test

Fundamental Considerations in the
Development of Biorelevant
Dissolution Test and Essentials of
IVIVC in Drug Development
1-Day Intensive Program
Umesh V. Banakar, PhD
Professor & President
Banakar Consulting Services
Carmel, IN 46032 USA
Presented to
Novartis (India) Ltd.
Hyderabad, INDIA
Sponsored by
Sotax (India) Ltd
Mumbai, INDIA
August 28, 2012

Fundamental Considerations in the Development of Biorelevant Dissolution Test and Essentials of
Preface
The in vitro dissolution test has emerged as the single most crucial test that has the potential to predict in
vivo availability. While dissolution testing is a regular quality control procedure, it plays a critical
role during all phases of drug (formulation) development. Thus, the dissolution test can be employed
prospectively – while developing a formulation with the appropriate drug release characteristics, and
retrospectively – to assess whether a dosage form is releasing the drug at prescribed/predetermined
rate and extent from batch-to-batch. The principal assumption underlying these two applications of
this test is that the dissolution test is able to adequately represent, if not predict, the biological
performance, i.e., bioavailability, of the drug.
There is a need to understand what it takes to develop a ‘Biorelevant Dissolution Test’ method which can
accomplish the abovementioned attributes. Issues concerning the dissolution process, the dissolution
test methodology, factors that influence dissolution process and thereby the dissolution performance,
criteria for selection of a dissolution test method, ways to compute and interpret dissolution data,
methods to determine and interpret IVIVC, are but a few of the many factors that need to be
comprehensively evaluated during the development of a dissolution test. Consequently, the
dissolution test method development is often challenging to the professionals working in drug
product development.
As of date, in vitro dissolution tests seem to be the most reliable predictors of in vivo availability. Although
official tests have great practical value, the fact that there is still a need for a test more directly
related to bioavailability has been recognized. While the bioavailability of drug substances and drug
products in humans can provide a confirmatory evidence of a potential relationship between
dissolution and physiological availability, it is often impractical to perform extensive and expensive
human testing. As a result, the essentials of what is involved in developing and demonstrating an in
vitro - in vivo correlation is necessary.
The presentation will focus on fundamental considerations in the development of 'Biorelevant Dissolution
Test' and understanding the essentials of IVIVC in drug product development.
The author (UVB) wishes to acknowledge with gratitude Millennium Pharmaceuticals Inc., Cambridge,
MA 02139 for sponsoring this program. UVB is indebted to his wife Suneeta for her continuous
unselfish support. Last, but not the least, UVB would like to thank all the well wishers for their
support that is often taken for granted, however, needs to be recognized.
Umesh V. Banakar, Ph.D., Professor and President, Banakar Consulting Services, Carmel, IN 46032
[umeshbanakar@juno.com]

Fundamental Considerations in the Development of
Biorelevant Dissolution Test and Essentials of IVIVC in Drug Development
Umesh Banakar, PhD, Professor and President, Banakar Consulting Services,
Carmel, IN 46032 USA
Table of Contents
I. Introduction, Objectives and Scope
II. Biorelevant Dissolution Test Method Development
Part 1: BCS Considerations
III. Biorelevant Dissolution Test Method Development
Part 2: Compendial versus Noncompendial
IV. Biorelevant Dissolution Test Method Development
Part 3: IR Solid Dosage Forms
V. Biorelevant Dissolution Test Method Development
Part 4: MR Solid Dosage Forms
VI. Biorelevant Dissolution Test Method Development
Part 5: Regulatory Considerations
VII. In Vitro - In Vivo Correlations
Part 1: Basics of Correlation
VIII. In Vitro - In Vivo Correlations
Part 2: Difficulties in Correlating Dissolution and Bioavailability
IX. In Vitro - In Vivo Correlations
Part 3: Regulatory Perspective
X. In Vitro - In Vivo Correlations
Part 4: Data Analyses - in vitro and in vivo
XI. In Vitro - In Vivo Correlations
Part 5: Setting-up IVIVC
XII. In Vitro - In Vivo Correlations
Part 6: Applications and Perspectives
XIII. Concluding Remarks
Q &A

Module I
• Introduction
• Objective and Scope

Pharmaceutical Systems (Types)
– Physical property based
• Disintegration
• Non-disintegrating
– Functional property based (regulatory
based)
• Immediate release
• Modified release
– Enteric coated
– Others (PR/SR/CR/DR/ER/…)
– Carrier system based
• Solid (dissolution testing required)
• Semi-solid (dissolution testing required)
• Liquids (dissolution testing required
except for true solutions
BCS-UVB

