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Pharm Sem -II Roll no:13 Department of Quality Assurance Guided By: Mr. Jignesh Shah S.J.Thakkar Pharmacy College, Rajkot . 1Slide 2: 2 CONTENTS Introduction AHU HVAC Qualification Validation parameterINTRODUCTION: INTRODUCTION To 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 3WHAT IS CLEAN ROOM? : WHAT IS CLEAN ROOM? 4 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)WHY CLEAN ROOM NECESSARY? : 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. Protects product, personnel & environment. Avoid rejection thereby heavy losses in terms of money & time 5HOW IT IS ACCOMPLISHED? : HOW IT IS ACCOMPLISHED? A clean room is continuously flushed with highly filtered air that is forced in through HEPA filters. 6TYPES OF CLEAN ROOMS : 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.) 7FOUR BASIC PRINCIPLES OF CLEAN ROOM : FOUR BASIC PRINCIPLES OF CLEAN ROOM Not To Bring Any Dust Not To Accumulate Any Dust Not To Generate Any Dust To Remove Any Dust Quickly 8INTRODUCTION: INTRODUCTION Air handling systems, Play a major role in the quality of pharmaceuticals. Must be designed properly, by professionals. Must be treated as a critical system. 9INTRODUCTION: 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 loss of product and profit 10INTRODUCTION: INTRODUCTION HVAC 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 11US FDA: 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 appropriate on air supplies to production areas. 12EU GUIDELINES (PREMISES & EQUIPMENT): EU GUIDELINES (PREMISES & EQUIPMENT) Under 3.12, Production areas shall be effectively ventilated with air control facilities including temperature & where necessary humidity and filtration. 13SCHEDULE – M PART – 1 (GMP FOR PREMISES AND MATERIALS): SCHEDULE – M PART – 1 (GMP FOR PREMISES AND MATERIALS) 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 Frequency of Monitoring 14INTRODUCTION: INTRODUCTION HVAC (AHU) is HEART of Pharmaceutical Industries 15INTRODUCTION: INTRODUCTION HVAC Area - 1 Area - 2 Area - 3 Area - 4 Impure Air I M P U R E A I R Impure Air Pure Air 90% 10% Return Air Exhaust 16CONTAMINATION: CONTAMINATION What are contaminants ? Contaminants are Products or substances other than the product being manufactured. Foreign products. Particulate matter. Micro-organisms. Endotoxins (degraded micro-organisms). Cross-contamination is a particular case of contamination 17CONTAMINATION: CONTAMINATION Cross-Contamination From where does Cross-Contamination originate? Poorly designed air handling systems and dust extraction systems Poorly operated and maintained air handling systems and dust extraction systems Inadequate procedures for personnel and equipment Insufficiently cleaned equipment 18CONTAMINATION: CONTAMINATION Cross-contamination can be minimized by: Personnel procedures Adequate premises Use of closed production systems Adequate, validated cleaning procedures Appropriate levels of protection of product Correct air pressure cascade 19AIR FLOW PATTERNS: AIR FLOW PATTERNS Prefilter AHU Main filter Uni-directional Turbulent Turbulent 1 2 3 20Slide 21: 21 Workbench (vertical ) Cabin/ booth Ceiling AIR FLOW PATTERNSHVAC QUALIFICATION: HVAC QUALIFICATION To 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: HVAC QUALIFICATION QULIFICATION VALIDATION 23: 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 Change control References to documents THE VALIDATION MASTER PLAN 24USER REQUIREMENT SPECIFICATION: USER REQUIREMENT SPECIFICATION It mainly requires: Room temperatures and relative humidities Clean room classifications for the areas i.e. B. C. or D. Single pass or re-circulated HVAC systems ? Room pressures / Air flow directions GMP requirements. 25USER REQUIREMENT SPECIFICATION: USER REQUIREMENT SPECIFICATION Capacity of HVAC depends on, Room Volume. No. of Air Changes Required. Production / Consumption Data Seasonal fluctuation. Air Classification of Rooms. Future Development. 26USER REQUIREMENT SPECIFICATION: USER REQUIREMENT SPECIFICATION Parameters to be defined in Levels of Protection : Air cleanliness requirements filters type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter & micro-organisms. User Requirement Specification should be approved by Production, Engineering and QA Heads. 27DESIGN 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 QUALIFICATIONDESIGN QUALIFICATION: DESIGN QUALIFICATION Compliance 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. 7. Details all equipment that must be ordered. 