EMA Guidance on MR Dosage Form - PQRI

Safeguarding public health
European <strong>Guidance</strong> on Modified
Release Dosage Forms
Terry Shepard,
Pharmacokinetics Assessor
Medicines and Healthcare products Regulatory Agency
London
PQRI Workshop on Application of IVIVC in Formulation
Development
September 5 - 6, 2012
Bethesda, Maryland
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Disclaimer
The views expressed during this
presentation are those of the
speaker and do not necessarily
represent the views of the MHRA
or the <strong>EMA</strong>/CHMP.
Slide 2
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Outline
European Regulatory System
Status of European <strong>Guidance</strong> on MR Products
MHRA Experience
Key Messages and Opportunities
Slide 3
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European Regulatory System
CHMP
Assessors in National Agencies
National MAs,
National Scientific
Advice
<strong>EMA</strong> … …
Working Parties
e.g. Scientific
Advice/Guidelines
MA: marketing authorisation
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European <strong>Guidance</strong> on MR Products
(currently in revision)
www.ema.europa.eu
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European <strong>Guidance</strong> relating to IVIVC
(currently in revision)
IVIVC Topic Covered
Quality
Section
Clinical
Section
Levels of IVIVC: definitions
Levels of IVIVC: advantages, disadvantages of different levels
Role of IVIVC
• establishing discriminatory power of in vitro dissolution test (Quality)
• clinical relevance of in vitro dissolution tests and associated dissolution
specifications (PK and Clinical)
Programme rationale: choice of formulations for IVIVC study X-ref
Programme rationale: choice of reference formulation
Programme rationale: extending IVIVC beyond IVIVC batches
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European <strong>Guidance</strong> relating to IVIVC
(currently in revision)
IVIVC Topic Covered
Quality
Section
Clinical
Section
Study design: in vitro study design (dissolution media, sampling times) -
Study design: in vivo study design (number of subjects, sampling times) -
IVIVC data analysis: acceptable methodology for model development X-ref
IVIVC validation: assessment of predictability X-ref
IVIVC development and validation: reporting -
Applications: specification setting -
Applications: waiver of BE studies for product variations -
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Why do companies develop IVIVCs
in vitro dissolution = surrogate for BE study
save time and money
Why do regulators encourage IVIVCs
Approval Process
Post-approval
Benefit
Risk
Reassurance that
positive benefit/risk
balance is maintained
throughout life of product
Approval
CHMP Opinion + Annexes (SmPC, Conditions)
Refusal or
Withdrawal
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Examples of MR Product Variations:
Methods
Search of Sentinel database
“granted licenses prolonged release formulations”
385 licenses/69 companies
“Type II variations - pharmaceutical”
63 licenses of interest
Compiled all variations for 63 licenses
3 representative examples +
additional points from 4-5 others
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MR Product Variations: Example 1
23 variations
II
1b
1a
5 pharmaceutical variations
6
5
4
3
2
MA: 2001 1
Label/Leaflet
9
8
7
10
11
12
13
14
23
22
21
20
19
18
17
16
15
2011: 2.5/year
Pharmaceutical variations:
Change chemical identification test
Remove score line
Increase pack size
Change manufacturing site
Change dissolution specification
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MR Product Variations: Example 2
58 variations
II
1b
16 pharmaceutical variations
MA: 1998
1a
Label/Leaflet
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
58
57
56
55
54
53
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
2011: 4.5/year
Pharmaceutical variations:
Change manufacturing site x2
Change batch size, manufacturing
process
Change product specification
(microbiological)
Change storage site
Change analytical methods
Change frequency of IPC
Change shelf life dissolution
specification
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MR Product Variations: Example 3
54 variations
1b
II
MA: 2004
1a
1
2
3
4
5
6
7
8
Label/Leaflet
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
29
28
54
53
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
30 pharmaceutical variations Pharmaceutical variations:
2011: 9/year
Manufacturer, batch release site x 3
Batch size
In process control spec
Add pack size
Add storage and release site
Extend shelf life
Minor change to manufacturing process
Add packaging site
Change manufacturer of active
Change dissolution method, specification
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MR Product Variations: Example 3 (cont’d)
Supporting evidence:
Quality Overall Summary
Batch data
Stability data
IVIVC (Level A)
MA: 2004
1
2
3
4
5
6
7
8
16
15
14
13
12
11
10
9
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
Var 17: 2007
54
53
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
2011: 9/year
Purpose of Variation:
To update the dissolution test
method in line with the USP
monograph and to change the
specification time points and
limits.
