Applications of IVIVC in Formulation Development - PQRI

Application of IVIVCs in
Formulation Development
Douglas F Smith
PQRI Workshop on Application of IVIVC
in Formulation Development
September 5 - 6, 2012
Bethesda, Maryland

In Vitro/In Vivo Correlations - Goals
Establish a correlation between in vitro drug
dissolution and in vivo drug absorption
Develop a model that can accurately predict
bioavailability characteristics for a drug product based
on dissolution profile characteristics

Applications of IVIVC
Understanding key formulation variable(s)
Biowaivers for changes in drug product
Lower strengths
New strengths
Changes in components and/or composition (within
SUPAC guidelines)
- Release rate controlling
- Non-release rate controlling
Changes in manufacturing site, process and/or
equipment (within SUPAC guidelines)
Setting dissolution specifications
Justification of limits other than +/-10%

Development of IVIVC
In vitro release
(Dissolution at
multiple pH and
agitations)
Administration to
healthy volunteers
(Crossover design)
Design of MR
Formulations
IVIVC
Deconvolution
(Absorption)

Practical Application: In Vivo and In Vitro Data
Required
In Vivo Data – Bioavailability Studies
At least 2 test formulations with different release rates (3 or more
recommended)
Solution, immediate release, or IV reference (unit impulse response)
Crossover studies in fasted subjects
Parallel studies acceptable (common treatment across studies)
In Vitro Data – Dissolution Studies
Test formulations should exhibit at least 10% difference in dissolution
USP apparatus I (basket @ 100 rpm) or II (paddle @ 50 rpm) preferred
Adjust dissolution conditions to fit in vivo data/obtain proper discrimination
If dissolution is faster or slower than in vivo absorption, adjust the time scale

Case Study 1
BCS Class III Drug
Fraction absorbed approximately 80%
Reformulation of a currently marketed modified release
formulation
IVIVC desired to support site change for manufacture
of reformulated drug product

Plasma Concentrations Following Oral
Administration
5
4
Formulation B (Fast Release)
Formulation A (Slow Release)
Formulation C (Medium Release)
Market Product Reference
IR Reference
[Drug] (ng/mL)
3
2
1
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Time (Hours)

Dissolution and Absorption Profiles – Water as
Dissolution Medium
Drug Dissolution
Drug Absorption
100
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
Slow Release
Medium Release
Fast Release
Cumulative Relative Percent Absorbed
80
60
40
20
Slow Release
Medium Release
Fast Release
0
0
0 2 4 6 8 10 12 14 16
0 2 4 6 8 10 12 14 16
Time (Hours)
Time (Hours)

IVIVC Model – Water as Dissolution Medium
Cumulative Percent Absorbed
100
80
60
40
Slow Release
Formulation
Medium Release
Formulation
Fast Release
Formulation
Slow and Fast IVIVC
R 2 = 0.949
20
0
0 20 40 60 80 100
Cumulative Percent Dissolved

IVIVC Validation
Internal Validation
Predict plasma concentration-time profiles, C max and AUC values using in
vitro dissolution data for the formulations that were used to develop the
IVIVC
Average absolute percent prediction error (%PE) of 10% or less for C max
and AUC and no individual %PE of individual formulation more than 15%
validates IVIVC
External Validation
Predict plasma concentration-time profiles, C max and AUC values using in
vitro dissolution data for a formulation that was not used in the
development of IVIVC
%PE of 10% or less for C max and AUC validates IVIVC
Proof of external validation provides greater
confidence in IVIVC than internal validation

Level A IVIVC Validation – Water as
Dissolution Medium
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Slow
Release
Fast
Release
63.4 66.0 4.15 1.77 2.02 14.3
74.1 78.2 5.54 3.45 3.00 13.2
Average %PE 4.84 Average %PE 13.7
External Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Medium
Release
66.8 67.2 0.67 2.26 2.22 1.77
AUC units: ng-hr/mL, C max units: ng/mL

Dissolution and Absorption Profiles - Acetate
Buffer as Dissolution Medium
Drug Dissolution
Drug Absorption
100
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
Slow Release
Medium Release
Fast Release
Cumulative Relative Percent Absorbed
80
60
40
20
Slow Release
Medium Release
Fast Release
0
0
0 2 4 6 8 10 12 14 16
0 2 4 6 8 10 12 14 16
Time (Hours)
Time (Hours)

