an overview of biologics manufacturing processes and things to consider from development to...
TRANSCRIPT
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Welcome
Tracking Single-Use & Scale-Up Best Practices [Webinar Series]
Webinar #2: An Overview of Biologics Manufacturing Processes and Things to Consider from Development to Commercial Scale
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An Overview of Biologics Manufacturing Processes and Things to Consider from Development to Commercial Scale
Kevin Lauziere
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About Your Presenter – Kevin Lauziere
• Degree in Biochemistry from Boston College, and has worked for a number of companies in the Boston area including Genzyme, BASF Bioresearch Center, Abbott Bioresearch Center and Bristol-Myers Squibb.
• Worked in the process development area early in career designing methods for purifying proteins to be scaled up to the manufacturing level.
• Currently a consultant with over 27 years in the industry currently working with The Quantic Group, Ltd.
• Over the years he has contributed to the design, start-up and validation of two commercial manufacturing facilities working with both internal and external engineering resources.
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Outline
• Overview of a typical biologics manufacturing process that uses mammalians cells for protein expression
• Discuss the importance of process development and the influence this has on commercial scale equipment design and operations
• Discuss how automation can be used for running some process operations and the pros and cons of using it
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Overview of a typical biologics manufacturing process
Ion Exchange
Chromatography
Hydrophobic
Interaction
Chromatography
Viral
FiltrationUF/DF
Fine Purification
Formulation
Bulk Fill
Affinity
Chromatography
Product Capture
low pH Viral
inactivation
Spinner or
Shake
Flask
Cell
bank
vialSeed Bioreactors
Production
Bioreactor
Depth
Filtration
Cell Culture
Clarified
HarvestCentrifugation
Clarification
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Overview of a typical biologics manufacturing process
• Vial Thaw and Seed Train
• Seed Bioreactor
• Production Bioreactor
• Harvest/Clarification
• Chromatography
• Tangential Flow Filtration
• Virus Filtration/Inactivation
• Formulation and Bulk Fill
• Sampling and Testing of Process Intermediates
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Vial Thaw and Seed Train
• Typically a single vial of cryogenically preserved cells is thawed to start the seed train for a mammalian cell culture process. Vial thaw can be accomplished:
• At room temperature
• In a water bath
• In a heating block
• In an incubator
– Resuspension process
• Typically use an enriched medium to dilute any cryopreservatives
• Transfer thawed cells into different volumes to target a specific range for initial cell density
• Viability ranges vary with each process
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Vial Thaw and Seed Train
• The number of stages in a seed train vary with every process
– It may utilize T-flasks, shake flasks, spinners and or wave bags
– Volume of the culture varies and this puts demands on the design and footprint of the manufacturing area
• Considerations include:
– Number of containers at each stage
– Are there multiple trains running in parallel
– Equipment needed (biosafety cabinets, incubators)
– Utilities
– Classification of the rooms
– Open or closed processing
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Seed Bioreactor
• Seed Bioreactor
– Used for cell expansion –goal to obtain sufficient number of cells at a target cell density to seed the production bioreactor
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Seed Bioreactor
• Seed Bioreactor
– Size and number
– Method of inoculation
– Area classification
– Parallel trains – add process robustness and provide backup in the event of a lost seed bioreactor
– Requirements for additions
– Process control strategy
• pH
• Dissolved Oxygen
• Agitation
• Temperature
– Automation and process monitoring
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Production Bioreactor
• Size
• Area classification
– Closed processing
• Parallel trains
• Requirements for additions
• Process control strategy
– pH
– Dissolved Oxygen
– Agitation
– Temperature
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Production Bioreactor
• Harvest criteria
– Viability
– Titer
– Duration
• Automation and process monitoring
– Glucose
– Lactate
– pCO2
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Harvest/Clarification
• Initial crude clarification – separates cells and cellular debris from harvest broth
• Method
– Centrifugation
– Depth Filtration
– Microfiltration
– Combination of these (i.e. centrifugation and depth filtration)
• Area classification
• Redundant equipment
• Automation
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Chromatography
• Number of steps
– Resin chemistry
– Order of steps
• Loading conditions
• Volume of eluates
– Volume measurement
• Scale of columns
– Single or multiple cycles per lot
• Based on amount of product and column capacity
– Resin cost is also considered
– Buffer volumes (1x buffers or concentrates)
• Dilution strategy
– Flowrate ratio
– Conductivity setpoint
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Chromatography
• Eluate vessel size and capability
– Process sampling
– Mixing
– Temperature control
– Process intermediate manipulations
– Filtration (In-line or post processing)
• Area classification
• Processing temperature
– Column operation temperature versus hold temperature for process intermediates
• Redundant equipment
• Automation
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Tangential Flow Filtration
• System size
– Volume
• Starting volume
• Final volume
– Processing time
• Amount of membrane surface area
• Pump sizing
– Operating conditions
• Transmembrane pressure
• Crossflow rate
– Amount of product
• Final concentration
• System hold up
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Tangential Flow Filtration
• Diafiltration
– Number of volumes exchanged (5X, 8X, 10X)
– Concentration at which diafiltration is performed
– Solubility (Isoelectric point)
• Area classification
• Processing temperature
• Automation
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Virus Filtration/Inactivation
• Filtration
– Membrane surface area
– Pore size
– Filter material compatibility
– Physical room change during the process
– Volume
– Processing time
• Product concentration
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Virus Filtration/Inactivation• Inactivation by pH adjustment
– Product degradation
– Duration of hold
– Volume
– Strength of acid and base used for adjustment
– Rate of addition
• Inactivation by detergent
– Volume
– Duration of hold
– Removal of detergent
• Area classification
• Processing temperature
• Automation
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Formulation and Bulk Fill
• Environment
– Open or closed processing
– Temperature
• Containers
– Material of construction
– Leachables
– Container closure
– Labeling
– Volume
– Source and Condition
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Formulation and Bulk Fill
• Open fill
– Performed in a biosafety cabinet (Grade A, Class 100)
– Grade B, Class 1000 room
• Rooms like this are expensive to build
• Closed fill
– Performed in a Grade C, Class 10,000 area where all connections are closed
• Sampling strategy
– Number of samples
– Container type
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Formulation and Bulk Fill
• Bulk fill room
– Single product use
– Multi-product use
• Scheduling
• Room Turnover Process
• Shared Equipment
• Shared Personnel
• Temperature
– Product stability
– Type of label
– Operational considerations
• Affect on staff and their ability to perform tasks
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Thank You
Questions?
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#1 Tracking Single-Use : An Introduction to Single-Use Manufacturing Systems Including a Survey of Technology, New Developments and Economic and Operational IssuesTuesday, January 19, 2016 / 1pm-2pm (ET)Presenter: Geoff Hodge
Next Up: High Level Recombinant Protein Production in Insect Cell CultureTuesday, January 26, 2016 / 1-2pm (ET)Presenter: Dr. Kamal Rashid
#2 An Overview of Biologics Manufacturing Processes and Things to Consider from Development to Commercial ScaleMonday, January 25, 2016 / 1-2pm (ET)Presenter: Kevin Lauziere