Cleanroom Classification in Pharma

A cleanroom is a room in which viable & non viable particle count, temperature, humidity & differential pressure is maintained within standard and defined ranges.In this article you will learn all about the cleanroom classification in pharma.

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 pharma 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

Cleanroom classification in pharma is per 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

1. ISO 1
2. ISO 2
3. ISO 3
4. ISO 4
5. ISO 5
6. ISO 6
7. ISO 7
8. ISO 8
9. 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.
•  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 

Also Read

1. Pass Box In Pharma
2. HVAC or Heating Ventilation & Airconditioning System.
3. Loop Circulation system for purified water.
4. Why we Use only 70% IPA
5. Reconciliation in pharmaceutical industries.
6. How to become a skilled pharmacist?