IVIVC Model – Acetate Buffer as Dissolution
Medium
Cumulative Percent Absorbed
100
80
60
40
Slow Release
Formulation
Medium Release
Formulation
Fast Release
Formulation
Slow and Fast IVIVC
R 2 = 0.989
20
0
0 20 40 60 80 100
Cumulative Percent Dissolved

Level A IVIVC Validation – Acetate Buffer
as Dissolution Medium
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Slow
Release
Fast
Release
63.4 65.9 3.94 1.77 1.83 3.22
74.1 78.2 5.47 3.45 3.15 8.64
Average %PE 4.69 Average %PE 5.93
External Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Medium
Release
66.8 67.1 0.41 2.26 2.16 4.56
AUC units: ng-hr/mL, C max units: ng/mL

Dissolution of Target Formulation – Acetate
Buffer as Dissolution Medium
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
Medium Release
Formulation
Target Release
Formulation
Candidate Target
Release Formulation
0
0 2 4 6 8 10 12
Time (Hours)

Plasma Concentrations Following Oral Tablet
Administration
5
4
Observed Levels for Target
Formulation
Observed Levels for Market
Product Reference
[Drug] (ng/mL)
3
2
1
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Time (Hours)

Level A IVIVC Validation – Acetate Buffer
as Dissolution Medium
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Slow
Release
Fast
Release
63.4 65.9 3.94 1.77 1.83 3.22
74.1 78.2 5.47 3.45 3.15 8.64
Average %PE 4.69 Average %PE 5.93
External Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Medium
Release
Target
Release
66.8 67.1 0.41 2.26 2.16 4.56
87.1 85.5 1.87 3.92 3.56 9.18
AUC units: ng-hr/mL, C max units: ng/mL

Setting of Dissolution Specifications
Dissolution at Release
Dissolution at Release (%)
and After 3 Months (%)
Time (Hr) Mean -10% +10% -3 SD +3 SD Mean - 3SD +3 SD
2 21 11 31 15 27 22 16 28
4 53 43 63 47 59 54 49 59
5 64 54 74 58 70 65 60 69
8 85 75 95 78 92 86 82 91
12 97 87 107 90 104 98 93 103
Simulated Bioavailability Parameters
Parameter Mean -10% +10% -3 SD +3 SD Mean - 3SD +3 SD
AUC 69.8 62.7 77.0 64.9 73.9 69.6 65.0 73.6
% Diff from
Mean -- 10.2 10.4 7.0 6.0 -- 6.6 5.6
% Diff Low
to High -- 18.6 12.2 -- 11.6
Cmax 2.76 2.47 3.04 2.55 2.97 2.76 2.64 2.89
% Diff from
Mean -- 10.4 10.2 7.6 7.5 -- 4.2 4.8
% Diff Low
to High -- 18.8 14.1 -- 8.6

Case Study 2
BCS Class II Drug
Highly variable pharmacokinetics
AUC and Cmax dependent upon input rate
Reformulation of generic formulation to IR reference
drug products at three dose levels
Controlled release required to achieve bioequivalence
to reference drug product
IVIVC desired to support change in tablet coating and
change in site of manufacture

Mean Plasma Concentration-Time Profiles Following
Administration of Low Dose Reformulation Candidates
1400
[Drug] (pg/mL)
1200
1000
800
600
8.0% Polymer
4.5% Polymer
5.25% Polymer
6.25% Polymer
6.5% Polymer
7.0% Polymer
0% Polymer
Reference
400
200
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (Hours)

Dissolution of Low Dose Reformulation Candidates by
QC Release Method (USP Monograph)
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
4.5% Polymer
5.25% Polymer
6.25% Polymer
6.5% Polymer
7.0% Polymer
8.0% Polymer
0
0 20 40 60 80 100
Time (Minutes)

% Polymer Prediction Model to Achieve Bioequivalence
for Low Dose Formulations
2.5
C max
and AUC Geometric Mean Ratios
2.0
1.5
1.0
% Polymer vs C max
Ratio
R 2 = 0.9995
% Polymer vs AUC Ratio
R 2 = 0.9996
Maximum GMR for C max
% Polymer = 6.40
Minimum GMR for AUC
0.5
0 2 4 6 8
% Polymer
% Polymer = 6.98

