Regulatory Response to BCS in Japan BCS : 日本における ... - NIHS

Harmonization, Globalization and Innovation in Pharmaceutical
Science and Technology, September 26, 2005
Regulatory Response to BCS in Japan
Nobuo Aoyagi, Ph.D.
National Institute of Health Sciences

In pharmaceutical regulation, it is
important to reduce burdensome tests
while efficacy and safety are ensured
maximally.
In bioequivalence (BE) tests, human
tests should be reduced as much as
possible where dissolution test may be
used as a surrogate. But…

Flufenamic acid
capsule
Kaniwa,
Int.J.Cl.Pharm.Ter.Tox.,
21, 56, 1983
% dissolved
% dissolved
Paddle at 120 rpm
100
80
60
40
20
0
80
60
40
20
A
B
C
D
0 60 120 180
Time (h)
pH 7.6
Indomethacin
100
capsule pH 7.2
Concentration (ug/ml)
Serum concentration
Concentration (ug/ml)
10
2.5
2.0
1.5
1.0
0.5
8
6
4
2
0
0 2 4 6 8
Time (h)
Capsule C
Capsule D
Capsule A
Capsule B
Aoyagi, Int.J.Cl.Pharm.Ter.Tox.,
23, 529, 1985
0
0 30 60
Time (min)
0.0
0 2 4 6 8
Time (h)

Outline
• Concept of BCS
• BE Test in Japan
• Reason for Not using BCS
• Conclusion

Unreliable in vitro/in vivo correlation (IVIVC)
Limit the use of dissolution test as a surrogate for
human test in BA/BE studies
Other approaches are needed
without relying on IVIVC alone
Mechanistic analysis of drug absorption

Biopharmaceutics Classification System (BCS)
Permeability
Low High
High
Class 1
High solubility (HS)
High permeability (HP)
Class 3
Solubility
High solubility (HS)
Low permeability (LP)
Low
Class 2
Low solubility (LS)
High permeability (HP)
Class 4
Low solubility (LS)
Low permeability (LP)
HS : Highest dose is soluble in

Rate limiting step in gastrointestinal (GI) absorption
BCS GI absorption IVIVC
Class 1
Gastric emptying-limited
Not expected
(HS / HP)
if dissolution is rapid
Class 2
Dissolution-limited Expected
(LS / HP)
Class 3
(HS / LP)
Class 4
(LS / LP)
Permeability-limited Not expected
Dissolution or ?
permeability-limited
IVIVC : in vitro/in vivo correlation

Great Contribution of BCS in
Pharmaceutical Regulation
• Enable the use of dissolution test for
Biowaiver of minor change in
formulation & manufacturing in U.S.A.
• Currently being used for biowaiver of
multi-source products in WHO Guideline

Cinnarizine
capsules
Ogata, Int.J.Pharm.
29, 113, 1986
Concentration (ng/ml)
100
80
60
40
20
Normal subject
B
C
Concentration (ng/ml)
100
80
60
40
20
Achlorhydric
subject
B
C
0
0 2 4 6 8
Time (h)
0
0 2 4 6 8
Time (h)
Achlorhydria (%)
80
60
40
20
0
10 20 30 40 50 60 70
Age (year)
Achlorhydric subject (%) in
each age category
Morihara, Biol.Pharm.Bull., 24, 313,2001

• BE test for whom and in whom ?
• How to assure BE in normal and achorhydric
subjects? Can we require BE tests in both groups?
• Is dissolution testing truly of no use for BE
assessment ?
Need to clarify why in vitro/in vivo
correlations are unreliable

In Vivo : Dynamic
In Vitro : Static
pH 1.2 - 7.6
Fluid volume 5 - 200 ml
pH 3.1- 6.7
Contraction

To predict in vivo performance, dissolution test
must be done under various conditions (different
pH, ionic strength, agitation etc).
Not suitable for BE test
Is there simpler approach ?
Based on current understanding of GI physiology
and learned knowledge, discriminative
dissolution tests should be established that are
able to discriminate Bioinequivalent products.
What is the discriminative dissolution tests ?

