cleanroom, classification, design and

Cleanrooms Slide 1 of 68November 2014

Tehran University of Medical SciencesSchool of Pharmacy

Cleanrooms

Classification, Design and Testing

Ahmadreza BarazeshUnder the supervision of Dr. Vatanara



References ISO 14644

– Part 1: Classification of air cleanliness– Part 2: Continued compliance with– Part 3: Metrology and test methods– Part 4: Design, construction and start-up

WHO Technical Report Series, No. 902, 2002– Annex 6: Good manufacturing practices for sterile pharmaceutical products

WHO Technical Report Series, No. 961, 2011– Annex 5: WHO guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems

for non-sterile pharmaceutical dosage forms

– Annex 6: WHO good manufacturing practices for sterile pharmaceutical products

PIC/S GMP Guide (Part I: Basic Requirements For Medicinal Products)

PIC/S Guide To Good Manufacturing Practice For Medicinal Products - Annexes

Disclaimer: The TUMS logo included, neither indicates that the lecturer is an official lecturer of TUMS nor the content is approved by TUMS. It is just indicative of the department in which the lecture was prepared and presented.



ScopeWhat will be covered during this presentation:

A Brief review on cleanroom classification

Introduction of Design Concepts and Considerations based on ISO 14644 Series Standards, PIC/S and WHO Guidelines.

Testing Methods and Procedures According to



IntroductionCleanrooms provide for the control of airborne contamination

to levels appropriate for accomplishing contamination-sensitive activities.

– Aerospace,

– Microelectronics,

– Pharmaceuticals,

– Medical devices,

– Healthcare (Hospitals)

– Food.



DefinitionsCleanroom: room in which:

– The concentration of airborne particles is controlled, – Constructed and used in a manner to minimize the introduction, generation,

and retention of particles inside the room,– Other parameters (temperature, humidity, and pressure) are controlled

Installation: cleanroom or one or more clean zones, together with all associated structures, air-treatment systems, services, and utilities.

Classification: level of airborne particulate cleanliness, represents maximum allowable concentrations (in particles per cubic metre of air) for considered sizes of particles



Definitions

Particle: Solid or liquid object which, for purposes of classification of air

cleanliness, falls within a threshold size in the range from 0.1 to 5µm

Occupancy states

As-built: installation is complete, all services functioning, no production equipment, materials, or personnel present

At-rest: no personnel present

Operational: the installation is functioning in the specified manner, specified number of personnel present and working



ClassificationThe particulate cleanliness of air shall be defined in one or

more of three occupancy states, viz. “as-built”, “at-rest”, or “operational”

The maximum permitted concentration of particles, Cn, for each considered particle size, D,

In which, N is the ISO classification number, which shall not exceed a value of 9. (ISO Class 1 to 9)



Classification



Classification

Graphical representation of ISO-class concentration limits for selected ISO classes



Classification PIC/S Guide To GMP For Medicinal Products Annex 1



Classification WHO Technical Report Series, No. 902, 2002 Annex 6



Classification WHO Technical Report Series, No. 902, 2002 Annex 6

This comparison is defined based on at-rest limitations.



Classification

Class

maximum particles/m3

FED STD 209E

equivalent

EU GMP Classification≥0.1 µm ≥0.2 µm ≥0.3 µm ≥0.5 µm ≥1 µm ≥5 µm

ISO 1 10 2.37 1.02 0.35 0.083 0.0029

ISO 2 100 23.7 10.2 3.5 0.83 0.029

ISO 3 1,000 237 102 35 8.3 0.29 Class 1

ISO 4 10,000 2,370 1,020 352 83 2.9 Class 10

ISO 5 100,000 23,700 10,200 3,520 832 29 Class 100 Grade A and Grade B

ISO 6 1.0×106 237,000 102,000 35,200 8,320 293 Class 1,000

ISO 7 1.0×107 2.37×106 1,020,000 352,000 83,200 2,930 Class 10,000 Grade C

ISO 8 1.0×108 2.37×107 1.02×107 3,520,000 832,000 29,300 Class 100,000 Grade D

ISO 9 1.0×109 2.37×108 1.02×108 35,200,000 8,320,000 293,000 Room air



Classification PIC/S Guide To GMP For Medicinal Products Annex 1



Classification: Designation The designation of airborne particulate cleanliness for clean rooms and

clean zones shall include:– the classification number, expressed as “ISO Class N”;

– the occupancy state

– the considered particle size(s), and the concentration(s), 0,1µm through 5 µm.

