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Sterile Facilities

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Sterile Facilities

  1. 1. Basics Of Sterile Liquids Manufacturing
  2. 2. Sterile Liquids Manufacturing – Basic Tenets • Product Protection is Highest Priority • Closed Processing is Preferred Method for Product Protection • Ultra-clean laminar flow air is your friend • Sterile Manufacturing can be accomplished in a variety of ways • All aspects of the manufacturing process must work together to successfully perform sterile manufacturing • Administrative controls should not be the primary means of performing sterile manufacturing 2
  3. 3. Sterile Liquids Manufacturing – What it Takes • Clean Air • Clean Water • Cleanable Facilities • Cleanable Equipment or Single Use Equipment • Validated Systems/Validated Process • Proper Gowning • Product/Component Protection Activities & Procedures • Proper Flows • Warehousing • Quality Assurance & Quality Control Activities 3
  4. 4. Sterile Liquids Manufacturing – What Can DME Do • Facility Design • HVAC System Design • Process Definition/Process Description • Unit Operation Description • Equipment Specification • Clean Utilities System Design • Equipment Sizing • Plant Utilities Design 4
  5. 5. Sterile Liquids Manufacturing – DME’s Deliverables • Facility Layout Drawing(s) • Area Classification Drawing(s) • Air Flow Diagrams • Material/Personnel/Waste/Product Flow Diagrams • Electrical Single Line Drawing(s) • Lighting/Security/Fire Alarm/IT Device Plans • Equipment Arrangement Drawing(s) 7
  6. 6. Sterile Liquids Manufacturing – DME’s Deliverables • PFDs • P&IDs • Equipment Specifications • Gowning Philosophy • Product Protection Philosophy 8
  7. 7. Glossary of Terms • Sterile Liquid Filtration – use of a sterilizing grade, 0.2 micron-rated cartridge filter for removal of microorganisms. • Aseptic processing – bringing sterile components and sterile product together in an extremely high quality environment to insure microorganism free filled products. • Parenteral – pharmaceutical product that is injected into the body (vein, muscle). • Endotoxins / Pyrogens – fever-causing cell debris. • Terminal sterilization – non-invasive sterilization of filled container using UV or Gamma radiaton, Heat, or other means. 9
  8. 8. Glossary of Terms • Barrier/Isolation Technology – strategies to isolate hazardous products from manufacturing personnel; isolation of environmental elements that may contaminate to the product. • Cytotoxic compound – toxic compounds that have carcinogenic, mutagenic and/or teratogenic effect. • Potent compound – a drug product that achieves a desired medical effect with a very small amount of an active ingredient. 10
  9. 9. Glossary of Terms • Room Pressurization – a means of providing directional air flow in order to achieve product protection. • Bio-burden – microbiological count or level. • Bio-burden Reduction – activity or process step implemented in order to reduce microbe count • Laminar Flow Area – zone of clean (HEPA filtered) directional air flow that provides high quality environmental conditions for aseptic processing. • Uni-Directional Flow – European designation for laminar flow. 11
  10. 10. Sterile Manufacturing Facilities – Air Quality 12 FDA Maximum number of particles permitted /m3 In operation Class .5 µm 5 µm ISO 5 3,520 29 NA NA NA ISO 7 352,000 2,930 ISO 8 3,520,000 29,300 EU Maximum number of particles permitted /m3 At rest In operation GR .5µm 5µm .5µm 5µm A 3,520 20 3,520 20 NA NA NA NA NA B 3,520 29 352,000 2,900 C 352,000 2,900 3,520,000 29,000 D 3,520,000 29,000 Not defined Not defined
  11. 11. Sterile Manufacturing - Unit Operations • Raw Material Weighing & Dispensing • Component Preparation • Antigen Thawing • Formulation • Filling / Stoppering / Capping • Lyophilization (Freeze-drying) • Terminal Sterilization of Product – Cook it in a container 13
