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The Fundamentals of Dissolution

1 2015 All rights reserved

Agilent Dissolution Seminar Series

Welcome

Agilent Dissolution

Seminar Series

Terry Way BPharm MAPS

Dissolution Science Consultant

Agilent Technologies

2



Program Outline

1. The Dissolution Technique

2. Dissolution Automation - Sampling

3. Dissolution Automation - Direct Measurements

4. Dissolution Apparatus Qualification

5. Fundamental Principles of Drug Release

6. Current Trends in Dissolution Testing

3

AN OVERVIEW OF THE

DISSOLUTION TECHNIQUE

4



Introduction

The dissolution test has evolved to become a definitive tool used to characterize the performance characteristics of solid oral dosage forms.

As dosage forms have become more unique over the last fifty years, the dissolution apparatus has required continuous improvement and modification to provide suitable conditions for performance testing of a wide variety of products.

However, probably 99% of dissolution testing is performedon traditional tablets and capsules.

5

What do we test?

Dissolution is not just about orally ingested products such as tablets and capsules.

We also test :suspensions and powders coated beads and granulesointments, creams, gelstransdermal patches implants, stentsmedicated contact lenseswound care productsbone cementpowders for inhalationchewing gums, etc.

6



Dissolution - DefinitionGoogle search:

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7

Dissolution - Definition

Academic definition:

Dissolution is the process by which a solid substance enters into a

solvent to form a solution.

Pharmaceutical definition:

Dissolution is a test used throughout the life cycle of a pharmaceutical

product to evaluate the rate of release of a drug substance from the

dosage form.

8

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An Overview of Dissolution

Generally, active pharmaceutical

ingredients (API) are mixed with

inactive excipient materials and

pressed into a tablet or filled into

a capsule.

9


In the body, a pharmaceutical active ingredient must be in solution before it

can be absorbed by the blood and ultimately carried to the receptor site to

render a therapeutic effect.

Dissolution is the process by which that active ingredient enters into a

solvent to yield a solution.

10




Solid oral dosage forms typically

begin to disintegrate and dissolve in

the stomach.

The resulting solution passes into the

small intestine where dissolution

continues.

Surface areas:

Stomach ~0.5m2

Small Intestine ~200m2

11


The dissolved active ingredient is

absorbed into the blood stream

through the walls of the small

intestine.

The blood carries the active

ingredient to the site of therapeutic

effect.

12




Basically, the dissolution test mimics the first few stages of this process

under very controlled laboratory conditions (in vitro).

For immediate release products:

Wetting in the stomach

Disintegration in the stomach

Deaggregation in the stomach

Dissolution in the stomach and intestine

Permeation through the intestinal wall

Absorption into the blood stream

Transit to the therapeutic site (via liver)

Decomposition and elimination

13


Dissolution is an important tool for characterizing the biopharmaceutical

properties of a pharmaceutical product at different stages throughout its life

cycle.

Product Development

API characterisation, Formulation evaluation, Stability testing

Bioavailability / Bioequivalence

In Vitro / In Vivo Relationships

Quality Control

Pass / Fail product release

Scale-Up and Post-Approval Changes

Raw materials, Formulation, Process, Manufacturing site

14




Dissolution is one the three primary tests used to release a finished drug

product:

Assay determines the overall potency of the batch and ensures the

accuracy of the finished drug product.

Dose Uniformity determines the consistency among the individual

dosage units and ensures the precision of the manufacturing process.

Dissolution ensures that the performance of the finished drug product is

consistent with the release rates of the API as determined in bioavailability

studies during the clinical trials.

15


Dissolution assesses the performance of drug products

To be effective, the test should be:

Predictive

Comparative

Discriminatory

Reproducible

16



COMPENDIAL

DISSOLUTION TESTING

17

Compendial Requirements

The requirements for dissolution testing were harmonised through the ICH

Q4B Guidelines in 2006:

The pharmacopial texts are based on the original USP General Chapters

and but, despite harmonisation there are still various regional differences.

18/112



Apparatus

A general description of the assembly which is common to both Apparatus 1

and 2 is included in the description for Apparatus 1:

Vessels

glass or other inert, transparent material

cylindrical with hemispherical bottom

partially immersed in a water bath or heated by a heating jacket

1L, 2L or 4L nominal capacity

a fitted cover may be used to retard evaporation

Motor with speed-regulating device

An apparatus that permits observation of the specimen and stirring element

during the test is preferable.

19/112

Dissolution Vessels

Vessels

Apparatus 1 and 2 typically use a 1000mL hemispheric shaped vessel made

of glass or suitably inert material.

Media volume should be between 500 and 1000mL with 900mL used

historically.

The 1L vessel has dimensions of 98 -106mm i.d. and 160 - 210mm in height.

20



Large volume vessels have been required for testing APIs with low solubility and also larger veterinary formulations

21

2-Liter vessel has dimensions of 98-106mm id and 280-300mm in height.

4-Liter vessel has dimensions of 145-155mm id and 280-300mm in height.

