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AutoclavesQualification & ValidationBy Holger Fabritz

Autoclaves: Qualification & ValidationContents Types of autoclavesRegulatory AspectsGMP Risk AnalysisURS / FDSDesign QualificationInstallation Qualification / Operational QualificationPerformance Qualification / Process ValidationResponsibilitiesSummaryHolger Fabritz-Expertentreff 14. September 2007 in Baden2 of 39

Autoclaves: Qualification & Validation- Types of Autoclaves - Steam AutoclavesSterilisation with Steam / Air Mixture Saturated Steam with possible initial vacuum sequence(s)Cooling with Air cooled down by heat exchangerHot Water Spray AutoclavesSterilisation with Spraying of Water (Flooding with water)Cooling with Water cooled down by heat exchangerHot Air SterilisersHolger Fabritz-Expertentreff 14. September 2007 in Baden3 of 39

Autoclaves: Qualification & Validation- Types of Autoclaves -Large Steam AutoclaveRevolving Steam Autoclavexxx chambers,Holger Fabritz-Expertentreff 14. September 2007 in Baden4 of 39

Autoclaves: Qualification & Validation- Regulatory Aspects - Ph. Eur. 6 5.1.1, Methods of Preparation of Sterile Products 5.1.2, Biological Indicators of Sterilisation 5.1.5, Application of the F0 Concept to Steam Sterilisation ofAqueous Preparations USP 29 55 Biological Indicators - Resistance Performance Tests 1035 Biological Indicators for Sterilisation 1211 Sterilization and Sterility Assurance of CompendialArticlesHolger Fabritz-Expertentreff 14. September 2007 in Baden5 of 39

Autoclaves: Qualification & Validation- Regulatory Aspects GMP-Regulations EU-GMP-Guideline Part 1, Annexes 1, 15 & 17 Code of Federal Regulations (CFR) 21, Part 210: Current GoodManufacturing Practice in Manufacturing, Processing, Packing ofHolding of Drugs; General 21 CFR Part 211: Current Good Manufacturing Practice for finishedPharmaceuticals 21 CFR Part 11: Electronic Records; Electronic SignaturesFDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing Documentation for Sterilisation Process ValidationEuropean Medicines Agency (EMEA) CPMP/QWP/054/98 Corr., Decision Trees for the Selection ofSterilisation Methods CPMP/QWP/3015/99, Note for Guidance on Parametric ReleaseHolger Fabritz-Expertentreff 14. September 2007 in Baden6 of 39

Autoclaves: Qualification & Validation- Regulatory Aspects - GAMPThe Good Automated Manufacturing Practice (GAMP) Guide forValidation of Automated Systems in Pharmaceutical Manufacture,Vol. 4PDA Technical ReportsPDA Technical Report No. 1, Validation of Steam Sterilisation CyclesHTM (Health Technical Memorandum)2010; Sterilisation; Part 3: Validation and verification; NHS Estates;Department of Health; UKInternational, European and National Standards (ISO / EN /DIN) / OthersEN 285, Sterilisation, Steam Sterilisation, Large SterilisersDIN 58950, Sterilisation , Steam Sterilisers for PharmaceuticalProductsEN 554, Sterilisation of Medical Devices.Holger Fabritz-Expertentreff 14. September 2007 in Baden7 of 39

Autoclaves: Qualification & Validation- GMP Risk Analysis GMP Risk Analysis at the beginning of the qualification activities: Definition of GMP-relevant issues to be considered in the design and furtherqualification steps: GMP relevance of single components(e.g. heat exchanger, sterilisation chamber, valves) Control System computer validation, definition of the GMP-relevantinstrumentation including requirements for accuracy and recording, GMPrelevant sensors (double measurement of critical parameters) Utilities: quality of media piping quality Material specification incl. necessary certificates Additional test devices(e.g. WIT-test possibility for aeration filter, incl. sensors) Documentation including welding documentation, wiring check, softwaredocumentation etc. Possibility to have a traceability to the subsequent qualification steps Influence of Risk Analysis on Engineering activities (URS) & basisfor DQ / IQ / OQ / .Holger Fabritz-Expertentreff 14. September 2007 in Baden8 of 39

