Dissolution Apparatus

Qualification
Lucinda (Cindy) Buhse, PhD
Acting Director, Office of Testing and Research

Challenges for Dissolution Testing for the 21st Century

May 3, 2006

1
 Goals

• Understand the sources of variability

• Set up and operate dissolution apparatus
to minimize uncertainty

2
 Outline

• Current State of Calibration

• Variability
• Opportunities for Improvement – Alternate
approaches
– Gage R&R
– Mechanical Calibration
• Future Research

3
 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 stainless
steel cylinder element.
• Apparatus 7, Reciprocating Holder, for transdermal delivery
systems and also a variety of dosage forms
 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
5
 Current State: Mechanical Calibration

Set-up Parameters: USP

Shaft Wobble No significant wobble

Basket Wobble (Bottom Rim) + 1mm

Height check/Basket or Paddle Depth as 25 + 2 mm

measured at Basket or Paddle bottom
Vibration No significant vibration
Rotational speed + 4%
Vessel/Shaft Centering 2 mm from centerline

6
 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 7
 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
8
 USP Calibrator Limits (Lot O0C056)
vs
Distribution of DPA Laboratory Results
______ DPA Distribution
______ USP Limits (2004)
Basket
Limits: 53 - 77%
DPA: 72.6% ± 5.4%
50 60 70 80 90 100
n=36

Paddle
Limits: 27 - 48%
DPA: 31.7% ± 2.0%
n=24
0 10 20 30 40 50

% of Label Claim
9
 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

10
 Mechanical Calibration: Vessel Centering and
Vessel Verticality affect Hydrodynamics

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

• Data Range: 26.3 – 44.5%:

% Label Claim at 30 min.

Mechanical Calibration Status Avg. SD
Vessels Centered (Avg. of 30) 29.2 1.0
Vessels Offset 1 mm (Avg. of 12) 30.6 1.8
Vessels Offset 2 mm (Avg. of 12) 35.6 3.9
Vessels Tilted ~1º (Avg. of 12) 31.4 1.2
Vessels Tilted ~2º (Avg. of 12) 36.3 2.6

11
 Variability: Dissolved Gas

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

90 100

80 90
Label Claim

Label Claim
70
80
70

Dissolution
60
%%ofDissolution

60
50
50
40
40

%% of
30 30
non-degassing(n=6) non-degassing(n=3)
20 20
USP degassing (n=6) DPA degassing (n=6)
10 He sparging(n=6) 10 He sparging(n=9)

0
0
0 20 40 60 80 100 120
0 20 40 60 80 100 120

Time (min) Time (min)

Product 3: paddle, 50 rpm, pH 7.4 buffer

non-degassing (n=3)
60
DPA degassing (n=3)
50
% of Label Claim

40

30

20

10

0
0 20 40 60 80 100 120 12
Time (min)
 Variability: Media

PERCENT DISSOLVED PLOT PERCENT DISSOLVED PLOT

pH 7.2 110

110
100

100
90
90
80
80

% of Label Claim
% of Label Claim

70
70
60
60

50 50

40 40
1
1
30 2 30 2
3 3
20 4
4 20 5
5 6
10 6 10
0
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0 1 2 3 4 5 6

Dissolution Time (Hours) Dissolution Time (Hours)

pH 7.2 pH 6.8
13
 Variability
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?
14
 Variability: Sinkers

Commercial Sinker 3 Wire Turns

PERCENT DISSOLVED PLOT PERCENT DISSOLVED PLOT

110 110

100 100

90 90

80 80

% of Label Claim
% of Label Claim

70 70

60 60

50 50

40 40

30 30

20 1 20 1
2 2
3 10 3
10 4
4
5 5
0 0 6
6
0 10 20 30 40 50 60 0 10 20 30 40 50 60

Dissolution Time (Minutes) Dissolution Time (Minutes)

60% - 72% Dissolved at 30 min. 89% – 99% Dissolved at 30 min.

