TESTING OF SEMI-SOLIDS AND OTHER NON-ORAL … OF SEMI-SOLIDS AND OTHER NON-ORAL DOSAGE FORMS...

Agilent Dissolution Seminar Series

1© - 2013 All Rights Reserved

TESTING OF SEMI-SOLIDS AND OTHER NON-ORAL DOSAGE FORMS

Semi-Solids

The requirement for testing the release rate of drugs from semi-solid dosage forms has increased in recent years.

Products tested include ointments creamspastesgels

lotions

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Dissolution Apparatus

Semi-Solids

USP has recently (May, 2012) published a proposed General Chapter <1724> “Semisolid Drug Products - Performance Tests”. This provides general information on testing semi-solids including descriptions of three apparatus:

– Vertical Diffusion Cells

– Immersion Cell

– Insert for Apparatus 4

USP also proposes to include specific procedures and acceptance criteria in a revised General Chapter <724>

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Dissolution Apparatus Semi-Solids

FDA provides guidance for testing semi-solids:

“SUPAC-SS: Nonsterile Semisolid Dosage Forms Scale-Up and Post Approval Changes: Chemistry, Manufacturing, and

Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation”.

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USP Vertical Diffusion Cell

Three versions of this apparatus are described based on the classic Franz cell.

Model A

• volume ~7ml

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Dissolution Apparatus USP Vertical Diffusion Cell

Model B Model C

• - volume ~5ml - volume ~10ml

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USP Vertical Diffusion Cell

Recommended stirring speed is 600rpm

Test period 4-6 hours

Commercial apparatus for performing these tests is now becoming available.


PermeGear, Inc.

Immersion Cell Method

Used in conventional dissolution testers with a special vessel and “mini-paddle”.

Volume of medium: 50-200ml

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Immersion Cell Method

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Dissolution Apparatus Flow-Through Cell Method

Used in Apparatus 4 equipment

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Rectal / Vaginal Preparations

Preparations include suppositories, pessaries, vaginal tablets and vaginal rings.

These dosage forms are usually designed to soften and/or melt to release the drug.

Currently the only compendial requirements are described in Ph. Eur.

Typical apparatus for testing includes:• Apparatus 1 - Baskets

• Apparatus 2 - Paddles (using Stationary Baskets)

• Apparatus 4 - using special cell (Ph. Eur.)

• Swirling conical flasks

Equipment for Dissolution Testing of Non-Oral Dosage Forms

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The problem with the basket-type tests is that the mesh can be blocked as the product melts.

This is overcome with special Palmeri baskets

• these are sometimes used with beads to enclose the product and provide a

simulation of the physiological environment.


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The Ph. Eur. device is used in conventional Apparatus 4 Flow-through Cell systems.

This is designed to separate the flowing medium from the molten lipophilic excipients.


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Vaginal rings are often tested in swirling flask apparatus in incubators

• typically in 250ml saline at 130rpm for 12 hours


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Chewing Gums

Medicated chewing gums have become popular especiallyfor Nicotine.

Ph. Eur. describes one apparatus in 2.9.40 - Dissolution Test for Medicated Chewing Gums

• “The gum is artificially chewed by the horizontal pistons, and the vertical piston ensures that the

gum stays in the right place between chews.”

• Volume of medium ~20ml

• “60 chews per minute”


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Chewing GumsEquipment for Dissolution Testing of Non-Oral Dosage Forms

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USP has an Advisory Panel looking into a suitable procedure

Inhalations

There are currently no requirements for dissolution testing of particulates from MDI/DPI aerosol products.

A USP Advisory Committee agreed that there was no necessity to publish standards for dissolution testing of such products (PF34-4, 2008).


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Inhalations

Various devices have been used for research purposes:

• Powder cell in Apparatus 4 using whole formulation

• Collected fractions from Anderson Cascade Impactor:

– filters from each fraction placed between membranes in a special cell for

Apparatus 4

• Using NGI apparatus, special collection cups are covered with a

membrane and dissolution measured in Apparatus 2:


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QUALIFICATION OF DISSOLUTION APPARATUS

Analytical Instrument Qualification

Good Manufacturing Practices (GMP) regulations (e.g. FDA’s 21 CFR 211.160 (b)(4)) require companies to establish procedures ensuring the fitness for use of instruments that generate data supporting regulated product testing.

• No definitive guidance for the qualification of analytical instruments.

USP proposed a General Chapter <1058> on Analytical Instrument Qualification in 2005

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Apparatus Qualification

Published in USP-NF in 2009

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Apparatus Qualification Analytical Instrument Qualification

USP <1058> provides a scientific approach to AIQ and considers AIQ as one of the major components required for generating reliable and consistent data.

• “AIQ is the collection of documented evidence showing that an instrument

performs suitably for its intended purpose.”

• Users of analytical equipment should:

– validate their procedures

– calibrate their instruments

– perform additional instrument checks

• System suitability tests

• In-process control samples

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USP <1058> definitions:

Design Qualification (DQ)

• documented collection of activities that define the functional and

operational specifications of the instrument and criteria for selection of the

vendor, based on the intended purpose of the instrument.

• Prior to purchase

Installation Qualification (IQ)

• documented collection of activities necessary to establish that an

instrument is delivered as designed and specified, and is properly installed

in the selected environment, and that this environment is suitable for the instrument.

• performed at time of installation

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Apparatus Qualification USP <1058> definitions:

Operational Qualification (OQ)

• documented collection of activities necessary to demonstrate that an

instrument will function according to its operational specification in the

selected environment.

