Approaches to IVIVC Development for Regulatory Success

Approaches to IVIVC Development for Regulatory Success

Safeguarding public health
Approaches to IVIVC
Development for Regulatory
Success
Terry Shepard,
Pharmacokinetics Assessor
Medicines and Healthcare products Regulatory Agency
London
PharmSci 2012
12th - 14th September 2012
Nottingham, UK
©
Disclaimer
The views expressed during this
presentation are those of the
speaker and do not necessarily
represent the views of the MHRA.
Slide 2
©
Outline
Revision of European Guidance on MR Products
MHRA Experience
Nuances in IVIVC Development
Key Messages and Opportunities
Slide 3
©
European Guidance on MR Products
(currently in revision)
www.ema.europa.eu
Slide 4
©
European Guidance relating to IVIVC
(currently in revision)
Quality
Section
Clinical
Section
Levels of IVIVC: definitions
9
9
Levels of IVIVC: advantages, disadvantages of different levels
9
9
• establishing discriminatory power of in vitro dissolution test (Quality)
• clinical relevance of in vitro dissolution tests and associated dissolution
specifications (PK and Clinical)
9
9
Programme rationale: choice of formulations for IVIVC study
9
X-ref
Programme rationale: choice of reference formulation
9
9
Programme rationale: extending IVIVC beyond IVIVC batches
9
9
IVIVC Topic Covered
Role of IVIVC
Slide 5
©
European Guidance relating to IVIVC
(currently in revision)
Quality
Section
Clinical
Section
Study design: in vitro study design (dissolution media, sampling times)
9
-
Study design: in vivo study design (number of subjects, sampling times)
-
9
IVIVC data analysis: acceptable methodology for model development
X-ref
9
IVIVC validation: assessment of predictability
X-ref
9
-
9
Applications: specification setting
9
-
Applications: waiver of BE studies for product variations
9
-
IVIVC Topic Covered
IVIVC development and validation: reporting
Slide 6
©
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
Reassurance that
positive benefit/risk
balance is maintained
throughout life of product
Slide 7
©
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
Slide 8
©
MR Product Variations: Example 1
2011: 2.5/year
23 variations
23
22
21
II
Label/Leaflet
20
19
18
17
1b
16
1a
15
14
5 pharmaceutical variations
13
12
11
10
9
8
7
6
5
4
3
MA: 2001
Pharmaceutical variations:
•
•
•
•
•
Change chemical identification test
Remove score line
Increase pack size
Change manufacturing site
Change dissolution specification
2
1
Slide 9
©
MR Product Variations: Example 2
2011: 4.5/year
58 variations
58
57
56
55
54
53
52
II
51
Label/Leaflet
50
49
48
47
46
45
44
43
42
41
1b
40
1a
39
38
37
36
35
34
33
16 pharmaceutical variations
32
31
30
29
28
27
26
Pharmaceutical variations:
•
•
25
24
23
22
21
20
•
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
MA: 1998
3
2
1
•
•
•
•
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
Slide 10
©
MR Product Variations: Example 3
2011: 9/year
54 variations
54
53
52
51
50
II
49
Label/Leaflet
1b
48
47
46
45
44
43
42
41
40
39
38
37
1a
36
35
34
33
32
30 pharmaceutical variations
8
7
6
5
4
MA: 2004
3
2
1
Pharmaceutical variations:
•27
26
25
•
24
23
22
•
21
20
19
•
18
17
•
16
15
14
•
13
12
•
11
10
9
•
•
•
31
30
29
28
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
Slide 11
©
MR Product Variations: Example 3 (cont’d)
2011: 9/year
Supporting evidence:
•
•
•
•
54
53
Quality Overall Summary
Batch data
Stability data
IVIVC (Level A)
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
Purpose of Variation:
To update the dissolution test
method in line with the USP
monograph and to change the
specification time points and
limits.
