World Health Organization 23 April, 2017 Supplementary Training Modules on Good Manufacturing Practice Heating, Ventilation and Air- Conditioning (HVAC) Part 4: Commissioning, qualification and maintenance WHO Technical Report Series, No. 961, 2011. Annex 5 Part 4: Commissioning, qualification and maintenance Section 8

World Health Organization HVAC 23 April, 2017 Objectives To understand key issues in commissioning, qualification and maintenance of HVAC systems 8.

World Health Organization 23 April, 2017 HVAC Documentation requirements to assist in commissioning, qualification and maintenance Description of design, installation and functions Specifications, requirements Manuals Operating procedures Instructions for performance control, monitoring and records Maintenance instructions and records Training of personnel programme and records

World Health Organization HVAC 23 April, 2017 Commissioning Commissioning (is integrated in qualification) and includes: Setting up, balancing, adjustment and testing of entire HVAC system It helps to ensure it meets URS and capacity Acceptable tolerances for parameters set before commissioning Precursor to qualification Commissioning   8.1.1 Commissioning should include the setting up, balancing, adjustment and testing of the entire HVAC system, to ensure that it meets all the requirements, as specified in the user requirement specification (URS), and capacities as specified by the designer or developer. The commissioning plan should start at the early stages of a project so that it can be integrated with qualification and verification procedures.     8.1.4 Acceptable tolerances for all system parameters should be specified prior to commencing the physical installation.    8.1.6 Commissioning should be a precursor to system qualification and process validation. 8.1.1, 8.1.4, 8.1.6

World Health Organization HVAC 23 April, 2017 Commissioning (2) Records and data include: Installation records – documented evidence of measured capacities of the system Acceptance criteria set for system parameters Training of personnel (e.g. operation and maintenance) O&M manuals, schematic drawings, protocols, reports 8.1.2 The installation records of the system should provide documented evidence of all measured capacities of the system.   8.1.3 Acceptance criteria should be set for all system parameters. The measured data should fall within the acceptance criteria. 8.1.5 Training should be provided to personnel after installation of the system, and should include operation and maintenance. 8.1.2, 8.1.3, 8.1.5

World Health Organization HVAC 23 April, 2017 Qualification Validation is an extensive exercise Qualification of the HVAC system is one component in the overall approach that covers premises, systems/utilities, equipment, processes, etc. Risk-based approach for HVAC qualification See also full guidelines on "Validation" in WHO TRS No 937, 2005, Annex 4. 8.2 Qualification 8.2.1 Validation is a many-faceted and extensive activity and is beyond the scope of these guidelines. Qualification and validation guidelines are included in: Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 937), Annex 4 (see also Fig. 28) Companies should do risk assessment exercises to determine what the scope and extent of qualification. 8.2.1

World Health Organization HVAC 23 April, 2017 Qualification Described in a Validation Master Plan (VMP) Reflects the nature and extent, test procedures, and protocols DQ, IQ, OQ, and PQ Risk analysis to determine critical and non-critical parameters, components, subsystems and controls 8.2.2 The qualifi cation of the HVAC system should be described in a validation master plan (VMP). 8.2.3 It should defi ne the nature and extent of testing and the test procedures and protocols to be followed. 8.2.4 Stages of the qualifi cation of the HVAC system should include DQ, IQ, OQ and PQ. 8.2.5 Critical and non-critical parameters should be determined by means of a risk analysis for all HVAC installation components, subsystems and controls. 8.2.2 - 8.2.5

