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1、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 o
2、f instruments Chamber leak test “Utilities” Validation Physical issues Validation Microbiological issues Validating a lyophilization process Process Controller Risk Analysis,GMP collection and collation of supplier operating and working instruction, and maintenance requirements; calibration requirem
3、ents; verification of materials of construction.”,INSTALLATION QUALIFICATION,Outline Pre-requirements Reference specs 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 Produc
4、ts 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,Qualifi
5、cation 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 contro
6、l 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 co
7、ntrol 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 f
8、unctionality11. 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
9、 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
10、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.”,
11、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
12、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 approa
13、ch 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 biobur
14、den 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
15、 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 moni
16、toring 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
