QbD Approach to Dissolution Through Understanding of the Release Mechanisms and Critical In Vivo Parameters Andreas Abend Merck West Point, PA
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QbD Approach to Dissolution
Through Understanding of the
Release Mechanisms and Critical In
Vivo Parameters
Andreas Abend
Merck
West Point, PA
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Outline
General considerations of dissolution
Formulation development
QC method
Part A: Prior knowledge/risk assessment approach
BCS based understanding of dissolution methodology in the absence of
IVIVC
Part B: IVIVC/R approach
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Purpose of Dissolution testing
Guide formulation design and assess product quality The only product test that truly measures the effect of
formulation and physical properties of the API on therate of drug solubilization
The only test that can monitor if the rate of drugsolubilization is impacted by product storage conditions
It is the “best” surrogate for bio- performance if IVIVC can’tbe established
Required by many regulatory authorities for solid oral
dosage forms, transdermal patches and oral suspensions
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The evolution of our understanding of the DP
characteristics from a dissolution perspective
Pre Phase 1 --- Phase 1 --- Preliminary and Final Market Image
Formulation understanding QC method
“QbD execution”
Design space experiments
QTPP
RA tools
Monitor process/ refine
SUPAC
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Evolution of the method
Early development:
Disso method with bio relevant media – key in guidingformulation development in the absence of human in-vivo data:
Little value having a QC method at this stage Although required, limited value of a QC method at this stage of clinical
development
Post Prove of Concept- preliminary market formulationdevelopment:
Dissolution method gains much more importance as a “bio- performance”/ quality method:
Pivotal clinical studies (i.e. dose ranging, Phase III) Drug Product Process and components are usually defined
Exploring the Design Space and process scale-up: critical to have theright method in place
Important to ensure consistent quality (consistency in clinical trials)
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Early DP development stage Dissolution Method -
General Considerations…..
Prospective method
Desired Method attributes:
Should allow ranking of potential range of drug product
formulation types (i.e. DFC, LFC, simple tablets) to maximizedrug substance exposure
Typically not sensitive of small changes within oneformulation type
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Case Study 1- Formulation ranking:
Goal to identify the formulation that is likely giving maximum
exposure in Phase I Clinical trials:
• API properties:
• BCS Class II with low aqueous solubility
• 1.3ug/mL in aqueous and 7.7ug/mL in FaSSIF
• Formulation:
• Bench mark tox formulation
• Three Liquid filled capsules
• Two dry filled capsules (50mg Standard pharmaceutical ingredients
present in the formulation)
• Dissolution experiment
• Bio-relevant Medium: FaSSIF
• Non-sink condition
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FaSSIF Dissolution of MK-6526
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
110.0
0 10 20 30 40 50 60 70 80 90 1 00 110 120
time (min)
% C
l a i m
C:I:T
C:T
I:T
WG:C
WG:TPGS
SA:TPGS
LFC
DFC
Tox formulation
In-vitro dissolution and in-vivo Dog pK results
0.0
0.5
1.0
1.5
2.02.5
3.0
3.5
4.0
4.5
0 4 8 12 16 20 24
Time (hr)
C o n c ( u M )
DFC (10% Vit. E TPGS) LFC (Im:Tw)
SA Vehicle (20% Vit. E TPGS)
In-vitro dissolutionMedia FaSSIF
Apparatus USP II
Agitation 100 rpm
LFC
Tox formulation
DFC
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Dissolution method development strategy – PMF
development
Usually limited human pK-data available Phase I formulation typically not the formulation going forward and
process conditions, API, excipients selection, etc. evolve
May test further formulations in Bio Comparison studies before makingfinal PMF definition
With the additional human pK-data and formulation informationopportunity to look for in-vitro and in-vivo relationship
Desired method attributes: Guide formulation selection and fine-tuning
Become more formulation specific
Predictive of in-put variables that may impact bio-performance
Builds on prior knowledge including BCS classification system
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Case Study 2:
• API properties: BCS Class IV with low aqueous solubility across pH1.0-6.0
• Formulation: Tablets (doses: 100 -400 mg potency) with 25-50%drug load; Standard pharmaceutical ingredients present in theformulation. Immediate release dosage form.
