Managing and Maintaining HVAC systems by y599Uwa

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									          Managing and Maintaining
              HVAC Systems
                              Badrig Baghdikian
                                April 10 2003
                                                ENGINEERING



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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                                       Agenda
• Review of Regulatory Documents
      – FDA Compliance Program Guidance Manual Program
      – PIC/S Inspection of Utilities
      – ISO 14-644 Part 4
• Systems to put in place to ensure the compliance
  throughout the facility life-cycle
      – Designing HVAC Systems
      – Commissioning & Qualification
      – Life-Cycle Activities
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                                           Life-Cycle
  URS                                 PQ                 RV             RV             RV
                                                       Preventative Maintenance
     FS                         OQ                     Calibration

                                                       Unplanned Maintenance
       DS                     IQ
                                                       Monitoring

                                                       Cleaning
              Construction

 Check the Key Design Parameters                       Check the Procedures, Documentation
      vs. the process/products                          needed to maintain the installations
and the Qualification Documentation                            in a validated status
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                 Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                          ISPE Brussels Conference – April 2003
            FDA Drug Manufacturing
                  Inspection




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    FDA system-based approach for
             inspections
•    Quality System
•    Facilities & Equipment System
•    Materials System
•    Production System
•    Packaging and Labelling System
•    Laboratory Control System

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Facilities & Equipment System

• Relates to 21 CFR 211 Subparts B,C, D and J
•    This system includes the measures and activities which provide an
     appropriate physical environment and resources used in the production
     of the drugs or drug products. It includes:
      – Buildings and Facilities along with Maintenance
      – Equipment Qualifications (installation and operation); equipment calibration
        and preventative maintenance; and cleaning and validation of cleaning
        processes as appropriate. Process performance qualification will be
        evaluated as part of the inspection of the overall process validation which is
        done within the system where the process is employed; and,
      – Utilities that are not intended to be incorporated into the product such as
        HVAC, compressed gases, steam and water systems



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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
           Facility and Equipment System:
         Examples of failures that can lead to a
                    Warning Letter
• Contamination with filth, objectionable microorganisms, toxic
  chemicals or other drugs chemicals, or a reasonable potential for
  contamination, with demonstrated avenues of contamination, such
  airborne or through unclean equipment
• Pattern of failure to validated cleaning procedures of non-dedicated
  equipment. Lack of demonstration of effectiveness of cleaning of
  dedicated equipment
• Pattern of failure to document investigation of discrepancies
• Pattern of failure to establish/follow a control system for implementing
  changes in the equipment
• Pattern of failure to qualify equipment, including computers

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
              Facilities and Equipment Systems

• “For each of the following, the firm should have written
  and approved procedures and documentation resulting
  therefrom.”




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
   Facilities : written and approved procedures
     and documentation resulting therefrom
      – Cleaning and maintenance
      – Facility lay-out and air-handling systems for prevention of cross-
        contamination
      – Specifically designed areas for the manufacturing operations
        performed by the firm to prevent contamination or mix-ups
      – General air handling systems
      – Control system for implementing changes in the building
      – Lighting, potable water, washing and toilet facilities, sewage and
        refuse disposal
      – Sanitization of the building, use of rodenticides, fungicides,
        insecticides, cleaning and sanitizing agents

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
  Equipment: written and approved procedures
    and documentation resulting therefrom
      –   Equipment installation and operational qualification where appropriate
      –   Adequacy of equipment design, size, and location
      –   Equipment surfaces should not be reactive, additive, or absorptive
      –   Appropriate use of equipment operations substances (lubricants, coolants,
          refrigerants, etc…) contacting products/containers/etc.
      –   Cleaning procedures and cleaning validation
      –   Controls to prevent contamination, particularly with any pesticides or any other
          toxic materials, or other drug or non-drug chemicals
      –   Qualification, calibration and maintenance of storage equipment, such as
          refrigerators, and freezers for ensuring that standards , raw materials, reagents, etc.
          are stored at the proper temperatures
      –   Equipment qualification, calibration and maintenance, including computer
          qualification/validation and security
      –   Control system for implementing changes in the equipment
      –   Equipment identification practices (where appropriate)
      –   Documented investigation into any unexpected discrepancy
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                  PIC/S Aide-Mémoire
                  Inspection of Utilities
                                       June 2002



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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
               PIC/S A Aide-Memoire
• Purpose: Areas that could be evaluated
  during the GMP inspection of HVAC
  systems, Pharmaceutical Water, Steam, and
  Medicinal Gases.




