PDA COURSE - Facility Design

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Design and Construction Features for Aseptic Areas

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PDA COURSE - Facility Design

  1. 1. Facility Design
  2. 2. The Aseptic Manufacturing Plant GMP Requirements: o 21 CFR Part 211
  3. 3. 211.42 Design and Construction Features for Aseptic Areas Floors, walls & ceilings of smooth, hard and cleanable surface materials Temperature and humidity controls Air supply filtered through HEPA filters under positive pressure Environmental monitoring program Cleaning and disinfecting program Equipment maintenance program
  4. 4. Walls, Floors and Ceiling Surfaces Smooth, cleanable finish that is impervious to water, cleaning and sanitizing solutions Constructed of materials that resist chipping, flaking, oxidizing or other deterioration o epoxy terrazzo, Mipolam o cement plaster o plastics
  5. 5. Aseptic Filling Process Flow Diagram Raw Formulation/ Sterile Materials Filling Lyophilization Compounding Filtration Component Preparation Capping Packaging
  6. 6. Sterile / Aseptic Operations Sampling Raw & Packaging Material Storage Dispensing Formulation / Compounding Sterile Filtration Component Prep Filling Cleaning Lyophilization (Freeze Drying)
  7. 7. Sterile / Aseptic Operations (cont.) Capping Terminal / Post Sterilization Labeling Packaging o Cartoning o Case Packaging Warehouse Distribution o Conditioned Space o Refrigerated o Frozen
  8. 8. Sterile / Aseptic Operations (cont.) Support Areas o Quality Control / Quality Assurance o Laboratory o Chemical o Microbiology o Stability o Process Utilities o Pure Steam o PW, WFI o Pharmaceutical Compressed Gasses
  9. 9. Critical Process Systems Component Preparation Formulation/Compounding Filter/Steam Sterilization Aseptic Processing Operation Liquid Fill/Packaging
  10. 10. Critical Processing Zone
  11. 11. Process in Key Element (GMP) Aseptic Processing Protect Product from Area Contamination o Product Formulated o By Process o Product Sterilized o By People (filtration) o By Environment o Product Filled o By Materials o Product Sealed
  12. 12. Definition-- Contaminant Anything that should not be in or on the product o Microorganisms o Pyrogens o Non-viable particulates
  13. 13. Contamination Control Terminal Sterilization Aseptic Sterile Manufacturing o Type of Product o Critical Processing Steps o Product Exposure o Acceptance Criteria
  14. 14. Contamination Control Personnel Gowning Personnel Aseptic Gowning
  15. 15. Design Considerations Closed Systems That do not Expose Products Where Product Can be Exposed, Conduct Operations in Clean Rooms Design Equipment and Piping for Sterile Operation Use Pyrogen Free Water for process and Final Rinses of Equipment Sterile Filter Product Solutions Low temperature Processing
  16. 16. Key Design Issues Vessel Mixing - Agitator Design Sanitary Piping Design CIP Circuit Design Temperature Control Equipment Design Process Controls - Interlocks Equipment Arrangement - Facility Layouts
  17. 17. Key Facility Issues Layout That o Support the Process o Facilitate Operations o Provide Appropriate Space o Provide Proper Flow of Materials, People & Waste o Prevent Mix - up o Prevent Contamination Material and Design Details that o Do not Contaminate o Provide Ease of Cleaning & Maintenance
  18. 18. Key Facility Issues (cont.) Internal Environments That o Provide suitable Conditions of Temperature, Humidity & Particulate Control o Room Pressurization & Directional Airflows Which Prevent Contamination o Prevent Bacterial Growth or Infestation o Segregate Hazardous Area
  19. 19. Utility Requirements Clean Utilities o Water-for-Injection (WFI) o Clean Steam o USP Purified Water o Clean-in-Place (CIP) General Utilities o Plant Steam o Chilled Glycol and Water o Compressed Gasses
  20. 20. Water-For-Injection (WFI)
  21. 21. WFI System Components Feed Water Pretreatment WFI Production WFI Storage & Distribution WFI Cooling For Use
  22. 22. Water-For-Injection (WFI)
  23. 23. Typical Storage & Distribution Network
  24. 24. Key Definitions For Successful System Minimum Distance Sloped Piping Drainability Valve Combinations Component Selection Access For Operation Access For Maintenance
  25. 25. Common Pitfalls Dead Legs Excessive Clamps The Use of Non Sanitary o Instruments o Valves o Equipment
  26. 26. Clean In Place (CIP)
  27. 27. Cleaning Is Mandated By cGMP 21 CFR 211.67 “ Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. “
  28. 28. CIP (Clean In Place System)
  29. 29. CIP System Design Steps Identify Equipment and Systems to be Cleaned Design Equipment to facilitate Cleaning Arrange Equipment & Piping to Facilitate Cleaning Establish Level of Cleanliness o Define How Clean is Clean Investigate Cleaning Compounds Develop Cleaning Cycle Parameters Design CIP Fluid Circulation System
  30. 30. Cleaning Process Variables Time / Sequence Temperature Flow rate / Pressure Cleaning Agent selection Cleaning Agent Concentration Return water Resistivity
  31. 31. Clean Steam System
  32. 32. Clean Steam Application Autoclave Operation Equipment Sterilization (SIP) HVAC Humidification
  33. 33. SIP Advantages Only Technique for Large Equipment Obviates the Need for Large Autoclaves Reduces Clean Room Operation Activity Enhanced System Integrity o Reduction of Aseptic Connections o Reduction of Flexible Hoses
