Clean Room (PowerPoint) by bm1991

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									“CLEAN ROOM”
Design & Operation

       Lecture 8
Chris Soh Yee Chang
Sterile 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 processed
    from sterile materials, or sterilized by filtration,
    before final packing in sterile containers.
• Sterile products require preparation
  in a controlled environment.

    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                                 Interlocking-

                       Laminar                Room
     Product Flow

                       Aseptic Area          Changing Area
       Flow                          E                        D

                                  Glass Preparation           Washing
                                 window       Area               Area
                                                  C                        B

Entrance                         A           Corridor
                     Storage Area              Utility Area       Toilet
A. Outside Clean Room
B. Washing Area
C. Preparation Area

                      Pass Box
D. Changing Area
E. Aseptic Area
   Important Features               of
        Clean Room
Limited airborne particles
 Known air flow pattern and controlled
 Controlled temperature & humidity
 Regulated air pressure
 Special construction & materials
 Controlled operating procedure
Environmental   Control                         of
       Clean Room
Environmental 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)
                                    FEDERAL STANDARD 209E
                        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...tllI... n!
      I'                                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
                                  240        35.0         265         7.50      106     3.00                 35.3     1.00
                                3 500        99.1         757        21.4       Ing          75              in n       Z
                                                                                                                      -VU f) Q )

M 2,5                      10 12 400        350         2 650        75.0      060
                                                                               1       30.0              353         10.0
 M3                            35 000       991         7 570       214       3 090    87.5              1
                                                                                                         000         28.3
M3.5                     100                        26 500           750    10600      300             3530         100
 M4                                                     ' 700
                                                        Sr        P 140     30 900     875           10 000         283
M 4.5                    000
                         1                                                                           35 300         1
                                                                                                                    000               247             7.00
 M5                                                                                                1 UU UUU                           618             17.5
M 5.5 10 000                                                                                       353 000                          2 470         70.3
MC                                                                                                000 Don
                                                                                                    1                               6 180        175
M6                                                                                                3 530 0i                         24 700        700
 M                                                                                             10 000 000                           61800       1
Air Quality
• 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
(HEPA = High Efficiency Particulate Air
     • 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
     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
    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
-Aseptic Area = +++
-Changing Area = ++
-Component Area = +
The minimum air changes for Class
10,000 is 20L/hr and the velocity is 90
The air flow can be reduced during non-
operating hours.
                           SUPPLY AIR                                              SUPPLY NR

                         ANAL ALTERS                                Fl LTFRS

                    fLOOH OHAI iNOS

                                           1 .1u
       Figure 1
Uu%%llnu,s laminar flow or 'vertical Laminar           Figure 3 : Coliventional flow or
                 fuss for sterile area            rrR>,tr-urlitlirt•ctic rral flUr%% for       ,tt'rile area
• The temperature in the room should be
  maintained at 20 + 2°C.
  •   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)
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
-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
-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
-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.
             Area closest to the outside. In this area
             personnel should change the outer
Black Area   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
Grey Area
             this area for personnel to wash their
             Area nearest to the aseptic room. The
             cleanliness of this area must be
White Area   maintained at the same level as the
             aseptic room. Personnel should wear
             their sterile gowns in this area before
             entering the aseptic room.
4. Aseptic Area:
-Filling medicaments into final containers
using aseptic technique.
-Air quality is 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.
 •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
  -concrete with sealing materials e.g epoxy
  resins, polyurethane, acrylates etc (resistant to
  chemical, cleaning fluids)
   Wall surfaces must be made of non-inflammable
   or fire-resistant and covered with a smooth and
   washable finish.
   Examples of suitable materials:
   -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-to-
   ceiling joints and wall-to-floor joints.

   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
Windows should be of adequate size
and made of glass so that it give better
supervision of personnel can be carried
Windows are not for ventilation, should
therefore be non-openable.
-Work Benches,      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
    All piping and fixtures should be fitted
    inside the walls.

   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.
 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.

Double         Disp

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
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

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