66% ± 4% 95% ± 4% 15
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”

16
 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
17
 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

18
 DPA Gage R&R Study

Operator 1 2

Apparatus A B A B

Vessel 123456 123456 123456 123456

6 repetitions

19
 Comparison of % of Label Claim at 30 Minutes
for Two Apparatuses

39 39 t Test
38 38
#A-#B
37 37
Assuming unequal variances
36 36
#A-B%Diss@30

Difference 0.41356 t Ratio 1.606076

#A-B%Diss@30

35 35
Label Claim

Std Err Dif 0.25750 DF 140.5884

34 34
%Diss0@30

Upper CL Dif 0.92264 Prob > |t| 0.1105

33 33
Lower CL Dif -0.09551 Prob > t 0.0553
32 32
31 Confidence 0.95 Prob < t 0.9447 -1.0 -0.5 .0 .5 1.0
31
%of

30 30
29 29
28 Means and Std Deviations
28
27
27 #A #B Level Number Mean Std Dev Std Err Mean Lower 95% Upper 95%
#A #B
A B #A 72 32.2868 1.62056 0.19098 31.906 32.668
A B
Apparatus #B 72 31.8732 1.46555 0.17272 31.529 32.218
Apparatus

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

USP apparatus 2 in testing NCDA#2 tablets.

20
 Comparison of Variance Components

80 Apparatus A

70 Variance Components
% of Total Variance

Apparatus B
60
50
40
30
20
10
0

Tablet Vessel Operator

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.
21
 30 Minute Dissolution for Individual Vessels for
Apparatus A

39
3839 •Some vessels are above average
3738
and some below.
3637
#A-%Diss@30

3536 •Vessels were moved to different

#A-%Diss@30

3435
Label Claim

positions and trends above and

%Diss0@30

3334 below average were found to follow

3233 the vessel and not the shaft
3132
%of

position.
3031
2930 •Although apparatus was level and
2829 shafts were vertical, vessels were
2728 found to be not vertical because of
27 1 2 3 4 5 6
1 2 3 4 5 6 unevenness around their rims.
Vessel
#A-vessels
Vessel
#A-vessels

22
 Reminder: Vessel Verticality/Centering and
Hydrodynamics

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

• Data Range: 26.3 – 44.5%:

% Label Claim at 30 min.

Mechanical Calibration Status Avg. SD
Vessels Centered (Avg. of 30) 29.2 1.0
Vessels Offset 1 mm (Avg. of 12) 30.6 1.8
Vessels Offset 2 mm (Avg. of 12) 35.6 3.9
Vessels Tilted ~1º (Avg. of 12) 31.4 1.2
Vessels Tilted ~2º (Avg. of 12) 36.3 2.6
23
Comparison of Variance Components after
2 Point Centering for Apparatus A

100
90 Variance Components
% of Total Variance

80
70
60 Y

50 1pt centering
Apparatus #A

40 Apparatus #B
2pt centering
30
20
10
0

Tablet Vessel Operator

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

component of the variability.

24
 Mechanical Calibration Tolerances

USP ASTM Proposal

Shaft Wobble No significant ≤ 1 mm total run out
wobble
Vessel/Shaft Centering 2 mm from 1 mm from centerline
centerline at 2 points
Vessel Wall Verticality ≤ 1 degree
Height check/Basket or Paddle 25 + 2 mm 25 + 2 mm
Depth as measured at Basket
or Paddle bottom
Shaft Verticality None Centered in bubble
level at 2 pts 90°° apart
Rotational speed + 4% + 2 rpm
Basket Wobble (Bottom Rim) + 1mm + 0.5mm
(≤ 1.0mm total) 25
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
26
 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.

27
 Vibration
1. 1999 Collaborative Study: Displacement
2. 1998 Japanese Study: Acceleration
Apparatus 1, 50 rpm, Enteric Coated product Average of 5 – 8
Low Vibration Acceleration < 0.01 m/s2 32 ± 1
High Vibration: Acceleration > 0.09 m/s2 39 ± 4

3. 2005 Study by Bryan Crist and Dan Spisak, Varian Inc. : Frequency
Apparatus 2, 50 rpm 10 mg Prednisone USP Lot #O0C056 Average 6
Benchmark 34 ± 4

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

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

28
 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
29
 Future Research

• Hydrodynamics
• Vibration
• New approaches to assess drug
release (PAT, spectroscopy, first
principles and modeling)

30
 Acknowledgements

• Terry Moore
• Zongming Gao
• Benjamin Westenberger
• Jim Allgire
• Anjanette Smith
• Ajaz Hussain
• PhRMA Dissolution Working Group

31