Mean Dissolution and Absorption Profiles of Drug From
Low Dose Formulation Candidates
Dissolution
Absorption
100
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
8% Polymer
5.25% Polymer
4.5% Polymer
6.25% Polymer
6.5% Polymer
7% Polymer
Cumulative Relative Percent Absorbed
80
60
40
20
8% Polymer
5.25% Polymer
4.5% Polymer
6.25% Polymer
6.5% Polymer
7% Polymer
0
0
0 2 4 6 8 10 12
0 2 4 6 8 10 12
Time (Hours)
Time (Hours)

Absorption Versus Dissolution Relationship for Drug From
Low Dose Reformulation Candidates
100
80
4.5% Polymer
5.25% Polymer
6.25%% Polymer
6.5% Polymer
7% Polymer
8% Polymer
IVIVC Model
R 2 = 0.906
Absorption
60
40
20
0
0 20 40 60 80 100
Dissolution

Internal and External Predictability Measures of the Level A
IVIVC for Drug from Low Dose Formulation Candidates
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
8.0%
Polymer
7.0%
Polymer
4.5%
Polymer
5.25%
Polymer
6.25%
Polymer
6.5%
Polymer
3829 3990 4.21 488 476 2.41
4456 4624 3.77 461 518 12.2
5357 5581 4.19 706 716 1.42
Average % PE 4.06 Average % PE 5.36
External Predictability
5252 5428 3.35 628 650 3.50
4963 5116 3.08 578 572 1.00
4454 4613 3.57 494 523 5.79
AUC units: pg-hr/mL, C max units: pg/mL

Dissolution Specifications For Low Dose
Formuation
Dissolution
IVIVC Based
Absence of IVIVC
Time (Hr) Mean Lower Upper Lower Upper
1 48 39 57 38 58
4 78 69 87 68 88
12 82 NLT 73 NLT 72
Parameter
Simulated Bioavailability Parameters
AUC 4834 4240 5322 4179 5382
% Diff from Mean
-- 12% 10% 14% 11%
% Diff Lower to
Upper -- 20% 22%
Cmax
578 531 649 525 655
% Diff from Mean
-- 8% 12% 9% 13%
% Diff Lower to
Upper -- 18% 20%

Dissolution Specifications For Low Dose
Formuation
Dissolution
FDA Proposed
Wyeth Proposed
Time (Hr) Mean Lower Upper Lower Upper
1 48 38 58 36 60
4 78 68 88 69 87
12 82 NLT 80 NLT 73
Parameter
Simulated Bioavailability Parameters
AUC 4834 4339 5302 4257 5216
% Diff from Mean
-- 10% 10% 12% 8%
% Diff Lower to
Upper -- 18% 18%
Cmax
578 544 659 558 688
% Diff from Mean
-- 6% 14% 3% 19%
% Diff Lower to
Upper -- 17% 19%

Controlled Release Formulation – IR or MR
PK and PD profile is that of an IR drug product
Clinical safety and efficacy profile is that of an IR drug
product
Product does not meet requirements of MR dosage
formulation
No reduction in dosing frequency
No reduction in plasma concentration fluctuations
No modified release characteristics exhibited in plasma concentration-time
profile
Are changes to formulation subject to SUPAC-IR
guidance or SUPAC-MR guidance

% Polymer Prediction Model to Achieve Bioequivalence
for Medium Dose Formulations
2.0
C max
Ratios BA Study
1.8
AUC Ratios BA Study
C max
Ratios BE Study
AUC Ratios BE Study
C max
and AUC Geometric Mean Ratios
1.6
1.4
1.2
1.0
Maximum GMR for C max
% Polymer = 5.24
0.8
Minimum GMR for AUC
% Polymer = 6.19
0.6
0 2 4 6 8
% Polymer

% Polymer Prediction Model to Achieve Bioequivalence
for High Dose Formulations
1.8
C max
and AUC Geometric Mean Ratios
1.6
1.4
1.2
1.0
0.8
0.6
0.4
% Polymer = 2.89
% Polymer = 3.95
C max
Ratios BA Study
AUC Ratios BA Study
C max
Ratios BE Study
AUC Ratios BE Study
Maximum GMR for C max
Minimum GMR for AUC
0.2
0.0
0 2 4 6 8
% Polymer