Autoclaves: Qualification & Validation- GMP Risk Analysis 1234567Process step /Possible failureGMP RiskExplanationTests / MeasuresTraceability[ Y/N ]EquipmentDComponents withproduct contactInadequate material of steelsurfacesYACorrosion could deteriorate the product.Steel: 316L min. certified by EN10204 2.2Inadequate plastics orgasketsYAMaterial might not be inert againstproduct.Plastics/gaskets: Food graded materials certified acc. to CFRTitle 21 §177.2600.Wrong surface finishesYARough surface might lead to adherence ofproduct or bad cleanability.Surface finishing or surface roughness is defined andproven. Certificate of manufacturer is available.Bad quality of weld seams(pipework)YAWeld seams of product or clean mediapipes have another material andsurface roughness than the tubes.Risk of porosities or materialimpurities.Weld seams of stainless steel pipes should be welded underinert gas conditions and with appropriate weldingmaterial (TIG technique).s. a.As far as technically possible orbital welding should beapplied.When pipework is completed, the weldseams cannot be checked visibly anymore.Weld seams of pipework for product or clean media transfershould be visually checked by endoscope.Required by ISPE publications100% of handmade weld seams and an appropriatepercentage of orbital weld seams have to be checkedaccordingly.Requirement of good documentationpractice.Test report contains every weld seam with a single test.Quality of weld seams is nottraceable.Holger Fabritz[ A/B/C ]-YBExpertentreff 14. September 2007 in BadenIQO PQ QNC/Q VA9 of 39

Autoclaves: Qualification & Validation- User Requirement Specification (URS) - To be issued by the User (Pharmaceutical Enterprise)Basis for GMP Risk Analysis and influenced by the results (e.g.documentation requirements, number of critical sensors)Reference to Pharmacopoeias, guidelines and standards to be used( EMEA CPMP/QWP/054/98 Decision trees for the selection ofsterilisation methods)Description of the sterilisation process (e.g. standard sterilisation,F0-sterilisation) on basis of the product propertiesDefinition of all (as possible) relevant GMP-critical points (e.g.sterility of cooling media, coldest spots)Definition of the user needs for documentation and operation (e.g.batch documentation, operating instructions etc.)Holger Fabritz-Expertentreff 14. September 2007 in Baden10 of 39

Autoclaves: Qualification & Validation- User Requirement Specification (URS) - Completed by detailed technical specifications: Volume of sterilisation chamber Standards for electrical standards, wiring, valves, Standards for materials to be used (stainless steel)includingsurface roughness ( 0,8 µm or higher values?) Interfaces to existing systems Drying / Air Filters (e.g. for stoppers for dry powder filling, cleanroom clothes)Definition of requirements for FAT / SATHolger Fabritz-Expertentreff 14. September 2007 in Baden11 of 39

Autoclaves: Qualification & Validation- User Requirement Specification (URS) - Detail description of requirements for Computer Validation Audit Trail User Access Backup / Recovery Disaster RecoveryDefinition of requirements for qualification(in case that supplier should support qualification) Combined with commercial requirements as request for anoffer to be submitted to different potential suppliersHolger Fabritz-Expertentreff 14. September 2007 in Baden12 of 39

Autoclaves: Qualification & Validation- Functional Design Specification (FDS) - To be issued by the potential suppliersFDS should comprise detailed proposals for technical solutions forthe URS requirementsAll requirements of the URS must be commented by the supplier(can be met or can’t be met)In case of deviation from a requirement of the URS, an explanationand alternative proposals for technical solutions are necessaryHolger Fabritz-Expertentreff 14. September 2007 in Baden13 of 39

Autoclaves: Qualification & Validation- Project Implementation stallationIQ/SATCommissioningTest Runs/Start-upOQPQProcessOptimisationPV / CVProductionRe-Val.Change Control / RequalificationHolger Fabritz-Expertentreff 14. September 2007 in Baden14 of 39

Autoclaves: Qualification & Validation- Design Qualification (DQ) - is performed by documented comparison of URS and FDS, focussedon GMP- relevant topicsall requirements set up be the URS (resulting from the risk analysis)should be met, traceability to risk analysis and URS should be givendeviations from the requirements of the URS must be evaluatedwhether acceptable or not ( GMP-requirements)Supplier Audits (quality system, software development) should beimplemented in this phaseNote: Implementation of supplier audit in ComputerValidation strategy necessary Approval of DQ protocol and report respective approval ofURS/FDS comparison by defined persons (VMP) Start of project change controlHolger Fabritz-Expertentreff 14. September 2007 in Baden15 of 39

Autoclaves: Qualification & Validation- Summary of RA/URS/FDS/DQ -Some practical experiences: Results of GMP Risk Analysis are often not considered in URSGMP Risk Analysis too detailed(discussion about construction of valves)Important company standards are not added to URS(Welding standards for pipes)FDS does not answer URS (standard documents by suppliers)Design Qualification finalised too late / after FATChanges are performed but without change control.Mistakes in early project stages lead toirritations/discussions/deviations during IQ/OQ/PQHolger Fabritz-Expertentreff 14. September 2007 in Baden16 of 39

