(tǒng)性能達到預(yù)期。Backpressure and flow rates should be appropriate for the column to be used and specified in specifications an

57、d test procedures.背壓和流速應(yīng)適合所用色譜柱，并在標準和檢驗方法中指定。Column efficiency should be appropriate （number of theoretical plates） to ensure good chromatography.柱效應(yīng)適當（理論塔板數(shù)）以確保良好的色譜效果。Risks associated with columns, such as“chiral columns ”, should be controlled.色譜柱相關(guān)風險，如“手性柱”應(yīng)受控。Flow rate, loading capacity and bac

58、kpressure should be appropriate to ensure desired and constant retention time.流速度、載量和背壓應(yīng)適當，以確保獲得理想穩(wěn)定的保留時間。The use of columns should be recorded in a traceable manner. This includes, for example, a unique identification number, number of injections and washing.色譜柱的使用應(yīng)以可追蹤的方式記錄。其中包括例如唯一識別號、進針數(shù)和沖洗Colum

59、ns should be washed (cleaned orflushed) according to defined procedures which define the steps and parameters, such as sequence and flow rate.色譜柱應(yīng)根據(jù)指定的程序清洗(清潔或沖洗)，在程序中規(guī)定沖洗步驟和參數(shù)如順序和流速。Columns should be stored in a manner that ensures that they are not damaged. 色譜柱存貯方式應(yīng)確保其不受損壞。Equilibrating columns be

60、fore, and temperature control of column and mobile phase during analysis, should be done when specified.分析前柱平衡、分析中柱溫控制和流動相如有規(guī)定應(yīng)遵守。theRemoval of contaminants and regeneration of columns should only be considered when appropriate procedures for this had been developed.只有在已制訂了適當程序時，才可考慮清除色譜柱污染物和再生。SAMP