1. Basics Of Sterile Liquids
Manufacturing

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
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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
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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
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7. 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)
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8. Sterile Liquids Manufacturing – DME’s Deliverables
• PFDs
• P&IDs
• Equipment Specifications
• Gowning Philosophy
• Product Protection Philosophy
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9. 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.
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10. 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.
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11. 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.
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12. Sterile Manufacturing Facilities – Air Quality
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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

13. 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
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14. Sterile Manufacturing - Unit Operations
• External Vial Washing
• Inspection – Manual/Automatic
• Container Closure Testing
• Coding
• Final Packaging
• CIP/SIP
• Clean Utility Generation – WFI/CS/CCA
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15. 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
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16. 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
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17. 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
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18. 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
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19. 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
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20. Sterile Manufacturing Design Considerations
• Recipe Control/Data Archiving
• Control System Requirements
• Cleaning Requirements
• Material Handling and Processing
• Sterility/Pyrogen Control Requirements
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21. Sterile Manufacturing - Containment Reqts
• Hazards Classification
• Levels of Protection
• Equipment Design
• Procedural Solutions – Time Segregation
• Barrier/Isolation Technology
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22. Sterile Manufacturing - Process/Facility Issues
• Laminar Flow Areas
• Closed Processing
• Barriers/Isolators
• Controlled Areas – local, general
• Classification Criteria
• Gowning, Airlocks, etc.
• Line Layout
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23. 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)
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24. 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
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25. Sterile Manufacturing – Sterility Control
• Steam-in-Place Systems
• Autoclaves
• Depyrogenation Ovens / Tunnels
• Terminal Sterilizers
• Sterile Filtration
• WFI Flushes
• Aseptic Processing
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26. 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
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27. 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
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28. Sterile Manufacturing – Advanced Technology
• Robotic Filling
• Camera Inspection