A K1 B K2 C
IVIVC?
A: Drug in dosage form
B: Drug dissolved in the gut
C: Drug in blood/systemic circulation
D: Drug dissolved in in vitro dissolution
system
K1: in vivo dissolution rate constant
K2: in vivo drug absorption rate constant
K3: in vitro dissolution rate constant
UVB
Correlation
K3
D

Objectives and Scope
•Fundamentals of Dissolution Testing
•Biorelevant Dissolution
•Discriminative Biorelevant Dissolution Testing
•Basics of IVIVC
•Can dissolution be correlated to bioavailability
•Essentials in Setting up IVIVC
• Beyond Traditional IVIVC (time permitting)
Outside the scope ……
•Drug specific method development
•USP Dissolution Methods - instrumentation
•Mechanics/mathematics of IVIVC
•Interpretation and Drug Specific IVIVC
UVB

Module II
Biorelevant Dissolution Test
Method Development
Part 1: BCS Considerations

• Revisiting BCS
• Designing Intrinsic Dissolution Test
• Interpretation of Results
and Drawing Inferences
• Connecting Intrinsic and
Apparent Dissolution Test
UVB

• Biopharmaceutics
Classification System (BCS)
– IR
• Based on Drug Solubility and
Permeability
– Case 1: High Solubility – High Permeability
– Case 2: Low Solubility – High Permeability
– Case 3: High Solubility – Low Permeability
– Case 4: Low Solubility – Low Permeability

• Requirements
– What is the rate limiting step in
vivo?
– Can this step be measured in vitro?

Designing Intrinsic Dissolution
Test
•Agitation Intensity
•pH of dissolution medium
•Sink volume
•Particle size
•Solubility class
•Target dosage form
•Others

Intrinsic Dissolution Test
Interpretation of results and
drawing conclusions:
•Agitation Intensity In/Dependency
•pH In/Dependency
•Sink volume – Dose size
•Particle size impact
•Solubility class
•Magnitude of Kin
•Others
UVB

Intrinsic and Apparent
Dissolution Test Relationship
•Agitation Intensity
In/Dependency
•pH In/Dependency
•Sink volume – Dose size
•Particle size impact
•Solubility class
•Magnitude of Kin
•Others
UVB

Module III
Method Development
Part 2: Compendial versus
Noncompendial

• Current USP
XXV
• Dissolution
<711>
– Apparatus 1
– Apparatus 2
Dissolution <711>
– Apparatus 1
– Apparatus 2
– Apparatus 3
– Apparatus 4
– Apparatus 5
– Apparatus 6
– Apparatus 7
UVB

Bioavailability Parameters and
Dissolution
• Absorption
• Distribution
• Metabolism
• Elimination / excretion
• Dissolution rate constant (in vitro / in vivo)
• Total amount dissolved (in vitro / in vivo)
• Which one is dissolution
dependent?
UVB

BIORELEVANCE OF DISOLUTION
TEST
• Solubility of drug
• Partitioning of drug (logP)
• Type of formulation
• Site of drug administration
• Potential of drug release/dissolution
• Is dissolution rate-limited
absorption
UVB

BIORELEVANCE OF DISOLUTION
TEST -2
• Potential site of drug absorption
• In vivo site where dissolution
criteria are met
• In vivo where most likely IVIVC is
observed
• Chemistry of the drug
• Physicochemical properties of the
drug
• Intrinsic dissolution consideration
UVB

PHARMACEUTICAL SYSTEMS
AND DISSOLUTION TEST
CONDITIONS
• Immediate Release
formulations
• Modified Release formulations
• Disintegrating/Non-
disintegrating systems
• Solid, Semi-solid and Liquid
formulations
• Dose strength and
Drug:Excipient Ratio
UVB

CONDITIONS - 2
• Drug solubility and sink conditions
• Influence and importance of
hydrodynamics
• pH profiling: Necessary or
otherwise
• Physiological considerations
• Active metabolite considerations
UVB

CONDITIONS - 3
• In vivo dissolution site
considerations
• Absorption site considerations
• BA under fasted and fed states
• Simulation of dissolution under fed
state
• In vivo BA, f value, for the drug
UVB

