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									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

…’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,
  – Prior qualification/validation studies
  – Change control
  – Preventative maintenance
  – Calibration
  – Performance data
  – New/current validation strategies or
                      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
  – 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
      May change based on review/re-qualification
      Frequencies may differ for same type of
       equipment or systems that have different
       uses within the processes
                                     Maintaining Validation
 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
  – 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
  – 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
 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
 Re-qualification:
   – Based on review assessment
                         Maintaining Validation
Specific Processes: Environment
 Review: (annually)
   – Routine Environmental Monitoring data (counts and
   – 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
   – Any changes in procedures and/or batch records that
     may impact the process.
 Re-qualification:
   – Based on review assessment
                     Maintaining Validation
 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
 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.

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