Cleanroom Standards An Overview

MODULE 2

A Presentation by S.Syed Noor Mohamed (wasimexpress@gmail.com)

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 1963. Conventional and unidirectional cleanrooms were discussed. Measurement of particles of 0.5 m by means of optical particle counters was defined. Why 0.5 m? 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 environments 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

Operational:

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 14644-1 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 biocontamination 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 Practice. 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

EU GGMP
The maximum permitted number of particles in the At rest condition. EU GGMP Grade A & B FS 209E 100 ISO 5

Grade C Grade D

10000 100000

7 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 USFDA. 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 0.5m 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 acceptable.

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 environment.

US FDA- Controlled Area

NMT 100000 particles of 0.5m 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 contamination.

US FDA

WHO 2002

Schedule M

Cleanroom contamination Classification

Particles in Outdoor Air

Number of Particles/m3 on Outdoor Air
Size in Microns >0.1 >0.3 >0.5 Dirty 10000000000 300000000 30000000 Normal 3000000000 90000000 7000000 Clean 500000000 20000000 1000000

Schedule of Mandatory Tests to Demonstrate Continuing Compliance in Cleanrooms Test Parameter

Particle Count Test Particle Count Test

Class
<= ISO 5 >ISO 5

Maximum Time Interval

6 Months 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 Interval

Installed Filter Leakage

Containment Leakage Recovery Airflow Airflow Visualization

All Classes 24 Months

All Classes 24 Months All Classes 24 Months All Classes 24 months

Cleanroom Environmental Monitoring

Test Particle Monitoring in air HEPA Filter Integrity Testing Air Changes Rate Calculation Air Pressure Differentials Temperature and Humidity Microbiological monitoring by settle plates and / or swabs in aseptic areas Frequency 6 monthly Yearly 6 Monthly Daily Daily Daily, and at decreased frequency in other areas

END OF MODULE - 2