COMPENDIAL DISSOLUTION
TESTS
AND BIORELEVANCE
• Disintegration and Dissolution tests
• Dissolution test Assembly(ies)
• Compendial dissolution media
• Use of solubility modifiers
(surfactants, etc.)
• Compendial dissolution test
medium volume
UVB

COMPENDIAL DISSOLUTION
TESTS
AND BIORELEVANCE - 2
• Hydrodrynamics in compendial
methods
• pH profiling or otherwise
• Acceptance criteria
• Q versus Rate parameter
Quality Control Tests !!!!
UVB

NONCOMPENDIAL DISSOLUTION
TESTS
AND BIORELEVANCE
• Modifications in Test Assembly(ies)
• Combination of compendial
methods
• Hydrodynamics modifiers
• Nontraditional dissolution media
• Solubility modifiers (noncompendial
!)
• Intrinsic dissolution test
UVB

Development of
Suitable Dissolution
Method
– Europe: no monographs on
formulations or individual
methods necessary
– Critical criteria
• Properties of dosage form
– Geometry: mono or multi-particulate
– Technology: conventional or
modified
• Properties of drug substance
– Solubility
– Wettability
– Stability
– Others

Dissolution Method
Development
– Intrinsic dissolution
• Determination of intrinsic
dissolution rate constant
• Low and high K intrinsic
• Implications and projections
– Physical and chemical
parameters
• Drug substance / active
ingredient
• Drug substance + excipient
combination
• [D + excipient] and process
• Dosage form / drug carrier
system
– Solubility
– Crystal structure
– Other

Development of a Biorelevant
Dissolution Test (General Scheme)
– Determine BCS of the drug and the
dosage form
– Choice of appropriate test apparatus
– Choice of appropriate medium for the
test
– Dissolution test medium and its
characteristics (dissolved gases,
nontraditional pHs, enzymes, etc.)
– Hydrodynamics (available and
optimized) of medium
– Duration of the dissolution test with
regard to formulation type and drug
properties
– Setting criteria for evaluation of the
test results

Dissolution Test (Secondary
Considerations)
– Relation between intrinsic and
apparent dissolution tests
– Stage of drug development
– Prospective, or retrospective,
test development
– Test for NDA and / or ANDA
product
– Test for IR or MR product
– Monograph available or
otherwise (generics)

Dissolution Test
– Choice of appropriate test
apparatus
• Compendial versus noncompendial
• Compendial with modification(s)
• Can the essential considerations be
accommodated?
• Drug substance and dosage form
requirements

Dissolution Test
– Choice of appropriate medium
for the test
– Dissolution test medium and its
characteristics (dissolved gases,
nontraditional pHs, enzymes,
etc.)

Dissolution Test
– Different media suggested /
available
• Buffers at pHs: 1.2, 4.5, 6.8, 7.5
• Buffers with or without enzymes
• Simulated gastric fluid surfactant
• Simulated intestinal fluid
• Fasted simulated small intestinal fluid
• Fed simulated small intestinal fluid
• Ensure plus, milk (fat grades)
• Co-solvent systems (solubizers)
• Organic solvents
• Aerated / deaerated media
– Deaeration methods, age, etc.
• Others

Dissolution Test
– Important considerations
• Stage of drug development
• Volume of dissolution medium
• Duration of the test
• Type of formulation and formulation
excipients
• Planarity and turbulence resultant
to mixing
• Is discrimination or sensitivity the
evaluation criterion?

Dissolution Test
– Duration of the dissolution test
with regard to formulation type
and drug properties
• Type of dosage form: IR or MR
• Rapidly dissolving or otherwise
• BCS and type of dosage form /
drug properties
• Sampling protocol
• Regions of the profile
• Duration of the test and stability of
the drug / product

Dissolution Test
– Setting criteria for evaluation of
the test results
• Comparative tests
• Comparative test results
• Establishing in vitro equivalence
• Stage of drug development
• Pre-biostudies or post-biostudies
• Method transfer post IVIVC to QC

Module IV
Method Development
Part 3: IR Solid Dosage
Forms

• Strategy development for design
• In vitro evaluation of formulations
• Biorelevant dissolution test(s) and
demonstrating discrimination
• Selection of Formulation from prototype
to pivotal
• Beyond F1/F2 analysis
• Potential prediction of in vivo availability
and Bioequivalence
• Definitive BE studies

Designing an Immediate Release
Generic Pharmaceutical
 API matters most (generally)
 Route of synthesis –
 Polymorph(s)
 Formulation composition/component
 Others