• Process: Roller compaction process; API and excipients are rollercompacted. The granules are lubricated with SSF and magnesiumstearate followed by compression and film coating.
• Dissolution mechanism: Spans from fast disintegration of tablets toslow disintegration of tablets
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Case Study 2: In-vitro dissolution and in-vivo
human pK results
0
1000
2000
3000
4000
50006000
7000
8000
9000
0 2 4 6 8 10 12Time (hour)
P l a s m a C o n c e n t r a t i o n
Formulation 1
Formulation 2
0
20
40
60
80
100
120
0 0.5 1 1.5 2 2.5 3
Time (hr)
% D
i s s o l v e
Formulation I
Formulation II
In-vitro dissolution
Media water
Apparatus USP II
Agitation 100 rpm
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Dissolution method development strategy – Pivotal/ late
stage Clinical development
Formulation Identified, Dose(s) Identified -- Initial Quality Risk assessment
Evaluate the in-put variables on Drug Product Quality API, Excipients, Drug product manufacturing process
Identify Critical Process Parameters
Explore the process design space
Design Space: where the process works
Develop the Control Strategy
Desired Dissolution Method requirements:
Method should be sensitive to the process parameters/ in-put variablesthat may affect bio-performance
Method should be stability indicating, i.e. pick-up changes that are bio-
relevant
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Closer look at dissolution testing in the context of
QbD
“Final” Formulation going into pivotal clinical studies has
been defined
CQAs have been identified
Need to ensure adequate methods are in place to control CQAs
In-vivo performance is usually always a CQA…
Dissolution testing is at this stage often the only test that probes drug
substance release
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Requirements of a bio-relevant method in a QbD
context
In general methods should assure the quality of the drugproduct
Dissolution method (or surrogates) should assure consistent
bio-performance of the drug product
Should be sensitive to in-puts/ variables that have beenidentified to impact bio-performance
How can this be done?
1. Establish IVIVC (or IVIVR)
2. Use prior knowledge and appropriate risk assessment
3. A combination of both
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Part A: Prior
knowledge/risk assessmentapproach
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Biopharmaceutical Classification System
I
III
High solubility
High permeability
High solubility
Low permeability
IV
Low solubility
Low permeability
II
Low solubility
High permeability
Low Low
10
1.0
0.1
0.01
Volume to Dissolve Max Dose (ml)
I
III
High solubility
High permeability
High solubility
Low permeability
I
III
High solubility
High permeability
High solubility
Low permeability
IV
Low solubility
Low permeability
II
Low solubility
High permeability
High
10
1.0
0.1
0.01
Volume to Dissolve Max Dose (ml)
A p p
a r e n t P e r m e a b i l i t y ( X 1 0 6 )
G.L. Amidon et al.
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Dissolution Mechanism based on BCS
Formulateddrug
Absorbeddrug
Solubilizeddrug kd k p
k d = dissolution rate (solubility, formulation)
k p = permeability rate (API structure)
kd & kp fast - Well absorbed
BCS Class I, like dosing an oral solution
kd >> kp - permeation control BCS Class III, still like dosing an oral solution
kd << kp - dissolution controlled
BCS Class I (ER or CR), or Class II & IV (IR)
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Dissolution Mechanism based on BCS
Formulated drug
or “granule”Solubilized
drug k
d
Drug Particle k
id
k dd
k dd = disintegration (cohesive properties of the formulation)
k id = solubilization of the drug (API particle size or surfacearea)
Understanding the relative importance of k dd and k id provides
a mechanistic framework to assess where dissolution tests addsvalue
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Dissolution Mechanism based on BCS
k dd
>> kid
- intrinsic dissolution control
Critical attribute is API particle size or surface area
k dd
<< kid
- disintegration controlled
Cohesive properties of the formulation are important
Critical attribute is disintegration of product
k dd
~ kid
Fast release – neither cohesive properties nor physical
properties are important, Critical attribute is disintegration
Slow release - both cohesive properties and physical
properties may be important, Critical attribute is dissolution
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A Design Perspective on Dissolution Testing
Specific
GeneralDissolution
Disintegration
or Erosion
Intrinsic Rateof API
Solubilization
PorosityAPI
Particle Size
API
Surface
AreaHardness
Increased
Specificity of
Quality
Attribute
“A Biopharmaceutical Classification System Approach to Dissolution: Mechanisms and Strategies” W. E. Bowen, Q. Wang,
W. P. Wuelfing, D. L. Thomas, E. Nelson, Y. Mao, B. Hill, M. Thompson, R. A. Reed In"Biopharmaceutics Applications in Drug Development " R. Krishna and Lawrence Yu, Ed.; Springer, 2008, 290.
