CLEAN ROOM

Design & Operation

Lecture 8 PHR213 Chris Soh Yee Chang

Introduction
Sterile pharmaceuticals:

Any dosage form devoid of viable microorganisms. Terminally Sterilized - prepared in a clean
fashion, transferred to its final container, sealed, and sterilized. Aseptically Prepared - aseptically processed from sterile materials, or sterilized by filtration, before final packing in sterile containers.

2 types of sterile product:

Introduction
Sterile products require preparation in a controlled environment.

CLEAN ROOM

Clean Room: a controlled environment

is a premise that specially designed, constructed, serviced and used with the intention of eliminating microbial and particulate contamination in manufacturing sterile products.

Designing & Operating Clean Room:

Clean Room set-up:

Storage area Washing area Changing area Preparation area Aseptic area

Plan Layout
Material/Tool Product Flow

Interlockingdoor Airlock Room

Laminar Flow Cabinet

Personnel Flow

Aseptic Area
E

Changing Area
D

Pass-box

Glass Preparation window Area C A Corridor Utility Area

Washing Area
B

Entrance

Storage Area

Toilet

A. Outside Clean Room

B. Washing Area

C. Preparation Area
Pass Box

D. Changing Area

E. Aseptic Area

Important Features Clean Room

Limited airborne particles

of

Known air flow pattern and controlled Controlled temperature & humidity Regulated air pressure Special construction & materials Controlled operating procedure

Environmental Control Clean Room

Maximum no. of airborne particles greater

of

Environmental Cleanliness Standards (Clean Room Standards)

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)

FEDERAL STANDARD 209E

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

Class limits
Class nl... I' tllI... n!

0.1 im

0.2 pmt

tin

Volume units S1 English (m3) 350 1 240 3 500 (ft3)

Volume units 3 75,7

Volume units
30.9 106 Ing 0.875 3.00

Volume units

Volume units
(ft3) 0.283

(ft3)
2.14

9.91 35.0

10.0
35.3 in n
353 1 000 3530 10 000 35 300
1 UU UUU

265
757 2 650

7.50
21.4
75.0

1.00
Zf) Q ) -VU

99.1
350 991

75 30.0
87.5

M 2,5 M3
M3.5 M4 M 4.5 M5

10 12 400 35 000 100

060 1
3 090 10600 30 900

10.0 28.3 100 283 1 000 247 7.00 17.5 70.3 175 700 1 750

7 570
26 500 'r S 700

214
750 P 140

300 875

000 1

618
2 470 6 180 24 700 61 800

M 5.5 10 000

353 000

MC M6
M

000 1 Don
3 530 0i 10 000 000

 An aseptic area should be supplied with good

quality air. To satisfy the requirements of Class 10,000 or Class 100,000, the air entering this area should pass through HEPA filters.

Air Quality

(HEPA = High Efficiency Particulate Air Filters)

 The outside air should be filtered through

i. Roughing filter

- at the intake of fresh air ii. Pre-filter - remove large particles & protect main filter iii. HEPA filter - at or as close as possible to the inlet of the clean room

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 the air flow pattern.

Air flow and Pressure Differentials

Aseptic area should be maintained at a

pressure higher than the atmosphere to prevent contamination. The air flow should be from the aseptic area to a less clean area (eg from the changing area to the component preparation area) The pressure differential between the aseptic room and outside area is between 10 - 15 pascal or 0.05 inches of water gauge.

The pressure differentials should be as follows:

-Aseptic Area = +++ -Changing Area = ++ -Component Area = +

The minimum air changes for Class 10,000 is 20L/hr and the velocity is 90 ft/min. The air flow can be reduced during nonoperating hours.

SUPPLY AIR

SUPPLY NR

ANAL ALTERS

FINAL Fl LTFRS

fLOOH OHAI iNOS

1 .1

u
Figure 3 : Coliventional flow or
rrR>,tr-urlitlirtcticrral flUr%% for ,tt'rile area

Figure 1 flow or 'vertical Laminar Uu%%llnu,s laminar fuss for sterile area

Temperature

The temperature in the room should be

maintained at 20 + 2C.

Humidity

The relative humidity should be maintained between RH 35 - 50 %.

The need for laminar flow cabinet (work benches) or barrier isolators. The compounding area must be separated from the general pharmacy and must be controlled (particle, temperature, humidity) environment.

There must be detailed cleaning and sanitizing procedures in order to maintain the cleanliness of the compounding environment.

