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G. Ruggirello,Ph.D. Qualification and Risk Analysis,130,/,XX,VALIDATION and RISK ANALYSISSteam Sterilization and Lyophilizzation,A route from process principles to a safe and compliant product.,The awareness of a documented evidence.,CONTENT,Regulatory,aspects,Moist Heat,Sterilization,Choosing the right,process,Validating,a sterilization,process,Calibration of,instruments,Chamber leak,test,“Utilities,”,Validation ,Physical issues,Validation Microbiological,issues,Validating a lyophilization process,Process Controller,Risk Analysis,GMP,&,VALIDATION,1972 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,Report,The,AIR was not properly removed from the,chamber,The drain of the chamber was blocked by pieces of,glasses,The lower section of the load did not reach the sterilization,temperature,The temperature recorder showed this anomaly but people thought it was not working,properly,Sterility tests were carried out only on the upper layers of the,load,GMP & VALIDATION,Validation,Main,concepts,Personnel,Equipment,Process/Products,Instruments,Documents and,SOP,Qualified,trained,To,be qualified (IQ, OQ, PQ,),To be,validated,Suitable, calibration has to be planned and,documented,Up-to,date, distributed, maintained under,control,Terminal Moist-Heat Sterilization,Engineering Equipment Implications,Chapter 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 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 Sterilization,CONTENT,Regulatory,aspects,Moist Heat,Sterilization,Choosing the right,process,Validating,a sterilization,process,Calibration of,instruments,Chamber leak,test,“Utilities,”,Validation ,Physical issues,Validation Microbiological,issues,Validating a lyophilization process,Process Controller,Risk Analysis,What is being Sterilized,?,Porous Loads,Hard Goods,Equipment Parts,Components,Glass,Stainless steel,Polymeric Materials,Waste Liquids,Non-Porous,Loads,Finished,Products,Laboratory,Media,In-process,Fluids,Waste,Liquids,Polymeric,Materials,Defining the sterilization,process,Defining the sterilization process,Temperature and Time for an,effective sterilization,Can not be defined by physical,methods,Have to be preliminary investigated according to a microbiological,approach,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 guideline HTM 2010,Part,2,Clause,3.24,(,i.e. 15 minutes,121-124C), reported also in the standard EN 285, point,8.3.1.2,BIOBURDEN,Thermic resistance of the,product,Overkill,Bioburden,Integrated,(,B,ioburden,/,Biological,indicators,),Validation approaches,:,Defining the sterilization process,Balance must be Maintained,Attaining sterility must not be accomplished with loss of,product stability.,Maintaining stability must be accompanied with adequate,assurance of sterility.,Defining the sterilization process,Defining the sterilization process,Demonstrated,PNSU,Expected,Shelf,Life,Information Needed,For,Validation,Heat Input to,Materials,Bioburden,Method,Bioburden / BI,Method,Overkill,Method,CONTENT OF THE PRESENTATION,Regulatory,aspects,Moist Heat,Sterilization,Choosing the right,process,Causes of,failure,Validating a sterilization,process,Calibration of,instruments,Chamber leak,test,“Utilities,”,Validation ,Physical issues,Validation Microbiological,issues,Sterilizer Process,Controller,Risk Analysis,Validation,What,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 assurance 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 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 pre-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 validated status,),Validation,P,rocess,P,roduct,Equipment,Rules and,standards,Characteristics,Handling,Wrapping,Terminally sterilized,Sterilization ?,Terminal sterilization ?,Sterilization method ?,Validation,Stages of the qualification of,a piece of equipment,should include DQ, IQ, OQ and PQ.,User Requirements,Specifications,Functional,Specifications,Design,Specifications,Project execution,Installation,Qualification,Operational,Qualification,Performance,Qualification,Related to,Related to,Related to,Design Qualification,VALIDATION LIFECYCLE,DESIGN QUALIFICATION,The documents of the projects at disposal specify in an exaustive way the 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,identified,DESIGN QUALIFICATION,The,project documents are correctly approved by the competent 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 cGMPs 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 & Instrument 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 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 2004,INSTALLATION QUALIFICATION,The Rules Governing Medicinal Products in the European Union “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 supplier operating and working instruction, and maintenance requirements;,calibration requirements;,verification of materials of construction.”,INSTALLATION QUALIFICATION,Outline,Pre-requirements,Reference specs & purch. order,Procedure verification,Critical instruments calibration verif.,“as-built” drawings,Main components verification,Utilities connection verification,Lubricants verification,Attachments,INSTALLATION QUALIFICATION,INSTALLATION QUALIFICATION,INSTALLATION 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 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 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 2004,OPERATIONAL 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 Operational 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 Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation ,PI 006-2, 1 July 2004,OPERATIONAL 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 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 2001,OPERATIONAL QUALIFICATION,Outline,Procedure verification,Critical instruments calibration verif,.,Functional verification,OPERATIONAL QUALIFICATION,OPERATIONAL QUALIFICATION,Qualification of steam autoclaves,Operational Qualification,INDICE,9. Verification of supporting documentation 9.1 Verification of SOPs 9.2 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 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 tightness,(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. Attachments,Documented 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, 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 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:,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 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 2001,PERFORMANCE