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Volume to Dissolve Max Dose (ml)
1e-31e-21e-11e+01e+11e+21e+31e+41e+51e+61e+71e+8
Papp(x10
6 )
0.1
1
10
Merck IR Formulation BCS Experience Space
II
IV
BCS Class I
BCS Class II
BCS Class III
BCS Class IV
I
III
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Disintegration Test
or capsule rupture test
Fast dissolution(<15 mins, 85%)?
CQA
Tablet disintegration
capsule rupture
Yes
Case 3
BCS Classification I/III
Immediate release Dosage Forms (N = 15)
(N = 13)
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Case Study 3: BCS Class I/IIIFast release with disintegration controlled dissolution
API properties: Borderline BCS Class I/III permeability
with high aqueous solubility (>40 mg/mL) at pH 1-7.5
Formulation: tablets (doses: 25 - 200 mg) with 32% drug
load; Standard pharmaceutical ingredients present in the
formulation Process: Direct compression process; API & excipients are
blended and then lubricated with magnesium stearate and
sodium stearyl fumarate, followed by compression.
Dissolution mechanism: tablet disintegration followed by
rapid solubilization of drug particles
Critical Quality Attribute: tablet disintegration
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70
80
90
100
0 15 30 45 60
Time, min
% D
i s s o l v e
pH 1.2
pH 4.5
pH 6.8
water - 50 mM NaCl
water
Dissolution in Physiological pHs
Test conditions
Media varied
Apparatus USP I
Agitation 100 rpm
Slowest profile has > 90% release in 10 minutes
Case Study 3: BCS Class I/IIIFast release with disintegration controlled dissolution
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Dissolution
75
80
85
90
95
100
10 15 20 25
Hardness, kP
% D
i s s o l v e d a t 1 0 m i
Disintegration
0
20
40
60
80
100
120
140
160
10 15 20 25
Hardness, kP
D i s i n t e g r a t i o n , s e
c o n
Impact of Tablet Hardness on Dissolution and Disintegration
Disintegration is the more sensitive method and serves as a
better indicator for product quality than a dissolution test
Case Study 3: BCS Class I/IIIFast release with disintegration controlled dissolution
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Disintegration Test
or capsule rupture test
Fast dissolution(<15 mins, 85%)?
CQA
Tablet disintegration
capsule rupture
Yes
Consider reformulationOr process change
No
Yes
Characterization of dissolutionmechanism
Perform Dissolution of
dosage form
and granules.
No
Case 3
Disintegration/erosion
control?
Yes
Case 4
BCS Classification I/III
Immediate release Dosage Forms (N = 15)
(N = 1)
(N = 13)
Fast dissolution(<15 mins, 85%)?
