Dissolution Measurement System: Current State and Opportunities for Improvement

Dr. Lucinda Buhse Director, Division of Pharmaceutical Analysis

1

Measurement System for Dissolution Rate

• Apparatus • Current State of Calibration and Validation • Sources of Variability • Opportunities for Improvement 2

USP Dissolution Apparatus

• • • • • • •

Apparatus 1 Apparatus 2

-

Basket Paddle

(37º) (37º)

Apparatus 3 - Reciprocating Cylinder Apparatus 4 – Flow-Through Cell

(37º) (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 3

Apparatus 1 Basket Apparatus 2 Paddle

4

Apparatus 3 (shown)

Glass reciprocating cylinder

Apparatus 7 Holders

a) 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 5

Apparatus 4: Flow Through Cells

6

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 7

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

8

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

 • Basket Wobble (bottom rim)

+ 0.5



C) (+ 1mm)

9

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) JP, BP and EP: No calibrator tablets 10

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 11

Current State: Method Development / Validation Development –Discriminatory? Repeatable?

• Instrument – which one to use?

• Media • Degassing • Sinkers

Validation:

• 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)

12

Managing Variability

• Total variability

σ 2 Total • Assuming independent variable (if not independent for example interaction between measurement and product a covariance term needs to be included) • σ 2 Total

=

σ 2 Product

+

σ 2 Measurement • σ 2 Measurement

=

σ 2 Repeatability

+

σ 2 Reprodicibility

• Common Cause Vs. Special Cause variability • Process capability:

Customer Needs Process Ability 13

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 14

Variability: Instrument Suitability Set-up Parameters:

Shaft Wobble Vessel/Shaft Centering Height check/Basket or Paddle Depth as measured at Basket or Paddle bottom Vibration as measured at center of vessel support plate while operating at 100 rpm/head above plate, 900 ml medium in vessels Rotational speed Basket Wobble (Bottom Rim)

USP No significant wobble DPA ≤ 0.5 mm total run out 2 mm from centerline 1 mm from centerline 25 + 2 mm 25 + 1 mm No significant vibration ≤ 0.1 mil displacement + 4% + 1mm + 1 rpm ≤ 0.1mm total

15

Variability: Media and Degassing Total Dissolved Gas and Oxygen Meter A B

Used for determining water quality in agriculture, fisheries and industry 16

Variability: Media and Degassing Total Gas Pressure and Oxygen Gas Pressure in Water Degassing by Various Methods

720 620 520 420 320 220 120 20 PT Atm-PT PO2 Atm-PO2 At mo sp he re D PA U SP

Methods

H e-f or1 H r N 2-f or1 H r 17

Product 1: paddle, 50 rpm, DI Water 90 80 70 60 50 40 30 20 10 0 0 20 40 60

Time (min)

80 non-degassing(n=6) USP degassing (n=6) He sparging(n=6) 100 120 60 Product 3: paddle, 50 rpm, pH 7.4 buffer non-degassing(n=3) 50 DPA degassing (n=3) 40 30 20 10 0 0 10 20 30 40 50 60 70

Time (min)

80 90 100 110 120 Product 2: basket, 100 rpm, pH 1.2

100 90 80 70 60 50 40 30 20 10 0 0 20 non-degassing(n=3) DPA degassing (n=6) He sparging(n=9) 40 60

Time (min)

80 100 120

Variability: Media and Degassing

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Variability: Media or Manufacturing?

PERCENT DISSOLVED PLOT pH 7.2

110 100 90 80 70 60 50 40 30 20 10 0 0.0

0.5

1.0

1.5

2.0

Dissolution Time (Hours) 2.5

1 2 3 4 5 6 3.0

pH 7.2

110 100 50 40 30 90 80 70 60 20 10 0 0

PERCENT DISSOLVED PLOT

1 2 3 4 5 6 1 2 3 4 Dissolution Time (Hours) 5

pH 6.8

19 6

Variability: Media or Manufacturing?

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.

20

Variability: Media or Manufacturing?

Microscope Images of the Coating

21

Variability Sinkers

Product 1: paddle, 50rpm, DI water, off-center 10mm 60.0

50.0

40.0

30.0

20.0

10.0

center (n=3) off-center(n=3) 0.0

0 10 20 30 40 50 60 70

Time (min)

80 90 100 110 120 Sinkers are sometimes needed to hold product at the bottom of the dissolution vessel.

22

Variability Sinkers

110 100 90 80 70 60 50 40 30 20 10 0 0

Commercial Sinker PERCENT DISSOLVED PLOT

10 20 30 40 Dissolution Time (Minutes) 50 1 2 3 4 5 6 60 60% - 72% Dissolved at 30 min.

66% ± 4%

3 Wire Turns PERCENT DISSOLVED PLOT

110 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 Dissolution Time (Minutes) 50 1 2 3 4 5 6 60 89% – 99% Dissolved at 30 min.

95% ± 4% 23

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 24

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” 25

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 26

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?) 27

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 28

Acknowledgements

• Terry Moore • Zongming Gao • Lawrence Yu • Ajaz Hussain

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100 80 60 40 20 0 50 100 80 60 40 20 0 0 10 20 30 40 50 10-mg Prednisone Tablet DPA Distribution USP Limits

Paddle Limits: 27 - 48% DPA: 31.7 +/- 2.0

n=24

60 70

% Dissolved

80 90 100

Basket Limits: 53 - 77% DPA: 72.6 +/- 5.4

n=36

30