Critical physicochemical properties of
API (s)
 Crystalinity
 Particle size and distribution
 Polymorph(s) considerations
 Solubility profile – pH and organic solvents
 Analytical considerations
 Impurity profile
 Compatibility with excipient(s)
 Stability profile (including tracking of
impurities)
UVB

Immediate Release Pharmaceutical
Biopharmaceutical considerations
In vitro Dissolution considerations
 Compendial/monograph requirements
 Define dissolution test protocol
 Biorelevant condition(s)
 Sampling protocol (honoring monograph reqmts.)
 Rate assessment should be feasible
 Set discriminatory criteria
 Define Acceptance Criteria
In vitro Equivalence Assessment
 F1 and F2 Analyses (all testing conditions)
 Rate comparisons
 Extent comparisons
 In-process formulation and dosage form testing
UVB

Case Study 1
• Poorly soluble drug
• No metabolism
• Low dose
• Short Tmax
• Long terminal elimination half-life

Case Study 2
• Poorly soluble
• Relatively low dose
• Low BA
• Not so short Tmax
• Long half-life
• Active metabolite

Module V
Method Development
Part 4: MR Solid Dosage
Forms

• Defining Rate-limiting component
• In vitro evaluation of formulations
• Biorelevant dissolution test(s) and
demonstrating discrimination
• Beyond F1/F2 analysis
• Potential prediction of in vivo availability
UVB

Designing Dissolution Method:
Modified Release Pharmaceuticals
 API matters less (generally)
 Formulation composition/component
 Processing/Technology
 Others
UVB

Designing Dissolution Method
Modified Release Pharmaceutical
Critical physicochemical properties of
API (s)
 Crystalinity, Particle size and distribution
 Polymorph(s) considerations
 Solubility profile – pH and organic solvents
 Analytical considerations
 Impurity profile
 Compatibility with excipient(s)
 Stability profile (including tracking of
impurities)
 Selection of excipients (rationale and function)
UVB

Modified Release Pharmaceutical
In vitro Dissolution considerations
 Compendial/monograph requirements
 Define dissolution test protocol
 Biorelevant condition(s)
 Technology driven Noncompendial
modifications !!
 Sampling protocol (long duration +
Clinical endpoint considns.)
 Rate assessment of paramount
importance
 Set discriminatory criteria
 Define Acceptance Criteria
UVB

Modified Release Pharmaceutical (contd.)
In vitro In/Equivalence Assessment
 F1/F2 Analyses (all testing conditions)
 Rate comparisons
 Extent comparisons
 In-process formulation and dosage form
testing
UVB

Case Study 1
• Low dose
• Poor solubility
• OD
• Medium Tmax
• Short half-life
• No metabolite

Case Study 2
• Low dose
• Poor solubility
• OD
• Medium Tmax
• Short half-life
• Active metabolite

Case Study 3
• FDC
• Low dose + high dose
• Poor + high solubility
• OD
• Significantly different Tmaxs [2]
• Significantly different half-lifes
[2]
• No metabolite

Module VI
Method Development
Part 5: Regulatory
Expectations

Regulatory Assessment
of Oral SR/CR Products
Biorelevant dissolution
assessment (justification)
 In relation to technology used
 In relation to the manufacturing process
 In relation to predicting BA and thereby BE
 In relation to therapeutic endpoint
 DEMONSTRATING DISCRIMINATION
 In relation to „future‟ QC specs
 others

In vitro equivalence
 Rate controlling step(s)
 Biorelevant or otherwise
 In relation to Monograph requirements (if
applicable)
 Potential for predicting in vivo performance
 Beyond f1 and f2 analyses
 Release rate analyses
 Simulation, prediction and Goodness of Fit
 Others

Setting dissolution/drug release
specifications (QC)
 IVIVC based
 Non-IVIVC based
 Technology (employed) specific
 FDA Guidance based
 Clinical endpoint based
 Others
Justification is mandatory
through discriminatory analyses

Module VII
In Vitro - In Vivo Correlations
Part 1: Basics of Correlation

• The process of developing a
drug from discovery to the
market is long, arduous and
challenging, to say the least.
• Along the way, one often
comes across crossroads with
respect to arriving at a
reasonable balance between
risks and benefits going
beyond achieving clinical
targets.
UVB

