HVAC Validation

GMP Platform--supporting better manufacturing of pharmaceuticals HVAC Validation 1 Introduction Heating, Ventilation and Air Conditioning System (HVAC)  HVAC systems can have an impact on product quality  It can provide comfortable conditions for operators  The impact on premises and prevention of contamination and cross-contamination to be considered at the design stage  Temperature, relative humidity control where appropriate  Supplement to basic GMP © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 2 HVAC system consists of:             Air conditioner AHUs Dehumidifier / Heater Filters (Pre & HEPA) Dust Extractors Ducting (For delivery of controlled air) Supply Fans Smoke Detector Dampers Humidity / Temperature / Pressure sensors Bag Filters Heating / Cooling Coils © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 3 Area 1 Fresh Air Area 2 I M P U R E HVAC Impure air Pure air Area 3 A I R Area 4 Return Air Exhaust air © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 4 HVAC Components Exhaust Air Grille Silencer Weather louvre Flow rate controller Fan Control damper + Humidifier Prefilter Cooling coil Heating with coil droplet separator Filter Secondary Filter Heater Terminal filter Production Room Recirculated air © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 5 All Rights Reserved. EA-05-02-00 6 .Validation of HVAC systems It includes: Commissioning  Qualification  Maintenance © Copyright CM Plus Corporation. EA-05-02-00 7 . All Rights Reserved.  Acceptable tolerances for parameters  Training of personnel © Copyright CM Plus Corporation. balancing. adjustment and testing of entire HVAC system to ensure it meets requirements in URS.Commissioning  Precursor to qualification  Includes setting up. e.g. air flow. EA-05-02-00 8 . protocols. reports © Copyright CM Plus Corporation. All Rights Reserved. system pressures  O&M manuals.Conti… Records and data maintained include: Installation records – documented evidence of measure capacities of the system  Data: design and measurement for. schematic drawings. Qualification  To ensure that equipment is designed as per requirement. © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 9 .  Action of proving that any equipment works correctly and leads to the expected results. installed properly. © Copyright CM Plus Corporation.HVAC Qualification Validation Master Plan QUALIFICATION User Requirement Specification Design Qualification Installation Qualification Operation Qualification Performance Qualification Re. EA-05-02-00 10 . All Rights Reserved.Qualification.  The qualification of the HVAC system should be described in a validation master plan (VMP).  The validation master plan should define the nature and extent of testing and the test procedures and protocols to be followed.  A change control procedure should be followed © Copyright CM Plus Corporation. All Rights Reserved.Conti…  Manufacturers should qualify HVAC systems using a riskbased approach. EA-05-02-00 11 . components. EA-05-02-00 12 . alert and action limits © Copyright CM Plus Corporation. subsystems and controls  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. All Rights Reserved. operating ranges.Conti…  Risk analysis to determine critical and non-critical parameters. EA-05-02-00 13 . All Rights Reserved. equipment and processes to be validated  Documentation format to be used for protocols and reports  Planning and scheduling  Change control  References to documents © Copyright CM Plus Corporation.Validation master plan This document should contain :  Validation policy  Organizational structure of validation activities  Summary of facilities. systems. return and exhaust air quantities  Room air change rates  Room pressures (pressure differentials)  Room clean-up rate  Particulate matter. microbial matter (viable and non-viable)  HEPA filter penetration test © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 14 .Qualification Typical parameters to be included in qualification:  Temperature  Relative humidity  Supply. and change control Tests performed according to protocols and procedures for the tests  Results recorded and presented in report © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 15 .Conduct of test :  Time intervals and procedure to be defined by the manufacturer  Influenced by the type of facility and level of protection  Requalification. calculate air change rate 12 months Verify air change rates Airflow volume Velocity measurement 12 months Verify unidirectional airflow and or containment condition Airflow velocity © Copyright CM Plus Corporation.Schedule of tests to demonstrate continuing compliance Test procedure and key aspects Maximum time Objective interval Test Parameter Particle count test Readings and positions 6 months or 12 Verifies months depending cleanliness on Class Particle count Measure pressure difference 12 months Absence of Air pressure crossdifference contamination Measure supply and return air. All Rights Reserved. EA-05-02-00 16 . 