  34. 34. HVAC
  35. 35. Key HVAC Issues Design to Eliminate Airborne Contamination o Terminal HEPA Filters in Air Supply Duct o Return Air Taken From Low Points o Laminar Air Flow Over Exposed Product o High Air Change Rate o Higher Pressure in Cleaner Areas Suppress Microbial Growth o Relative Humidity 30 to 50 percent o Temperature Control
  36. 36. Definitions--Cleanroom A room in which the air supply, air distribution, filtration of air supply, materials of construction, and operating procedures are regulated to control airborne particle concentrations so that appropriate air cleanliness levels can be met.
  37. 37. Definitions--Unidirectional airflow cleanroom (Laminar) A cleanroom in which the filtered air entering the room makes a single pass through the work area in a parallel-flow pattern, with a minimum of turbulent-flow areas. Unidirectional airflow rooms typically have HEPA or ULPA filter coverage of 80% or more of the ceiling (vertical flow) or one wall (horizontal flow).
  38. 38. Definitions--Non-unidirectional airflow cleanroom A cleanroom in which the filtered air entering the room or passing through the work zone is characterized by non-uniform velocity or turbulent flow. Such rooms exhibit non-uniform, random airflow patterns throughout the enclosure.
  39. 39. Definitions--Uniform airflow An unidirectional airflow pattern in which the point-to-point readings are within +20% of the average airflow velocity for the total area of the unidirectional flow work zone.
  40. 40. Definitions--HEPA Filter High Efficiency Particulate Air filter--An extended-medium, dry-type filter in a rigid frame having a minimum particle-collection efficiency of 99.97% for 0.3µm, near-monodisperse dioctyl phthalate (DOP) particles (or equivalent substitute such as poly-alpha olefin, PAO).
  41. 41. Definitions--ULPA Filter Ultra-low Penetration Air filter--An extended- medium, dry-type filter in a rigid frame having a minimum particle-collection efficiency of 99.999% for particles 0.12µm and larger.
  42. 42. cGMPs Impact on HVAC Systems AHU Systems HVAC System Components Building Automation Systems Testing, Balancing, and Cleaning Validation
  43. 43. Sterile Area HVAC Flow Diagram
  44. 44. HVAC Control Temperature and Humidity Air Pressure Air Filtration o Pre-filters o HEPA Filters o ULPA Filters
  45. 45. HVAC Control Diagram
  46. 46. Federal Standard 209E Class 100 is not more than 100 0.5µm or greater particles per cubic foot of air when at least two sample locations are tested and a statistical analysis of the test data is performed at a 95% confidence limit. Class 10,000 is the same with not more than 10,000 0.5µm or greater particles … Class 100,000 is …100,000 0.5µm or greater particles...
  47. 47. Typical Clean Zone Classifications Non-sterile equipment/component prep and compounding-- Class 100,000 Aseptic Core-- Class 10,000 Filling Room-- Class 10,000 or 1000 Laminar Flow over Filling Line--Class 100
  48. 48. Area Classification
  49. 49. AHAC Area Coverage
  50. 50. Critical Areas for Aseptic Processing Airborne particle count: Class 100 Velocity of air: 90 FPM + 20% Air changes: several hundred per hour Airborne microbes NMT 3 CFU/m3 Surface cleanliness 3 CFU per 24-30 cm3 (USP) Personnel Aseptic Gowning
  51. 51. Controlled Areas for Aseptic Processing Airborne particle count: Class 10,000 Velocity of air: 60 FPM + 20% Air changes (minimum): NLT 45 per hour Airborne microbes: NMT 20 CFU/m3 Surface cleanliness: 5 CFU per 24-30 cm3 (USP)
  52. 52. Controlled Areas for Aseptic Processing Airborne particle count: Class 100,000 Velocity of air: N/A Air changes (minimum): NLT 20 per hour Airborne microbes: NMT 100 CFU/m3 Surface cleanliness: 5 CFU per 24-30 cm3 (USP)
  53. 53. ISO/TC209 International Organization for Standardization, Technical Committee 209
  54. 54. GMP Compliance - Facility Design Requirements Layouts that: o Facilitate appropriate space and operations o Provide proper flow of material, people and waste Material and design details that: o Provide ease of cleaning and maintenance o Wearing surface and impact resistance Service maintenance access o Utility requirements o Service corridors and walkable ceilings
  55. 55. GMP Compliance - Facility Design Requirements (Cont.) Operational Adjacency and Process Flow o Personnel, Material, Product, Equipment, Waste Modular Design Process Utilities and Building Systems Integration/Access Code Compliance o Egress, ADA/Accessibility, Fire Resistance, Safety
  56. 56. Area Classification
  57. 57. Construction Material Selection HVAC Criteria o Cleanability o Air cleanliness class o Fit for intended use o Temperature and o Sterilization relative humidity Clean Build Protocol o Airflow and pressurization o Defines how construction materials Support Services and personnel enter o Water, steam, gases, and exit the vacuum, electrical construction site o Instrumentation
  58. 58. Documentation & Validation Quality MUST be involved from the project beginning Must keep accurate records Prove that the facility & equipment are built to the design criteria Tested and certified Officially commissioned for use

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