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    HVAC Key Design parameters
•    Need for separate systems
•    Level of filtration (filter specs)
•    Recirculation or make-up air
•    Location of filters
•    Position of inlet and air return, dust extractors
•    Temperature, Humidity
•    Air Changes
•    Pressure differentials
•    Design of ducting
•    Easy and effective cleaning
•    Alarm system
•    Air-Flow Direction – LAF and/or Turbulent

•    Crucial question: How do you prevent cross-contamination by air?

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
               Key Design Parameters
FOCUS           (CROSS) – CONTAMINATION
3.10            Ventilation points accessible from outside the manufacturing area
3.14            In cases where dust is generated, specific provisions to avoid cross contamination
5.10            At every stage of processing, products and materials should be protected from micobial
                and other contamination
5.11            Prevention of generation and dissemination of dust
5.18            Contamination of starting material or of a product by another material or product
5.20            Measures to prevent cross-contamination and their effectiveness should be checked
                periodically according to set procedures
A1: 29-31       Pressure dfferentials. Warning system in case of failure or air supply.Indication of
                pressure differentials. Records and documentation.
A15: 9/10       Design Qualification


ISO 14 644-4    Design and Construction.
EN 1822         HEPA filters
EN 779          Particle air filters for general ventilation
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Qualification of HVAC systems
•   DQ, IQ, OQ, PQ
•   Average speed and uniformity of air flow
•   Pressure differentials
•   Air Changes
•   Integrity and air-tightness of terminal installed final filters
•   Number of particules
•   Recovery tests
•   Air Temperature
•   Smoke tests
•   Re-qualification (parameters for re-qualification)
•   Change Control

•   Crucial Questions:
     – How have you implemented recommendations and correct deviations
        mentioned in the qualification reports?
     – How is responsible for evaluating if re-qualification is necessary?
     – What are the requirements for regular re-qualification?
     – Show me your deviations and change control reports for HVAC?
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
 Qualification of HVAC systems
FOCUS            QUALIFICATION / VALIDATION
4.26             There should be written procedures and the associated records of actions taken or
                 conclusions reached where appropriate, for:
                 Validation, Equipment (...) calibration, Maintenance , (...), Environmental Monitoring
5.21             Validations studies should reinforce GMP (...) Results and conclusions should be
                 recorded.
5.22             Consistency of processes
5.24             Processes and proceduress should undergo periodic critical re-validation to ensure that
                 they remain capable of achieving the intended results.
5.37             Critical processes should be validated
A1 : 30          Air Flow patterns.
A15: 2-18        Pressure differentials. Air flow patterns.


ISO 14 644 -1    Classification of Air Cleanliness
ISO 14 644 - 2   Specifications for testing and monitoring to prove continued compliance with ISO 14
                 644 - 1
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Walkaround tour: Confront differences between design specifications,
    drawings, and reality, unplanned maintenance, and change control and
                                following items

•    Are rooms for the production of medicinal products equipped with HVAC in accordance
     with GMP requirements?
•    Location of filters
•    Position of inlets and air returns
•    Dust extractors
•    Pressure differences (across filters, between production and adjacent rooms)
•    Log-books: maintenance and calibration
•    Monitoring of other process parameters
•    HVAC alarm systems function

•    Crucial questions:
      – How do you challenge your alarm system?
      – Place and procedure for sampling
      – Where and how do you weigh and refill starting materials?
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
      Confront differences between design/drawings and reality
                      Unplanned Maintenance
                          Change Control
FOCUS            WALKAROUND
3.6              Dedicated and self-contained facilities for particular medecinal products. Campaigns
                 and Validation
3.7              Lay-out according to sequence of operations and requisite cleanliness levels
3.12             Production areas should be effectively ventilated with air control facilities appropriate
                 to the product, the operations, and the external environement.
 4.27            Clear operating procedures for manufacturing and test equipment
A 1 : 29         Pressure differentials
A 2 : 14         Air filtration units specific to the processing area concerned and no recirculation for
                 pathogens.