Autoclaves: Qualification & Validation- Factory Acceptance Test (FAT) / Site Acceptance Test (SAT) -FAT Qualification staff should join FATPreliminary documentation should be available and should bechecked during FAT (incl. IQ and OQ - protocols)First formal check of P&I-Diagram by qualification staffDefinition of test program on basis of suppliers possibilitiesStructured FAT can substitute some IQ(OQ)-testingSAT Basis for SAT should be mechanical completion of autoclaveSAT should be performed as Pre-IQ / Pre-OQ /can substitute some IQ / OQ testing.Holger Fabritz-Expertentreff 14. September 2007 in Baden17 of 39

Autoclaves: Qualification & Validation- Installation Qualification (IQ) -Holger Fabritz-Expertentreff 14. September 2007 in Baden18 of 39

Autoclaves: Qualification & Validation- Installation Qualification (IQ) IQ - Checked P&I-Diagram - Holger Fabritz Expertentreff 14. September 2007 in Baden 19 of 39

Autoclaves: Qualification & Validation- Installation Qualification (IQ) - Further points to be checked Calibration of the different sensors Three points for temperature/pressure One point for timer or paper speed of the recorder Availability of relevant SOPs (operation, maintenance), at least asdraft version Check of the supplier documentation Completeness Formal correctness Correctness of contentFinalisation of IQ Deviations must be evaluated In case of GMP-critical deviations (e.g. wrong type of sensors), IQnot successful remedy of deviation and repetition of IQ (ChangeControl) In case of non GMP-critical deviations, a pre-approval of the IQ ispossible in order to start next qualification stepHolger Fabritz-Expertentreff 14. September 2007 in BadenSOPSOP1.1.2.2.3. Calibration3. CalibrationCertificateCertificate20 of 39

Autoclaves: Qualification & Validation- Operational Qualification (IQ) Pre-requisites (Pre-)Approval of IQ Used measuring devices (e.g. Kaye system, data loggers) shouldbe calibrated before performing measurement (and afterwards)Function testing of all procedures & sequences Tightness and stability of piping after performing a sterilisationcycle (Visual checks!) Loading and unloading tests Interlocks of doors Check of programs Fractionated pre-vacuum Heating phase Equilibration time Sterilisation time Drying and Cooling Correct re-start after power failureHolger Fabritz-Expertentreff 14. September 2007 in Baden21 of 39

Autoclaves: Qualification & Validation- Operational Qualification (OQ) - Points to be checkedCheck of alarms Temperature too high or too low Pressure too high or too low (pressure variations) Time limits of process steps Utility supply Cable break of sensors .Computer Validation related points User access and audit trail Data storage / Print Out Electromagnetic failure, radio frequency test .Holger Fabritz-Expertentreff 14. September 2007 in Baden22 of 39

Autoclaves: Qualification & Validation- Operational Qualification (OQ) Points to be checked Check of steam quality (should be covered byqualification of clean steam system)Check of chamber tightness Possible acceptance criteria: pressure drop 1,3 mbar / min Procedure: Evacuation of the chamber on a predefined pressureand closing of all valves. Measurement for 10 minBowie-Dick-Test for sterilisation cycles with saturated steam Use of test kids Colour change of indicator completeIntegrity of aeration filter Water Intrusion Test for hydrophobic filtersHolger Fabritz-Expertentreff 14. September 2007 in Baden23 of 39

Autoclaves: Qualification & Validation- Operational Qualification (OQ) veon AutoclaveTrayTrayAll operation parameters inspecificationHolger Fabritz-Expertentreff 14. September 2007 in Baden24 of 39

Autoclaves: Qualification & Validation- Operational Qualification (OQ) - Points to be checked:Heat distribution check of the empty chamber (Identification ofcold spots) Acceptance Criteria Correct process incl. recording without alarms Pre-defined maximum standard deviation not exceeded forvalidation sensors Pre-defined maximum allowed deviation from the mean value forsingle

1211 Sterilization and Sterility Assurance of Compendial Articles - Regulatory Aspects - 6 of 39 Autoclaves: Qualification & Validation Holger Fabritz - Expertentreff 14. September 2007 in Baden GMP-Regulations EU-GMP-Guideline Part 1, Annexes 1, 15& 17 Code of Federal Regulations (CFR) 21, Part 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing of .