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Case Study 4: BCS Class I/IIIErosion Controlled Dissolution
API properties: API 1: Borderline BCS I/III permeability with high aqueous
solubility (>40 mg/mL) at pH 1-7.5; API 2: BCS III with high aqueous
solubility (~200 mg/mL) at pH 1-7.5
Formulation: Combination tablets. Standard pharmaceutical ingredients
present in the formulation
Process: Wet granulation process; Fluid-bed wet granulation of API 1 and API2. The granules are dried and blended with microcrystalline cellulose and
magnesium stearate followed by compression and film coating
Dissolution mechanism: Tablet erosion followed by rapid solubilization of
drug particles; controlled by tablet erosion
Critical Quality Attribute: tablet disintegration
Case Study 4 BCS Class I/III
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Case Study 4 – BCS Class I/III
Erosion Controlled Dissolution
0
20
40
60
80
100
0 15 30 45 60
Time (min)
% R e l e a s e
Disintegration time: 30 mins
Disintegration time: 19 mins
Disintegration time: 17 mins
granules
Correlation of Dissolution and Disintegration
Test conditions
Media Water
Apparatus USP II
Agitation 75 rpm
y = -1.6531x + 121.7
R2
= 0.9968
70
75
80
85
90
95
15 17 19 21 23 25 27 29 31
Disintegration Time, minutes
% D
i s s o l v e d @
1 5 - m i n u t e s
Strong correlation between dissolution and disintegration
Both methods monitor critical quality attributes sufficiently
Disintegration is recommended for simplicity
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Consider reformulationOr process change
Characterization of dissolutionmechanism
Perform Dissolution of
dosage form
and granules.
Fast dissolution(<15 mins, 85%)?
Disintegration/erosion
control?
Disintegration Test
or capsule rupture test
Fast dissolution(<15 mins, 85%)?
CQA
Tablet disintegration
capsule rupture
Yes
No
Yes
No
YesCase 3Case 4
BCS Classification I/III
Immediate release Dosage Forms (N = 15)
No
Case 5
Monitor dissolution
profiles
CQA
Granule properties
or others
(N = 1)(N = 13)
(N = 1)
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Case Study 5: BCS Class I
API properties: BCS Class I with high aqueous solubility (0.1
mg/mL) at pH 1-7.5. Formulation: Tablets (dose: 4 mg); Standard pharmaceutical
ingredients present in the formulation
Process: Wet granulation process; Granulated in water. The
granules were dried, blended with starch and magnesium stearatefollowed by compression
Dissolution mechanism: Fast tablet disintegration followed by
drug release from granules and rapid solubilization of drug
particles; Controlled by drug release from granules
Critical Quality Attribute: Granule particle size
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Case Study 5 – BCS Class I
Dissolution Controlled by Granule Particle Size
0
20
40
6080
100
120
0 15 30 45 60 75
Time (minutes)
% R e l e a s
e
< 150 um
> 150 um
Test conditions
Media WaterApparatus USP II
Agitation 50 rpm
Overall dissolution profile is dependent on the granule size distribution
Dissolution profile is monitored for quality control
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Summary of BCS Class I/III Experience
Overall Design Principle: Rapid dissolution – so like dosing an
oral solution Formulation: Tablets, Capsules or Oral Disintegrating Tablets Process: Direct compression, Wet Granulation, Roller
Compaction, Encapsulation or Freeze Drying
Dissolution mechanism: tablet or capsules disintegration followedby rapid solubilization of drug particles, i.e. k dd << k id
Critical Quality Attribute: Design for Disintegration (i.e. to makeit like dosing an oral solution)
Merck Biopharmaceutical Experience: In 3 out of 3 cases
examined, the solid oral dosage form has been bio-equivalent toan oral solution
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Volume to Dissolve Max Dose (ml)
1e-31e-21e-11e+01e+11e+21e+31e+41e+51e+61e+71e+8
0.1
1
10
Flexeril
Proscar Dexamethasone
L000124467
L000854384
Vasotec
Maxalt
MK0431
L000222628
L001169872
Pepcid
L000845704
Fosamax
BCS Class I
BCS Class II
BCS Class III
BCS Class IV
P a p p
( x 1 0
6 )
Merck BCS Class II & IV IR Formulations
III
IIIIV
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Volume to Dissolve Max Dose (ml)
1e-31e-21e-11e+01e+11e+21e+31e+41e+51e+61e+71e+8
0.1
1
10
P a p p
( x 1 0
6 )
Dissolution Media Selections
Aqueous
Surfactant
N/A
III
IIIIV
BCS Classification II/IV
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BCS Classification II/IV
Immediate Release Dosage Form
API solubilized
in formulation(LFCs, etc.)
