English translation of Attachment 3 of PSEHB/PED Notification No.

0319-1, dated
March 19, 2020

Guideline for Bioequivalence Studies for Formulation

Changes of Oral Solid Dosage Forms

Index

Section 1: Introduction
Section 2: Terminology
Section 3: Levels of formulation changes and required tests
1. Levels of formulation changes
2. Required tests
Section 4: Dissolution tests
Section 5: Judgement of dissolution equivalence

Appendix 1. f2 (similarity factor) and time points for comparisons

Appendix 2. Adjusting dissolution curves with lag times
Appendix 3. Method to evaluate effect of film coating on dissolution
Appendix 4. Levels of formulation changes and required tests

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Section 1: Introduction
This guideline describes the principles of procedures of bioequivalence studies for post-
approval changes in the components and composition of oral solid dosage forms other than
the active ingredients, which is hereafter called the formulation changes. The objective of
the guideline is to assure the bioequivalence between products before and after the
formulation change. The tests required for bioequivalence assessment differ depending on
the levels of the formulation changes from the original product whose therapeutic efficacy
and safety were established by clinical studies or whose bioequivalence to the innovator
product was demonstrated by a human bioequivalence study.

Section 2: Terminology
Standard formulation: The formulation for which therapeutic efficacy and safety were
established by clinical studies or bioequivalence to the innovator product was demonstrated
by a human bioequivalence study.

Reference product: The dissolution test (Sec. 4.) should be performed with three lots of
the product before the formulation change, using the following dissolution medium 1) or
2) (limited to the paddle methods at 50 rpm, with 6 vessels or more). Among the three lots,
the one which shows intermediate dissolution should be selected as the reference product.
In the case of Level A change, the specification test conditions can be used when the
dissolution specifications are established in the specifications and test procedures of the
reference product. When the average dissolutions of the three lots reach 85% within 15
minutes, any lots can be used as the reference product.
1) The specification dissolution medium when the dissolution specifications are established
in the specifications and test procedures.
2) Among the dissolution media described in the dissolution conditions in Sec. 4., when
the average dissolution of at least one lot reaches 85%, the dissolution medium
providing the slowest dissolution should be selected. When the average dissolution of
any of the lots does not reach 85%, the dissolution medium providing the fastest
dissolution should be used.

Test product: A product after the formulation change. It is recommended to use a lot
manufactured at the same lot size as the full-scale production. However, a lot manufactured
at a scale of not less than 1/10 of a full-scale production also can be used. The
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manufacturing method of the test product and full-scale production products should be the
same, and quality and bioavailability of both products should be equivalent.
In the case of extended release products, the test product should not significantly differ
from the reference product in size and shape of dosage form, specific gravity and release
mechanism. The dissolution profiles of the test product should be similar to those of the
reference product as required in Sec. 3.B.IV.4 of the Guideline for Bioequivalence Studies
of Generic Products (an attachment of Division-Notification No. 487 of the Pharmaceutical
and Food Safety Bureau dated, on December 22, 1997, (partial revision in PSEHB/PED
Notification No.0319-1, dated March 19, 2020).

Products containing poorly soluble drugs: See Sec. 3.A.V.3.3 of the Guideline for
Bioequivalence Studies of Generic Products.

Section 3: Levels of formulation changes and required tests

1. Levels of formulation changes
The level of formulation changes is calculated based on the standard formulation. The
degree of the changes should be evaluated by separated-calculation of difference of content
(%) regarding “function of excipient and component” as shown in Table 1 and Table 2.
When the calculation is equal to or less than Level B, change level is B. When the
calculation is more than Level B and equal to or less than Level C, the change level is C.
When the calculation is more than Level C and equal to or less than Level D, the change
level is D. The changes more than Level D are Level E.
The level of the formulation changes of the following 1) - 3) is Level A irrespective of
the levels in Table 1 and Table 2.
1) Changes of components described as "trace use".
2) Except narrow therapeutic range drugs, the change of excipients categorized as
"Others" within the range not more than 0.5% (w/w) where the total weight of
formulation is not changed with compensation of the weight change by increasing or
reducing fillers.
3) Except narrow therapeutic range drugs, the exchange of colorant, sweeteners, and
flavoring agents categorized as "Others" in the same use within the range not more
than 1.0% (w/w) as a sum of absolute values of the difference of content (% w/w).
(e.g. change of sweeteners to other sweeteners). When replacing the excipient with a

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 different amount, the amount of filler can be adjusted not to change the total weight
of formulation.
Except narrow therapeutic range drugs, when the change of the film coating weight is
not more than 7.0% (w/w) of core tablet and it is demonstrated that the film coating does
not affect dissolution according to Appendix 3, the change level is B irrespective of the
film coating change levels of Table 2.
The highest level of these changes is defined as the formulation change level to the
product. However, in the case of enteric-coated products, the changes in the diameter of
the units having substantial enteric function from less than 4 mm to more than 4 mm or
more, or vice versa, the change level is E.

