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CLEANROOMDesign & Operation

Lecture 8

PHR213

Chris Soh Yee Chang


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IntroductionSterile pharmaceuticals:

Any dosage form devoid of viable microorganisms.

2 types of sterile product:Terminally Sterilized- prepared in a clean

fashion, transferred to its final container, sealed,

and sterilized.

Aseptically Prepared- aseptically processedfrom sterile materials, or sterilized by filtration,

before final packing in sterile containers.


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Introduction

Sterile products require preparationin a controlled environment.

CLEAN ROOM


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Clean Room:

a controlled environment

is a premise that specially designed,constructed, serviced and used with the

intention of eliminating microbial andparticulate contaminationinmanufacturing sterile products.


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Designing & OperatingClean Room:


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Clean Room set-up:

Storage area

Washing area

Changing area

Preparation area

Aseptic area


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Interlocking-Plan Layoutdoor

Airlock

Laminar RoomFlow

Material/ToolCabinet

Product Flow

Changing AreaAseptic Area

Personnel DFlow E

Glass Preparation WashingPass-box window Area Area

BC

ntrance A Corridor

Storage Area Utility Area Toilet


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A. Outside Clean Room


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B. Washing Area


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C. Preparation Area

Pass Box


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D. Changing Area


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E. Aseptic Area


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Important Features of

Clean RoomLimited airborne particles

Known air flow pattern and controlled

Controlled temperature & humidity

Regulated air pressure

Special construction & materials

Controlled operating procedure


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Environmental Control of

Clean RoomEnvironmental Cleanliness Standards(Clean Room Standards)Maximum no. of airborne particles greater

than defined particle size that are permitted in

a given volume of air.

Classification systems:

-British Standard 5295

-Federal Standard 209E (USA)-ISO 14644-I (June 1999)


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FEDERAL STANDARD 209E

AIRBORNE PARTICULATE CLEANLINESS CLASSES

Class limits are given for each class name. The limits designate specific concentrations (particles per unitvolume) of airborne particles with sizes equal to and larger than the particle sizes shown.

Class limits

nl... ...n!Class I' tllIe 0.1 im 0.2 pmt 5 tin

Volume units Volume units Volume units Volume units Volume units

S1 English (m3) (ft3) 3 (ft3) (ft3)

350 9.91 75,7 2.14 30.9 0.875 10.0 0.283

1240 35.0 265 7.50106

3.00 35.3 1.00

3 500 99.1 757 21.4 Ing 75 inn Z-VU f) Q )

M 2,5 1012 400 350 2 650 75.0 1060 30.0 353 10.0

M3 35 000 991 7 570 214 3 090 87.5 1000 28.3

M3.5 100 26 500 750 10600 300 3530 100

M4 ' rS 700 P 140 30 900 875 10 000 283

M 4.5 1000 35 300 1000 247 7.00M5 1 UU UUU 618 17.5

M 5.5 10 000 353 000 2 470 70.3

MC 1000 Don 6 180 175

M6 3 530 0i 24 700 700

M 10 000 000 61800 1750


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Air Quality

An aseptic area should be supplied with good

quality air. To satisfy the requirements ofClass 10,000 or Class 100,000, the air

entering this area should pass through HEPA

filters.

(HEPA= High Efficiency ParticulateAirFilters)


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The outside air should be filtered through

i. Roughing filter

- at the intake of fresh airii. Pre-filter

- remove large particles & protectmain filter

iii. HEPA filter- at or as close as possible tothe inlet of the clean room


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HEPA filters should be terminally mounted. HEPA

filters should have a minimum efficiency of

99.99%.

HEPA filters should be fixed in such a way that all joints

and surfaces of the filters can be scanned for leakages.

Air enter the room through filters in the ceiling (inlet).

The air return should be from the lower part of the room

(outlet).

The position of HEPA filters is critical in determining theair flow pattern.


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Air flow and Pressure DifferentialsAseptic area should be maintained at a

pressure higher than the atmosphere to

prevent contamination.The air flow should be from the aseptic areato a less clean area (eg from the changing

area to the component preparation area)The pressure differential between the asepticroom and outside area is between 10 - 15

pascal or 0.05 inches of water gauge.


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The pressure differentials should be asfollows:

-Aseptic Area = +++

-Changing Area = ++

-Component Area = +


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The minimum air changes for Class10,000 is 20L/hr and the velocity is 90

ft/min.The air flow can be reduced during non-operating hours.


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SUPPLY AIR SUPPLY NR

FINALANAL ALTERS Fl LTFRS

fLOOH OHAI iNOS

1 1.u

Figure 1Uu%%llnu,s laminar flow or 'vertical Laminar Figure3 :Coliventional flow orfuss for sterile area rrR>,tr-urlitlirtcticrral flUr%% for ,tt'rile area


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Temperature

The temperature in the room should be

maintained at 20 + 2C.


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Humidity

The relative humidity should be

maintained between RH 35 - 50 %.