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% Released in vitro
% Released in vivo
MR Product Variations: Example 3 (cont’d)
100
100
Upper limit (UL)
Proposed Low and High
80
upper limit
80
60
target
60
Target (Pivotal Batch)
Lower limit (LL)
+
40
20
lower limit
0
0 20 40 60 80 100
40
% Released in vitro
IVIVC
Predicted C(t)
20
0
0 4 8 12 16 20 24
Time (h)
Time (h)
Relative Bioavailability
PK Parameter UL/LL UL/Target LL/Target
Cmax 116 113 97.1
AUC 112 106 94.9
Dissolution Profiles
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% Released in vitro
% Released in vivo
MR Product Variations: Example 3 (cont’d)
100
100
Upper limit (UL)
Proposed Low and High
80
upper limit
80
60
target
60
Target (Pivotal Batch)
Lower limit (LL)
+
40
20
lower limit
0
0 20 40 60 80 100
40
% Released in vitro
IVIVC
Predicted C(t)
20
0
0 4 8 12 16 20 24
Time (h)
Time (h)
Relative Bioavailability
PK Parameter UL/LL UL/Target LL/Target
Cmax 116 113 97.1
AUC 112 106 94.9
Dissolution Profiles
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% Released in vitro
% Released in vivo
MR Product Variations: Example 3 (cont’d)
100
100
Upper limit (UL)
Proposed Low and High
80
upper limit
80
60
target
60
Target (Pivotal Batch)
Lower limit (LL)
+
40
20
lower limit
0
0 20 40 60 80 100
40
% Released in vitro
IVIVC
Predicted C(t)
20
0
0 4 8 12 16 20 24
Time (h)
Time (h)
Relative Bioavailability
PK Parameter UL/LL UL/Target LL/Target
Cmax 116 113 97.1
AUC 112 106 94.9
Dissolution Profiles
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% Released in vitro
% Released in vivo
MR Product Variations: Example 3 (cont’d)
100
100
Upper limit (UL)
Proposed Low and High
80
upper limit
80
60
target
60
Target (Pivotal Batch)
Lower limit (LL)
+
40
20
lower limit
0
0 20 40 60 80 100
40
% Released in vitro
IVIVC
Predicted C(t)
20
0
0 4 8 12 16 20 24
Time (h)
Dissolution Profiles
Time (h)
Relative Bioavailability
PK Parameter UL/LL UL/Target LL/Target
Cmax 116 113 97.1
AUC 112 106 94.9
1. All batches within specification
bioequivalent to each other
2. Proposed limits considered appropriately
supported
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% Released in vitro
% Released in vivo
MR Product Variations: Example 3 (cont’d)
100
100
80
Upper limit (UL)
Proposed Low and High
80
60
upper limit
target
60
Target (Pivotal Batch)
Lower limit (LL)
+
40
20
lower limit
0
0 20 40 60 80 100
40
% Released in vitro
IVIVC
Predicted C(t)
20
0
0 4 8 12 16 20 24
Time (h)
Dissolution Profiles
Time (h)
Relative Bioavailability
PK Parameter UL/LL UL/Target LL/Target
Cmax 116 113 97.1
AUC 112 106 94.9
1. All batches within specification
bioequivalent to each other
2. Proposed limits considered appropriately
supported
Conclusion: Proposed change will not
have a detrimental effect on quality,
safety or efficacy of the product.
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% Released in vitro
% Released in vivo
MR Product Variations: Example 3 (cont’d)
100
80
Upper limit (UL)
Proposed Low and High
100
1. Anchor 80to clinical batches.
60
upper limit
target
60
Target (Pivotal Batch)
Lower limit (LL)
+
40
20
2. Relationship to BE limits.
lower limit
0
0 20 40 60 80 100
40
% Released in vitro
IVIVC
3
Predicted C(t)
20
0
0 4 8 12 16 20 24
Time (h)
Dissolution Profiles
Time (h)
Relative Bioavailability
PK Parameter UL/LL UL/Target LL/Target
Cmax 116 113 97.1
AUC 112 106 94.9
1. All batches within specification
bioequivalent to each other
2. Proposed limits considered appropriately
supported
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% Released in vitro
Dissolution Limits in Product Specifications:
Relationship to BE Limits
100
Upper limit (UL)
Proposed Low and High
IVIVC
in vitro = surrogate for in vivo
(BE) study
80
Target (Pivotal Batch)
60
Lower limit (LL)
40
20
0
0 4 8 12 16 20 24
Time (h)
Dissolution Profiles
Time (h)
80% 125%
Test/Ref (%)
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% Released in vitro
Dissolution Limits in Product Specifications:
Relationship to BE Limits
100
80
Upper limit (UL)
Proposed Low and High
Target (Pivotal Batch)
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
C max .”
