蒸汽灭菌和冻干工艺的验证及风险分析-意大利CTPGiuseppeRuggirello2012年注射剂工业大会.ppt

VALIDATION and RISK ANALYSIS Steam 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 (Bioburden / 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,Process,Product,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 system 10. 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 functionality 11. 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 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 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 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 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,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 Pro