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AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING

AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING. A presentation By Pharm R.A.BINITIE Assistant Director Drug Evaluation and Research Directorate NAFDAC. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING. OUTLINE INTRODUCTION OBJECTIVES REGULATORY IMPERATIVE APPLICATIONS

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AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING

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  1. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING A presentation By Pharm R.A.BINITIE Assistant Director Drug Evaluation and Research Directorate NAFDAC

  2. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING OUTLINE • INTRODUCTION • OBJECTIVES • REGULATORY IMPERATIVE • APPLICATIONS • HVAC SYSTEM • PRODUCT PROTECTION • CONCLUSION • REFERENCES

  3. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING INTRODUCTION (I) • Air handling system plays a major role in the quality of pharmaceutical product manufacturing( all types). • It is the technology of indoor and manufacturing space environmental control and or comfort • It regarded as one of the most important utility in drug product manufacturing (a critical system) • The manufacturing environment or space is very critical to product quality and is premised / dependent on the air handling system which controls the level of containment ( pressurization)and cleanliness( room classification)

  4. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING INTRODUCTION (II) • The uncontrolled environment can lead to product degradation, loss of product, and economic issue-profit , product contamination/cross contamination • The manufacturing environment is critical for products and considers these factors(GMP environment) :light , temp, humidity, air movement, microbial contamination, particulate contamination, • Air handling system to satisfy GMP/regulatory requirements must be suitably designed, installed, qualified/Validated, monitored and maintained by professionals ( GEP)

  5. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING OBJECTIVES • To understand the need for air handling system in the pharmaceutical industry • The technical requirements for air handling system • Different types of air handling system • Qualification and validation of HVAC system • Monitoring and maintenance

  6. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING WHY AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING • Needed to condition and provide the ideal GMP environment or air space cleanliness needed for the various pharmaceutical processes and controls in manufacturing . • A critical factor of Quality Assurance for pharmaceutical products( Clean areas/space for manufacturing) • Issue of personnel comfort, satisfaction and safety • As a means of containment control ( airborne particulate)and prevent Contamination and cross contamination • Avoid product rejection Contamination only mentioned in the presentation

  7. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING REGULATORY IMPERATIVES • NAFDAC cGMP Regulatory Guidelines for Pharmaceutical Products 2106 – entrenches/prescribes Air handling system in manufacturing; viz Sections 3.20 : Production areas Section 3.22 : Dust Controls Section 3.25 : Storage of equipment air requirement Section 3.26 : Air Supply to manufacturing space and laboratory operations. Section: laboratory design(for microbiology section) Section 3.28: storage area for materials Section 3.42-3.46 : HVAC system section 4.3a-d: Qualification & Validation ( equipment and utilities) etc Other sections not included on this slide

  8. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING APPLICATIONS OF AIR HANDLING SYSTEM An ideal cGMP environment for manufacturing (HVAC system) should provide: • Product protection: protect from contamination , cross contamination, prevent contamination by operatives, correct conditions of humidity and temperature. • Personnel protection: prevent contact with dust, prevent contact with fumes, good comfort condition • Environment protection: No dust discharge, no fumes discharge, no effluent discharge • Preservation of materials and equipment Handling, holding and storage • Maintenance of animals and equipment • The GMP environment is only possible with an Air Handling System

  9. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING WHAT IS AIR HANDLING SYSTEM • Air handling system is regard as HVAC and refers to Systems which are mechanical arrangements that treats outside air to produce cleaned (from dust and microbes) conditioned air ( temperature and humidity) which is circulated or re-circulated for use in controlled and critical areas within the pharmaceutical manufacturing space • OR • Can be simply said to be a utility system used to provide air ventilation, heating, cooling and air conditioning services to a building or a pharmaceutical space for drug manufacturing • The Acronym HVAC means: H= Heating, V= Ventilation; A= Air; C= Conditioning

  10. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING HVAC SYSTEM • HVAC system comprises of Air Handling Unit ( AHU) connected to a ductwork ventilation system that distributes the conditioned air through the building and returns it to the air handler(AHU). • Air Handling Unit (AHU) is a device used to condition and circluate air as a part of HVAC. It is usually a large metal box containing a blower, heating or cooling elements, filter racks or chambers, sound attenuators and dampers

  11. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING INSIDE AN AIR HANDLING UNIT

  12. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING SCHEMATIC OF AIR HANDLING UNIT (AHU) AHU SECTION

  13. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING AIR HANDLING SYSTEM/HVAC COMPONENTS • Ducting ( for delivery of controlled air) • Fan component • Vibration isolator (flex joint) • Heating and /or coiling coil • Filter compartment ( houses pre and post filters) • HEPA Filter • Mixed (re-circulated + outside ) air duct • Louvers ( Weather) • Damper ( fixed adjustment of volume of air) • Dehumidifiers • Flow rate controller • Humidity, Temperature, Pressure sensors, alarms and audit log system • Dust extractors

