Complying with USP & ASTM Standards for qualification of dissolution apparatus

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Date: 25th & 26th July 2017

(SATISH KAKODKAR)

Teledyne Hanson Research

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• Established in 1951 in Los Angeles, California

• 1969: First company to commercialize

• 1974: First company with sample-automation

• Today: Full line of dissolution & transdermal

test systems and automation platforms

• We work extensively with experts from USP,

FDA and industry experts & consultants

• Serve on a number of USP expert panels

committees, AAPS committees and

subcommittees

• Our instruments are found in pharmaceutical,

biotech, contract research and manufacturing,

USFDA government research, USP,

universities, military, nutraceutical and

cosmetic laboratories worldwide.

• Acquired Hanson Research in Dec. 2016

• Technologies on the sea floor for oil & gas

exploration

• Military defense systems

• Aviation and deep space systems

• Pollution and ambient air monitoring

• Electronic signal measurement

• “Everywhere you look”

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Complying with USP & ASTM Standards for qualification of dissolution apparatus

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Complying with USP and ASTM Standards for Dissolution Apparatus Qualification

1. Overview of qualification methods

2. USP

• Performance Verification Test (PVT)

• USP Tool Kit

3. Enhanced Mechanical Calibration

4. Best Practices for successful instrument qualification

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Complying with USP and ASTM Standards for Dissolution Apparatus Qualification

1. Overview of qualification methods

2. USP

• Performance Verification Test (PVT)

• USP Tool Kit

3. Enhanced Mechanical Calibration

4. Best Practices for successful instrument qualification

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Overview of dissolution instrument qualification

USFDA: Two approved methods of performing dissolution instrument qualification & calibration:

• USP <711>

• Semi-annual mechanical verification & chemical test (PVT)

• Most widely adopted around the world

• Enhanced mechanical calibration

• ASTM E2503-13 or

• Recommended by the USFDA for CGMP calibration requirements as an alternative to the USP method

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1. Complying with USP and ASTM Standards for Dissolution Apparatus Qualification

1. Overview of qualification methods

2. USP

• Performance Verification Test (PVT)

• USP Tool Kit

3. Enhanced Mechanical Calibration

4. Best Practices for successful instrument qualification

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USP Qualification Method

1. Mechanical verification according to <711>

• Specifies the physical geometries of the instrument/apparatus

• Often requires the manufacturer’s certified tools and a trained operator

• Every six months or anytime the instrument is moved or changed

• Must be documented

2. Performance Verification Test (PVT)

• Formerly “Apparatus Suitability Test” and “Calibrator Tablets”

• Chemical calibration using Prednisone tablets (“reference standard tablets”)

• Every six months or anytime the instrument is moved or changed

• Same formulation since 1999

• In 2010 the acceptance criteria changed

• Since 2010, the industry started experiencing high PVT failure rates

• Sensitive to vibration, deaeration, centering and hemispherical bottom

• In 2015 the USP prednisone tablets were recalled

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The Performance Verification Test:Dissolution Procedure

1. Deaerate the medium (USP method)1. Heat to 41-45º C2. Filter through a 0.45 µm membrane filter3. Stir under reduced pressure for 5 minutes at less than 100

mbar

2. Deliver the media to the vessels1. 500 mL ±1% or 5 mL2. Use caution not to reaerate3. Equilibrate to 37º C ±0.5º C

3. Deliver the dosage1. Baskets: Must be dry, then lower in to medium2. Paddles: Uniform delivery, resting at the bottom3. Can stagger the start

4. Sample withdrawal1. Approximately 30 mL2. 30 minutes3. USP sample location

5. Sample filtration, 0.45 µm PVDF syringe filter1. Immediately after withdrawal2. Waste 5 mL3. Collect into test tubes and cool to ambient

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The Performance Verification Test:Analytical Procedure

