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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
SciencesOctober 25, 2005
Topics
Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005
Discussion Next Steps
System Suitability
USP <1225> 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.
Types of Dissolution Systems Suitability Studies
Chemical Calibration The term is a misnomer—it 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
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)
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
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
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]
Topics
Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005
Discussion Next Steps
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
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
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
Sample Xbar and S Control Charts for Apparatus 2, 30 Minutes
X-BAR/S Chart for LGAP2_30 with Alpha = .00270
0 50 100 150 200 250REP
3.33.43.53.63.73.83.94.0
ME
AN
CENTERUCL
LCL
0 50 100 150 200 250REP
0.0
0.1
0.2
0.3
0.4
SIG
MA
CENTER
UCL
LCL
Representative CV’s (%)
CV total
CV between
-lab
CV within-
lab
CV between + within-
lab
CV apparatus/
tablet/ assay
Prednisone - basket
4.5 2.5 3.7 3.2 3.5
Prednisone - paddle
10.0 8.1 3.0 7.0 6.7
Sal’c acid - basket
4.2 2.8 1.8 3.1 2.7
Sal’c acid - paddle
7.4 5.1 2.8 5.2 5.2
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
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
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
Topics
Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005
Discussion Next Steps
Calibrator to Control Product Variability
Total product variability,
σ2total = σ2
product + σ2measurement
σ2total for calibrator = σ2
calibrator + σ2 C*measurement
Since σ2 calibrator is not known use σ2
total for calibrator
σ2total for calibrator is given in the acceptable
ranges σ2
total = σ2product + calibrator range
Argument against USP RS in dissolution system suitability delivered at various venues
Restating Concerns About Calibrator Variability
This argument does not hold; maybe σ2
total < σ2product + calibrator range
Calibrator variability does not contribute to product variability
Topics
Systems Suitability Studies for Dissolution Collaborative Study Design and Analysis Variances: Correction to May 2005
Discussion Next Steps
Next Steps
Continued work to improve chemical calibration, e.g., approach to avoid ‘multiple testing’
Acknowledge that dissolution is ‘case by case’—resolved with ‘flexible monograph’—differences 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.