Design Target
API remains in
solution
Disintegration Test
or capsule rupturetest
Yes
Case 6
C St d 6 BCS Cl II/IV
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Case Study 6: BCS Class II/IVCapsule Rupture Controlled Dissolution
API properties: BCS Class IV with low aqueous solubilityat pH 1.0-7.0.
Formulation: Liquid Filled Capsules (LFC). Dose: 0.1 -50 mg. The drug is fully dissolved in the liquid core of theLFC
Process: API was dissolved in liquid vehicle, which is thenfiltered, and filled into hard (or soft) gelatin capsules
Dissolution mechanism: capsule disintegration followedby dispersion of liquid content
Product Design Target: API is solubilized in formulation
BCS Classification II/IV
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BCS Classification II/IV
Immediate Release Dosage Form
API solubilized
in formulation(LFCs, etc.)
Design Target
API remains in
solution
Disintegration Test
or capsule rupturetest
Yes
Dissolution mechanism
characterization
Perform Dissolution of dosageform, API (different PSD)
and/or granules
No
Case 6 Consider reformulation
Or process change
k id rate limiting?
k id rate limiting?
CQA
API Particle
size, etc
YesNo
Yes
Control API particle
size, etc.
Case 7
Case Study 7: BCS Class II/IV
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Case Study 7: BCS Class II/IVDrug solubilization controlled dissolution
API properties: BCS Class IV with low aqueous solubility
across pH 1.0-7.5.
Formulation: Capsules (dose: 100 mg) with 67% drug load;
Standard pharmaceutical ingredients present in the
formulation Process: API and excipients are dry blended, then
lubricated with magnesium stearate. The powder blend is
then filled in hard gelatin capsules.
Dissolution mechanism: Rupture of capsule shell followedby API dissolution. Controlled by API solubilization
Critical Quality Attribute: Physical properties of API
C S d 7 BCS Cl II/IV
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0.0
20.0
40.0
60.0
80.0
100.0
0 20 40 60 80 100
Time, minutes
A v e r a g e % D
i s s o l v e d
Sieve Cut < 75 microns
Sieve Cut 180-250 microns
Sieve Cut > 355 microns
Case Study 7: BCS Class II/IVDrug solubilization controlled dissolution
API particle size modulates dissolution
Test conditions
Media 2% Tween
Apparatus USP II
Agitation 100 rpm
C S d 7 BCS Cl II/IV
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Impact of API PSD on Capsule Dissolution
API PSD should be controlled and monitored
Case Study 7: BCS Class II/IVDrug solubilization controlled dissolution
BCS Classification II/IV
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Dissolution mechanism
characterization
Perform Dissolution of dosageform, API (different PSD)
and/or granules
Immediate Release Dosage Form
Consider reformulation
Or process change
API solubilized
in formulation(LFCs, etc.)
k id rate limiting?
k id rate limiting?
CQA
API Particle
size, etc
Design Target
API remains in
solution
Disintegration Test
or capsule rupturetest
Yes
No
YesNo
Yes
Disintegration
or capsule rupture
limited?
No
Control API particle
size, etc.
Case 6
Case 7
CQA
Formulation
properties
No
Monitor dissolution
profiles
Case 8
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Case Study 8: BCS Class II/IV
API properties: API 1: BCS II with low solubility across pH
1-7.5; API 2: BCS Class IV with low aqueous solubilityacross pH 3.0-7.5 Formulation: Combination drugs in capsules (strength:
200/100 mg); Standard pharmaceutical ingredients presentin the formulation
Process: Roller compaction process; API’s and excipientsgranulated via roller-compaction. Granules are milled,lubricated with magnesium stearate and encapsulated in hardgelatin capsules.
Dissolution mechanism: Rapid rupture of capsule shell
followed disintegration of capsule plug and drug releasefrom granules. Controlled by plug disintegration andrelease from granules.