QUALIFICATION,Defining the sterilization process,Demonstrated,PNSU,Expected Shelf,Life,Information Needed,For,Validation,Heat Input to Materials,Bioburden,Method,Bioburden / BI,Method,Overkill,Method,Validation approaches,Overkill,(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 12-log reduction of the bioburden and therefore only minimal information on the bioburden is required,Bioburden,(from PDA, TM#1,revised, Draft 13, Glossary,):,A process which provides a probability of survival of less than 1 in 10,6,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 bioburden,Validation approaches,BB/BI or “combination,”,(from PDA, TM#1,revised, Draft 13, Glossary,):,A process which provides a probability of survival of less than 1 in 10,6,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 the number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburden,Validation approaches,D and z,values,If the Biological Indicators are used to release the production batches the resistance of the inoculated spore has to be,.,Verified,Determined,BIs from the shelf,Homemade BIs,Validation approaches,Microbiological qualification,Microorganism resistance,D: decimal reduction,time,The 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,destruction,The number of degrees of temperature which causes a 10-fold variation of D (or, more generally, of the sterilization rate,),Microorganism 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 qualification,Validation approaches,D and z values,determination,B.I.E.R.,Biological Indicator Evaluator,Resistomer,time,temperature,Real,Theoretical,Squared curve for a BIER vessel,Biological Indicator Evaluator Resistometer,Validation issues,Calibration,Leak,test,Validation activities (physical,),Thermocouples,calibration,Heat,distribution,Heat,penetration,Sterilizatio,Cycle,Verification of,calibration,Procedura di convalida (Microbiologica),Review of,results,Maintaining the,validation,Validation,Calibration,Temperature,Pressure,Time,Validation issues,Calibration,Leak,test,Validation activities (physical,),Thermocouples,calibration,Heat,distribution,Heat,penetration,Sterilizatio,Cycle,Verification of,calibration,Procedura di convalida (Microbiologica),Review of,results,Maintaining the,validation,Validation leak test,Validation issues,Calibration,Leak,test,Validation activities (physical,),Thermocouples,calibration,Heat,distribution,Heat,penetration,Sterilizatio,Cycle,Verification of,calibration,Procedura di convalida (Microbiologica),Review of,results,Maintaining the,validation,Heat distribution and penetration,The Uniformity has to be referred to the empty chamber or to the free space of the loaded,chamber,Temperature,sensors,The Heat Penetration is referred to the inner part of the products:,Temperature sensors,Biological Indicators,Temperature mapping,Lethality maps,Application,Considerations,Place in the most difficult to sterilize,location,Use for,validation,Use for routine,monitoring,Maps Use FO Calculated From Each Thermocouple,Location,Lethality maps,Maps Use FO Calculated From Each Thermocouple,Location,Lethality maps,Front of Chamber,Lethality Map, Lower Shelf,Lethality maps,Applications,Certain identification of the cold,points,Placement of BI in least lethal (worst case) location(s,),Correct replication of the exposition environment of the,BIs,Lethality maps,Random BI,Distribution,BI,BI,BI,BI,BI,Lethality maps,Cluster BI,Distribution,BIs,Lethality maps,Water for sterilization may,be,Initially present in the bulk of sealed containers of aqueous solutions (steam is the heating medium,),Transferred from the steam (heating and sterilizing medium) to the surface of the product and / or,into,Possible failure causes,Water transfer and,heating,Are obtained by condensation of the feed,steam,Demand uniform thermodynamic properties inside the autoclave,(temperature, pressure and chemical composition,),Possible failure causes,Uniform conditions in the autoclave may be affected,by,Ineffective air,removal,Poor quality of feed,steam,a)Excess of,superheat,b)Presence of non condensable,gases,Ineffective air/steam,homogenization,Inadequate superheated water,distribution,Possible failure causes,The 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 causes,Non condensable,gases,All the efforts to eliminate air become useless if non condensable gases re-enter with,steam,The above is less critical if condensate is continuously sucked out of the chamber and not simply drained via a steam,trap,Possible failure causes,CONTENT,Regulatory,aspects,Moist Heat,Sterilization,Choosing the right,process,Validating,a sterilization,process,Calibration of,instruments,Chamber leak,test,“Utilities,”,Validation ,Physical issues,Validation Microbiological,issues,Validating a lyophilization process,Process Controller,Risk Analysis,OPERATIONAL QUALIFICATION,8Verification of documentation,8.1Standard Operative Procedures,8.2Calibration certificate of critical instruments,9Verification of system functionalities,9.1Input/Output,9.2Alarms,9.3Production receipes,9.4Security and Access,9.5Back-up & Restore,10Operational verification,10.1Maximum and minimum temperature of shelfs,10.2Control loop (for temperature of the shelf),10.3Temperature distribution,10.4Temperature of condenser,10.5Vacuum system,10.6Vacuum deep,10.7Leak Rate of system and lyophilizater chamber,10.9Cleaning In Place,10.9Sterilization cycle,10.10Load lyophilization,10.11Defrost of condenser,Lyophilization,Verify that the Ultimate Cooling Temperature and the Ultimate Heating Temperature comply to technical specifications.,Maximum and minimum temperature of shelfs,Lyophilization: OQ,Condenser temperature,Verify that the Condenser Cooling Rate and the Ultimate Condenser Cooling Temperature comply to technical specifications.,Verification of shelf temperature,Shelf Temperature,:,Verificatin of control loop for the temperature. Usual acceptance criteria: +/- 1.5 C respect to the set-point.,Temperature distribution,Verification of temperature distribution in the shelfs,Example:,5 TCs by shelf.,Test temperature: -40, +20, +40 C,Max temperature diff: 2 C (between TCs on different shelfs).,Lyophilization: OQ,Verify that, in the system free of humidity, the Evacuation Rate and the Ultimate Vacuum) comply to the technical specifications.,Verification of Vacuum System,Verify the performance of control loop for vacuum system. The acceptance criteria should be +/- 5 microbar of the set-point.,Verification of
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