  14. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING

  15. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING TYPICAL INSTALLATION OF AHU UNIT (VISUAL)

  16. Exhaust air treatment Fresh air treatment (make-up air) Terminal air treatment at production room level + Production Room Central air handling unit AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING HVAC MAIN SUBSYSTEMS

  17. OVERVIEW OF HVAC COMPONENTS Flow rate controller Silencer Fan Filter Weather louvre Control damper + Humidifier Prefilter Terminal filter Production Room Cooling coil with droplet separator Heating coil AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING

  18. Adsorber wheel Humid room air Regeneration air Humid room air Air heater AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING Air-handling unit Control damper for airflow AHU with fan Variable Speed Controller Filter Pressure Gauges

  19. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING CHARACTERISTICS OF AIR HANDLING SYSTEM/HVAC • Turbulent air flow ( air flow pattern) • Unidirectional airflow ( air flow pattern) • Filter position ( Terminal Position, air recirculation system) • Fresh air (100%)/Once through / external air • Air re-circulation • Return air systems (positions low wall air return) • Overpressure requirements • Local extraction system( deduster, canister)

  20. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING FUNCTIONS OF AIR HANDLING SYSTEM (HVAC) • Control airborne particulate , dust and micro-organisms through air filtration using HEPA filters • Maintains room pressures ( in areas that must remain cleaner that surrounding areas (+ve) • Reduces contamination by air flow from cleaner areas toward adjoining space through doors, , ceiling openings ( reduces chances of contamination) • Maintains space moisture RH(by cooling to due point temperature and using desiccant dehumidifiers) • Maintains space temperature ( can affect product directly or indirectly) All to minimise and prevent contamination and cross contamination

  21. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING WHAT CAN AIR HANDLING SYSTEM NOT DO • Cannot clean up contaminated surfaces, room or equipment • Do not compensate for workers who do not follow procedures

  22. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING QUALITIES AND ATTRIBUTES OF A GOOD HVAC SYSTEM • Suitably designed, installed, Qualified / validated and maintained (GEP) to meet GMP requirements for the intended purpose • Reliable and economical to run • Supported by appropriate documentation (lay outs, SOPs, reports of commissioning, qualification and validation, monitoring and maintenance records etc

  23. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING CLEAN AIR SUPPLY CONCEPTS There are two basic concepts of clean air delivery for pharmaceutical production: • Full Fresh air or Make up air • Recirculation or Return air All to provide the need conditioned clean air for intended clean room required for manufacturing areas. What is clean area/ room/space? • A closed room supplied with filtered ( purified air ) in which the particulate and microbial contamination load is below specified level. And is used in such a way to minimise introduction, generation and retention of contaminants

  24. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING CLEAN AREA/ROOM CONSIDERATIONS • All pharmaceutical facilities belong to one/ certain or other class of clean rooms • Facility classification are based on clean air supply that matches the requirement for manufacturing process/product • Clean rooms classification differs for sterile and non sterile and can be classified as such: • Non sterile operations/controlled or non aseptic • Sterile operation/critical areas/aseptic applications • Examples of clean room requirements for some product lines: eg tablets class D (10,000) topical and oral liquids belong to class C(10,000) sterile preparations/injectable – class A or B(100)

  25. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING CLEAN AREA CLASSIFICATION CONSIDERATIONS • Clean Room Classification defined in the state of “as built”, “at rest ,” or “in-operation” • Clean rooms are also Categorized by way of which supply air is distributed : • Generally two air configuration: Unidirectional -UDAF (Laminar) LAF or RLAF) . This achieved by Vertical down displacement of room air or by horizontal laminar flow) – defined air velocity • Or Non –Unidirectional air flow • EU classification is based on alphabet system A,B,C,D; FDA numerical eg class 100; 1000; 10,000; and 100,000

  26. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING CLEAN ROON CLASIFICATION CONSIDERATIONS • WHO & EC,EU, PIC/S, TGA: classes A,B, C, D • USFDA : critical and Controlled • ISE: level1,2,or 3 • INSERT PICTURE OR SLIDE of classification??????

  27. at rest in operation as built air air air AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING DEFINITIONS OF ROOM CONDITION

  28. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING AIR FILTRATION AND CONTROL OF CONTAMINANTS • External Air contaminants are removed by filtration • Internal contaminants are controlled by dilution and flushing or by displacement air flow • Airborne particulates and level of filtration are considered critical in Air Handling system • The filtered air entering a production room can be derivable from • 100% fresh air/external air or • a proportion re-circulated ( Mixed with external/fresh air) • New technologies: barrier technology/isolator technology

  29. Air types Fresh air (make-up air) Exhaust air + Supply air Production Room Return air (recirculated) AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING Types of Air encountered in HVAC system: fresh air, supply air, recirculated and exhaust air