  12. 12. Sterile Manufacturing - Unit Operations • External Vial Washing • Inspection – Manual/Automatic • Container Closure Testing • Coding • Final Packaging • CIP/SIP • Clean Utility Generation – WFI/CS/CCA 14
  13. 13. Sterile Manufacturing - Product Types • Vaccines – Sanofi, GSK, Takeda • Oncology Drugs – Boston Biopharma, BMS • Renal/Dialysis Solutions – Haiti Project • Intravenously Administered Medicines • Analytical Products • Opthalmic Products – Imprimis • Burn Treatment Products • Biologicals - Probiomed 15
  14. 14. Sterile Manufacturing - Production Issues • Product Demand/Product Portfolio • Batch Size/Compounding Design • Vial Processing Speed • Production Shift Philosophy • Cleaning/Sterilizing Requirements • Utility Capacity • Equipment Utilization • Container Inspection Approach 16
  15. 15. Sterile Manufacturing - Production Issues • Lyophilization Cycle Duration – can be days • Lyophilizer Loading/Unloading – Partially Closed Vials • Transport of Partially Stoppered Vials – mobile ISO 5 • Processing of Multiple Container Types – vials & syringes • Processing Containers from Tubs – robotics required • Sterilization of RABS & Isolators – fogging with VHP 17
  16. 16. Sterile Manufacturing - Production Issues • Fill Volume Accuracy – Correct Dosage • Formulation Accuracy – Correct Composition • Formulation Homogeneity – Correct Composition • Product Integrity – Cold Chain, Purity • Product Protection – Aseptic Simulation • Product-Specific Process Considerations 18
  17. 17. Sterile Manufacturing Design Guidance/Requirements • ISPE Design Guide – Sterile Mfg Facilities • Current Available Technology – Vendor Driven • cGMP Requirements (FDA, MCA, EU, PICS, WHO) • Safety Requirements (OSHA, NFPA, etc.) • Containment Requirements 19
  18. 18. Sterile Manufacturing Design Considerations • Recipe Control/Data Archiving • Control System Requirements • Cleaning Requirements • Material Handling and Processing • Sterility/Pyrogen Control Requirements 20
  19. 19. Sterile Manufacturing - Containment Reqts • Hazards Classification • Levels of Protection • Equipment Design • Procedural Solutions – Time Segregation • Barrier/Isolation Technology 21
  20. 20. Sterile Manufacturing - Process/Facility Issues • Laminar Flow Areas • Closed Processing • Barriers/Isolators • Controlled Areas – local, general • Classification Criteria • Gowning, Airlocks, etc. • Line Layout 22
  21. 21. Sterile Manufacturing - Facility Design Issues • Safety vs. cGMPs • Maintenance vs. cGMPs • Electrical Classification of Processing Areas • Fire Protection of Processing Areas • Spill Containment / Cleanup Procedure • Equipment Washdown • Drainage Systems • Low Wall Returns & Return Wall Space • Firewalls/Runoff Collection System (for handling flammables) 23
  22. 22. Sterile Manufacturing - cGMP Design Issues • Piping Systems (Hookup Stations) • Vessel Maintenance (Lifting Systems) • Solids/Liquids Additions • Laminar Flow / Uni-Directional Zones • Formulation Vessel Design • Glovebox / BioSafety Cabinet Design • Sterile System Design 24
  23. 23. Sterile Manufacturing – Sterility Control • Steam-in-Place Systems • Autoclaves • Depyrogenation Ovens / Tunnels • Terminal Sterilizers • Sterile Filtration • WFI Flushes • Aseptic Processing 25
  24. 24. Sterile Manufacturing - Pressurization Reqts • Vessel overpressurization for product protection • Vessel overpressurization for product transfer and filtration • Vacuum for raw material transfer • Facility overpressurization for product protection • Facility underpressurization for product containment 26
  25. 25. Sterile Manufacturing -Utility System Reqts • High Purity Water – (USP purified, WFI, hot, ambient, point-of-use coolers, subloops, etc.) • Clean Steam • Process Venting • Process Vacuum • Process Heating/Cooling/Chilling • Process Waste (solvent, contaminated aqueous) • Air / Nitrogen • Process Chilled Glycol 27
  26. 26. Sterile Manufacturing – Advanced Technology • Robotic Filling • Camera Inspection

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