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Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
Alternatives To Lyophilization Visiongain Lyo Searles
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Alternatives To Lyophilization Visiongain Lyo Searles

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

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