Dissolution Vessels

Apparatus 1 - Baskets

Used for testing tablets and capsules where disintegrated granules or beads

would pass through the 10# of the disintegration test but would be retained

on the 40# of the dissolution basket - dissolution progressing inside the

basket.

The original acceptance criteria required

75% dissolution within a specified period.

Beyond this time, particles could be small

enough to pass through the basket mesh

and fall to the bottom of the vessel.

22/112



Apparatus 1 - Baskets

More commonly used today for non-disintegrating products.

The basket mesh must remain clear throughout the test but is prone to

occlusion by bubbles and undissolved materials such as gelatinous or waxy

excipients which inhibit the flow of media through the basket.

Often used for testing enteric products where the pH must be changed.

23/112

24

USP Apparatus 1



USP Apparatus 1

Baskets

The historical USP 40 mesh dissolution basket has 40 openings per linear

inch. Openings are equal in both directions producing a standard square

weave. USP specifies that 40 mesh (40 x 40) screen be manufactured with

wire having a nominal 0.25mm diameter.

Harmonized basket specifications are now referred to as 0.22-0.31 mm wire

diameter with wire openings of 0.36-0.44 mm.

25

USP vs. JP Basket

USP 40-mesh Basket JP 36-mesh Basket

Microscopic comparison in identical scale show the JP basket with

larger wire and fewer openings

Test results under identical conditions reveal lower results for

Prednisone calibrator tablets tested in the JP basket

26



USP Apparatus 1

Baskets

Dissolution baskets are fragile and require proper handling and care.

Attachment or removal from the basket shaft requires holding the upper rim.

When not in use, store in a protective case.

Carefully inspect for damage or excessive wear since defective or misshaped

baskets will affect test results.

A basket with gold coating 2.5 m thick (0.0001 inch) is an allowable

variation of the standard 40-mesh basket.

27

28



USP Apparatus 1

Starting a dissolution test with baskets:

The product is placed in a dry basket and attached to the shaft.

The shaft is lowered into the vessel to the correct height.

Then rotation is started.

Dissolution should occur within the basket.

29

Apparatus 2 - Paddles

Baskets are unsuitable for testing products that release small

particles e.g. tablets made by direct compression or powder-

filled capsules. Hence, paddles were introduced as an

alternative test.

Also used for testing powders and suspensions.

The dissolution process should occur throughout the

dissolution medium with good mixing provided by adequate

speed - usually 50-75rpm.

pH change can be achieved by addition of buffer concentrates.

With slower speeds (and for some hydrophobic products)

coning is a problem:

30/112



31

USP Apparatus 2

USP Apparatus 2

The paddle apparatus consists of a metallic or suitably inert, rigid blade and shaft comprising a single entity.

A suitable two-part detachable design may be used provided the assembly remains firmly engaged during the test.

The paddle blade and shaft may be coated with a suitable inert material.

32



USP Apparatus 2

Starting a dissolution test with paddles:

The dosage unit must be allowed to settle to the bottom of the vessel prior to

rotating the paddle.

Unfortunately some types of dosage forms may float to the surface,

especially capsules.

33

Apparatus 2 - Paddles

Sinkers are often used to prevent products floating:

A small, loose piece of nonreactive material,

such as not more than a few turns of wire helix,

may be attached to dosage units that would otherwise

float. (USP Sinker)

An alternative sinker device :

(Japanese Sinker)

Other validated sinker

devices may be used.

34/112



Special Apparatus

Stationary Basket assembly

35/112

Basket for USP FelodipineExtended Release Tablets

Peak Vessel

The peak vessel reduces the

inherent inconsistencies in the

hydrodynamics of standard

hemispherical dissolution vessels.

An inverted peak is incorporated

into the bottom of the vessel,

displacing the unstirred zone,

preventing cone formation

Especially useful for bead

formulations.

Non-Compendial Dissolution Apparatus




Mini-Paddle Apparatus

Mini-Basket Apparatus

Based on USP Apparatus 1&2

100 or 200 mL vessels

Minimum volume ~30 ml

Tablets, Capsules

37


38



THE DISSOLUTION TEST

39

The Dissolution Environment

A very sturdy surface should be used to support the dissolution

apparatus.

The apparatus with full water bath and full vessels may weigh

up to 100 kg.

Benches should not impart vibration on the dissolution

apparatus.

Vibration has been shown to have a significant effect on dissolution rates.

Effects of both higher and lower dissolution rates have been seen.

40




Sources of Vibration

Fume hoods

Vacuum pumps

Construction

Mechanical shakers

Bench top centrifuges

Ultrasonic baths

Heater circulators or pumps

Worn parts or bearings

41


Lighting should be sufficient to perform visual observations.

Visual observations may offer clues to dissolution behavior.

Unusual observations should be documented

Considerations should be made for light sensitive products.

Local sinks and purified water sources for media prep and

disposal

Media handling and preparation equipment must not impart

vibration to the dissolution apparatus

42




Suitable media degassing equipment

Dedicated vessels and shafts (each apparatus)

Sufficient bench space for sample handling and analytical

measurement

43

The Dissolution Test

44

The analyst is responsible for verification of the physical

parameters.