• After installation or major repair

Performance Qualification (PQ)

• documented collection of activities necessary to demonstrate that an

instrument consistently performs according to the specifications defined by

the user, and is appropriate for the intended use

• Performed after completion of OQ and periodically at specified intervals for

each instrument

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USP <1058> definitions:

Performance Qualification (PQ):

• Usually based on the instrument’s application and may consist

of analyzing known components or standards

• PQ tests may be modular or holistic

• PQ tests should be based on good science and reflect the general intended use of the instrument

• When an instrument fails to meet PQ test specifications, it requires maintenance or repair

Requirements for dissolution equipment

OQ

• after installation or repair

– conformance to mechanical specifications

PQ

• after installation, repair and at regular intervals

– conformance to mechanical specifications

– Performance Verification Test

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Qualification of Dissolution Apparatus

USP requirements for pharmacopœial dissolution tests were first introduced in 1970 for 6 monographs.

The basic concepts of the dissolution apparatus were established by empirical means rather than sound scientific and engineering considerations.

It very quickly became obvious that tests with different apparatus produced different results

• apparatus was often custom-made

• control of mechanical parameters was inadequate

• vibration was thought to be a key factor but couldn’t be conveniently

quantified at the time.

Use of a “calibrator” was suggested

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Apparatus Qualification Mechanical Qualification

Specifications and tolerances for the apparatus itself are given in the General Chapters

Tolerances for operating parameters are also provided, some more specific than others, e.g.

• speed ±4%

• temperature ±0.5°C

• rotation without significant wobble

• no significant vibration

These specifications and tolerances are the minimum standards allowable and have since been supplemented by tighter

standards published by various authorities including USP, FDA, ASTM, FIP

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Mechanical Qualification

FDA published “The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2” in 2006:

• Enhanced Mechanical Calibration (MC or MQ) of dissolution apparatus may be used as an alternative to the current Apparatus Suitability

procedure for Dissolution Apparatus 1 and 2 described in USP <711>

• The Mechanical Calibration procedure should specify the frequency at

which each calibration step is performed

• Either the USP procedure or an appropriate Mechanical Calibration method executed according to a written procedure will satisfy the CGMP

requirement for calibration of the laboratory apparatus…

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In collaboration with FDA, in 2007 ASTM published “Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus”

• outlines the procedures and tolerances for enhanced mechanical

calibration

• Moore et al published an “Implementation Guidance” document in 2010

– The Open Drug Delivery Journal, 2010, 4, 14-20

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2.2 Once a unit meets all of the mechanical specifications included in

this practice, it is considered calibrated and further calibration with

dissolution calibrator tablets is not required.

Abstract: This guidance is intended to serve as a companion document for ASTM

Standard E 2503-07, “Standard Practice for Qualification of Basket and Paddle

Dissolution Apparatus”, by providing practical information useful for the

implementation of mechanical calibration. Particular focus is placed on use of the

available tools to make the required measurements.




In 2007, USP published the “Dissolution Toolkit - Procedures for Mechanical Calibration and Performance Verification Test”

This provides

• “...a description of best practices associated with the mechanical

calibration and performance verification test for the USP basket and paddle

dissolution apparatuses and test assemblies.”

• very detailed mechanical calibration procedure along with measuring

techniques, tools required, and frequency of measurement

• detailed procedures for the use and interpretation of the USP Performance

Verification Test (PVT)

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Specifications and Tolerances

Parameter ICH (USP, JP, EP)

FDA DPA-LOP.002

ASTM E2503-07

USP Toolkit Ver 2.0

Basket and Paddle Depth

25 ± 2 mm 25 ± 2 mm 25 ± 2 mm(or <8%)

23-27 mm

Rotational Speed

± 4% of specified rate

± 2 rpm of target

Larger of ± 2 rpm or within 2% of target

± 1 rpm of target

Shaft Wobble No significant wobble

≤ 1.0 mm total runout


≤ 1.0 mm total wobble

Shaft Verticality

Not measured ≤ 0.5°from vertical

Within Bubble NMT 0.5°from vertical

Basket Wobble

± 1 mm ≤ 1.0 mm total runout


≤ 1.0 mm total wobble

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Apparatus Qualification Specifications and Tolerances

Parameter ICH (USP, JP, EP)

FDA DPA-LOP.002

ASTM E2503-07

USP Toolkit Ver 2.0

Vessel/ShaftCentering

NMT 2 mm from center axis

≤ 1.0 mm from center line

≤ 1.0 mm from center line

NMT 2.0 mm difference (4 -90°positions)

Vessel Verticality

Not Measured ≤ 1.0°from vertical (2 - 90°positions)

≤ 1.0°from vertical (2 -90°positions)

NMT 0.5°from vertical

Vessel Plate Level

Not Measured Not Measured Not Measured NMT 0.5°from horizontal

Performance Verification Test (PVT)

USP Prednisone Tablets RS

Not Measured Not Measured USP Prednisone Tablets RS

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Apparatus Suitability

Initially, the primary purpose of the USP Apparatus Suitability test with Prednisone and Salicylic Acid tablets was to indicate the influence of environmental factors and vibration on the apparatus since most other parameters could be controlled by

mechanical measurements

The original test became known as “Calibration” although this was not a true indication of the test being performed; later

changed to “Performance Verification Test” (PVT)

The PVT, has been responsible for detecting problems

associated with dissolution apparatus that are found to be within mechanical tolerances


The Apparatus Suitability Test became a USP requirement for all dissolution equipment in 1978

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Determine the acceptable performance of the dissolution test assembly

periodically. The suitability for the individual apparatus is demonstrated

by the Apparatus Suitability Test.