  30. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING FRESH AIR ( 100%)/ONCE THROUGH SYSTEM (1) • Applicable to factory dealing with toxic products • Low risk of cross contamination • Provides • The exhaust air filtration depends on the degree of contaminants and local environmental regulations • Offers abundant oxygen rich fresh air for dilution of contaminants • Air leakage between the supply and exhaust air should be prevented, supply air pressure should be higher that the exhaust air pressure • Exhaust fan may be located remote from the AHU making ducting simpler

  31. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING FRESH AIR ( 100%)/ONCE THROUGH SYSTEM (2) • Usually more expensive to run ( heating and cooling demand) • High filter loading resulting in frequent filters replacement • Additional requirement for air treatment(scrubber, dust collectors) • Applicable in laboratory hood, API plant handling highly inflammable materials, oral solid dosage plant( OSD) where potent /product/materials are exposed.

  32. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING VENTILATION WITH 100% FRESH AIR (no air re-circulation) Washer (optional) Exhaust Unit W Central Air Handling Unit

  33. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING

  34. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING RECIRCULATION SYSTEM (1) • A proportion or % of re-circulated air mixed with fresh air/external air • Requires installation of HEPA filters in the supply air stream to remove contaminants which may be placed terminally or in AHU ( H13 HEPA filter recommended) • Single product facility may not require HEPA • Not suitable for fumes or dust from highly toxic processes

  35. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING • RECIRCULATION SYSTEM (2) • Proportioning of fresh (external air) to re-circulated air can be fixed or variable air volumes( temperature and no of operatives, ) • Less air filter loading –lower maintenance cost ( variable air flow) • Energy saving/cost • Complex design and high level of automation • Chances of cross contamination from system failures • Applicable for OSD manufacturing , sterile operations, Final bulk APIs

  36. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING VENTILATION WITH RECIRCULATED AIR + MAKE UP AIR Exhaust Unit Central Air Handling Unit Return air

  37. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING AIR FLOW PATTERN (1) • The air flow pattern is used to control the internal contaminant by dilution or displacement flow • May be unidirectional or turbulent flow • Turbulent can cause particulate settled on the ground to be re-entrained in the air. • Vertical down flow is the preferred ( displacement flow)

  38. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING AIR FLOW PATTERN (2) • Usually class 100 (must have unidirectional ( laminar) with 100% HEPA Coverage on the ceiling or wall and return on opposite side • Class 1000 and above are generally non unidirectional with supply air outlet at the ceiling and return at the floor level • Return grill – positioned low down , not near a door opening into an adjacent lower pressure room ( to prevent reverse air leakage to the high pressure room during door opening • Return risers should be fitted with manually operated dampers

  39. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING AIR FLOW PATTERN Uni-directional / laminar displacement of dirty air Turbulent dilution of dirty air 0,30 m/s

  40. AIR HANDLING SYSTEM IN PHARMACEUTICALMANUFACTURING AIR FLOW PATTERN (II) Prefilter AHU Main filter Ceiling exhausts 2 3 1 Low level exhausts

  41. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING AIR FLOW PATTERN (III) Workbench (vertical) Cabin/ booth Ceiling

  42. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING POSITIONING OF FILTERS • The required cleanliness or purity of air can be achieved with effective cleaning of the external air or recirculated air through correctly designed and installed filters to meet the specifications or requirements for intended activity or manufacturing operation. • Filter location can be in the AHU, terminal …………….???? • filters are of various types , specifications and classes TYPES OF AIR FLTERS • Ultra Low Particulate Air filter( ULPA) • High Efficiency particulate air filter( HEPA) • Packed towers • Membrane filter cartridges • Hydrophobic filters

  43. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING SPECIFICATIONS FOR FILTERS • Simple MERV (1-16), pre filters (10, 20, 50µ efficiency 80-90% , secondary filters(5µ: efficiency up to 99%), HEPA filters (0.3µ: efficiency upto 99.99 CLASSES OF FILTERS • Coarse (Dp < 10µ , G1-G4, Fine ( 1.0µ <Dp <10µ : F5 –F9); HEPA( H10-H14) &ULPA(U15-U16) both of Dp < 1.0µ) Filter efficiency testing should be linked to the standard test methods ( different test methods could give different results for same filter)

  44. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING FILTERS

  45. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING HEPA FILTER

  46. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING POSITIONING OR LOCATION OF FILTER IN AHU (1) TERMINAL ( AHU OR ROOM SUPPLY VENT

  47. + Production Room Production Room AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING POSITIONING OF HEPA FILTERS (2) AHU mounted final filter Filter in terminal position HEPA Filter HEPA Filter

  48. AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING POSITIONING OF FILTERS (3) Prefilter AHU Main filter Ceiling exhausts 2 3 1

  49. POSITIONING OF FILTERS (4) Final filter AHU Prefilter 1 2 AIR HANDLING SYSTEM IN PHARMACEUTICAL MANUFACTURING

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