蒸汽滅菌和凍干工藝的驗(yàn)證及風(fēng)險(xiǎn)分析1課件

1、CONTENTRegulatory aspectsMoist Heat SterilizationChoosing the right processValidating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidating a lyophilization processProcess ControllerRisk AnalysisGMP & VALIDA

2、TION1972 DEVENPORT INCIDENT (UK)Infusional solutions, produced at the Devemport Hospital, caused three patient deceases.The ROSENHEIM Report found the causes in a not correct sterilization treatment. Extracted from the ROSENHEIM ReportThe AIR was not properly removed from the chamberThe drain of the

3、 chamber was blocked by pieces of glassesThe lower section of the load did not reach the sterilization temperatureThe temperature recorder showed this anomaly but people thought it was not working properlySterility tests were carried out only on the upper layers of the loadGMP & VALIDATIONValidation

4、Main concepts Personnel Equipment Process/Products InstrumentsDocuments and SOPQualified, trainedTo be qualified (IQ, OQ, PQ)To be validatedSuitable, calibration has to be planned and documentedUp-to date, distributed, maintained under controlTerminal Moist-Heat SterilizationEngineering Equipment Im

5、plicationsChapter 3 of EU-GMP (Premises and Equipment)21 CFR part 211.63, 211.65, 211.67 (Equipment)Annex 11 UE GMP (Computerised systems) 21 CFR part 211.68 (Automatic, mechanical and electronic equipment)21 CFR part 11 (Electronic records Electronic Signatures)GAMP (Good Automated Manufacturing Pr

6、actice)Validation21 CFR parts 210-211 (211.100, 211.110, 211.213)21 CFR part 820 (820.75)EU GMP (Cap. 5.21 5.24) EU GMP Annex 15: (Qualification and Validation)Compliance Policy Guide Sec. 490.100 (Process Validation Requirements for Drug Products Subject to Pre-Market Approval)Terminal Moist-Heat S

7、terilizationCONTENTRegulatory aspectsMoist Heat SterilizationChoosing the right processValidating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidating a lyophilization processProcess ControllerRisk Analysis

8、What is being Sterilized?Porous LoadsHard GoodsEquipment PartsComponentsGlassStainless steelPolymeric MaterialsWaste LiquidsNon-Porous LoadsFinished ProductsLaboratory MediaIn-process FluidsWaste LiquidsPolymeric MaterialsDefining the sterilization processDefining the sterilization processTemperatur

9、e and Time for an effective sterilizationCan not be defined by physical methodsHave to be preliminary investigated according to a microbiological approachShould comply with minimum requirement such as the traditional “Fo of 8 or more” reported in the Proposed Rules of the FDA (1976, Clause 212.240),

10、 or the grid of table 4 of the guideline HTM 2010, Part 2, Clause 3.24 (i.e. 15 minutes 121-124C), reported also in the standard EN 285, point BIOBURDENThermic resistance of the productOverkillBioburdenIntegrated (Bioburden / Biological indicators)Validation approaches:Defining the sterilization pro

11、cessBalance must be MaintainedAttaining sterility must not be accomplished with loss ofproduct stability.Maintaining stability must be accompanied with adequateassurance of sterility.Defining the sterilization processDefining the sterilization processDemonstrated PNSUExpected Shelf LifeInformation N

12、eededFor ValidationHeat Input to MaterialsBioburdenMethodBioburden / BIMethodOverkillMethodCONTENT OF THE PRESENTATIONRegulatory aspectsMoist Heat SterilizationChoosing the right processCauses of failureValidating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validatio

13、n Physical issuesValidation Microbiological issuesSterilizer Process ControllerRisk AnalysisValidationWhat has to be validated? A process ? A product ?A piece of equipment ?Lets consider the definition of “validation”Validation is establishing documented evidence which provides a high degree of assu

14、rance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics (FDA Guideline on General Principles of Validation, 1987)Validation is a defined strategy of inter-related practices and procedures which in combination with routin

15、e production methods and quality control techniques provides documented assurance that a system is performing repetitively as intended and/or that a product conforms to its pre-determined specifications (PDA TM#1 revised, Draft 13, Glossary)ValidationCommon items: - Specify - Document - Verify the e

16、ffectiveness - Verify the reproducibilityThe scope of validation is the process or the productThe new PDA definition considers validation as a “ongoing process” (maintaining the validated status)ValidationProcessProductEquipmentRules and standardsCharacteristicsHandlingWrappingTerminally sterilizedS

17、terilization ?Terminal sterilization ?Sterilization method ?ValidationStages of the qualification of a piece of equipment should include DQ, IQ, OQ and PQ.User Requirements SpecificationsFunctionalSpecificationsDesignSpecificationsProject execution InstallationQualificationOperationalQualificationPe

