Contamination control in Cleanroom_ Dr. A. Amsavel

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Contamination Control In Cleanroom

• Dr. A. Amsavel, M.Sc., B.Ed., Ph.D.,

GMP
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An Overview

• Basics of Contamination
• Sources of Contamination
• Environment Specification
• Elements of Cleanroom Design and Qualification
• Definitions
• Control of Contaminations
• People, Cleaning, Environment Material
• Operation, Monitoring and Control
• Documents and Records

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Contamination Control

• Why Contamination control in cleanroom is
  significant in pharmaceuticals manufacturing?.
• To ensue the Patient safety
• To ensure quality, purity, safety and efficacy of
  the products
• To meet GMP requirement
• To meet regulatory Requirement
• Minimize the risk of product defective
• Quality of product should be built into design
  and systems during manufacturing, NOT BY TESTING
• Contamination may pose risk to the patients
• Set the systems, practices and procedures to
  eliminate or minimise the introduction of
  contaminant into a product / process.

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• How does the manufacturing environment affect
  quality, contamination and cross-contamination?
• How do we arrive at an optimal environment ?
• The following will ensures the Product Quality
  And prévention of contamination and
  cross-contamination.
• Best Clean Room design and maintenance- HVAC
• Prevention / restriction of source of
  contaminants
• Monitoring and Control procedures
• Effective Cleaning
• Training and practices.

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What are the possible Contaminants

• Contaminants Any unwanted substance present in
  or on a material or any surface within a Clean
  Area

Physical Chemical Biological Control/ Removal
Dust Organic Compounds Bacteria Air Filtration Thermal Disinfectant Electro-magnetic Electrostatic discharge Electrical radiation Cleaning operational control
Dirt Inorganic Salts Fungus Air Filtration Thermal Disinfectant Electro-magnetic Electrostatic discharge Electrical radiation Cleaning operational control
Grit Vapour Spore Air Filtration Thermal Disinfectant Electro-magnetic Electrostatic discharge Electrical radiation Cleaning operational control
Fibre Mist Virus Air Filtration Thermal Disinfectant Electro-magnetic Electrostatic discharge Electrical radiation Cleaning operational control
Fly ash, shoots Fume / Smoke Human skin cells Air Filtration Thermal Disinfectant Electro-magnetic Electrostatic discharge Electrical radiation Cleaning operational control
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Sources of Contamination

• Major Sources of Contamination and Controls

Source Reduce / Removal
1 Personnel Training, Practice, PPEs, Gowning, Hygiene
2 Environ-ment Facility , HVAC design, Clean room, Air filtration, Cleaning, Operation and Maintenance
3 Equipment Cleaning, Maintenance
4 Material Restriction, de-dust/ de-contamination
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Particle Size of Matters in the Air
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Selection of Filters for HVAC
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Cleanroom

• Cleanroom Requirement
• To translate the qualitative concept of clean
  to a quantifiable parameters for environment
  control ,environment specification /
  classification is required.
• For classification we measure the suspended
  contaminant density or numbers of suspended
  particles per unit volume. The lower the
  contaminant density, the cleaner the environment.

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Definition

• CleanroomISO 14644-11999, 2.1.1.Room in
  which the concentration of airborne particles 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
• Changing RoomRoom where people using a
  cleanroom may change into, or out of, cleanroom
  apparels.
• AirlockIntermediate room or area that is
  usually ventilated, and used to minimise the
  transfer of airborne contamination from one area
  to another

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Definition

• ContaminantAny particulate, molecular,
  non-particulate and biological entity that can
  adversely affect the product or process
• DisinfectionRemoval, destruction or
  de-activation of micro-organisms on objects or
  surfaces
• HEPA  (High Efficiency Particulate Air)
• Filter element rated between 85 and 99.995
  removal efficiency.
• CleanlinessCondition of a product, surface,
  device, gas, fluid, etc. with a defined level of
  contamination
• NOTE Contamination can be particulate,
  non-particulate, biological, molecular or of
  other consistency

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Definition

• Filter leakage testtest performed to confirm
  that the final filters are properly installed by
  verifying that there is absence of bypassleakage
  in the installation, and that the filters and the
  grid system are free of defects and leaks
• Airflow The average airflow velocity, volume
  and uniformity in a cleanroom or an installation,
  as well as to determine air supply volume flow
  rate.
• Air Change A measure of the amount of air moving
  in or out of a space because of leakage or
  mechanical ventilation. One air change is a
  volumetric flow of air equal to the cubic content
  of the space.