1. Prepare two Prednisone standard solutions1. Working standard, control standard

2. Must be prepared within 24 hours of use

3. Absorptivity (AU per mg/mL) within 1% of each other

2. UV measurements1. 242 nm

2. 1.0 cm path length

3. Calculate absorptivity using Beer’s law (AU per mg/mL)

4. UV calibration USP <851>

3. Single-Stage or Two-Stage1. Must specify before starting test

2. Single-Stage requires two test runs

3. Single-Stage is required for 12-vessel testers

4. Two-Stage may not require second test run if %CV is tight

enough

4. Use the USP PVT calculation tool1. http://apps.usp.org/app/USPNF/pvtCalculationTool/page.html

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Common PVT Failures

• Preparation of Prednisone standard solution• Inadequate mixing or dilution volumes• Too old

• Deaeration• Two-stage transfer (into cylinder, into vessel)• Rate and method of pouring, pouring height• Introduction of cold baskets and time lag

• Vessel centering• <711> hasn’t changed: NMT 2 mm from vertical axis of

vessel

• Hemispherical bottom• From <711>: “The vessel is cylindrical with a

hemispherical bottom”

• Vibration• From <711>: No significant vibration

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Does a PVT failure mean the instrument does not comply with <711>?

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USP <711>:

Performance Verification Test, Apparatus 1 and 2:

“…The apparatus is suitable if the results obtained are within the acceptable range

stated in the technical data sheet specific to the lot used and the apparatus tested”.

PVT Variables:

1. Accuracy of calibration tools and operator training

2. Deaeration method and execution

3. “Hemispherical bottom”

4. The prednisone tablet

5. Cold baskets

6. Sample timing: vessel offsets

7. Sample location: “A zone midway…”

8. Filtration method, execution and timing

9. UV-Vis method, accuracy, execution

10. Operator

Does a PVT failure mean the instrument does not comply with <711>?

• Instruments that comply with USP <711> and meet other PVT variables may still fail the PVT

• “Run it again”

• USP website: “USP provides some recommendations to help customers achieve a successful PVT in the Dissolution Toolkit”

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USP Dissolution ToolkitProcedures for Mechanical Calibration and Performance Verification TestApparatus 1 and Apparatus 2

• USP response after years of industry frustration and failed tests

• Only a ”recommendation”

• Strongly suggested?

• Tighter mechanical specifications

• In many cases by half

• If the PVT procedure and the Prednisone tablets are both robust and discriminating, why the need to recommend tighter mechanical specifications?

• In most cases, rigorous mechanical alignments and adjustments are required to pass the PVT

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v1.0 October, 2007

v2.0 March, 2010

USP <711> vs. USP Toolkit Examples

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USP <711> USP Toolkit 2.0

Bench level N/A NMT 1° in 2 directions

90deg apart

Vessel Verticality N/A NMT 0.5 degree from

vertical measured at 2

points 90deg apart.

Shaft Verticality N/A NMT 0.5° from vertical in

2 orthogonal positions

Centering ≤ 2 mm from vertical

axis

≤ 1 mm from vertical

axis

Wobble No significant wobble ≤ 1 mm

Deaeration If dissolved gasses

influence the results,

gasses should be

removed prior to testing

≤ 6 ppm

USP <711> vs. Toolkit Example: Centering

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17Toolkit ± 1 mm

<711>

USP Apparatus Qualification Summary

• Mechanical qualification to <711> followed by PVT (prednisone test)

• PVT failures are common

• Many variables effect PVT results, not just the apparatus

• USP responds by recommending use of the Toolkit

• 2010 acceptance criteria based on ISO approach

• Summary: A mechanically-compliant instrument may not pass the PVT

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1. Complying with USP and ASTM Standards for Dissolution Apparatus Qualification

1. Overview of qualification methods

2. USP

• Performance Verification Test (PVT)

• USP Tool Kit

3. Enhanced Mechanical Calibration

4. Best Practices for successful instrument qualification

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Enhanced Mechanical Qualification

• An enhanced mechanical calibration procedure can minimize variation within App 1 and 2

• Recommended by the Pharmaceutical Research and Manufacturers of America (PhRMA) Dissolution Calibration Subcommittee in 2000 as a “value added means of calibration”

• Endorsed by the USFDA for CGMP compliance in 2005 after extensive testing showed that mechanical compliance to USP <711> resulted in extensive dissolution test variability

• In 2006, USFDA’s Division of Pharmaceutical Analysis published the Mechanical Qualification of Dissolution Apparatus 1 and 2 procedure (DPA-LOP.002)

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FDA Guidance for Industry

• January, 2010

• “The enhanced MC procedure recommended in this guidance can be used as an alternative to the current Apparatus Suitability procedure for USP Dissolution Apparatus 1 and 2 described in USP General Chapter <711> Dissolution.”

