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.
Flexible Aseptic Manufacturing
FLEXIBLE ASEPTIC MANUFACTURING TRADITIONAL VS. FLEXIBLE ASEPTIC MANUFACTURINGSteve Walter, Josh RussellGMP Technology Specialist Principal EngineerCDI Life Sciences AST
Objective / AgendaProvide an overview and comparison between traditionaland 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
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
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
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
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
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
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
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
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
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
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
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
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.
Flexible, Multi-Format Facility Fill Suite Size: 3600 SF / 335 SM
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
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
Acknowledgements:Andrew Scherer, President, SmartFit Modular George Wiker, Principal, SmartFit Modular Chris Tyree, Ompi North America
Thank You!Joshua Russell, Principle Engineer – Life SciencesAutomated Systems of Tacoma (AST)4110 South Washington St. Tacoma, WA 98409(253) email@example.comSteven Walter, GMP Technology SpecialistCDI Life Sciences1801 Market Street, Ste. 1300, Philadelphia, PA 19103(215) 282-8349Steven.firstname.lastname@example.org