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Cleanroom Design

• Following parameters should be taken into account
  while designing of Cleanroom
• Room classification (ISO Norms)
• Temperature Humidity
• Air changes Make-up Air
• Filter grades to meet particles (Viable
  non-viable)
• Differential pressure cascade
• Airflow velocity patterns
• Flow patterns (turbulent and uni-directional)
• GMP criteria critical process requirements
• Noise Vibration in Duct and Electrostatic
  discharge
• Ref guideline ISO-14644-1,2, 4 Clean room
  standard design, and construction

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  Cleanroom Class Limits
Ref ISO Standard 14644-1
ISO Classifi- cation Number Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below
ISO Classifi- cation Number gt 0.1µm gt 0.2m gt 0.3µm gt 0.5µm gt 1µm gt 5.0µm
ISO Class 1 10 2
ISO Class 2 100 24 10 4
ISO Class 3 1000 237 102 35 8
ISO Class 4 10000 2370 1020 352 83
ISO Class 5 100000 23700 10200 3520 832 29
ISO Class 6 1000000 237000 102000 35200 8320 293
ISO Class 7 352000 83200 2930
ISO Class 8 3520000 832000 29300
ISO Class 9 35200000 8320000 293000
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Cleanroom Requirement
ISO Class Air flow (fpm)_at_ Air Changes M3/m2 per hour HEPA Coverage as of Ceiling
1 70 - 100 gt750 100
2 70 - 100 gt750 100
3 70 - 100 gt750 100
4 70 100 500 600 100
5 70 - 100 225-275 _at_ 100
6 NA 70-160 33 - 40
7 NA 30-70 10 - 15
8 NA 10 20 05 -10
_at_ ASHRE ISO14644-4 Industrial standard _at_ ASHRE ISO14644-4 Industrial standard _at_ ASHRE ISO14644-4 Industrial standard _at_ ASHRE ISO14644-4 Industrial standard
For ISO Class-8 HEPA filters or 95 ASHRE HEPAs
recommended
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Cleanroom Monitoring
ISO 14644-2 Specifications for testing and
monitoring to prove continued compliance to
ISO-14644-1
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Filters

• HEPA Filters
• The HEPA filters media is constructed by much
  higher percentage of fine diameter glass fibre
  in ULPA filter the percentage of fine glass fibre
  is even higher than that of HEPA.
• The filter consist of the filter media folded
  into deep pleats, separated by corrugated
  aluminum, PVC or any other suitable medium, and
  packed into a rigid frame made of treated
  plywood, particle board or metal. The filter pack
  is cemented into the rigid frame using epoxy, PVC
  etc.
• Electrostatic Air filter (5 8kV -5kV)
• High Efficiency at sub-micronic levels,
  relatively ineffective with larger particle.
  Lower efficiency as compared to HEPA
• Charged particle escaping can cause damage
  downstream.
• Arcing causes temporary localized loss of
  efficiency, resulting in release of collected
  contaminant

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Consideration for Cleanroom

• Ensure the following are considered while
  commissioning of cleanroom
• Identification of the clean zones and size of
  control zones
• Air locks Change rooms, interlocks, air
  curtains
• Temperature RH control, dehumidifier,
• Number of AHUS, sélection of filters , Air flow
  pattern
• Instruments for monitoring
• HEPA, Insulation of Structure ducts
• Proper treatment of fresh / make-up air
• Effectively balance air quantities in area
  needing exhaust
• Floors, walls, ceilings should be smooth finish
  and easy to clean.
• Drains, coving, area for washing and storage of
  equipments and accessories
• Note Recommended pressure differential between
  two adjacent zones is 15Pa, but pressure
  differentials of between 5Pa and 20Pa may be
  acceptable.

