DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS

1. Pharmacy Compounding Advisory Committee July 13-14, 2000 DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS Brian Rogers, Ph.D. Office of New Drug Chemistry Center for Drug Evaluation and Research Food and Drug Administration Rockville, Maryland

2. Background Metered Dose Inhalers (MDIs) • Pressurized system • Contains liquefied gas (propellant) • Propellant suspends drug substance • Provides energy • Surfactant - stabilize suspension formulation • Co-solvents - formulation aid • Dispense micrograms to milligrams API per actuation • Small precise volume delivered (25 - 100 mL)

3. Background Metered Dose Inhalers (MDIs) • Sequence of events: • Formulation expelled from valve • Liquefied gas vaporizes • Propelling and dispersing drug substance • Dispersed drug substance characterization • Particle size distribution (PSD) • Dose content distribution (dose content uniformity)

4. Background Dry Powder Inhalers (DPIs) • Contains micronized drug substance with or without carrier • Lactose - most common carrier • Energy supplied by: • Patient inspiration • Compressed gas • Motor-driven impeller • Current designs • Pre-metered • Device-metered

5. BackgroundDPI Current Designs INHALATION POWDERS (DPIs) Patient-Driven or Power-Assisted DEVICE-METERED DOSE PRE-METERED DOSE DIRECT TRANSFER SINGLE DOSE MULTIPLE DOSE

6. Background Dry Powder Inhalers (DPIs) • Further interactions - drug substance, carriers, and components of the container/closure system. • Gravitational • Fluid dynamic • Electrostatic • Van der Waals • Capillary forces • Responsible for differences in fluidization behaviors

7. Background General Concepts for MDIs and DPIs • Aerodynamic particle size - Affects deposition • Smaller particles - greater airway penetration • Patients need fine particles (< 5 mm) • Effective particle sizes - narrow range • Larger particles • Systemic exposure only • No clinical benefit • Classical BE and BA are usually not applicable • Dose too small for blood analysis • BE studies hindered • 85 - 90% of dose absorbed through GI tract

8. Difficulties in Compounding Drug Delivery System • Dosing and performance • Design • Reproducibility • Performance characteristics • Affects safety and efficacy • Formulation compatibility • Metering valve • Canister lining - corrosion of underlying metal • Drug absorption into plastic components • Swelling • Leaching

9. MDI COMPONENTS - Canister and Actuators

10. MDI COMPONENTS - Metering Valve

11. Difficulties in Compounding Drug Delivery System • Actuator function • Generates aerosol particles • Directs plume • Influences velocity • Controls medication delivered • Controls particle size distribution • Valve function • Measure formulation • Provide leak-proof seal

12. DISKUS DPI CROSS-SECTION

13. Difficulties in Compounding Drug Delivery System • Sophisticated and complex • Crucial to drug dosing accuracy and reproducibility • Direct effect on potency, purity, and quality • Indirectly affects safety and effectiveness

14. Difficulties in Compounding Drug Formulation and Consistency • Mixture of micronized or solubilized drug substance in matrix of oily excipient material, propellant, and possibly a co-solvent • Composition and physical chemical properties of each component is crucial to performance. • Composition has direct effect on extent of agglomeration and suspension stability

15. Difficulties in Compounding Drug Formulation and Consistency • Important drug substance properties: • particle size distribution • particle morphology • solvates and hydrates • clathrates • morphic forms • amorphous character • solubility profile • moisture and/or residual solvent content • microbial quality • pH profile (pKa) • specific rotation • All of the above properties must be controlled during production

16. Difficulties in Compounding Drug Formulation and Consistency • Important aspects of formulation liquid phase: • Propellant, co-solvent, surfactant identity, concentration, and quality • Relative proportions of volatile components influence pressure • Polarity, surface tension, and density are critical properties