Apparatus Suitability Test, Apparatus 1 and 2— Individually test 1

tablet of the USP Dissolution Calibrator, Disintegrating Type and 1 tablet

of USP Dissolution Calibrator, Nondisintegrating Type, according to the

operating conditions specified. The apparatus is suitable if the results

obtained are within the acceptable range stated in the certificate for that

calibrator in the apparatus tested.




Initially, 8 tests required:

• 50mg Prednisone Calibrator Tablets - disintegrating

– baskets and paddles both at 50 and 100rpm

– tested in 900ml water for 30 minutes

• 300mg Salicylic Acid Calibrator Tablets - non-disintegrating

– baskets and paddles both at 50 and 100rpm

– tested in 900ml phosphate buffer for 30 minutes

• Acceptance criteria (upper and lower limits ) applied to each individual position.

• Variation between positions was not considered.

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Apparatus Qualification Apparatus Suitability

USP rationalised the requirements in 1997:

• With experience of the tests, it was found that just testing at a single speed

gave sufficient information.

• If the equipment was only used with one apparatus (baskets or paddles) then the tests were only required with that apparatus.

In 1999, a new 10mg Prednisone tablet formulation was introduced

• tested in 500ml water

• this formulation was found to be extremely sensitive to mechanical

variations in the apparatus and also to experimental procedures such as degassing of the medium.

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With these new tablets, industry started to have problems meeting the requirements and the credibility of the test was doubted.

After many experiments, it was found that there was no significant problem attributable to the tablets and the procedure was shown to be a very sensitive, holistic test for qualification of dissolution equipment.

It was also concluded that sufficient information was obtained from the Prednisone tablet tests and additional testing with the

Salicylic Acid tablets was no longer necessary

• the requirement to test with Salicylic Acid tablets was withdrawn in

December 2009.

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The problem with the original requirement to evaluate individual positions:

- Is this acceptable?

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25.0

30.0

35.0

40.0

45.0

50.0

55.0

60.0

65.0

0 1 2

1


The procedure and requirements for the Apparatus Suitability Test have been the subject of extensive review over several years.

USP revised the concept of the test from a test on each individual position in a dissolution tester to the ISO approach of “instrument proficiency testing” based on tests on the whole instrument.

This introduced Performance Verification Testing (PVT)

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Performance Verification Testing (PVT)

• Statistical analysis of the results of tests on all positions of an apparatus

now required.

• Both the Mean of the results and the % Coefficient of Variation must pass the acceptance criteria.

• The Prednisone tablets were renamed as “Reference Standard Tablets” to remove the implication of “calibration”.

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2009 revision to USP <711>

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APPARATUS SUITABILITY

The determination of suitability of a test assembly to perform dissolution testing must include conformance to the dimensions and tolerances of the apparatus as given above. Determine the acceptable performance of the dissolution test assembly periodically. The suitability for the individual apparatus is demonstrated by the Performance Verification Test.

Performance Verification Test, Apparatus 1 and 2—Test USP Prednisone Tablets RS according to the operating conditions specified. 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.

Ph. Eur. 2.9.3

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Apparatus suitability. The determination of suitability of a test assembly to

perform dissolution testing must include conformance to the dimensions

and tolerances of the apparatus as given above.


periodically.

Apparatus suitability— The determination of suitability of a test assembly

to perform dissolution testing must include conformance to the dimensions

and tolerances of the apparatus as given above.


periodically.

J.P. 6.10


USP has always regarded mechanical calibration as a pre-requisite for the Apparatus Suitability Test

• not an alternative as implied by FDA

The new approach with the statistical evaluation of the Performance Verification Test has shown that much dissolution apparatus has been inadequately controlled in the past.

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Apparatus Qualification USP Performance Verification Test

PVT provides experimental proof that the dissolution test assembly is suitable for dissolution testing

• Apparatus 1 and Apparatus 2

– Prednisone RS tablets

• Apparatus 3

– Chlorpheniramine Maleate Extended Release RS tablets

(requirement withdrawn from end of February)

• Apparatus 4

– currently not available (no monographs use App. 4)

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USP Performance Verification Test

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Apparatus Qualification The USP ISO-based PVT Test

PVT now designed as a Single-Stage testing approach i.e. two consecutive runs using all positions of an instrument

• Collect the results as % prednisone dissolved at 30 min of two consecutive runs on the dissolution assembly

• Calculate the overall geometric mean (GM) and the mean of the variances of both runs

• Compare the obtained results with the applicable acceptance limits

PVT passes if both values meet acceptance criteria

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Optional Two-Stage testing

Possibility of stopping after the first step

Step 1:

• Perform one test with all positions of the dissolution assembly and

calculate % prednisone dissolved at 30 min

• Determine the geometric mean (GM) and percent coefficient of variation

(%CV)

• Compare the GM and %CV to the acceptance criteria.

If both values meet acceptance criteria, test finished

• If not, go to Step 2

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Apparatus Qualification Optional Two-Stage testing

Step 2:

• Perform an additional test and record the percent dissolved value

• Determine the geometric mean (GM) and percent coefficient of variation

(%CV) for this second test

• Compute a pooled (from Step 1 and 2) GM and the mean of the variances

of both runs

• Compare to the acceptance criteria.

