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This document provides an overview and introduction to HVAC systems for oral solid dosage manufacturing. It discusses the need for HVAC to protect products, personnel, and the environment. Proper HVAC system design and components are important for controlling temperature, humidity, and preventing contamination and cross-contamination. The document focuses on air filtration, airflow patterns like unidirectional and turbulent flow, and pressure differentials to prevent infiltration and cross-contamination between areas. Maintaining appropriate cleanroom classifications through HVAC in both operational and non-operational states is also covered.

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HVAC Fasika Mekete, Technical advisor 10/25/2019 Islamabad
Heating, Ventilation and Air- Conditioning (HVAC) Part 1: Introduction and overview
HVAC Objectives To understand: • The need for HVAC systems • The role of HVAC in protection: – Product – Personnel – Environment • The role of HVAC in dust control • HVAC system design and its components • Commissioning, qualification and maintenance
HVAC Introduction and Scope • 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
HVAC • This presentation focuses on HVAC systems for OSD • To fully understand the technical issues, it is important to know the definitions of the terms used These include: • Contamination and Cross-contamination • As built, at rest, in operation • Infiltration, exfiltration etc
For example: What is contamination? It is "the undesired introduction of impurities (chemical/ microbial/ foreign matter into or on to starting material or intermediate – during sampling, production, packaging or repackaging". Impurities could include products or substances other than the product manufactured, foreign products, particulate matter, micro-organisms, endotoxins (degraded microorganisms), etc. HVAC
What is Cross-contamination? "Contamination of a starting material, intermediate product, or finished product with another starting material or product during production". Cross-contamination can result from, e.g. 1. Poorly designed, operated or maintained air-handling systems and dust extraction systems 2. Inadequate procedures for, and movement of personnel, materials and equipment 3. Insufficiently cleaned equipment HVAC
Cross-contamination can be minimized by, e.g. 1. Personnel procedures 2. Adequate premises 3. Use of closed production systems 4. Adequate, validated cleaning procedures 5. Appropriate levels of protection of product 6. Correct air pressure cascade HVAC
Factors contributing to quality products Starting materials Personnel Procedures Validated processes Equipment Premises Environment Packing materials HVAC
HVAC Consider the following when designing an HVAC system: • Layout of the premises • Product range • Airlocks, Lobbies, Doors • Required pressure differentials • Air flows • Temperature and relative humidity • Prevention of contamination and cross contamination
HVAC This presentation further focuses on three concepts of the system: • Product protection – Contamination – Cross-contamination – Environmental conditions • Personnel protection – Prevent contact – Comfort conditions • Environment protection
HVAC Protection: Product and personnel • Areas of manufacturing should be classified as "clean areas; clean zones; cleanrooms; or controlled areas” • To achieve a clean area classification – control : – Building finishes and structure – Air filtration – Air change rate – Room pressure – Temperature – Relative humidity – Material and personnel flow – Outside environment – Occupancy and type of product
HVAC • Air filtration and air change rate needed to attain classification • Risk assessment. :Normally need 6 – 20 air changes per hour • Air change rate is dependent on factors, e.g. – Required condition – Product characteristics – Quality of filtration of air – Particles generated (operators, machines, process) – Room configuration – Supply and return / extract air locations – Air required (room heat load, containment) – Balance and room pressure requirements
HVAC The classification should be achieved in the state as specified (1): • "As built" – Bare room, without equipment or personnel
HVAC The classification should be achieved in the state as specified (2): • "At rest" – Equipment may be operating, but no operators present
HVAC The classification should be achieved in the state as specified (3): • "In operation" – Normal production process with equipment and personnel – Clean up time validated – normally about 20 minutes
HVAC Control of contaminants • Protect materials and products during manufacture • Airborne contaminants – effective ventilation and filtration • External contaminants - effective filtration • Internal contaminants - dilution and flushing, or displacement airflow • Level of protection: Airborne particulates and level of filtration considered critical
Therapeutic risks ManufacturingEnvironment requirements CleanroomClassA/B CleanroomClassC Cleanrm.ClassD Others HVAC
HVAC Level of protection and air cleanliness determined according to: • Product to be manufactured • Process to be used • Product susceptibility to degradation • Personnel should not be a source of contamination
Tools to help achieve the desired Level of Protection Air Handling System Production Room With Defined Requirements Supply Air Outlet Air HVAC
Cleanroom Class defined by Critical Parameters Air Handling System Additional Measures Tools to help achieve the desired Level of Protection (2) HVAC
Examples of Levels of Protection Types of Clean room classes • A, B, C, D • Critical and controlled • Level 1, 2 or 3 • ISO4.8, 5, 7 or 8 HVAC
HVAC Examples of levels of protection Example of areaConditionLevel Area with normal housekeeping, e.g. warehouse GeneralLevel 1 Area where steps are taken to protect exposed material/product, e.g. dispensing ProtectedLevel 2 Area with defined, controlled, monitored environmental conditions to prevent contamination and degradation ControlledLevel 3
All operations within a pharmaceutical facilility should be correlated to well-defined clean room classes, and can be included in a hygiene concept. Example: List other…. XFilling for aseptic process XFilling for terminal sterilisation XDepyrogenisation of containers XXXPreparation of solutions for aseptic filling XPreparation of solution for terminal sterilisation XWashing of containers DCBACleanroom Class HVAC
Heating, Ventilation and Air- Conditioning (HVAC) Part 2: Air flows, Pressure concepts
HVAC Objectives To continue from previous section of Part 1, now focus on: • Air filtration and air flow patterns • The role of HVAC in dust control • HVAC system design and its components (part 3) • Commissioning, qualification and maintenance (part 4)
HVAC Air Filtration • Degree of filtration of air is important to prevent contamination • Type of filters to be used is dependent on: – Quality of ambient air, – Return air / re-circulation – Air change rates – National requirements – Products and required class of clean room etc. • Manufacturer to determine, select and install appropriate filters for use
HVAC Levels of protection and recommended filtration Recommended filtrationLevel of protection Primary filters, e.g. EN779 G4Level 1 Production area with 100% outside air: Primary plus secondary filter (e.g. EN779 G4 plus F8 or F9 filters) Level 2 Production facility operating on re-circulated plus ambient air, where potential for cross-contamination exists: Primary plus secondary plus tertiary filters (e.g. EN779 G4 plus F8 plus EN1822 H13 filters) (For full fresh air system, without recirculation, G4 and F8 or F9 filters are acceptable) Level 3
HVAC Contamination can be prevented by considering: • Appropriate materials of construction of HVAC components • Placement of components (e.g. upstream of final filters) • Design and appropriate access (from outside) to dampers, filters and other components • Personnel operations and protection • Airflow direction • Air distribution component design, installation and location • Diffusers (type, design, location) • Air supply and air exhaust location
HVAC Induction diffuser
HVAC Perforated plate
HVAC Swirl type diffuser
HVAC Airflow patterns Filtered air entering a production room or covering a process can be  turbulent, or  unidirectional (laminar) – GMP aspect – economical aspect Other technologies: barrier technology/isolator technology.