20
19
18
17
16
15
Var 17: 2007
14
13
12
11
10
9
8
7
6
5
4
MA: 2004
3
2
1
Slide 12
©
MR Product Variations: Example 3 (cont’d)
100
100
Proposed
Low(UL)
and High
Upper
limit
Target (Pivotal Batch)
60
+
% Released in vivo
80
% Released in vitro
upper limit
80
target
60
→
40
lower limit
20
Lower limit (LL)
0
0
20
40
60
80
100
% Released in vitro
40
IVIVC
Predicted C(t)
20
PK Parameter
Cmax
AUC
0
0
4
8
Time (h)
UL/LL
116
112
Relative Bioavailability
UL/Target
113
106
LL/Target
97.1
94.9
12
Time (h
Dissolution Profiles
Slide 13
©
MR Product Variations: Example 3 (cont’d)
100
100
Proposed
Low(UL)
and High
Upper
limit
Target (Pivotal Batch)
60
+
% Released in vivo
80
% Released in vitro
upper limit
80
target
60
→
40
lower limit
20
Lower limit (LL)
0
0
20
40
60
80
100
% Released in vitro
40
IVIVC
Predicted C(t)
20
PK Parameter
Cmax
AUC
0
0
4
8
Time (h)
UL/LL
116
112
Relative Bioavailability
UL/Target
113
106
LL/Target
97.1
94.9
12
Time (h
Dissolution Profiles
Slide 14
©
MR Product Variations: Example 3 (cont’d)
100
100
Proposed
Low(UL)
and High
Upper
limit
Target (Pivotal Batch)
60
+
% Released in vivo
80
% Released in vitro
upper limit
80
target
60
→
40
lower limit
20
Lower limit (LL)
0
0
20
40
60
80
100
% Released in vitro
40
IVIVC
Predicted C(t)
20
PK Parameter
Cmax
AUC
0
0
4
8
Time (h)
UL/LL
116
112
Relative Bioavailability
UL/Target
113
106
LL/Target
97.1
94.9
12
Time (h
Dissolution Profiles
Slide 15
©
MR Product Variations: Example 3 (cont’d)
100
100
Proposed
Low(UL)
and High
Upper
limit
Target (Pivotal Batch)
60
+
% Released in vivo
80
% Released in vitro
upper limit
80
target
60
→
40
lower limit
20
Lower limit (LL)
0
0
20
40
60
80
100
% Released in vitro
40
IVIVC
Predicted C(t)
20
PK Parameter
Cmax
AUC
0
0
4
8
Time (h)
Dissolution Profiles
UL/LL
116
112
Relative Bioavailability
UL/Target
113
106
LL/Target
97.1
94.9
12
Time (h
1.
2.
All batches within specification
bioequivalent to each other
Proposed limits considered appropriately
supported
Slide 16
©
MR Product Variations: Example 3 (cont’d)
100
100
Proposed
Low(UL)
and High
Upper
limit
Target (Pivotal Batch)
60
+
% Released in vivo
80
% Released in vitro
upper limit
80
target
60
→
40
lower limit
20
Lower limit (LL)
0
0
20
40
60
80
100
% Released in vitro
40
IVIVC
Predicted C(t)
20
PK Parameter
Cmax
AUC
0
0
4
8
Time (h)
Dissolution Profiles
UL/LL
116
112
Relative Bioavailability
UL/Target
113
106
LL/Target
97.1
94.9
12
Time (h
1.
All batches within specification
bioequivalent
to each
other will not
Conclusion:
Proposed
change
2. a Proposed
limits effect
considered
have
detrimental
on appropriately
quality,
supported
safety or
efficacy of the product.
Slide 17
©
MR Product Variations: Example 3 (cont’d)
100
100
Anchor to clinical batches.
80
Target (Pivotal Batch)
% Released in vitro
upper limit
80
60
+
% Released in vivo
Proposed
Low(UL)
and High
Upper
limit
1.
target
60
→
40
lower limit
2. Relationship to BE limits.
20
Lower limit (LL)
0
0
20
40
60
80
100
% Released in vitro
40
IVIVC
3
Predicted C(t)
20
PK Parameter
Cmax
AUC
0
0
4
8
Time (h)
Dissolution Profiles
UL/LL
116
112
Relative Bioavailability
UL/Target
113
106
LL/Target
97.1
94.9
12
Time (h
1.
2.
All batches within specification
bioequivalent to each other
Proposed limits considered appropriately
supported
Slide 18
©
Dissolution Limits in Product Specifications:
Relationship to BE Limits
IVIVC → in vitro = surrogate for in vivo
(BE) study
100
Proposed
Low(UL)
and High
Upper
limit
80
% Released in vitro
Target (Pivotal Batch)
60
Lower limit (LL)
40
20
0
0
4
8
Time (h)
12
Time (h
80%
Test/Ref (%)
125%
Dissolution Profiles
Slide 19
©
Dissolution Limits in Product Specifications:
Relationship to BE Limits
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
Cmax.”
