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&VALIDATI
2、ON1972 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 chamb
3、er 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&VALIDATIONValidationMain con
4、cepts 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 ImplicationsChapt
5、er 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 Practice)Validation 21 CFR
6、 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 SterilizationCONTENTRegulatory asp
7、ectsMoist Heat SterilizationChoosing the right processValidating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidating a lyophilization processProcess ControllerRisk AnalysisWhat is being Sterilized?vPorous
8、LoadsHard GoodsEquipment PartsComponentsGlassStainless steelPolymeric MaterialsWaste LiquidsNon-Porous Loads Finished Products Laboratory Media In-process Fluids Waste Liquids Polymeric MaterialsDefining the sterilization processDefining the sterilization processTemperature and Time for an effective
9、 sterilizationCan not be defined by physical methodsHave to be preliminary investigated according to a microbiological approach1.Should 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),or the grid of table 4 of the
10、 guideline HTM 2010,Part 2,Clause 3.24(i.e.15 minutes 121-124C),reported also in the standard EN 285,point 8.3.1.2BIOBURDENThermic resistance of the productOverkillBioburdenIntegrated(Bioburden/Biological indicators)Validation approaches:Defining the sterilization processBalance must be MaintainedvA
11、ttaining sterility must not be accomplished with loss ofvproduct stability.vMaintaining stability must be accompanied with adequatevassurance of sterility.Defining the sterilization processDefining the sterilization processCONTENT OF THE PRESENTATIONRegulatory aspectsMoist Heat SterilizationChoosing
12、 the right processCauses of failureValidating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesSterilizer Process ControllerRisk AnalysisValidation What has to be validated?A process?A product?A piece of equipment
13、?Lets consider the definition of“validation”Validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics(FDA Guideline on General Principles o
14、f Validation,1987)Validation is a defined strategy of inter-related practices and procedures which in combination with routine 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 pr
15、e-determined specifications(PDA TM#1 revised,Draft 13,Glossary)Validation Common items:-Specify -Document -Verify the effectiveness -Verify the reproducibility The scope of validation is the process or the product The new PDA definition considers validation as a“ongoing process”(maintaining the vali
16、dated status)ValidationProcessProductEquipmentRules and standardsCharacteristicsHandlingWrappingTerminally sterilizedSterilization?Terminal sterilization?Sterilization method?ValidationStages of the qualification of a piece of equipment should include DQ,IQ,OQ and PQ.User Requirements Specifications
17、FunctionalSpecificationsDesignSpecificationsProject execution InstallationQualificationOperationalQualificationPerformanceQualificationRelated toRelated toRelated toDesign QualificationVALIDATION LIFECYCLEDESIGN QUALIFICATION The documents of the projects at disposal specify in an exaustive way the
18、equipment,the systems,and the installations that compose that project The documents related to the user requirements 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 c
19、ompetent functions upon what established in the quality plan of the project The functional specs(basic design)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 cGMP
20、s and eventual applicable guidelines“Installation Qualification is an essential step preceding the Process 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&I
21、nstrument Drawings,(P&I.Ds)and Plant Functional Specifications developed during the project planning 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
22、 all installed equipment satisfies the planned requirements.”Recommendations on Validation 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 Un
23、ion “Good manufacturing practices”Annex#15 Final Version Qualification and Validation 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 suppl
24、ier operating and working instruction,and maintenance requirements;calibration requirements;(a)verification of materials of construction.”INSTALLATION QUALIFICATIONOutlinePre-requirementsReference specs&purch.orderProcedure verificationCritical instruments calibration verif.“as-built”drawingsMain co
25、mponents verificationUtilities connection verificationLubricants verificationAttachmentsINSTALLATION QUALIFICATIONINSTALLATION QUALIFICATIONINSTALLATION QUALIFICATION“OQ is an exercise oriented to the engineering function,generally referred to as commissioning.Studies on the critical variables(param
26、eters)of the operation of the equipment or systems will define the critical 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 im
27、portant at this stage to assure all operational test data conform with 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 2004OPERATIONA
28、L QUALIFICATION“It is expected that during the Operational Qualification 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 Ope
29、rational Qualification should allow the finalisation of operating 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
30、 Master Plan,Installation and Operational Qualification,Non-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;(a)tests to inclu
31、de condition or set of conditions encompassing upper and lower 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 QUALIFIC
32、ATIONOutlineProcedure verificationCritical instruments calibration verif.Functional verificationOPERATIONAL QUALIFICATIONOPERATIONAL QUALIFICATIONQualification of steam autoclavesOperational QualificationINDICE9.Verification of supporting documentation 9.1 Verification of SOPs 9.2 Verification of th
33、e equipment calibration installed on the system10.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 fai
34、lure 10.5 Verification of the protection system with 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.
35、10 Verification of the back pressure 10.11 Verification 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.Usu
36、ally they will be designed,to this aim,some 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 considera
37、tions,can be different from the ones 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 faciliti
38、es,systems or equipment;(a)tests 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 QUALIFICATIO
39、NDefining the sterilization processValidation approachesOverkill(from PDA,TM#1 revised,Draft 13,Glossary):A cycle which provides a minimum 12-log reduction of a resistant biological indicator with a known D-value of not less than 1 minute at 121.1C.This approach assures substantially greater than a
40、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 probability of survival of less than 1 in 106 for the most resistant bioburden expected in the load.It requires informati
41、on 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,Draft 13,Glossary):A process which provides a probability of survival of less than 1 in 106 for the bioburden as demonstrate
42、d 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 the number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburdenValidation approaches
43、D 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 shelfHomemade BIsValidation approachesMicrobiological qualificationMicroorganism resistance D:decimal reduction time The time required
44、,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 destruction The number of degrees of temperature which causes a 10-fold variation of D(or,more generally,of the sterilization rate)Micro
45、organism resistance BIER Biological Indicator Evaluator Resistometer To verify the resistance(D,z)of the commercial Bis (Overkill approach)To determine and verify the resistance of the self-made Biological Indicator(Bioburden approach)Microbiological qualificationValidation approachesD and z values
46、determinationB.I.E.R.Biological Indicator Evaluator ResistomertimetemperatureRealTheoreticalSquared curve for a BIER vessel Biological Indicator Evaluator ResistometerValidation issuesCalibrationLeak testValidation activities(physical)Thermocouples calibration Heat distribution Heat penetration Ster
47、ilizatio Cycle Verification of calibration Procedura di convalida (Microbiologica)Review of resultsMaintaining the validationValidation CalibrationValidation issuesCalibrationLeak testValidation activities(physical)Thermocouples calibration Heat distribution Heat penetration Sterilizatio Cycle Verif
48、ication of calibration Procedura di convalida (Microbiologica)Review of resultsMaintaining the validationValidation leak testValidation issuesCalibrationLeak testValidation activities(physical)Thermocouples calibration Heat distribution Heat penetration Sterilizatio Cycle Verification of calibration
49、 Procedura di convalida (Microbiologica)Review of resultsMaintaining the validationHeat distribution and penetration The Uniformity has to be referred to the empty chamber or to the free space of the loaded chamberTemperature sensors The Heat Penetration is referred to the inner part of the products
50、:Temperature sensorsBiological Indicators Temperature mappingLethality mapsApplication Considerations Place in the most difficult to sterilize location Use for validation Use for routine monitoringLethality mapsLethality mapsFront of ChamberLethality Map,Lower ShelfLethality mapsApplicationsLethalit
