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Dissolution Apparatus

Qualification

Lucinda (Cindy) Buhse, PhDActing Director, Office of Testing and Research

Challenges for Dissolution Testing for the 21st Century

May 3, 2006

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Goals

• Understand the sources of variability

• Set up and operate dissolution apparatus

to minimize uncertainty

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Outline

• Current State of Calibration

• Variability

• Opportunities for Improvement – Alternate

approaches

– Gage R&R

– Mechanical Calibration

• Future Research

USP Dissolution Apparatus

• Apparatus 1 - Basket (37º)

• Apparatus 2 - Paddle (37º)

• Apparatus 3 - Reciprocating Cylinder (37º)

• Apparatus 4 – Flow-Through Cell (37º)

• Apparatus 5 – Paddle over Disk (32º), Transdermal Delivery System, use paddle and vessel from Apparatus 2 with a stainless steel disk assembly to hold the transdermal on the bottom of vessel.

• Apparatus 6, Cylinder (32º), Transdermal Delivery System, use Apparatus 1 except replace the basket shaft with a stainlesssteel cylinder element.

• Apparatus 7, Reciprocating Holder, for transdermal delivery systems and also a variety of dosage forms

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Current State for Dissolution Test Methods

• Usually Apparatus 1 (Basket) or Apparatus

2 (Paddle)

• USP Equipment Set-Up and Calibration

Criteria

• Instrument Suitability

–Mechanical Calibration (affecting

hydrodynamics)

–Calibrator Tablets

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Current State: Mechanical Calibration

Set-up Parameters:

2 mm from centerlineVessel/Shaft Centering

+ 4%Rotational speed

No significant vibrationVibration

25 + 2 mmHeight check/Basket or Paddle Depth as

measured at Basket or Paddle bottom

+ 1mmBasket Wobble (Bottom Rim)

No significant wobbleShaft Wobble

USP

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Calibrator Tablets

1970’s: USP Calibrator Tablets Introduced

– Disintegrating – 50 mg Prednisone (Upjohn)

– Non Disintegrating – 300 mg Salicylic Acid (Hoffman LaRoche)

1997: 50 mg Prednisone replaced with 10 mg Prednisone manufactured at University of Maryland

2004: USP begins search for replacement for 10 mg Prednisone tablet

USP: Both Calibrators on a given apparatus (i.e. 4 calibration tests if instrument is used for paddle and basket methods)

EP: Introducing concept?

JP: No calibrator tablets

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Calibrator Tablets

• Every 6 months

• 10 mg Prednisone Tablet (Lot O0C056)• Basket: 53 – 77% (now 51-81%)

– (DPA 72.6% +/- 5.4, n=36)

• Paddle: 27 – 48% (now 26-47%) – (DPA 31.7% +/- 2.0, n=24)

• Salicylic Acid Tablet (Lot Q0D200)• Basket: 23 – 30%

• Paddle: 17 – 25%

• Action with Out of Specification value

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USP Calibrator Limits (Lot O0C056)

vs

Distribution of DPA Laboratory Results

0 10 20 30 40 50

______ DPA Distribution

______ USP Limits (2004)

Basket

Limits: 53 - 77%

DPA: 72.6% ± 5.4%

n=36

Paddle

Limits: 27 - 48%

DPA: 31.7% ±±±± 2.0%

n=24

% of Label Claim

50 60 70 80 90 100

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Variability

• Instrument Suitability– Apparatus Variability

– Operator

– Calibrator Assignment Variability• Manufacturing of Calibrator Tablet

• Stability

• Instrument Set-up

• Degassing

• Product Specific– Media including degassing

– Manufacturing

– Dissolution equipment parameters (clips, sensitivity to set-up)

– Sinkers

– Determinative Step

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Mechanical Calibration: Vessel Centering and

Vessel Verticality affect Hydrodynamics

1.231.4Vessels Tilted ~1º (Avg. of 12)

2.636.3Vessels Tilted ~2º (Avg. of 12)

3.935.6Vessels Offset 2 mm (Avg. of 12)

1.830.6Vessels Offset 1 mm (Avg. of 12)

1.029.2Vessels Centered (Avg. of 30)

SDAvg.

% Label Claim at 30 min.

