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INTRODUCTIONTo understand: The need and reason for pharmaceutical air handling systems. The technical requirements for air handling systems. Different types of air handling systems. Qualification and Validation requirements 3
WHAT IS CLEAN ROOM? A room in which the concentration of airborne particle is controlled and which is constructed and used in a manner to minimize the introduction, generation and retention of particles inside the room and in which other relevant parameters. e.g.. Temperature, humidity and pressure, are controlled as necessary. (ISO 14644-1) 4
WHY CLEAN ROOM NECESSARY?It controls 3 types of contamination transfer Air borne contamination Direct contamination by personnel, equipment etc. Contamination from fluids like cleaning fluids, solutions etc.As airborne particulate are reduced, chances of particles entry in the process reduced. 5Protects product, personnel & environment.
HOW IT IS ACCOMPLISHED? • A clean room is continuously flushed with highly filtered air that is forced in through HEPA filters. 6
TYPES OF CLEAN ROOMS Horizontal Clean Room – Horizontal Laminar flow (HEPA filters in a wall force clean air from one side of the room to other.) Vertical Clean Room – Vertical Laminar flow (HEPA filters on the ceiling push clean air down to the floor.) 7
FOUR BASIC PRINCIPLES OF CLEANROOM Not To Bring Any Dust Not To Accumulate Any Dust Not To Generate Any Dust To Remove Any Dust Quickly 8
INTRODUCTIONAir handling systems, Play a major role in the quality of pharmaceuticals. Must be designed properly, by professionals. Must be treated as a critical system. 9
INTRODUCTION The manufacturing environment is critical for product quality. Environment consists of, Light Temperature Humidity Air movement Microbial contamination Particulate contamination Uncontrolled environment can lead to product degradation product contamination 10 loss of product and profit
US FDA 21 CFR part 211 (Requirement for building & Facilities)Under 211.42 (c)Operation shall be performed within the specifically defined areas and such other controls, necessary to prevent contamination or mix ups.Temperature and Humidity controlled.An air supply filtered through HEPA filter under positive pressure.A system of monitoring environmental conditions.Under 211.46 (C)Air filtration system, including pre-filters and particulate matter air filtration shall be used when 12 appropriate on air supplies to production areas.
EU GUIDELINES(PREMISES & EQUIPMENT) Under 3.12, Production areas shall be effectively ventilated with air control facilities including temperature & where necessary humidity and filtration. 13
SCHEDULE – MPART – 1 (GMP FOR PREMISES ANDMATERIALS)Under point 8.21,The licensee shall prevent mix-ups and cross contamination of Drug Materials and Drug Products (from environment dust) by proper air handling system. Part 1A (GMP for Sterile preparation) Section 3 – Details of HVAC system Section 4 – Parameterrs for Validation and 14 Frequency of Monitoring
INTRODUCTION HVAC (AHU) is HEART of Pharmaceutical Industries 15
INTRODUCTION Area - 1 I Area - 2 M 9 P 0 U HVAC R %Impure Air Pure Air Area - 3 E A I Area - 4 R 10% Return Air Impure Air 16Exhaust
CONTAMINATION W are contaminants ? hat Contaminants are 1. Products or substances other than the product being manufactured. 2. Foreign products. 3. Particulate matter. 4. Micro-organisms. 5. Endotoxins (degraded micro-organisms). Cross-contamination is a particular case of 17 contamination
CONTAMINATIONCross-ContaminationFrom where does Cross-Contamination originate?1. Poorly designed air handling systems and dust extraction systems2. Poorly operated and maintained air handling systems and dust extraction systems 183. Inadequate procedures for personnel and equipment
CONTAMINATIONCross-contamination can be minimized by:1. Personnel procedures2. Adequate premises3. Use of closed production systems4. Adequate, validated cleaning procedures5. Appropriate levels of protection of product6. Correct air pressure cascade 19
AIR FLOW PATTERNSWorkbench (vertical) Cabin/ booth Ceiling 21
HVAC QUALIFICATIONTo ensure that equipment is designed as per requirement, installed properly.Action of proving that any equipment works correctly and leads to the expected results. 22
HVAC QUALIFICATION N TIO CA I LIF QU VALIDATION 23
HE VALIDATION MASTER PLAN This document should contain • Validation policy Organizational structure of validation activities Summary of facilities, systems, equipment and processes to be validated Documentation format to be used for protocols and reports Planning and scheduling 24 Change control References to documents
USER REQUIREMENTSPECIFICATION Capacity of HVAC depends on, 1.Room Volume. 2.No. of Air Changes Required. 3.Production / Consumption Data 4.Seasonal fluctuation. 5.Air Classification of Rooms. 6.Future Development. 26
USER REQUIREMENTSPECIFICATIONParameters to be defined in Levels of Protection :Air cleanliness requirements1. filters type and position,2. air changes,3. air flow patterns,4. pressure differentials,5. contamination levels by particulate matter & micro-organisms. 27• User Requirement Specification should be approved by Production, Engineering and
DESIGN QUALIFICATION Based on the URS supplier designs the equipment-First step in the qualification of new HVAC systems. It documents the design of the system and will include : 1. Functional Specification. 2. Technical / Performance specification for equipment. 3. Detailed Air Flow Schematics. 4. Detailed layout drawing of the system. 28
DESIGN QUALIFICATIONCompliance with GMPs and other regulatory requirements.Ensures that design, 1. meets the user requirements. 2. details facility airflow and pressure cascade philosophy. 3. takes into account process and personnel flow (cross-contamination issues) 4. Details materials of construction. 5. Details safety requirements. 6. Full details of the intended construction prior to implementation. 29 7. Details all equipment that must be ordered.