- including that the equipment is clean.




Prepare dissolution media

and properly deaerate.

USP Method: Heat media to

41C, vacuum filter through

0.45m filter, continue to pull

vacuum for 5 additional

minutes.

45


Care must be taken in measuring the dissolution media to maintain the volumetric accuracy at 1%.

Volumetric accuracy is based on dissolution media measured at room temperature.

46




Alternatively, dissolution media may be weighed.

47


Measure and carefully

introduce dissolution

media to the vessel.

Have materials ready

for the test including

all sampling

equipment.

48



Allow media in each vessel to

reach 37 C 0.5 C and use

immediately.

49



Always handle dosage units with gloves (not cotton), forceps or tweezers which will not scratch or damage the surface of the dosage unit.

Examine the six dosage units. Do not use chipped, cracked or capped tablets

50




Option: Record the dosage

unit weights? Weight is for

information and investigation

purposes only.

Dosage units are to be

chosen at random and may

not be selected or discarded

based on weight.

51


Have analyst notebook or dissolution worksheets for recording information. All information must be recorded directly into analyst notebooks or official batch record worksheets.

52




Prepare to drop tablets. Lower

paddles to proper height, or

suspend baskets until ready to

begin the test.

Note: Apparatus 1 baskets

should be tested immediately

after placing the tablet inside

and clipping to the shaft.

Exposure to humidity can alter

test results.

53


Prepare calibrated timer.

Record times as tablets are dropped.

54




For the paddle apparatus, drop the dosage units into non-rotating medium.

They must settle to the bottom of the vessel before rotation of the shaft

begins. Then start rotation.

Visually inspect the dosage forms for air bubbles immediately after dropping.

For the basket apparatus, lower the baskets into non-rotating medium.

When at the correct height, immediately start rotation.

Record any unusual observations.

55


Most immediate release tablets disintegrate very rapidly and will reaggregate in the form of a cone on the bottom of the vessel.

As the active drug goes into solution during the dissolution process, some excipient material may be visible on the bottom of the vessel at the end of the test.

56




Withdraw sample at the proper time 2% (a 30 minute sample must be pulled within 36 seconds) and filter immediately.

Temperature must be taken a second time at least, generally after the last sample is pulled and before the shaft has stopped

57

The samples are withdrawn at a depth halfway between the top of the paddle (or basket) and the top of the medium and not less than 1cm from the wall of the vessel.


58




Filtration stops the dissolution process

and defines the end of the first phase of

the test which is basically a sample

preparation period executed under strictly

controlled physical parameters.

59


Once the sample has been filtered the second phase of the testing begins to

determine the analytical concentration of the sample.

Analytical concentration is generally determined through UV-Vis

spectroscopy or HPLC analysis. HPLC is primarily used for drug products

containing multiple active components or for stability testing.

The responses from the analytical finish will be used to calculate the amount

of sample released from the dosage form within the specific time interval.

60



USP Acceptance Table

Immediate Release Forms

Stage Number Tested Acceptance Criteria

S1 6 Each unit is Q + 5%.

S2 6 Average of 12 units (S1 + S2) is Q and no

unit is < Q 15%.

S3 12 Average of 24 units (S1 + S2 + S3) is Q,

not more than 2 units are < Q 15% and no

single unit is less than Q 25%.

If a sample fails either Stage S1 or S2, proceed to the next stage and test

the number of units indicated.

61

What is Q?

Q, as it relates to dissolution is commonly used in the USP for

immediate release and delayed release dosage forms.

The quantity of Q is the amount of dissolved active ingredient

specified in the individual monograph expressed as a

percentage of the labeled content.

62



CONCEPTS OF DISSOLUTION

AUTOMATION

63

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 Automated Methods

64



The Concept of Dissolution Automation

65


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.

66




The entire dissolution test is a series of unit operations, any

one of which may be manual or automatic:

Setup

The dissolution test

Sampling

Analysis and data reduction

Cleanup and changeover

67

Advantages and Limitations of Automation

Advantages of Automated Dissolution

Accuracy

Precision

Time saving buying time

Throughput cycle time reduction

Documentation of events

Data capture

68



Limitations of Dissolution Automation

Limitations of Automated Dissolution

Personnel

Synchronizing & sequential time demands

Evaporation

Altered hydrodynamics

Sample archiving

Validation

21 CFR Part 11

69

Future Challenges for Automation of Dissolution

Network control of dissolution systems

Video monitoring and recording

Remote data processing and report generation

Remote control of laboratory operations from home

70



Early Dissolution Automation

71

Simple Automation of Sample Collection

A fraction collector with peristaltic pump.

