Difficulties associated with compounding metered dose inhalers and dry powder inhalers
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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.

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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


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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 (< 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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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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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


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