1、G.Ruggirello,Ph.D.Qualification and Risk Analysis1/XXVALIDATION and RISK ANALYSISSteam Sterilization and Lyophilizzation A route from process principles to a safe and compliant product.The awareness of a documented evidence.G.Ruggirello,Ph.D.Qualification and Risk Analysis2/XXCONTENT Regulatory aspe
2、cts Moist Heat SterilizationChoosing the right process Validating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidating a lyophilization processProcess ControllerRisk AnalysisG.Ruggirello,Ph.D.Qualification
3、and Risk Analysis3/XXGMP&VALIDATION1972 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.G.Ruggirello,Ph.D.Qualification and Risk Analysis4/XXExtracted from the R
4、OSENHEIM ReportThe AIR was not properly removed from the chamberThe drain of the 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
5、 were carried out only on the upper layers of the loadGMP&VALIDATIONG.Ruggirello,Ph.D.Qualification and Risk Analysis5/XXValidationMain concepts Personnel Equipment Process/Products InstrumentsDocuments and SOPQualified,trainedTo be qualified(IQ,OQ,PQ)To be validatedSuitable,calibration has to be pl
6、anned and documentedUp-to date,distributed,maintained under controlG.Ruggirello,Ph.D.Qualification and Risk Analysis6/XXTerminal Moist-Heat SterilizationEngineering Equipment ImplicationsChapter 3 of EU-GMP(Premises and Equipment)21 CFR part 211.63,211.65,211.67(Equipment)Annex 11 UE GMP(Computerise
7、d systems)21 CFR part 211.68(Automatic,mechanical and electronic equipment)21 CFR part 11(Electronic records Electronic Signatures)GAMP (Good Automated Manufacturing Practice)G.Ruggirello,Ph.D.Qualification and Risk Analysis7/XXValidation 21 CFR parts 210-211(211.100,211.110,211.213)21 CFR part 820(
8、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 SterilizationG.Ruggirello,Ph.D.Qualification and Risk Analysis8/XXCONTENT Regulatory aspe
9、cts Moist Heat SterilizationChoosing the right process Validating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidating a lyophilization processProcess ControllerRisk AnalysisG.Ruggirello,Ph.D.Qualification
10、and Risk Analysis9/XXWhat is being Sterilized?Porous Loads Hard Goods Equipment Parts Components Glass Stainless steel Polymeric Materials Waste LiquidsNon-Porous Loads Finished Products Laboratory Media In-process Fluids Waste Liquids Polymeric MaterialsDefining the sterilization processG.Ruggirell
11、o,Ph.D.Qualification and Risk Analysis10/XXDefining the sterilization processTemperature and Time for an effective sterilization1.Can not be defined by physical methods2.Have to be preliminary investigated according to a microbiological approach3.Should comply with minimum requirement such as the tr
12、aditional“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 guideline HTM 2010,Part 2,Clause 3.24(i.e.15 minutes 121-124C),reported also in the standard EN 285,point 8.3.1.2G.Ruggirello,Ph.D.Qualification and Risk Analysis11/XX BIOBURDEN The
13、rmic resistance of the product Overkill Bioburden Integrated(Bioburden/Biological indicators)Validation approaches:Defining the sterilization processG.Ruggirello,Ph.D.Qualification and Risk Analysis12/XXBalance must be MaintainedAttaining sterility must not be accomplished with loss ofproduct stabil
14、ity.Maintaining stability must be accompanied with adequateassurance of sterility.Defining the sterilization processG.Ruggirello,Ph.D.Qualification and Risk Analysis13/XXDefining the sterilization processG.Ruggirello,Ph.D.Qualification and Risk Analysis14/XXCONTENT OF THE PRESENTATION Regulatory asp
15、ects Moist Heat SterilizationChoosing the right processCauses of failure Validating a sterilization processCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesSterilizer Process ControllerRisk AnalysisG.Ruggirello,Ph.D.Qualification and Ri
16、sk Analysis15/XXValidation What has to be validated?A process?A product?A piece of equipment?Lets consider the definition of“validation”G.Ruggirello,Ph.D.Qualification and Risk Analysis16/XXValidation is establishing documented evidence which provides a high degree of assurance that a specific proce
17、ss 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 routine production methods and qual
18、ity 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)ValidationG.Ruggirello,Ph.D.Qualification and Risk Analysis17/XX Common items:-Specify -Doc
19、ument -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 validated status)ValidationG.Ruggirello,Ph.D.Qualification and Risk Analysis18/XXProcessProductEquipment