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
     Monitoring of HVAC systems
•    Environmental Monitoring (particle, humidity, temperature, micro-organisms)
•    Chemical residue testing




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
       Monitoring of HVAC systems
FOCUS            MONITORING - ALARMS - ACTIONS
4.15
A1 : 4           The areas should be monitored (particulate claenliness).
A1 : 5           The areas should be monitored (microbiological cleanliness)
A1 : 6           Appropriate alert and alarm limits should be set for the results of particulate and
                 microbiological cleanliness. If these limits are exceeded, operating procedures should
                 prescribe corrective actions.




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Maintenance and Calibration of
           HVAC systems
•    Maintenance program
•    Calibration program
•    SOP’s
•    Records
•    Breakdown/Emergency including challenge of alarms systems

•    Crucial question:
      – The interaction between unplanned maintenance and re-qualification




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
       Maintenance And Calibration
FOCUS            CALIBRATION
3.41             Measuring, weighing, recording and control equipment should be calibrated and
                 checked at defined intervals by appropriate methods. Adequate records of such tests
                 should be maintained.




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
            Documentation of HVAC
                  Systems
•    Technical data
•    SOP’s, records : maintenance and calibration, validation, monitoring,
     deviations, change control
•    Validation Protocols and reports
•    As-Built engine drawings




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
           Documentation for HVAC
                  Systems
FOCUS            PROCEDURES – LOG BOOKS
4.1              Specifications, Instructions, Procedures, Records
4.26             There should be written procedures and the associated records of actions taken or
                 conclusions reached, where appropriate, for : Validation, Equipment (...) Calibration,
                 Maintenance, (...), Environmental Monitoring (...)
4.28             Log Books should be kept for major or critical equipment recording, as appropriate, any
                 validations, calibrations, maintenance, cleaning or repairs operations, including the
                 dates and identity of people carrying the operations out.
4.29             Log Books should also record in chonological order the use of major or critical
                 equipment and the areas where the products have been processed.




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4

               Cleanrooms and Associated
                 Controlled Environments
          Part 4 – Design Construction Start-Up

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    ISO 14 644 – 4: Environmental
      Requirements (Check-List)
• Cleanliness                                       • Humidity
• Air Pattern type                                  • Rate of RH rise/fall
• Airflow direction                                 • Pressurization
• Air Velocity                                      • Pressurization
• Air Circulation system                              Differentials
  and configuration                                 • Pressurization rate of
• Dry Bulb Temperature                                Change
• Rate of DB T° rise/fall                           • Vibration
                                                    • Ionization
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    ISO 14 644 – 4: Documentation
•    Record of an Installation
•    Operational Instructions
•    Instructions for Performance Monitoring
•    Maintenance Record
•    Record of Operation and Maintenance Training




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4
• Record of an installation
      – A description of the installation
      – A set of final and approved performance test data,
        recording of the values of all conditions defined in the
        specification for the installation and achieved during
        commissioning, testing and start-up procedures
      – A set of drawings and specifications describing the
        completed and approved “as-built” installation and its
        components
      – A list of parts and equipment and any recommendation
        for stocking spare parts
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4
• Operational Instructions
      – Schedules of checks and inspections to be completed
        prior to the start-up of the installation
      – Schedules of the acceptance range of critical
        performance parameters specified
      – Procedures to start and stop the installation under
        normal conditions and failure mode situations
      – Procedures to be adapted in the event of alert or action
        levels being reached

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4
• Instructions for Performance Monitoring
      –   Test and measurement frequency
      –   Description of test and measurement methods
      –   Action plan in the event of non-compliance
      –   Frequency required for assembly, analysis and retention
          of performance data to enable trends to be analyzed




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4
• Maintenance instructions
      – Definition of safety procedures prior carrying out maintenance or repairs
      – Specification of maintenance actions to be taken when the acceptance
        range of any critical parameter is exceeded
      – Agreed definition and methods of permitted adjustments
      – Methods of checking and calibrating control, safety, and monitoring
        devices
      – Requirements for checking and replacing all wearing parts
      – Specification for cleaning of the installation or components prior to,
        during and after maintenance work
      – Definition of actions, procedures and tests required after maintenance is
        completed
      – Inclusion of any user-specific or relevant regulatory authority
        requirements
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4
• Maintenance record
      – Definition of maintenance tasks
      – Identification and approval of personnel undertaking
        the maintenance
      – Date of carrying out the maintenance
      – A condition report prior to undertaking the maintenance
      – A list of spare parts used
      – A report upon completion of the maintenance