NfG CPMP/QWP/604/96
60
40
20
Lower limit (LL)
All batches within dissolution
specification limits should be
bioequivalent to each other.
1
80% 125%
Test/Ref (%)
0
0 4 8 12 16 20 24
Time (h) Time (h)
Dissolution Profiles
All batches should be bioequivalent
to target (pivotal batch).
2
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% Released in vitro
Dissolution Limits in Product Specifications:
Relationship to BE Limits
100
80
60
40
Upper limit (UL)
Proposed Low and High
Target (Pivotal Batch)
Lower limit (LL)
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
C max .”
NfG CPMP/QWP/604/96
All batches within dissolution
specification limits should be
bioequivalent to each other. 1
1
20
0
0 4 8 12 16 20 24
Time (h)
Dissolution Profiles
Time (h)
80% 125%
Test/Ref (%)
UL/LL
UL/target
LL/target
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% Released in vitro
Dissolution Limits in Product Specifications:
Relationship to BE Limits
100
80
60
Upper limit (UL)
Proposed Low and High
Target (Pivotal Batch)
Lower limit (LL)
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
C max .”
NfG CPMP/QWP/604/96
All batches should be bioequivalent
to target (pivotal batch). 2
40
2
20
UL/LL
150% (off-scale)
0
0 4 8 12 16 20 24
Time (h)
Dissolution Profiles
Time (h)
80% 125%
Test/Ref (%)
UL/target
LL/target
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% Released in vitro
Dissolution Limits in Product Specifications:
Relationship to BE Limits
100
80
Upper limit (UL)
Proposed Low and High
Target (Pivotal Batch)
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
C max .”
NfG CPMP/QWP/604/96
60
40
20
Lower limit (LL)
All batches within dissolution
specification limits should be
bioequivalent to each other.
1
80% 125%
Test/Ref (%)
0
0 4 8 12 16 20 24
Time (h) Time (h)
Dissolution Profiles
All batches should be bioequivalent
to target (pivotal batch).
2
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% Released in vitro
% Released in vitro
Impact of IVIVC Validation Range on
Justification of Dissolution Limits
100
IVIVC batches
100
80
80
Dissolution limits
60
60
40
40
20
0
0 4 8 12 16 20 24
Time (h) Time (h)
20
3
0
0 4 8 12 16 20 24
Time (h) Time (h)
Choice of formulations: widest possible range of dissolution
behaviour, balancing need to keep release mechanism the same.
… consider extending IVIVC range.
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Stage
Information Question
Implications for MR Development Program
Target
Specification
Prototype Selection
Formulation
Optimisation
Scale-up
Post-approval
Changes
What in vitro
characteristics will
achieve in vivo
target
Which prototypes
should be tested
in vivo
How must we alter
in vitro release to
achieve in vivo
target
What is a significant
change in the in
vitro profile
• Drug PK
• In vitro dissolution
• Drug PK
• Many batches
• Conc-time data (+IVIVC)• Conc-time data (+IVIVC)
• In vitro dissolution • In vitro dissolution
• Drug PK
• Drug PK
… where extending range of IVIVC, showing applies to pivotal batches - need to consider in
design of these studies and include a reference formulation – requires prospective approach.
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European <strong>Guidance</strong> relating to IVIVC
(currently in revision)
IVIVC Topic Covered
Programme rationale: choice of
formulations for IVIVC study
Programme rationale:
extending IVIVC beyond IVIVC
batches
Applications: specification
setting
Key Points
widest possible range of dissolution behaviour, balancing
need to keep release mechanism the same
sometimes need to extend range of IVIVC, sometimes need
to show applies to pivotal batches; need to consider in
design of these studies and include a reference formulation
alignment to average BE criteria
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Key Messages and Opportunities
Discriminatory Power of
Dissolution Tests
Anchor to Clinical
Batches
ICH Q8
Use IVIVC to interpolate
within a validated range
of dissolution
Q10
Align dissolution
specification to average
BE limits
Opportunities to contribute:
Breakout session H
Upon publication of draft guidance
(ema.europa.eu)
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