Particle and Droplet Size Distribution: Comparisons and Methods

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Particle and Droplet Size Distribution
Comparisons and Methods

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

Annual Meeting Baltimore, MD November 7-11, 2004
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Disclaimer

• The views expressed herein represent my thoughts
  on these issues and do not necessarily reflect
  FDA policy or procedures. Any implementation of
  my ideas or concepts should be brought to the
  attention of the responsible review Division
  prior to implementation. These changes will be
  evaluated on a case-by-case basis.

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Profiles Specifications and Labeling

• (1) What is the best way to compare profiles
  obtained from particle sizing methods (between
  different impactor types and laser diffraction) -
  both for purposes of quality control and for
  comparison of different products?

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Quality Control of MDIs

• Different impactor types
• Conversion to new impactor design (post approval)
  
• Choosing between two competing designs in methods
  development (pre-approval)

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Choosing Between Two Alternative Designs in
Methods Development

• Factors to consider Profile-related
• Appropriate fractionation
• PSD profile of the complete delivered dose
• Adequate resolution of fine particle mass
  fraction (lt5 mcm) of the delivered dose
• Capability to distinguish between acceptable and
  unacceptable drug product batches

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Choosing Between Two Alternative Designs in
Methods Development

• Factors to consider Instrument-related
• Information on precision of manufacture of
  impactor units and accessories
• Consideration for allowed tolerances and material
  of construction
• Information on calibration of the unit

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Choosing Between Two Alternative Designs in
Methods Development

• Validation - Is variability associated with
  product or method?
• Method-Related
• CI-Related Inherent variability associated with
  the deposition
• Analysis-Related Variability due to sampling,
  collection, or analysis Overlaps with
  CI-related
• Product-Related
• Formulation
• Container/Closure
• Manufacturing
• Within unit (beg. to end of canister), Between
  units (beg. to end of batch), and Between batches

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Comparison of Different Products (MDIs)

• Control variables to minimize differences between
  comparators - prevent confounding of effects
• Excipients
• Particle size of drug substance (suspension)
• Valve function
• Propellant
• Beginning- to end-of-canister
• Metering chamber dimensions vs formulation
  concentration
• Container/closure change evaluation with same
  formulation

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Comparison of Different Products (MDIs)

• Comparison of different products' PSD profiles is
  easy - not clear what constitutes significant
  differences.
• No meaningful comparison possible for apples and
  oranges
• Even same product gives different distributions
  under different experimental conditions

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Laser Diffraction vs Cascade Impactor

• Laser diffraction - Non-aerodynamic
• Insufficient sampling of aerosol plume
• Not appropriate stand-alone for medical aerosols

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Profiles Specifications and Labeling

• (2) What is the most meaningful way to set
  specifications for CI results?

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Setting APSD Acceptance Criteria

• Evaluate available stage data
• Develop PSD profiles Evaluate trends
• Within unit (beg. to end of canister)
• Between units (beg. to end of batch)
• Between batches
• Determine stage groupings for optimal control
• Large variability will not justify wider
  acceptance criteria Review issue
• Less than two-fold range in critical stages and
  groupings
• Narrow therapeutic index drugs may need tighter
  target range than two-fold range - medical input

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Setting APSD Acceptance Criteria

• FPM proportionality concerns apply
• Stages 0-2 inappropriate for inclusion in fine
  particle mass - Andersen CI _at_ 28.3
• Minimize stages per group
• Overly large groupings mask shifts
• Group definitions - Appropriate for QC
• Consider clinical relevance of the size ranges
• Allow monitoring of trends during shelf-life

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Profiles Specifications and Labeling

• (3) For multiple strength products, does
  deposition on individual stages need to be
  proportional to the label claim dose?

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Dose Proportionality

• FPM proportionality as critical as dose
  proportionality
• Individual stages normally too variable
• Stage groupings should be proportional
• Case by case basis
• Carefully documented
• Medical input

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Dose Proportionality

• Drug - Therapeutic Index - absorption -
  physicochemical properties - all play a role
• Gross Disproportionality
• May affect approvability

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Nasal Sprays and Nebulizers

• (4) Is there any value in measuring particles or
  droplets lt5 micrometers for nasal sprays?

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Nasal Sprays and Nebulizers

• Parallel methods necessary
• Validated laser method
• ACI for rough characterization (lt10 mcm)
• Comparator for bioequivalence
• Growth effects if lung deposition increases
  systemic absorption (corticosteroids)
• Good up-front characterization
• Necessary for changes in container/closure
  re-evaluation

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Impaction Testing

• (7) How and how often should impactors be
  mensurated and what is the proper acceptance
  criteria?

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Impaction Testing

• Should know how often from experience and
  manufacturer recommendations
• 6 months recommended by Andersen
• Manufacturer specifications or tighter if issues
  are known
• More often needed if abrasive suspension results
  during testing -
• Salt as API - Both wear and corrosive effects
• Abrasive excipients - wear during analysis
• Plate coating materials may be protective
• Testing frequency, etc.