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                            ISO 14 644 - 4
• Record of operation and maintenance training
      – Report of the training content
      – Identification of the personnel providing and receiving
        the training
      – Training date and duration
      – A report upon each period of training as it is completed




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
 Systems to put in place to ensure the
  compliance throughout the facility
              life-cycle



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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
          Designing HVAC Systems




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
        A Project Development Process

• Knowing the Product
• Knowing the Processes
• Good Engineering Practice
• Impact Assessment : Defining the Critical
  Systems/Components/Parameters
• Enhanced Design Review

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Impact Assessment: Direct Impact
                Systems
•    The system has direct contact with the product
      – Air is in contact with the product (aseptic processing)
•    The system provides an excipient, or produces an ingredient or solvent
•    The system is used for cleaning or sterilizing
•    The system preserves product status
      – Air will help the product to remain under suitable environmental conditions
•    The system produces data which are used to accept or reject product
      – Data from Environmental Monitoring Systems
•    The system is a process control system that may affect product quality and
     there is no system for independent verification of control system performance
     in place


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Component Criticality Assessment
               Process
•    The component is used to demonstrate compliance with the registered process
•    The normal operation or control of the component has direct effect on product
     quality
•    Failure or alarm of the component has a direct effect on product quality or
     efficacy
•    Information from the component is recorded as part of the batch record, lot
     release data, or other GMP-related documentation
•    The component has direct impact with product or product components
•    The component controls critical process elements that may affect product
     quality, without independent verification of the control system performance
•    The component is used to create or preserve a critical status of a system


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
 Example: HVAC Design for Aseptic
            Facilities
•    Process knowledge                                    – External
            •   Product flows                                   •   Re-circulated air
            •   Container/closure Flow                          •   Filters
            •   Operator intrusion                              •   Air intakes
            •   Equipment                                       •   Location of the facility
            •   …
•    Sterilizers type                               •    HVAC design measures
•    Potential sources of contamination                   –   Dilution versus turbulent
                                                          –   Air change rates (particle gain/recovery
      – Internal:                                             time)
            • HVAC system                                 –   Air Filtration arrangements
            • Process and operation                       –   HEPA filter testing
            • Operators                                   –   Terminal HEPA filters
            • Introduction of equipment and               –   Standby systems
              components                                  –   Air Leakages
            • Introduction of materials                   –   UDAF
            • Adjacent less controlled areas
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
           HVAC for Aseptic Facilities:
              Critical Parameters
• Product specific                                  • Others that may impact:
  conditions                                              –   Room Air Flow patterns
• Environmental conditions                                –   Recovery Period
                                                          –   Noise Levels
• Acceptable UDAF
                                                          –   Product OEL
  patterns and velocities for
  critical areas
• Temperature/Humidity
• Pressure Differentials
• Air Change Rates
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
          Example: HVAC Design OSD
                   Facilities
•    Product Knowledge                              •    Degree of Product Exposure:
      –   Toxicity /Potency                               – Closed
      –   Physical properties                             – Open
      –   Hygroscopicity                                  – Intermittent exposure
      –   Solubility for cleaning
      –   Light sensitivity
                                                    •    Facility Flexibility
      –   Sensitization                                   – Single product
•    Process Knowledge                                    – Multiple products in dedicated
                                                            equipment
      –   Blending
      –   Granulation                                     – Multiple products in multi-use
                                                            equipment
      –   Drying
      –   Milling
      –   Compression
      –   Coating

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
         HVAC Design OSD Facilities:
            Critical Parameters
• Temperature/Relative Humidity: Critical
• Airborne Particulates for avoiding Cross-Contamination:
  Critical
            • Level 1: general
            • Level 2: protected
            • Level 3: controlled
• (Room pressure differentials)
• (Air change rates)
• Other Parameters
      – OEL levels
      – Hazardeous Environments
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
Commissioning and Qualification