72



Multi-test Automation with Sample Collection

73

Advanced Automation of Sample Collection

New 850-DS Sampler



850-DS Dissolution Sampling StationOverview

Integrated syringe pump and fraction

collector

Streamlined design for ease of use and

reliable, repeatable operation

One sampler per dissolution apparatus

for ultimate flexibility

Built-in options and components for all

types of dissolution methods

Data export features ideal for paperless

environments

850-DS Dissolution Sampling StationOptions Printer, Filter Module

Standard:

Media replacement

Automated cleaning

Optional:

Built-in printer

Filter module (for dissolution

methods requiring 0.45m

filtration)



850-DS Dissolution Sampling StationOptions Sample Trays

Standard:

16 x 100 mm (up to 14 mL) 96 positions

Optional:

12 x 32 mm (2 mL vials) 96 positions

Agilent HPLC tray* 100 positions

Well plate (dual)* 192 positions

2 mL vials (dual)* 108 positions

*Requires needle block adjustment

850-DS Dissolution Sampling StationFeatures Color Touch Screen

Icons appear for key alerts Active tray format displayed prominently

Real-time display of method progress and remaining time points.



850-DS Dissolution Sampling StationFeatures Pump and Filtration

Easily disable filtration when not required

Improved sampling needle to prevent

clogging / coring of septa

Filter module incorporated to

save valuable bench space

Faster pump = more frequent time points

Stored volume calibration for repeatable precision

and accuracy

850-DS Dissolution Sampling StationFeatures Replacement Media and Cleaning

Automated cleaning and media replacement

is standard on all 850-DS sampling stations

An automated cleaning cycle can be added to the

end of any method to keep the system operating

properly and extend the life of internal components.



850-DS Dissolution Sampling StationFeatures User Levels and Data Export

Place instrument in specific Mode to restrict changes / access.

Three (3) data export options:

Printer, Serial Port, SD Card

Useful for method transfer (to another 850-DS) or LIMS integration.

Data export options:

SD Card or RS232

850-DS Dissolution Sampling StationSystem Configurations

708-DS Dissolution Apparatus

Cary 60 UV-Vis Spectrophotometer

8454 Diode-Array Spectrophotometer

850-DS Sampling Station (with Filter Module)

Bio-Dis Reciprocating Holder or

Apparatus 7 Reciprocating Cylinder

Dissolution Workstation Software



Automated Dissolution Analysis

UV-Visible Spectroscopy

HPLC

83


Pros

Fast

Reliable

Robust

Cost

Validation

84




Cons

Traditionally single component

Timing demands

Staggering starts

Excipient interference

Dilution

Cell pathlength

85

Fibre Optic Dissolution

86



Fibre-Optic Dissolution Testing

The use of fibre-optics for the determination of drugconcentrations during a dissolution test has

become a useful alternative to conventional

sampling techniques in research and development

as well as quality control environments.

First used in the late 1980s, several publicationsappeared in 1995 and full commercial systems

became available by 1999.

Fibre-Optic Dissolution Testing

The system allows continuous in-situ analysis ofdrug concentrations without the need for sample

withdrawal and preparation.

More comprehensive data can be obtained at a faster rate and the results can be interpreted

instantaneously.

Taking spectroscopy to the vessel: the flow-cell is immersed directly in the dissolution medium pump light not liquid



Advantages of Fibre Optics

No Sampling

Analysis in real time, igh speed collection

Increase in amount of collectable data

No Fluidics

pumps, valves

tubing

flow cells

No issues with liquid handling systems

carryover

leaking

adsorption / desorption

Procedure

Measure medium blanks

Measure Standards

Staggered start

Static or non-resident probes?

Optional post-run standards



Basics of Fibre-Optics

Quartz fibre transmits light by total internal reflection

Flexible (within limits)

Two fibres per probe

One coupled to source of mono-/poly-chromatic light

One coupled to detector

Direct Transmittance Transreflectance

Transreflectance Dip Probe



Dip Probe in-situ

Multiplexed Scanning Spectrophotometer



Multiplexed Scanning Spectrophotometer

One scanning spectrophotometer reading all fibres/vessels

Advantages

Only one detector/spectrometer to validate

Highest dynamic range

No stray light

Minimum solarization

Uses only low wavelengths when needed.

Use of a pulsed lamp allows light to be on only when measuring.

Disadvantages

Sequential data collection

Typical Dissolution



Considerations for Fibre-Optics

Excipient and bubble interference

Sticky residues

Cell path length

Optical fouling

Ease of blanking and standardization of each

probe

Filters (or lack thereof)

Validation

Significance of Probe Positioning



Problems

Interference in light path

Bubbles

degassing essential

No Filtration

Particles

Excipients

Typical Drug Spectrum

0

0.1

0.2

0.3

0.4

0.5

230 250 270 290 310 330 350 370 390

Wavelength (nm)

Ab

so

rban

ce

True drug absorption = measured - excipients

Baseline Correction



Baseline Correction

The spectrum of the interference should be flat to properly

perform the correction.

It only works as long as the total absorbance of the active, the

excipients, and the fibers is less than the maximum absorbance

limit of the spectrophotometer.

Active + Excipients + Fibers < Maximum Absorbance

0

0.5

1

1.5

2

2.5

3

AB

S (

AU

)

Active Excipients Fibers Total

Baseline Correction



Fibre-Optic Dissolution

Some products are suitable .. and some are not

Agilent Cary 60 with Fibre-Optics

Linear over 3.5 absorbance units.