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Qualification of HVAC

• Ensure that the following parametres are
  considered, tested, qualified and documented
  during qualification of cleanroom and HVAC
  system
• Differential pressure between rooms
• Temperature and RH level and uniformity test
• Determination of differential pressure on filters
• Determination of air flow velocity
• Measurement of air volume and uniformity air
  exchange rate
• Airflow parallelism test
• Determination of airflow patterns
• Determination of room classification (airborne
  particle count mapping)

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Qualification of HVAC

• Filter installation leak test (challenge test)
• Qualification test shall confirm that HEPA and
  ULPA filters are properly installed. There is no
  by-pass leakage in the installation (frame,
  gasket seal, and filter bank framework) and the
  filters are free of defects and small leaks in
  the filter medium and frame seal.
• Tests are performed by introducing an aerosol
  challenge upstream of the filters and scanning
  immediatly downstream of the filters and support
  frame or sampling in a downstream duct.

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Qualification of HVAC

• Determination of the recovery time
• This test is not recommended for unidirectional
  airflows. Perform thet test that clean room or
  clean zone is capable of returning to its
  specified cleanliness class within a finite time,
  minimum hold hold time to addrres the account
  of power failure, start (recovery), mode change,
  use of changing rooms, etc.
• The key factors for a successful HVAC
  qualification are
• The understanding of interfaces beween product
  purity / characteristic, process, clean zones,
  HVAC functions and clean rooms requirements,
• The knowledge concerning general and HVAC
  specific tests,
• The structured identification of critical
  functions and operations, appropriate measures
  (design, qualification, calibration, and
  validation activities) in a documented way.

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Qualification Documents

• Document the qualification with supported by
  appropriate documents.
• Protocols reports of DQ, IQ, OQ PQ consists
  of
• Conceptual documents, URS,
• PO, approved diagrams, SAT, FAT
• OQ PQ, Test parameters with acceptance
  criteria, test results, test methods, raw data,
  supporting data (printouts, electronic data,
  visual etc), MOC, calibration certificates,
  manuals, etc..
• Drawings Layout, as-built drawings with zone
  classification, men and material flow, etc.

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Operational Controls

• Consider the following for effective
  operational controls and monitoring to prevent
  the contaminations.
• HVAC system and environment
• Production Process
• Cleaning Maintenance
• Training Personnel Practices Gowning, Clothing
  Hygiene etc
• Seasonal Effects influence of variation in
  temperature RH
• Disinfection- type, concentration, rotations
• Non-Product contact Equipment
• Raw materials Components
• Tools Utensils

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Personnel

• Personnel should be trained in a manner that
  minimizes the possibility of contamination being
  generated or transferred or deposited on or into
  the product.
• A policy concerning jewelry, cosmetics or
  similar material to control the contamination
• Training on the following areas , but not
  limited to
• GMP, Procedure, Processes and Operation, cleaning
  of area equipment
• Clean room practices , gowning, aseptic
  technique, health, Safety risk, and relevant
  intervention procedure,
• Also train on the cause and consequences , if it
  is not followed
• Assess the effectiveness of training
• Validation /verification and Monitoring as
  required. eg bio-burden In gown, finger etc

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Personnel

• Establish procedure for Practice good sanitation,
  personal hygiene, health habits and operations in
  the cleanroom.
• Avoid direct contact with intermediates or APIs
  or drug products
• Instruction to follow cleanliness, use of clean
  clothing, proper washing, bathing, nail cut, and
  use of disinfectant, gowning, change over and
  all clean room practices.
• Use of PPEs, covers for head, face, hands and
  arms, proper gowning to reduce the exposure and
  contamination. Eg dead skin cells , hair fall,
  sweat, etc
• Personal and other items shall be restricted to
  the cleanroom
• Cleaning of equipment as per procedure and ensure
  the line clearance.
• Ensure the above is followed always even no one
  is watching

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Definition Type of Disinfectants

• Antiseptic An agent that inhibits or destroys
  microorganisms on living tissue including skin,
  oral cavities, and open wounds.
• Disinfectant A chemical or physical agent used
  on inanimate surfaces and objects to destroy or
  remove infectious fungi, viruses, and bacteria,
  but not necessarily their spores.
• Cleaning Agent An agent for the removal from
  facility and equipment surfaces of product
  residues that may inactivate sanitizing agents or
  harbor microorganisms.

