Cleanroom Standards by jtl17221


									 Cleanroom Standards
     An Overview
                MODULE – 2

A Presentation by

S.Syed Noor Mohamed
           Cleanroom Standards
The first standard written for cleanroom was published
by the American Air force on March 1961.

It was known as Technical Manual (T.O) 00-25-203.

The concepts were
  – Clean room design
  –Airborne particle standards
  –Entry procedures, clothing
  –Restriction of certain articles
  –Cleaning of materials
  –Procedure for cleaning the room
           Cleanroom Standards
The first Federal standard 209 was produced in the year
•   Conventional and unidirectional cleanrooms were
• Measurement of particles of ≥0.5 µm by means of
   optical particle counters was defined.

Why 0.5 µm?
“Art of achievable”
• At that time this was the smallest size that was easily
    measured by optical particle counters.
         Federal Standard 209
First Federal Standard 209 was published in 1963
The revisions
• 209A – 1966
• 209B – 1973
• 209C – 1987
• 209D – 1988
• 209E – 1992
Federal Standard 209
Federal Standard 209
       ISO Standard – 14644-1
TC 209: Cleanrooms and associated controlled

The first document published in 1999 is
ISO 14644-1.

“Classification of Air Cleanliness”
ISO Standard – 14644-1
ISO Standard – 14644-1
ISO Standard – 14644-1
        ISO Standard – 14644-1
The classification of the room be carried out in
different occupancy states.
• As Built
• At-rest
• Operational
         ISO Standard – 14644-1
As Built :
The condition where the installation is complete
with all services connected and functioning, but
with no production equipment materials or
personnel present

At Rest:
The condition where the installation is complete
with equipment installed and operating in a
manner agreed between the customer and
supplier, but with no personnel present.
        ISO Standard – 14644-1

The condition where the installation is functioning
In the specified manner, with specified number
of personnel present and working in the manner
Agreed upon.
         ISO Standard – 14644-1
Part 1 : Classification of air cleanliness
Part 2 : Specifications for testing and monitoring
          to prove continued compliance with ISO
Part 3 : Metrology and test methods
Part 4 : Design, Construction, and startup
Part 5 : Operation
Part 6 : Terms and definitions
Part 7 : Separative enclosures (clean air hoods,
         gloveboxes, isolator, mini environments)
Part 8 : Molecular contamination
Part 9 :Classification of surface particle cleanliness
   ISO Standard – 14644 - Versions
Part 1 : 1999
Part 2 : 2000
Part 3 : 2005
Part 4 : 2001
Part 5 : 2004
Part 6 : 2007
Part 7 : 2004
Part 8 : 2006
Part 9 : Under Development
         ISO Standard – 14698
  “Cleanrooms and Associated Controlled
 Environments – Biocontamination Control”

Part 1 : General principles and methods
Part 2 : Evaluation and interpretation of bio-
         contamination data

ISO 14698 -1 : 2003
ISO 14698 -2 : 2003
ISO Class 3 – Special Requirements
Cleanroom Industry Design- Thumb Rule
                 EU GGMP
European Union Guide to Good Manufacturing

The most recent pharmaceutical standard used
In Europe came into operation on January 1997.
It was revised in 2003.

For the manufacture of sterile medicinal products
Four grades of airborne cleanliness are given.
                EU GGMP
The maximum permitted number of particles in
the “At rest” condition.

EU GGMP       FS 209E       ISO

Grade A & B   100           5

Grade C       10000         7

Grade D       100000        8
                    EU GGMP
Examples of cleanroom conditions required for
Different operations.
            “Terminally Sterilized Products”
Grade A
• Filling of products, when unusually at risk.

Grade C
• Preparations of solutions, when unusually at risk.
  Filling of products.

Grade D
• Preparation of solutions and components for
  subsequent filling.
                     EU GGMP
Examples of cleanroom conditions required for
Different operations.
                 “Aseptic Preparations”
Grade A
• Aseptic preparation and filling.

Grade C
• Preparation of solutions to be filtered.

Grade D
• Handling of components after washing.
                 EU GGMP

Microbiological monitoring also required to
demonstrate the microbiological cleanliness of
the cleanroom during production.
                                 EU GGMP

• These are average values
• Individual settle plates may be exposed for less than 4 hours.

• Appropriate alert and action limits should be set for the results of particulate and
  microbiological monitoring. If these limits are exceeded, operating procedures
  should prescribe corrective action.
                  US FDA
Guideline on Sterile Drug Products Produced by
Aseptic Processing.
• This document was published in 1987 by
• Revised on September 2004

• Critical Area
• Controlled Area
                    US FDA
Critical Area:-
“one in which the sterilized dosage form,
containers, and closures are exposed to the
environment. Activities that are conducted in
this area include manipulations of these
sterilized materials/product prior to and during
filling/closing operations.”
            US FDA - Critical Area
• NMT 100 particles of 0.5µm per cubic foot
  – Measured NMT 1 foot away from work site
  – Upstream of the air flow
• Air should be supplied a the point of use as HEPA
  filtered laminar air flow.
• Velocity 90 ± 20 feet per minute
• Not more than 1 colony forming unit per 10 cubic feet
• Should have positive pressure differential relative to
  adjacent less clean areas
• A pressure differential of 0.05 inch of water is
                      US FDA
Controlled Area:-
“An area in which it is important to control the
environment, is the area where un-sterilized
product, in-process materials, and container/
closures are prepared. This includes areas
where components are compounded, and
where components, in-process materials, drug
products and drug product contact surfaces of
equipment, containers, and closures, after final
rinse of such surfaces, are exposed to the plant
         US FDA- Controlled Area
•   NMT 100000 particles of 0.5µm per cubic foot.
•   NMT 25 colony forming units per 10 cubic feet.
•   Sufficient air flow.
•   Positive pressure differential relative to adjacent
    uncontrolled areas.
    – 20 air changes per hour
    – Pressure differential of at least 0.05 inch of water
• When doors are open, outward airflow should
  be sufficient to minimize ingress of
WHO 2002
Schedule M
Cleanroom contamination
             Particles in Outdoor Air

Number of Particles/m3 on Outdoor Air

Size in Microns   Dirty         Normal       Clean

>0.1              10000000000   3000000000   500000000

>0.3              300000000     90000000     20000000

>0.5              30000000      7000000      1000000
Schedule of Mandatory Tests to Demonstrate
   Continuing Compliance in Cleanrooms

Test Parameter         Class       Maximum Time

Particle Count Test    <= ISO 5    6 Months

Particle Count Test    >ISO 5      12 Months

Air Pressure Difference All Classes 12 Months

Airflow                All Classes 12 months
  Schedule of Optional Tests to Demonstrate
    Continuing Compliance in Cleanrooms

Test Parameter             Class      Maximum Time

Installed Filter Leakage   All Classes 24 Months

Containment Leakage        All Classes 24 Months

Recovery Airflow           All Classes 24 Months

Airflow Visualization      All Classes 24 months
       Cleanroom Environmental Monitoring

Test                              Frequency

Particle Monitoring in air        6 monthly
HEPA Filter Integrity Testing     Yearly
Air Changes Rate Calculation      6 Monthly
Air Pressure Differentials        Daily
Temperature and Humidity          Daily

Microbiological monitoring by     Daily, and at decreased
settle plates and / or swabs in   frequency in other
aseptic areas                     areas

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