Mechanical Calibration Status

• 10 mg Prednisone Tablets, Lot PRED96-21, paddle, 50 RPM, degassed water

• Data Range: 26.3 – 44.5%:

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Variability: Dissolved Gas

0

10

20

30

40

50

60

70

80

90

0 20 40 60 80 100 120

Time (min)

% Dissolution

non-degassing(n=6)

USP degassing (n=6)

He sparging(n=6)

% of Label Claim

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120

Time (min)

% Dissolution

non-degassing(n=3)

DPA degassing (n=6)

He sparging(n=9)

% of Label Claim

0

10

20

30

40

50

60

0 20 40 60 80 100 120

Time (min)

% of Label Claim

non-degassing (n=3)

DPA degassing (n=3)

Product 1: paddle, 50 rpm, DI Water Product 2: basket, 100 rpm, pH 1.2

Product 3: paddle, 50 rpm, pH 7.4 buffer

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PERCENT DISSOLVED PLOT

pH 7.2

0

10

20

30

40

50

60

70

80

90

100

110

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Dissolution Time (Hours)

% of Label Claim

1

2

3

4

5

6

PERCENT DISSOLVED PLOT

0

10

20

30

40

50

60

70

80

90

100

110

0 1 2 3 4 5 6

Dissolution Time (Hours)

% of Label Claim

123456

pH 7.2 pH 6.8

Variability: Media

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What are the sources of variability at pH 6.8?

• Product handling during testing?

• Instrumentation variation?

– Vessel defects?

– Inconsistent Centering?

– RPM variations

– Etc.

• Tablet to tablet differences?

Variability

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Variability: Sinkers

PERCENT DISSOLVED PLOT

0

10

20

30

40

50

60

70

80

90

100

110

0 10 20 30 40 50 60

Dissolution Time (Minutes)

% of Label Claim

123456

PERCENT DISSOLVED PLOT

0

10

20

30

40

50

60

70

80

90

100

110

0 10 20 30 40 50 60

Dissolution Time (Minutes)

% of Label Claim

123456

60% - 72% Dissolved at 30 min.

66% ± 4%

89% – 99% Dissolved at 30 min.

95% ± 4%

Commercial Sinker 3 Wire Turns

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Alternative Approach to Dissolution Calibration

and Validation

• Perform stringent mechanical calibration to replace the need for a calibrator tablet

• ID and control all sources of variability

– Apparatus type including sinkers

– Set-up, calibration and operational parameters

– Media including degassing

• Understand interaction between instrument and product during pharmaceutical development

• If necessary, establish an internal reference (bio-batch or clinical batch) for system suitability and stability

• Confirm suitability using Gage R&R using pivotal clinical trial product or pivotal “bio-batch”

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Gage R&R Design

• Chance to characterize variability on clinical or

bio-batch

– Sample from throughout manufacturing process to

demonstrate control

– Benchmark variability for establishing specifications

– Establish internal reference

• For design include variables such as

– Location (beginning, middle and end of lot)

– Instrument

– Operator

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DPA Gage R&R Study

•Product: NCDA#2 10mg Prednisone Tablet• Stable

• History at DPA – known to be sensitive to degassing and instrument set up

•Design of Study:• 2 operators

• 2 mechanically calibrated USP Apparatus (Paddle)

• Nested study design, N= 2x2x6

• 6 replications for each operator on each apparatus

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Operator 1 2

Apparatus A B A B

Vessel 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6

6 repetitions

DPA Gage R&R Study

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Comparison of % of Label Claim at 30 Minutes

for Two Apparatuses

Based on ANOVA results, no significant differences are seen between two

USP apparatus 2 in testing NCDA#2 tablets.

#A-B%Diss@30

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30

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32

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34

35

36

37

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#A #B

Apparatus

#A-#B

Assuming unequal variances

Difference

Std Err Dif

Upper CL Dif

Lower CL Dif

Confidence

0.41356

0.25750

0.92264

-0.09551

0.95

t Ratio

DF

Prob > |t|

Prob > t

Prob < t

1.606076

140.5884

0.1105

0.0553

0.9447 -1.0 -0.5 .0 .5 1.0

t Test

#A

#B

Level

72

72

Number

32.2868

31.8732

Mean

1.62056

1.46555

Std Dev

0.19098

0.17272

Std Err Mean

31.906

31.529

Lower 95%

32.668

32.218

Upper 95%

Means and Std Deviations

%Diss0@30

A B

#A-B%Diss@30

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34

35

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37

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#A #B

Apparatus

%of Label Claim

A B

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Comparison of Variance Components

0

10

20

30

40

50

60

70

80

% of Total Variance

OperatorTablet Vessel

Variance Components

Results• Tablet is the main contribution to the variance.

• Variability component from vessels for Apparatus A is larger than for Apparatus B.

• Operator contributes minimally to variability for DPA.

Apparatus A

Apparatus B

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30 Minute Dissolution for Individual Vessels for

Apparatus A

#A-%Diss@30

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30

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36

37

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1 2 3 4 5 6

#A-vessels

%Diss0@30

Vessel

•Some vessels are above average

and some below.