Example designation:– ISO Class 4; operational state; considered sizes: 0,2µm (2 370 particles/m3), 1 µm

(83 particles/m3)



Airborne particle physical control:– Filtration (HEPA)– Dilution (Higher Airchange Rate)– Isolation HEPA

class retention (total) retention (local)

E10 > 85% ---E11 > 95% ---E12 > 99.5% ---H13 > 99.95% > 99.75%H14 > 99.995% > 99.975%U15 > 99.9995% > 99.9975%U16 > 99.99995% > 99.99975%U17 > 99.999995% > 99.9999%



Classification: PIC/S Grade A: The local zone for high risk operations:

– Filling zone, open ampoules and vials, making aseptic connections. – Provided by a LAF work station with a homogeneous air speed in a

range of 0.36 – 0.54 m/s (guidance value)– A unidirectional air flow and lower velocities may be used in closed

isolators and glove boxes.

Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone.

Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.



PIC/S General Paragraphs Clean Areas:

– Entry through airlocks for personnel and/or for equipment and materials.

– Supplied with air has passed through filters of an appropriate efficiency.

The various operations of component preparation, product preparation and filling in separate areas within the clean area

Manufacturing operations:– Product is terminally sterilized,– Conducted aseptically at some or all stages.

In order to meet “in operation” conditions, areas should be designed to reach certain air-cleanliness levels in the “at rest” occupancy state.



PIC/S General Paragraphs “In operation” classification may be demonstrated during normal

operations, simulated operations or during media fills (worst-case)

Clean rooms and clean air devices should be routinely monitored– Monitoring locations based on risk analysis and the results of classification

– Grade A: full duration of critical processing

– Grade A: Such a frequency and sample size that all interventions, transient events is captured and alarms triggered

– Grade B: The same as grade A; the sample frequency may be decreased.

– Grade C and D: in accordance with the principles of quality risk management.



PIC/S General ParagraphsTerminally Sterilized Products

– Preparation of components and most products should be done in at least a grade D environment

• Where the product is at a high or unusual risk of microbial contamination Grade C

– Filling of products for terminal sterilization Grade C• Where the product is at unusual risk of contamination from the environment,

filling Grade A with Grade C background.

– Preparation and filling of ointments, creams, suspensions and emulsions should grade C before terminal sterilization



PIC/S General ParagraphsAseptic Preparation

– Components after washing Grade D

– Handling of sterile starting materials, unless subjected to sterilization or filtration Grade A with Grade B background.

– Otherwise Grade C

– Handling and filling of aseptically prepared products Grade A

– Transfer of partially closed containers, as used in freeze drying, either in a Grade A environment with grade B background or in sealed transfer trays in a grade B environment



PIC/S Paragraphs on Premises All exposed surfaces should be smooth, impervious and unbroken

To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment.

False ceilings should be sealed.

Sinks and drains should be prohibited in grade A/B areas

Changing rooms should be designed as airlocks, The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads.



PIC/S Paragraphs on Premises Both airlock doors should not be opened simultaneously; interlocking

system or a visual and/or audible warning system should be operated.

A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade. a pressure differential of 10-15 pascals

It should be demonstrated that air-flow patterns do not present a contamination risk.

A warning system should be provided to indicate failure in the air supply.



Planning and Design A project plan shall be developed to define the requirements of the

products, the processes and the scope of the installation.

A process equipment list shall be compiled, and shall include the critical requirements for each piece of process equipment.

Diversity factors shall be defined, considering peak and average demand for each utility and environmental control system.

A contamination control concept shall be developed for each zone of an installation.



Design: Control and segregation concepts

For economic, technical and operational reasons, clean zones are often enclosed or surrounded by further zones of lower cleanliness.

The zones with the highest cleanliness demands is reduced to the minimum size.

