The USP Performance Test Dissolution Systems Suitability Studies

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The USP Performance Test Dissolution Systems
Suitability Studies

• Walter W. Hauck, Ph.D.
• USP Consultant
• Presentation to Advisory Committee for
  Pharmaceutical Sciences
• October 25, 2005

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Topics

• Systems Suitability Studies for Dissolution
• Collaborative Study Design and Analysis
• Variances Correction to May 2005 Discussion
• Next Steps

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System Suitability

• USP lt1225gt and ICH Q2b to ensure that the
  validity of the analytical method is maintained
  whenever used. Typical variations are the
  stability of the analytical solutions, equipment,
  and analysts. System suitability tests are
  based on the concept that the equipment,
  electronics, analytic operations, and samples to
  be analyzed constitute an integral system that
  can be evaluated as such.

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Types of Dissolution Systems Suitability Studies

• Chemical Calibration
• The term is a misnomerit is a periodic Systems
  Suitability or system verification study
• USP calibrator tablets support this type of study
• The approach evaluates the system as a whole
  (apparatus plus operator plus procedures)
• Acceptance ranges for dissolution values of the
  calibrator tablets determined by collaborative
  studies for each new lot (e.g., new Prednisone
  Lot P)
• Other Approaches
• Mechanical Calibration
• Engineering Approaches

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Terminology

• Apparatus
• One vessel
• One stirring element
• One position in the assembly
• Assembly
• One motor
• Same temperature controller
• Multiple apparatuses (6 or more)
• Also called bath
• Experiment
• Single units tested in all apparatuses in the
  assembly (in the collaborative study, n 6)

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Systems Suitability Chemical Calibration

• Calibration procedure
• For assembly under study, use standard
  dissolution procedure test all apparatuses in
  the assembly
• Assembly/apparatus must be mechanically
  calibrated
• Acceptance applied to each position (apparatus)
• If one position result is unacceptable then
  entire assembly is also unacceptable
• Increased risk of failing due to multiple testing
• Evaluates the integrated function of the system
  to prepare a dissolution sample

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Systems Suitability Mechanical Calibration

• If a mechanical system is properly aligned and
  conforms to tolerances established for all such
  systems, then the operation of the system should
  be suitable
• Dissolution test apparatus and assembly are
  mechanical systems
• If mechanical calibration is the only control, no
  further check on the system is performed and
  system is assumed to be suitable

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Systems Suitability Mechanical Calibration

• Deficiency of purely mechanical calibration
• Assumes that the integrated system is no more
  than the sum of its parts
• Does not evaluate that standard flow of medium is
  achieved
• Limited understanding of the appropriate range
  and measurement mode for vibration
• Difficulty of determining that vessel is suitable
  (surface irregularity, deviation from hemisphere
  and cylinder)

List of suggested improved mechanical tolerances
in Dissolution Calibration Recommendations for
Reduced Chemical Testing and Enhanced Mechanical
Calibration, PhRMA Dissolution Calibration
Subcommittee, PF 26(4) July-Aug. 2000
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Topics

• Systems Suitability Studies for Dissolution
• Collaborative Study Design and Analysis
• Variances Correction to May 2005 Discussion
• Next Steps

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Collaborative Study Design

• Standard product (tablet)
• Standard procedures employed
• Determine range of results from
  mechanically-calibrated assemblies
• Determine bounds for acceptable results
• 25-35 collaborating laboratories, international

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Design Evolution

• Originally, each lab performed one experiment per
  condition (e.g., basket at 50 rpm)
• Beginning with 2003, each lab performs two
  experiments per condition with separate operator
  and equipment
• Allows separation of inter-laboratory and
  intra-laboratory (intermediate) precision

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Analysis Considerations

• Analysis is preceded by a control chart analysis
  to select labs/experiments for inclusion in
  determination of acceptance ranges
• Follows what had been PhRMA procedure
• Statistical analysis determines three variances
• apparatus/tablet/assay
• between-experiment, with-in laboratory
• between-laboratory

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Sample Xbar and S Control Charts for Apparatus 2,
30 Minutes
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Representative CVs ()
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Comments

• Variability due to the combination of apparatus,
  tablet, and assay is low, particularly for the
  basket (Apparatus 1)
• Assay variability around 2 CV, so much of the
  contribution from apparatus/tablet/assay is due
  to the assay

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Determination of Acceptance Ranges

• Acceptance range based on sum of the three
  variances
• Intended to represent range of values to be
  expected from a random tablet tested at a random
  laboratory using good practice

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Issue for Acceptance Ranges

• Ranges determined for a single tablet, but
  applied to sets of 6 and must pass all 6
• Possible solutions
• Standard statistical multiple testing adjustment
  i.e., widen the intervals to 99 from 95
• Allow retesting
• Set acceptance ranges on sample mean and standard
  deviation as done in collaborative study i.e.,
  would the data qualify for inclusion in the
  determination of the acceptance range

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Topics

• Systems Suitability Studies for Dissolution
• Collaborative Study Design and Analysis
• Variances Correction to May 2005 Discussion
• Next Steps

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Calibrator to Control Product Variability
Argument against USP RS in dissolution system
suitability delivered at various venues

• Total product variability, s2total s2product
  s2measurement
• s2total for calibrator s2 calibrator s2
  Cmeasurement
• Since s2 calibrator is not known use s2total for
  calibrator
• s2total for calibrator is given in the acceptable
  ranges
• s2total s2product calibrator range

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Restating Concerns About Calibrator Variability

• This argument does not hold maybe s2total lt
  s2product calibrator range
• Calibrator variability does not contribute to
  product variability

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Topics

• Systems Suitability Studies for Dissolution
• Collaborative Study Design and Analysis
• Variances Correction to May 2005 Discussion
• Next Steps

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Next Steps

• Continued work to improve chemical calibration,
  e.g., approach to avoid multiple testing
• Acknowledge that dissolution is case by
  caseresolved with flexible monographdifferenc
  es acceptable if bioequivalent
• Assess various approaches to Systems Suitability
  for the dissolution procedure e.g., develop
  methodology to measure fluid flow that is
  applicable in QC environment (engineering
  approach)
• Setting acceptance criteria for marketed dosage
  forms (not calibrators) tolerance interval
  approach based on clinical trial batches (see
  Hauck et al., Pharmaceutical Research 2005)
• USP willing to work with all stakeholders on
  complex science/technical issues for Performance
  test Quality by Design approaches should be
  highly valuable.

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