Discriminative dissolution test
IR products
No dose-dumping
• Low mechanical stress (e.g. Paddle method)
• Low agitation (e.g. 50 rpm)
• Multiple pHs in a physiological pH range
• No surfactant
especially under vigorous conditions
CR products
Dose-dumping
• Low and high mechanical stress (Paddle and
Disintegration apparatus)
• Low and high agitation (50 and 200 rpm)
• Multiple pHs in a physiological pH range
• Low and high concentrations of surfactant
• Low and high ionic strength

Paddle method
Dissolution Test for IR products
Acidic drug Basic drug Coated product
Neutral drug
50 rpm pH 1.2 pH 1.2 pH 1.2
pH 5.5-6.5 pH 3.0-5.0 pH 3.0-5.0
pH 6.8-7.5 pH 6.8 pH 6.8
Water Water Water
100 rpm A discriminative pH between pH 1.2 – 7.5

Paddle, 50 rpm
100
Predicted Level
0.8
80
60
40
20
pH 1
Convolution
0.6
0.4
0.2
A
B
0
0.0
100
0.8
80
60
40
20
pH 4
0.6
0.4
0.2
A
B
0
0.0
% dissolved
100
80
60
40
20
0
pH 7
0 20 40 60
Concentration (ug/ml)
0.8
0.6
0.4
0.2
0.0
A
B
0 2 4 6
Time (min)
Time (h)

Similar dissolution at all pHs by
discriminative in vitro tests
Likely bioequivalent without
subject-formulation interaction
No need of strict human study
(decrease of sample size or waiver of
human study)

Different dissolutions under one
of conditions
They may not be bio-inequivalent
inequivalent
in some types of subjects
Strict human study using discriminative
subjects such as achlorhydric subject

100
80
60
40
20
0
Dissolution Predicted Observed
pH 1
0 20 40 60
.
.
A
E
Convolution
7
6
5
4
3
2
1
0
0 5 10 15 20 25
7
6
5
4
3
2
1
Normal
subjects
0
0 5 10 15 20 25
% dissolved
100
80
60
40
20
0
0 20 40 60
Time (min)
pH 7
Metronidazole Tablets
Concentration (ug/ml)
7
6
5
4
3
2
1
0
0 5 10 15 20 25
Time (h)
Concentration (ug/ml)
7
6
5
4
3
2
1
0
Achlorhydric
subjects
0 5 10 15 20 25
Time (h)
Ogata. Int.J.Pharm.Ther.Tox.
23, 277, 1985.

Use of Dissolution Test in BE Assessment
1. Generic drug
• Exemption from 90 % confidence interval (C.I.)
If dissolutions are similar, test products will be
approved even if 90 % C.I. of Cmax or AUC is
out of 80 - 125 %.
• Strict human test using specific subjects
If dissolutions differ at pH 6.8, achlorhydric
subjects are required in human test.
2. Minor change in formulation and different strengths
If dissolutions are similar, , human test can be
exempted for all drugs.

BCS was not introduced in our BE tests, although
we discussed its advantage and disadvantage.
Why ?
The reason will be shown in following slides.

Bioavailability
Same
Bioavailability
Dissolution in
digestive tract
Same
Dissolution in
digestive tract
Formulation
Manufacturing
Reference product
Identical
Formulation
Manufacturing
Test product

Bioavailability
Differ
Bioavailability
Dissolution in
digestive tract
Differ
Dissolution in
digestive tract
Formulation
Manufacturing
Reference product
Differ
Formulation
Manufacturing
Test product
Solubility and permeability are not directly related
to difference in BA

Reason 1
Solubility and permeability are not
immediate causes for Bioinequivalence
which is mainly caused by differences in
formulation & manufacturing.

Reason 2
In U.S.A., BCS is employed to increase the use
of dissolution test for Biowaiver in minor change
in formulation & manufacturing while it will
decrease the use in Japan, if introduced, where
multimedia dissolution tests are extensively
applied (BCS does not give merits).
BE can be assured by the
multimedia test without relying
on BCS?
BE of most IR products will be assured

• Strict requirement using specific subjects
if dissolutions differ
• Waiver of 90 % confidence interval
if dissolutions are similar
Consequently compel
To produce generic products showing
comparable in vitro dissolutions
Most generic companies
have enough capability
Accumulation of in vitro and in vivo data in generic
companies (1997-2005)

Questionaire Survey to Generic Companies (n=14)
March, 2005
Q : All your products,
showing similar dissolution,
passed human BE test ?
Failed
(27 %)
Question to failed
companies
Q : Percentage of
failed products / total
Passed
(73 %)
< 5 %
(All companies)
Failure ratio of human BE test < 1.4 % (= 27 × 5 %)

Multimedia dissolution tests used in
Japan function well to ensure BE even
for generic IR products which differ from
innovator products in formulation and
manufacturing.

