A cleanroom is a room in which viable & non viable particle count, temperature, humidity & differential pressure is maintained within standard and defined ranges.
Cleaning is a strict requirement for cleanrooms and it is necessary to maintain their defined cleaning level all the time.Cleanrooms play a critical role in the manufacturing of pharmaceutical products.
- Cleanroom classification in pharmaceutical industries is based on the size of particles and the number of particles per cubic meter of air.
- There are specified limits of particle count,microbial counts and air changes for the cleanrooms.
Cleanroom Classification In Pharma
Clean rooms are classified according to following standards,
- ISO 14644-1
- Federal Standards (FS 209)
- European Standards
According to ISO 14644-1
Classification of cleanrooms ap per ISO 14644-1 is as follows
- ISO 1
- ISO 2
- ISO 3
- ISO 4
- ISO 5
- ISO 6
- ISO 7
- ISO 8
- ISO 9
In ISO there are 9 cleanroom classes, ISO 1 to IOS 9.ISO 1 is the cleanest from all classes of ISO and ISO 9 is least clean or dirtiest in all ISO classes but cleaning level of ISO 9 is superior than a regular room. In pharmaceutical Industries following ISO, classes are generally required
- ISO 5
- ISO 6
- ISO 7
- ISO 8
According to FS 209
According to the federal standard, FS 209 Cleanrooms are classified as,
- Class100
- Class1000
- Class 10,000
- Class100,000
According To The EU GMP
- Grade A
- Grade B
- Grade C
- Grade D
FS 209 is replaced by ISO 14644-1 but these terms are still in use. In ISO particle are taken as particles/m³ (cubic meter)and in FS 209 particles were taken as particles/ft³(cubic feet)
A simple comparison of cleanrooms classification for pharmaceutical industries is as follow,
| ISO | EU GMP | FS |
| Class 5 | Grade A | Class 100 |
| Class 6 | Grade B | Class 1000 |
| Class 7 | Grade C | Class 10,000 |
| Class 8 | Grade D | Class 100,000 |
Particle Size Range
In pharmaceutical industries, two ranges of particle sizes are considered for classification of cleanrooms
- One is ≥0.5 micron (equal to or greater than 0.5 microns)
- Other is ≥5.0 micron (equal to or greater than 5.0-micron particles)
ISO 5 /Grade A
ISO class 5 or Grade A is the cleanest area in the pharma industries.
Particle count,air changes & microbial count for ISO class 5 are as follows.
| Particles ≥0.5 micron | 3520/m³ |
| Particles ≥5.0 micron | 29/m³ |
| Air changes/hr | 240-480 |
| Microbial count EU | <1 cfu/m³ |
Grade A is maintained under laminar airflow hood (LAF) and critical activities listed below are performed in this grade,
- Filling
- Sealing
- Aseptic manufacturing(If sterile filtration is not done)
- Handling of sterile starting materials.
- Manufacturing and filling of sterile creams, ointments, emulsions and suspension (when product is exposed and is not subsequently filtered)
ISO 6 /Grade B
ISO class 6 or grade B is the second most cleaned grade in pharmaceutical industries.
Particle count,air changes & microbial count for ISO class 5 are as follows.
| Particles ≥0.5 micron | 35200/m³ |
| Particles ≥5.0 micron | 293/m³ |
| Air changes/hr | 150-240 |
| Microbial count EU | 10 cfu/m³ |
Grade B is the background area of Grade A mean area where laminar airflow hood (LAF) is placed.
ISO 7 /Grade C
ISO class 7 or grade C is the third cleanest area after grade A & B in pharmaceutical industries.
Particle count,air changes & microbial count for ISO class 5 are as follows.
| Particles ≥0.5 micron | 352000/m³ |
| Particles ≥5.0 micron | 2930/m³ |
| Air changes/hr | 60-90 |
| Microbial count EU | 100 cfu/m³ |
Following activities are performed in Grade C,
- Solution preparation ( if sterile filtration is to be done later on)
- Manufacturing and filling of creams,ointments,emulsions and suspension before terminal sterilization.
- Liquid manufacturing area at rest is Grade C.
ISO 8/ Grade D
ISO class 8 is the fourth number class in pharmaceutical industries.
| Particles ≥0.5 micron | 3520,000/m³ |
| Particles ≥5.0 micron | 29300/m³ |
| Air changes/hr | 5-48 |
| Microbial count EU | 200 cfu/m³ |
Following activities are performed in grade D area.
- Washing of components.
- Â Handling of components after washing
- Tablet,Capsule section(OSD) is Grade D at rest.
- Liquid manufacturing area in operation is Grade D.
Prevention Of Cross Contamination In Cleanrooms
All clean rooms are separated from other cleanrooms & corridors through the Airlock system to prevent cross contamination.
Airlocks maintain the cleaning standard of clean rooms through proper air changes. Air changes are maintained by the HVAC system.
Read details of Airlock System in following article
Types of airlocks in pharmaceuticals
In cleanrooms, the air is filtered through HEPA filters.HEPA filter stands for High-efficiency particulate air filter.HEPA filters remove particles of 0.3 microns and supply clean air in clean rooms.
Occupancy State Of Cleanrooms
Following are occupancy States of the cleanrooms
At Rest
At rest mean, all the equipment are installed in a cleanroom and the HVAC system is operational but manufacturing activity is not performed.
It means the area is cleaned and no operator is performing manufacturing activity.
At rest particle count in cleanrooms is as follow,
Grade A
| ≥0.5 micron | 3520 particles/cubic meter |
| ≥5.0 micron | 29 particles/Cubic meter |
Grade B
| ≥0.5 micron | 35200 particles/cubic meter |
| ≥5.0 micron | 293 particles/cubic meter |
Grade C
| ≥0.5 micron | 352000 particles/cubic meter |
| ≥5.0 micron | 2930 particles/cubic meter |
Grade D
| ≥0.5 micron | 3520000 particles/cubic meter |
| ≥5.0 micron | 29300 particles/cubic meter |
In Operation
In operation means all the equipment are installed in a cleanroom and HVAC system is operational and manufacturing activity is going on in the cleanroom.
It means the area is cleaned and operators are performing manufacturing activity in a cleanroom.
In Operations particle count in cleanrooms is as follow,
Grade A
| ≥0.5 micron | 3520 particles/cubic meter |
| ≥5.0 micron | 29 particles/cubic meter |
Grade B
| ≥0.5 micron | 352000 particles/cubic meter |
| ≥5.0 micron | 2930 particles/cubic meter |
Grade C
| ≥0.5 micron | 3520000 particles/cubic meter |
| ≥5.0 micron | 29300 particles/cubic meter |
Grade D
| ≥0.5 micron | Not Defined |
| ≥5.0 micron | Not Defined |
Note:
- EU volume 4 Annex 1 and WHO Annex 6 describe
- 5.0 micron=20 particles/Cubic meter both for at rest and operation.
Temperature and Humidity Control
Temperature and relative humidity or RH is critically controlled in the cleanrooms for human comfort & for the stability of the products.
The general limit for temperature is 20 to 25 °C & relative humidity is maintained at 55±5%.
The humidity & temperature for moisture & heat sensitive products can be adjusted as per requirement.
Differential Pressure In Cleanrooms
Difference of atmospheric pressure between one area and adjacent areas is known as differential pressure.
As per WHO guidelines of HVAC 10 to 15 Pascal differential pressure must be maintained.
Read detailed article on Differential pressure