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Motivation – The Business Case

Manufacturing platforms to enable targeted treatment of individuals and small patient populations by Fernando Muzzio , Director, ERC Bozena Michniak-Kohn , School of Pharmacy Pavlo Takhistov , Food Science. Motivation – The Business Case.

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Motivation – The Business Case

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  1. Manufacturing platforms to enable targeted treatment of individuals and small patient populationsby Fernando Muzzio, Director, ERCBozena Michniak-Kohn, School of PharmacyPavlo Takhistov, Food Science

  2. Motivation – The Business Case • Polypharmacy - ability to fill capsules and vials with multiple ingredients in variable ratios in a convenient and safe manner • Small scale manufacturing - make anywhere from 10 to 100,000 product units where we control composition by design • Clinical supply manufacturing - testing 100% of the product non-destructively • Extemporaneous dispensing in hospitals - ability to fill single product units with multiple ingredients in variable ratios in a convenient and safe manner, testing 100% of the product non-destructively • Personalized medicine - ability to fill single product units with multiple ingredients in variable ratios in a convenient and safe manner; testing 100% of the product non-destructively

  3. Flexible dosing: The market need • ~ 40% of product portfolio would benefit from flexible dosing • Cancer (manage side effects) • HIV and other infectious diseases that require flexible multidrug approaches • Drugs that need to be titrated (anticoagulants, insulin) • Geriatric patients taking multiple drugs • Pediatrics • Hormone replacement • CNS (Schizophrenia, ADD) • “Personalized Medicine” has focused on “Omics” • Learning to determine dosage/bioavailability (PK/PD) profile needed by individuals or small sub-populations • However, we do not have technology for manufacturing flexible formulations under approvable conditions • Products are developed and approved for fixed formulations • Batch processes manufacture large number of nearly identical units

  4. Pilot study • Pilot project to demonstrate microdosing into capsules • Goal: to microdose controlled amounts of solutions and suspensions into capsules at a rate of 300 units per hour • Outcomes: From scrap to proof of concept in one year – at a cost of $250,000 • Case studies developed • Non-destructive analytics implemented • Prototype assembled

  5. Microdrop dispensing: principle of operation

  6. Formulations • Case study formulations were created to span range of pharmaceutical fluids • Drug in solution • Drug in nanosuspension • Criteria for formulations include: • Formulation viscosity • API must be appropriately soluble in excipients • Multiple excipients must be miscible • Formulation should be stable (with respect to time, temperature, etc) • Particles in suspension must be smaller than 5 microns to avoid inline filter • Feasibility of particle size reduction using HPH • Limited by viscosity • High solids concentrations difficult to process

  7. Formulations • Solution Case Study: • Ibuprofen • Poorly water soluble, widely studied • C13H18O2 • Carbitol Cellosolve (Diethylene glycol monoethyl ether) • Low viscosity (3.85cP @ 25 C), capable of dissolving large concentrations of ibuprofen • 90:10 Carbitol Cellosolve: Castor Oil • Dissolved 30% by weight Ibuprofen

  8. Formulations • Nano-suspension: • Emulsified for 15 min at 20,000 rpm • 2 HPH precycles at 500 bar • 20 HPH cycles at 1500 bar • Indomethacin (nano) • MCT: Tween 80 • Poorly Soluble Drug • Low Dose Drug

  9. Analytics • The linearity of the curves enables them to determine the concentration of active inside of the supply line. • Raman spectroscopy can be used in the supply line to non-destructively assay the active concentration. This method will be particularly useful in manufacturing scale applications. Schematic of Backscattering in the Supply Line Ibuprofen in ethanol at various wavelengths

  10. Analytics • Raman spectroscopy calibration curves taken at the capsule. • The linearity of the curves enables them to determine the concentration of active inside of a capsule. • Raman spectroscopy can be used in the supply line and at the capsule to non-destructively assay the active concentration. This method will be particularly useful in extemporaneous dispensing applications.

  11. Microdosing Technologies - Implementation Solenoid Valve Linearity demonstrates each device is capable of dispensing pharmaceutical solutions Positive Displacement Valve Piezoelectric Valve

  12. Microdosing Technologies - Implementation • The solenoid and positive displacement devices are capable of dispensing pharmaceutical suspensions. • Further study is needed to dispense suspensions using the piezoelectric dispensing device. Solenoid Valve Piezoelectric Dispensing Device Positive Displacement Valve

  13. Microdosing Technologies - Implementation Pressure Regulator Fluid Reservoirs Pressurized Air Tank Solenoid Valves Piezoelectric Dispensing Device Valve Controller JetDrive Controller Weighting Module Stage Controller Computer

  14. Show movie

  15. Microdosing Technologies - Optimization • Each valve was characterized with respect to viscosity, drop volume, and total volume dispensed. • This information can be used to determine a priori which valve will be best suited for a specific application with a required fluid viscosity and dispensed volume

  16. Microdosing Technologies - Optimization Volume each device can dispense in 1 sec

  17. Microdosing Technologies - Optimization Performance of positive displacement valve with respect to its critical parameter stroke volume for the solutions and suspension. RSD of weight of drops of indomethacin suspension (case study formulation)

  18. Syringes and Vials • Main dispensing route for high weight biomolecules • Improved ease of use and convenience improves patient compliance • User preference drives increases in drug product market share in competitive markets • Formulation improvements, reduced frequency of administration and injection devices • The market for more convenient and easy to administer injectable products is expanding

  19. Pilot study: syringes filling • Small molecule API: 30 wt% Ibuprofen in 90:10 Carbitol Cellosolve: Castor Oil • Large molecule API: 2mg/mL Human Serum Albumin in Water

  20. Conclusions: Drop on Demand (DOD) technology for capsules, vials, syringes • Proof of concept available • Integrated system can fill multiple drugs into a single dose with complete control of concentrations • Can fill capsules for oral delivery, vials and syringes for parenterals • Can handle solutions and suspensions • Non destructive analytics developed (SORS) Drop On Demand Schematic to be used in this project

  21. fjmuzzio@yahoo.com 732-445-3357

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