Qualification of HVAC systems Tony Gould

WHO reference WHO Technical Report Series, No. 937, 2006 - Annex 2 "Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms" Comprehensive guide May also be applied to other dosage forms Not intended to be prescriptive – risk principles apply

World Health Organization HVAC 19 April 2017 Objectives To understand key issues in commissioning, qualification and maintenance of HVAC systems 8.

World Health Organization 19 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 program and records

World Health Organization HVAC World Health Organization 19 April 2017 Commissioning Precursor to qualification Includes setting up, balancing, adjustment and testing of entire HVAC system to ensure it meets requirements in URS and capacity Acceptable tolerances for parameters Training of personnel 8. Commissioning, qualification and maintenance 8.1 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 specifi ed in the user requirement specifi cation (URS), and capacities as specifi ed by the designer or developer. 8.1.2 The installation records of the system should provide documented evidence of all measured capacities of the system. 8.1.3 The data should include items such as the design and measurement fi gures for airfl ows, water fl ows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals). 8.1.4 Acceptable tolerances for all system parameters should be specifi ed prior to commencing the physical installation. 8.1.5 Training should be provided to personnel after installation of the system, and should include operation and maintenance.

World Health Organization HVAC World Health Organization 19 April 2017 Commissioning (2) Records and data maintained include: Installation records – documented evidence of measure capacities of the system Data: Design and measurement for e.g. air flow, system pressures O&M manuals, schematic drawings, protocols, reports 8.1.3 The data should include items such as the design and measurement fi gures for airfl ows, water fl ows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals). 8.1.4 Acceptable tolerances for all system parameters should be specifi ed prior to commencing the physical installation. 8.1.5 Training should be provided to personnel after installation of the system, and should include operation and maintenance. 8.1.6 O & M manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system.

World Health Organization HVAC World Health Organization 19 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. See also full guidelines on "Validation" in WHO TRS No 937, 2006, Annex 4. Risk based approach for HVAC qualification 8.2 Qualifi cation 8.2.1 Validation is a many-faceted and extensive activity and is beyond the scope of these guidelines. Qualifi cation and validation guidelines are included in: Expert Committee on Specifi cations for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 937), Annex 4 (see also Fig. 28).

World Health Organization HVAC World Health Organization 19 April 2017 Qualification (2) Described in a Validation Master Plan (VMP) VMP to include the nature and extent of tests, and protocols DQ, IQ, OQ, and PQ Risk analysis to determine critical and non-critical parameters, components, sub-systems 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.

World Health Organization HVAC World Health Organization 19 April 2017 Qualification (3) 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 8.2.5 Critical and non-critical parameters should be determined by means of a risk analysis for all HVAC installation components, subsystems and controls. 8.2.6 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 qualifi cation 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 qualifi ed. The heat transfer system, chemical drier or steam humidifi er, which is producing the humidity controlled air, is further removed from the product and may not require operational qualifi cation. Figure 28 Qualifi cation is a part of validation Equip 1 Equip 2 Equip 3 Equip 4 Equip 5 Equip 6 QUALIFICATION VALIDATION Equip 7 System 2 System 1 Process Equip, equipment. 80 Figure 29 System operating ranges • A room cleanliness classifi cation is a critical parameter and, therefore, the room air change rates and HEPA fi lters should be critical parameters and require qualifi cation. Items such as the fan generating the airfl ow and the primary and secondary fi lters are non-critical parameters, and may not require operational qualifi cation. 8.2.8 Non-critical systems and components should be subject to GEP and may not necessarily require qualifi cation. 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 defi ned during the design stage. 8.2.11 The manufacturer should defi ne design conditions, normal operating ranges, operating ranges, and alert and action limits.

HVAC Design conditions and normal operating ranges set to achievable limits OOS results recorded

World Health Organization HVAC 19 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 19 April 2017 Qualification (7) 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

World Health Organization HVAC World Health Organization 19 April 2017 Qualification (6) Conduct of the tests: Time intervals and procedure to be defined by the manufacturer Influenced by the type of facility and level of protection See also ISO 14644 for methods of testing Re-qualification, and change control 8.2.18 The maximum time interval between tests should be defi ned by the manufacturer. The type of facility under test and the product level of protection should be considered. Note: Table 3 gives intervals for reference purposes only. The actual test periods may be more frequent or less frequent, depending on the product and process. 8.2.19 Periodic requalifi cation of parameters should be done at regular intervals, e.g. annually. 8.2.20 Requalifi cation should also be done when any change, which could affect system performance, takes place.