3. Detailed Air Flow Schematics. © Copyright CM Plus Corporation. All Rights Reserved. Technical / Performance specification for equipment.Design Qualification (DQ)  First step in the qualification of new HVAC systems.  Compliance with GMPs and other regulatory requirements. Functional Specification. 4. Detailed layout drawing of the system. 2. EA-05-02-00 17 .  It documents the design of the system and will include: 1. Takes into account process and personnel flow (crosscontamination issues) 4. Details all equipment that must be ordered. 7. Details facility airflow and pressure cascade philosophy. EA-05-02-00 18 . Meets the user requirements. Full details of the intended construction prior to implementation.Conti… • Ensures that design 1. © Copyright CM Plus Corporation. Details materials of construction. 6. All Rights Reserved. 5. 3. 2. Details safety requirements. Installation Qualification (IQ) IQ should include:  Instrumentation checked against current engineering drawings and specifications  Properly served by the required utilities  Verification of materials of construction  Installation of equipment and with piping  Calibration of measuring instruments  Operation manuals and spare parts lists to assure the proper and continuous operation of the system  Components are installed at specified location © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 19 . EA-05-02-00 20 . model. I. (all deviations will have been recorded and assessed. © Copyright CM Plus Corporation.. All Rights Reserved.D.  Completed calibration of measuring instruments.  A fully verified installation that complies with the documented design.)  All equipment documentation and maintenance requirements would be documented. Personnel responsible for activities and Date. IQ Document should contain Instrument name. No.Conti…. EA-05-02-00 21 . • Calibration verification: To provide a list of critical instrumentation and control panel and to document that they have been identified and calibrated in accordance with the approved procedure • SOP verification: To verify that required SOPs exist in either draft or final form and must be current and approved for use. • Utilities Connection Verification: Utilities supported to HVAC need to be verified to assure that they are installed properly.Conti…. All Rights Reserved. © Copyright CM Plus Corporation. EA-05-02-00 22 . • Change Parts and Replacement Parts Verification • Maintenance Procedures Verification • Critical Systems Change Request Procedure verification • Lubricants Verification © Copyright CM Plus Corporation.Conti…. All Rights Reserved. All Rights Reserved. through documented testing. • Scope of OQ is to test the individual components of the system such as AHU.Operation Qualification • The purpose of OQ is to establish. © Copyright CM Plus Corporation. EA-05-02-00 23 . blowers and others. • The purpose of OQ is to verify and document that an HVAC system provides acceptable operational control under “at-rest” conditions. that all critical components are capable of operating within established limits and tolerances. © Copyright CM Plus Corporation. All Rights Reserved. • Ability to maintain any critical parameters stated in the DQ consistently.Conti… Operation Qualification Checks • Ability to provide air of sufficient quality and quantity to ensure achievement of specified clean room conditions. • Ability to maintain temperature. relative humidity and pressure set points. EA-05-02-00 24 . Conti…. sometimes referred to as ‘worst case’ conditions. • Includes the tests that have been developed from knowledge of processes. systems and equipment. All Rights Reserved. © Copyright CM Plus Corporation. EA-05-02-00 25 . • Tests to include a condition or a set of conditions encompassing upper and lower operating limits. All Rights Reserved.OQ also includes: • Testing Equipment Calibration Verification • Instrumentation Calibration verification • SOP Verification • Operation Qualification tests © Copyright CM Plus Corporation. EA-05-02-00 26 . All Rights Reserved.  