Maintaining Validation Joe Rogalewicz Director, Quality GlaxoSmithKline Biopharmaceuticals Maintaining Validation The GSK Biopharm Facility is designed as a multi- product development and launch site for GSK bulk biological substances derived from recombinant DNA technologies. Maintaining Validation All equipment, systems, and processes utilized in the manufacture, testing, and storage of bulk biological substances have been qualified/validated. Maintaining Validation Identification and initial validation of equipment, systems, and processes may be obvious and requirements predictable …... Maintaining Validation …..it’s what you do not see in maintaining equipment, systems, and processes in a validated state that presents the challenge! Maintaining Validation Validation Maintenance Program Purpose of this program is to ensure equipment, systems, and processes are maintained in a state of validation within its useful lifecycle. Maintaining Validation Key Elements: – Periodic Reviews – Periodic Re-qualification Maintaining Validation Periodic Reviews Scope: Encompasses all equipment, systems, processes – Prior qualification/validation studies – Change control – Preventative maintenance – Calibration – Performance data – New/current validation strategies or requirements Maintaining Validation Periodic Re-qualification Scope: Degree of re-qualification based on periodic review, equipment, systems, and processes. – None required based on review – Minimal, reduced performance qualification studies performed – Full re-qualification may be deemed necessary based on review outcome Maintaining Validation Program Elements: – Specific validation maintenance procedures and forms prepared for each equipment/system type – Summary reports are developed and approved for the execution of each procedure – Schedule for all validation maintenance activities – A five year review report will also be prepared for equipment and systems that only requires a review to assure calibration and maintenance remains up to date Maintaining Validation Program Elements: – Frequency based on equipment/system/process criticality. May change based on review/re-qualification results Frequencies may differ for same type of equipment or systems that have different uses within the processes Maintaining Validation Examples: Equipment Type Frequency - (Years) Rationale Freezer -80 (Product) 1 Direct product impact. Freezer -80 (Sample) 2 No direct product impact. Harvest Tank 2 The sterilization is verified during the production process. The process is verified using media. Contaminations are investigated at each occurrence. Heater Block 5 Maintained on the equipment list and the control elements are located in the In-House metrology system. HVAC 1 Supports critical room classifications. Incubators 3 No direct product impact. Liquid N2 freezer 1 Direct product impact. Media Tank-Fixed 3 The sanitization is verified during the production process. The process is routinely verified using media. Contamination’s are investigated at each occurrence. MicroFiltration Skid 2 The sterilization is verified during the production process. The process is routinely verified using media. Contaminations are investigated at each occurrence. Maintaining Validation General Equipment/Systems: Review: – prior validations – change controls - large number of small changes or significant change with no revalidation? – preventative maintenance – process performance and testing failures – internal audit reports – validation strategies/regulatory requirements Maintaining Validation Exceptions: – Unique qualified systems (i.e. centrifuges, hoods, and water baths) may be excluded from the validation maintenance program. – Verification or an assessment of proper performance will be maintained through the change control program, instrumentation calibration, and certification testing efforts. – The validation maintenance assessment will capture that all this information is in the five year report and verify if the equipment is still In-Service. Maintaining Validation Specific Processes: Sterilization Review: – General equipment requirements Re-qualification: – Abbreviated or full sterilization testing regimen based on the outcome of the review. – SIP/SOP of equipment may be challenged according to the family concept. If the equipment and configurations are identical, only one of the units must undergo SIP/SOP validation. Maintaining Validation Specific Processes: Utilities Review: (annually) – General equipment requirements – Routine QC laboratory results/trends – Exception reports. – Daily utility system operational logs and system logbooks Re-qualification: – Based on review assessment Maintaining Validation Specific Processes: Cleaning Review: (annually) – General equipment/system requirements – Soils and cleaning cycles Re-qualification: – All validated equipment must undergo cleaning validation maintenance annually. – Family approach on a rotating basis. – One satisfactory study using the identical testing approach, sampling procedures, testing methods documented in the initial validation and cleaning capability limits achieved during initial validation Maintaining Validation Specific Processes: Computer Systems Review: (per system) – Deviations – Change controls – Interim validation work – End user processes. – License and support agreements – Disaster recovery programs – Training programs Maintaining Validation Specific Processes: Computer Systems (cont.) – Access permissions and user population is accurate within the system – Number of users and system capacities. – Performance and stability of the system including problem/incident/ change logs for signs of undesirable trends Re-qualification: – Based on review assessment Maintaining Validation Specific Processes: Environment Review: (annually) – Routine Environmental Monitoring data (counts and isolates) – Changes in disinfectants and sanitization schedules, gowning procedures, flows, new equipment, facility modifications, maintenance and any other qualifications performed during the past year. Re-qualification: – Based of review assessment Maintaining Validation Specific Processes: Aseptic Processes Review: (annually) – Contamination rates – Environmental monitoring results for the affected processes – Any changes in procedures and/or batch records that may impact the process. Re-qualification: – Based on review assessment Maintaining Validation General: All documentation generated in the execution of validation maintenance is made part of the permanent validation file for the equipment or system. The interval between protocol execution and validation maintenance starts from the month and year of the start of approval for the previous summary report. Maintaining Validation Conclusion: A dynamic, comprehensive, validation maintenance program ensures equipment, systems, and processes remain in a validated state of control providing consistency and reproducibility in the manufacture of biological substances.