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

Pharmacy Compounding Advisory Committee

July 13-14, 2000

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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 L)

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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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BackgroundDry 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

PRE-METEREDDOSE

DEVICE-METEREDDOSE

DIRECT TRANSFER

SINGLE DOSE MULTIPLE DOSE

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BackgroundDry 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 m)– 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 CompoundingDrug 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 CompoundingDrug 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 CompoundingDrug 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 CompoundingFacilities 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 CompoundingTesting

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 CompoundingTesting

• 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