This document provides an overview of dissolution specifications. It discusses the purpose of specifications in ensuring drug product quality and consistency. It reviews specifications for different dosage forms like immediate-release, extended-release, and delayed-release as outlined in USP <711>. The presentation discusses factors to consider in justifying specifications scientifically, including drug properties, formulation, manufacturing processes, and clinical data. It provides an example of using an IVIVC model to help establish clinically relevant dissolution methods and specifications.

1. Jian-Hwa Han
USP Dissolution Workshop
Rio de Janeiro - Brazil
May 20-21, 2013
Knowing Your
Dissolution
Specifications
SUB-TITLE, DATE

2. • Purpose of Specification
• Dissolution: Regulatory NDA Filing Support
• Specifications for Different Dosage Forms
• Dissolution Criteria for Stage Testing – USP <711>
• Justification of Specifications
• Scientific Assessment
• Clinically Relevant Dissolution Methods and Specifications
o An Ideal Approach for Setting CRS
o IVIVC Model
• Examples
• Conclusions
Presentation Outline
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013
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3. • The quality of drug products is determined by their design,
development, in-process controls, GMP controls, and
process validation, and by specifications applied to the
product throughout development and manufacture
• Specifications are chosen to confirm the quality of the drug
products, i.e. ensure the Safety and Efficacy of drug products
• Assure manufacture consistency for the quality of product
Purpose of Specifications
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4. An Overview from NDA Filing Preparation: (Dissolution Focused)
• 3.2.P.2 Pharmaceutical Development
• 3.2.P.2.2 Drug Product
• 3.2.P.5 Controls of Drug Product
• 3.2.P.5.1 Specifications
• 3.2.P.5.2 Analytical Procedures
• 3.2.P.5.3 Validation of Analytical Procedures
• 3.2.P.5.6 Justification of Specifications
• 3.2.P.8 Stability
Dissolution: Regulatory NDA Filing Supports
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5. • Immediate-Release Dosage Forms
• Delayed-Release Dosage Forms
• Extended-Release Dosage Forms without IVIVC
• Minimum of 3 points required
• Last time point should be the time where 80% of label claimed amount
is dissolved
• Specifications set to pass at Stage 2 level of testing of the USP
acceptance criteria
• Extended-Release Dosage Forms with IVIVC
(ICH Q6A, Decision Tree #7-3)
Specifications for Different Dosage Forms
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3. What are appropriate acceptance ranges? [extended release]
YES
NO
NO
YES
YES
NO
YES
NO
Are bioavailability
data available for batches
with different drug release rates?
Is drug release independent of
in vitro test conditions?
Can an in vitro / in vivo
relationship be established?
(Modify in vitro test conditions
if appropriate.)
Use all available stability, clinical, and
bioavailability data to establish
appropriate acceptance ranges.
Use the in vitro / in vivo
correlation, along with
appropriate batch data, to
establish acceptance ranges.
Are acceptance
ranges >20% of the
labeled content?
Provide appropriate
bioavailability data
to validate the
acceptance ranges.
Finalize acceptance ranges.

6. USP <711> - Immediate-Release Dosage Forms
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Stage
Number
Tested Acceptance Criteria
S1 6 Each unit is not less than Q + 5%.
S2 6 Average of 12 units (S1 + S2) is equal to or greater than Q,
and no unit is less than Q - 15%.
S3 12 Average of 24 units (S1 + S2 +S3) is equal to or greater than
Q, not more than 2 units are less than Q - 15%, and no unit
is less than Q - 25%.

7. USP <711> - Immediate-Release Dosage Forms (cont.)
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IR - Q: NLT 80% at 30 minutes
30
40
50
60
70
80
90
100
110
0 10 20 30 40 50 60
Time, minutes
%LC
S1
≥85%
Individuals only
S2: N = 12, Mean ≥ 80%;
Individuals ≥ 65%
S3: N = 24, Mean ≥ 80%;
Individuals ≥ 55%;
NMT 2 units are < 65%
Individuals only

8. USP <711> - Extended-Release Dosage Forms
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Stage
Number
Tested Acceptance Criteria
L1 6 No individual value lies outside each of the stated ranges and no
individual value is less than the stated amount at the final test
time.
L2 6 The average value of the 12 units (L1 + L2) lies within each of the
stated ranges and is not less than the stated amount at the final
test time; none is more than 10% of labeled content outside each
of the stated ranges; and none is more than 10% of labeled
content below the stated amount at the final test time.
L3 12 The average value of the 24 units (L1 + L2 + L3) lies within each of
the stated ranges, and is not less than the stated amount at the
final test time; not more than 2 of the 24 units are more than 10%
of labeled content outside each of the stated ranges; not more
than 2 of the 24 units are more than 10% of labeled content below
the stated amount at the final test time; and none of the units is
more than 20% of labeled content outside each of the stated
ranges or more than 20% of labeled content below the stated
amount at the final test time.

