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

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DIFFICULTIES ASSOCIATED WITH COMPOUNDING
METERED-DOSE INHALERS AND DRY POWDER INHALERS
Pharmacy Compounding Advisory Committee July
13-14, 2000

• Brian Rogers, Ph.D.
• Office of New Drug Chemistry
• Center for Drug Evaluation and Research
• Food and Drug Administration
• Rockville, Maryland

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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)

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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)

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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

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BackgroundDPI Current Designs

INHALATION POWDERS (DPIs) Patient-Driven or
Power-Assisted
DEVICE-METERED DOSE
PRE-METERED DOSE
DIRECT
TRANSFER
SINGLE DOSE
MULTIPLE DOSE
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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

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Background

• General Concepts for MDIs and DPIs
• Aerodynamic particle size - Affects deposition
• Smaller particles - greater airway penetration
• Patients need fine particles (lt 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

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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

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MDI COMPONENTS - Canister and Actuators
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MDI COMPONENTS - Metering Valve
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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

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DISKUS DPI CROSS-SECTION
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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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Difficulties in Compounding

• Testing
• Examples of complex tests necessary to ensure
  product quality
• Particle size distribution
• Moisture content
• Leak rate
• Leachables
• Microbial limits

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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

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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

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Difficulties in Compounding

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

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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

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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.

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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