There is a constant quest for
increasing efficiency and cost
effectiveness in the drug
development process.
In this pursuit, a question often
surfaces relating to exploring
avenues where in vitro
surrogate experiments can
be developed and used to
predict in vivo outcomes.
UVB

Such surrogate tests could impact
various stages of drug development
including setting of quality
specifications of the final
product, provided an appropriate
in vivo – in vitro correlation
[IVIVC] can be established.
The place and significance of such
IVIVCs is most encountered during
the assessment of a drug product
under development to potentially
predict its bioefficacy and possibly
its ultimate therapeutic efficacy,
among others.
UVB

“………Establishment of a
rational relationship between a
biological property produced by
a dosage form, and a
physicochemical property or
characteristic of the same
dosage form……..The
relationship between the two
properties, biological and
physicochemical, is then
expressed quantitatively.”
US-FDA guideline/USP
<1088>

• Correlation is defined as an
attempt to explore a
relationship between two
variables.
• Variable may be defined as a
process comprising of an
input (cause) function and the
resultant output (effect).
UVB

• Examples:
Dissolution (input) Amount
Dissolved
(effect)
* Characterized as amount of drug
dissolved as a function of time
• Dissolution (in vivo) Amount in
blood (output)
* Characterized as plasma-drug-
concentration as a function of time
Aging (cause) Color of hair!!
(effect)
UVB
(Process)
(Process)
(Process)

Correlation
– In vitro – In vivo
• Physicochemical property
– Dissolution
• Biological property
– Pharmacokinetics
– Dependent on system
UVB

• Requirements of a Correlation
(1)
– Dependent and independent
variables have to be
correlatable.
– There has to be at least one
distinct common factor or
similarity between two
variables. Otherwise, one is
correlating apples with
oranges!
– Similarity in the process
component within two
variables is explored
UVB

Requirements of a Correlation (2)
The significance of an IVIVC in
drug development is established
from:
• Coefficient of correlation: r
• Coefficient of determination: r2
• Coefficient of dependability
• Probability factor: p value
• Relevance of correlation
UVB

• Types of Correlations
– Linear (positive and negative)
– Exponential (positive and
negative)
– Polynomial (positive and
negative)
– Probability / Probit
– Others
• For simplicity, linear correlation
is preferred.
UVB

• Parameters of a Linear
Correlation
• Slope Δ y / Δ x
• Intercept: y value when x = 0
• Interpretation of Correlation
Meaning of a slope:
Provides insight into the function represented
on the X-axis
Meaning of intercept:
Provides information about the dependent
variable when X is functionally non-existent or
not required
UVB

Interpretation of a
Correlation (Part 2)
In addition to the items listed
in Part 1
Statistically sound
Should provide an insight into
the processes that are
correlated or represented
UVB

Module VIII
Part 2: Difficulties in Correlating
Dissolution and Bioavailability

Mechanics of IVIVC:
Challenges
In vivo vs in vitro system inherent
differences
2-step vs 1-step ….
Duration of test ….
Functionality of test (1st order vs
arithmatic) ….
Dissolution dependent function –
characterization ?
What to correlate: function, response,
parameter ..
The issue of metabolite vs administered
drug ….
Regulatory vs realistic correlation !!
Mathematical vs clinical …………
What is the ultimate objective of IVIVC ??
UVB

In vivo vs in vitro system
inherent differences….1
2-step vs 1-step ….
Dissolution in vivo is a prerequisite for
Bioavailability, and not the reverse
When in vivo dissolution is the rate-
limiting, then chances for predicting
bioavailability (IVIVC) are enhanced
UVB

inherent differences ….2
Duration of test ….
In vitro dissolution test:
IR products – 0.5 h – 2 h
MR products – 3 h – 30 h
Bioavailability test: 5 x elimn. Half-life
(t1/2)
___________________
Fluoxetene 20 mg Capsules (Prozaic)
Dissolution Test Duration: 120 min [2 h]
Bioavailability Duration: 5 x 80 h = 400 h
UVB

Functionality of test (1st order vs
arithmatic)
Dissolution/Drug Release function: Arithmetic Y
as f(X)
Bioavailability function: First Order – ln(Y) as f(X)
[Exponential]
Factors influencing bioavailoability have long time to
express ….
Discriminatory - Bio-relevant dissolution test is
required –
drug-specific
product-specific
UVB