If both values meet acceptance criteria, PVT passed

If GM and/or %CV do not meet the acceptance criteria the test has failed and further work is needed.

USP does not offer guidance as to which approach to use.

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Acceptance Limits for the PVT with Prednisone tablets:

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Apparatus Qualification From experience...

The most common causes of failure are:

• procedural

– improper degassing

– inaccurate dispensing

– resident sampling probes and/or thermometers

– sampling technique

• equipment (this is the purpose of the test)

– poor quality vessels

– apparatus alignment

– vibrations

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Causes of failure

The most common cause of PVT failures due to the procedure is degassing.

The recommended degassing technique is simple and efficient

• Heat media to 41-45°C

• Vacuum filter (<100mBar)

through 0.45µm filter

• Continue to pull vacuum for

5 additional minutes.

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Apparatus Qualification De-aerated vs. Non-de-aerated Medium



The Prednisone Test

Cone formation is an essential and critical characteristic of the test

• dissolution occurs at the surface of the cone

• saturated solution in the centre

• any disturbance of the cone changes the results

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Apparatus Qualification Dispensing

The medium should be used immediately after degassing

• temperature should not fall below 37°C

• dispense gravimetrically

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Sampling

Samples should be taken at the correct time from the correct position

• 30 minutes ±2% (±36 seconds)

• mid-point between surface of

medium and top of paddle or basket, at least 1cm from vessel wall

• take a large sample (20-30ml)

• filter immediately

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Apparatus Qualification Vessels

The most common cause of PVT failures due to the apparatus is the vessels.

Vessels usually made by traditional glass-blowing techniques

• Each vessel is more or less unique since they are essentially hand-made,

individual flaws add to hydrodynamic variability

• Modern manufacture of vessels is better controlled and individual vessels

may be certified

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Vessels

The compendial specification is not well-defined:

… made of glass or other inert, transparent material

… cylindrical with a hemispherical bottom

… sides are flanged at the top

… for a nominal capacity of 1 liter, the height is 160mm to 210mmand its inside diameter is 98mm to 106mm

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Apparatus Qualification Vessels

Even with perfect manufacture, “within specification” differences are significant

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Surface +17% Area

Volume of -10%Cylinder

Volume of +27%Hemisphere

98mm ID for 900ml 106mm ID



Vessels

Vessel Dimensions – Inner Diameter

• Sets of 6 vessels from 10 different manufacturers

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99

100

101

102

103

104

105

0 2 4 6 8 10 12

Source

Avera

ge In

ner

Dia

mete

r (m

m)

DISSOLUTION MECHANICAL QUALIFICATION STANDARDS

Dissolution Mechanical Qualification Standard Requirements

General MQ Requirements:

•Check vessel, basket and paddle dimensions on receipt

•Perform maintenance procedures recommended by manufacturer

•Perform mechanical qualification:

• After apparatus is moved

• After apparatus is repaired

• After 6-months from previous calibration

•Perform “Operational Checks” at each time of use


Check Dimensions Upon Receipt:

Paddle, Basket/Shaft, and Vessel apparatus components must be verified that they conform with the harmonized standard USP <711> Dissolution (USP, JP, EP)

• Individual measurements for each dimension of each component must be documented

• Certificates of Conformance (COC) may be obtained from Agilent to document conformance.

• Otherwise, measurements must be documented by the end user.


Perform Maintenance Procedures:

•Lubricate moving parts

•Check belt for wear and proper

tension

•Check power cords and cable

connections for wear

•Check alignment of belt, pulleys and spindle housing

•Clean water bath, replace tubing if necessary and use algaecide

approved for heater/circulators


Mechanical Qualification Requirements:

•Shaft Wobble

•Paddle/Basket Shaft Verticality

•Basket Wobble

•Vessel Centering

•Vessel Verticality

•Paddle/Basket Depth

•Rotational Speed




Operational Checks (document each time of use):

•Basket/shaft examination

•Paddle examination

•Vessel examination

•Vessel Temperature

•Vibration


Basket and Basket Shaft, must be free from:

• Defects

• Rusting

• Corrosion

• Loose wires

• Clogged mesh openings

• Dented sides or bottom

• Knicks, dents or misshapen appearance

• O-ring are not compliant; three clips required


Paddle Examination, must be free from:

• Defects

• Rusting

• Corrosion

• Peeling or loose coating

• Knicks, dents or misshapen appearance


Vessel Examination, must be free from:

• Scratches

• Cracks

• Pits

• Residue

• Surface irregularities

TOOLS FOR MECHANICAL QUALIFICATION


Height:

Wobble:

282




Temperature Level

…The Agilent 280-DSFast – less than 35 minutes

Simple – only two devices

Easy to Use - software prompts every measurement

Data Capture - standardized reporting, historical tracking and trending by serial number (instrument, vessel, paddle, basket, etc)

21 CFR Part 11 Compliant -Certificates of Conformance - storage and tracking

Control - Agilent dissolution apparatus during measurement

280-DS Mechanical Qualification SystemComponents

Vessel Module

Instrument Module

Temperature ProbePersonal Computer

(Optionally Supplied)

Software

280-DS Mechanical Qualification SystemVessel Module

Vessel Module (VM) once placed in the vessel will measure:

Spindle Speed (RPM)

Shaft Wobble

Basket Wobble

Shaft Verticality

Vessel Verticality

Vessel/Shaft Centering

(upper and lower)