Room light immune.

Split beam dual Si diode detectors.

High intensity Xenon flash lamp.

80 readings a second.

Scanning speed up to 24,000 nm/min




Very large dynamic working range, 0.0001 3.5 AU

Lamp only flashes when taking a reading giving it an extremely long life.

Very low baseline noise

Fast monochromotor, does not photobleach samples or fibres.


No warm up or stabilisation time for the lamp

Full UV-Vis 190 1100nm range.

Dedicated fibre optic dissolution software.

Full suite of stand-alone applications.

Monochromator

Sample

Detector

Xe Light

source

Entrance

slit

Exit slit

Fast Dispersion

element

Superior Optical Design.pdfSuperior Optical Design.pdf



Agilent 616 Fibre Optic Multiplexer

16 channel system for dual bath capability.

Purpose built for dissolution testing & Cary 60.

Each fibre is individually connected to the multiplexer.

Highest optical transmission of any system on the market allowing it to easily read in high turbidity solutions.

Agilent 616 Fibre Optic Multiplexer

High precision & high speed channel to channel movement.

Raw absorbances on a single channel @ 80 readings a second

Raw absorbances on multiple channels @ 6 readings every second

Full dissolution reports, graphs, and % dissolved data @ 6 readings every 30 seconds.



Agilent Fibre Optic Probes.

Specially designed for dissolution testing.

600 micron silica/silica fibers for optimised transmission down to 190 nm.

1, 2, 5, 10, 20 & 50 mm tips available.

Streamlined to minimize hydrodynamic influence.

Agilent UV Dissolution Software

110

A full suite of applications is included

such as:

Simple/Advanced Reads

Scan

Concentration

Scanning Kinetics

Validate

Align

UV Dissolution

Fibre Optic Multiplexer is fully compatible with all applications



UV Dissolution Hardware Configuration

111

Compatible equipment includes:

All Agilent dissolution apparatus

705, 708, 709, 7000, 7010, 7025 &

7030.

Non-Agilent dissolution apparatus

may also be used with a resident

probe setup.

UV Dissolution - Method Setup

112

Fully flexible timepoints

Actual times

(HHH:MM:SS) or intervals are

entered

No limit to number of stages




113

Tester Settings:

Apparatus type

Initial spin (RPM & time)

Spindle (RPM)

Infinity spin (RPM & time)

The Temperature page includes the

bath and vessel temperature

settings as well as tolerance

specifications


114

Standard Options:

Several online standard options

are available including: Pre &

Post Cycle Standard, Bridged

Mean, and Running Mean

Enhanced flexibility for

percentage and mg dissolved

calculations

Capsule Blank correction is also

available




115

Standard Options:

An option to measure a Check

Standard with a variable

tolerance field

Control Limits may be set up

to flag any out-of-tolerance

standards measured at any

time throughout the test


116

Analysis Options:

Analysis is possible using a single

wavelength, a scan range, or single

and scan

Scan analysis offers the choice

between mean or second derivative

Single and scan analysis allows you

to specify a wavelength for analysis,

and collect data at surrounding

wavelengths for possible

recalculation.




117

Analysis Options:

Full background Correction is

available using a single wavelength

or mean values of a scan range, to

correct for excipients in your solution.

UV Dissolution: Fiber Optic

118

The probe can be programmed to

dwell slightly under the vessel

media surface between time points.

This prevents drying of particles

and bubble formation while

minimizing hydro-dynamic

disturbance.



UV Dissolution: Fiber Optic

119

Multiplexer calibration and

probe performance is

monitored through the FO Mux

Calibration application.

Cary 60 Tests - Validate

120

Easy setup and execution of

routine calibration

Quick tests to monitor

instrument performance

and/or troubleshoot

Complete record of all tests

with time/date stamp



UV Dissolution: 21 CFR 11 Compliance

21 CFR Part 11 Compliance

121

UV Dissolution: 21 CFR 11 Compliance.

122

Spectroscopy Database

Administrator (SDA)

Spectroscopy Configuration

Manager (SCM)

Can be installed on a central

server or the local PC

The Win UV Dissolution software

runs off the local PC with

Windows 7 32- or 64- bit



Agilent Dissolution Seminar Series

Welcome

Replacement Media - 20 mL



No Replacement Media - 10 mL

QUALIFICATION OF DISSOLUTION

APPARATUS

126



Analytical Instrument Qualification

Good Manufacturing Practices (GMP) regulations

(e.g. FDAs 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 on Analytical

Instrument Qualification in 2005

127

Published in USP-NF in 2009

128



Analytical Instrument Qualification

USP 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

129

USP 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

130



USP 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

131

USP definitions:

Performance Qualification (PQ):

Usually based on the instruments 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

132



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

133

Qualification of Dissolution Apparatus

USP requirements for pharmacopial 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 couldnt be conveniently quantified at the time.

Use of a calibrator was suggested

134



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 0.5C

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

135


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

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

136




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

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.