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The need for laminar flow cabinet (workbenches) or barrier isolators.

The compounding area must be separatedfrom the general pharmacy and must becontrolled (particle, temperature, humidity)environment.

There must be detailed cleaning and sanitizingprocedures in order to maintain the cleanlinessof the compounding environment.


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Environmental monitoring must beroutinely performed in order to prove that

the compounding environment isproperly maintained. There must bedocumentation to prove control.


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-The air quality in this area should bemaintained at a minimum level of Class

100,000.-Sinks and other related facilities shouldbe made available in this room.


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2. Mixing Area:

-This room is used for mixing

medicaments and preparation of eyedrop bottles.

-Sinks and other related facilities should

be made available in this room.


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3. Changing Area:

-This room is used for personnel to

change into clean apparel beforeentering the aseptic area.

-The air quality in this area should be

maintained at a minimum level of Class100,000.


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-This room should be designed as an air

lock with 3 distinct areas. The 3 areas

should be clearly designated either witha cross-over bench or a line on the floor.

-The areas can be classified as black,

grey and white area.


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Area closest to the outside. In this area

Black Areapersonnel should change the outerclothing and place them in the locker.

An intermediate zone. Personnel enters

Grey Area

this area after changing their shoes.Wash basins/sinks should be provided inthis area for personnel to wash theirhands.

Area nearest to the aseptic room. The

White Area

cleanliness of this area must be

maintained at the same level as theaseptic room. Personnel should weartheir sterile gowns in this area beforeentering the aseptic room.


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4. Aseptic Area:

-Filling medicaments into final containers

using aseptic technique.-Air quality in this area should bemaintained at a minimum of Class 10,000.-Minimum area of the room is 50 sq.ft.

(depending on the size of the cabinet(LFC) and the number of personnel).


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-This room should have the highest

pressure compared to the outside (or

other rooms) and there should be a netflow of air from this room to other areas.

-This room should be kept dry and clean.

-Sinks or pipes should not be located

within this area.


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-Floors:Flat, smooth, non-porous, non-shedding, easilycleaned & disinfected, and be constructed to

minimize microbial/particulate contamination.

Examples of suitable materials:

-polyvinylchloride (PVC) sheets with seamsbeen heat welded (to eliminate pocket ofcontamination)

-concrete with sealing materials e.g epoxyresins, polyurethane, acrylates etc (resistant tochemical, cleaning fluids)


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-Walls:

Wall surfaces must be made of non-inflammableor fire-resistant and covered with a smooth andwashable finish.

Examples of suitable materials:-concrete

-plaster board

The wall surfaces should be painted with epoxy

paint or 8-hydroxyquinoline, pentachlorophenoladded paint (anti-fungal).

No sharp corners for wall-to-wall joints, wall-to-ceiling joints and wall-to-floor joints.


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-Ceiling:

The surfaces of the ceiling must be

smooth and free from cracks. Ceiling

should be fixed in such a way that itlooks as if it is one-piece. Examples

of suitable materials: -laminated

gypsum board. -painted or vinylcovered gypsum plaster.


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-Doors and Windows:

Doors should be of adequate size formovements of personnel and equipments.Depending on the types of doors, all doorsurfaces should be painted. Joints should besealed with silicones or polyurethane sealants.Door should swing into the aseptic room sothat opening of the door can be done without

using hands (hands-off method).Interlocking doors are preferred (only one sidemay be opened at any time).


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All joints at the windows should besealed.

Windows should be of adequate sizeand made of glass so that it give bettersupervision of personnel can be carriedout.

Windows are not for ventilation, shouldtherefore be non-openable.


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-Work Benches, Shelves and

Cabinets:

All surfaces should be made of materialsthat are smooth, non-porous and able to

withstand disinfectants.


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-Sinks and Other Fixtures:

Sinks should made of stainless steel.

Knee or elbow type operated taps are

suitable.

All piping and fixtures should be fittedinside the walls.


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-Equipment

Only essential equipment should beinstalled in or taken into clean area. All

equipment should be designed,constructed & installed so that it may beeasily disinfected or cleaned.

Should be arranged within the area to

provide lowest possible resistance to theair flow.


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-Personnel

Operators must be specially trained for sterileproduct manufacture & principles of GMP includehigh standards of personal hygiene and cleanliness.

Only authorized persons are accessible to theaseptic area (all non essential personnel andvisitors being excluded).

Must be equipped with suitable protective clothingduring operation in aseptic area.

Regular medical inspection of staff for skin lesions,wounds, respiratory infection that could result incontamination of environment or product.


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HoodRespirator

mask

Double Dispglove

gown

Bootcover


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ConclusionBuilding a clean room is a complex exercisecarried out in order to assure the productqualitywithin the overall guidelines of good

manufacturing practices in the pharmaceuticalindustry.

A clean facility must effectively controlcontamination from personnel, raw materials,processes and overall construction of the

facility to meet with the specifications andrequirements of the end-user and regulatoryauthorities.


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IT IS A TOUGH JOB

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