• “…the MC tolerances specified in USP <711> for the dissolution apparatus assembly are not as comprehensive or as stringent as those in the enhanced MC procedures recommended in this guidance”.

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FDA Guidance for Industry

• “An example of of an appropriately enhanced MC procedure is that used by CDER/DPA titled Mechanical Qualification of Dissolution Apparatus 1 and 2 [DPA-LOP.002] "

• Alternative methods of mechanical calibration can also be used to setup and maintain dissolution equipment, provided the chosen method is comparably enhanced to the FDA-recommended MC procedure so that mechanical variables that could significantly affect the accuracy and precision of test results are adequately controlled10”.

• “10 See also ASTM E2503-07, Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus”.

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American Society for Testing and Materials

• Formed in 1898

• In 2001 name changed to ASTM International

• Over 12,000 ASTM standards used around the world to improve product quality, enhance heath and safety, strengthen market access and trade, and build consumer confidence.

• More than 30,000 technical expert members representing 140 countries contribute to ASTM standards

• In accordance with the guiding principles of the WTO

• Offices in Washington, D.C., Belgium, Canada, China and Peru

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Examples of ASTM Standards

• Quality and performance of iron castings used in automobiles

• Standard practice for Emergency Medical Dispatching

• Standard test methods for calibration of microwave ovens

• Standard test methods for flammability of marine surface finishes

• Standard practice for liquid chromatography

• Standard practice for qualification of basket and paddle dissolution apparatus

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ASTM E2503-13Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus

• Under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical Products

• Direct responsibility of Subcommittee E55.03 on General Pharmaceutical Standards

• Enhanced mechanical calibration

• Tighter than <711>

• No chemical test

• Approved and recommended by the US FDA as of Jan. 2010

• Reviewed and updated every six years “-13”) © 2

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FDA MQ [DPA-LOP.002] & ASTM E2503

• Evaluates and specifies tight tolerances for the following:• Vessel & Shaft Centering

• Wobble for Basket Shafts, Baskets, and Paddles

• Basket/Paddle Height

• Vessel Verticality

• Shaft Verticality

• Motor Speed

• Vessel Temperature

• Dimensions for Paddles, Baskets, Basket Shafts, and Vessels

• Recommends the following be evaluated on a daily basis:• Basket, Paddle, Vessel condition

• Vessel Temperature

• Vibration (Qualitative evaluation)

• USP PVT is not required for calibration

• ASTM recommends requalification after a relocation, repair, or at a frequency to be determined by the existing quality system.

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Comparison

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USP <711> (1) USP Toolkit 2.0 (4) FDA MQ

(DPA-LOP.002) (2)

ASTM E2503 (3)

Shaft Verticality N/A NMT 0.5° from

vertical in 2

orthogonal positions

Vertical in 2

directions 90° apart.

NMT 0.5° from

vertical

Vertical in 2

directions 90° apart.

The bubble should

be centered within

the lines

Centering NMT 2 mm from

vertical axis

NMT 1 mm from

vertical axis

Top and bottom must

be within 1.0 mm of

center line

Vessel axis NMT 1

mm from center line

of shaft or surrogate

shaft

Wobble No significant

wobble

NMT 1 mm NMT 1 mm total run-

out of shaft

measured 2 cm

above basket or

blade

NMT 1.0 mm total

run-out of shaft

measured 2 cm

above basket or

blade

Deaeration If dissolved gasses

influence the results,

gasses should be removed

prior to testing

≤ 6 ppm N/A N/A

(sequence of document release)

ASTM Specifications and Tools

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• Shaft Wobble• Runout gauge touches the turning shaft

about 2 cm above the top of paddle blade or basket shaft.

• Total indicated reading (TIR) is not to exceed 1.0 mm.

• Basket Wobble• Runout gauge touches the bottom rim of

the turning basket.

