1. 1 Clean room HVAC Design for Pharmaceutical Facilities Presented by: Mr. S. B. Khan M.Pharm Semester- I Department of Pharmaceutics, NDMVPS’s College of Pharmacy Nashik-422002. Under Guidance of: Dr. M. P. Wagh Asst. Proffessor Department of Pharmaceutics, NDMVPS’s College of Pharmacy, Nashik-422002.

2. 2 Enclosures :  Sterile Manufacturing At Glance  Cleanroom HVAC Design  Clean Room : REGULATORY POINT OF VIEW  Cleanroom Layout  Contribution Of HVAC And The Meaning...  Design Parameters  Components Of HVAC System And Specifications  HEPA FILTER : At Glance  Monitoring And Testing Of HVAC Clean Room  Validation  Clean Room Of Future  Cummary  References

3. 3 Sterile Manufacturing At Glance

4. 4 Sterile preparations are products absolutely free of micro organisms, pyrogens and particulate matter. Importance of sterile administration(Parentrals) Rapid in Action Produces a direct result Drugs are absorbed directly into the bloodstream Do not irritate the digestive system Precise dose to a targeted area

5. 5 Difficulties in sterile administration  allergic reaction  Introduction of microorganisms  Injections can cause injury to tissue, nerves, veins, and other vessels  Needle can strike a bone  Cost  Communicable diseases

6. 6 Challenges in Clean room and sterile Mfg  contamination with micro-organisms, endotoxins and particles  ledges, shelves, cupboards and equipment  Doors, ceilings  Sinks and drains  Personnel, clothing

7. 7 Cleanroom HVAC Design : Introduction Federal Standard 209 In determination of key parameters like temperature, humidity, pressures, filtration, airflow parameters and classification of cleanrooms. Purpose limiting the presence of sub-micron particles and modifying inadequate environmental conditions NEED electronic, high-tech, semiconductor, pharmaceutical, aerospace, medical and many other industries

8. 8 Unidirectional And The Non-unidirectional Flow Design Unidirectional speed between 60 to 90 FPM Remove particles before they settle onto surfaces Remain parallel used when low airborne concentrations of particles or bacteria are present Air changes per unit of time greater in unidirectional flow design

9. 9 Cleanroom layout

10. Design Details materials used must be nonshedding, nonporous and resistant to microbial growth finished surfaces must be hard, smooth and easy to clean junctions of room surfaces withstand repeated disinfection number of openings in the clean-room fabric Concealed door-closer mechanisms 10

11. 11 Floors, walls, ceilings must be Chemical-proof Bacteriostatic Stable in dimension Colour fast Good resistance to surface spread of flame Sound absorbing Slip-resistant Resistant to abrasion Impact resistant Easily cleaned Colour-coded (between areas of different functions) “Soft” to walk on for operator comfort

12. 12 Classification Of Clean Room : REGULATORY POINT OF VIEW

13. 13 Clean Room Class Class Limits "not to exceed" particles per cu ft for particle sizes shown 0.1  m0.2  m0.3  m0.5  m5m5m 135.07.503.01.0-- 1035075.030.010.0-- 100--750300100-- 1000-- 10007.0 10000-- 1000070.0 10000-- 100000700 Classification Of Clean Room : REGULATORY POINT OF VIEW

14. 14 Contribution of HVAC And The Meaning...

15. 15 Support the manufacture of quality pharmaceutical products A heating system (“H” in HVAC) A ventilating system (“V” in HVAC) A cooling system (“AC" in HVAC)

16. HVAC system design parameters Energy efficiency Cleanliness Cost Temperature uniformity Humidity control Chemical exhaust efficiency Noise control 16

17. 17 Common problems of a wrongly designed cleanroom HVAC system Insufficient air flow Inadequate laminarity Fail to pressurize to specified pressure level Big stagnition zones Ineffective chemical vapor exhaust Too high noise Temperature variation above specifications Humidity variation above specifications

18. 18 “ CLEANLINESS, CLEANLINESS and CLEANLINESS ”

19. 19 What can HVAC do? Control airborne particles, dust and micro- organisms Maintain room pressure (delta P) Maintain space moisture (Relative Humidity) Maintain space temperature