Unidirectional/laminar displacement of dirty air Turbulent dilution of dirty air Airflow patterns HVAC
HVAC
PrefilterAirflow patterns AHU Main filter Unidirectional TurbulentTurbulent 1 2 3 HVAC
HVAC Unidirectional airflow (UDAF) Often used in weighing and sampling areas (Airflow Protection Booths) and provides: • Dust containment and product and operator protection Note: For Airflow Protection Booths (APB): • Airflow velocity should not affect balance (may be lower than for Class A areas) • Position of material, balance, operator determined and validated – no obstruction of airflow or risk
Workbench (vertical) Cabin/booth Ceiling Airflow patterns HVAC
HVAC Unidirectional airflow (UDAF): • Sampling and weighing area classification – same as other processing areas following sampling and dispensing • Dust containment shown through smoke tests as part of validation / qualification • Location and type of return and exhaust grilles • Cleaning and maintenance • Will discuss examples in the following figures
HVAC
HVAC
HVAC
HVAC
HVAC
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HVAC
HVAC Infiltration • Prevent infiltration of unfiltered, contaminated air from outside • Facilities normally under positive pressure to the outside • Building structure well sealed • Some cases - negative pressure (e.g. penicillin manufacture). Special precautions to be taken. See separate guidelines
HVAC Cross-contamination • Multiproduct facility – even if in different areas - risk for cross contamination (dust from area to area) • Correct direction of air movement and pressure cascade • Normally, corridors positive to cubicles and cubicles positive to atmosphere • Consider building structure, ceilings, walls, doors etc • Different concepts discussed in following slides
HVAC Displacement concept • Not a preferred method (Found in older facilities) • Based on low pressure differentials and high airflows • Air supplied to the corridor – then through the doors (grilles) to the cubicles • Air extracted at the back of the cubicle • Velocity high enough to prevent turbulence in doorway
HVAC Pressure differential concept • Used where there is low dust in areas. Alone or in combination with other control techniques • High pressure differential, low airflow, and airlocks • Airlock types include: Cascade, sink and bubble type (See next slides) • Sufficient pressure differential required to ensure containment and prevent flow reversal – but not so high as to create turbulence • Consider effect of other items such as equipment and extraction systems in cubicles
HVAC • Essential / critical parameter here is pressure differentials • Risk assessment may be done • High enough to achieve containment; low permissible when airlocks are used • No flow reversal should take place – therefore appropriate limits e.g. 5Pa to 20 Pa • No turbulence • No overlap (two adjacent rooms)
HVAC • Adequate room pressure differential indication provided • Each critical room pressure must be traced back to ambient pressure (by summation of the room pressure differentials) – provides actual absolute pressure • Gauges with appropriate range and graduation scale to enable accurate reading; analogue or digital; as pressure differentials or absolute pressures • Normal operating range, alert and action limits defined and displayed • OOS condition should be easily identifiable
HVAC
HVAC • Calibrated and qualified monitoring devices, verified at intervals • Linked to alarm system • Monitoring and recording of results • Doors open to higher pressure, self closers • Doors interlocked where possible
HVAC • Dust extraction system design is important as it may impact on pressure cascade • Central systems interlocked with AHUs • No airflow between rooms through common system • What happens in the case of component failure?
HVAC Airlocks and Material Pass-though-hatches (PTH) • Can be used to separate two zones • Dynamic and passive PTH • Also designed as bubble, sink or cascade • See next slides for design principles
HVAC
HVAC What type of airlock is this? How does it work? Any examples of where It can be used?
HVAC Physical barrier concept • In some cases, impervious barriers are used to prevent cross-contamination • Closed systems • Pump or vacuum transfer
HVAC Temperature and relative humidity (RH) • Consider materials and product requirements as well as operator comfort in the design of the HVAC • Where conditions are required, provide for control, monitoring and recording • Alert and action limits; minimum and maximum limits • Premises appropriately designed • HVAC design to achieve and maintain conditions in different seasons
HVAC Relative humidity (RH) • Low RH areas need well sealed walls and ceilings, and preferably air locks • Remove or add moisture as necessary • Dehumidification – Refrigerated dehumidifiers - cooling media – Chemical dehumidifiers • Humidifiers should not be sources of contamination – Use of pure steam or clean steam – No chemicals that can have a detrimental effect
HVAC Relative humidity (RH) • Humidifiers should be well drained - no accumulation of condensate • Avoid evaporative systems, atomizers, water-mist sprays • Suitable duct material • Insulation of cold surfaces • Air filters not immediately downstream of humidifiers • Chemical driers – used if not sources of contamination
Dust Control • Where possible - dust and vapour removed at source • Point of use extraction – fixed points or movable hood – plus general directional airflow in room • Ensure sufficient transfer velocity in extraction system to prevent dust settling in ducting – Calculations and measurements • Periodic checks for build up • Risk analysis – airflow direction HVAC
HVAC Dust Control (2) • Normally air supplied through ceiling diffusers, near the door • Air extracted from low level (rear) • Extraction of vapours – consider density of vapour • Handling harmful products – additional steps needed – e.g. barrier technology, glove boxes – totally enclosed garments with air-breathing systems • Fresh air rate supply – comfort, odour and fume removal, leakage, pressure control, etc.
HVAC
HVAC
HVAC
HVAC
HVAC Dust collection system Exhaust air dust  Exhaust air from equipment and some areas of production can carry heavy loads of dust, vapours and fumes (e.g. FBD, coating, weighing)  Filtration may be needed to protect environment (see National legislation)  Location of the inlet and exhaust points relative to one other important to prevent contaminants taken into inlet air 6.1.1 – 6.1.2
HVAC Exhaust air dust  Wet scrubbers can also be used  Contaminated air is collected  Dust is treated with a mist/spray / water  Clean air is exhausted
Objectives In the following slides, we will study the components of air- handling systems in order to: 1. Become familiar with the components 2. Know their functions 3. Become aware of possible problems HVAC
Heating, Ventilation and Air- Conditioning (HVAC) Part 3: HVAC systems and components
Objectives In the following slides, we will study the components of air- handling systems in order to: 1. Become familiar with the components 2. Know their functions 3. Become aware of possible problems HVAC
+ Production Room Exhaust air treatment Central air handling unit Terminal air treatment at production room level Fresh air treatment (make-up air) HVAC Main subsystems
HVAC Components Components in HVAC may include, depending on need: • Filters • Fans – no fan failure; including supply air fans, return air fans, exhaust air fan, dust extract system fans • Driers – Drying of air with chemical driers, e.g. rotating desiccant wheel • Frost coils for preheating air
HVAC General • Pharmaceutical products should be manufactured in areas of appropriate cleanliness • Prevent contamination and cross-contamination • Design of HVAC dependent on various factors e.g. – Outside air quality – Recirculation of air (or not) – Products and range of products • Risk assessment to determine clean room conditions.