• TIR is not to exceed 1.0 mm

ASTM Specifications and Tools

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• Vessel Centering

• A sweep gauge is used to measure the center alignment in two places

ASTM Specifications and Tools

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• Paddle and Basket Height

• An adjustable depth gauge measures the distance between the bottom of the paddle blades or baskets and the bottom of the vessel.

• 25 mm +/- 2 mm

• Same as <711>

ASTM Specifications and Tools

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• Vessel Verticality

• NMT 1° from vertical at 2 points 90°apart.

• Measuring at 2 points proves the vessel is not skewed in one direction.

• Not mentioned in <711>

Diagram of a vessel from above

Red dots indicate points where verticality is measured

ASTM Specifications and Tools

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• Shaft Verticality• Measured in the operating position

• A challenge for some instrument manufacturers.

• Shaft must be vertical in two positions 90° apart.

• Not required in <711>

Diagram of a vessel from above

White circle is the shaft

Red dots indicate measurement points

ASTM Specifications and Tools

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Vessel Verticality Shaft Verticality

ASTM Specifications and Tools

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• Serialized accessories

• Baskets

• Basket shafts

• Paddles

• Vessels

• All serialized accessories should have a Certificate of Conformity or Certificate of Analysis

• If no certificate exists, measurements must be taken and recorded

ASTM Summary

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• 100% mechanical evaluation

• Measurement needed for all critical specifications

• Vessels and apparatus are validated per position

• Break a vessel or replace a basket, repeat validation in the position only!

• COA or COC for vessels and apparatuses

Required Tools

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• Digital level

• Validation tool kit

• Vibration meter

• Tachometer

• Thermometer

• All NIST traceable

Timeline

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JUNE 2006

• USFDA DPA-LOP.002 MQ of Dissolution Apparatus 1 & 2

AUG 2007

• <711> removed "calibrator tablets" and replaced it with "reference standard tablets.

• “Apparatus Suitability Test” replaced with “PVT”

OCT 2007

• USP Toolkit 1.0 which provides more mechanical explanation

• Matches <711>

JAN 2010

• USFDA's Guidance for Industry.

• Acceptance and recommendation for enhanced mechanical calibration (FDA MQ or ASTM) in lieu of the PVT

MAR 2010

• Acceptance criteria of PVT changed

• USP Toolkit 2.0 as a more rigorous mechanical qualification to aid in the passing of the PVT

1. Complying with USP and ASTM Standards for Dissolution Apparatus Qualification

1. Overview of qualification methods

2. USP

• Performance Verification Test (PVT)

• USP Tool Kit

3. Enhanced Mechanical Calibration

4. Best Practices for successful instrument qualification

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Best Practices

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• If the apparatus conforms to <711> or USP Toolkit, why does the PVT sometimes fail?

• The PVT is a test of the entire procedure, including the operator, the instrumentation and the tablets

• Enhanced mechanical calibration is simpler, less expensive and more reasonable

• Ensure the instrument is certified-compliant to ASTM at the factory

• Use organizational tools to keep apparatuses in the same position

• Perform basic checks of the system and accessories before each test run

• Beware of instrument characteristics such as user-initiated paddle/basket height adjustments

• Use the PVT as operator certification, not apparatus qualification

If you must perform PVTs

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• Follow the USP Toolkit

• Use a robust deaeration method• The leading cause of PVT failures

• Per USP Toolkit: “Other deaeration procedures are permissible, but they should be demonstrated to be equivalent to the USP procedure”.

• Consider a multi-vessel simultaneous media preparation tool

• Check the inner walls of the vessels• Use the best tool on earth

• Consider Super Precision Vessels which are molded

• Ensure vessels are locked into place• Try to avoid non-locking glass-flanged vessels

• Carefully examine paddle blades and basket mesh

• Standardized tablet introduction (ADD Covers)

• Tester that allows for staggered start

• Manual-sampling cannulas that ensure uniform, repeatable sample location accuracy

Hanson Media-Mate PlusTM

QUESTIONS?

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THANK YOU

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www.TeledyneHanson.com

Satish.kakodkar@teledyne.com