Basket/Paddle height

280-DS Mechanical Qualification SystemVessel Module

280-DS Mechanical Qualification SystemInstrument Module (IM)

The Instrument Module (IM) is placed on the vessel plate to measure:

Vessel Plate Level

Vibration

Temperature



280-DS Mechanical Qualification SystemHow it Works

280-DS Mechanical Qualification SystemA Protected Investment

Patent Pending

The Advantage for MQ

Time Savings (35-min vs 2-days with PVT)

Ease of use allows shorter qualification intervals

Data that helps you pinpoint possible problems

Now have the ability to trend parameter

variation over time

No guesswork associated with manual and analog gauges

No standards or tablets to purchase

Provides instant failure investigation

information

Reports exact information required by Enhanced MQ Standards

PVT OR MQWHAT IS RIGHT FOR YOUR LABORATORY?

PVT or MQWhat Is Right For Your Laboratory?

PVT Advantages:

•Holistic test with actual controlled tablets

•Conforms closely to USP <1058> Analytical Instrument Qualification, requirement for Performance Qualification

•New USP Acceptance Criteria provides for geometric mean and variability

•Detects issues with Vessel Quality

•Detects environmental issues

•PhRMA studies showed PVT should be maintained until a definitive vibration specification is developed


PVT Advantages:

When a PVT failure is observed it is a situation that requires investigation.

The PVT does not tell us exactly what

is wrong but if we proceed without

resolution, the consequences may be catastrophic!




PVT Disadvantages:

•Time – takes days to perform

•Expense:

• Cost of USP prednisone tablets

• Cost of USP reference standards

• Analyst’s time away from production

•FDA claims of USP tablet variability


MQ Advantages:

•Simplicity

•Speed – generally a few hours

•Performed more often

•Tighter specifications and tolerances will lead to less

mechanical variability


MQ Disadvantages:

•Misinterpretation of Certificates of Conformance for components – These are not to be confused with manufacturing conformance certificates which state parts are manufactured according to USP specifications

•Subjectivity of Component Examination at time of use

•Does not account for:

• Vessel Quality

• Vibration

• Deaeration

• Other Laboratory Environment Issues


Primary reason customers in transition to MQ:

•Anticipated savings for time and money

•Anticipated reduction in frequency and intensity of investigations

Common misconceptions about transition from PVT to MQ:

•Perceived variability in USP Prednisone PVT – cited by FDA

•Requirement for individual component “Certificates of Conformance” is not necessary

•MQ will reduce apparatus variability, however, vessel quality and effects of vibration will not be challenged


Current Situation with PVT vs EMC

PVT is only a USP requirement

• Conformance to USP is only required for products with USP monographs

marketed in the USA

• USP General Notices 6.30 allows alternative validated procedures

• Federal law states that FDA should enforce USP requirements

• FDA inspectors have issued 483s to companies who have just abandoned

PVT with no documented justification of EMC as an alternative procedure

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Current Situation with PVT vs EMC

There has recently been debate around the industry about the necessity of PVT using the Prednisone Tablets.

FDA and FIP have indicated that they do not consider PVT essential if there is an adequate enhanced mechanical calibration regime.

PVT is required by the USP but is only suggested by other pharmacopœias.

• USP states that enhanced mechanical calibration is an essential pre-requisite to PVT.

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CONCEPTS OF DISSOLUTION AUTOMATION

The Concept of Automation

•Where a sufficiently large number of similar units are to be subjected routinely to the same type of examination, automated methods of analysis may be far more efficient and precise than manual methods.

•USP<16> Automated Methods

The Concept of Dissolution Automation

•Dissolution consists of a series of unit operations.

•Traditionally, these unit operations, when performed manually, are quite technique-dependant which may cause

inconsistencies in test results.


Dissolution unit operations may be manual or automatic.

• Setup

• The dissolution test

• Sampling

• Analysis and data reduction

• Cleanup and changeover

Dissolution - Unit Operations

Setup

• Media preparation

– Manual intervention

– Degassing

– Preheating

• Media dispensing

– Clean & purge

– Volumetric

– Gravimetric

• Tablets

• Capsule weights - retrieval

• Weighing of dosage units

• Protection

– Light

– Humidity

– Temperature




The Dissolution Test

• USP apparatus maintained/validated

• Temperature monitoring

• Introduction of dosage units per USP

• Sequential or simultaneous

• Time start

• Starting rotation

• Evaporation control


Sampling and sample handling

• Rinse and purge of sample lines

• Filters/filter changer

– Appropriate/compatible

– Backflush

• Sample cannula resident or non-resident

• Sample transfer - adsorption issues?

• Number of sampling intervals

• Various time intervals required

• Sample volume - accuracy

• Replacement media - accuracy

• Sample collection in capped HPLC vials or tubes


Analysis and data reduction

• Sample integrity preserved

• System suitability

• Sample changer/autosampler

• Calculations

• Statistical manipulation

• Graphics

• Storage/archiving


Cleanup and changeover

• Stop the test

• Removal of test media

• Clean in place vs. manual clean

• Rinse all product contact equipment

• Rinse sample lines

• Prepare for next run


•The entire dissolution test is a series of unit operations, any one of which may be manual or automatic.

•When planning automation survey the test as a whole system

and decide which of the unit operations should be automated.

•Automation and its cost effectiveness must be analyzed by comparing the advantages along with the disadvantages.