World Health Organization HVAC 23 April, 2017 Qualification Direct impact components and critical parameters should be included Non-critical systems and components are subjected to Good Engineering Practices (GEP) Acceptance criteria and limits defined in design stage Design conditions, normal operating ranges, operating ranges, alert and action limits 8.2.6 Any parameter that may affect the quality of the pharmaceutical product, or a direct impact component, should be considered a critical parameter. 8.2.7 All critical parameters should be included in the qualification process. Note: A realistic approach to differentiating between critical and noncritical parameters is required, to avoid making the validation process unnecessarily complex. Example: • The humidity of the room where the product is exposed should be considered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system should, therefore, be qualified. The heat transfer system, chemical drier or steam humidifier, which is producing the humidity controlled air, is further removed from the product and may not require operational qualification. A room cleanliness classification is a critical parameter and, therefore, the room air change rates and HEPA filters should be critical parameters and require qualification. Items such as the fan generating the airflow and the primary and secondary filters are non-critical parameters, and may not require operational qualification. 8.2.8 Non-critical systems and components should be subject to GEP and may not necessarily require qualification. 8.2.9 A change control procedure should be followed when changes are planned to the direct impact HVAC system, its components and controls that may affect critical parameters. 8.2.10 Acceptance criteria and limits should be defined during the design stage. 8.2.11 The manufacturer should define design conditions, normal operating ranges, operating ranges, and alert and action limits. 8.2.6 - 8.2.11

World Health Organization HVAC 23 April, 2017 Design conditions and normal operating ranges set to achievable limits OOL results recorded and investigated 8.2.10 The design condition, normal operating ranges, operating range and alert and action limits should be defined and be realistic.   8.2.11 Out-of-limit results (e.g. action limit deviations) should be recorded and their impact should be investigated. 8.2.12 The relationships between design conditions, normal operating range and validated acceptance criteria (also known as proven acceptable range) 8.2.10 – 8.2.12

World Health Organization HVAC 23 April, 2017 Qualification – examples of aspects to consider DQ – Design of the system, URS (e.g. components, type of air treatment needed, materials of construction) IQ – Verify installation e.g. relevant components, ducting, filters, controls, monitors, sensors, etc. includes calibration where relevant

World Health Organization HVAC 23 April, 2017 Qualification Typical parameters to be included in qualification (based on risk assessment): Temperature Relative humidity Supply, return and exhaust air quantities Room air change rates Room pressures (pressure differentials) 8.2.13 For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualified may include: — temperature — relative humidity — supply air quantities for all diffusers — return air or exhaust air quantities — room air change rates — room pressures (pressure differentials) — room airflow patterns — unidirectional flow velocities — containment system velocities — HEPA filter penetration tests — room particle counts — room clean-up rates — microbiological air and surface counts where appropriate — operation of de-dusting — warning/alarm systems where applicable. 8.2.13

World Health Organization HVAC 23 April, 2017 Qualification Typical parameters to be included in qualification (based on risk assessment) (2): Room air flow patterns Room clean-up rate Particulate matter, microbial matter (viable and non-viable) HEPA filter penetration tests Containment system velocity Warning/alarm systems 8.2.13 For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualified may include: — temperature — relative humidity — supply air quantities for all diffusers — return air or exhaust air quantities — room air change rates — room pressures (pressure differentials) — room airflow patterns — unidirectional flow velocities — containment system velocities — HEPA filter penetration tests — room particle counts — room clean-up rates — microbiological air and surface counts where appropriate — operation of de-dusting — warning/alarm systems where applicable. 8.2.13.

World Health Organization HVAC 23 April, 2017 Conduct of the tests: Time intervals and procedure to be defined by the manufacturer - based on risk assessment (influenced by the type of facility and level of protection) See also ISO 14644 for procedures Requalification, and change control Documents: system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings 8.2.14. The maximum time interval between tests should be defined by the manufacturer. The type of facility under test and the product level of protection should be considered. No   8.2.15 Requalification should also be done when any change, which could affect system performance, takes place. 8.2.16 Clean-up or recovery times normally relate to the time it takes to “clean up” the room from one condition to another, e.g. the relationship between “at-rest” and “operational” conditions in the clean area may be used as the criteria for clean-up tests. Therefore, the clean-up time can be expressed as the time taken to change from an “operational” condition to an “at rest” condition. 8.2.17 If energy-saving procedures such as reducing the airflow during non-production hours are used, precautionary measures should be in place to ensure that the systems are not operated outside the defined relevant environmental conditions. These precautionary measures should be based on a risk assessment to ensure that there is no negative impact on the quality of the product. 8.2.18 Documents that should be included in the qualification manuals should include system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings, etc. 8.2.14 – 8.2.18