Case Study 3
BCS Class I Drug
Development of MR dosage for an existing IR market
product
Initial IVIVC developed with data from slow, medium
and fast release formulations
Small scale batches
Lowest strength to be marketed
IVIVC desired to support change in process
parameters and change in site of manufacture

In vitro release and in vivo absorption
profiles from 75 mg Formulations
Dissolution
Absorption
100
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
0
Slow Release
Medium Release
Fast Release
Dissolution Conditions:
- USP I (baskets)
- 100 rpm
- 0.9L Water
- 37 o C
Cumulative Percent Absorbed
80
60
40
20
0
Slow Release
Medium Release
Fast Release
0 2 4 6 8 10 12
Time (Hours)
0 4 8 12 16 20 24
Time (Hours)

In Vitro / In Vivo Relationship for 75mg
Capsules
100
Slow Release
Medium Release
Fast Release
Linear Regression
R 2 = 0.932
80
Cumulative Percent Absorbed
60
40
20
0
0 20 40 60 80 100
Cumulative Percent Dissolved

Internal and External Predictability Measures of the Level A
IVIVC
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
Slow
Release
Medium
Release
Fast
Release
853 916 7.37 45.3 40.8 10.0
885 917 3.62 53.1 42.8 19.4
880 908 3.23 58.8 54.0 8.13
Average % PE 4.74 Average % PE 12.5
External Predictability
2x75mg 1703 1622 4.74 96.5 94.0 2.59
1x150mg 1647 1622 1.51 94.4 91.1 3.50
AUC units: mcg-hr/mL, C max units: mcg/mL

Demonstration of in vitro release
independence of dissolution test conditions
Dissolution tests for 75mg and 150mg formulations
USP I (baskets) and USP II (paddles) at 50, 75 and 100 rpm
Dissolution media of water, SGF (without enzymes) and SIF (without
enzymes
All dissolution profiles similar to reference profile (USP I, 100 rpm, water)
- f 2 > 65
Dissolution tests for 225mg formulations
USP I (baskets) at 100 rpm
Dissolution media of water, SGF (without enzymes), buffers at pH 4.5, 6.8
and 7.4
All dissolution profiles similar to reference profile (USP I, 100 rpm, water)
- f 2 > 78

In Vitro / In Vivo Relationship for 75mg and
150mg Formulations
100
80
Study 1 75 mg US Mfg
Study 1 75 mg PR Mfg
Study 1 150 mg PR Mfg
Study 2 75 mg US Mfg
Study 2 150 mg PR Mfg
IVIVC Model
R 2 = 0.971
Cumulative Percent Absorbed
60
40
20
0
0 20 40 60 80 100
Cumulative Percent Dissolved

Internal Predictability Measures of the Level A IVIVC
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
2x75mg 1703 1556 8.66 96.5 94.4 2.18
Study 2
1x150mg 1647 1559 5.35 94.4 94.1 0.32
Study 2
2x75mg 2248 2187 2.71 150 130 13.1
Study 1
1x150mg 2242 2200 1.87 149 130 12.8
Study 1
2x75mg 2224 2175 2.20 144 130 9.69
Study 1
Average % PE 4.16 Average % PE 7.61
AUC units: mcg-hr/mL, C max units: mcg/mL

Case Study 4
BCS Class III Drug
Fraction absorbed approximately 80%
Development of MR dosage for which no IR market
product
Multiple strengths developed to achieve same in vitro
dissolution release profile
50mg – 70% HPMC
75mg – 57% HPMC
100mg – 50% HPMC
200mg – 30% HPMC
IVIVC desired to support development of other
strengths

MR Tablet Dissolution Profiles in 0.9% NaCl
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
50 mg
100 mg
200 mg
0
0 4 8 12 16 20 24
Time (Hours)

50 mg MR Tablet Dissolution Profiles in
Alternate Media
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
0.9% NaCl - Reference Media
Water, f 2
= 72
0.1N HCl (pH 1.0), f 2
= 60
0.1N HCl / 0.2M Phosphate (Two-Stage), f 2
= 66
0.02M Acetate (pH 4.5), f 2
= 81
0.05M Phosphate (pH 6.8), f 2
= 96
0
0 4 8 12 16 20 24
Time (Hours)