137


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)

138




139

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



Specifications and Tolerances

Parameter ICH

(USP, JP, EP)

FDA

DPA-LOP.002

ASTM

E2503-07

USP

Toolkit Ver 2.0

Vessel/Shaft

Centering

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

141

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

142




The Apparatus Suitability Test became a USP requirement for all

dissolution equipment in 1978

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.

143


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.

144




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.

145


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 themselves 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.

146




The problem with the original requirement to evaluate individual

positions:

- Is this acceptable?

25.0

30.0

35.0

40.0

45.0

50.0

55.0

60.0

65.0

0 1 2

1

147


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)

148




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.

149

2009 revision to USP

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.

150



Ph. Eur. 2.9.3

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

151


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.

152



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 2012)

Apparatus 4

currently not available (no monographs used App. 4 until 2013)

153

USP Performance Verification Test

154



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

155

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

156



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.

157

Acceptance Limits for the PVT with Prednisone

tablets (July 2015):

158



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

159

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 41-45C

Vacuum filter (



De-aerated vs. Non-de-aerated Medium

161

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

162



Dispensing

The medium should be used immediately after degassing

temperature should not fall below 37C

dispense gravimetrically

163

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

164



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

165

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 210mm

and its inside diameter is 98mm to 106mm

166



Vessels

Even with perfect manufacture, within specification differences are significant

Such differences can change dissolution results

Surface +17% Area

Volume of -10%Cylinder

Volume of +27%Hemisphere

98mm ID for 900ml 106mm ID

167

Vessels

Vessel Dimensions Inner Diameter

Sets of 6 vessels from 10 different manufacturers

99

100

101

102

103

104

105

0 2 4 6 8 10 12

Source

Avera

ge In

ner

Dia

mete

r (m

m)

168



MECHANICAL QUALIFICATION STANDARDS

169

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

170




Requirements

Check Dimensions Upon Receipt:

Paddle, Basket/Shaft, and Vessel apparatus components must be verified that they conform with the harmonized standard USP 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.

171


Requirements

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

172




Requirements

Mechanical Qualification Requirements:

Shaft Wobble

Paddle/Basket Shaft Verticality

Basket Wobble

Vessel Centering

Vessel Verticality

Paddle/Basket Depth

Rotational Speed

173


Requirements

Operational Checks (document each time of use):

Basket/shaft examination

Paddle examination

Vessel examination

Vessel Temperature

Vibration

174




Requirements

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

175


Requirements

Paddle Examination, must be free from:

Defects

Rusting

Corrosion

Peeling or loose coating

Knicks, dents or misshapen appearance

176




Requirements

Vessel Examination, must be free from:

Scratches

Cracks

Pits

Residue

Surface irregularities

177

TOOLS FOR MECHANICAL QUALIFICATION

178




Height:

Wobble:

179


Temperature Level

180



The Agilent 280-DS

Fast 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

181

280-DS Mechanical Qualification System

Components

Vessel Module

Instrument Module

Temperature ProbePersonal Computer

(Optionally Supplied)

Software

182



280-DS Mechanical Qualification SystemVessel Module (VM)

Once placed in the vessel

this will measure:

Spindle Speed (RPM)

Shaft Wobble

Basket Wobble

Shaft Verticality

Vessel Verticality

Vessel Centering

Basket/Paddle height


Instrument Module (IM)

The Instrument Module (IM) is placed on

the vessel plate to measure:

Vessel Plate Level

Vibration

Temperature

184




How it Works

185

280-DS Mechanical Qualification SystemSoftware Capabilities

Configuration files maintain all relevant

apparatus data including serial numbers of

critical components

Method files may be chosen from a pre-loaded

list of regulated procedures or customized based

on specific internal requirements

All necessary controls available for use in a 21

CFR Part 11 environment including User

Groups, Audit Trails, etc.

Text directions as well as graphics instruct the

user how and when to perform each

measurement

All results are stored within a database that may

be created locally or on a secure network




Select specific positions to be tested for quick investigations

Record exact orientation of vessel within the data file

Filter past reports using various criteria including dates, operator,

apparatus, etc.

Conveniently monitor system and/or method changes with built-in audit

trail reports

Inspect individual position measurements

using the data trending capability

Certificates for all components can be

stored and linked within Apparatus file.


Comprehensive Reporting:



280-DS Mechanical Qualification SystemVibration Monitoring

PVT OR MQ

WHAT IS RIGHT FOR YOUR LABORATORY?

190



PVT or MQ

What Is Right For Your Laboratory?

PVT Advantages:

Holistic test with actual controlled tablets

Conforms closely to USP Analytical Instrument Qualification, requirement for Performance Qualification

New USP Acceptance Criteria provide statistical interpretation of results for an instrument as a whole.

Detects issues with Vessel Quality

Detects environmental issues

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

191

PVT or MQ


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!

192



PVT or MQ


PVT Disadvantages:

Time takes significant time to perform

Expense:

Cost of USP prednisone tablets

Cost of USP reference standards

Analysts time away from production

Expertise - requires training and experience

FDA claims of USP tablet variability

193

PVT or MQ


Time Savings (35-min vs a few hours 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

194



PVT or MQ


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

196

PVT or MQ


Primary reason customers 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

197



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

198

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

pharmacopias.

