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1、LABORATORY CONTROLS,实验室控制体系December 2006,Laboratory Controls,实验室控制体系,2,CGMP Regulation for Laboratory Controls,21 CFR 211.160(b)Laboratory controls shall include the establishment of scientifically sound and appropriate specifications,standards,sampling plans,and test procedures designed to assure t
2、hat components,drug product containers,closures,in-process materials,labeling,and drug products conform to appropriate standards of identity,strength,quality,and purity.,Laboratory Controls,实验室控制体系,3,CGMP Regulation for Laboratory Controls,21 CFR 211.160(b)(1)Laboratory controls shall include:Determ
3、ination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components,drug product containers,closures,and labeling used in the manufacture,processing,packing,or holding of drug products.,Laboratory Controls,实验室控制体系,4,CGMP Regulation for Labor
4、atory Controls,21 CFR 211.160(b)(2)Laboratory controls shall include:Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials.Such samples shall be representative and properly identified.,Laboratory Controls,实验室控制体系,5,CGMP R
5、egulation for Laboratory Controls,21 CFR 211.160(b)(3)Laboratory controls shall include:Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products.Such samples shall be representative and properly identified.,Laboratory Controls,实验室控制
6、体系,6,Laboratory Controls(ICH Q7A),11.1 General ControlsThere should be documented procedures describing sampling,testing,approval,or rejection of materials and recording and storage of laboratory dataAll specifications,sampling plans,and test procedures should be scientifically sound and appropriate
7、 to ensure that raw materials,intermediates,APIs,and labels and packaging materials conform to established standards of quality and/or purity.,Laboratory Controls,实验室控制体系,7,Laboratory Controls(ICH Q10 Draft,Pharmaceutical Quality System),Independent Quality UnitResponsibilities(In-house and outsourc
8、ed manufacturing)QC and QAInvestigation of Atypical and OOS eventsCorrective Action and Preventative Action(CAPA)Change managementManagement review of product and process quality,Laboratory Controls,实验室控制体系,8,Laboratory Controls,Establishment ofSampling PlansSpecifications StandardsTest Procedures,T
9、esting forComponentsIn-process MaterialsFinal ProductsContainers and ClosuresDrug products(DS&DP)All Above,Laboratory Controls,How Do We Establish a Laboratory Control System to Meet CGMP Requirement?,Laboratory Controls,实验室控制体系,10,Documentation,If you do not document it,you have not done it.Raw dat
10、a entryTraceabilityCorrectionTaped-in data/diagramsData invalidationNotebook witness,review and approvalStorageArchiving Retrieving,Laboratory Controls,实验室控制体系,11,RECORD RETENTION实验室档案的保存,All records(batch,electronic chromatographic data for HPLC analysis of drug components and finished products)sho
11、uld be backed up and maintained for at least one year after the expiration dateA system should be in place to manage raw data and laboratory notebooksDaily use logbooks should be kept for all instrument in laboratory,Laboratory Controls,实验室控制体系,12,STANDRD OPERATION PROCEDUR(SOP)实验室标准操作程序,Different T
12、ypes of SOPsGlobal SOPs-General policy for instrument management(IQ,OQ,PQ/PV),method validation(guidelines),SOP management(creation,revision,and retirement),documentation(laboratory notebook,document archiving,retention,etc),change control and other documents management.Local SOPs-Testing procedure,
13、calibration protocol,method validation,data recording forms,data processing,etc.,Laboratory Controls,实验室控制体系,13,STANDRD OPERATION PROCEDURE(SOP)实验室标准操作程序,All components,manufacturing materials,in-process materials,packaging material,and labeling should be inspected and tested according to written pr
14、ocedure(s)prior to release,Laboratory Controls,实验室控制体系,14,LABORATORY CONTROL SYSTEM 实验室控制系统,General Requirements The Laboratory facilities should be adequate and have adequate equipment for the facilitation of its function The responsible heads of various functional groups should have the necessary
15、education,training,and experience to perform their functions Procedures for the proper cleaning,maintenance and storage of lab glassware/utensils should be in place,Laboratory Controls,实验室控制体系,15,LABORATORY CONTROL SYSTEM 实验室控制系统,General RequirementsLaboratory reagents,chemical supplies,and prepared
16、 solutions(e.g.,mobile phases)should be identified and given expiration dates(and/or marked with date of a bottle is opened).Expiration dates may be justified by the known stability of relevant chemical/biochemical entities.USP reference standards should be used or in-house reference standards shoul
17、d be certified against USP standards.Otherwise,in-house primary standards should be established via validated methodology.The instrument shall be properly calibrated and maintained(preventative maintenance,or PM)on a periodic basis which is justified by the performance and usage of the instrument.,L
18、aboratory Controls,实验室控制体系,16,LABORATORY INSTRUMENTS实验室仪器,21 CFR 211.160(b)(4)The calibration of instruments,apparatus,gauges,and recording devices at suitable intervals in accordance with an established written program containing specific directions,schedules,limits for accuracy and precision,and p
19、revisions for remedial action in the event accuracy and/or precision limits are not met.Instruments,apparatus,gauges,and recording devices not meeting established specifications shall not be used,Laboratory Controls,实验室控制体系,17,LABORATORY INSTRUMENTS实验室仪器,GeneralThe laboratory instruments should be p