20、Rules 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 SpecificationsFunctionalSpecificationsDesignSpecificationsPr
21、oject execution InstallationQualificationOperationalQualificationPerformanceQualificationRelated 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 th
22、at 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 competent functions upon what established in th
23、e 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 cGMPs and eventual applicable guidelines“Installat
24、ion 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&Instrument Drawings,(P&I.Ds)and Plant Functiona
25、l 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 all installed equipment satisfies the planned
26、 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 Union “Good manufacturing practices”Annex#15 Fin
27、al Version Qualification and Validation July 2001“IQ should include,but not limited to,the following:(a)installation of equipment,piping,services and instrumentation checked to current engineering drawing and specifications;(b)collection and collation of supplier operating and working instruction,an
28、d maintenance requirements;(c)calibration requirements;(d)verification of materials of construction.”INSTALLATION QUALIFICATIONOutlinePre-requirementsReference specs&purch.orderProcedure verificationCritical instruments calibration verif.“as-built”drawingsMain components verificationUtilities connec
29、tion verificationLubricants verificationAttachmentsINSTALLATION 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 equipme
30、nt 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 important at this stage to assure all o
31、perational 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 2004OPERATIONAL QUALIFICATION“It is expected that d
32、uring 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 Operational Qualification should allow t
33、he 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 Master Plan,Installation and Operati
34、onal Qualification,Non-Sterile Process Validation,Cleaning Validation PI 006-2,1 July 2004OPERATIONAL QUALIFICATION“OQ should include,but not limited to,the following:(a)tests that have been developed from knowledge of process,systems and equipment;(b)tests to include condition or set of conditions
35、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 QUALIFICATIONOutlineProcedure verification
36、Critical instruments calibration verif.Functional verificationOPERATIONAL QUALIFICATIONOPERATIONAL QUALIFICATIONG.Ruggirello,Ph.D.Qualification and Risk Analysis32/XXQualification of steam autoclavesOperational QualificationINDICE9.Verification of supporting documentation 9.1 Verification of SOPs 9.
37、2 Verification of the 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
38、in case of power failure 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 tightne
39、ss(if applicable)10.10 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 indi
40、cated in the URS.Usually 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,aft
41、er the due considerations,can be different from the ones that represent the limit of the process.PERFORMANCE QUALIFICATION“PQ should include,but not limited to,the following:(a)tests,using production material,qualified substitutes or simulated product,that have been developed from knowledge of the p
42、rocess and the facilities,systems or equipment;(b)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 2001P
43、ERFORMANCE QUALIFICATIONG.Ruggirello,Ph.D.Qualification and Risk Analysis35/XXDefining the sterilization processG.Ruggirello,Ph.D.Qualification and Risk Analysis36/XXValidation approachesOverkill(from PDA,TM#1 revised,Draft 13,Glossary):A cycle which provides a minimum 12-log reduction of a resistan
44、t biological indicator 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 requiredG.Ruggirello,Ph.D.Qualification and Risk Analysis37/XXBioburden(from
45、 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 information on the number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburdenVali
46、dation approachesG.Ruggirello,Ph.D.Qualification and Risk Analysis38/XXBB/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 demonstrated using a resistant biological indicator with a known D-value
47、.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 approachesG.Ruggirello,Ph.D.Qualification and Risk Analysis39/XXD and z
48、 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,at a s
49、pecific 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)Microorganis
50、m 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 qualificationG.Ruggirello,Ph.D.Qualification and Risk An