Critical Quality Attribute: granule density
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Test conditions
Media 2% SDS
Apparatus USP II
Agitation 50 rpm
Roller Compaction Pressure vs. Dissolution in Capsules
0
20
40
60
80
100
0 15 30 45 60 75
Reference BatchClinical Batch, 18 mm Disk, Loose Plug
131-B: 60 bar Roll Pressure, Hand-filled Capsule
131-2: 90 bar Roll Pressure, Hand-filled Capsule
131-3: 120 bar Roll Pressure, Hand-filled Capsule
% D
i s s o l v e d
Time (minutes)
Case Study 8: BCS Class II/IV
Monitor drug release by dissolution
BCS Classification II/IV
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Dissolution mechanism
characterization
Perform Dissolution of dosageform, API (different PSD)
and/or granules
Immediate Release Dosage Form
Consider reformulation
Or process change
API solubilized
in formulation(LFCs, etc.)
Kid rate limiting?
Kid rate limiting?
Disintegration
or capsule rupture
limited?
CQA
API Particle
size, etc
CQA
Formulation
properties
CQA
API remains in
solution
Disintegration Test
or capsule rupturetest
Yes
No
YesNo
Yes
No
No
Monitor dissolution
profiles
Control API particle
size, etc.
Case 6
Case 7Case 8
CQA
Tablet disintegration
capsule rupture
Yes
Case 9
C S d 9 BCS Cl II/IV
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Case Study 9: BCS Class II/IV
API properties: BCS Class IV with low solubility across pH
3.0-7.5. Highly soluble at gastric pH (>200 mg/mL) Formulation: Capsules (doses: 200 - 400 mg) with 65% drug
load. Standard pharmaceutical ingredients present in the
formulation
Process: Roller compaction process; API and excipients
granulated via roller-compaction. Granules are milled,
lubricated with magnesium stearate, and encapsulated in hard
gelatin capsules
Dissolution mechanism: Capsule rupture followed by rapid
release from granules. Controlled by capsule rupture Critical Quality Attribute: Capsule rupture (cross-linking)
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Case Study 9: BCS Class II/IV
Dissolution Profiles in 0.1N HCl
0
20
40
60
80
100
0 10 20 30 40 50Time (Minutes)
% D
i s s o l v e
Unstressed Capsules
Stressed capsules (40C/75% 48 hrs)
Granules
Test conditions
Media 0.1 N HCL
Apparatus USP II
Agitation 50 rpm
Monitor drug release by disintegration
S f CS Cl / i
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Summary of BCS Class II/IV Experience
Overall Design Principle: Solubilization enhancement e.g.
LFC’s, API physical properties – reduce particle size,increase surface area – add solubilizing agents, etc.
Formulation: Capsules, Tablets, ODT’s
Process: Direct compression, Wet Granulation, Roller
Compaction, Freeze Drying, liquid filled gel caps Dissolution mechanism: varied, i.e. k id << k dd, k dd << k id ,
k dd ~ k id
Critical Quality Attribute: Disintegration, API physical
properties, dissolution
C l i
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Conclusions
BCS based drug release testing leads to:
Focus on value added specifications in alignmentwith QbD principles and approaches
Removal of non-value added specifications
BCS Class I/III IR products – ability to eliminatedissolution testing and replace with disintegrationtesting
BCS Class II/IV IR products – ability to drill down tokey quality attributes and replace dissolution testingconsistent with the design of the product – somedissolution testing still adds value
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Part B
IVIVC/R approach
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IVIVC/IVIVR approach
IVIVC/R
Drug Product
CQA
CPP
In-vitro
Dissolution
In-vivo
human PK
Dissolution
Method
Development
Patients
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IVIVC/ IVIVR
High probability for CR products Consistent with existing SUPAC guidance, this provides highest degree
of regulatory flexibility
Lower probability for IR products Disso in BCS I and III formulations often too fast
Absorption and metabolism may also make it difficult to deconvolute thedata
BCS II higher chance of achieving
Remember dissolution driven by drug solubility
BCS IV
Often no relationship between dissolution rate and pK achievable
Possible relationships between dissolution and