Dissolution (in vivo) dependent function
in bioavailability process and its
characterization ?
Absorption is dissolution dependent,
however, for establishing IVIVC entire
bioavailability performance has to be
used (including distribution, and
elimination)
Dissolution test presumes that post
dissolution/release of the drug
complete and rapid/instantaneous
absorption occurs
UVB

What to correlate:
function, response, parameter ..
Complete in vivo performance
(bioavailability) and complete
in vitro performance (dissolution)
has to be correlated
UVB

The issue of active metabolite vs
administered drug ….
Dissolution Test: Administered drug (parent
drug)
Bioavailability Test: Active metabolite
__________________
Naltrexone and 6-beta-naltrexol) – active
metabolite
Dissolution Test: Naltrexone from tablet
Bioavailability Test: Plasma-6-beta-naltrexol-
concn.
UVB

Regulatory vs realistic correlation
!!
UVB

Mathematical vs clinical …………
[Semi]quantitative based correlations
between bioavailability (parameters)
and dissolution (parameters) are
explored ….
Pharmacokinetic (bioavailability) –
Pharmacodynamic (clinical) correlation
is presumed ….
UVB

What is the ultimate objective of
IVIVC ??
To set up IVIVC based dissolution test
(in vitro test) quality specifications to
ensure batch-to-batch consistency
with respect to quality !!!!
UVB

Correlation
Can dissolution and
bioavailability be correlated ?
Misconception/Myth:-
Amount of drug dissolved should equate
(correlate) with amount of drug bioavailable
(absorbed)
The pursuit should be:-
Are the changes in the bioavailability
performances between formulations
predictable in/from the respective dissolution
performances of these products ?
UVB

Module IX
Part 3: Regulatory Perspective

Basics of In Vitro – In Vivo Correlations
IVIVC …1
• Classes of In Vitro – In Vivo
Correlations
– Pharmacological Correlations:
based on clinical observations
– Semi-quantitative Correlations:
based on blood levels or urinary
excretion data
– Quantitative Correlations:
resultant to absorption kinetics
– Most of the published correlations
fall within the second class; the
most valuable are those based on
absorption kinetics.
UVB

Basics of In Vitro – In Vivo Correlations IVIVC
….2
• Essentially there are two
basic types of correlations
that are employed while
comparing in vivo – in vitro
data:
– Quantitative Correlations
– Rank Order Correlations
UVB

….3
• IVIVC – Poor Correlations
– Differences seen in BA data
not seen in dissolution data
– Order of rates reversed
– Significant differences seen in
dissolution tests NOT
observed in BA data
– Dissolution inconsistent with
BA data
UVB

….4
• Methods for Correlation
– Numerical deconvolution /
convolution
– Statistical moment analysis
– Model-dependent methods
• Loo-Reigelman
• Wagner-Nelson
– Regression type correlation
of distinct single parameters
UVB

Basics of In Vitro – In Vivo Correlations
IVIVC ….5
– Human data supplied for IVIVC
– Bioavailability studies should have
enough subjects
– IVIVCs use the fasted state
– Any in vitro method can be used
– Preferred apparatus (1, 2, 3 or 4)
– CDER should be consulted if other is
used
UVB

….6
•Deciphering Levels of
Correlation
•Level A / I
–Analogous parameters
–Complete profiles
–Degree of superimposability
• Time-scaling factor
UVB

….7
•Deciphering Levels of
Correlation
•Level B / II
–Analogous parameters
–Complete profiles
–Model independent parameters
–PK / Kinetic parameters
representing entire function
UVB

….8
• Deciphering Levels of
Correlation
• Level C / III
– Analogous parameters
– Complete profiles
– Relevant PK / kinetic
parameters
• Level D / IV (!)
– Accidental correlations
UVB

….9
• Developing a Correlation:
Procedure for developing a
Level A correlation
“The plasma level or urinary excretion
data obtained in the definitive BA study
of the MR DDS are treated by a
deconvolution procedure. The resulting
data may represent the drug input rate
of the dosage form. It is also
considered to represent in vivo
dissolution when the rate controlling
step of the DDS is it dissolution rate.
Any deconvolution procedure (i.e.
Mass balance or mathematical
deconvolution) will produce acceptable
results.”
UVB

….10
• Developing a Correlation
The batch used in the pivotal
BA study is subjected to in
vitro dissolution evaluation,
and the effect of varying the
dissolution conditions
investigated
–Variables to be studied
• Apparatus
• Mixing intensity
• Dissolution media
UVB

