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Alternatives To Lyophilization Visiongain Lyo Searles Presentation Transcript

  • 1. 1
    Alternatives to Lyophilization
    AKTIV-DRY
    Jim Searles Ph.D.
    Aktiv-Dry LLC, Boulder, Colorado
    jsearles@aktiv-dry.com
    Visiongain 3rd Annual Lyophilization Conference
    Ensuring optimum formulations for pharmaceuticals and biologicals
    25 February 2010, Boston
  • 2. 2
    Why consider alternatives to lyophilization?
    Capital and operating costs
    New routes of administration
    Dry powder inhalation
    Direct powder injection
    Value-added injection presentations
    Pre-filled reconstitution/injection devices
    Markets are shifting to single-dose primary contianers
    Powders are more versatile
  • 3. 3
    Product Attributes
    Particle size
    Reconstitution time
    Void volume
    Flowability
    Container
    Residual solvent (usually water)
    Product activity & stability
    Crystallinity
    Sterility
    Bulk intermediate or final drug product
  • 4. 4
    Aerosolization
    Aktiv-Dry PuffHaler®
  • 5. ImmunojectTM by AktiVax
    5
    Requires dry stable
    powder:
    • Fast reconstitution
    • 6. Low void volume (avoids bubbles)
    Freeze drying not suitable
  • 7. 6
    Alternatives Discussed in This Presentation
    Conventional spray drying
    Bubble drying®
    Spray-freeze drying
    Stirred freeze drying
    Foam drying
  • 8. 7
    Process Attributes
    Mass yield
    Continuous or Batch?
    Product stresses
    Final product form
    Powder or cake
    Reconstitution
    Container
    Robustness
    Controllability
    Measurability
    Scale(s) available
    Closed system processing?
    Capital cost
    Operational cost
  • 9. 8
    Pharma Spray Drying
    Niro A/S
  • 10. 9
    Niro A/S
    Pharma Spray Drying
  • 11. 10
    Niro A/S
    Industrial Spray Drying
  • 12. 11
    Spray Drying
  • 13. 12
    Spray-Dried Products
    Pharmaceuticals
    Insulin (Exubera)
    Analgesics
    Antibiotics
    Enzymes
    Plasma/plasma substitutes
    Vaccines
    Vitamins
    Yeasts
    Speciality chemicals
    Catalysts
    Detergents
    Dyestuffs
    Fine organic/inorganic chemicals
    Foodstuffs and dairy products
    Baby food
    Cheese/ whey products
    Coconut milk
    Coffee/ coffee substitutes
    Coffee whitener
    Eggs
    Flavours
    Maltodextrine
    Mild
    Soup mixes
    Soy- based food
    Spices/ herb extracts
    Sugar-based food
    Tea
    Tomato
    Vegetable protein
    Ceramics
    Advanced ceramic formulations
    Carbides
    Ferrites
    Nitrides
    Oxides
    Silicates
    Steatites
    Titanates
    Polymers
    ABS
    e-PVC
    PMMA
    UF/MF resins
    Agro- chemicals
    Chelates
    Fungicides
    Herbicides
    Insecticides
  • 14. 13
    AKTIV-DRY
    F
    P
    T
    T
    Filters
    CO2
    Product
    T Ctrl
    Drying
    Chamber
    P
    Drying Gas Flow Control
    T
    vF
    H2O
    vF
    CO2 Flow Control Pump
    N2
    F
    Back-pulsed
    double
    filter
    Product Flow Control Pump
    Bubble Drying System
  • 15. 14
    Bubble Drying®
    Also known as
    Carbon dioxide assisted nebulization with a Bubble Dryer®(CAN-BD)
    Supercritical assisted atomization (SAA)
    Effervescent atomization
    Dry powder generation
    Respirable particle size (1-5 um for needle-free delivery) or larger
    Gentle low-temperature processing conditions
    Amenable to sterile, contained closed-system processing
    Dry powder delivery in the field promises improved consistency over liquid nebulization
    Gentler than jet milling
    Particle coating or co-particles
    Replacement for freeze drying & spray-freeze drying
    Wide Diversity of Product Types
    Vaccines, antibodies, proteins, siRNA’s, small-molecules
  • 16. 15
    AKTIV-DRY
    Flow Restrictor Tube
    ID = 75 m
    10 cm
    Bubble Dryer Nebulizer
    Near-critical or
    Supercritical CO2
    (80 to 100 atm)
    Drug Solution or Suspension
    Emulsion of product
    stream in liquid CO2
    CO2 flashes upon
    rapid 100X
    decompression to
    atmospheric
    pressure
    Restrictor Tip
  • 17. 16
    AKTIV-DRY
    Bubble Dried Particles
    Same formulation lyophilized
  • 18. 17
    Bubble Drying Variations
    Non-aqueous solvents
    2-pass operation
    Combination of 3 streams (cross)
    Coated particles
    Composite particles
    Slowly dissolving (PLA or PLGA)
    Readily soluble
    AKTIV-DRY
  • 19. 18
    Wide Range of Bubble Dried® Materials
    *hydrophobic
  • 20. 19
    AKTIV-DRY
    Bubble Dried Aqueous 10% NaCl
  • 21.