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Possible relationships between dissolution and
drug exposure in subjects – Case A
% c h
a n g e i n - v i v o
p K
- p a r a m e t e r
0
-10
% drug dissolved in-vitro time per time unit (min)
-20
Case A – no IVIVC/R
Dickinson et. al (2008) AAPS Journal 10:380-90
Dickinson (2009), Applied Biopharmaceutics and QbD for Dissolution/ Release Specification setting:Product Quality for Patient Benefit;
“C A”
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“Case A”
No changes in pK-parameters observed within the tested
batches Dissolution method is sensitive to process parameters and
other in-put variables
Would suggest using % release/ time “Q” value(s) to provide process
control if required
In-put variable changes are justifiable as long as within the
above experience range
Assessment should be based on FMEAC analysis
Changes that result in disso profiles outside the experience/ spec range
likely require in-vivo justification
Possible relationships between dissolution and
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Possible relationships between dissolution and
drug exposure in subjects – Case B
% c
h a n g e i n - v
i v o
p K - p a r a m e t e
r0
-20
% drug dissolved in-vitro time per time unit (min)
-40 Case B - IVIVC
-60
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“Case B”
IVIVC is achievable!
In-vitro Method can directly assess the magnitude of in-vivo
changes due to process or other in-put variable changes
As existing SUPAC already suggests, this method can be used
to justify scale-up and post – approval changes in lieu of BE
studies
Possible relationships between dissolution and
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pdrug exposure in subjects – Case C
% c
h a n g e i n - v
i v o
p K - p a r a m e t e r
0
-20
% drug dissolved in-vitro time per time unit (min)
-40
Case C
-60
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“Case C”
Suggests IVIVR or even IVIVC possible
setting the disso spec to the slowest acceptable profile.
Any result above appears to provide adequate in-vivo
performance
Any dissolution result below the proposed spec may
indicate non-acceptable change
Since IVIVC possible one can directly assess the extent of
the pK-changes
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Conclusion
Part A of this presentation highlights the use of priorknowledge, QbD tools and good science to assure consistentproduct quality
Establishing IVIVC/R provides most direct link to bio-
performance Stronger link between in-vivo and in-vitro performance as compared to
using empirical approaches (F2)
Might be costly up-front investment
QbD frame-work allows for regulatory flexibility – this should be a strongincentive
But remember- achieving IVIVC/R might not always bepossible at least with the current in-vitro and in-silico toolsavailable
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Acknowledgements
Bill Bowen Steve Biffar
Kim Gallagher
John Higgins
Brian Hill
Craig Ikeda
Kiki Luna
Yun Mao
Eric Nelson
Robert Reed
Denise Thomas
Mark Thompson Qingxi Wang
Conrad Winters
Pete Wuelfing
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Thank you!
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References
W. E. Bowen, Q. Wang, W. P. Wuelfing, D. L. Thomas, E. Nelson, Y. Mao, B. Hill, M.Thompson, R. A. Reed, “A Biopharmaceutical Classification System Approach to
Dissolution: Mechanisms and Strategies”, in Biopharmaceutics Applications in Drug
Development " by R. Krishna and Lawrence Yu (Editor); Springer, 2008, 290
P.A Dickinson, Wang Wang Lee, Paul W. Stott, Andy Townsend, John Smart, Parviz
Ghaharamani, Tracey Hammett, Linda Billet, Sheena Behn, Ryan C. Gibb, Bertil
Abrahamsson, AAPS Journal, Vol. 10, No. 2, June 2008, p.380-390 Paul Dickinson et al. (2009), Applied Biopharmaceutics and QbD for Dissolution/ Release
Specification setting: Product Quality for Patient Benefit
Amidon, G.L., H. Lennernäs, V.P. Shah, and J. R. Crison, "A theoretical basis for a
biopharmaceutics Drug Classification: The correlation of in vitro drug product dissolution and
in vivo bioavailability." Pharmaceutical Research 12 (3, March), 413-420, 1995