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                   Prior to Qualification
•    Impact assessment
•    Component Criticality Assessment
•    Validation Master Plan
•    Training
•    Procedures to handle the modifications
     subsequent to qualification (punch lists)

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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
               HVAC Commissioning
                   (Example)
•    Balance testing                                •    Verification of the proper operation of
•    Sound measurement testing                           air coils, air handling units, fans and air
                                                         filters, including tests sequences,
•    Vibration Testing                                   shutdown and start-up
•    Alarms and Interlocks Testing                  •    P&ID walkdown, resulting in an “As-
•    Air Flow rate testing in Ductworks                  Built” P&ID
•    Air Volume supply and return, testing          •    Utilities Check
     and balancing                                  •    Instrumentation calibration
•    Fan RPM and Amperage                           •    Electrical power tests
•    Temperature, humidity (coil duties) and        •    Motor Run Tests
     static pressure tesing (duct leakage)          •    Lubrification tests
•    Differential Pressure Testing and              •    Isometric Drawings check
     balancing                                      •    Safety Checks
•    Loop Checks                                    •    Dynamic situations (start-up, change-
                                                         over...) and impacts on pressure
•    HEPA filter interity testing                        cascades...
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
       Major HVAC Environmental
           Critical Parameters
•    Product specific parameters
•    Environmental conditions (airborne environmental requirements)
•    Unidirectional flows and velocities in critical areas
•    Air Flow patterns to show protection of the product
•    Temperature/humidity
•    Differential pressures against contamination
•    Air Change rates
•    Room Air Flow pattern (turbulent)
•    Recovery period
•    Occupational product exposure limits
•    Fresh air rinsing period after sanitization
•    Supply and extract points locations
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                        Other Parameters
• Ducts cleaning and desinfecting
• Ducts air-tightness




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
Qualification and Commissioning
            Guide: IQ
• Critical Instrumentation Calibration
• Document Review and Check, including:
      – Testing/Balancing report
      – P&ID check of critical components
      – Loop check for critical components
• HEPA filter integrity data review
• Installation check of critical components
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
Qualification and Commissioning
            Guide: OQ
• Critical instruments still in calibration
• Critical alarms and interlocks testing
• Temperature, humidity, differential pressure
  testing under static and dynamic conditions
• SOP review


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
Qualification and Commissioning
            Guide: PQ
• Monitoring and testing for particulate levels
  (surface and airborne)
      – Static (non-viable/viable) Particulate
        Monitoring
      – Dynamic (non-viable/viable) Particulate
        Monitoring


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                   Life-Cycle Activities




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                Maintenance Programs
•    PM programs                                    •    Documentation Management
•    SOP’s                                          •    As-Built drawings
•    Records                                        •    Training
•    Parts Lists                                    •    Sub-contractor management
•    Identification                                 •    Self-inspection
•    Lubricants
•    Log-Books: for maintenance
     /validation/calibration




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                                 Calibration
•    3.41 Measuring, weighing, recording and control equipment should be
     calibrated and checked at defined intervals by appropriate methods. Adequate
     records of such tests should be maintained.
•    4.26 There should be written procedures and the associated records of actions
     taken of conclusions reached, where appropriate for: (...) calibration (...)
•    21 CFR 211.68 requires that automatic, mechanical, electronic equipment to
     be routinely calibrated, inspected or checked according to written program.
     Written reports shall be maintained.
•    21 CFR Part 820.72 requires that Calibration procedures shall include specific
     directions and limits for accuracy and precision. When accuracy and precision
     limits are not met, there shall be provisions for remedial actions to reestablish
     the limits (…). These activities shall be documented. Calibration standards
     (…) shall be traceable to national or international standards.
•    21 CFR 11.10 requires that when electronic records and signatures are used the
     system shall be validated.
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
          HVAC Monitoring / Alarms on
             Critical Parameters
• Monitoring of HVAC critical parameters is usually done with a system
  independent from the control system. The Building Management
  System then may not need to be validated.
      –   T°/HR
      –   Differential Pressure
      –   Particle Counts
      –   Air velocities in UDAF
      –   Airborne Microbiological Levels
• Appropriate alert and alarm limits should be set for the results of
  particulate and microbiological cleanliness. If these limits are
  exceeded, operating procedures should prescribe corrective actions


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
    Note on Continuous Particle Counting

• Correlation from a small amount of data in operation
  compared to at rest qualification data
• Worst case identification
• Sampling frequency
• Interpretation of data for problem identification
• Determination of alarm limits and actions to be taken




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
         Change Control: Definition
     A formal system by which qualified representatives of
     appropriate disciplines review proposed and actual changes
     that might affect the validated status of facilities, systems,
     equipment of processes. The intent is to determine the need
     for action that would ensure and document that the system
     is maintained in a validated state.




