Parvovirus Filtration Best Practices - 25 Years of Hands-On Experience
Flexible Aseptic Manufacturing
1. FLEXIBLE ASEPTIC
MANUFACTURING
TRADITIONAL VS. FLEXIBLE ASEPTIC
MANUFACTURING
Steve Walter, Josh Russell
GMP Technology Specialist Principal Engineer
CDI Life Sciences AST
2. Objective / Agenda
Provide an overview and comparison between traditional
and flexible aseptic manufacturing, the impact to facility,
operations, and cost.
•Industry Trends & General Requirements
•Traditional Aseptic Processing Overview
•Flexible Aseptic Processing Overview
•Comparison Between Tradition and Flexible Approaches
•Operational Differences
•Cost & Savings
3. Trends & General Requirements
• Small scale, high value, patient
focused
• Fast turnaround time and clinic
responsiveness becoming more
critical
• New products are highly potent
at the filling stage
• Leaner, modular, simpler
• Superior flexibility – multi-format,
multi-product, multiple dosing
options
4. Traditional Aseptic Processing
CNC CNC/Grade D Grade C CNC
Comp
Wash Depyro Fill Stopper Capping
Prep
Comp
Wash Depyro
Prep
Comp De- Tub
Prep Bag Decon
5. Traditional Aseptic Processing
• Dedicated fill-finish capabilities for a specific
container type or “format”
• Adding additional container filling capabilities is a
significant investment in facilities, time and
equipment
• Processing challenges include glass on glass
contact, machine jams, broken containers, etc.
• Very efficient for high volume dedicated products
where flexibility is not necessary
6. Flexible Aseptic Processing
• Integrates best in industry Flexibility is the
technologies antidote to uncertainty
• Simplifies the manufacturing
process
• Ability to fill multiple container
formats & sizes
• Common facility with reduced
floor space and utilities
• Increased asset utilization
7. Enabling Technologies
• Ready-To-Fill Containers
• Vials, Syringes, Cartridges
and Infusion Bags
• WFI Washed, <1
EU/Container, EtO Sterilized
• Cartridges have line seal &
crimp cap placed, and
oriented like a pre-filled
syringe
• No glass on glass contact
• Ready-To-Use
Components
9. Enabling Technologies
• Isolator Barrier
“Automation of other
Technology + Robotics process steps, including
• Provides full separation the use of technologies
between the operator and such as robotics, can
the process further reduce risk to the
• Compatible with VHP bio- product.”
decontamination Guidance for Industry: Sterile Drug Products
Produced by Aseptic Processing — Current
• Recipe driven operation Good Manufacturing Practice (Pg.10)
• Maximum flexibility and
functionality
• Negligible particle
generation
10. Flexible Aseptic Processing
Grade D or C CNC
Rapid
Comp Decon
Capping
Prep Chamber
• Consolidated manufacturing process that allows
multiple container formats to be filled and finished on a
single system.
• Interchangeable robot tooling specific to container
11. Comparison
ASEPTIC PROCESSING COMPARISON
Criteria RABS Isolator Robotic Isolator
Stainless walls, sealed unit,
Hard walls, interlocked Stainless walls, sealed unit, minimal glove ports,
doors, glove ports, transfer glove ports, transfer ports, transfer ports, bio-decon
Physical Attributes ports bio-decon system system
Room Classification ISO 7 Min ISO 8 ISO 8
Separate AHU & HVAC or
Room HVAC or Separate Separate AHU & HVAC, Leak Integrated , Leak Tight,
Air Handling AHU Tight, Outside Venting Outside Venting
Automatic, Shorter
Duration depending on
Bio-Decon Manual, Glove Autoclaving Automatic components
Environmental
Monitoring Portable or Built-In Built-In Built-In / Automated
Class 5 or 7 Gowns, Glove Class 8 Gowns, Glove Port
Gowning Port Usage Usage Class 8 Gowns
Glove Testing Visual, Automatic Visual, Automatic If Required
12. Comparison
ASEPTIC PROCESSING COMPARISON
Criteria RABS Isolator Robotic Isolator
Mousehole, Load Lock, Mousehole, RTP, Transfer RTP, Transfer Isolator,
Material Transfer RTPs, DRAWERS Isolator Staging Isolator
Gowning, Aseptic Barrier Control System,
Technique, Barrier Cleaning, Transfer Methods, Glove Barrier Control System,
Emphasis of Training Transfer Methods, Glove Inspection & Testing, Bio- Transfer Methods, Bio-
SOPs Inspection & Testing Decontamination Decontamination
Limited / # Of Modules or
Capacity All Speeds All Speeds filling heads
Minimized: Gowning
functions, Minimal
Minimized: Minimal Component Prep, Support
gowning functions, equipment: A/C, Depyro
Floor Space Component Prep Varies and Wash not required
Minimal: Automatic -
Machine settings are stored
Access for Change Easy with Open Doors / as recipe. Some pieces of
Over Gowned with open doors Manual tooling
Operating Costs High Medium Low
Low - Repeatability of
Moderate - Risk with Medium - Utilizing FAT/SAT Robots and no
Validation Complexity Airflows results interventions
13. Operational Differences
Criteria Isolator Flexible
Glove Testing Visual / Automatic Visual / Automatic –
(Qty) (Qty - Minimal)
Training / SOPs Aseptic Technique / Limited Operator
Transfer interface during set up
Component Prep Varies No Wash / Depyro
Change Over Operator Set Up Programmed with
integrated tooling
Utilization Depends on Set Up, Reduced process steps
Change Out and – Increased Up Time
Product Path Cleaning / Steam In Single Use Assembly
Place
14. Operational Differences
Criteria Isolator Flexible
Receipt of Packed Glass Tub / Tray RTU
Materials
Component Prep Unwrap / Wash Unwrap / Stage
Waste Packaging Trays / Tubs utilized
Discarded through capping
Sterilization / Low Driven lower with smaller
Decontamination environment and isolated
Time decontamination
Operators Required for setup, Automated – setup,
changeover changeover
15. Impact to Layout
Area Isolator (SF/SM) Flexible (SF/SM)
Vial Filling & Capping 2100 / 195 900 / 84
Gowning 120 / 11 120 / 11
Degowning 80 / 8 80 / 8
Material Air Lock 100 / 9 100 / 9
(MAL)
Comp Prep / Material Note * 300 / 28
Staging
Total Area 2400 / 223 1500 / 140
35 – 40% Decrease in required functional areas
* Component prep area is included in the overall area of
vial filling & capping.