INSTALLATION QUALIFICATION IQ Should include, Instrumentation checked against current engineering drawings and specifications Verification of materials of construction Installation of equipment and with piping Calibration of measuring instruments requirements Collection and collation of supplier operating and working instructions and maintenance requirements 31
INSTALLATION QUALIFICATION Practical aspect of IQ (Cont….) Calibration of measuring instruments. Calibration of additionally used instruments. Initial cleaning records. Basic commissioning checks. Maintenance requirements. IQ process checks that the correct components are installed in the correct location. Materials of construction 32 Spare parts Change controls
INSTALLATIONQUALIFICATION IQ Document should contain, Instrument name, model, I.D. No., Personnel responsible for activities and Date. A fully verified installation that complies with the documented design. (all deviations will have been recorded and assessed.) All equipment documentation and maintenance requirements would be documented. 33 Completed calibration of measuring instruments.
OPERATION QUALIFICATIONISPE definition : The purpose of OQ is to establish, through documented testing, that all critical components are capable of operating within established limits and tolerances.The purpose of OQ is to verify and document that an HVAC system provides acceptable operational control under “at-rest” conditions. 34
OPERATION QUALIFICATION 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.Ability to maintain any critical parameters stated in the DQ consistently. 35
OPERATION QUALIFICATIONIncludes the tests that have been developed from knowledge of processes, systems and equipment.Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as ‘worst case’ conditions. 36
OPERATION QUALIFICATION IQ reports must be completed and signed off. OQ protocols to be written and approved prior to completion. Measurement reports are required to demonstrate achievement of critical parameters as detailed in DQ.Eg: * 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 37 * All drawings etc. – done in ‘as-built’ status * All maintenance/ cleaning instructions available * All O & M staff to be trained to use and maintain the
PERFORMANCE QUALIFICATION The purpose of PQ is to verify and document that an HVAC system provides acceptable control under ‘ Full Operational ‘ conditions. PQ should follow successful completion of IQ and OQ. PQ verifies that over time, the critical parameters, as defined in the DQ are being achieved. 38
PERFORMANCE QUALIFICATION PQ Should include,Tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and facilities, systems or equipment.Test to include a condition or set of conditions encompassing upper and lower operating limits.PQ is used to demonstrate consistent achievement of critical parameters over time. 39 ( under manufacturing conditions)
QUALIFICATIONCOMPLETE DOCUMENTATIONVerification of design documentation, including Description of installation and functions Specification of the requirementsInstructions for performance controlOperating proceduresMaintenance instructionsMaintenance recordsTraining of personnel (program and records)Environmental records 40Discussion on actions if OOS valuesWalking around the plant
VALIDATIONDocument act of proving that any procedure, process, system / equipment ACTUALLY leads to expected results. To ensure that system provides continuously required environmental conditions. 41
VALIDATION PARAMETERS 1. Air flow measurement 2. Room air changes per hour. 3. Filter Integrity Testing (HEPA Leak test) 4. Pressure Differentials 5. Particulate count measurement 6. Recovery test 7. Temperature and Relative Humidity 8. Air Flow Pattern 9. Microbial Count 42
VALIDATION PARAMETERSA. PHYSICAL TESTS A1. NON-VIABLE PARTICLE COUNTS•Equipment •Optical Particle Counter (Discrete Particle Counter) •Air sample is drawn into the instrument & passed through light scattering device. The signal that this generates is electronically processed to display particle counts at different size ranges.•Sample Volume •1 cubic ft•Sample Time 43 •1 Min
VALIDATION PARAMETERS Sample Location (ISO 14644) No. of sampling location = NLT Sq. Rt.A Where A = Area of entrance plan in Sq.Meter No. of location rounded to nearest higher integer Minimum location 3 Evenly distributed within the area under test and at a position related to the working activity (typically at bench height 1m from the 44 floor and NMT 1 Ft from work station.).