9. USP <711> - ER Dosage Forms, Example
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Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
1: NMT 25% at 2 hours
(No Dose Dumping)
2: %LC within 50%~70%
at 6 hours
(Controlled Release)
3: NLT 80% at 9 hours
(Full Release of Drug)
1: NMT 25% at 2 hours
(No Dose Dumping)
2: %LC within 50%~70%
at 6 hours
(Controlled Release)
3: NLT 80% at 9 hours
(Full Release of Drug)
1: NMT 25% at 2 hours
(No Dose Dumping)
2: %LC within 50%~70%
at 6 hours
(Controlled Release)

10. USP <711> - ER Dosage Forms, Example: L1
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Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
L1: Individuals only
All within the stated range 3: NLT 80% at 9 hours
1: NMT 25% at 2 hours
2: %LC within 50%~70% at 6 hours

11. USP <711> - ER Dosage Forms, Example: L2
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Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
1: none is > 35% at 2 hours
2: %LC within 40~80% at 6 hours
L2: N = 12 ( 6 + 6 )
Averages meet L1 criteria
(No one outside the purple circle) 3: none is < 70% at 9 hours

12. USP <711> - ER Dosage Forms, Example: L3
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Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
1: none is > 45% at 2 hours
NMT 2 units > 35%
2: %LC within 30~90% at 6 hours
NMT 2 units are between Purple
and red circles
L3: N = 24 ( 6 + 6 + 12 )
Averages meet L1 criteria
(No one outside the Red circle)
3: NLT 60% at 9 hours
NMT 2 units < 70%

13. Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12
Time, minutes
%LC
USP <711> - ER Dosage Forms,
Dissolution Data Space
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L1
L2
L3

14. USP <711> - Delayed-Release Dosage Forms
Acid Stage
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A
Number
Tested Acceptance Criteria
A1 6 No individual value exceeds 10% dissolved.
A2 6 Average of the 12 units (A1 + A2) is not more than 10%
dissolved, and no individual unit is greater than 25%
dissolved.
A3 12 Average of the 24 units (A1 + A2 + A3) is not more than 10%
dissolved, and no individual unit is greater than 25%
dissolved.

15. USP <711> - Delayed-Release Dosage Forms
Buffer Stage
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B
Number
Tested Acceptance Criteria
B1 6 Each unit is not less than Q + 5%
B2 6 Average of the 12 units (B1 + B2) is equal to or greater than
Q, and no unit is less than Q - 15%.
B3 12 Average of the 24 units (B1 + B2 + B3) equal to or greater
than Q, and not more than 2 units is less than Q - 15%, and
no unit is less than Q - 25%.

16. IR - Q: NLT 80% at 30 minutes
0
10
20
30
40
50
60
70
80
90
100
110
-10 0 10 20 30 40 50 60
Time, minutes
%LCUSP <711> - DR + IR Dosage Forms, Example
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A1: < 10%
A2 & A3: < 25%
B1
B2
B3
[Acid Stage]
B1
B2
B3
B1
B2

17. Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
-2 0 2 4 6 8 10 12 14
Time, minutes
%LCUSP <711> - DR + ER Dosage Forms, Example
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A1: < 10%
A2 & A3: < 25%
[Acid Stage]
B3
B1
B2

