CLEAN ROOM TECHNOLOGY

Clean room’s for Pharmaceutical Production

A 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.
 Importance of Clean room
 Sterile product
 Dispensing area
 Cross Contamination
 Personal Safety
 Personal Convenience
 In the field of research
 Top ten issues to design a clean room
1. Clarity about the GMP and standard used.
2. Unidirectional airflow specification and qualification.
3. Clean room pressurization.
4. Air change rates and recovery time in non-unidirectional systems.
5. Clean room configuration for the service and maintenance of process
equipment.
6. Validation of building control systems.
7. Real time particle monitoring systems.
8. Retest and requalification frequency.
9. Bio decontamination by fumigation/ sterilization methods.
10. High efficiency particulate air (HEPA) filters leak testing.
 Clean room standards

 ISO standard: ISO class 1, 2, 3 ………. 9

 US Federal standard: Class 1, 10, 100 ….. 100,000
 Class M1, M1.5, M2 …….. M7
 British standard: Class C, D, E, F, G, H, J, K, L, M.

All the standards are based on the measurement of maximum number of particles of
varying sizes which may be present in a specified volume of air.
 Class X clean room – means that particle count in the air is not more than X per
cubic feet ( ft3 ) of 0.5 µm and larger in size.
 ISO X clean room - means that particle count in the air is not more than 10 X per
cubic meter ( m3 ) of 0.1 µm and larger in size.

Class 100 area Strict aseptic and clean room

operations
Class 10,000 area Buffer zone around class 100 area
(handling pre cleaned containers, process
filtration, gowning of personnel)

Class 100,000 area Laboratories, packaging area.

 US FEDERAL STD 209E clean room Standards
maximum particles / ft³
ISO
Class
≥ 0.1 µm ≥ 0.5 µm ≥ 5.0 µm equivalent

1 35 1 ISO 3

10 350 10 ISO 4

100 100 ISO 5

1,000 1,000 7 ISO 6

10,000 10,000 70 ISO 7

100,000 100,000 700 ISO 8

 ISO 14644-1 clean room standards
maximum particles / m³
FED STD 209E
Class
≥ 0.1 µm ≥ 0.5 µm ≥5.0 µm equivalent

ISO 1 10
ISO 2 100 4
ISO 3 1,000 35 Class 1
ISO 4 10,000 352 Class 10
ISO 5 100,000 3,520 29 Class 100
ISO 6 1,000,000 35,200 293 Class 1000
ISO 7 352,000 2,930 Class 10,000
ISO 8 3,520,000 29,300 Class 100,000
ISO 9 35,200,000 293,000 Room air
 European Union Guide to GMP

maximum particles / m³
Microbial
Class
≥ 0.5 µm ≥5.0 µm growth(CFU)

A 3500 0 ‹1

B 350000 2000 ‹5

C 3500000 20000 ‹50

D Not defined ‹100

 Environmental control in clean rooms
The environment in a sterile product manufacturing area is classified
based on its intended use.
Classification Clean room standard Intended use
(US FED STD)
Critical or 100 (Allowable particle 100, alert Sterile products, containers and closures are directly
Level I level 50) exposed; sterile filtration, filling and sealing is performed.
Controlled or 10,000 (Allowable particle 10,000, Area adjacent to level I area; area for storage of unexposed
Level II alert level 7,000) sterile raw materials, products, containers etc.

Ancillary Or 100,000 (Allowable particle 100,000, Washing and cleaning of product and accessories; product
Level III alert level 80,000) preparation and sterilization area.
Non classified Final inspection, labeling and packaging; warehouse for raw
materials and finished products.
Design of environmental contamination control system
HVAC
Heating, ventilation and air conditioning system is an integral part
of environmental contamination control system.
The purpose of HVAC system is to provide a specified set of
environmental conditions required for the manufacturing process.

Temperature control: 68-74F (19-23C)

Lower temperature maybe required in some cases, such as when
wearing poorly ventilating garments. Proper temperature setting
reduces perspiration which, in turn, provides comfort and decreases
chance of contamination.
Humidity control
RH usually maintained in the range of 45 - 55%. Some products may require 15 -
30% RH, such as freeze dried products.

Airborne contamination control

Filters having required level of performances are employed to remove
contamination. This includes the use of HEPA filters to generate a strictly aseptic
area.
High efficiency particulate air filter (HEPA filter)
At least 99.97% efficient in removing particles of 0.3 µm size and larger
HEPA filters are made of glass fibers associated with fillers or electrostatic precipitators.
► 10 – 20 complete air changes per hour is desirable.
► Air is also conditioned for temperature and humidity control.
► Pre filters are always used.
► Air velocity employed: 100 ± 2 ft. / min.
Vertical air flow system is usually used in larger area during aseptic operation
(air flow from ceiling to floor).

► Horizontal air flow system is usually employed in small work benches.

 Evaluation / Monitoring of clean room environment

Method Principle of operation Type

Settling plates Gravitational falling of microorganisms over agar Biologic

plates in a given time and area
Slit sampler Measured volume of air drawn under vacuum and Biologic
impacted on moving agar plates
Liquid impinger Measured volume of air bubbled through liquid Biologic
nutrient medium with impingement in liquid
Membrane filter Measured volume of air drawn through filter which Biologic and
sampler is then incubated in nutrient agar plates and / or Particulate
examined microscopically for particle count
Light scattering Particles scatter light which is directed to photo Particulate
instrumental counter detector tube for detection and counting.