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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

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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

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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)

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10

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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

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50

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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

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100

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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

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30

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90

100

110

0 10 20 30 40 50 60

Dissolution Time (Minutes)%

of

Labe

l Cla

im

123456

PERCENT DISSOLVED PLOT

0

10

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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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% 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