18、rformanceQualificationRelated toRelated toRelated toDesign QualificationVALIDATION LIFECYCLEDESIGN QUALIFICATION The documents of the projects at disposal specify in an exaustive way the equipment, the systems, and the installations that compose that projectThe documents related to the user requirem

19、ents specifications, to the basic design (or functional) and to the detail design (or executive) are clearly identifiedDESIGN QUALIFICATION The project documents are correctly approved by the competent functions upon what established in the quality plan of the projectThe functional specs (basic desi

20、gn) and the engineering documents (detail design) of the system under exam are based on the needs of the user (user requirements) The design has been carried out considering a compliance to the cGMPs and eventual applicable guidelines“Installation Qualification is an essential step preceding the Pro

21、cess Validation exercise. It is normally executed by the Engineering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping & Instrument Drawings, (P&I.Ds) and Plant Functional Specifications developed during the project pl

22、anning stage. During the project planning stage, Installation Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented record that all installed equipment satisfies the planned requirements.”Recommendations on Validation

23、Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004INSTALLATION QUALIFICATIONThe Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validatio

24、n July 2001“IQ should include, but not limited to, the following:installation of equipment, piping, services and instrumentation checked to current engineering drawing and specifications;collection and collation of supplier operating and working instruction, and maintenance requirements;calibration

25、requirements;verification of materials of construction.”INSTALLATION QUALIFICATIONOutlinePre-requirementsReference specs & purch. orderProcedure verificationCritical instruments calibration verif.“as-built” drawingsMain components verificationUtilities connection verificationLubricants verificationA

26、ttachmentsINSTALLATION QUALIFICATIONINSTALLATION QUALIFICATIONINSTALLATION QUALIFICATION“OQ is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the equipment or systems will define the critica

27、l characteristics for operation of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorized, implemented and resulting data collected and evaluated.It is important at this stage to assure all operational test data conform with

28、pre-determined acceptance criteria for the studies undertaken.”Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004OPERATIONAL QUALIFICATION“It is expected that during the Operational Qualific

29、ation stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules.”“The completion of a successful Operational Qualification should allow the finalisation of operati

30、ng procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment.”Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-

31、Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004OPERATIONAL QUALIFICATION“OQ should include, but not limited to, the following:tests that have been developed from knowledge of process, systems and equipment;tests to include condition or set of conditions encompassing upper and l

32、ower operating limits, sometimes referred to as “worst case” conditions.”The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001OPERATIONAL QUALIFICATIONOutlineProcedure verificationCritical instrumen

33、ts calibration verif.Functional verificationOPERATIONAL QUALIFICATIONOPERATIONAL QUALIFICATIONQualification of steam autoclavesOperational QualificationINDICE9. Verification of supporting documentation 9.1 Verification of SOPs 9.2 Verification of the equipment calibration installed on the system10.

34、Operational verification of the system 10.1 Verification of the input/output signals of the control system 10.2 Verification of the alarms operation 10.3 Verification of the operational sequences 10.4 Verification of the behavior in case of power failure 10.5 Verification of the protection system wi

35、th password 10.6 Verification of the operator interface 10.7 Verification of the monitoring and control devices functionality 10.8 Verification of the vacuum pump functionality (if applicable) 10.9 Verification of the vacuum tightness (if applicable) 10.10 Verification of the back pressure 10.11 Ver

36、ification of the heat distribution in empty room 10.12 Verification of the door interlock system functionality11. AttachmentsDocumented verification that the system is able to fulfill, in a constant and repetitive way, all the tasks indicated in the URS.Usually they will be designed, to this aim, so

37、me challenges for the verification of the process parameters and of the operative conditions, in the established intervals of variability, in compliance with the data reported in the official records. The conditions limit to the challenge, after the due considerations, can be different from the ones

38、 that represent the limit of the process.PERFORMANCE QUALIFICATION“PQ should include, but not limited to, the following:tests, using production material, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment;tests

39、to include a condition or set of conditions encompassing upper and lower operating limits.”The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001PERFORMANCE QUALIFICATIONDefining the sterilization pr

40、ocessDemonstrated PNSUExpected Shelf LifeInformation NeededFor ValidationHeat Input to MaterialsBioburdenMethodBioburden / BIMethodOverkillMethodValidation approachesOverkill(from PDA, TM#1 revised, Draft 13, Glossary):A cycle which provides a minimum 12-log reduction of a resistant biological indic

41、ator with a known D-value of not less than 1 minute at 121.1C. This approach assures substantially greater than a 12-log reduction of the bioburden and therefore only minimal information on the bioburden is requiredBioburden(from PDA, TM#1 revised, Draft 13, Glossary):A process which provides a prob

42、ability of survival of less than 1 in 106 for the most resistant bioburden expected in the load. It requires information on the number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburdenValidation approachesBB/BI or “combination”(from PDA, TM#1 revised, Dra

