This document provides an overview of sterile liquids manufacturing, including key tenets, requirements, processes, and design considerations. The main points are: 1) Sterile manufacturing requires clean air, water, facilities, equipment, validated processes, and quality control to successfully produce sterile products. Closed processing methods are preferred for product protection. 2) Key unit operations include formulation, filling, stoppering, lyophilization, inspection, and terminal sterilization. Facilities must consider production needs like batch size and container types. 3) Designing sterile facilities requires meeting regulations while addressing safety, containment, utilities, and automation needs to ensure robust and compliant manufacturing.

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