World Health Organization HVAC World Health Organization 19 April 2017 Qualification (4) 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) 8.2.17 For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualifi ed 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 airfl ow patterns — unidirectional fl ow velocities — containment system velocities — HEPA fi lter 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.

World Health Organization HVAC 19 April 2017 Qualification (5) Typical parameters to be included in qualification (based on risk assessment) (2): Room clean up rate Particulate matter, microbial matter (viable and non-viable) HEPA filter penetration tests Containment system velocity Warning/alarm systems

World Health Organization HVAC 19 April 2017 Schedule of tests to demonstrate continuing compliance *Test procedure as per ISO 14644 Test procedure* and key aspects Maximum time interval Objective Test Parameter Particle counter. Readings and positions 6 months or 12 months depending on Class Verifies cleanliness Particle count test Measure pressure difference 12 months Absence of cross- contamination Air pressure difference Measure supply and return air, calculate air change rate Verify air change rates Airflow volume Velocity measurement Verify unidirectional airflow and or containment condition Airflow velocity

World Health Organization HVAC 19 April 2017 Recommended optional strategic tests *Test procedure as per ISO 14644 Test procedure* and key aspects Maximum time interval Objective Test Parameter Filter media and filter seal integrity 12 months Verify filter integrity Filter leakage Airflow direction and pressure differential Verify absence of cross-contamination Containment leakage Time taken maximum 15 minutes Verify clean-up time Recovery (time) Airflow direction, documented evidence Verify required airflow patterns Airflow visualization

Cleanroom monitoring program (1) World Health Organization 19 April 2017 HVAC Cleanroom monitoring program (1) Routine monitoring program as part of quality assurance Additional monitoring and triggers e.g. Shutdown Replacement of filter elements Maintenance of air handling systems Exceeding of established limits

World Health Organization 19 April 2017 HVAC Cleanroom monitoring program (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

World Health Organization 19 April 2017 HVAC Cleanroom monitoring program (3) Cleanrooms should be monitored for micro-organisms and particles air Example of a sampling point

Definition of Conditions World Health Organization 19 April 2017 HVAC Definition of Conditions air as built at rest in operation

World Health Organization 19 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 Air flow 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 19 April 2017 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Turbulent / mixed airflow Description Uni-directional airflow / LAF Recovery time Room classification (airborne particle) Temperature, humidity N/A 2 2,3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) The recovery time (clean-up time) is also an important parameter to be determined. Once doors have been opened and people have been entering a room, the original conditions have been disturbed and, for a short while, before recovering, the room does not always correspond to the laid down parameters. It is important to know how long this period is. There are no regulations laid down as to how long this clean-up time should be. However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification, should be less than 15 minutes. It should also be remembered that a room is to be qualified “in operation” when it has a certain number of people in it. After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded. Temperature and humidity can also be important (comfort in clean areas, stability of effervescent products, etc.)

World Health Organization HVAC World Health Organization 19 April 2017 Maintenance Procedure, program and records for planned, preventative maintenance E.g. Cleaning of filters, calibration of devices Appropriate training for personnel Change of HEPA filters by suitably trained persons Impact of maintenance on: Product quality 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 Maintenance personnel should receive appropriate training. 82 8.3.3 HEPA fi lters should be changed either by a specialist or a trained person. 8.3.4 Any maintenance activity should be assessed critically to determine any impact on product quality including possible contamination. 8.3.5 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 requalifi cation of an area as a result of an interruption of the service.

World Health Organization 19 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)

HVAC and Quality Risk Management What about risk assessment/risk management in HAVC systems? Recommended risk assessment prior to qualification Design requirements Qualification (GMP) vs GEP Ongoing performance Ongoing maintenance

HVAC and Quality Risk Management Type of products and materials Product range Campaign Cleaning Design, age, changes Monitoring results (OOLs)

World Health Organization 19 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