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
           Change Control Procedure
• Orange Guide Annex.15 – 43 & 44
      – Written procedures should be in place to describe the actions to be taken if
        a change is proposed to process equipment/environment (or site), or any
        other change that may affect product quality. Change Control procedures
        should ensure that sufficient data are generated to demonstrate that the
        revised process will result in a product of desired quality, consistent with
        the approved specification
      – All changes that may affect product quality should formally requested,
        documented, and accepted. The likely impact of the change of facilities,
        systems and equipment on the product should be evaluated, including risk
        analysis. The need for, and the extent of re-qualification and re-validation
        should be determined.


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
          When a Change Control in
          HVAC Systems is needed?
• A part is changed by a non-identical one (fan, filter,
  gasket...).
• Modification of a parameter of a critical system (e.i.
  control parameters settings: P, I, D factors, sampling rates)
• Air Flows modifications
• Modification in the control program
• ...
• All Preventative Maintenance SOP’s should have been
  approved and no change-control needed after intervention.
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
Change Control procedure : example
CC Number            By administrator

Description and justification of the proposed modification                By initiator

Assessment of the impact on Quality, EHS with the                  By initiator with the
help of a Check-List                                               help of specialists
List of actions required before start-up         By initiator with the help of specialists
List of actions required for CC Closure:
Modification of current documentation, training
                                                      By initiator with the help of specialists

Approval CC document             By Manager Maintenance/QA/Validation/User/EHS

WORK

Authorization to re-start the equipment              By User/QA/EHS

CC Closure          By administrator
 ___________________________________________________________________________________________________
             Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                      ISPE Brussels Conference – April 2003
              Revalidation (Annex 15)
• Definition: A repeat of the process validation to provide the assurance
  that changes in the process/equipment introduced in accordance with
  change control procedures do not adversely affect process
  characteristics and product quality

• Annex 15 – 45 : Facilities, systems, equipment and processes,
  including cleaning, should be periodically evaluated to confirm that
  they remain valid. Where no significant changes have been made to the
  validated status, a review with evidence that facilities, systems,
  equipment and processes meet the prescribed requirements fulfils the
  need for revalidation.


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                    Need for Revalidation
• Revalidation can be performed as a result of an
  event-based or time-based assessement.
• Event-based revalidation
      – After a change made to the system that is outside the
        scope of the original validation
• Time-based revalidation at defined interval
      – Ensure that the sum of incremental changes made
        within the scope of the current validation have not
        pushed the system outside the original scope of
        validation
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                    Examples in HVAC
•    Complex HVAC system with air-tight dampers for desinfection, pressure
     differentials controlled by VAV, air flow maintained by variable speed drive,
     inlets with constant air volume
•    A time-based revalidation will verify if the system has not evoluated towards
     unstable conditions, due to incremental manual adjustments on dampers, or
     filters clogging, loss of controlling valves authority, wearing of mechanical
     components, air-tighness due to mechanical mis-adjustment: this re-validation
     could for example include air flow/pressure measurement in ducting, testing af
     transitory situations...
•    A re-validation (media fill) will only be required if critical aspects has been
     adulterated such as modification of air flows, room lay-out...

      “Recognizing the complexity of systems”
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                      Management Tools

            How to implement organizational
          systems that will ensure continuously
                    the Compliance?