HVAC General • Two basic concepts of air delivery – a re-circulation system, and – a full fresh air system (100% outside air supply). • Recirculation – determine the amount of fresh air based on criteria: – to compensate for leakage and loss – to comply with national building regulations; and – for odour control.
HVAC General • Validated automated monitoring systems (e.g. Building management systems (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system) - capable of indicating any out-of-specification condition without delay e.g. by means of an alarm – Also helps with preventive maintenance and trend logging – Critical alarms easily identifiable, visible and/or audible • Fan interlock failure matrix • Fan failures can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airflow reversal.
HVAC Air distribution • Positioning of supply and extract grilles to provide effective room flushing. • Low-level return or exhaust air grilles preferred. • If not possible, a higher air change rate may be needed to achieve a specified clean area condition, e.g. where ceiling return air grilles are used. • There may be alternative locations for return air
HVAC
+ Production Room Exhaust air Return air (recirculated) Fresh air (make-up air) Supply air Air types HVAC
HVAC Recirculation systems • Increased risk of contamination and cross-contamination. • Need HEPA filters (EN1822 classification of H13) • HEPA filters may not be required: – a single product facility and there is evidence that cross-contamination would not be possible. – No dust generated e.g. secondary packing • HEPA filters installed in the air-handling unit or terminally placed – If terminally mounted - not with flexible ducting • If highly toxic processes – never recirculate
Ventilation with recirculated air + make-up air Central Air-Handling Unit Return air Exhaust Unit HVAC
HVAC Full fresh-air systems • 100% fresh air normally used in a facility dealing with toxic products or solvents, where recirculation of air with contaminants should be avoided • Degree of filtration of the exhaust air depends on the exhaust air contaminants and local environmental regulations • HEPA filters in the exhaust system normally when handling hazardous materials
HVAC
Ventilation with 100% fresh air (no air recirculation) W Washer (optional) Central Air-Handling Unit Production Rooms Exhaust Unit HVAC
HVAC Energy-recovery wheels • Risk assessment to determine cross-contamination risks • Should not become a source of possible contamination • Alternatives include crossover plate heat exchangers and water-coil heat exchangers • Prevent air leakage between the supply air and exhaust air – exhaust air system operates at a lower pressure than the supply system.
HVAC
HVAC
HVAC Components Components in HVAC may include, depending on need: • frost coils to preheat the air • reheaters for humidity control, moisture eliminators • automatic air volume control devices • sound attenuators • snow eliminators, dust eliminators, • fresh air precooling coils
FilterSilencer Terminal filter Weather louvre Control damper FanFlow rate controller Humidifier Heating coil Cooling coil with droplet separator Production Room Overview components + Prefilter Exhaust Air Grille Heater Secondary Filter Recirculated air HVAC
• Weather louvre • Silencer • Flow rate controller • Control damper • To prevent insects, leaves, dirt and rain from entering • To reduce noise caused by air circulation • Automated adjustment of volume of air (night and day, pressure control) • Fixed adjustment of volume of air Components (1) HVAC
• Heating unit • Cooling unit/ dehumidifier • Humidifier • Filters • Ducts • To heat the air to the proper temperature • To cool the air to the required temperature or to remove moisture from the air • To bring the air to the proper humidity, if too low • To eliminate particles of predetermined dimensions and/or microorganisms • To transport the air Components (2) HVAC
Control damper for airflow De-humidification Filter Pressure Gauges AHU with fan Variable Speed Controller Humid room air Air heater Regeneration air Humid room air Adsorber wheel Dry air Air-handling unit HVAC
Humidifier Silencer Heating and cooling units HVAC
Primary panel filter Secondary filter HEPA or tertiary filter HVAC
Swirl Type air diffusors with terminal filters1 Filter 2 Tightening frame 3 Register outlet 4 Screw fixation for register 1 2 3 4 HVAC
• Flow rate controller • Control damper • Humidifier • Cooling battery • Filters • Ducts • Blocked • Poorly adjusted, bad pressure differential system • Bad water/steam quality/ poor drainage • No elimination of condensed water/ poor drainage • Incorrect retention rate/damaged/badly installed • Inappropriate material/internal insulator leaking Problems with components HVAC
Heating, Ventilation and Air- Conditioning (HVAC) Part 4: Commissioning, qualification and maintenance
HVAC Objectives • To understand key issues in commissioning, qualification and maintenance of HVAC systems
• 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 • programme and records Documentation requirements to assist in commissioning, qualification and maintenance HVAC
HVAC Commissioning Commissioning (is integrated in qualification) and includes: • Setting up, balancing, adjustment and testing of entire HVAC system • It helps to ensure it meets URS and capacity • Acceptable tolerances for parameters set before commissioning • Precursor to qualification
HVAC Commissioning (2) Records and data include: • Installation records – documented evidence of measured capacities of the system • Acceptance criteria set for system parameters • Training of personnel (e.g. operation and maintenance) – O&M manuals, schematic drawings, protocols, reports
HVAC 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. • Risk-based approach for HVAC qualification
HVAC Qualification • Described in a Validation Master Plan (VMP) • Reflects the nature and extent, test procedures, and protocols • DQ, IQ, OQ, and PQ • Risk analysis to determine critical and non-critical parameters, components, subsystems and controls
HVAC Qualification • 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
HVAC 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
HVAC Qualification 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)
HVAC Qualification Typical parameters to be included in qualification (based on risk assessment) (2): • Room air flow patterns • Room clean-up rate • Particulate matter, microbial matter (viable and non-viable) • HEPA filter penetration tests • Containment system velocity • Warning/alarm systems
HVAC Conduct of the tests: • Time intervals and procedure to be defined by the manufacturer - based on risk assessment (influenced by the type of facility and level of protection) • See also ISO 14644 for procedures • Requalification, and change control • Documents: system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings
HVAC Qualification • 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
