dissolution measurement system: current state and opportunities for improvement
DESCRIPTION
Dissolution Measurement System: Current State and Opportunities for Improvement. Dr. Lucinda Buhse Director, Division of Pharmaceutical Analysis. Measurement System for Dissolution Rate. Apparatus Current State of Calibration and Validation Sources of Variability - PowerPoint PPT PresentationTRANSCRIPT
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Dissolution Measurement System:Current State and Opportunities for
Improvement
Dr. Lucinda Buhse
Director, Division of Pharmaceutical Analysis
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Measurement System for Dissolution Rate
• Apparatus• Current State of Calibration and Validation• Sources of Variability• Opportunities for Improvement
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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
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Apparatus 1 Basket
Apparatus 2
Paddle
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Apparatus 3 (shown)
Glass reciprocating cylinder
Apparatus 7 Holdersa) Reciprocating disk sample holder b) Transdermal system holder - angled disk (32º)c) Transdermal system holder - cylinder (32º)d) Oral extended-release tablet holder—rod, pointed for gluing e) Oral extended-release tablet holder—spring holder
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Apparatus 4: Flow Through Cells
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Current State for Dissolution Test Methods
Most use:• Apparatus 1 (Basket) or Apparatus 2 (Paddle)
• USP Equipment Set-Up and Calibration Criteria
• One point acceptance criteria for Immediate Release
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Current State for Dissolution Test Methods
• Instrument Suitability– Choice of instrument– Mechanical Calibration (affecting
hydrodynamics)– Calibrator Tablets (USP, not EP, BP or JP)
• Method Development / Validation
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Current State: Instrument Suitability
USP Mechanical Calibration Parameters include:• Basket/Shaft Wobble (No significant wobble)• Vessel/Shaft Centering (2 mm from centerline)• Height check/Basket or Paddle Depth as measured at
basket bottom or Paddle bottom (25 + 2 mm)• No significant vibration• Rotational speed (+ 4%)• Vessel Temperature (37.0 + 0.5 C)• Basket Wobble (bottom rim) (+ 1mm)
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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 Maryland2004 : 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)
JP, BP and EP: No calibrator tablets
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Current State: Instrument Suitability
Calibrators• 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 O)• Basket: 23 – 29%• Paddle: 17 – 26%
• Action with Out of Specification value• Gets in the way of continuous improvement
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Current State: Method Development / Validation
Development –Discriminatory? Repeatable?• Instrument – which one to use?• Media• Degassing• SinkersValidation:• Determinative Step – Main Focus
– Linearity and Recovery– Filtering– Stability of solutions– Interferences
Even if we don’t understand development, we need to understand variability of our system (product, measurement, random)
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Managing Variability
• Total variability σ2Total
• Assuming independent variable (if not independent for example interaction between measurement and product a covariance term needs to be included)
• σ2Total = σ2
Product + σ2Measurement
• σ2Measurement = σ2
Repeatability + σ2Reprodicibility
• Common Cause Vs. Special Cause variability
• Process capability:
Customer NeedsProcess Ability
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Current State: Variability
• Instrument Suitability– Apparatus Variability– Operator Set-up– 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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Variability: Instrument Suitability
Set-up Parameters:
Shaft Wobble No significant wobble
≤ 0.5 mm total run out
Vessel/Shaft Centering 2 mm from centerline
1 mm from centerline
Height check/Basket or Paddle Depth as measured at Basket or Paddle bottom
25 + 2 mm 25 + 1 mm
Vibration as measured at center of vessel support plate while operating at 100 rpm/head above plate, 900 ml medium in vessels
No significant vibration
≤ 0.1 mil displacement
Rotational speed + 4% + 1 rpm
Basket Wobble (Bottom Rim) + 1mm ≤ 0.1mm total
USP DPA
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Used for determining water quality in agriculture, fisheries and industry
AB
Total Dissolved Gas and Oxygen Meter
Variability: Media and Degassing
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20
120
220
320
420
520
620
720
Methods
Pre
ss
ure
(m
mH
g)
PT PO2
Atm-PT Atm-PO2
Total Gas Pressure and Oxygen Gas Pressure in Water Degassing by Various Methods
Variability: Media and Degassing
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0
10
20
30
40
50
60
70
80
90
0 20 40 60 80 100 120
Time (min)
% D
isso
luti
on
non-degassing(n=6)
USP degassing (n=6)
He sparging(n=6)
Variability:
Media and Degassing
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120
Time (min)
% D
isso
luti
on
non-degassing(n=3)
DPA degassing (n=6)
He sparging(n=9)
0
10
20
30
40
50
60
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (min)
% D
iss
olu
tio
n
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 PLOTpH 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)
% o
f La
be
l Cla
im
123456
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)
% o
f Label C
laim
123456
pH 7.2 pH 6.8
Variability: Media or Manufacturing?
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What are the sources of variability at pH 6.8?
• Product handling during testing?
• Tablet to tablet differences?
• Instrumentation variation? – Vessel defects? – Inconsistent Centering? – RPM variations– Etc.
Variability: Media or Manufacturing?
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Microscope Images of the CoatingVariability: Media or Manufacturing?
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Variability Sinkers
0.0
10.0
20.0
30.0
40.0
50.0
60.0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (min)
% D
iss
olu
tio
n
center (n=3)
off-center(n=3)
Product 1: paddle, 50rpm, DI water, off-center 10mm
Sinkers are sometimes needed to hold product at the bottom of the dissolution vessel.
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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
Labe
l Cla
im
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)
% o
f La
bel C
laim
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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Opportunities for Improvement
• Alternative regulatory approach to dissolution calibration and validation– Understand and control measurement system variability– Understand the product specific sources of variability– Understand relationship between physicochemical properties
and dissolution results
• Understand the benefits and limitations of different dissolution apparatus – develop scientific criteria
• Investigate new approaches to assess product quality and availability
• Communication and training of FDA personnel
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Alternative approach to dissolution calibration and validation
• Stringent Mechanical Calibration to replace the need for a calibrator tablet
• ID and Control all sources of variability– Apparatus Type including sinkers– Set-up Parameters– Media including degassing
• Understanding of interaction between instrument and product during pharmaceutical development
• If necessary, establish an internal calibrator (biobatch or clinical batch) for system suitability and stability
• Confirm suitability using Gauge R&R using pivotal clinical trial product or pivotal “bio-batch”
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Gauge R&R Design
• Chance to characterize variability on an internal reference– Make it representative – Controlled manufacturing process
• For design include variables such as– Instrument– Personnel – Media
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Understand the benefits and limitations of different dissolution apparatus
• Use design and development information to help choose an apparatus
• Model dissolution environments and understand hydrodynamics from first principles
• Look beyond apparatus 1 and 2 to alternative systems that may be easier to model and test (i.e., flow through?)
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Investigate new approaches to assess product quality and availability
• New tools to assess product and media variability– Spectroscopy? NIR, RAMAN, Terahertz
• PAT including feedback loops• First principles and modeling
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Acknowledgements
• Terry Moore
• Zongming Gao
• Lawrence Yu
• Ajaz Hussain
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0
20
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60
80
100
0 10 20 30 40 50
0
20
40
60
80
100
50 60 70 80 90 100
% Dissolved
Paddle
Limits: 27 - 48%
DPA: 31.7 +/- 2.0
n=24
Basket
Limits: 53 - 77%
DPA: 72.6 +/- 5.4
n=36
10-mg Prednisone Tablet
DPA Distribution
USP Limits