200 mg MR Tablet Dissolution Profiles in
Alternate Media
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
0.9% NaCl - Reference Media
Water, f 2
= 97
0.1N HCl (pH 1.0), f 2
= 46
0.1N HCl / 0.2M Phosphate (Two-Stage), f 2
= 57
0.02M Acetate (pH 4.5), f 2
= 94
0.05M Phosphate (pH 6.8), f 2
= 96
0
0 4 8 12 16 20 24
Time (Hours)

MR Tablets Absorption Profiles
100
Cumulative Percent Label Claim Absorbed
80
60
40
20
50 mg
100 mg
200 mg
0
0 4 8 12 16 20 24
Time (Hours)

In Vitro / In Vivo Relationship for MR Tablets
100
80
Cumulative Percent Absorbed
60
40
20
0
50 mg
100 mg
200 mg
Linear Regression
R 2 = 0.991
0 20 40 60 80 100
Cumulative Percent Dissolved

Validation of Level A IVIVC for MR Tablets
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
2x50 mg 4754 4273 10.1 169 172 1.82
1x100 mg 4626 4273 7.64 173 172 0.75
1x200 mg 9383 8550 8.88 321 333 3.58
Average % PE 8.88 Average % PE 2.05
External Predictability
2x75 mg 7037 6480 8.94 246 264 7.35
AUC units: mcg-hr/mL, C max units: mcg/mL

Approaches to a Level A IVIVC
Traditional Approach
Non-traditional Approach
% absorbed Vs % dissolved
mg absorbed Vs mg dissolved
One strength
Multiple strengths
Multiple formulations with different
levels of rate-controlling parameter
Multiple formulations with different
levels of rate-controlling parameter
Differences among formulations in
both % and mg released profiles
Differences among formulations only
in mg released profiles
Point to point relationship between in
vitro dissolution (%) and in vivo
dissolution (%)
Point to point relationship between in
vitro dissolution (mg) and in vivo
dissolution (mg)

FDA Guidance on Development, Evaluation
and Application of IVIVCs
Traditional Approach
“Level A Correlation is . . . . comparison of fraction of drug absorbed to the fraction
of drug dissolved”
“release rates, as measured by percent dissolved, for each formulation studied,
should differ adequately (e.g., 10%)”
“most commonly seen processes”
Non-traditional Approach
“Alternative approaches to developing Level A IVIVCs are possible”
“Whatever the method used to establish a Level A IVIVC, the model should predict
the entire in vivo time course from the in vitro data. In this context, the model refers
to the relationship between in vitro dissolution of an ER dosage form and an in vivo
response such as plasma drug concentration or amount of drug absorbed”
“Release rate: Amount of drug released per unit time as defined by in vitro or in vivo
testing”

MR Tablet Dissolution Profiles (Cumulative %
Dissolved in 0.9% NaCl)
100
Cumulative Percent Label Claim Dissolved
80
60
40
20
50 mg
100 mg
200 mg
0
0 4 8 12 16 20 24
Time (Hours)

MR Tablet Dissolution Profiles (Cumulative mg
Dissolved in 0.9% NaCl)
200
50 mg (70% HPMC)
100 mg (50% HPMC)
200 mg (30% HPMC)
Cumulative mg Label Claim Dissolved
160
120
80
40
0
0 4 8 12 16 20 24
Time (Hours)

MR Tablets Absorption Profiles (Cumulative
% Absorbed)
100
Cumulative Percent Label Claim Absorbed
80
60
40
20
50 mg
100 mg
200 mg
0
0 4 8 12 16 20 24
Time (Hours)

MR Tablet Absorption Profiles (Cumulative mg
Absorbed)
200
50 mg (70% HPMC)
100 mg (50% HPMC)
200 mg (30% HPMC)
Cumulative mg Label Claim Absorbed
160
120
80
40
0
0 4 8 12 16 20 24
Time (Hours)