Test Medium of Dissolution tests for Minor Changes
in Excipients (Level 2 in USA = Level C in Japan)
U.S.A.
Japan
BCS
For all drugs
Class 1 : 0.1N HCl Multi-media ( pH 1.2,
Class 2 : Compendial medium pH 3-6, pH6.8, Water)
Class 3 : Multi-media (0.1N HCl,
pH 4.5, pH 6.5, pH7.5)
Class 4 : (Human test)
BCS Simplify
dissolution medium
Multiple PHs are necessary
to ensure BE in normal and
achlorhydric subjects and to
check formulation effects

% dissolved
100
50
0
100
0 20 40 60 80
Time (min)
pH 1.2
(USP Medium)
A
E
pH 7.2
Concentration (ug/ml)
6
4
2
A - Fasting
E - Fasting
A - Fed
E - Fed
% dissolved
50
0
0
0 5 10 15 20 25 30 35
0 20 40 60 80
Time (h)
Time (min)
Metronidazole (Class 1) : sugar coated tablets
Ogata, Int.J.Cl.Pharm.Ther.Tox. 24, 279, 1986

pH 1.2
(USP Medium)
80
pH 4.6
Normal subject
350
Achlorhydric
subject
% dissolved
60
40
20
A
C
Concentration (ng/ml)
300
250
200
150
100
50
A
C
0
0 10
0 20 40 60
Time (min)
0
0 2 4 6
Time (min)
Diazepam (Class 1) : plain tablets
0 2 4 6
Time (min)
Ogata. Int.J.Pharm.Ther.Tox., 23, 277 (1985)

Reasons for Not using BCS
• Solubility and permeability are properties of drugs but
not properties of formulation & manufacturing that cause
Bioinequivalence.
• BCS is used to increase the use of dissolution test in USA
while it will decrease the use in Japan where dissolution
tests are extensively applied (BCS does not give merits).
• BE of most IR products will be assured by the multimedia
dissolution test used in Japan which does not need BCS.
• BCS is employed to simplify dissolution tests in U.S.A. but
can’t be in Japan. Multimedia test is needed when effects
of excipients on dissolution and BE assurance in normal
and achlorhydric subjects are considered.
• Permeability is still not known for many drugs, making it
difficult to use BCS in our regulation because regulatory
equivalence tests can’t be shown for such drugs.

Disadvantage of dissolution test
• Difficult to emulate in vivo condition completely
due to our limited understanding of gastrointestinal
(GI) variables affecting dissolution.
• Difficult to assess excipient’s effect on permeability
• Difficult to assess GI transition of drug products
which affects dissolution.
• Artificial sink condition (large fluid volume,
addition of surfactant)
Difficult to predict in vivo performance of some
products containing low solubility drugs and some
modified release products.

Use of BCS as a Risk Factor
BCS is currently not employed in Japan, which,
however, should be used as a risk factor when
dissolution test is expanded to “Biowaiver” for
major changes in formulation and manufacturing
and even for generic products, when the
disadvantages of dissolution tests are considered.
By the combination use of dissolution test and
BCS, significant bio-inequivalence
inequivalence problems will
be avoided, leading to the reduction of patient’s s risk
(Immediate application of dissolution test for all
classes of drugs is risky).

Risk Factors to be Considered for Biowaiver
Low Risk
High
BCS Class 1 Class 4
Dosage form
Drug release
Therapeutic window
Diseases
Adverse effect
Elimination half life
Simple
IR
Wide
Nonserious
Mild
Long
Complicated
CR
Narrow
Serious
Severe
Short

To use dissolution test for biowaiver
• Give a theoretical bases for using
dissolution tests
BCS (U.S.A)
• Increase the reliability of dissolution
test by improving the test
Multimedia test (Japan)

Conclusion
• BCS enables the use of dissolution test for biowaiver in
USA, which, however, is not used in Japan with several
reasons (extensive use of dissolution tests in Japan,
solubility & permeability are not immediate causes of
bioinequvalence).
• When use of dissolution tests is expanded to biowaiver
for major changes in formulation & manufacturing and
for generics, BCS should be considered as a risk factor.
• BCS will contribute to develop predictable new drugs
and to decrease meaningless IVIVC studies.
• Considering inter-subject difference in gastrointestinal
physiology, it is important to establish dissolution tests
that are able to ensure BE in various subjects.