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    Alternatives To Lyophilization Visiongain Lyo Searles Alternatives To Lyophilization Visiongain Lyo Searles Presentation Transcript

    • 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
      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
      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
      Aerosolization
      Aktiv-Dry PuffHaler®
    • ImmunojectTM by AktiVax
      5
      Requires dry stable
      powder:
      • Fast reconstitution
      • Low void volume (avoids bubbles)
      Freeze drying not suitable
    • 6
      Alternatives Discussed in This Presentation
      Conventional spray drying
      Bubble drying®
      Spray-freeze drying
      Stirred freeze drying
      Foam drying
    • 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
    • 8
      Pharma Spray Drying
      Niro A/S
    • 9
      Niro A/S
      Pharma Spray Drying
    • 10
      Niro A/S
      Industrial Spray Drying
    • 11
      Spray Drying
    • 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
    • 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
    • 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
    • 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
    • 16
      AKTIV-DRY
      Bubble Dried Particles
      Same formulation lyophilized
    • 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
    • 18
      Wide Range of Bubble Dried® Materials
      *hydrophobic
    • 19
      AKTIV-DRY
      Bubble Dried Aqueous 10% NaCl
    • 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
    • 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
    • 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)
    • 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
    • 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.”
    • 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?
    • Example Procedure
      27
      Vaccine. 2010 Feb 3;28(5):1275-84.
      • 1 mL vial fill volume
      • Place vials on the freeze dryer shelf at 15 C, and allow to equilibrate for 10 min
      • Reduce the chamber pressure to 50 mTorr
      • Initiates foaming
      • Hold for 24 h for primary drying
      • 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
      • Process loss similar to lyophilization
      • 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”
    • 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”
    • 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
    • Another Direct Comparison
      32
      Live attenuated measles vaccine
      Foam
      Lyo
      SD
      SD+AD
      Vaccine. 2010 Feb 3;28(5):1275-84.
    • 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