HVAC Schedule of tests to demonstrate continuing compliance *Test procedure as per ISO 14644 Test procedure* and key aspects ConsiderationsObjectiveTest Parameter Particle counter. Readings and positions Number of readings and positions Verifies cleanlinessParticle count test Measure pressure difference Continuous. Defined limits Absence of cross- contamination Air pressure difference Measure supply and return air, calculate air change rate See ISO 14644Verify air change ratesAirflow volume Velocity measurementVelocity and containment Verify unidirectional airflow and or containment condition Airflow velocity
HVAC Recommended optional strategic tests *Test procedure as per ISO 14644 Test procedure* and key aspects ConsiderationsObjectiveTest Parameter Filter media and filter seal integrity For HEPA filtersVerify filter integrityFilter leakage Airflow direction and pressure differential Containment, smoke and air pressure Verify absence of cross-contamination Containment leakage Time taken maximum 20 minutes Certain classesVerify clean-up timeRecovery (time) Airflow direction, documented evidence Clean to dirty area, uniformly. Video Verify required airflow patterns Airflow visualization
Cleanroom monitoring program (1) • Routine monitoring program as part of quality assurance • Additional monitoring and triggers, e.g. 1. Shutdown 2. Replacement of filter elements 3. Maintenance of air-handling systems 4. Exceeding of established limits HVAC
Cleanroom monitoring programme (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 HVAC
Cleanrooms should be monitored for microorganisms and particles HVAC Service Room Warehouse A/Lock1 AirLock2 Air Shower Sampling Rooom Service Corridor (contains Vacuum & RO water supply) Weighing Tablet 1 Tablet 2 Liquids Mix Softgel Capsule Packing Emergency Exit Clean Corridor Equipment Wash Air Lock 3 Sterile eyedrops dispensing & aceptic filling 2 Stage personnel entry for eyedrops Male Change 2 Male Change 1 Female Change 1 Female Change 2 Packed Goods Quarantine Air Lock 4 Primary & Secondary Packing Example of a sampling points
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 Airflow pattern 2 2 N/A 2, 3 2, 3 Optional 2 2 2 N/A 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) HVAC
HVAC Maintenance • Procedure, programme and records for planned, preventative maintenance – e.g. cleaning of filters, calibration of devices • Keep O&M manuals, drawings etc. • Appropriate training for personnel • Change of HEPA filters by suitably trained persons • Impact of maintenance on: –Product quality and Qualification
HVAC Premises may influence HVAC design / performance. Therefore consider: • Adequate airlocks, change rooms, passages • Required pressure cascades • Detailed diagrams available with pressure cascades, air flow directions and flow routes for personnel and materials should be prepared and maintained; • Change room classification
• 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) Inspecting the air-handling system HVAC
 Appropriate design of AHUs and HVAC system  Correct components, and MOC  Ensuring appropriate cleanliness of air, environmental conditions (e.g. temperature and RH), and area classification to prevent contamination and cross-contamination  Qualification data to support claims  Regular calibration, maintenance and cleaning Take home message. What is essential? HVAC
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 Conclusion HVAC
Group Session Service Room Warehouse A/Lock1 AirLock2 Air Shower Sampling Rooom Service Corridor (contains Vacuum & RO water supply) Weighing Tablet 1 Tablet 2 Liquids Mix Softgel Capsule Packing Emergency Exit Clean Corridor Equipment Wash Air Lock 3 Sterile eyedrops dispensing & aceptic filling 2 Stage personnel entry for eyedrops Male Change 2 Male Change 1 Female Change 1 Female Change 2 Packed Goods Quarantine Air Lock 4 Primary & Secondary Packing HVAC
Group Session – modified layout Secondary Packing 30Pa 0Pa 20Pa 30Pa 0Pa 0Pa 10Pa 10Pa 10Pa 20Pa20Pa 40Pa 50Pa 60Pa 50Pa 40Pa 15Pa 15Pa Primary Packing Change MAL 3 Air Lock 30Pa Post Staging 30Pa 30Pa 0Pa 15Pa15Pa 20Pa 20Pa 30Pa 20Pa 0Pa 10Pa Service Room Air Lock 4 Packed Goods Quarantine Female Change 2 Female Change 1 Male Change 1 Male Change 2 PAL Sterile eyedrops dispensing & asceptic filling MAL 4 Equipment Wash Clean Corridor Emergency Exit Softgel Capsule PackingLiquids MixTablet 2Tablet 1 Weigh Booth (contains Vacuum & RO water supply) Service Corridor Sampling Rooom Air Shower MAL2 MAL1 Warehouse MAL = Material Air Lock PAL = Personnel Air Lock HVAC
Questions?
Thank You

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Hvac

  • 1.
    HVAC Fasika Mekete, Technicaladvisor 10/25/2019 Islamabad
  • 2.
    Heating, Ventilation andAir- Conditioning (HVAC) Part 1: Introduction and overview
  • 3.
    HVAC Objectives To understand: • Theneed for HVAC systems • The role of HVAC in protection: – Product – Personnel – Environment • The role of HVAC in dust control • HVAC system design and its components • Commissioning, qualification and maintenance
  • 4.
    HVAC Introduction and Scope •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
  • 5.
    HVAC • This presentationfocuses on HVAC systems for OSD • To fully understand the technical issues, it is important to know the definitions of the terms used These include: • Contamination and Cross-contamination • As built, at rest, in operation • Infiltration, exfiltration etc
  • 6.
    For example: Whatis contamination? It is "the undesired introduction of impurities (chemical/ microbial/ foreign matter into or on to starting material or intermediate – during sampling, production, packaging or repackaging". Impurities could include products or substances other than the product manufactured, foreign products, particulate matter, micro-organisms, endotoxins (degraded microorganisms), etc. HVAC
  • 7.
    What is Cross-contamination? "Contaminationof a starting material, intermediate product, or finished product with another starting material or product during production". Cross-contamination can result from, e.g. 1. Poorly designed, operated or maintained air-handling systems and dust extraction systems 2. Inadequate procedures for, and movement of personnel, materials and equipment 3. Insufficiently cleaned equipment HVAC
  • 8.
    Cross-contamination can beminimized by, e.g. 1. Personnel procedures 2. Adequate premises 3. Use of closed production systems 4. Adequate, validated cleaning procedures 5. Appropriate levels of protection of product 6. Correct air pressure cascade HVAC
  • 9.
    Factors contributing to qualityproducts Starting materials Personnel Procedures Validated processes Equipment Premises Environment Packing materials HVAC
  • 10.
    HVAC Consider the followingwhen designing an HVAC system: • Layout of the premises • Product range • Airlocks, Lobbies, Doors • Required pressure differentials • Air flows • Temperature and relative humidity • Prevention of contamination and cross contamination
  • 11.
