Utility Systems Process Systems – ‘Direct Impact Systems’ Contact the Product Contact Materials that will Ultimately Become Part of the Product Could Otherwise Directly Impact Product Quality Examples 1 Purified Water (Deionised) WFI Clean Steam Nitrogen Sterile Air Utility Systems Process Systems – ‘Indirect Impact Systems’ Do Not Contact the product or Material that will Ultimately Become part of the product Generally Site or Building Systems (Not Tailored to Sterile Manufacturing Facilities) Deal with a Side Effect of the Manufacturing Process Examples 2 HVAC for non classified areas Chilled Water Potable Water Floor Drains Waste Disposal Exercise 3 - Direct or Indirect Utilities A: What Utilities are Direct or Indirect for the process of filling product into Mobile Vessels? Instrument Air for isolation/ control valves Glycol for temperature control of vessel jacket WFI is used for CIP (Clean in Place) CS (Clean Steam) is used to Steam in Place (SIP) the vessel before filling 3 Exercise Answers A: What Utilities are Direct or Indirect for the process of filling product into Mobile Vessels? Instrument Air for isolation/ control valves Glycol for temperature control of vessel jacket Direct as it comes in contact with product path and potentially the product. Quality is critical to successful cleaning also. CS (Clean Steam) is used to Steam in Place (SIP) the vessel before filling 4 Indirect as it will never come directly in contact with product. WFI is used for CIP (Clean in Place) Indirect as it will never come directly in contact with product. Direct as it comes in contact with product path and potentially the product. Quality is critical to successful cleaning also. Utility Systems Direct Impact Systems – Key Considerations 5 Material of Construction in Sterile Core Should be 316L Stainless Steel Surface Finish Should be at Least 0.5m (Preferably < 0.4m) Utilities May Require Point-of-Use Filtration in Sterile Core Pipework in Sterile Core Should be Electropolished Materials of Construction Must be Compatible with Sterilisation Methods in Area As Many Components as Possible Should be Located Outside Sterile Core Pipework and Components in Cleanroom Must be Designed and Installed in Accordance with ASME BPE 2002 (Bio-Pharmaceutical Engineering) HVAC – Heating, Ventilation & Air Conditioning Contamination From People is the Greatest Source of Contamination in an Aseptic Facility People Contribute 80% of Airborne Contamination in Cleanrooms Special Cleanroom Clothing is Worn to provide a barrier Between person and Environment High Personal Hygiene Standards Essential Minimise Number of People in Sterile Core HVAC System Must Maintain the Cleanroom Environment Requirements by Removing Airborne Contamination and Replacing it With Suitably Filtered Air 6 Definition of Environmental Requirement Depends on Cleanroom Classification Grade A Classification Table ISO EN 14644 EUDRALEX EUDRALEX FS209D (#) (at rest) (in operation) (in operation) ISO 3 1 ISO 4 10 ISO 5 Grade A&B Grade A ISO 6 1,000 ISO 7 Grade C Grade B 10,000 ISO 8 Grade D Grade C 100,000 - - Grade D* Pharmaceutical - - - * With local monitoring * Now Withdrawn 7 100 Unclassified HVAC Guideline on Sterile Drug Products Produced by Aseptic Processing States: 8 Air in Critical Areas Should be Supplied at the Point-of-Use as HEPA Filtered Laminar Flow Air Having a Velocity Sufficient to Sweep Particulate Matter Away From the Filling Area. Normally a Velocity of 90 Feet Per Minute (0.46 m/sec.), Plus or Minus 20% is Adequate. Critical Areas Should Have a Positive Pressure Differential Relative to Less Clean Areas; a Pressure Differential of 0.05 inch of Water (12.5 Pascals) is Acceptable. HVAC - Exercise 4 Apply Pressure Cascade Principle to Aseptic Facility Layout Below (Use Pressure of 37.5Pa for Aseptic Pressure Room 1) Based on Figure 5.4: ISPE Guideline Volume 3 Airlock (Not Directly Pressure Controlled) Changing Room Cooling Area Aseptic Processing Room 1 Packing Hall (Nor Directly Pressure Controlled) Autoclave Autoclave Loading Room Pass Through Component Preparation Aseptic Processing Room 2 (To Suite Connecting Areas) Washing / Sterilising Tunnel 9 HVAC - Exercise Answers Based on Figure 5.4: ISPE Guideline Volume 3 Airlock (Not Directly Pressure Controlled) Changing Room 12.5 Pa Cooling Area 37.5 Pa Aseptic Processing Room 1 Packing Hall (Nor Directly Pressure Controlled) Autoclave 25 Pa Autoclave Loading Room 12.5 Pa 37.5 Pa Pass Through Component Preparation Aseptic Processing Room 2 12.5 Pa (To Suite Connecting Areas) Washing / Sterilising Tunnel 10 QUESTIONS??? 11 clement.farrar@gmail.com Take 10 minutes! 12 Additional Slides Sterilisation Example 13 Sterilisation Example Given: Micro-organism : Bacillus Stearothermophilus Initial Count: 1 million (106) spores D121 Value: 1.5min (i.e. at 121oC it will take 1.5 mins to reduce number of viable Bacillus Stearotherm – ophilus by 1 log reduction) Q1: What is the SAL? Q2: What sterilising time (t) is required to achieve an SAL of 10-6? 14 Sterilisation Example Answer 1 LRV = Sterilisation time D121 LRV = 15 min 1.5 min LRV = 10 log reduction 15 SAL = Initial bioburden count – LRV = 106 – 10 Logs = 10-4 Sterilisation Example Answer 2 LRV = t/D or LRV x D121 Value = t 16 SAL = 10-6 LRV Required = Initial Bioburden - SAL LRV = 106 – 10-6 = 12 Log Reduction LRV = 12 LRV x D121 Value = Sterilisation hold time 12 x 1.5 = 18min