Environmental monitoring must be routinely performed in order to prove that the compounding environment is properly maintained. There must be documentation to prove control.

Clean Room Design, Construction & Operation

1. Preparation Area:
-This room is used for the purpose of preparing components, ie to open the outer wrappings and to sanitize the materials. -All components should be taken in or out of the aseptic area through hatches or pass-box.

-The air quality in this area should be maintained at a minimum level of Class 100,000. -Sinks and other related facilities should be made available in this room.

2. Mixing Area:
-This room is used for mixing medicaments and preparation of eye drop bottles. -Sinks and other related facilities should be made available in this room.

3. Changing Area:
-This room is used for personnel to change into clean apparel before entering the aseptic area. -The air quality in this area should be maintained at a minimum level of Class 100,000.

-This room should be designed as an air lock with 3 distinct areas. The 3 areas should be clearly designated either with a cross-over bench or a line on the floor. -The areas can be classified as black, grey and white area.

Black Area

Area closest to the outside. In this area personnel should change the outer clothing and place them in the locker. An intermediate zone. Personnel enters this area after changing their shoes. Wash basins/sinks should be provided in this area for personnel to wash their hands. Area nearest to the aseptic room. The cleanliness of this area must be maintained at the same level as the aseptic room. Personnel should wear their sterile gowns in this area before entering the aseptic room.

Grey Area

White Area

4. Aseptic Area:
-Filling medicaments into final containers using aseptic technique. -Air quality in this area should be maintained 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).

-This room should have the highest pressure compared to the outside (or other rooms) and there should be a net flow 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.

-Floors:

Flat, smooth, non-porous, non-shedding, easily

cleaned & disinfected, and be constructed to minimize microbial/particulate contamination. Examples of suitable materials:

-polyvinylchloride (PVC) sheets with seams been heat welded (to eliminate pocket of contamination)
-concrete with sealing materials e.g epoxy resins, polyurethane, acrylates etc (resistant to chemical, cleaning fluids)

-Walls:
Wall surfaces must be made of non-inflammable or fire-resistant and covered with a smooth and washable finish. Examples of suitable materials: -concrete -plaster board The wall surfaces should be painted with epoxy paint or 8-hydroxyquinoline, pentachlorophenol added paint (anti-fungal). No sharp corners for wall-to-wall joints, wall-toceiling joints and wall-to-floor joints.

-Ceiling:
The surfaces of the ceiling must be smooth and free from cracks. Ceiling should be fixed in such a way that it looks as if it is one-piece. Examples of suitable materials: -laminated gypsum board. -painted or vinyl covered gypsum plaster.

-Doors and Windows:

Doors should be of adequate size for movements of personnel and equipments. Depending on the types of doors, all door surfaces should be painted. Joints should be sealed with silicones or polyurethane sealants. Door should swing into the aseptic room so that opening of the door can be done without using hands (hands-off method). Interlocking doors are preferred (only one side may be opened at any time).

All joints at the windows should be sealed. Windows should be of adequate size and made of glass so that it give better supervision of personnel can be carried out. Windows are not for ventilation, should therefore be non-openable.

-Work Benches, Cabinets:

Shelves

and

All surfaces should be made of materials that are smooth, non-porous and able to withstand disinfectants.

-Sinks and Other Fixtures:

Sinks should made of stainless steel. Knee or elbow type operated taps are suitable.

All piping and fixtures should be fitted inside the walls.

-Equipment
Only essential equipment should be installed in or taken into clean area. All equipment should be designed, constructed & installed so that it may be easily disinfected or cleaned. Should be arranged within the area to provide lowest possible resistance to the air flow.

-Personnel
Operators must be specially trained for sterile product manufacture & principles of GMP include high standards of personal hygiene and cleanliness. Only authorized persons are accessible to the aseptic area (all non essential personnel and visitors being excluded). Must be equipped with suitable protective clothing during operation in aseptic area. Regular medical inspection of staff for skin lesions, wounds, respiratory infection that could result in contamination of environment or product.

Respirator mask

Hood

Double glove

Disp gown

Boot cover

Conclusion
Building a clean room is a complex exercise carried out in order to assure the product quality within the overall guidelines of good manufacturing practices in the pharmaceutical industry. A clean facility must effectively control contamination from personnel, raw materials, processes and overall construction of the facility to meet with the specifications and requirements of the end-user and regulatory authorities.

IT IS A TOUGH JOB