….11
– In vitro dissolution curve is then compared
to the drug input rate curve (degree of
superimposibility)
• Position one curve on another
• Comparing equation constants
• Plot fraction absorbed in vivo versus
fraction released in vitro
• For Level A, result would be a straight
line with a slope (may be) equal to 1
• Intercept probably not 0 due to lag time
UVB

….12
– Behavior such that drug release is
independent of variables studied
• General, robust Level A correlation
– Behavior such that drug release is
dependent on variables of dissolution
• Establish conditions that best correlate
with in vivo [discriminatory]
UVB

Module X
Part 4: Data Analyses
- In vitro and In vivo

Computation of
Dissolution
Measurement
– Cumulative amount of drug
released as a function of time
– Percent dose related as a
function of time
– Amount remaining to be
released as a function of time
UVB

• Dissolution Profile: Desirable
Characteristics
– Complete
– Frequently / Adequately
Sampled
– Sensitive / Discriminatory
– Reproducible
– Validated
UVB

• Questions
– Should we be interested in
USP specifications
– What is dissolution profiling?
How does it differ from pH
profiling?
– Should we be interested in
particular regions of the
dissolution profile?
– Is a complete dissolution
profile necessary? If yes, when
(Development or QC)?
UVB

Sampling During
Dissolution Testing
– Frequent and adequate
– Should capture critical regions of
profile
– Provide for discrimination and
sensitivity analysis
– User friendly
UVB

Dissolution Profile
(Critical Components)
– IR products
• Early-phase dissolution (critical)
• Later-phase dissolution (less
critical)
– MR products (technology-based
products)
• Early-phase dissolution (critical)
• Middle-phase dissolution (less
critical)
• Later-phase dissolution (critical)
UVB

Bioavailability Assessment
• PK Parameters (BA Investigations)
– Absolute Bioavailability [F]
• F = [(AUC po) * Dose po] / [(AUC
i.v) * Dose i.v]
– Relative Bioavailability [f]
• F or F rel = [(AUC test) * Dose test]
/ [(AUC ref) * Dose ref]
– Half-Life = 0.693 / terminal phase rate
constant
= 0.693 / β
– AUC (Cp as a function of time)
• AUC t1 – t2 = 0.5 * (c1 + c2) * (t2 –
t1)……..
– AUC 0 → * = AUC 0 → t last + AUC t last → inf
= AUC 0 → t + tail-end
correction
= AUC 0 → t + Cp last / β

• Statistical Analysis
Assumptions
– Subjects are randomly
assigned to study sequences
– Variances between groups
and treatments are
comparable
– Main effects for standard
minimum 3 x 3 crossover
study should be additive (no
interactions)
UVB

Single Dose
– AUC 0 → t (trapezoidal rule)
– AUC 0 → * (trapezoidal rule +
tail-end correction)
– Cmax
– Tmax
– Terminal Phase
• Rate constant (apparent)
• Half-life (apparent)
UVB

• Single-Dose Fasting Three-
Way Crossover BA Study
– Subjects
• Minimum 24, healthy, 18 – 50 years old,
within 10 – 15% of IBW (male or non-
pregnant females)
• Written, informed consent required
– Overnight fast for at least 10 hours
– Restrictions
– Blood Samples
– Subject monitoring
UVB

• Sampling and Sampling
Interval: Reasons and
Rationale
– Adequate characterization of
bioavailability
• Rate: Cmax and Tmax
• Extent: AUC 0-t AUC 0-*
– Complete characterization of
bioavailability
• 3 – 5 half-lives post administration
– Characterization of critical biological
processes
• Absorption: predominantly pre-Cmax
• Elimination: terminal phase or the 4th
or 5th half-life period
– Acquire adequate number of points on
bio-profile
– Clinically relevant

• Sampling Interval – Some
Rules of Thumb
– Adequate and subject friendly (as
much as possible)
– Frequent, but not necessary
(minimum 4 – 5 samples during
each phase is sufficient)
– Should be able to capture the Cmax
region
– Should be able to capture the clean
terminal phase
– More frequent during absorption
phase
– Less frequent during distribution
and elimination phase
UVB

Module XI
Part 5: Setting up IVIV Correlation

Frequently Employed Techniques
for Correlating IVIV Data
– Numerical Deconvolution /
Convolution
– Statistical Moment Analysis
– Model-Dependent Methods By
• Loo-Riegelman
• Wagner-Nelson
– Regression-Type Correlation
of distinct in vivo and single
in vitro parameters
UVB