    HVAC This presentation furtherfocuses on three concepts of the system: • Product protection – Contamination – Cross-contamination – Environmental conditions • Personnel protection – Prevent contact – Comfort conditions • Environment protection
  • 12.
    HVAC Protection: Product andpersonnel • Areas of manufacturing should be classified as "clean areas; clean zones; cleanrooms; or controlled areas” • To achieve a clean area classification – control : – Building finishes and structure – Air filtration – Air change rate – Room pressure – Temperature – Relative humidity – Material and personnel flow – Outside environment – Occupancy and type of product
  • 13.
    HVAC • Air filtrationand air change rate needed to attain classification • Risk assessment. :Normally need 6 – 20 air changes per hour • Air change rate is dependent on factors, e.g. – Required condition – Product characteristics – Quality of filtration of air – Particles generated (operators, machines, process) – Room configuration – Supply and return / extract air locations – Air required (room heat load, containment) – Balance and room pressure requirements
  • 14.
    HVAC The classification shouldbe achieved in the state as specified (1): • "As built" – Bare room, without equipment or personnel
  • 15.
    HVAC The classification shouldbe achieved in the state as specified (2): • "At rest" – Equipment may be operating, but no operators present
  • 16.
    HVAC The classification shouldbe achieved in the state as specified (3): • "In operation" – Normal production process with equipment and personnel – Clean up time validated – normally about 20 minutes
  • 17.
    HVAC Control of contaminants •Protect materials and products during manufacture • Airborne contaminants – effective ventilation and filtration • External contaminants - effective filtration • Internal contaminants - dilution and flushing, or displacement airflow • Level of protection: Airborne particulates and level of filtration considered critical
  • 18.
  • 19.
    HVAC Level of protectionand air cleanliness determined according to: • Product to be manufactured • Process to be used • Product susceptibility to degradation • Personnel should not be a source of contamination
  • 20.
    Tools to helpachieve the desired Level of Protection Air Handling System Production Room With Defined Requirements Supply Air Outlet Air HVAC
  • 21.
    Cleanroom Class defined by CriticalParameters Air Handling System Additional Measures Tools to help achieve the desired Level of Protection (2) HVAC
  • 22.
    Examples of Levelsof Protection Types of Clean room classes • A, B, C, D • Critical and controlled • Level 1, 2 or 3 • ISO4.8, 5, 7 or 8 HVAC
  • 23.
    HVAC Examples of levelsof protection Example of areaConditionLevel Area with normal housekeeping, e.g. warehouse GeneralLevel 1 Area where steps are taken to protect exposed material/product, e.g. dispensing ProtectedLevel 2 Area with defined, controlled, monitored environmental conditions to prevent contamination and degradation ControlledLevel 3
  • 24.
    All operations withina pharmaceutical facilility should be correlated to well-defined clean room classes, and can be included in a hygiene concept. Example: List other…. XFilling for aseptic process XFilling for terminal sterilisation XDepyrogenisation of containers XXXPreparation of solutions for aseptic filling XPreparation of solution for terminal sterilisation XWashing of containers DCBACleanroom Class HVAC
  • 25.
    Heating, Ventilation andAir- Conditioning (HVAC) Part 2: Air flows, Pressure concepts
  • 26.
    HVAC Objectives To continue fromprevious section of Part 1, now focus on: • Air filtration and air flow patterns • The role of HVAC in dust control • HVAC system design and its components (part 3) • Commissioning, qualification and maintenance (part 4)
  • 27.
    HVAC Air Filtration • Degreeof filtration of air is important to prevent contamination • Type of filters to be used is dependent on: – Quality of ambient air, – Return air / re-circulation – Air change rates – National requirements – Products and required class of clean room etc. • Manufacturer to determine, select and install appropriate filters for use
  • 28.
    HVAC Levels of protectionand recommended filtration Recommended filtrationLevel of protection Primary filters, e.g. EN779 G4Level 1 Production area with 100% outside air: Primary plus secondary filter (e.g. EN779 G4 plus F8 or F9 filters) Level 2 Production facility operating on re-circulated plus ambient air, where potential for cross-contamination exists: Primary plus secondary plus tertiary filters (e.g. EN779 G4 plus F8 plus EN1822 H13 filters) (For full fresh air system, without recirculation, G4 and F8 or F9 filters are acceptable) Level 3
  • 29.
    HVAC Contamination can beprevented by considering: • Appropriate materials of construction of HVAC components • Placement of components (e.g. upstream of final filters) • Design and appropriate access (from outside) to dampers, filters and other components • Personnel operations and protection • Airflow direction • Air distribution component design, installation and location • Diffusers (type, design, location) • Air supply and air exhaust location
  • 30.
  • 31.
  • 32.
  • 33.
    HVAC Airflow patterns Filtered airentering a production room or covering a process can be  turbulent, or  unidirectional (laminar) – GMP aspect – economical aspect Other technologies: barrier technology/isolator technology.
  • 34.
    Unidirectional/laminar displacement of dirtyair Turbulent dilution of dirty air Airflow patterns HVAC
  • 35.
  • 36.
  • 37.
    HVAC Unidirectional airflow (UDAF) Oftenused in weighing and sampling areas (Airflow Protection Booths) and provides: • Dust containment and product and operator protection Note: For Airflow Protection Booths (APB): • Airflow velocity should not affect balance (may be lower than for Class A areas) • Position of material, balance, operator determined and validated – no obstruction of airflow or risk
  • 38.
    Workbench (vertical) Cabin/boothCeiling Airflow patterns HVAC
  • 39.
    HVAC Unidirectional airflow (UDAF): •Sampling and weighing area classification – same as other processing areas following sampling and dispensing • Dust containment shown through smoke tests as part of validation / qualification • Location and type of return and exhaust grilles • Cleaning and maintenance • Will discuss examples in the following figures
  • 40.
  • 41.
  • 42.
  • 43.
  • 44.
  • 45.
  • 46.
  • 48.
    HVAC Infiltration • Prevent infiltrationof unfiltered, contaminated air from outside • Facilities normally under positive pressure to the outside • Building structure well sealed • Some cases - negative pressure (e.g. penicillin manufacture). Special precautions to be taken. See separate guidelines
  • 49.
    HVAC Cross-contamination • Multiproduct facility– even if in different areas - risk for cross contamination (dust from area to area) • Correct direction of air movement and pressure cascade • Normally, corridors positive to cubicles and cubicles positive to atmosphere • Consider building structure, ceilings, walls, doors etc • Different concepts discussed in following slides
  • 50.