17. Difficulties in Compounding Drug Formulation and Consistency • Factors adversely affecting formulation physical stability: • Preferential interaction of suspended drug substance with container components • Settling and creaming resulting from differential densities • Less homogeneous suspension - inconsistent dose delivery and particle size distribution • Beginning- to end-of-canister variability • Canister-to-canister variability • Batch-to-batch variability • Properties of liquid phase need to be optimized to minimize the above effects

18. Difficulties in Compounding Drug Formulation and Consistency • Formulation components • Require very careful control of impurities and degradation products • Minor change in concentration or dose - large change in toxicological properties • Montreal Protocol - CFC Propellants • Formulation of MDIs and DPIs • Complex composition and high overall complexity • Require dedicated manufacturing environment • Product-to-product uniformity • Critical for dosing accuracy • Difficult to achieve • Necessary for maintaining safety and efficacy

19. Difficulties in Compounding Complexity of Compounding • Multiple, complicated and interrelated steps • Significant potential for error • Formulation • Container and closure system design and performance characteristics • Internal temperature control • Monitor and control external environmental conditions • Manufacturing parameters • Assay of concentrate • Pressure filling • In-line heating • Aging

20. Difficulties in Compounding Complexity of Compounding • Errors - high potential to adversely affect safety and/or effectiveness • Careful control critical for: • Dosing reproducibility • Performance • Stability • Bioavailability

21. Difficulties in Compounding Facilities and Equipment • Complex formulation and container and closure system • Stringent environmental controls required • Air cleanliness • Humidity • Temperature • High temperatures or humidity • Disruptive to particle size distribution • Resulted in recalls of commercial products • Sophisticated equipment required • Crimper • Pressure filler • Propellant pump • Precise product filler

22. Difficulties in Compounding Training • Training required for production and quality assurance • Special formulation requirements • Critical attributes of container and closure system • Lack of proper training in formulating requirements may affect all aspects of product performance • Inadequate training in quality assurance will prevent timely detection of formulation errors.

23. Difficulties in Compounding Testing Examples of complex tests necessary to ensure product quality: • Particle size distribution • Moisture content • Leak rate • Leachables • Microbial limits

24. Difficulties in Compounding Testing Particle size distribution - Cascade impactor • More critical for MDIs and DPIs • Not solely determined by initial drug substance particles • Change in PSD • Decrease in efficacy • Increase in systemic exposure • Critical independent variables - complex • Formulation • Valve • Mouthpiece • Inability to meet particle size distribution specifications has resulted in product recalls

25. Difficulties in Compounding Testing • Moisture Content • Most critical for MDI suspension formulations and for DPIs • Strict limits needed to prevent changes • Particle size distribution • Morphic form • Crystal growth and aggregation • Leak Rate • Affects internal canister pressure • Influences performance of actuator and valve • Delivery of the proper dose to the patient • Leakage may influence formulation composition • Change particle size distribution and/or dose content uniformity • Failure to meet specifications have resulted in product recalls

26. Difficulties in Compounding Testing Leachables • Compounds extracted into formulation from • Elastomers • Plastic components • Requires identification and quantitation • Concentration profile established • Make evident undisclosed changes

27. Difficulties in Compounding Testing Microbial Limits • Total aerobic count • Total yeast and mold count • Freedom from pathogens • Additional testing is necessary for product development • Ensure formulation does not support microbial growth • Microbial quality is maintained throughout the expiration dating period

28. Conclusion • Because of the above complex and necessary criteria for compounding, MDI and DPI drug products present demonstrable difficulties in this endeavor • These difficulties would likely have an adverse effect on the safety and effectiveness of such drug products.

29. Conclusion Difficulties in compounding result from the following characteristics and requirements: • Sophisticated drug delivery systems • Require extensive development • Dosing accuracy (dose uniformity and particle size distribution) • Reproducibility of delivered dose • Product-to-product uniformity critical - difficult to achieve • Reproducible bioavailability - difficult to achieve • Sophisticated formulation required • Compounding of MDI and DPI products - complex • Sophisticated facilities and equipment required • Specialized technical training essential • Difficult to perform testing required