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Definition Type of Disinfectants

• Sanitizing Agent An agent for reducing, on
  inanimate surfaces, the number of all forms of
  microbial life including fungi, viruses, and
  bacteria.
• Sporicidal Agent An agent that destroys
  bacterial and fungal spores when used in
  sufficient concentration for a specified contact
  time. It is expected to kill all vegetative
  microorganisms.
• Sterilant An agent that destroys all forms of
  microbial life including fungi, viruses, and all
  forms of bacteria and their spores. Sterilants
  are liquid or vapor-phase agents

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Methods of Cleaning

• Vacuum cleaning
• Use HEPA/ULPA installed vacuum cleaners to
  remove larger particles and other debris.
• Use in unidirectional strokes to minimize air
  turbulence.
• Also can be used to removing excess water and
  suspended particles and faster drying after wet
  mopping.
• Wet cleaning
• Mopping is an effective method in gross or
  intermediate cleaning for removing particulate
  residues.
• Establish procedure and clear instruction for
  mopping
• Disinfectant preparation, type of mops, no. of
  buckets, instruction for stroking, overlapping,
  direction of mopping, rinsing squeezing with
  water, frequency of changing solutions

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Methods of Cleaning

• Wet cleaning
• Scrubbing Use machine or manual cleaning to
  remove stains or heavily soiled areas / equipment
  surface by scrubbing and then clean by mopping
  or wiping.
• Damp cleaningWiping techniques are used in most
  phases of cleaning. Wiper should be dampened with
  the appropriate cleaning solvent/solution.
  Wiping should always be done in unidirectional,
  overlapping strokes, proceeding from most
  critical to least critical areas.

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Cleaning of Cleanroom

• Cleaning of SurfacesIdentify the surfaces
  according to criticality to the product or
  process and establish the cleaning techniques to
  the required level of cleanliness. Validate the
  cleaning verify the efficacy of disinfectant.
• Floors, Walls, doors, grills, windows and
  vertical surfacesClean the upstream surfaces
  during at-rest state. Remove products from the
  area or cover the items.
• Ceilings, diffusers and lamp fixturesWipe
  thoroughly as per damped wiper as per frequency.
  Clean after repair or replacement. Eg. Bulbs
• Tables and other critical horizontal
  surfacesUse damp wipers and cleaning solution
  to remove the contamination

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Cleaning of Cleanroom

• Chairs, furniture and laddersWipe these
  surfaces from top to bottom. Include cushions,
  supports, and wheels if appropriate.
• Cross-over benches, garment and supply cabinets,
  lockers periodically empty and clean interiors
  and surfaces by wiping
• Rubbish bins and containersRubbish bins and
  containers can be lined with plastic bags to
  remove the refuse and protect container surfaces.
  All bins should be removed to general,
  non-critical areas and remove the rubbish.
• Cleanroom mats and sticky flooringCleanroom
  mats and sticky flooring should be cleaned by wet
  mop or maintained on a regular basis. Use vacuum
  cleaner as required.

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Cleaning Frequency

• Schedule / Frequency for cleaning
• Most routine cleaning operations should be
  performed as per established frequency at regular
  basis. Other cleaning may require on certain
  frequency or when needed.
• Daily cleaning (once in 24hours) Clean room
  floors, walls, doors etc. Air locks, changing
  operational areas should be cleaned at least
  daily. Vacuuming and or mopping floors, and
  wiping the surfaces
• Periodic cleaningSurfaces not cleaned on a daily
  basis should be cleaned periodically like weekly,
  bimonthly or monthly etc eg storage areas,
  service areas, pipes and fittings.
• Intensive cleaning efforts should be taken after
  holidays or planned shutdowns

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Non-routine Cleaning

• Cleaning after modification, construction or
  maintenanceEffective cleaning after construction
  is essential to control and eliminate
  contamination sources.
• Cleaning during emergency situationsProcedures
  should be instituted for cleaning in the case of
  a gross contamination event.
• Special cleaning during shut down
• environmental incident like major equipment,
  utility failures or spills contamination due to
  failure or ineffective routine cleaning