Table 1 Levels of Changes in Uncoated Product

Difference of Content (% W/W )
Compared to Standard Formulation
Function of Excipient and Component Ｂ Ｃ Ｄ

Disintegranting agents
Starch ３．０ ６．０ ９．０
Others １．０ ２．０ ３．０
Binders ０．５０ １．０ １．５
Lubricants・Polishers
Stearate salts ０．２５ ０．５０ ０．７５
Others １．０ ２．０ ３．０
Fluidizing agents
Talc １．０ ２．０ ３．０
Others ０．１０ ０．２０ ０．３０
Fillers ５．０ １０ １５
Others １．０ ２．０ ３．０
(Preservatives, Sweeteners, Stabilizers, etc.) 1)
Sum of absolute values of difference of content (%) of changed components ５．０ １０ １５

1)
A change level of excipients categorized as "Others" is also determined by separated-calculation of difference of content (%)
regarding the respective use.
Ignore the components of which composition is described as "trace use".

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Table 2 Levels of Changes in Coated Product
Difference of Content or Rate of Change (%
W/W)
Compared to Standard Formulation
Part Function of Excipient and Component Ｂ Ｃ Ｄ
Core Disintegranting agents
Starch ３．０ ６．０ ９．０
Others １．０ ２．０ ３．０
Binders ０．５０ １．０ １．５
Lubricants・Polishers
Stearate salts ０．２５ ０．５０ ０．７５
Others １．０ ２．０ ３．０
Fluidizing agents
Talc １．０ ２．０ ３．０
Others ０．１０ ０．２０ ０．３０
Fillers ５．０ １０ １５
Others １．０ ２．０ ３．０
(Preservatives, Sweeteners, Stabilizers, etc.) 1)

Sum of absolute values of difference of content (%) of changed ５．０ １０ １５

components
Film coating 2) Sum of absolute values of difference of content (%) of changed ５．０ １０ １５
components in film coating layer 1)

Rate of change (%) of film coating weight/cm2 of surface area of １０ ２０ ３０

core 3)

Sugar coating Sum of absolute values of difference of content (%) of changed ５．０ １０ １５
components in sugar coating layer 1)
Rate of change (%) of sugar-coating weight/cm2 of surface area of １０ ２０ ３０
core 3)
1)
A level of changes of excipients categorized as "Others" is also determined by separated-calculation of difference of content (%)
regarding respective use.
Ignore the components of which composition is described as "trace use".
2)
All coatings, such as water-proofing coating, under coating, enteric coating, and release control coating, are included except
sugar coating.
3)
The surface area of the core is calculated depending on the shape of the formulation. When it is impossible to calculate the
surface area of the shape, it is allowed to assume that the shape of the core is a sphere and the specific gravity of the core is not
changed with the formulation change.

2. Required Tests
For solubility-enhanced products, the dissolution test of the reference product should be performed

according to the conditions shown in Sec. 3 A.V.3.4) of the Guideline for Bioequivalence Studies of

Generic Products. If dissolution of the product reaches 85% within the specified time in three or more

conditions by the paddle method at 50 rpm, the testing conditions should follow those of oral immediate

release products other than products containing poorly soluble drugs. In other cases, the testing

conditions should follow those of products containing poorly soluble drugs.

Level A

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 When the dissolution test is established in the specifications and test procedures of the
reference product, the dissolution test should be performed using 12 vessels or more under
the testing conditions specified in the specifications. However, when it is not established,
perform the dissolution test under the condition shown in Sec. 4. The test and reference
products are regarded as bioequivalent, if their dissolution profiles are judged to be
equivalent according to the criteria in Sec. 5. When the test and reference products are not
regarded as bioequivalent from the results of the dissolution test, a bioequivalence study
should be performed according to the Guideline for Bioequivalence Studies of Generic
Products.