18. • Relevant Development Data
• Dissolution Method Development/Validation
• Formulation/Process Development
• Dissolution Test Results for Scale-up/Validation Batches
• Stability Data of Registration Batches at all conditions and
packaging
• Dissolution Data of Batches used in Pivotal Clinical Trials and/or
in Confirmatory Bioavailability Studies
Justification of Specifications
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19. • Physico-chemical properties of the drug substance(s): (such as)
o Solubility & pH-dependency
o pKa
o particle size distribution
o Polymorphic forms
o Others
• Impacts from formulation:
o Formulation design and operating principles (e.g., disso mechanism)
o Excipient properties and functions
o Stability of the drug product
o Efficacy (BA/BE) vs. Dissolution
• Proposed in-vitro dissolution method:
o Media selection
o Apparatus type
o RPM, DPM, Flow rate
o Time points for data collection
Scientific Assessment – Factors may Affect
Dissolution Behavior and Product Performance
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20. • Identify critical factors could impact drug release of the product: (such as)
o Formulation compositions
o Particle size distribution
o Moisture
o Compression force, tablet hardness, friability etc.
• Manufacturing processes, especially those having potential to influence the
release profile of the drug
o E.g., process-induced phase transformation ….
o Control strategy of critical process parameters (CPP’s)
• Available in-vitro dissolution data from development, clinical, bio-availability,
and primary stability batches for a discerning trend on long term storage
(i.e. real time stability data are generated for these lots. Ability to predict
long term stability depends on formulation design, release mechanism….)
• The proposed shelf-life of the drug product based on the stability data as well
as other drug product attributes
Scientific Assessment (cont.)
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21. • Clinical Relevant Specifications (CRS) are those specifications
that help to establish consistent in vivo performance as proven
by their ability to reject batches with inadequate in vivo
performance
• Clinical Relevant Dissolution Methods
o Can be use to define the Design Space for formulation and
process
o Products can be approved based only on the comparability
of their dissolution profiles without having to conduct in
vivo studies
(Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual
Meeting, Washington, DC, October 23, 2011)
Clinical Relevant Dissolution Methods and
Specifications
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22. (Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual
Meeting, Washington, DC, October 23, 2011)
An Ideal Approach for Setting CRS
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23. USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013
23
Illustration: Level A IVIVC (2009 LOL conference)
Deconvolution
Observed or predicted Cp profilesIn vitro drug release
Estimated in vivo input
Disposition Function
IV or IR Cp profiles
IVIVC model
Biostudy
In vivo
-
0.200
0.400
0.600
0.800
1.000
0 5 10 15 20
Time (hr)
%Released
A
B
C
Modeling
relationship
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25
T(hr)
%Released
A
B
C
Convolution
C(t) = f(t)*C(t)
(1) Validation
(2) Prediction
IVIVC plot
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
110.0
0.0 10.0 20.0 30.0 40.0 50.0
In vitro
Invivo
A
B
C
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 4 8 12 16 20 24
Time (hr)
PlasmaConc.
IR
IV
Y. Qiu. In: Developing Oral Dosage Forms: Pharmaceutical Theory and Practice. Edited by Y. Qiu et al..
Academic Press, San Diego, CA. 2009. pp-379-408

24. (Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual
Meeting, Washington, DC, October 23, 2011)
Example –
Selecting the Appropriate Specifications
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25. (Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual
Meeting, Washington, DC, October 23, 2011)
Example –
Evaluation against Bulk Density and Particle Size
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26. (Reference: “Setting Specifications for Dissolution Testing of NR Formulations”,
Presentation by Dr. Alexander Pontius, EUFEPS, Barcelona, Feb. 23-24, 2011)
Example – +/- 10% of bio-lot per Specifications for
ER/MR (At least 3 Spec time points)
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27. (Reference: “Setting Specifications for Dissolution Testing of NR Formulations”,
Presentation by Dr. Alexander Pontius, EUFEPS, Barcelona, Feb. 23-24, 2011)
Example –
Impact from Packaging
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28. (Reference: “Setting Specifications for Dissolution Testing of NR Formulations”,
Presentation by Dr. Alexander Pontius, EUFEPS, Barcelona, Feb. 23-24, 2011)
Example –
Impact from Coating
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29. Conclusions –
• The dissolution specifications are established through the
collaborations among Analytical, Formulation, PK and regulatory
functions, and the CMC team
• Start accumulating the knowledge and collecting the data from Day
1 of development
• Dissolution method needs to be (i) discriminatory and (ii) bio-
relevant if achievable
• Establishing the appropriate dissolution specifications will assure:
o Manufacture of the dosage form is consistent
o Consistent throughout the product’s life cycle
o Each dosage unit within a batch will have the same
pharmaceutical qualities
o To show an adequate safety and efficacy* profile [* disso
alone can’t really reflect efficacy without IVIVC/IVIVR]
29
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013

30. • Dr. Jian-Hwa Han is employed at Abbvie
• Ms. Susan George, Dr. Yihong Qiu and Dr. Paul D.
Curry, Jr. are employed at Abbvie who have
contributed for scientific discussions and reviewing
the presentation materials
• Abbvie fully supports USP’s activities and events
• USP provides the traveling fund for this presentation
Disclosures
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31. Q&A

32. SUB-TITLE, DATE
Back Up Slides

33. ICH Q6A, Decision Tree #7-3
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33
3. What are appropriate acceptance ranges? [extended release]
YES
NO
NO
YES
YES
NO
YES
NO
Are bioavailability
data available for batches
with different drug release rates?
Is drug release independent of
in vitro test conditions?
Can an in vitro / in vivo
relationship be established?
(Modify in vitro test conditions
if appropriate.)
Use all available stability, clinical, and
bioavailability data to establish
appropriate acceptance ranges.
Use the in vitro / in vivo
correlation, along with
appropriate batch data, to
establish acceptance ranges.
Are acceptance
ranges >20% of the
labeled content?
Provide appropriate
bioavailability data
to validate the
acceptance ranges.
Finalize acceptance ranges.