Movement of material and personnel between adjacent clean zones gives rise to the risk of contamination transfer,

management of material and personnel flow



Design: Control and segregation concepts



Design: Personnel flow and Material flow

Personnel flows considered:– Manufacturing personnel– Maintenance personnel– Quality control personnel

Material flows considered:– Raw materials– Finished goods – Waste– Product (In-process, Intermediate & Final)– Equipment

• Clean and dirty components• Portable equipment• Product containers




Desirable Layout Less Desirable Layout



Design: Air Flow Patterns

Air flow patterns: – Cleanroom airflow patterns can be categorized as either

unidirectional or non-unidirectional (or mixed)

Unidirectional airflow– ISO Class 5 and cleaner– may be either vertical or horizontal– airflow rely upon a final filtered air supply and– return inlets are nearly opposite air supplies to maintain the

airstream straight



Design: Air Flow Patterns

non-unidirectional airflow cleanrooms

– Air flow outlets located in multiple positions. Filter outlets may be distributed at equal intervals or grouped over the core process.

– The final filter location may be remote, (avoid contamination ingress between filters and cleanroom)

– Return air locations in non-unidirectional airflows are not as critical

– Distribute the returns to minimize dead zones within the cleanroom



Disturbance of unidirectional airflow



Contamination Control Concepts



In order to protect cleanrooms from contamination from adjacent less clean spaces

Displacement concept (low pressure differential, high airflow) – by means of a low turbulent "displacement" airflow, >0,2 m/s

Pressure differential concept (high pressure differential, low airflow) – The pressure differential in the range of

5 - 20 Pa, to allow doors to be opened and to avoid unintended turbulence.

Physical barrier concept – Use of an impervious barrier to prevent contamination transfer to a

clean zone from a less clean zone.

Design: Segregation Concepts



Design: Layout of an installationGeneral Considerations: Size: of cleanroom should be minimum. if a large space is required, it

should be divided, with or without physical barriers.

Workstation siting and organization: critical workstations away from, major traffic pathways.less clean operations site downstream of cleaner operations.

Ancillary areas and adjacent cleanrooms: – Pressure or flow differentials,

– Access and communication arrangements (such as airlocks, speech panels and intercoms

cross-contamination from less clean zones does not

compromise the cleaner zones.



Design: Layout of an installationGeneral Considerations (contd.)

Utility services and ancillary equipment– General: Utility services should be designed and installed such that

the cleanroom is not compromised by contamination.

– exposed piping, tubing and cable runs should be minimized,

– Vacuum-cleaning equipment

– Sprinkler systems

– Communication systems: to reduce personnel movement

– Glazing: Avoid heat loss and solar gain, non-opening double glaze



Design: Layout of an installationAccess:

General: The number of openings should be minimized. Normal (non-emergency) access should be through airlocks for both personnel and material.

Airlocks: In order to maintain pressure differential and integrity of during entry and exit, airlocks or transfer hatches (pass-throughs) are normally required.

Emergency exits: Emergency exits should be provided with means to show that they have been opened.



Design: Layout of an installationAccess (contd.) Changing rooms: Have three functional zones:

– Entry: access from ancillary. appropriate for removal, storage, disposal and/or redonnning of garments not permitted within the cleanroom;

– Transition zone: where garments or personal equipment dedicated to the cleanroom are stored, donned or removed.

– Inspection/access zone: where inspection of the completed gowning is accomplished and provides access to cleanroom.

The three functional zones may be separated by a physical barrier (e.g. a stepover bench or airlock)



Changing Rooms



Design: Layout of an installation The following requirements should be defined:

– number of people passing through the gowning procedure– the gowning procedure (i.e. what garments are to be taken off and put on)– the frequency of garment replacement.

Consideration should be given to the following provisions:– Storage and disposal of garments;– Storage before use and disposal of consumable items– Storage of personal items;– Hand-washing and drying or other decontamination processes;– Display or posting of gowning sequence, with clear instructions;– full-length mirrors to check effective fit.



Design: Construction and materials The materials used should be selected to meet the requirements of the

installation, and should take into account the following:a) the cleanliness class;

b) effects of abrasion and impact;

c) cleaning and disinfection methods and frequencies;

d) chemical/microbiological attack and corrosion.

Surface cleanliness and cleanability of materials of construction

Fittings in airlocks: Minimum horizontal surfaces



Design: Construction and materials Ceilings: Ceilings should be sealed, penetration points should be kept

minimum.