    HVAC Displacement concept • Nota preferred method (Found in older facilities) • Based on low pressure differentials and high airflows • Air supplied to the corridor – then through the doors (grilles) to the cubicles • Air extracted at the back of the cubicle • Velocity high enough to prevent turbulence in doorway
  • 51.
    HVAC Pressure differential concept •Used where there is low dust in areas. Alone or in combination with other control techniques • High pressure differential, low airflow, and airlocks • Airlock types include: Cascade, sink and bubble type (See next slides) • Sufficient pressure differential required to ensure containment and prevent flow reversal – but not so high as to create turbulence • Consider effect of other items such as equipment and extraction systems in cubicles
  • 52.
    HVAC • Essential /critical parameter here is pressure differentials • Risk assessment may be done • High enough to achieve containment; low permissible when airlocks are used • No flow reversal should take place – therefore appropriate limits e.g. 5Pa to 20 Pa • No turbulence • No overlap (two adjacent rooms)
  • 53.
    HVAC • Adequate roompressure differential indication provided • Each critical room pressure must be traced back to ambient pressure (by summation of the room pressure differentials) – provides actual absolute pressure • Gauges with appropriate range and graduation scale to enable accurate reading; analogue or digital; as pressure differentials or absolute pressures • Normal operating range, alert and action limits defined and displayed • OOS condition should be easily identifiable
  • 54.
  • 55.
    HVAC • Calibrated andqualified monitoring devices, verified at intervals • Linked to alarm system • Monitoring and recording of results • Doors open to higher pressure, self closers • Doors interlocked where possible
  • 56.
    HVAC • Dust extractionsystem design is important as it may impact on pressure cascade • Central systems interlocked with AHUs • No airflow between rooms through common system • What happens in the case of component failure?
  • 57.
    HVAC Airlocks and MaterialPass-though-hatches (PTH) • Can be used to separate two zones • Dynamic and passive PTH • Also designed as bubble, sink or cascade • See next slides for design principles
  • 58.
  • 59.
    HVAC What type ofairlock is this? How does it work? Any examples of where It can be used?
  • 60.
    HVAC Physical barrier concept •In some cases, impervious barriers are used to prevent cross-contamination • Closed systems • Pump or vacuum transfer
  • 61.
    HVAC Temperature and relativehumidity (RH) • Consider materials and product requirements as well as operator comfort in the design of the HVAC • Where conditions are required, provide for control, monitoring and recording • Alert and action limits; minimum and maximum limits • Premises appropriately designed • HVAC design to achieve and maintain conditions in different seasons
  • 62.
    HVAC Relative humidity (RH) •Low RH areas need well sealed walls and ceilings, and preferably air locks • Remove or add moisture as necessary • Dehumidification – Refrigerated dehumidifiers - cooling media – Chemical dehumidifiers • Humidifiers should not be sources of contamination – Use of pure steam or clean steam – No chemicals that can have a detrimental effect
  • 63.
    HVAC Relative humidity (RH) •Humidifiers should be well drained - no accumulation of condensate • Avoid evaporative systems, atomizers, water-mist sprays • Suitable duct material • Insulation of cold surfaces • Air filters not immediately downstream of humidifiers • Chemical driers – used if not sources of contamination
  • 64.
    Dust Control • Wherepossible - dust and vapour removed at source • Point of use extraction – fixed points or movable hood – plus general directional airflow in room • Ensure sufficient transfer velocity in extraction system to prevent dust settling in ducting – Calculations and measurements • Periodic checks for build up • Risk analysis – airflow direction HVAC
  • 65.
    HVAC Dust Control (2) •Normally air supplied through ceiling diffusers, near the door • Air extracted from low level (rear) • Extraction of vapours – consider density of vapour • Handling harmful products – additional steps needed – e.g. barrier technology, glove boxes – totally enclosed garments with air-breathing systems • Fresh air rate supply – comfort, odour and fume removal, leakage, pressure control, etc.
  • 66.
  • 67.
  • 68.
  • 69.
  • 70.
    HVAC Dust collection system Exhaustair dust  Exhaust air from equipment and some areas of production can carry heavy loads of dust, vapours and fumes (e.g. FBD, coating, weighing)  Filtration may be needed to protect environment (see National legislation)  Location of the inlet and exhaust points relative to one other important to prevent contaminants taken into inlet air 6.1.1 – 6.1.2
  • 71.
    HVAC Exhaust air dust Wet scrubbers can also be used  Contaminated air is collected  Dust is treated with a mist/spray / water  Clean air is exhausted
  • 72.
    Objectives In the followingslides, we will study the components of air- handling systems in order to: 1. Become familiar with the components 2. Know their functions 3. Become aware of possible problems HVAC
  • 73.
    Heating, Ventilation andAir- Conditioning (HVAC) Part 3: HVAC systems and components
  • 74.
    Objectives In the followingslides, we will study the components of air- handling systems in order to: 1. Become familiar with the components 2. Know their functions 3. Become aware of possible problems HVAC
  • 75.
    + Production Room Exhaust airtreatment Central air handling unit Terminal air treatment at production room level Fresh air treatment (make-up air) HVAC Main subsystems
  • 76.
    HVAC Components Components in HVACmay include, depending on need: • Filters • Fans – no fan failure; including supply air fans, return air fans, exhaust air fan, dust extract system fans • Driers – Drying of air with chemical driers, e.g. rotating desiccant wheel • Frost coils for preheating air
  • 77.
    HVAC General • Pharmaceutical productsshould be manufactured in areas of appropriate cleanliness • Prevent contamination and cross-contamination • Design of HVAC dependent on various factors e.g. – Outside air quality – Recirculation of air (or not) – Products and range of products • Risk assessment to determine clean room conditions.
  • 78.
    HVAC General • Two basicconcepts of air delivery – a re-circulation system, and – a full fresh air system (100% outside air supply). • Recirculation – determine the amount of fresh air based on criteria: – to compensate for leakage and loss – to comply with national building regulations; and – for odour control.
  • 79.
    HVAC General • Validated automatedmonitoring systems (e.g. Building management systems (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system) - capable of indicating any out-of-specification condition without delay e.g. by means of an alarm – Also helps with preventive maintenance and trend logging – Critical alarms easily identifiable, visible and/or audible • Fan interlock failure matrix • Fan failures can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airflow reversal.
  • 80.
    HVAC Air distribution • Positioningof supply and extract grilles to provide effective room flushing. • Low-level return or exhaust air grilles preferred. • If not possible, a higher air change rate may be needed to achieve a specified clean area condition, e.g. where ceiling return air grilles are used. • There may be alternative locations for return air
  • 81.
  • 83.