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Cleaning of Area Equipment
Surface Cleaning agent Frequency
Floors Spill areas Around drains Path men movement Access ports, passbox Doors Handles Sinks, Benches, tools Trash containers Use Dettol, lysol or savlon as Disinfectant ate recommended strength. Surfactant if required ( solvent / water for spill area) Daily, change over Wipe or mob
Walls, ceilings, grills Trolley, pallets Disinfectant Surfactant if required Weekly Wipe or mob
Equipment accessories Pipelines, sampling tools Utensils, Water /Solvent Surfactant if required Batch to batch/ change over. As per procedure
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Microbial Contaminants and Control
Microbial Contaminants Sources / enhances Control
Human Skin Flora StaphylococcusPropionibacterium acnes Operator contamination Gowning Material Traced back to one operator Skin infection Non-sterile drug product Gowning control Proper disinfectant Rotation Rinsing Cleaning and sanitization Cleaning Validation of Floors, Walls Equipment
Fungal Spores PenicilliumAspergillusCladosporium etc Items brought to Cleanroom Bags, Boxes, Intervention Equipment, Pallets, Pallet Jacks, Shoes, Shoe Covers Raw Materials, high RH temperature Gowning control Proper disinfectant Rotation Rinsing Cleaning and sanitization Cleaning Validation of Floors, Walls Equipment
Bacterial SporesBacillus cereus Bacillus circulansgroup Paenibacillus glucanolyticus Cleanroom Shoe Cover Process Vessels Raw Material Gowning control Proper disinfectant Rotation Rinsing Cleaning and sanitization Cleaning Validation of Floors, Walls Equipment
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Contaminants from Equipment

• Possible Contaminants from Equipment
• Product residues
• Previous APIs
• Intermediates
• Side products degradants
• Raw materials / Solvent
• Cleaning agent residues and breakdown
• Airborne matter
• Lubricants, ancillary material
• Possibly Bacteria, mould and pyrogens on long
  holding.

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Cleaning of Equipment

• Equipment and utensils shall be cleaned,
  maintained and sanitized at appropriate intervals
  to prevent contamination that would alter the
  safety, identity, strength, quality or purity of
  the drug product. (21 CFR 211.67)
• Establish Cleaning / sanitization procedures for
  cleaning of equipment.
• Validate the cleaning procedures and Analytical
  methods with recovery used for testing residue,
• Sampling procedures and Sampling locations
  (clearly defined)
• Acceptance criteria and rationale
• Frequency - for Between batches, product
  changeover
• Periodic re-evaluation and revalidation
• Routine monitoring equipment/ prior to start up

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Monitoring Testing of Cleaning

• Monitoring cleaning effectiveness and
  testingMonitoring and testing of cleanliness
  have to be determined and established to ensure
  the effectiveness and prevention of
  contamination.
• Routine visual inspection for surface cleanliness
  ie absence of strain, residue, soiling etc
• Method of checks Use high-intensity white light
  for visual check, use wet wipes by swap the
  surfaces and check for colouration and other
  methods like tape lift method and surface
  particle detector method.
• Bio-burden Use Contact plates or Surface
  swabbing

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Material

• Source of contamination
• Product/ process materials, Packaging materials,
  Bags, drums, Intervention Equipment, Pallets,
  Pallet Jacks are handled at clean room
• Action to prevent contamination
• Take all precaution and procedure that material
  does not compromise the cleanliness of the
  product or process
• Restrict the transfer of unwanted items
• Minimise the quantities of materials stored in
  the cleanroom,
• Protective storage or isolation., where necessary
• Cover the items before transfer and De-dust/
  de-contamination as required.
• Collect all used and waste materials and remove
  frequently

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Dcouements and Records

• Establish procedure for routine and non-routine
  monitoring activities in cleanroom.
• Pressure differential between rooms between
  filters
• Temperature RH
• Cleaning of floors other surface areas including
  disinfectant preparation rotation,
• Repair, replacements, maintenance and cleaning
• Environment monitioring Procedure for sampling,
  how many. where and how?
• Particulate count
• Bio-burden air filtration method plate exposure
  method
• Personal hygiene- Verification /self declaration
• Calibration of monitoring devices
• Deviation and investigation

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Reference

• ISO/DIS 14644 Cleanrooms and associated
  controlled environments
• Part 1 Classification of air cleanliness
• Part 2 Specifications for testing and monitoring
  to prove continued compliance with ISO 14644-1
• Part 4 Design, construction and start up
• Part 5 Operations
• WHO TRS- 961 Annex-5 Heating, ventilation and
  air-conditioning systems for non-sterile
  pharmaceuticaldosage forms

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• Thank you
• Dr. A. Amsavel
• Contact aamsavel_at_gmail.com