Advantages and Limitations of Automation




Advantages of Automated Dissolution

Accuracy

Precision

Time saving “buying time”

Throughput – cycle time reduction

Documentation of events

Data capture


Accuracy

• Maintained when hydrodynamics preserved

• Exact sampling position

• Precise timing

• Volume control including replacement media


Precision

• Sampling mechanics reproducible from analyst to analyst

• Enhanced reproducibility over manual sampling

• Universal filtering techniques

• Improved reliability


Time Savings and Throughput

• Allows personnel to perform other analytical tasks

• Allows additional dissolution runs to be outside the normal work span

• May eliminate overtime or shifts required for extended release products


Advantages must be compared to the limitations to determine the overall cost effectiveness and efficiency of automation in the dissolution environment.

Limitations of Dissolution Automation

Limitations of Automated Dissolution

Personnel

Synchronizing & sequential time demands

Evaporation

Altered hydrodynamics

Sample archiving

Validation

21 CFR Part 11




Personnel

• High cost staff support

• Higher level of training

• Maintenance personnel

• Programmers

• Validation

• IS and LIMS

• Quality assurance


Synchronizing & sequential time demands

• To withdraw and transfer a sample and be ready for the next time point

• Simultaneous equals more time points

• Sequential requires greater time intervals

• Time to complete one cycle of sampling


Staggering starts

• Robotic systems - no problem

• Tablet droppers - run/start unattended

• Manual start - simultaneous

• Manual start - sequential, triggered by audible signal, burdensome with 12 to 24 starts with 1 to 2 minute intervals


Evaporation

• Vessel covers may require more entry ports

– Dosing

– Sampling

– Cleanup and changeover

• Sample tubes or HPLC vials should contain a septum

• Temperature control?


Altered hydrodynamics

• Resident sampling probes alter hydrodynamics

• USP 26 now requires validation to show that there is no change in the

agitation characteristics of the test.

• Validation - not just the last time point.

• Validation consists of profiling used for submission or process changes.

Profile Comparison of Resident Vs. Non-resident Probes




Validation

• Unit operations - minimal

• Automation (single run) - moderate

• Total automation (multiple run) - exponential


Documentation must prove that the integrity of the automated dissolution method is maintained

• Gravimetric vs. volumetric

• Dilutions

• Resident sampling apparatus

• Additional valves


Documentation

• Validation Report

• Metrology Log

• Calibration

• PM Log

• Sample Log

• SOP’s

• Training


Select Automation Wisely

• Sensitivity to modifications may be formulation related,

qualification and validation of automated dissolution equipment

and testing has to be established on a case-by-case basis

• That “necessary feature” for an automated system may

compromise its usability this leads to the versatility paradox…

The Versatility Paradox

• Apparatus 1 & 2

• Multiple apparatus

• Multi media

• HPLC & UV-VIS

• Tablets & capsules

• Filtering issues

• Apparatus modifications

• Single/multi flow cell

Dissolution Automation, The Past

To look ahead we must look where we have been...



Dissolution Automation

Automation of dissolution apparatus considered in the early 1960s

• Automatic sampling

• Automatic media dispensing

• Automatic sampling for UV & fluorimeters

Early Dissolution Automation

Simple Automation of Sample Collection

A fraction collector such as the 8000 autosampler with peristaltic

pump supports complete and

unattended operation

The 8000 samples directly into

tubes or sealed HPLC vials

Ten time points may be collected per tray with up to twenty time

points collected with a tray

exchange

333

Advanced Automation of Sample Collection

Alternatively, a syringe pump and filter changer provide confident,

unattended acquisition of samples

normally required for HPLC analysis

As more dissolution methods move

towards HPLC analysis, the filter changer automatically integrates

filtration down to 0.45µm

Present Methods of Automated Dissolution Analysis

UV-Visible spectroscopy

UV-Visible multi-component analysis

HPLC

UV-Visible Spectroscopy

Pros

• Fast

• Reliable

• Robust

• Cost

• Validation



UV-Visible Spectroscopy

Cons

• Traditionally single component

• Timing demands

• Staggering starts

• Excipient interference

• Dilution

• Cell pathlength

Automated UV/Visible Multicomponent Analysis

Pros

• Speed

• Increased number of time points

• Uses multiple linear regression analysis

• Time and cost benefits

• Adaptable to fiber optics analysis

Automated UV/Visible Multicomponent Analysis

Cons

• Validation

• Excipients containing chromophores

• Excipients containing titanium dioxide cause light scattering

• Is total separation achieved?

• Actual vs. Theoretical results

Multicell online UV dissolution provides complete dissolution testing with sample analysis

Dedicated flow cells eliminate media cross contamination

Multicell online UV may be configured with two independently operating dissolution apparatus or, a single apparatus with sample archiving

Multicell Online UV Integration with Sample Archiving

Fiber-Optic UV-Visible Spectroscopy

• Brings spectroscopy to the vessel

• Eliminates sampling and fluidics

• Eliminates cross contamination

• Provides more data-points

• Hydrodynamics?

• Light scattering?