    + Production Room Exhaust air Return air (recirculated) Freshair (make-up air) Supply air Air types HVAC
  • 84.
    HVAC Recirculation systems • Increasedrisk of contamination and cross-contamination. • Need HEPA filters (EN1822 classification of H13) • HEPA filters may not be required: – a single product facility and there is evidence that cross-contamination would not be possible. – No dust generated e.g. secondary packing • HEPA filters installed in the air-handling unit or terminally placed – If terminally mounted - not with flexible ducting • If highly toxic processes – never recirculate
  • 85.
    Ventilation with recirculatedair + make-up air Central Air-Handling Unit Return air Exhaust Unit HVAC
  • 86.
    HVAC Full fresh-air systems •100% fresh air normally used in a facility dealing with toxic products or solvents, where recirculation of air with contaminants should be avoided • Degree of filtration of the exhaust air depends on the exhaust air contaminants and local environmental regulations • HEPA filters in the exhaust system normally when handling hazardous materials
  • 87.
  • 88.
    Ventilation with 100%fresh air (no air recirculation) W Washer (optional) Central Air-Handling Unit Production Rooms Exhaust Unit HVAC
  • 89.
    HVAC Energy-recovery wheels • Riskassessment to determine cross-contamination risks • Should not become a source of possible contamination • Alternatives include crossover plate heat exchangers and water-coil heat exchangers • Prevent air leakage between the supply air and exhaust air – exhaust air system operates at a lower pressure than the supply system.
  • 90.
  • 91.
  • 92.
    HVAC Components Components in HVACmay include, depending on need: • frost coils to preheat the air • reheaters for humidity control, moisture eliminators • automatic air volume control devices • sound attenuators • snow eliminators, dust eliminators, • fresh air precooling coils
  • 93.
    FilterSilencer Terminal filter Weather louvreControl damper FanFlow rate controller Humidifier Heating coil Cooling coil with droplet separator Production Room Overview components + Prefilter Exhaust Air Grille Heater Secondary Filter Recirculated air HVAC
  • 94.
    • Weather louvre •Silencer • Flow rate controller • Control damper • To prevent insects, leaves, dirt and rain from entering • To reduce noise caused by air circulation • Automated adjustment of volume of air (night and day, pressure control) • Fixed adjustment of volume of air Components (1) HVAC
  • 95.
    • Heating unit •Cooling unit/ dehumidifier • Humidifier • Filters • Ducts • To heat the air to the proper temperature • To cool the air to the required temperature or to remove moisture from the air • To bring the air to the proper humidity, if too low • To eliminate particles of predetermined dimensions and/or microorganisms • To transport the air Components (2) HVAC
  • 96.
    Control damper forairflow De-humidification Filter Pressure Gauges AHU with fan Variable Speed Controller Humid room air Air heater Regeneration air Humid room air Adsorber wheel Dry air Air-handling unit HVAC
  • 97.
    Humidifier Silencer Heatingand cooling units HVAC
  • 98.
    Primary panel filter Secondaryfilter HEPA or tertiary filter HVAC
  • 99.
    Swirl Type airdiffusors with terminal filters1 Filter 2 Tightening frame 3 Register outlet 4 Screw fixation for register 1 2 3 4 HVAC
  • 100.
    • Flow ratecontroller • Control damper • Humidifier • Cooling battery • Filters • Ducts • Blocked • Poorly adjusted, bad pressure differential system • Bad water/steam quality/ poor drainage • No elimination of condensed water/ poor drainage • Incorrect retention rate/damaged/badly installed • Inappropriate material/internal insulator leaking Problems with components HVAC
  • 101.
    Heating, Ventilation andAir- Conditioning (HVAC) Part 4: Commissioning, qualification and maintenance
  • 102.
    HVAC Objectives • To understandkey issues in commissioning, qualification and maintenance of HVAC systems
  • 103.
    • Description ofdesign, installation and functions • Specifications, requirements • Manuals • Operating procedures • Instructions for performance control, monitoring and records • Maintenance instructions and records • Training of personnel • programme and records Documentation requirements to assist in commissioning, qualification and maintenance HVAC
  • 104.
    HVAC Commissioning Commissioning (is integratedin qualification) and includes: • Setting up, balancing, adjustment and testing of entire HVAC system • It helps to ensure it meets URS and capacity • Acceptable tolerances for parameters set before commissioning • Precursor to qualification
  • 105.
    HVAC Commissioning (2) Records anddata include: • Installation records – documented evidence of measured capacities of the system • Acceptance criteria set for system parameters • Training of personnel (e.g. operation and maintenance) – O&M manuals, schematic drawings, protocols, reports
  • 106.
    HVAC Qualification • Validation isan extensive exercise • Qualification of the HVAC system is one component in the overall approach that covers premises, systems/utilities, equipment, processes, etc. • Risk-based approach for HVAC qualification
  • 107.
    HVAC Qualification • Described ina Validation Master Plan (VMP) • Reflects the nature and extent, test procedures, and protocols • DQ, IQ, OQ, and PQ • Risk analysis to determine critical and non-critical parameters, components, subsystems and controls
  • 108.
    HVAC Qualification • Direct impactcomponents 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
  • 109.
    HVAC Qualification – examplesof 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
  • 110.
    HVAC Qualification Typical parameters tobe included in qualification (based on risk assessment): • Temperature • Relative humidity • Supply, return and exhaust air quantities • Room air change rates • Room pressures (pressure differentials)
  • 111.
    HVAC Qualification Typical parameters tobe included in qualification (based on risk assessment) (2): • Room air flow patterns • Room clean-up rate • Particulate matter, microbial matter (viable and non-viable) • HEPA filter penetration tests • Containment system velocity • Warning/alarm systems
  • 112.
    HVAC Conduct of thetests: • Time intervals and procedure to be defined by the manufacturer - based on risk assessment (influenced by the type of facility and level of protection) • See also ISO 14644 for procedures • Requalification, and change control • Documents: system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings
  • 113.
    HVAC Qualification • Tests performedaccording 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
  • 114.
    HVAC Schedule of teststo demonstrate continuing compliance *Test procedure as per ISO 14644 Test procedure* and key aspects ConsiderationsObjectiveTest Parameter Particle counter. Readings and positions Number of readings and positions Verifies cleanlinessParticle count test Measure pressure difference Continuous. Defined limits Absence of cross- contamination Air pressure difference Measure supply and return air, calculate air change rate See ISO 14644Verify air change ratesAirflow volume Velocity measurementVelocity and containment Verify unidirectional airflow and or containment condition Airflow velocity
  • 115.
