Todays Biologics: From Bench Top to Bottle Michael Cicio Sr' Director of Manufacturing Lonza Biologi

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Todays Biologics From Bench Top to
BottleMichael CicioSr. Director of
ManufacturingLonza Biologics, Portsmouth NH
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Product Life Cycle

• Research to identify medical need and a molecule
  that has efficacy
• Bioengineer host cell expression vector to
  produce product
• Process development
• cell culture
• purification
• final formulation
• Clinical Studies Phase 1 and 2
• Process Optimization
• Clinical Study Phase 3
• Process Validation
• Regulatory Submission
• Commercial production

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Product Research and Bioengineering - Bench Top

• Host Cell (expression vector) Selection several
  platforms exist
• Insect
• bacteria
• yeast
• mammalian
• Bacteria and Mammalian most common host cells
• Bacteria E.Coli
• Mammalian CHO, Human, mouse

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Product Research and Bioengineering - Bench Top

• Companies tend to stay with a similar host
  (Bacteria or Mammalian) and fermentation
  platforms for all of their products because of
  expertise and fermentation system requirements
• Fermentation System Requirements
• Bacteria
• high gas flow rates to manage rapid growth rates
• high agitation rates
• different impellor designs than mammalian

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Product Research and Bioengineering - Bench Top

• Fermentation System Requirements
• Mammalian
• Perfusion constant feed and harvest
• Fed Batch inoculation and additional feeds over
  7-14 day period
• Batch Re-Feed harvest X of bioreactor every
  3-4 days and re-feed with fresh media. Run this
  reactor for 30-90 days

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Process development

• Three Main Process Aspects
• Cell Culture/Fermentation
• Purification
• Final Formulation
• Cell Culture/Fermentation (Main Components)
• Inoculum Expansion
• Seed Reactors
• Production Reactors
• Primary Recovery

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Process development

• Inoculum expansion
• t-flask, spinners, wave reactors
• media selection methotrexate
• CO2 control Passive, Activate
• closed vs open
• split ratios
• cell densities
• temperatures
• Seed Reactors
• scaled to match production reactor, usually
  stirred tanks
• automation control for
• pH, O2, temperature, agitation

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Process development

• Production Reactors
• different sizes and dimensions (200L to 20,000L)
• automation control for
• pH, O2, temperature, agitation
• Feed system
• Linked to Harvest/Primary Recovery

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Process development

• Harvest/Primary Recovery
• Centrifugation
• Microfiltration (MF)
• Ultrafiltration (post centrifugation or MF)

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Process development

• Purification
• chromatography matrixes
• membrane technologies
• DNA removal
• virus removal
• ultrafiltration/diafiltration
• (UF/DF)
• Virus Inactivation
• Final Formulation
• UF/DF
• Polysorbate Addition
• Dilution
• Refrigerate or Freeze

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Clinical Studies Phase 1 and 2

• Studies design to establish safety and efficacy
  profiles
• dosing requirements established
• general product and patient requirements are
  small
• highly depending on the protein activity and
  number of desired indications
• Manufacturing
• Pilot facility to test process and analytical
  methods at scale. Material can be used for
  animal studies.
• cGMP clinical facility for clinical study
  material
• does not have to be at final scale for Phase
  3/commercial
• process can change post production

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Process Optimization - Points for Consideration

• economics of manufacturing
• product requirements (projected demand)
• Scale of manufacture
• media optimization to drive titers high
• purification process streamlining to increase
  throughput
• purification modifications to allow processing of
  higher protein quantities

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Process Optimization

• use of disposable technologies
• disposables allow
• quicker start up times for new facilities and
  require minimal validation. No cleaning or SIP
  is required since they are single use.
• great flexibility for process design.
• assist in closing typically open operations
• cell culture disposable reactor systems
• purification membranes vs resins

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Process Optimization

• Final Formulation
• product stability shelf Life
• final product configuration
• liquid vs lyophilized
• delivery system
• syringe
• vial

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Clinical Study Phase 3

• Phase 3 studies are larger patient populations to
  provide statistical data related to product
  efficacy
• Results from this phase can make or break a drug
  candidate
• Study design and success criteria are critical to
  assure that results obtained reflect true drug
  performance
• Product material for these studies are typically
  manufactured in the facility that will produce
  validation runs and ultimately commercial
  material
• process change post phase 3 is very minimal.

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Process Validation

• Process Validation - the intent is to show that
  the process and equipment can reproducibly and
  consistently manufacture product that meets
  defined acceptance criteria
• Aspects of Process Validation
• define critical process parameters, forward
  process criteria, process criteria (limits)
• viral validation
• bioburden control strategy
• resin and membrane lifetime
• leachables, extractables
• bulk storage container
• closure integrity

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Process Validation

• Aspects of Process Validation (Cont)
• use validated equipment
• CIP, SIP, Equipment
• use validated analytical methods
• validation of Facility
• bioreactors (multiples)
• purification and bulk fill

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Process Validation

• Process Validation Runs
• At scale in equipment for commercial production
• Multiples of reactors must be used
• typically 5 runs
• Process and Product Analysis
• all aspects of process are sampled and tested to
  show consistency and ability to meet defined
  criteria
• product characterization is extensive

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Regulatory Submission

• FDA requires BLA (Biologics License Application).
• sBLA can be filed for additional manufacturing
  sites
• Industry moving to Common Technical Document
  (CTD).
• Standardized global regulatory submission
• Approval Process 8-18 months
• Pre-Approval Inspection is typically prior to
  product approval

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Regulatory Submission - Application Content (not
a complete list)

• vendors/suppliers
• raw materials
• control of IPCs
• CPPs, PP, limits
• product acceptance criteria
• product C of A
• stability (drug substance and drug product)
• storage conditions and product expiry
• shipping validation
• labeling and pack size

• facility description
• manufacturer
• process description
• process validation analytical data
• viral validation data
• adventitious agent safety evaluation
• filter information
• resin and membrane specifications
• media and buffer solutions
• batch records (completed set from validation run)

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Commercial Production

• Control, Control, Control
• any and all changes to equipment and/or process
  must be performed under change control
• excursions from the defined parameters must be
  documented and investigated for root cause and
  product impact
• significant excursions outside of the license
  must be pre-approved with regulatory agencies
  prior to release
• Quality systems must be audited internally to
  assure compliance
• executed records must be maintained and archived