20. 20 What HVAC can’t do? 1. HVAC can not clean up the surfaces of a contaminated places, room or equipment 2. HVAC can not compensate for workers who do not follow procedures

21. 21 Components Of HVAC System

22. Block Diagram 22

23. Local heating systems heat source, distributors, and Portable electric heaters, built-in electric resistance heaters, infrared heaters. and wood stoves Local cooling systems Air circulation devices, such as paddle or desk fans Local ventilating systems Local air-conditioning systems 23

24. 24 HEPA FILTER : At Glance

25. 25 Conclusion: High Efficiency Particulate Air capture a minimum of 99.97% of contaminants at 0.3 microns in size Filtration Mechanisms Inertial Impaction1 micro or more Sieving 1 micro or more Diffusionretension0.5 and less Electrostatic0.5 to 1 micro Interception

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27. Components FrameFilter media SeparatorAdhessive Gasket Testing Of HEPA Filter Efficiency : Hot DOP Integrity : Cold DOP Pressure Drop Air Velocity 27

28. Monitoring and Testing of HVAC Clean Room 28

29. : Monitoring and Testing of HVAC Clean Room Physical Air borne particulate matter HEPA integrity : Cold DOP Air Changes per hour Flow pattern in room Pressure Diff across filter Temperature and Humidity Microbiological Settling Plate Slit Plate Surface Sampling

30. Parameter Particulate monitoring in air HEPA filter integrity testing (DOP testing Air change rates Air pressure differentials Microbiological monitoring by settle plates Temperature and humidity Test Frequency 6 Monthly Yearly 6 Monthly Daily 30

31. Energy Efficient HVAC Cleanroom 31

32. 32 Interior Conditions · Temperature setpoint 70 F +- 2 F · Relative humidity 45% +-3% HVAC Air- Side Design Air velocity 65 fpm · Exhaust air requirements 4.5 cfm/ft2 (based on 1997 UBC/UFC increased minimum ventilation rate to 4 from 1 cfm/ft2) · Fewer or no silencers to dampen fan noise · Static pressure of 4” w.g. on makeup air units and 2” w.g. on recirculation air units · Fan efficiency 85% · Fan motor efficiency 94%

33. VALIDATION 33

34. Design Qualification. Identification of various systems, their functions, schematics & flow diagrams,sensors, dampers valves etc., Layout plans,critical parameters Operation Qualification various points of performance test readings, statement of compliance and noncompliance with the acceptance criteria Performance Qualification Test readings of all critical parameters under full operating conditions and full production 34

35. Clean Room Of Future 35

36. CUMMARY 36

37. As Per US GMP, Design and Construction Features Standard 209 Air should be of a high microbial quality HEPA filter bank along with mandatory terminal filters filtration regime in generally three stages Critical areas should have a positive pressure differential Remember, overstating quality requirements and tolerances may result in unnecessary costs... ! 37

38. References 1. J,E, F, Reynolds. Martindale: The Extra Pharmacopoeia, The Royal Pharmaceutical Society: London, 1996, pp.1218-20. 2.Guideline on Sterile Drug Products Produced by Aseptic Processes, FDA, pub. 1987. 3.Guidance for Submitting Documentation for Sterilization Process Validation in applications for Human and Veterinary Drug Products, FDA, pub. 1993. 4. ISO 13408-1 Aseptic Processing of Health Care Products. 5.Cleanrooms and Associated Controlled Environments, Classification of Air Cleanliness. Contamination Control of Aerospace Facilities. Technical Order 00-25- 203, U.S. Air Force, December l, 1972. 6. Current Practices in the Validation of Aseptic Processing. Technical Report No. 36, Parenteral Drug Association, Inc., Bethesda, MD, 2002. 7. ISPE. Pharmaceutical Engineering Guides for New and Renovated Facilities Bulk Manufacturing Facilities, 1996 8. ALLEN, EDWARD: HOW BUILDINGS WORK, OXFORD UNIVERSITY PRESS, NEW YORK, NY, 1980. 38

39. 9. How Buildings Work provides a complete, introductory level look at all components of a building. The chapter on air temperature and humidity control (pp. 75-90) gives a general introduction to HVAC systems. 10. United Kingdom Accreditation Service. General Criteria of Competence for Calibration and Testing Laboratories. M10. Middlesex: UKAS, 1989. 39

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