___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                Owner of HVAC systems
• Under the responsibility of the Maintenance Department
  for operation and maintenance (as Water systems)
• The culture needs to be aligned with QA expectations
• Teamwork is predominant for correct and common
  evaluations of the risks, the priorities, the deviations




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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                               The Challenge
Knowing the Equipment                                            Knowing the Product

           Engineers                                                       Pharmacists
          Technicians                                                       Biologists
                                                                            Chemists




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              Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                       ISPE Brussels Conference – April 2003
  Examples of Management Tools
• HVAC Team
      –   Maintenance
      –   QA
      –   User
      –   Engineering
      –   Calibration
      –   Validation
• Annual Equipment/System Review
• CMMS
• Engineering Documentation Coordinator: a procedure
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                                HVAC Team

• Objectives
      – Follow-up of regulatory expectations and standards
      – Periodic review of monitoring results and deviations (validation
        results, incidents) for determining action and investment plans
      – Follow-up of action plans according to regulatory status
      – Training initiatives
      – Follow-up of operational reports
      – Organization of annual equipment reviews



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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
        Annual Equipment/System Review

•    Team approach
      – Maintenance: with log-books (preventative and unplanned), key performance
        indicators, Root Cause Analysis, OEE, MTBF
      – Calibration: logs
      – QA: Deviations reports
      – Validation : Validation reports
      – Production : log-books, operational incidents

•    Objective:
      – Review all aspects and data related to one year operation of the system
      – Generate a compliance status of the SOP’s, related documentation, As-Built
        drawings, Actions Plans, Continuous Improvement
      – Build up a common culture and understanding of the critical aspects
      – On site training


___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
     Annual Equipment Review : Program
•   Documentation Review (according to VMP, impact assessment) for calibration,
    maintenance, production
     –   As Built
     –   Qualification file
     –   SOP’s (maintenance, calibration,...)
     –   Records (log-books Maintenance, production)
     –   Programs completion
     –   Equipment and Component lists and criticality
     –   Reliability and rounds data
     –   Consumption data (materials, energy)
     –   Environemental Monitoring data
     –   Deviation reports
•   Along with a Time line: list and analyse all events, deviations,...
     –   Calibration data
     –   Maintenance data (unplanned, predictive, corrective,…)
     –   Change Control Review
•   Can lead to a self-inspection


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
Computerized Maintenance Management
          System (CMMS)
From a analysis of Systems/Sub-Systems/Components Identification, all related data are
   linked and available in the database:

•    System/sub-system/component identification
•    Qualification/Routine validation data
•    Component/System Criticality
•    PM Maintenance SOP
•    Maintenance History
•    Calibration Data and History
•    Safety checks
•    Maintenance/Calibration/Safety Checks Programs
•    Component identification
•    Spare Parts Lists
•    Parts specifications
•    Inspections/Rounds Management
•    Change Control initiation
•    Log Books
___________________________________________________________________________________________________
            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                                  References
• ISO 14 644: Cleanrooms and Associated Controlled Environments
      – Part 4: Design, Construction and Start-up
      – Part 5: Operations (DIS)
•    ISO 14 698 Part 1 & 2 : Biocontamination Control
•    MCA Orange Guide, 1998 + annex 15 (July 2001)
•    PICS Aide-memoire : Inspection of Utilities (01/07/2002)
•    FDA Drug Manufacturing Inspections Program 7356.002 – 02/01/2002
•    FDA 21 CFR Part 210 – 211 (Rev.1-4-02)
•    FDA Guide on Sterile Drug Products Produced by Aseptic Processing
     (Draft 27/09/2002)


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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                             References (2)
• EN 1822: High Efficiency Particulate Filters
• EN 779: Particle Air Filters for general ventilation – Requirements,
  testing, marking
• ISPE Pharmaceutical Engineering Guides for New and Renovated
  Facilities
      – Volume 2 Oral Solid Dosage Forms (02/1998)
      – Volume 3 Sterile Manufacturing Facilities (01/1999)
      – Volume 5 Commissioning and Qualification (03/2001)
• ISPE Maintenance Baseline Guide (Draft)



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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003
                        Related Web Sites
•    www.iest.org
•    www.iso.org
•    www.fda.gov/cder
•    www.ispe.org
•    www.pda.org
•    www.regsource.com
•    www.picscheme.org
•    http:\\pharmacos.eudra.org
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            Regulatory Expectations for Utility Systems – Managing And Maintaining HVAC Systems –
                                     ISPE Brussels Conference – April 2003

								
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