• Drying of product on optical surfaces

Fiber-Optic Online UV Dissolution

Online Fiber-Optic analysis allows faster reading through in situmeasurement. Between measurements, probes are retracted just below

the surface of the media

Dissolution data is provided in real time through the integration of the

fiber-optic multiplexer contained in the Cary spectrophotometer



Automated HPLC Analysis of Dissolution Samples

• Chromatographic separation of multiple components

• Generally, automated unit operations

• Sampling

• Sample processing

• Autoinjection from HPLC

Online HPLC Integration

Achieve automatic sampling, filtration and

online LC analysis with the

integration of the Agilent 8020 autosampler/injector

station

Present Automation Challenges

•Designs to accommodate all aspects of a manual methods

•General complexity of automation projects

•Management support

•Customized hardware and software

•Long validation cycles

•Some systems productive, some not

Future Pathway for Automation

The corporate pharmaceutical environment

• Downsizing

• Productivity thrust

• Profitability thrust

• Industry consolidation, competitive pressure

• Accelerated drug discovery and development

• Increased regulatory issues

Future Pathway for Automation

The managerial pharmaceutical environment

• Affordability

• “Just-in-Time” analysis

• FDA compliance

• Method transferability

• Enhanced efficiency of workforce

• Utilization of lab space

Future Methods of Automated Analysis

•Our means to automate will eventually include the dissolution analysis of novel dosage forms which historically have been targets for automation.

•Along with the endless varieties of new dosage forms come the possibilities for new apparatus and adaptations of existing apparatus.



Future Challenges for Automation of Dissolution

•Designing and implementing new automated dissolution systems presents a complex task.

•Traditionally, automated systems are developed for targeted

applications.

•System hardware and software is generally configured with a particular application in mind.


The “Center Cut” concept

• Achieve core functionality with given applications.

• Accept that some manual intervention may be required.

• Accept that some methods are outliers.

• Accept that the easier the method, the easier it is to automate.


•The ease with which an existing system’s functionality can be extended depends upon:

• Ability of a dissolution apparatus to be incorporated into an automated application.

• Ability of the application software to adapt new hardware configurations.

•What new concepts will emerge in the next century?


1. Network control of dissolution systems

2. Remote control laboratory operations from home

3. Video operation and start

4. Remote data processing and report generation

5. Feedback sensors

6. Video recording


Will vibration concerns reemerge with the presence of analytical equipment in close proximity to the dissolution apparatus?

• Filter changers

• Transfer pumps

• Valves

• Computers

• Analytical systems


The implementation of automation in dissolution must not affect the basic principles of the dissolution test.

• Hydrodynamics

• Vibration

• Calibration

• Environment

• Sample integrity



Summary

•There are two components of the dissolution test

• The dissolution apparatus

• The analytical finish

•The dissolution apparatus cannot be compromised due to design limitations in automated sampling or to gain in speed and simplicity.

Summary

•Increase productivity

•Reduce analytical costs

•Shorten analytical cycle times

•Improve quality of data due to mechanical repeatability

•Increase reliability...

DISSOLUTION IN THE REGULATORY ENVIRONMENT

Pharmacopœias

• Harmonised through ICH:

– USP <711> Dissolution

– Ph.Eur. 2.9.3 Dissolution Test for Solid Dosage Forms

– JP General Tests - 6.10 Dissolution Test

Apparatus 1 – Basket

Apparatus 2 – Paddle

Apparatus 3 – Reciprocating Cylinder (not JP)

Apparatus 4 – Flow-Through Cell (JP App. 3)

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Regulatory Guidance

Pharmacopœias

USP <724> Drug Release

Apparatus 5 – Paddle over Disk

Apparatus 6 – Rotating Cylinder

Apparatus 7 – Reciprocating Holder

Ph.Eur. 2.9.4 Dissolution Test for Transdermal Patches

Disk Assembly Method (c.f. USP 5)

Extraction Cell Method

Rotating Cylinder Method (c.f. USP 6)

J.P. does not give any methods for transdermals.

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Regulatory Guidance Pharmacopœias

Ph.Eur. also provides other specific dissolution tests:

– 2.9.25 Dissolution Test for Medicated Chewing Gums

– 2.9.42 Dissolution Test for Lipophilic Solid Dosage Forms

USP is developing new General Chapters:

– <1094> Liquid-filled Capsules – Dissolution Testing and Related Quality Attributes – PF38(1) [Jan–Feb 2012]

– <1724> Semisolid Drug Products – Performance Tests – PF37(5) [May 2012]

360 / 17

Regulatory Guidance



Pharmacopœias

USP <1092> The Dissolution Procedure: Development and Validation

Ph.Eur. 2.9.3 provides guidance on use of automated systems

Ph.Eur. 5.17.1 Recommendations for Dissolution Testing

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Regulatory Guidance Pharmacopœias

Many other chapters involved in dissolution testing, e.g.

USP <16> “Automated Methods of Analysis”

USP <21> “Thermometers”

USP <31> “Volumetric Apparatus”

USP <41> “Weights and Balances”

USP <621> “Chromatography (HPLC)”

USP <701> “Disintegration”

USP <791> “pH”

USP <851> “Spectrophotometry and Light-Scattering”

USP <1051> “Cleaning Glass Apparatus”

USP <1087> “Intrinsic Dissolution”

USP <1088> “In Vitro and In Vivo Evaluation of Dosage Forms”

USP <1090> “In Vivo Bioequivalence Guidelines”

USP <1121> “Nomenclature”

USP <1151> “Pharmaceutical Dosage Forms”

USP <1225> “Validation of Compendial Procedures”

USP <1226> “Verification of Compendial Procedures”

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Regulatory Guidance

FDA Guidance Documents

www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances

IR Dissolution Guidance - Dissolution Testing of Immediate Release Solid Oral Dosage Forms; 1997

IVIVC Guidance - Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations; 1997

