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.