Analogous
– Functional similarity
– Parametric similarity
– Process similarity
– Complete profiles
– Degree of superimposibility
UVB

Analogous Parameter Employed
in IVIVC Determinations
In Vitro In Vivo
AUC AUC
Kr, Kd Ka, Kd, Kr
Tinf, Tmax Cmax
F(t), T(F),
MRT
Fa(t), T(Fa)
MDT MRT
UVB

Sample Data Set 2
• 3 Unique
formulations
(F1, F2, and
F3) Figure 2. Average In-VitroDissolution(APIRecovered)
0.00%
20.00%
40.00%
60.00%
80.00%
100.00%
0 20 40 60 80 100 120
Time (hrs)
AverageIn-VitroDissolution,(APIRecovered)
Error Bars = +/- %CV
Form
ul-
ation
Ave
rag
e %
CV
In-
Vitro
Perfor
mance
% LC
F1 5.34 109
F2 7.88 91
F3 11.8
2*
98
*Exceeds FDA
recommendation <10%
F1
F3
F2
f2 values between
formulations are all < 50,
indicative of dissimilar
dissolution

Curve Fitted Equations
Sample Data Set 2
In-Vitro Dissolution
Y = -a*exp(-k*t) + b
Where:
Y = % Drug
Dissolved
t = Time
a = The span of
dissolution
( 100)
b = The asymptote
of the
dissolution
curve ( 100)
k = The dissolution
rate constant
Formu
lation
k R2
F1 0.815 99.8%
F2 0.078 100.0
%
F3 0.021 99.7%

In-Vivo Results (PK)
Sample Data Set 2
• 3 Unique In-
Vivo PK
Results (F1,
F2, and F3)
Pharmacokineticsof API in Swine and Human
0
1
2
3
4
5
6
7
8
9
0 0.25 0.5 1 2 4 6 8 12 18 24 36 48 72 120 144 168 336 504 672
Time (hrs)
APIConcentrationinBlood(ng/mL)
Error Bars = +/- Standard Deviation
Relati
ve
% Diff
Cmax
%
Diff
AUC
F1 vs
F2
47 35
F2 vs
F3
50 22
F2
F3
F1
F1 - Human

Curve Fitted Equations
Sample Data Set 2
• In-Vivo (PK)
C = a + b*exp(-
0.5*(ln(t/c)/d)^2)
Where:
– C = Concentration
of API (ng/ml)
– t = Time (hrs)
– a, b, c, and d are
constants that
define the
concentration curve
Formula
tion
R2
F1
(Swine)
96.8%
F2 99.0%
F3 97.2%
F1
(Human)
99.7%

Level A: Fractional Response Times
Sample Data Set 2
Graph of In-Vitro Dissolution and In-Vivo PK FractionalResponse Times
(FRT)
y = 6.39x- 1.78
R2
= 0.98
y = 0.87x- 2.62
R2
= 0.97
y = 0.40x- 4.43
R2
= 0.95
-5
0
5
10
15
20
25
30
35
0 10 20 30 40 50 60 70 80 90
In-Vitro Dissolution FRT, (hours)
In-VivoPK(%AUC)FRT,(hours)
F2
F3
F1
 Fraction Dissolved (In-Vitro) vs
Fraction Absorbed (In-Vivo, PK)

Module XII
Part 6: Applications and Perspectives

IVIVC:
Applications and Perspectives
• Setting QC Specifications
• Biowaivers
• Dose-proportionate formulations
• Performance Based IVIVCs
UVB

Module XIII
Concluding Remarks
and Q and A

• Is it possible to simulate in vivo
conditions within the in vitro
dissolution test in the laboratory ….
• It surely is challenging ……..
• More important is – The
understanding of the
physiological/biological, i.e., in vivo
conditions is of paramount
importance to design an
appropriate biorelevant dissolution
test ….
• The quest for such a
dissolution test continues ….

Thinking is capital
Enterprise is the way
Hard work is the solution
His Excellency Dr. A.P.J. Abdul
Kalam
Hon. President of India
Nov. 28,
2007

THANK YOU
Dhanyawaad !!
muito obrigado !!!!
umeshbanakar@juno.com

Please ….
• Only easy/simple
questions that I
can answer !!!!

++ 317 440 7784 (mobile)
++ 317 334 0174
umeshbanakar@juno.com

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