World Health Organization HVAC World Health Organization 23 April, 2017 Qualification Tests performed according to protocols and procedures for the tests Results recorded and presented in report (source data kept) Traceability, e.g. devices and standards used, calibration records; and conditions specified Qualification (7) Tests should be done by following appropriate protocols and procedures. Normally, procedures should be as described in ISO 14644 All results should be recorded and presented in report (source data should be kept as these will be verified against the report by inspectors). For the tests and results – there should be sufficient traceability, e.g. devices and standards used, their calibration records; and conditions under which the tests were done should be specified

World Health Organization HVAC 23 April, 2017 Schedule of tests to demonstrate continuing compliance *Test procedure as per ISO 14644 Test procedure* and key aspects Considerations Objective Test Parameter Particle counter. Readings and positions Number of readings and positions Verifies cleanliness Particle count test Measure pressure difference Continuous. Defined limits Absence of cross- contamination Air pressure difference Measure supply and return air, calculate air change rate See ISO 14644 Verify air change rates Airflow volume Velocity measurement Velocity and containment Verify unidirectional airflow and or containment condition Airflow velocity 8. Table 3

World Health Organization HVAC 23 April, 2017 Recommended optional strategic tests *Test procedure as per ISO 14644 Test procedure* and key aspects Considerations Objective Test Parameter Filter media and filter seal integrity For HEPA filters Verify filter integrity Filter leakage Airflow direction and pressure differential Containment, smoke and air pressure Verify absence of cross-contamination Containment leakage Time taken maximum 20 minutes Certain classes Verify clean-up time Recovery (time) Airflow direction, documented evidence Clean to dirty area, uniformly. Video Verify required airflow patterns Airflow visualization 8. Table 3

Cleanroom monitoring program (1) World Health Organization 23 April, 2017 HVAC Cleanroom monitoring program (1) Routine monitoring program as part of quality assurance Additional monitoring and triggers, e.g. 1. Shutdown 2. Replacement of filter elements 3. Maintenance of air-handling systems 4. Exceeding of established limits

World Health Organization 23 April, 2017 HVAC Cleanroom monitoring programme (2) Particles and Microbiological contaminants Number of points/locations for monitoring determined, specified, documented in procedure and or protocol Sufficient time for exposure, and suitable sample size Identification and marking of sampling points Definition of transport, storage, and incubation conditions Results to reflect the procedure/protocol followed Define alert and action limits as a function of cleanliness zone/class See also ISO 14644

World Health Organization 23 April, 2017 HVAC Cleanrooms should be monitored for microorganisms and particles Example of a sampling points

World Health Organization 23 April, 2017 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Differential pressure on filters Turbulent / mixed airflow Description Uni-directional airflow / LAF Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Airflow pattern 2 N/A 2, 3 Optional 3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) This slide shows a series of tests to be carried out during qualification. There are different tests for the turbulent and for the uni-directional air flows. The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase. In order to keep the volume of air constant, the fan speed may increase, with the following consequences: Damage to filters, and passage of unfiltered air Particles and micro-organismes will be “pushed” through the filter units. (Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.) Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified. It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow. Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.