Sign off. EA-05-02-00 27 .Conti… OQ protocols to be written and approved prior to completion. (Compliance Certificate by Engineering Dept & QA) © Copyright CM Plus Corporation. It includes following:  All relevant SOPs should be in place  Temperature measurement report  Humidity measurement report  Differential pressure measurement report  Air flow direction measurement report  Room particle count measurement report  All maintenance/ cleaning instructions available  All O&M staff to be trained to use and maintain the system. EA-05-02-00 28 . © Copyright CM Plus Corporation. • PQ should follow successful completion of IQ and OQ. • PQ verifies that the critical parameters.Performance Qualification • The purpose of PQ is to verify and document that an HVAC system provides acceptable control under ‘Full Operational’ conditions. All Rights Reserved. as defined in the DQ are being achieved. Conti… PQ should include • Test to include a condition or set of conditions encompassing upper and lower operating limits. condition either or simulated as close as possible to the actual process © Copyright CM Plus Corporation. EA-05-02-00 29 . • Tests should be conducted under “in use”. All Rights Reserved. EA-05-02-00 30 . (under manufacturing conditions) • PQ and OQ tests are sometimes performed in conjunction with one another. All Rights Reserved. • Any changes to the HVAC system should be revalidated before proceeding to the PQ phase. © Copyright CM Plus Corporation.Conti… • PQ is used to demonstrate consistent achievement of critical parameters over time. • Filter Integrity Testing (HEPA Leak test) • Pressure Differentials • Particulate count measurement • Temperature and Relative Humidity • Air Flow Pattern • Microbial Count • Recovery test © Copyright CM Plus Corporation.Validation Parameters • Air flow measurement • Room air changes per hour. EA-05-02-00 31 . All Rights Reserved. © Copyright CM Plus Corporation.• Air flow measurement • Room air changes per hour. EA-05-02-00 32 . All Rights Reserved. • Filter Integrity Testing (HEPA Leak test) © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 33 . • © Copyright CM Plus Corporation. All Rights Reserved. Pressure Differentials EA-05-02-00 34 . • © Copyright CM Plus Corporation. All Rights Reserved. Particulate count measurement EA-05-02-00 35 . All Rights Reserved.• © Copyright CM Plus Corporation. Temperature and Relative Humidity EA-05-02-00 36 . All Rights Reserved.• © Copyright CM Plus Corporation. Air Flow Pattern EA-05-02-00 37 . Microbial Count EA-05-02-00 38 .• © Copyright CM Plus Corporation. All Rights Reserved. All Rights Reserved.• © Copyright CM Plus Corporation. Recovery test EA-05-02-00 39 . • Sample Volume • 1 cubic ft (or 1 cubic meter) • Sample Time • 1 Min 40 © Copyright CM Plus Corporation. NON-VIABLE PARTICLE COUNTS • Equipment • Optical Particle Counter (Discrete Particle Counter) • Air sample is drawn into the instrument & passed through light scattering device.Conti… A. The signal that this generates is electronically processed to display particle counts at different size ranges. All Rights Reserved. PHYSICAL TESTS A1. EA-05-02-00 40 . Conti… • Frequency: GMP compliance:. EA-05-02-00 41 .Quarterly Sch M . Critical environments: The particle concentration under the dynamic condition should not more than 100 particle of 0.6 Monthly • Acceptance criteria: 1. All Rights Reserved.5µm and larger per cubic meter (for class 100 area) © Copyright CM Plus Corporation. EA-05-02-00 42 .  Incline manometer 42 © Copyright CM Plus Corporation. PRESSURE DIFFERENTIALS – Introduction ● Correct degree of overpressure can be maintained relative to the adjacent areas of lower classification to ensure that air moves from clean areas to less clean areas.Conti… A2. All Rights Reserved. – Equipment  Electronic manometer (portable and easy to use). EA-05-02-00 43 . 43 © Copyright CM Plus Corporation. o Frequency of sampling Continuously by gauges / manometer & recorded daily. All Rights Reserved.Conti… o Sample location  Between adjacent areas connected either by a door or grille. Conti… o Acceptance Criteria • > 10 Pa between classified area & adjacent area of lower classification • > 15 Pa between classified area & unclassified area o Action • HEPA filter blockage • Increase fan speed • Increase air flow to specific area by altering dampers © Copyright CM Plus Corporation. All Rights Reserved. EA-05-02-00 44 . 45 + 20% (for Horizontal flows)  No value may deviate from the mean by more than +20 % © Copyright CM Plus Corporation.  Repeat twice at each location  For Grade A laminar flow workstations.  