20、roperly installed(IQ),qualified(OQ,PQ/PV),maintained(PM)and documented(qualification document,logbooks,etc),and calibrated according to the written procedure(s)Use Logbooks for instrument shall use hard bound books and be properly recorded and maintained,Laboratory Controls,实验室控制体系,18,CALIBRATION OF
21、 INSTRUMENTS实验室仪器校验,Written Program(or SOP)-Specific directions-Suitable intervals(schedule)-Parameters to be calibrated-Acceptance criteria(limits)-Previsions for remedial action(repair,revision of PM schedule,etc)Calibration Summary or Report,Laboratory Controls,实验室控制体系,19,VALIDATION 验证,Overall po
22、licy should include Validation process,cleaning procedures,analytical methods,in-process control test procedures,computerized system Persons responsible for design,review,and approval,Laboratory Controls,实验室控制体系,20,VALIDATION 验证,A laboratory should be qualified for all test methods it performs.The q
23、ualification can be done through Method transfer from a qualified laboratoryMethod validation/verification(e.g.,compendial methods).The qualification process should be documented before a method is used.Analysts should be properly trained in the test methods they perform.,Laboratory Controls,实验室控制体系
24、,21,VALIDATION 验证,Computer systems for control of process,data collection,etc.should be validated and validation process documented,Laboratory Controls,实验室控制体系,22,HPLC Method Validation(Compendial test requirements),Category I Analytical procedures for quantitation of major components of bulk drug s
25、ubstances or active ingredients(including preservatives)in finished pharmaceutical products.Category II Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products.These procedures include quantitative assays and limit te
26、sts.Category III Analytical procedures for determination of performance characteristics(e.g.,dissolution,drug release).Category IV Identification tests.,Laboratory Controls,实验室控制体系,23,HPLC Method Validation(Compendial test requirements),Laboratory Controls,实验室控制体系,24,Method Verification,USP(and othe
27、r harmonized compendial methods)test methods should be verified as suitable for actual condition of use and stability indicating.In general,other non-USP methods should be properly validated.,Laboratory Controls,实验室控制体系,25,FDA Form 483 Observations,ObservationThe analytical method used for impuritie
28、s in XXXXX API is not validated or properly verified for actual condition of use.The firm failed to demonstrate that the HPLC method used for related substances in stability study is stability indicating.The analytical instrument is properly calibrated,specifically,the noise and detector linearity a
29、re not included in annual calibration of HPLC used for related substance analysis.,Laboratory Controls,实验室控制体系,26,Verification of Compendial Procedure for Drug substances and Excipients,Laboratory Controls,实验室控制体系,27,Verification of Compendial Procedure for Dosage forms,Laboratory Controls,实验室控制体系,2
30、8,Standard,USP Standard Working StandardQualification and Re-qualification(Certification and Re-certification)StorageTreatment before use(if applicable,e.g.,drying),Laboratory Controls,实验室控制体系,29,STABILITY 稳定性试验,Stability protocol and appropriate storage conditions for stability program should be es
31、tablished(provision for ad hoc time point testing)Temperature and humidity of stability chamber should be validated and calibrated at regular intervals.Continuing chart recorder should be used to monitor temperature and humidityStability program should include meaningful and specific test methods(st
32、ability indicating methods),Laboratory Controls,实验室控制体系,30,STABILITY 稳定性实验,Reserve(retention)samples should be properly retained.First three commercial batches should be placed on stability study and one batch per year thereafter(if produced)Appropriate retest date should be established for APIs and
33、 shelf life for finished dosage forms,Laboratory Controls,实验室控制体系,31,Dissolution,Method verification/medium adjustment of USP methodsDissolution method needs to be discriminating and yet ruggedDissolution bath calibrationUSP calibration with standard compoundsMechanical calibration(speed,wobbling,et
34、c.),Laboratory Controls,实验室控制体系,32,Investigation of Atypical and Out-of-Specification(OOS)Events,Guidelines and SOPsResponsibilitiesDocumentationInitial recording of the event Initial impact assessment,possible root causeTiming of the investigationFinal report with root cause,impact assessment,and C
35、APAInvalidate data and re-testing(if applicable)Corrective action and preventative action(CAPA):e.g.,re-training of analysts,adding more detailed notes into analytical methods,instrument repair,etc.,Laboratory Controls,实验室控制体系,33,FDA Form 483 Observations,ObservationThe analytical method used for im
36、purities in XXXXX API is not validated or properly verified for actual condition of use.The firm failed to demonstrate that the HPLC method used for related substances in stability study is stability indicating.The analytical instrument is properly calibrated,specifically,the noise and detector line
37、arity are not included in annual calibration of HPLC used for related substance analysis.,Laboratory Controls,实验室控制体系,34,SUMMARY,A proper SOP system should be in placeRecords and documents should be properly maintainedInstrument should be properly maintained and calibratedMethods should be validated or verifiedStability should be conducted to support retest or expiration date for productsA proper procedure for atypical and OOS investigations should be established,