Walls: Materials and surface finishes should meet all general requirements.–Particular consideration to impact and abrasion. (rubbing strips, protective bars)–Cover strips or seals between panels should be smooth, with rounded edges–Use double glazing, with airtight seal, which can enable flush mounting–Doors should present as few horizontal surfaces as possible, thresholds avoided.–Consider use of push plates, automatic openings, or appropriate door-swing

Floors: Floors or floor coverings should be non-porous, slip-resistant, abrasion-resistant, conductive if necessary.



Design: Construction and materials



Design: Control of air CleanlinessAir filtration systems

– Air filtration systems including filter elements, mounting frames, housings, gaskets, sealants and clamping systems should be selected to suit both the cleanliness and using condition.

– Three basic stages of air filtration are recommended:• prefiltering of the outside air to ensure adequate quality of air supply • secondary filtering in the air conditioning plant to protect the final filters;• final filtering before cleanroom supply.

– “Sacrificial" filters or temporary filters: considered to protect the air cleanliness of air-handling systems during construction and commissioning.



HVAC Systems



Tests MethodsCleanroom tests:

– Required Tests: An airborne particle count test shall be carried out in order to classify an installation

– Optional Tests: • Airborne particle count for ultrafine and/or Micro-particles• Airflow test• Air pressure difference tests• Installed filter system leakage test• Air flow direction tests and visualization• Temperature, Humidity and Electrostatic tests• Particle deposition tests• Recovery tests• Containment leak tests



Tests MethodsAirborne particle count for classification and test measurement: Measurement of airborne particle concentrations with size 0.1 - 5 μm. A discrete-particle-counting, light-scattering instrument is used to

determine the concentration of airborne particles. Prior to testing, verify that all aspects of the cleanroom and functioning

in accordance with specifications.– Airflow rate or velocity tests;– Pressure difference test;– Containment leakage test;– Filter leakage test.



Airborne particle count for classification and test measurement:

Sampling– Minimum number of sampling point locations:

– Sampling locations evenly distributed, at the height of the work activity.

– Sample a sufficient volume of air that a minimum of 20 particles would be detected if the particle concentration for the largest considered particle size were at the class limit for the designated ISO class.

– The volume sampled at each location shall be at least 2 litres, with a minimum sampling time at each location of 1 min.

– Compute the overall mean of the averages, standard deviation, and 95% upper confidence limit from the average particle concentrations for all locations.

Tests Methods



Tests Methods Airborne particle count for ultrafine particles

– Smaller than 0,1μm– DPC, with a capability for accurate particle size definition up to at least 1μm.– Condensation nucleus counter (CNC)– Small sampling flow & long sampling tube diffusion loss.

Airborne particle count for macro-particles– Larger than 5 μm.– There are two general categories of macroparticle measurement methods.

• collection by filtration or inertial effects, followed by microscopic measurement• in situ measurement of the concentration and size of macroparticles with a time-of-flight

particle counter or DPC



Tests Methods Two general categories of macroparticle measurement methods:

– collection by filtration or inertial effects, followed by microscopic measurement of the number and size, or measurement of the mass of collected particles:

• filter collection and microscopic measurement will report macroparticles using particle size based upon the agreed diameter;

• cascade impactor collection and microscopic measurement will report macroparticles using particle size based upon the microscopist's choice of reported particle diameter;

• cascade impactor collection and weight measurement will report macroparticles using particle size based upon an aerodynamic diameter;

– In situ measurement of the concentration and size of macroparticles with a time-of-flight particle counter or a DPC:

• DPC measurement of particle size based upon an equivalent optical diameter;• Time-of-flight particle size measurement based upon an aerodynamic diameter.



Tests Methods

Airflow Test To measure airflow velocity and uniformity, and supply airflow rate

Measurement of velocity distribution is necessary in unidirectional airflow cleanrooms, and supply airflow rate in non-unidirectional cleanrooms.

Supply airflow rate (air volume supplied to the clean installation per unit of time) can also be used to determine the air changes.

Airflow rate is measured either downstream of final filters or in air supply ducts; both methods rely upon measurement of velocity of air passing through a known area.