16. Cost Impact - Facility
Space /Area Gr $/SF Isolator $ Isolator Flexible $ Flex
(US / €) (SF/SM) (US / €) (SF/SM) (US / €)
Vial Filling & C 425 / 2100 / 892,500 / 900 / 84 405,000 /
Capping 316 195 663,840 301,240
Gowning C 425 / 120 / 11 54,000 / 120 / 11 54,000 /
316 40,165 40,165
Degowning C 425 / 80 / 8 36,000 / 80 / 8 36,000 /
316 26,775 26,775
MAL C 425 / 100 / 9 45,000 / 100 / 9 45,000 /
316 33,475 33,475
Comp Prep / D 300 / Note * 0 300 / 28 90,000 /
Matl Staging 223 66,942
Totals 2400 / 1,027,500 / 1,500 / 630,000 /
223 764,254 140 468,594
* Component prep area is included in the overall area of
vial filling & capping.
19. Size, Cost & Equipment
• Facility Size
• Reduce operating areas by 30-40%
• Facility Cost
• Reduced engineering / design & construction costs
• Reduced construction / constructability challenges
• Reduced capital equipment investment
• Equipment Operations
• Eliminate washing and depryogenation operations from the
manufacturing site
• Increase equipment utilization
• Single fill line has the ability to process multiple container
formats
• Eliminates some of the most common routine interventions
20. Conclusions
• Flexible aseptic processing simplifies the traditional
aseptic manufacturing process
• Flexible aseptic processing leverages the strengths of
best in industry technologies to:
• Focus on core aseptic manufacturing processes
• Provide an adaptable platform capable of multi-
container format filling
• Minimize routine operator interventions
• Reduce facility size, utilities, cost, and validation
• Increase operational efficiency
22. Thank You!
Joshua Russell, Principle Engineer – Life Sciences
Automated Systems of Tacoma (AST)
4110 South Washington St. Tacoma, WA 98409
(253) 475-0200
jrussell@ast-inc.com
Steven Walter, GMP Technology Specialist
CDI Life Sciences
1801 Market Street, Ste. 1300, Philadelphia, PA 19103
(215) 282-8349
Steven.walter@cdicorp.com
Notas del editor
Products in current clinical pipelines are much more specific to patient and disease. Many companies are further stratifying their products by coupling it with a clinical diagnostics which in turn makes the product oriented to a specific patient sub-groups and is of higher value. Time to clinic and time to market is critical in order to maximize the financial gain for the particular product. Also patients depend on these critical products. Many of the products that are in the clinical pipeline tend to be point at the filling stage requiring containment of the product. Because the products are being produced at smaller volumes building leaner, modular and simpler facilities minimize the invested capital required to bring these products to market. Superior fill-finish flexibility allows the company to make a single fill line investment with the ability to manufacture multiple products irrespective of the format, product or dosing requirements.
Here is an chart that illustrates the various process involved in aseptically filling products in various formats on traditional dedicated fill lines. Each container format has a specific process and hence a specific machine for the given container. Before moving on, let’s take notice that there are several process commonalities between the formats. Vials and cartridges require a stopper and a cap, cartridges and syringes both have pistons inserted post filling
As illustrated on the previous slide traditional aseptic manufacturing is a dedicated process that is specific to the container format. You can’t make a traditional vial “mono-bloc” style filler fill and insert a piston into a syringe. The ability to add additional filling capabilities to a facility once you are fully invested in fill line for a particular container can be costly, have a long lead schedule and can be disruptive to current manufacturing operations. Suffice it to say, to be able to fill additional formats with traditional aseptic fill lines is a significant time and capital investment. Traditional fill lines especially for those handling non-nested containers can have some processing challenges like glass on glass contact, machine jams and broken or fallen containers to name a few. Traditional fill lines are very efficient for filling products and containers that do not require flexibility.
Flexible aseptic processing is an alternative approach, which leverages the commonalities between the various container fill-finish processes but using a single manufacturing platform. This is done by integrating industry leading technologies such as single-use disposables, isolator barrier technology, automation and robotics, and lastly ready-to-fill nested formats. Simplifies the manufacturing process by eliminating the container preparation process at the manufacturing site. The end result is a manufacturing process that has the flexibility to fill multiple container formats and sizes on a single modular platform. Some of the other key benefits derived from this is the ability to standardize the facility for not only your current manufacturing site, but you are able to transplant the same floor plan elsewhere globally because the equipment remains the same. Facility floor space and utilities required for the operation are also reduced. Lastly and more importantly a flexible asset can be utilized irrespective of the container to be processed.
Options are available for all formats to be supplied in ready-to-fill configurations just like BD has done for years with the Hypak syringe. Ompi’s EZ-Fill nested vials and cartridges have the same presentation as nested syringes having a nest which holds and locates the vial within the tub. A tyvek lid and liner seal the containers within the tub.