Level B
The dissolution test should be performed under the conditions shown in Sec. 4. When
the film coating change where it is demonstrated that the film coating does not affect
dissolution in products, and the average dissolution of the reference product does not reach
85% in any test conditions specified, the dissolution test in Level A defined above can be
used.
The test and reference products are regarded as bioequivalent, if their dissolution
profiles are judged to be equivalent according to the criteria in Sec. 5. When the test and
reference products are not regarded as bioequivalent from the results of the dissolution tests,
a bioequivalence study should be performed according to the Guideline for Bioequivalence
Studies of Generic Products.

Level C
For immediate release and enteric-coated products, perform the dissolution test shown
in Sec. 4 (unless the product containing poorly soluble drugs). The test and reference
products are regarded as bioequivalent, if their dissolution profiles are judged to be
equivalent according to the criteria in Sec. 5. However, in the case of products containing
the drugs in Table 3 (narrow therapeutic range drugs), the test and reference products are
regarded as bioequivalent, only if their average dissolution at 30 minutes are not less than
85% under all the testing conditions in Sec. 4, and at the same time, their dissolution
profiles are judged to be equivalent according to the criteria in Sec. 5. When the test and
reference products are not regarded as bioequivalent from the results of the dissolution test,
a bioequivalence study should be performed according to the Guideline for Bioequivalence
Studies of Generic Products.

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 For products containing poorly soluble drugs, perform a bioequivalence study
according to the Guideline for Bioequivalence Studies of Generic Products.
For extended release products, perform the dissolution test shown in Sec. 4 (unless the
product contains narrow therapeutic range drugs). The test and reference products are
regarded as bioequivalent, if their dissolution profiles are judged to be equivalent according
to the criteria in Sec. 5. When the test and reference products are not regarded as
bioequivalent from the results of the dissolution test, a bioequivalence study should be
performed according to the Guideline for Bioequivalence Studies of Generic Products.
For products that contain narrow therapeutic range drugs, perform a bioequivalence study
according to the Guideline for Bioequivalence Studies of Generic Products.

Level D
For immediate release products, perform the dissolution test shown in Sec. 4 (unless the
products containing poorly soluble drugs or products containing narrow therapeutic range
drugs). The test and reference products are regarded as bioequivalent, if their average
dissolution at 30 minutes are not less than 85% under all the testing conditions in Sec. 4,
and at the same time, their dissolution profiles are judged to be equivalent according to the
criteria in Sec. 5. When the test and reference products are not regarded as bioequivalent
from the results of the dissolution test, a bioequivalence study should be performed
according to the Guideline for Bioequivalence Studies of Generic Products.
For products containing poorly soluble drugs or products containing narrow therapeutic
range drugs, perform a bioequivalence study according to the Guideline for Bioequivalence
Studies of Generic Products.
Foe extended release products and enteric-coated products, perform a bioequivalence study
according to the Guideline for Bioequivalence Studies of Generic Products.

Level E
Perform a bioequivalence study according to the Guideline for Bioequivalence Studies
of Generic Products.

Table 3 Narrow Therapeutic Range Drugs 1)

Aprindine Carmazepine
Clindamycin Clonazepam
Clonidine Cyclosporine
Digitoxin Digoxin
Disopyramide Ethinyl Estradiol
Ethosuximide Guanethidine
Isoprenaline Lithium
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 Methotrexate Phenobarbital
Phenytoin Prazosin
Primidone Procainamide
Quinidine Sulfonylurea antidiabetic drugscompounds 2)
Tacrolimus Theophylline compounds 3)
Valproic Acid Warfarin
Zonisamide Glybuzole
1)
Whether drugs approved after 1999 belong to the narrow therapeutic category or
not, should be determined referring to the above listed drugs.
2)
Acetohexamide, glibenclamide, gliclazide, glyclopyramide, tolazamide,
tolbutamide
3)
Aminophylline, choline theophylline, diprophylline, proxyphylline, theophylline

Section 4. Dissolution tests

The dissolution test should be performed according to the conditions shown in Sec.
3.A.V, Sec. 3.B.IV, and Sec. 3C.IV. in the Guideline for Bioequivalence Studies of Generic
Products, however, the paddle method at 75 rpm cannot be used instead of that at 50 rpm.
In the case that active ingredient is adsorbed to excipients or vessels in water, 0.2% sodium
chloride solution can be used instead of water. When polysorbate 80 is added to the
dissolution media for the dissolution tests of products containing poorly soluble drugs, the
concentration should not exceed 0.1%. In the case of enteric-coated products, the following
test condition should be added. When sodium lauryl sulfate is used, the solubility of active
ingredient in the sodium lauryl sulfate-buffer solution should be not more than that in
polysorbate 80 buffer solution at the stipulated maximum concentration.