43、ft 13, Glossary):A process which provides a probability of survival of less than 1 in 106 for the bioburden as demonstrated using a resistant biological indicator with a known D-value. The biological indicator may not be fully inactivated during the sterilization cycle. It requires information on th

44、e number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburdenValidation approachesD and z valuesIf the Biological Indicators are used to release the production batches the resistance of the inoculated spore has to be.VerifiedDeterminedBIs from the shelfHomem

45、ade BIsValidation approachesMicrobiological qualificationMicroorganism resistanceD: decimal reduction timeThe time required, at a specific temperature T, to reduce the microbial population being considered by one logarithmic value, i.e. from 100% to 10%z: temperature coefficient of microbial destruc

46、tionThe number of degrees of temperature which causes a 10-fold variation of D (or, more generally, of the sterilization rate)Microorganism resistanceBIER Biological Indicator Evaluator ResistometerTo verify the resistance (D, z) of the commercial Bis (Overkill approach)To determine and verify the r

47、esistance of the self-made Biological Indicator (Bioburden approach)Microbiological qualificationValidation approachesD and z values determinationB.I.E.R.Biological Indicator Evaluator ResistomertimetemperatureRealTheoreticalSquared curve for a BIER vessel Biological Indicator Evaluator Resistometer

48、Validation issuesCalibrationLeak testValidation activities (physical)Thermocouples calibrationHeat distributionHeat penetrationSterilizatio CycleVerification of calibrationProcedura di convalida (Microbiologica)Review of resultsMaintaining the validationValidation CalibrationTemperaturePressureTimeV

49、alidation issuesCalibrationLeak testValidation activities (physical)Thermocouples calibrationHeat distributionHeat penetrationSterilizatio CycleVerification of calibrationProcedura di convalida (Microbiologica)Review of resultsMaintaining the validationValidation leak testValidation issuesCalibratio

50、nLeak testValidation activities (physical)Thermocouples calibrationHeat distributionHeat penetrationSterilizatio CycleVerification of calibrationProcedura di convalida (Microbiologica)Review of resultsMaintaining the validationHeat distribution and penetrationThe Uniformity has to be referred to the

51、 empty chamber or to the free space of the loaded chamberTemperature sensorsThe Heat Penetration is referred to the inner part of the products:Temperature sensorsBiological Indicators Temperature mappingLethality mapsApplication ConsiderationsPlace in the most difficult to sterilize locationUse for

52、validationUse for routine monitoringMaps Use FO Calculated From Each Thermocouple LocationLethality mapsMaps Use FO Calculated From Each Thermocouple LocationLethality mapsFront of ChamberLethality Map, Lower ShelfLethality mapsApplicationsCertain identification of the cold pointsPlacement of BI in

53、least lethal (worst case) location(s)Correct replication of the exposition environment of the BIsLethality mapsRandom BI DistributionBIBIBIBIBILethality mapsCluster BI DistributionBIsLethality mapsWater for sterilization may beInitially present in the bulk of sealed containers of aqueous solutions (

54、steam is the heating medium)Transferred from the steam (heating and sterilizing medium) to the surface of the product and / or intoPossible failure causesWater transfer and heatingAre obtained by condensation of the feed steamDemand uniform thermodynamic properties inside the autoclave (temperature,

55、 pressure and chemical composition)Possible failure causesUniform conditions in the autoclave may be affected byIneffective air removalPoor quality of feed steama)Excess of superheatb)Presence of non condensable gasesIneffective air/steam homogenizationInadequate superheated water distributionPossib

56、le failure causesThe one-to-one correspondence between P and T no longer exists if Only one single phase is present, either liquid or steam Other chemical components are present simultaneously with water (either liquid or steam) Possible failure causesNon condensable gasesAll the efforts to eliminat

57、e air become useless if non condensable gases re-enter with steamThe above is less critical if condensate is continuously sucked out of the chamber and not simply drained via a steam trapPossible failure causesCONTENTRegulatory aspectsMoist Heat SterilizationChoosing the right processValidating a st

58、erilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidating a lyophilization processProcess ControllerRisk AnalysisOPERATIONAL QUALIFICATION 8Verification of documentation8.1Standard Operative Procedures8.2Calibration

59、 certificate of critical instruments9Verification of system functionalities9.1Input/Output9.2Alarms9.3Production receipes9.4Security and Access9.5Back-up & Restore10Operational verification10.1Maximum and minimum temperature of shelfs10.2Control loop (for temperature of the shelf)10.3Temperature dis

60、tribution10.4Temperature of condenser10.5Vacuum system10.6Vacuum deep10.7Leak Rate of system and lyophilizater chamber10.9Cleaning In Place10.9Sterilization cycle10.10Load lyophilization10.11Defrost of condenserLyophilizationVerify that the Ultimate Cooling Temperature and the Ultimate Heating Tempe