Basics Of Sterile Liquids Manufacturing

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

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

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

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)

Sterile Liquids Manufacturing – DME’s Deliverables

• PFDs• P&IDs• Equipment Specifications• Gowning Philosophy• Product Protection Philosophy

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.

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.

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.

Sterile Manufacturing Facilities – Air Quality 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

EUMaximum number of particles

permitted /m3

At rest In operation

GR .5µm 5µm .5µm 5µm

A 3,520 20 3,520 20NA NA NA NA NA

B 3,520 29 352,000 2,900C 352,000 2,900 3,520,000 29,000

D 3,520,000 29,000 Not defined Not defined

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

Sterile Manufacturing - Unit Operations

• External Vial Washing

• Inspection – Manual/Automatic

• Container Closure Testing

• Coding

• Final Packaging

• CIP/SIP

• Clean Utility Generation – WFI/CS/CCA

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

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

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

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

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

Sterile Manufacturing Design Considerations

• Recipe Control/Data Archiving

• Control System Requirements

• Cleaning Requirements

• Material Handling and Processing

• Sterility/Pyrogen Control Requirements

Sterile Manufacturing - Containment Reqts

• Hazards Classification• Levels of Protection• Equipment Design• Procedural Solutions – Time Segregation• Barrier/Isolation Technology

Sterile Manufacturing - Process/Facility Issues

• Laminar Flow Areas• Closed Processing• Barriers/Isolators• Controlled Areas – local, general• Classification Criteria• Gowning, Airlocks, etc.• Line Layout

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)

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

Sterile Manufacturing – Sterility Control

• Steam-in-Place Systems• Autoclaves• Depyrogenation Ovens / Tunnels• Terminal Sterilizers• Sterile Filtration• WFI Flushes• Aseptic Processing

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

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

Sterile Manufacturing – Advanced Technology

• Robotic Filling• Camera Inspection