NfG CPMP/QWP/604/96
100
Proposed
Low(UL)
and High
Upper
limit
80
% Released in vitro
Target (Pivotal Batch)
60
Lower limit (LL)
All batches within dissolution
specification limits should be
bioequivalent to each other. 1
40
20
?
80%
0
0
4
8
Time (h)
12
Time (h
Test/Ref (%)
125%
All batches should be bioequivalent
to target (pivotal batch).
2
Dissolution Profiles
Slide 20
©
Dissolution Limits in Product Specifications:
Relationship to BE Limits
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
Cmax.”
NfG CPMP/QWP/604/96
100
Proposed
Low(UL)
and High
Upper
limit
80
% Released in vitro
Target (Pivotal Batch)
60
Lower limit (LL)
All batches within dissolution
specification limits should be
bioequivalent to each other. 1
40
1
20
UL/LL
0
0
4
8
Time (h)
12
UL/target
Time (h
LL/target
Dissolution Profiles
80%
Test/Ref (%)
125%
Slide 21
©
Dissolution Limits in Product Specifications:
Relationship to BE Limits
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
Cmax.”
NfG CPMP/QWP/604/96
100
Proposed
Low(UL)
and High
Upper
limit
80
% Released in vitro
Target (Pivotal Batch)
60
Lower limit (LL)
All batches should be bioequivalent
to target (pivotal batch).
2
40
2
20
UL/LL
150% (off-scale)
0
0
4
8
Time (h)
12
UL/target
Time (h
LL/target
Dissolution Profiles
80%
Test/Ref (%)
125%
Slide 22
©
Dissolution Limits in Product Specifications:
Relationship to BE Limits
“…limits are based on a maximal difference
of 20% in the predicted AUC and, if relevant
Cmax.”
NfG CPMP/QWP/604/96
100
Proposed
Low(UL)
and High
Upper
limit
80
% Released in vitro
Target (Pivotal Batch)
60
Lower limit (LL)
All batches within dissolution
specification limits should be
bioequivalent to each other. 1
40
20
?
80%
0
0
4
8
Time (h)
12
Time (h
Test/Ref (%)
125%
All batches should be bioequivalent
to target (pivotal batch).
2
Dissolution Profiles
Slide 23
©
Impact of IVIVC Validation Range on
Justification of Dissolution Limits
IVIVC batches
100
100
80
80
% Released in vitro
% Released in vitro
Dissolution limits
60
40
60
40
20
20
0
0
0
4
8
12
16
3
0
4
Time (h) Time (h)
8
12
16
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.
Slide 24
©
Stage
What in vitro
characteristics will
achieve in vivo
target?
Information
Target
Specification
Question
Implications for MR Development Program
• Drug PK
Prototype Selection
Which prototypes
should be tested
in vivo?
• In vitro dissolution
• Drug PK
Formulation
Optimisation
How must we alter
in vitro release to
achieve in vivo
target?
Scale-up
Post-approval
Changes
What is a significant
change in the in
vitro profile?
• 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.
Slide 25
©
European Guidance relating to IVIVC
(currently in revision)
IVIVC Topic Covered
Key Points
Programme rationale: choice of widest possible range of dissolution behaviour, balancing
formulations for IVIVC study
need to keep release mechanism the same
Programme rationale:
sometimes need to extend range of IVIVC, sometimes need
extending IVIVC beyond IVIVC to show applies to pivotal batches; need to consider in
batches
design of these studies and include a reference formulation
Applications: specification
setting
alignment to average BE criteria
Slide 26
©
Nuances in IVIVC Development
Choice of test formulations (QbD)
Choice of reference formulation (BCS)
Changing permeability
pH-dependent drug release
Time-scaling
GIT = Complex biological system
Pharmacokinetic linearity
Convolution/deconvolution
Average versus population IVIVC
Slide 27
©
Key Messages and Opportunities
ICH Q8
Discriminatory Power
of Dissolution Tests
Anchor to Clinical
Batches
Use IVIVC to
interpolate within a
validated range of
dissolution
Align dissolution
specification to
average BE limits
Q10
Opportunities to discuss/contribute:
•
•
Product specific: Scientific Advice (National/CHMP)
Upon publication of draft guidance (ema.europa.eu)
Slide 28
©
Safeguarding public health
Extra Slides
©
European Regulatory System
CHMP
National MAs,
National Scientific
Advice
Assessors in National Agencies
EMA
…
…
Working Parties
e.g. Scientific
Advice/Guidelines
MA: marketing authorisation
Slide 30
©