29INSTALLATION QUALIFICATION: INSTALLATION QUALIFICATION System Description Equipment Delivery Utilities / Facility / Environment Assembly & Installation 30INSTALLATION QUALIFICATION: 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 31INSTALLATION QUALIFICATION: 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 Spare parts Change controls 32INSTALLATION QUALIFICATION: INSTALLATION QUALIFICATION 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. Completed calibration of measuring instruments. Verification of Materials of construction. 33OPERATION QUALIFICATION: OPERATION QUALIFICATION ISPE 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. 34OPERATION QUALIFICATION: 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. 35OPERATION QUALIFICATION: OPERATION QUALIFICATION Includes 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. 36OPERATION QUALIFICATION: 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 * 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 system. * Sign off. (Compliance Certificate by Engineering Dept & QA) 37PERFORMANCE QUALIFICATION: 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. 38PERFORMANCE QUALIFICATION: 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. ( under manufacturing conditions) PQ is ongoing. 39QUALIFICATION COMPLETE DOCUMENTATION: QUALIFICATION COMPLETE DOCUMENTATION Verification of design documentation, including Description of installation and functions Specification of the requirements Instructions for performance control Operating procedures Maintenance instructions Maintenance records Training of personnel (program and records) Environmental records Discussion on actions if OOS values Walking around the plant Finally certification (Sign Off) by Engineering, User (Production) and QA Heads. 40VALIDATION: VALIDATION Document act of proving that any procedure, process, system / equipment ACTUALLY leads to expected results. To ensure that system provides continuously required environmental conditions. 41VALIDATION PARAMETERS: VALIDATION PARAMETERS Air flow measurement Room air changes per hour. Filter Integrity Testing (HEPA Leak test) Pressure Differentials Particulate count measurement Recovery test Temperature and Relative Humidity Air Flow Pattern Microbial Count 42VALIDATION PARAMETERS : VALIDATION PARAMETERS A. 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 1 Min 43Slide 44: 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 floor and NMT 1 Ft from work station.). VALIDATION PARAMETERS 44: Frequency Sch M - 6 Monthly GMP compliance – Quarterly Acceptance Criteria VALIDATION PARAMETERS 45Slide 46: 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. Frequency of sampling Continuously by gauges / manometer & recorded daily. VALIDATION PARAMETERS 46: 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 VALIDATION PARAMETERS 47: 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 Horizontal flows) * No value may deviate from the mean by more than + 20 % VALIDATION PARAMETERS 48: Air 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 VALIDATION PARAMETERS 49: 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. TEMPERATURE & RELATIVE HUMIDITY 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. Refer the psycrometric chart to check the relative humidity corresponding to the dry bulb temperature and wet bulb depression. 51 VALIDATION PARAMETERS: ACCEPTANCE CRITERIA Temperature : NMT 27 degree centigrade Humidity : NMT 55 % FREQUENCY :Daily 52 VALIDATION PARAMETERSSlide 53: A6 . AIR CHANGE RATE ( 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. 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 or by using a flow measuring hood which collects all of the air from the supply and gives an air supply volume directly. a 53 VALIDATION PARAMETERSSlide 54: Equipment Anemometer Sample 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 and dividing by the room volume. To achieve the level of cleanliness in an aseptic room and a clean support room the ACR should be greater than 20 air changes per hour. 55 VALIDATION PARAMETERSVALIDATION PARAMETERS : 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 mm in diameter (for settle plates) 55 mm (surface area 25 cm²) for contact plates. 56: 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. Incubation of samples, inverted, at 30 - 35C for at least 2 days is suitable for the growth of bacteria. VALIDATION PARAMETERS 57VALIDATION PARAMETERS: VALIDATION PARAMETERS Total Viable Count (Guidelines) Conditions : In operation Grade 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 C <100 <50 <5 <10 D <200 <100 <50 <100 58 Recommended Limits for microbiological monitoring of clean areasREFERENCES: REFERENCES “Validation in pharmaceutical industry” ; edited by P.P. sharma ;first edition 2007 ; 169-192 “Pharmaceutical Process Validation” ; An international 3 rd edition; edited by R. A. Nash and A. H. Wachter ; 413-432 59GTU QUESTIONS: GTU QUESTIONS Describe validation parameters of HVAC system 60Slide 61: Thanks 61 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.