Test: Paddle method at 50 rpm, using 900 mL of dissolution media adjusted at pH 6.0 by
0.01 mol/L of disodium hydrogen phosphate and 0.005 mol/L citric acid.

Section 5. Judgement of equivalence of dissolution profiles

Dissolution profiles of the test and reference products are judged to be equivalent, when
they meet both requirements (1) and (2) shown below under each dissolution test condition.
The average dissolution of the reference product should reach 85% within the testing time
specified at least under one test condition in the case of immediate release products and
enteric-coated products, and should reach 80% in the case of extended release products.
The prescribed testing time is specified in Sec. 3.A.V.2, Sec. 3.B.IV.2 or Sec. 3.C.IV.2 in
the Guideline for Bioequivalence Studies of Generic Products. In addition, when similarity
factor, f2 is used for the judgement, the time points for comparing dissolution rates specified

8
in Appendix 1(2) should be employed. When there is a lag time for dissolution of the
reference product in immediate release products and enteric-coated products, it is allowed
to adjust the dissolution curve with the lag time (Appendix 2), and the acceptance criteria
can be applied after the lag time, however, the difference in average lag time between the
test and reference products should be within 10 minutes.
When the dissolution comparison time points are less than 15 minutes, it is acceptable
that the dissolution profiles are estimated at 15 minutes. When the lag time between the
test and reference products is compensated, the 15 minutes means the time before the
adjustment.
In the case of enteric-coated products, it is acceptable that the dissolution profiles are
estimated at the stipulated dissolution time (after 2 hours) of pH 1.2 dissolution medium.

(1) Average dissolution rate

1) When the average dissolution of the reference product reaches 85% within 15 minutes:
the average dissolution of the test product reaches 85% within 15 minutes or is within
that of the reference product ±10% at 15 minutes.
2) When the average dissolution of the reference product reaches 85% at between 15 and
30 minutes: the average dissolution of the test product are within that of the reference
product ±10% at two appropriate time points when the average dissolution of the
reference product are around 60% and 85%. Or f2 value is not less than 50.
3) When the average dissolution of the reference product does not reach 85% within 30
minutes: the results meet one of the following criteria.
Immediate release products and enteric-coated products
a. When the average dissolution of the reference product reaches 85% within the
testing time specified: the average dissolution of the test product are within that of
the reference product ±10% at two appropriate time points when the average
dissolution of the reference product are around 40% and 85%. Or f2 value is not
less than 50.
b. When the average dissolution of the reference products reaches 50% and does not
reach 85% within the testing time specified: the average dissolution of the test
product are within that of the reference product ±8% at the testing time specified
and at an appropriate time point when the average dissolution of the reference
product reaches about a half of the average dissolution at the testing time specified.
Or f2 value is not less than 55.
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 c. When the average dissolution of the reference product does not reach 50% within
the testing time specified: the average dissolution of the test product are within
that of the reference product ±6% at the testing time specified and at an appropriate
time point when the average dissolution of the reference product is about a half of
the average dissolution at the testing time specified. Or f2 value is not less than 61.
However, when the average dissolution of the reference products is not more than
10% at the stipulated dissolution time, the average dissolution of the test product
is within that of the reference product ±6% at the testing time specified only.
Extended release products
a. When the average dissolution of the reference product reaches 80% within the
testing time specified: the average dissolution of the test product are within that of
the reference product ±10% at three appropriate time points when the average
dissolution of the reference product are around 30%, 50% and 80%. Or f2 value is
not less than 50.
b. When the average dissolution of the reference product reaches 50% and does not
reach 80% within the testing time point: the average dissolution of the test product
are within that of the reference product ±8% at the testing time specified and at an
appropriate time point when the average dissolution of the reference product
reaches about a half of the average dissolution at the testing time specified. Or f2
value is not less than 55.
c. When the average dissolution of the reference product does not reach 50% within
the testing time specified: the average dissolution of the test product are within that
of the reference product ±6% at the testing time specified and at an appropriate time
point when the average dissolution of the reference product is about a half of the
average dissolution at the testing time specified. Or f2 value is not less than 61.
However, when the average dissolution of the reference products is not more than
10% within the testing time specified, the average dissolution of the test product is
within that of the reference product ±6% at the testing time specified only.