In Vitro / In Vivo Relationship for MR Tablets
200
160
50 mg
100 mg
200 mg
Linear Regression
R 2 = 0.9897
Cumulative mg Absorbed
120
80
40
0
0 40 80 120 160 200
Cumulative mg Dissolved

Validation of Level A IVIVC for MR Tablets
Internal Predictability
Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE
2x50 mg 4754 4305 9.45 169 173 2.53
1x100 mg 4626 4306 6.93 173 173 0.06
1x200 mg 9383 8614 8.20 321 336 4.45
Average % PE 8.19 Average % PE 2.35
External Predictability
2x75 mg 7037 6453 8.30 246 266 8.16
AUC units: mcg-hr/mL, C max units: mcg/mL

INTERNAL AND EXTERNAL PREDICTABILITY MEASURES OF
LEVEL A IVIVC FOR 200 mg MR TABLETS
Batch
15% HPMC
Roller
Compact
MFG Site A
30% HPMC
Roller
Compact
MFG Site A
Batch
30% HPMC
Wet
Granulation
MFG Site B
Observed
AUC
Predicted
AUC
Intern al Predictability
Absolute
% PE
Observed
Cmax
Predicted
Cmax
Absolute
% PE
8870 9094 2.53 362 344 4.95
8984 9218 2.61 314 307 2.07
Observed
AUC
Average % PE 2.57 Averag e % PE 3.51
Predicted
AUC
External Predictability
Absolute
% PE
Observed
Cmax
Predicted
Cmax
Absolute
% PE
8540 8772 2.72 308 309 0.36
AUC units: ng·hr/mL; Cmax units: ng/mL

Evaluation of Dissolution Specifications
Time Point
Statistical Limits –
Statistical Limits –
Passing L1 Passing L1
95% Chance of 99% Chance of
Limits Based
on IVIVC
2 hours NMT 33% NMT 34% 17 – 37%
4 hours 33 – 50% 32 – 51% 32 – 52%
8 hours 50 – 73% 50 – 75% 52 – 72%
12 hours 63 – 95% 63 – 95% 69 – 89%
24 hours NLT 83% NLT 82% NLT 87%

Case Study 5
BCS Class I Drug
Development of IVIVC for Marketed MR Product
Change in process
Multiple strengths manufactured and exhibit same in
vitro dissolution release profile
Retrospective analysis of data available from 7 BA
studies
Drug has significant first-pass metabolism
Data from intubation study indicated increase in systemic availability in
distal GI
Correlation model developed using dissolution data
directly as input
First derivative of Weibull Function

Model Parameters of Dissolution Data

Model of Fraction of Drug Absorbed

Validation of the Model

Validation of the Model

Dissolution of Drug

Conclusions-Benefits of IVIVC
Provides framework for formulation development
Promotes prioritization of formulation efforts toward
compounds with bioavailability problems and
improves communication across disciplines
Places development of biorelevant dissolution method
formally into development process
Defines manufacturing parameters at an early stage in
the development process and facilitates early transfer
of formulation to manufacturing site
Reduces the risk of requiring Phase III to market BE
studies

IVIVCs – Lessons Learned
FDA guidance is just that, not a regulation or
requirement, but it is in the best interest of sponsor to
evaluate feasibility
Terminology in the guidance indicates sponsors are
allowed some flexibility in developing IVIVCs
Collaboration among various functional groups a
necessity (formulations, analytical, clinical, regulatory,
biopharmaceutics)
Timing
“Developing IVIVCs is not a science, it is an art.”

Acknowledgements
Pharmaceutical Sciences
Robin Enever
Technical Services
Stephen White
Mike Dey
John Pendregast
Richard DeNeale
Biopharmaceutics
Sridhar Duvvuri
Clinical
Phil Mayer
William McKeand
Formulations
Alice Nichols
Ron Warner
Steven Troy
John Michelucci
Deborah Sherman
Regulatory
David Korman
John Clark
James Murphy
Shaleish Singh
Simon Golec
Chris Diorio
Beth Kendsersky
Ian Armstrong
Chris Le
Analytical Services
Andy Beath
Lusan Yao
Patricia Mann
Brian Spencer
Marijo Weinzierl
Quality Operations
Joe DeVito
David Sheats
Deborah Parker
Consultants
Lewis Leeson
Scott Stevens
William Barr
William Jock
Mario Gonzalez