VALIDATION PARAMETERSFrequency Sch M - 6 Monthly GMP compliance – QuarterlyAcceptance Criteria AT REST IN OPERATION Grade Maximum number of permitted particles per cubic metre equal to or above 0.5µ 5.0µ 0.5µ 5.0µ A 3520 29 3500 29 B 35,200 293 3,52,000 2930 C 3,52,000 2,930 35,20,000 29,300 D 35,20,000 29,300 Not defined Not defined 45
VALIDATION PARAMETERS A2. 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. Equipment Electronic manometer (portable and easy to use), Incline manometer Sample Location Between adjacent areas connected either by a door or grille. 46 Frequency of sampling Continuously by gauges / manometer &
VALIDATION PARAMETERS – Acceptance Criteria > 10 Pa between classified area & adjacent area of lower classification > 15 Pa between classified area & unclassified area – Action HEPA filter blockage Increase fan speed Increase air flow to specific area by altering dampers 47
VALIDATION PARAMETERS A3. AIRFLOW VELOCITY Equipment :- Anemometer. Reading should be taken 10cm from the surface of filter. Record velocity reading from all the four corners and the Centre of the filter surface. Repeat twice at each location For Grade A laminar flow workstations, the air flow rates shall be 0.3 meter per second + 20% (for vertical flows) and 0.45 + 20% (for 48 Horizontal flows)
VALIDATION PARAMETERSAir velocity exceeding the stated value may cause excessive air movement & affect work zone protection.Air velocity below the limit may be insufficient to maintain critical work zone protection. Action: Deviation indicates blockage of filter Solution : Alteration of fan speed HEPA filter replacement 49
VALIDATION PARAMETERS A4. HEPA FILTER INTEGRITY TEST (DOP Test) Purpose : To confirm that there is no damage to filter, seals and there is no leakage of particles. Equipment : 1. Aerosol generator (Using Dioctylphthalate) 2. Photometer Scan at 1 inch from filter surface. Traverse at NMT 10Ft. Min. Cover entire range. Make separate passes at peripheries. 50
VALIDATION PARAMETERS A5. TEMPERATUR & RELATIVE HUMIDITY E Use a sling psycrometer to measure the dry bulb and wet bulb temperature of the air. Check the wick of the sling psycrometer, it should be always in wet conditions in order to record correct wet bulb temperature. Sling the psycrometer in air for about a minute’s time and record the dry bulb and wet bulb temperature. Check the wet bulb depression i.e. difference between dry bulb and wet bulb temperature. 51 Refer the psycrometric chart to check the
VALIDATION PARAMETERS A6. AIR CHANGE R ATE (ACR)Introduction Conventional clean rooms operate on the principle that the air supplied to the room is of sufficient quantity to dilute or remove the contamination generated within the room. 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. 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. 53 The ACR can be determined by measuring the mean air velocity at the supply HEPAs or grilles and
VALIDATION PARAMETERSEquipment AnemometerSample locations At least four positions are tested across the filter or grille face to obtain the mean supply air velocity.Frequency of sampling Sch M - 6 Monthly GMP compliance – Quarterly 54
VALIDATION PARAMETERS Results and interpretation of results The ACR (per hour) can be calculated using the following formula: ACR = Air supply volume (m³/s) x 3600/ Room volume (m³) Air Volume = Sum ( Avg. Velocity x Filter area) Where there is more than one supply HEPA in a room the air supply volume for each filter should be determined and the volumes summed (to give a total air supply volume) before multiplying by 3600 55 and dividing by the room volume.
VALIDATION PARAMETERS Requirement : Class B = 60, C & D = 20 ACPH Action • Change the filter • ACR to be rebalanced B. MICROBIOLOGICAL TESTS Solid growth media (e.g. settle and contact plates) Soybean Casein Digest Agar medium can be used for both Bacteria & Fungi tested. The recommended size of solid media is 90 56 mm in diameter (for settle plates) 55 mm (surface area 25 cm²) for contact
VALIDATION PARAMETERS• Sampling conditions 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 conditions Incubation of samples, inverted, at 20 - 25C for at least 5 days is suitable for the growth of mould and fungi. 57 Incubation of samples, inverted, at 30 - 35C for at least 2 days is suitable for the growth of
VALIDATION PARAMETERS Recommended Limits for microbiological monitoring of clean areas Total Viable Count (Guidelines) Conditions : In operationGrade EU Schedule – M US Air Sampling (90mm / 4 Hrs) (90mm / 2 Hrs) (90mm / 4 Hrs) (1000cc) A <1 <1 <1 <1 B <10 <5 <3 <7 58
REFERENCES1. “Validation in pharmaceutical industry” ; edited by P.P. sharma ;first edition 2007 ; 169-1922. “Pharmaceutical Process Validation”; An international 3rd edition; edited by R. A. Nash and A. H. Wachter; 413-432 59
GTU QUESTIONS • Describe validation parameters of HVAC system 60