Cleanroom Standards An Overview MODULE – 2 A Presentation by S.Syed Noor Mohamed (wasimexpress@gmail)

1. Cleanroom Standards An Overview MODULE – 2 A Presentation by S.Syed Noor Mohamed (wasimexpress@gmail.com)

2. 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

3. 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 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.

4. Federal Standard 209 First Federal Standard 209 was published in 1963 The revisions 209A – 1966 209B – 1973 209C – 1987 209D – 1988 209E – 1992

5. Federal Standard 209

6. Federal Standard 209

7. 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”

8. ISO Standard – 14644-1

9. ISO Standard – 14644-1

10. ISO Standard – 14644-1

11. ISO Standard – 14644-1 The classification of the room be carried out in different occupancy states. • As Built • At-rest • Operational

12. 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.

13. 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.

14. 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

15. 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

16. 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

17. ISO Class 3 – Special Requirements

18. Cleanroom Industry Design- Thumb Rule

19. 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.

20. EU GGMP

21. 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

22. 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.

23. 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.

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

25. 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.

26. 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

27. 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.”

28. 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 acceptable.

29. 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.”

30. 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 contamination.

31. US FDA

32. WHO 2002

33. Schedule M

34. Cleanroom contamination Classification

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

36. Schedule of Mandatory Tests to Demonstrate Continuing Compliance in Cleanrooms Test Parameter Class Maximum Time Interval 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

37. Schedule of Optional Tests to Demonstrate Continuing Compliance in Cleanrooms Test Parameter Class Maximum Time Interval 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

38. Cleanroom Environmental Monitoring TestFrequency 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

39. END OF MODULE - 2