BCS Guidance - Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BiopharmaceuticsClassification System; 2000

General BA/BE Guidance - Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations; 2003

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Regulatory Guidance FDA Guidance Documents

SUPAC-IR Guidance - SUPAC-IR: Immediate Release Solid Oral Dosage Forms Scale-Up and Post Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution and In Vivo Bioequivalence Documentation; 1995

SUPAC-MR Guidance - SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation; 1997

SUPAC-SS Guidance - SUPAC-SS: Nonsterile Semisolid Dosage Forms Scale-Up and Post Approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation; 1997

Dissolution tests database: www.accessdata.fda.gov/scripts/cder/dissolution

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Regulatory Guidance

REGULATORY AUDIT OBSERVATIONS

Common FDA 483 Observation for Dissolution

•Form 483s are commonly issued to companies as written observations or deviations from Current Good Manufacturing Practices (CGMP) as outlined in Chapter 21 of the Code of Federal Regulations or a deviation from written standard

operating procedures (SOPs).



FDA 483 Observations

•The robotic dissolution apparatus used in the analysis of the product was not validated prior to use.

•An unvalidated computer program was used to calculate dissolution sample results.


•The temperature of the dissolution media was at 36 °C (below specification).

•The analyst was measuring the temperature of the dissolution bath while holding the thermometer near the middle of the mercury column. This practice could cause erroneously high temperature readings due to body heat.


•There was no procedure for removing dissolved gases

from the dissolution media as required in the USP.

•Deaeration of dissolution media was performed by

pumping nitrogen through the media for five minutes. After

the deaeration process, bubbles were observed in the

media. There is no data to ensure that five minutes is

adequate to deaerate the media.


•Dissolution start and pull times were not recorded in the analysts’ notebook.

•Calibrated timing devices were not used when performing dissolution testing.

•The actual causes of dissolution problems have not been identified and the firm has not conducted a thorough investigation. No corrective measures have been taken to ensure stability of the product throughout its shelf-life.


•Non-validity of failing test results is not explained. Failing results are not recorded in laboratory notebooks.

•Dissolution apparatus used after its “calibration due” date without justification.

•The new dissolution bath was not calibrated prior to use.


•Dissolution times recorded on a scrap piece of paper which “were to be transferred to the analysts’ notebook.”

•Centering was not checked with a centering device. One of the shafts was clearly off-center.

•The dissolution bath was visibly shaken by a shaker apparatus on the same lab bench.




•A dissolution bath was visibly shaken by a disturbance on the other side of the wall.

•The dissolution apparatus paddles were peeling.

•After the dissolution run was started, the timer was not turned

on for approximately three minutes.


•All six tablets for a dissolution test were dropped in about one minute, but were withdrawn over a period of two minutes. The last two samples were taken beyond the time limit specified for the dissolution test.


•Sustained released dissolution samples which required change from SGF for the 1st hour time point to SIF for the 2nd hour time point were observed to take six minutes for the changeover and ten minutes to restart. The first vessels were in SIF for more

than one hour and the last vessels were in SGF for more than one hour.


•Start and stop times for dissolution tests are not documented to ensure that aliquots are taken within specified time limits.

•Media change at the one hour time point involved changing the dissolution vessels. The numbers marked on the vessels indicated that the vessels were not replaced in the same order.


•After the first time point sample was removed, the paddle blades were wiped, resulting in the removal of some material from the paddles.

•After withdrawal of the sample for the first time point, the excess sample in the syringe was discharged back into the vessel causing agitation of the remaining tablet fragments.


•The filters used for filtering dissolution samples have not been checked for adsorptive loss of drug.

•The potential for cross-contamination of samples was incurred since the same filter was used to filter all samples within a dissolution run.




•The type of filter to be used in sample preparation was not specified in the test procedure.

•The test procedure does not state that the first 5 mL of dissolution sample filtrate should be discarded. This practice leads to potential interference in the UV spectra.


•Dissolution samples for sustained release products are often held until all time points are pulled prior to analysis. Samples are sometimes held for more than a day, and there is no verification of the stability of sample solutions.


•Tests performed on the UV spectrophotometer were not done at the UV maximum as specified in the USP, But at one pre-set wavelength without a scan.

•There was no correction in the dissolution calculation for volume removed in sampling at previous time points.


•Several test samples showed dissolution results that were

significantly lower for the first tablet analyzed. The failure

investigation did not include a review of the analyst’s

procedures for setting up the equipment and did not

include calibration of the apparatus using USP calibration

tablets after the failures were noted.

THE DISSOLUTION DISCUSSION GROUP (DDG)

DDGwww.dissolution.com

• Worldwide users group for dissolution chemists

• Free, on-line, interactive bulletin board

• Provides annual and regional meetings around the world

• Place for practical answers to everyday questions on

dissolution



DDG Mission

The mission of the Dissolution Discussion Group (DDG) is to provide an independent forum to freely discuss the practical issues which challenge the pharmaceutical industry and affect the day-to-day task of developing, validating, and performing

dissolution tests and related chemical analyses.

Sources of Information

FDAwww.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances

USPwww.usp.orgwww.usppf.com

Controlled Release Societywww.controlledreleasesociety.orgwww.ukicrs.org

Dissolution Technologieswww.dissolutiontech.com

Thank you!

Terry [email protected]

TESTING OF SEMI-SOLIDS AND OTHER NON-ORAL … OF SEMI-SOLIDS AND OTHER NON-ORAL DOSAGE FORMS...

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