USP states that enhanced mechanical calibration is an essential pre-

requisite to PVT.

199



FUNDAMENTALS OF DRUG

RELEASE

- BIOPHARMACEUTICS

Bioavailability and Bioequivalence

FDA Definitions

Pharmaceutical Equivalence

Same active drug ingredient; same strength; same dosage form and route of administration; comparable labeling; meets compendial or other applicable standards of strength, quality, purity, and identity.

Bioavailability

The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

Bioequivalence

Two pharmaceutical equivalent drug products are bioequivalent if after drug administration, the bioavailabilities (rate and extent of drug availability) provide similar effects with respect to efficacy and safety.

201



Bioavailability and Bioequivalence

WHO Definitions

Pharmaceutical Alternative Products

They contain the same molar amount of the same pharmaceutical

ingredient but differ in dosage form and/or chemical form and are

administered by the same route.

Therapeutic Equivalence

They are pharmaceutically equivalent or alternatives and their safety and

efficacy are the same when administered by the same route..

Interchangeable Pharmaceutical Product

Therapeutically equivalent to a comparator product.

202

Biopharmaceutics Classification System (BCS)

The BCS is a scientific framework for classifying drug

substances based on their aqueous solubility and intestinal

permeability

When combined with the dissolution of the drug product, the

BCS takes into account three major factors that govern the rate

and extent of drug absorption from IR solid oral dosage forms:

solubility, intestinal permeability and dissolution

203



Biopharmaceutics Classification System - BCS

The BCS is effectively a risk tool adopted by regulatory agencies which:

characterises the absorption properties of a drug

characterises the likely clinical performance (PharmacoKinetics) of new and old formulations

BCS terminology is a useful way to describe the biopharmaceutical properties of a compound.

In August 2000 the FDA introduced this into guidance, which:

Sets solubility, permeability and dissolution limits

Allowed biowaivers (removal of bioequivalence studies) for Class 1 compounds/products due to their lower level of biopharmaceutical risk

204/112


205/112

1

3

2

4

SolubilityLow

Dose NOT soluble in

250 mL pH 1 to 7.5

Permeability

High

Extent of

absorption

>90%

For drugs in the Class 1 category, if dissolution >85% in 30mins, the FDA may waive the requirements for BA/BE studies.

HighDose soluble in

250 mL pH 1 to 7.5

Low

Extent of

absorption




Examples

206/112

Class 1: High Solubility High Permeability

Verapamil

Propranolol

Metoprolol

Class 3: High Solubility Low Permeability

Ranitidine

Cimetidine

Atenolol

Class 2: Low SolubilityHigh Permeability

Ketoprofen

Naproxen

Carbamazepine

Class 4: Low Solubility

Low Permeability

Furosemide

Hydrochlorthiazide

207

BCS - Solubility

The solubility class boundary is based on the highest dose strength of

an IR product that is the subject of a biowaiver request

A drug substance is considered highly soluble when the highest dose

strength is soluble in 250 ml or less of aqueous media over the pH

range of 1-7.5

The volume estimate of 250 ml is derived from typical BE study

protocols that prescribe administration of a drug product to fasting

human volunteers with a glass

(about 8 ounces) of water



208

BCS - Permeability

The permeability class boundary is based

directly on the rate of mass transfer of a drug substance in humans

across human intestinal membrane

Alternatively, non-human systems capable of predicting the extent

of drug absorption in humans can be used (e.g.; in vitro epithelial

cell culture methods, CaCo2 cells)

In the absence of evidence suggesting instability in the

gastrointestinal tract, a drug substance is considered to be highly

permeable when the extent of absorption in humans is determined

to be 90% or more of an administered dose based on a mass

balance determination or in comparison to an intravenous reference

dose

209

BCS - Dissolution

An IR drug product is considered rapidly dissolving when no less than

85% of the labeled amount of the drug substance dissolves within 30

minutes using

USP Apparatus I (basket) at 100 rpm,

or Apparatus II (paddle) at 50 rpm

A volume of 900 ml or less in each of the following media:

0.1 N HCl or Simulated Gastric Fluid USP without enzymes

pH 4.5 buffer

pH 6.8 buffer or Simulated Intestinal Fluid USP without

enzymes



In Vitro In Vivo Correlation?

In Vitro In Vivo

210/112

In Vitro In Vivo Correlation

Early practice was to develop dissolution requirements based on the in

vitro performance of clinically successful formulations.

Similarity in dissolution behavior has long been sought from the

perspectives of both bioavailability and quality control considerations.

The goal of the pharmaceutical scientist is to find a relationship between an

in vitro characteristic of a dosage form and its in vivo performance.

In vitroin vivo correlation, IVIVC, refers to the establishment of a rational

relationship between a biological property, or a parameter derived from a

biological property produced by a dosage form, and a physicochemical

property or characteristic of the same dosage form.