•Vessels were moved to different

positions and trends above and

below average were found to follow

the vessel and not the shaft

position.

•Although apparatus was level and

shafts were vertical, vessels were

found to be not vertical because of

unevenness around their rims.

#A-%Diss@30

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30

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34

35

36

37

38

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1 2 3 4 5 6

#A-vessels

%of Label Claim

Vessel

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Reminder: Vessel Verticality/Centering and

Hydrodynamics

1.231.4Vessels Tilted ~1º (Avg. of 12)

2.636.3Vessels Tilted ~2º (Avg. of 12)

3.935.6Vessels Offset 2 mm (Avg. of 12)

1.830.6Vessels Offset 1 mm (Avg. of 12)

1.029.2Vessels Centered (Avg. of 30)

SDAvg.

% Label Claim at 30 min.

Mechanical Calibration Status

• 10 mg Prednisone Tablets, Lot PRED96-21, paddle, 50 RPM, degassed water

• Data Range: 26.3 – 44.5%:

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Comparison of Variance Components after

2 Point Centering for Apparatus A

Y

Apparatus #A

Apparatus #B

1pt centering

2pt centering

0

10

20

30

40

50

60

70

80

90

100

% of Total Variance

Variance Components

OperatorVesselTablet

2 point centering to ensure verticality of the vessels eliminated the vessel

component of the variability.

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Mechanical Calibration Tolerances

+ 0.5mm

(≤ 1.0mm total)

+ 1mmBasket Wobble (Bottom Rim)

+ 2 rpm+ 4%Rotational speed

Centered in bubble

level at 2 pts 90°°°° apart

NoneShaft Verticality

25 + 2 mm25 + 2 mmHeight check/Basket or Paddle

Depth as measured at Basket

or Paddle bottom

1 mm from centerline

at 2 points

≤ 1 degree

2 mm from

centerline

Vessel/Shaft Centering

Vessel Wall Verticality

≤ 1 mm total run outNo significant

wobble

Shaft Wobble

USP ASTM Proposal

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Dissolution Testing Good Practices

• Apparatus Set Up• Vessel Dimensions

• Basket Dimensions (Basket Clips)

• Paddle Dimensions

• Belts and Ball Bearings

• Mechanical Calibration• Shaft Wobble

• Basket Wobble

• Vessel Centering

• Vessel Verticality

• Basket and Paddle Depth

• Paddle and Basket Shaft Verticality

• Rotational Speed

• Operation• Basket Examination

• Paddle Examination

• Vessel Temperature

• Vibration

• Sinkers

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Benefits of Mechanical Calibration and

Gage R&R

• The sources of variability in the dissolution measurement system can be identified and minimized.

• If done during clinical or bio-batch lot, knowledge of variability can assure development of meaningful specifications.

• An internal reference can be developed from the clinical or bio-batch which is more applicable to your product than the USP calibrator tablets.

• This approach provides a higher assurance of quality than the current system where OOS results may be caused by product failure OR measurement system variability.

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Vibration

1. 1999 Collaborative Study: Displacement

2. 1998 Japanese Study: Acceleration

39 ± 4High Vibration: Acceleration > 0.09 m/s2

32 ± 1Low Vibration Acceleration < 0.01 m/s2

Average of 5 – 8Apparatus 1, 50 rpm, Enteric Coated product

3. 2005 Study by Bryan Crist and Dan Spisak, Varian Inc. : Frequency

42 ± 9Vibration Displacement < 0.02 mils Frequency at 130 Hz

34 ± 2Vibration Displacement < 0.20 mils Frequency at 20 Hz

34 ± 4Benchmark

Average 6Apparatus 2, 50 rpm 10 mg Prednisone USP Lot #O0C056

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Hydrodynamics

Challenges

• Paddle method is operated at flow conditions between laminar and turbulent which makes modeling difficult and shear stress distribution is non-uniform at base of vessel.

• Degree of mixing with basket method is limited leading to solute stratification in the vessels, and the dosage form remaining in the basket is subjected to different shear stress than the fragments that settle at bottom of vessel.

• Hydrodynamic variables that are important to drug release for a calibrator tablet may or may not be important to drug release for the desired product.

Statements based on information from Dr. Armenante, Dr. Muzzio and Dr.Kakhi

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Future Research

• Hydrodynamics

• Vibration

• New approaches to assess drug

release (PAT, spectroscopy, first

principles and modeling)

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Acknowledgements

• Terry Moore

• Zongming Gao

• Benjamin Westenberger

• Jim Allgire

• Anjanette Smith

• Ajaz Hussain

• PhRMA Dissolution Working Group