  • 22. 21
    Live Measles Vaccine
    Microparticles that rapidly dissolve in moist respiratory mucosa and become the functional equivalent of the wet-mist measles vaccine successfully administered to more than 3 million children
    No greater loss of viral activity than in the present commercial lyophilization process
    Pass the WHO test for stability at 37 °C for one week
    First-ever dry powder inhaler for infants. Very low cost and complexity.
    Generates immune responses in Cotton rats and Rhesus macaques
  • 23. 22
    Spray Freeze Drying
    Process
    Spray freeze
    e.g. spray into liquid nitrogen
    Transfer into freeze dryer
    Freeze dry
    Not commercialized
    Effective for preservation of some material’s activity
  • 24. 23
    Alum-Adsorbed Vaccines
    Maa et al. 2003 J Pharm Sci. 92(2):319-332
    Hepatitis-B surface antigen (Alum-HBsAg) and Diphtheria and tetanus toxoids (Alum-DT)
    Freeze drying, spray drying, air drying, or spray freeze drying
    Only spray freeze drying yielded fully active vaccine
    Rapid freezing key
    Bubble Drying® has also yielded fully active, very stable flowable powders of alum-adsorbed HBsAg (Sievers et al. J Supercrit Fluids 42(3):385-39)
  • 25. 24
    Other SFD examples
    Split-virion and sub-unit influenza vaccines Maa et al. 2004 J Pharm Sci 93(7):1912 - 1923
    Anthrax vaccine Jiang et al. J Pharm Sci 95(1):80-96
    Inulin-stabilized influenza subunit vaccine Amorij et al. 2007 Vaccine 25:8707-8717
    Recombinant Human Interferon- Webb et al. 2002 J Pharm Sci 91:1474-1487
  • 26. 25
    Hosokawa
    “Stirred freeze drying comes down to injecting the material to be dried into the vessel, where it gets into contact with the freezing medium (usually carbon dioxide) and immediately solidifies in to granular material.”
    “Subsequently a vacuum is created in the machine, the product is kept in motion and the mixture is dried. Because sublimation occurs while the product is in motion, more vapour
    comes to the surface and the drying process evolves rapidly.”
  • 27. 26
    Foam Drying
    Investigated for proteins and vaccines
    Key References
    Victor Bronshtein 1998 patent
    Patents by Vu Truong-Le, MedImmune Vaccines (‘06, ‘08)
    Two 2007 papers by Abdul-Fattah et al.
    Pisal et al. 2006 paper
    Reconstitution time?
  • 28. Example Procedure
    27
    Vaccine. 2010 Feb 3;28(5):1275-84.
    • 1 mL vial fill volume
    • 29. Place vials on the freeze dryer shelf at 15 C, and allow to equilibrate for 10 min
    • 30. Reduce the chamber pressure to 50 mTorr
    • 31. Initiates foaming
    • 32. Hold for 24 h for primary drying
    • 33. Raise shelf temperature to 33 C for 24 hrs for secondary drying
  • 28
    Foam Drying
    Pisal et al. (2006) AAPS PharmSciTech 7(3) Article 60
    Used a conventional lyophilizer
    2 mL aqueous solution filled per 10-mL glass vial, with partially closed rubber stoppers
    • Live virus vaccine
    • 34. Process loss similar to lyophilization
    • 35. Stability was very good for one of the formulations tested
  • 29
    Live virus vaccine
    Abdul-Fattah et al. 2007 Pharmaceutical Research 24(4) 715-727
    Live attenuated parainfluenza virus vaccine
    Freeze drying, spray drying, and foam drying
    “the vaccine was most stable in the foam dried preparation with surfactant and least stable in spray dried preparations without surfactant
    Also least stable “all freeze dried preparations regardless of the presence of surfactant”
  • 36. 30
    Monoclonal Antibody
    Abdul-Fattah et al. 2007 J Pharma Sci 96(8), 1983-2008
    IgG1
    Freeze drying, spray drying, and foam drying
    “Preparations manufactured by foam drying were the most stable, regardless of the stabilizer level”
  • 37. 31
    Stability at 25 ºC from square-root-of-time kinetics
    Note: Bubble Dried® measles vaccine at 37 ºC: 0.8 log/wk0.5
    Abdul-Fattah et al. 2007 Pharmaceutical Research 24(4) 715-727
  • 38. Another Direct Comparison
    32
    Live attenuated measles vaccine
    Foam
    Lyo
    SD
    SD+AD
    Vaccine. 2010 Feb 3;28(5):1275-84.
  • 39. 33
    Acknowledgements
    Aktiv-Dry
    Brian Quinn
    Scott Winston
    Pankaj Pathak
    Pradnya Bhagwat
    Lia Rebits
    Dave Krank
    University of Colorado
    Prof. Bob Sievers
    Steve Cape
    Joseph Villa
    John Carpenter
    David McAdams
    Jessica Burger