World Health Organization HVAC 23 April, 2017 Maintenance Procedure, programme and records for planned, preventative maintenance e.g. cleaning of filters, calibration of devices Keep O&M manuals, drawings etc. Appropriate training for personnel Change of HEPA filters by suitably trained persons Impact of maintenance on: Product quality and Qualification 8.3 Maintenance 8.3.1 There should be a planned preventive maintenance programme, procedures and records for the HVAC system. Records should be kept.   8.3.2 Operating and maintenance (O&M) manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system. These documents should be kept up to date, containing any system revisions made. 8.3.3 Maintenance personnel should receive appropriate training. 8.3.4 HEPA filters should be changed either by a specialist or a trained person, and then followed by installed filter leakage testing. 8.3.5 Any maintenance activity should be assessed critically to determine any impact on product quality including possible contamination. 8.3.6 Maintenance activities should normally be scheduled to take place outside production hours, and any system stoppage should be assessed with a view to the possible need for requalification of an area as a result of an interruption of the service. 8.3.1 – 8.3.6

World Health Organization HVAC 23 April, 2017 Premises may influence HVAC design / performance. Therefore consider: Adequate airlocks, change rooms, passages Required pressure cascades Detailed diagrams available with pressure cascades, air flow directions and flow routes for personnel and materials should be prepared and maintained; Change room classification As the efficient operation of the air-handling system and cleanliness levels attained are reliant on the correct building layout and building finishes, the following items should be considered: adequate airlocks, such as personnel airlocks (PAL) and/or material airlocks (MAL), change rooms and passages should be provided to protect passage between different cleanliness conditions . These should have supply and extract air systems as appropriate; areas such as airlocks, change rooms and passages, should be designed so that the required pressure cascades can be achieved; detailed diagrams depicting pressure cascades, air flow directions and flow routes for personnel and materials should be prepared and maintained; where possible, personnel and materials should not move from a higher cleanliness zone to a lower cleanliness zone and back to a higher cleanliness zone; (if moving from a lower cleanliness zone to a higher cleanliness zone, changing /decontamination procedures should be followed); and the final stage of the changing room should, in the "at rest" state, be the same GMP classification grade as the area into which it leads. 9

World Health Organization 23 April, 2017 HVAC Inspecting the air-handling system Verification of design documentation, including description of installation and functions specification of the requirements Operating procedures Maintenance instructions Maintenance records Training logs Environmental records Discussion on actions if OOS values On site verification (walking around the site)

World Health Organization 23 April, 2017 HVAC Take home message. What is essential? Appropriate design of AHUs and HVAC system Correct components, and MOC Ensuring appropriate cleanliness of air, environmental conditions (e.g. temperature and RH), and area classification to prevent contamination and cross-contamination Qualification data to support claims Regular calibration, maintenance and cleaning What is essential in HVAC? As there are many variable in terms of what is required for appropriate production and control environments, the essential aspects to consider are (but not limited to) the following: Appropriate design of AHUs and HVAC system to provide sufficiently cleaned air, environmental conditions, and containment. All components should be of appropriate MOC and correctly placed Air should be free from contaminants and provide suitable and appropriate environmental conditions (e.g. temperature and RH), and pressure cascades where required to ensure containment. Areas classified should be maintained within their classification.

World Health Organization 23 April, 2017 HVAC Conclusion Air-handling systems: Play a major role in the quality of pharmaceuticals Should be designed properly, by professionals Should be treated as a critical system

World Health Organization 23 April, 2017 HVAC Group Session The diagram, which is given in handout 3-3-26, shows a layout of a small pharmaceutical plant for non-sterile tablets, liquids and soft-gel capsules, as well as aseptically filled eye-drops. The group session participants should indicate on the diagram the required cleanroom classes, room pressures (in Pa), as well as any architectural changes which they think necessary. (This layout is not ideal, but as many different types of operations have been incorporated in the facility as possible, so that different concepts can be addressed.) (Note to trainer: The next handout, 3-3-27, giving suggested modifications, should not be distributed until after the group discussion has taken place.)

World Health Organization 23 April, 2017 HVAC Group Session – modified layout MAL = Material Air Lock PAL = Personnel Air Lock This slide indicates the proposed additions, and can be displayed after the group session discussions have taken place. See handout 3-3-27.