Record velocity reading from all the four corners and the Centre of the filter surface. AIRFLOW VELOCITY  Equipment: Anemometer  Reading should be taken 10cm from the surface of filter.3 meter per second + 20% (for vertical flows) and 0. All Rights Reserved.Conti… A3. the air flow rates shall be 0. EA-05-02-00 45 . • Air velocity below the limit may be insufficient to maintain critical work zone protection. All Rights Reserved.Conti… • Air velocity exceeding the stated value may cause excessive air movement & affect work zone protection. • Deviation indicates the blockade of filter Solution: Alteration of fan speed or HEPA filter replacement © Copyright CM Plus Corporation. EA-05-02-00 46 . seals and no leakage of particles. Aerosol generator 2. All Rights Reserved. EA-05-02-00 47 . © Copyright CM Plus Corporation.  Make separate passes at peripheries. HEPA filter integrity test (DOP test)  Purpose : To confirm that no damage to filter.Conti… A4.  Equipment : 1. Photometer  Scan at 1 inch from filter surface. Conti… • Acceptance criteria: An unacceptable leak is defined as a penetration of 0. EA-05-02-00 48 .03% or more of particle. All Rights Reserved.97% efficient filter © Copyright CM Plus Corporation. 0.3µm and larger than the reference calibration curve for 99. Conti… A5.  Sling the psycrometer in air for about a minute’s time and record the dry bulb and wet bulb temperature. difference between dry bulb and wet bulb temperature. EA-05-02-00 49 . All Rights Reserved.e.  Check the wick of the sling psycrometer.  Check the wet bulb depression i. Temperature and Relative Humidity:  Use a sling psycrometer to measure the dry bulb and wet bulb temperature of the air. it should be always in wet conditions in order to record correct wet bulb temperature. © Copyright CM Plus Corporation. Conti…  Acceptance criteria: Temperature: 27oC Humidity: 45 ~ 55%  Frequency : Daily © Copyright CM Plus Corporation. EA-05-02-00 50 . All Rights Reserved. Conti… A6. All Rights Reserved. • The ACR can be determined by measuring the mean air velocity at the supply HEPAs or grilles and calculating the air change rate based on the mean air supply volume. © Copyright CM Plus Corporation. • This gives some idea as to how quickly contamination may be removed from the clean room provided there is acceptable mixing of air in the room. EA-05-02-00 51 .Air change rate: • Measurement of the air supply volume and determination of the air change rate (ACR) is a measure of the frequency of air turnover in the clean room. 6 Monthly GMP compliance – Quarterly © Copyright CM Plus Corporation.Conti…  Equipment: Anemometer  Sample locations At least four positions are tested across the filter or face to obtain the mean supply air velocity. EA-05-02-00 52 . All Rights Reserved. grille  Frequency of sampling Sch M . MICROBIOLOGICAL TESTS  Solid growth media (e.g.Conti… A7. settle and contact plates) Soybean Casein Digest Agar medium can be used for both Bacteria & Fungi tested. EA-05-02-00 53 .  The recommended size of solid media is 90 mm in diameter (for settle plates)  55 mm for contact plates. © Copyright CM Plus Corporation. All Rights Reserved. at 30 . EA-05-02-00 54 . All Rights Reserved.350C for at least 2 days is suitable for the growth of bacteria. © Copyright CM Plus Corporation.Conti… • Sampling condition: • Sampling in the at rest condition may be continued at an agreed frequency to monitor baseline contamination levels • The operational conditions and the activities being performed at the time of testing should be recorded • Incubation condition: • Incubation of samples. • Incubation of samples. inverted. inverted. at 20 – 25o C for at least 5 days is suitable for the growth of mould and fungi. 9cm2. or 2 in2 (FDA Aseptic Processing Guidelines) © Copyright CM Plus Corporation.Conti…  Acceptance criteria for Airborne Bioburden test: Critical Environment: no more than 1 CFU/m3.03 CFU/ft3(USP monograph)  Acceptance criteria for Surface Bioburden test: Critical Environment: no more than 1 CFU/12. or 0. EA-05-02-00 55 . All Rights Reserved. All Rights Reserved. No. edited by Fredrick J. sterile product 2ndEdition. (2006) • Validation of pharmaceutical process.240-256. Agalloco.Series. James P. (WHO Technical Report. 937). Annex 2. Carleton.References • Supplementary guidelines on good manufacturing practices for HVAC systems for non-sterile pharmaceutical dosage forms. EA-05-02-00 56 . © Copyright CM Plus Corporation. page no. EA-05-02-00 57 .THANK YOU FOR YOUR ATTENTION © Copyright CM Plus Corporation. All Rights Reserved.