Tests Methods: Air Flow Test

Procedure for unidirectional airflow installation test Supply airflow velocity

– Measured at approximately 150-300 mm from the filter face. – Number of measuring points should be the square root of 10 times

of area in m2 but no less than 4. At least 1 point for each filter outlet Uniformity of velocity within the cleanroom

– measured at approximately 150-300 mm from the filter face and the subdivision into grid cells should be defined

Supply airflow rate measured by filter face velocity – The results of the airflow velocity test can be used to calculate the

total supply airflow rate. Supply airflow rate in air ducts

– by volumetric flowmeters (orifice meters, Venturi meters and anemometers)



Tests Methods: Air Flow Test

Procedure for non-unidirectional airflow installation test Air volume supply rate and air-change rate are the most important

parameters.

Supply airflow rate measured at the inlet– Because of local turbulence, use of a flowhood that captures all of the air

issuing from each supply diffuser is recommended.

Supply airflow rate calculated from filter face velocity– Evaluation of the supply airflow rate without a flowhood may be done with

an anemometer downstream of each final filter. The supply airflow rate is determined from the airflow velocity multiplied by the area of exit.



Test Methods

Air pressure difference test Verify the capability of the complete installation to maintain the

specified pressure difference between separate spaces

With all doors closed, the pressure difference between the cleanroom and any surrounding should be measured and recorded.

The following should be considered:– installation of permanent measuring points;– take measurements near the middle of the cleanroom

away from any supply air inlets or return air outlet.



Test Methods

Installed filter system leakage test To confirm that the filter system is properly installed and that leaks have

not developed

Introducing an aerosol challenge upstream of the filters and scanning immediately downstream of the filters and support frame or by sampling in a downstream duct.

Applied to cleanrooms in “as-built” or in “at-rest” occupational states, and when commissioning new cleanrooms, or existing installations require re-testing, or after the final filters have been replaced

Detection of leakage by Scanning / Stationary remeasuring



Test Methods: Filter Leakage Test



Test Methods Apparatus and materials for installed filter system leakage tests

– Aerosol photometer– Discrete-particle counter (DPC)– Suitable pneumatic or thermal aerosol generator(s)– Suitable aerosol dilution system.– Suitable aerosol source substances



Test MethodsAirflow direction test and visualization

To confirm that the airflow direction and its uniformity conform to the design and performance specifications

can be performed by the following four methods:1. Tracer thread method;

silk threads, single nylon fibers, flags or thin film tapes and effective lighting2. Tracer injection method;

tracer particles illuminated by high intensity light sources (DI Water , alcohol/glycol)3. Airflow visualization method by image processing techniques; (Quantitative)4. Airflow visualization method by the measurement of velocity distribution.



Test Methods: Air Flow Visualization



Test MethodsTemperature test

– Capability to maintain the air temperature level within the control– Measured at a minimum of one location for each temperature-

controlled zone. – Measurement time should be at least 5 min with one value recorded

at least every minute.– Comprehensive temperature test:

• At least 1 h after the air-conditioning system has been operated• The number of measuring locations should be at least two. • Probe should be positioned at work-level height and at a distance of no less

than 300 mm from the ceiling, walls, or floor of the installation



Test MethodsHumidity test

– Capability to maintain the air humidity level – Expressed as relative humidity or dew point– The sensor should be located at least at one location for each

humidity control zone, and sufficient time should be allowed for the sensor to stabilize.

– The measurement time should be at least 5 min.



Test MethodsParticle deposition test

– Sizing and counting particles that can be deposited from the air onto product or work surfaces in the installation.

– Particles are collected on witness plates with surface characteristics similar to those of the at-risk surface

– Are sized and counted using optical microscopes, electron microscopes, or surface scanning apparatus.

– The witness plate should be placed in the same plane as the at-risk surface. And at the same electrical potential as the test surface.



Test MethodsRecovery test

– Ability of the installation to eliminate airborne particles.– Only important and recommended for non-unidirectional airflow

systems– This test is not recommended for ISO Classes 8 and 9. – 100:1 recovery time is defined as the time required for decreasing

the initial concentration by a factor of 0,01



Test MethodsContainment leak test

– Determine if there is intrusion of contaminated air into the clean zones from non-controlled areas

– Particle concentration outside should be greater than the cleanroom concentration by a factor of 103. If the concentration is less, generate an aerosol.

– To check for leakage through construction joints, cracks or service conduits, scan inside the enclosure at a distance of not more than 5 cm from the joint, at a scan rate of approximately 5 cm/s.

cleanroom, classification, design and

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