dissolution apparatus
TRANSCRIPT
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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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#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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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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37
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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