    HVAC Recommended optional strategictests *Test procedure as per ISO 14644 Test procedure* and key aspects ConsiderationsObjectiveTest Parameter Filter media and filter seal integrity For HEPA filtersVerify filter integrityFilter leakage Airflow direction and pressure differential Containment, smoke and air pressure Verify absence of cross-contamination Containment leakage Time taken maximum 20 minutes Certain classesVerify clean-up timeRecovery (time) Airflow direction, documented evidence Clean to dirty area, uniformly. Video Verify required airflow patterns Airflow visualization
  • 116.
    Cleanroom monitoring program(1) • Routine monitoring program as part of quality assurance • Additional monitoring and triggers, e.g. 1. Shutdown 2. Replacement of filter elements 3. Maintenance of air-handling systems 4. Exceeding of established limits HVAC
  • 117.
    Cleanroom monitoring programme(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 HVAC
  • 118.
    Cleanrooms should bemonitored for microorganisms and particles HVAC Service Room Warehouse A/Lock1 AirLock2 Air Shower Sampling Rooom Service Corridor (contains Vacuum & RO water supply) Weighing Tablet 1 Tablet 2 Liquids Mix Softgel Capsule Packing Emergency Exit Clean Corridor Equipment Wash Air Lock 3 Sterile eyedrops dispensing & aceptic filling 2 Stage personnel entry for eyedrops Male Change 2 Male Change 1 Female Change 1 Female Change 2 Packed Goods Quarantine Air Lock 4 Primary & Secondary Packing Example of a sampling points
  • 119.
    Qualification – examplesof 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 Airflow pattern 2 2 N/A 2, 3 2, 3 Optional 2 2 2 N/A 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) HVAC
  • 120.
    HVAC Maintenance • Procedure, programmeand records for planned, preventative maintenance – e.g. cleaning of filters, calibration of devices • Keep O&M manuals, drawings etc. • Appropriate training for personnel • Change of HEPA filters by suitably trained persons • Impact of maintenance on: –Product quality and Qualification
  • 121.
    HVAC Premises may influenceHVAC design / performance. Therefore consider: • Adequate airlocks, change rooms, passages • Required pressure cascades • Detailed diagrams available with pressure cascades, air flow directions and flow routes for personnel and materials should be prepared and maintained; • Change room classification
  • 122.
    • Verification ofdesign 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) Inspecting the air-handling system HVAC
  • 123.
     Appropriate designof AHUs and HVAC system  Correct components, and MOC  Ensuring appropriate cleanliness of air, environmental conditions (e.g. temperature and RH), and area classification to prevent contamination and cross-contamination  Qualification data to support claims  Regular calibration, maintenance and cleaning Take home message. What is essential? HVAC
  • 124.
    Air-handling systems:  Playa major role in the quality of pharmaceuticals  Should be designed properly, by professionals  Should be treated as a critical system Conclusion HVAC
  • 125.
    Group Session Service Room Warehouse A/Lock1 AirLock2 AirShower Sampling Rooom Service Corridor (contains Vacuum & RO water supply) Weighing Tablet 1 Tablet 2 Liquids Mix Softgel Capsule Packing Emergency Exit Clean Corridor Equipment Wash Air Lock 3 Sterile eyedrops dispensing & aceptic filling 2 Stage personnel entry for eyedrops Male Change 2 Male Change 1 Female Change 1 Female Change 2 Packed Goods Quarantine Air Lock 4 Primary & Secondary Packing HVAC
  • 126.
    Group Session –modified layout Secondary Packing 30Pa 0Pa 20Pa 30Pa 0Pa 0Pa 10Pa 10Pa 10Pa 20Pa20Pa 40Pa 50Pa 60Pa 50Pa 40Pa 15Pa 15Pa Primary Packing Change MAL 3 Air Lock 30Pa Post Staging 30Pa 30Pa 0Pa 15Pa15Pa 20Pa 20Pa 30Pa 20Pa 0Pa 10Pa Service Room Air Lock 4 Packed Goods Quarantine Female Change 2 Female Change 1 Male Change 1 Male Change 2 PAL Sterile eyedrops dispensing & asceptic filling MAL 4 Equipment Wash Clean Corridor Emergency Exit Softgel Capsule PackingLiquids MixTablet 2Tablet 1 Weigh Booth (contains Vacuum & RO water supply) Service Corridor Sampling Rooom Air Shower MAL2 MAL1 Warehouse MAL = Material Air Lock PAL = Personnel Air Lock HVAC
  • 127.
  • 128.

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  • #65  Dust control   Several operations can be generating dust. E.g. weighing, compressions, mixing of powders. 5.1 Wherever possible, dust or vapour contamination should be removed at source. Point-of-use extraction, i.e. as close as possible to the point where the dust is generated, should be employed. Spot ventilation or capture hoods may be used as appropriate.   5.2 Point-of-use extraction should be either in the form of a fixed high velocity extraction point or an articulated arm with movable hood or a fixed extraction hood.   5.3 Dust extraction ducting should be designed with sufficient transfer velocity to ensure that dust is carried away, and does not settle in the ducting. Periodic checks should be performed to ensure that there is no build up of the dust in the ducting.   5.4 The required transfer velocity should be determined: it is dependent on the density of the dust (the denser the dust, the higher the transfer velocity should be, e.g. 15–20 m/s).   5.5 Airflow direction should be carefully chosen, to ensure that the operator does not contaminate the product, and also so that the operator is not put at risk by the product.   5.6 Point extraction alone is usually not sufficient to capture all of the contaminants, and general directional airflow should be used to assist in removing dust and vapours from the room. Explain the principles, risks, procedures to be followed (e.g. cleaning, maintenance, operation) of the different types of dust collectors that can be used. These are at the point where dust is generated, common dust extraction systems, those that can be an integral part of a piece of equipment (e.g. some compression machines), moveable types.
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  • #68 Mobile type dust collectors can become the source of contamination if not used, cleaned, and controlled in the correct manner.
  • #69 Explain some key components of a dust collector, how the contaminated air is sucked in, treated, how the dust is collected and the treated air is exhausted. Discuss components such as blowers (fans), air velocity, bags, filters, pressure gauges etc
  • #70 Common duct collecting systems can result in powder/dust from one cubicle being deposited in another cubicle. Discuss design principles, dampers, airflow velocity, interlocking systems, pickup hoods, ducting (and cleaning), bags, shakers, fans, gates.
  • #71  6.1. General   6.1.1 It should be noted that protection of the environment is not addressed in this guideline, and discharges into the atmosphere should be compliant with relevant local and national environmental legislation and standards.   Dust, vapours and fumes could be possible sources of contamination; therefore, care should be taken when deciding on the location of the inlet and exhaust points relative to one other.
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