USP In Vitro And In Vivo Evaluation Of Dosage Forms

211



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Parameters to be Correlated

In Vivo data is taken from human pharmacokinetic studies

Overlapping of kinetic subprocesses

Apparent in vivo dissolution needs to be deconvoluted

at least distribution and elimination taken into account

Prerequisite is that in vivo dissolution is rate limiting step

In Vitro data is taken from dissolution experiments

Experimental design determines primary data

closed models (paddle) provide cumulative profiles

Open models (flow-through cell) provide fractionated profiles

No preference for model, profiles a convertible

213

In Vivo

Transformation of plasma levels to in vivo dissolution



214


The biological properties most commonly used are one or more

pharmacokinetic parameters obtained following the administration of the

dosage form

AUC

Cmax

The physicochemical property most commonly used is a dosage form's

in vitro dissolution behavior

% drug released under a given set of conditions

The relationship between the two properties, biological and physicochemical,

is then expressed quantitatively

215

IVIVC Correlation Levels according to USP

Level A

Highest category of correlation

Represents a point-to-point relationship between in vitro dissolution

and the in vivo input rate of the drug from the dosage form

Compares the % drug released versus % drug absorbed



216

IVIVC Correlation Levels

Level A Advantages:

A point-to-point correlation is developed

All in vitro dissolution data and all the in vivo plasma drug concentration profile data are used

An in vitro dissolution curve can serve as a surrogate for in vivo performance

A change in manufacturing site, method of manufacture, raw material supplies, minor formulation modification, and even product strength using the same formulation can be justified without the need for additional human studies

A truly meaningful (in vivo indicating) quality control procedure, which is predictive of a dosage form's performance, is defined

Can justify quality control limits

217

Level A IVIVC Example

0

2

4

6

8

0 2 4 6 8 10 12

Time (hr)

Pla

sma

Conce

ntr

atio

n (

ng/m

L)

Formulation 1

Formulation 2

0

20

40

60

80

100

0 1 2 3 4

Time (hr)

Perc

en

t d

rug

rele

ased

(%

)

Formulation 1

Formulation 2

Dissolution profiles for two different tablet formulations

Bioavailability from two different tablet formulations



218

Level B

Utilizes the principles of statistical moment analysis

Compares the mean in vitro dissolution time, MDT, to either the

mean residence time, MRT (mean time that the drug molecules

stay in the body), or the mean in vivo dissolution time

Utilizes all of the in vitro and in vivo data

Not considered to be a point-to-point correlation because it does

not reflect the actual in vivo plasma level curve

Cannot rely upon a Level B correlation alone to justify formulation

modification, manufacturing site change, excipient source change,

batch-to-batch quality, etc.

Cannot justify quality control limits


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Level B Correlation

In Vitro - In Vivo Correlation of Mean Dissolution Times

MDTvivo, tablet = MRTtablet - MRTsolution

-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6MDTvitro [h]

-0.5

0

0.5

1

1.5

2

2.5

MD

Tviv

o [

h]

RR

T1T1

T2T2

T3T3



220


Level C

Relates one dissolution time point (t50%, t90%, etc.) to one

pharmacokinetic parameter such as AUC, Cmax, or Tmax

Single point correlation

Does not reflect the complete shape of the plasma level, which

is the critical factor that defines the performance of finished

drug products

Has limited usefulness in predicting in vivo drug performance

Cannot be used to justify formulation modification,

manufacturing site change, excipient source change, batch-to-

batch quality, etc. or quality control limits

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Level C Correlation

Tmax vs. 30 minute dissolution (different formulation

variables)



222

Level C Correlation

Cmax vs. 30 and 60 minute dissolution (different

formulation variables)

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Immediate release and rapidly dissolving drug products

Difficult to obtain an IVIVC due to relationship of dissolution and

absorption in vivo

Rapid dissolution - may only obtain one or two dissolution

samples within short time period (e.g.;



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Extended release drug products

IVIVC works best for ER drug products where in vivo drug release is rate limiting step by design

Need to compare at least two formulation variables to set specification ranges

More rapid drug release

Less rapid drug release

Alternatively target vs. upper/lower side batches

Need to consider different USP Apparatus and/or different dissolution conditions

225


IVIVC is drug formulation dependent under specific dissolution

conditions

Generic drug products containing same pharmaceutical

ingredients may not have the same IVIVC



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Lack of In Vitro-In Vivo Correlation

May not be able to obtain an IVIVC for your drug product where :

Systemic drug absorption is the rate-limiting step for absorption

Variations in drug dissolution/release are not reflected in

variations in drug absorption

Dissolution is not rate limiting step

Drug dissolution test is not discriminating

May need to modify dissolution conditions

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Lack of In Vitro-In Vivo Correlation

Bioindicative dissolution method needed

Dissolution media do not reflect physiological conditions in the GI tract

pH in different regions of GI tract

Contents of GI tract

Liquids and solids

Fed or fasted state

Normal digestive enzymes

Water content

Other factors affecting systemic drug absorption

GI transit time

Pre-systemic drug elimination (first pass eff

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