(2) Individual dissolution rate

Each individual dissolution rate of the test product (out of n=12) should meet one of
the following criteria at the last point where the average dissolution of the test product
is compared to that of the reference product.
a. When the average dissolution of the reference product reaches 85% (80% for
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 extended release products): the number of the test product of which dissolution is
out of the range of the average dissolution of the test product ±15% and ±25%
should be "1 or less" and "0", respectively.
b. When the average dissolution of the reference product reaches 50% and does not
reach 85% (80% for extended release products): the number of the test product of
which dissolution is out of the range of the average dissolution of the test product
±12% and ±20% should be "1 or less" and "0", respectively.
c. When the average dissolution of the reference product does not reach 50%: the
number of the test product of which dissolution is out of the range of the average
dissolution of the test product ±9% and ±15% should be "1 or less" and "0",
respectively.

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Appendix 1. f2 (similarity factor) and time points for comparisons
(1) Definition of f2
The following equation defines f2, Ti and Ri show the average dissolution of the test and
reference products at the time point (i), respectively, and n is the number of time points at
which the average dissolution are compared.

 
 
 
 100 
f 2  50 log  
 
n

 ( Ti  Ri )
2
 
i 1
 1 
 n 

(2) Time points for f2

1) When the average dissolution of the reference product reaches 85% (80% for extended
release products) between 15 and 30 minutes: 15, 30, 45 minutes.
2) When the average dissolution of the reference product reaches 85% (80% for extended
release products) between 30 minutes and the testing time point specified: at Ta/4, 2Ta/4,
3Ta/4 and Ta, where Ta is the time point at which average dissolution of the reference
product reaches approximately 85% (80% for extended release products).
3) When the average dissolution of the reference product does not reach 85% (80% for
extended release products) within the testing time point specified: at Ta/4, 2Ta/4, 3Ta/4
and Ta, where Ta is the time point at which average dissolution of the reference product
reaches approximately 85% (80% for extended release products) of the amount
dissolved at the testing time point specified.

Appendix 2. Adjusting dissolution curves with lag times

The lag time is defined as the time when 5% of the labeled claim of the active ingredient
dissolves from the product. A lag time should be determined for respective product by
linear interpolation, and then respective dissolution curve is obtained by adjusting
dissolution curve with the lag time. Average dissolution curves of the test and reference
products are obtained, which can be used for the assessment of dissolution equivalence.

Appendix 3. Method to evaluate effect of film coating on dissolution

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1) When the average dissolution of the reference product reaches 85% in at least one test
condition: the dissolution tests of core tablets (or uncoated tablets) and film-coated tablets
for before and after the film-coating change should be performed under the conditions
shown in Sec. 4. Note that only the paddle method at 50 rpm should be used for the test of extended
release products. When the dissolution profile of the film-coated tablets before and after the

film-coating change is judged to be equivalent to the corresponding core tablets according

to the criteria in Sec. 5, it should be considered that the film coating does not affect
dissolution. Core tablets (or uncoated tablets) and film-coated tablets manufactured by the
same manufacturing method and process as those of the reference and test products can be
used.
2) When the average dissolution of the reference product does not reach 85% in any of the
test conditions: using a high solubility drug such as acetaminophen etc, core tablets of
which the components and composition except the active ingredient are the same and the
average dissolution of the core tablets reach 85% in all the test conditions are applied.
Using the obtained core tablets, model film-coated tablets before and after the film-coating
change are prepared respectively. The dissolution tests of the core tablets and model film-
coated tablets before and after the film-coating change should be performed under the
conditions shown in Sec. 4. Note that only the paddle method at 50 rpm should be used for
the test of extended release products. When the dissolution profile of the model film-coated
tablets before and after the film-coating changes are judged to be equivalent to the core
tablets according to the criteria in Sec. 5, it should be considered that the film coating does
not affect dissolution.
In any of the above cases of 1) or 2), when the composition rate is the same in the film-
coated tablets before and after the film-coating change, the dissolution comparison can be
done only for the thicker-film coated tablets (film-coated tablets of which the amount of
film coating is higher).
The above 1) or 2) can be also applied to the changes from plain tablets to film-coated
tablets and vice versa.

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Appendix 4. Levels of formulation changes and required tests
（Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage Forms）
Immediate/ Rapid 3)/Non-rapid
Level Therapeutic range1) Poorly soluble/Soluble Confirmation of bioequivalence
Extended Release dissolution
Non-narrow
When the dissolution specification is established: if the dissolution profiles are judged to be equivalent in the dissolution test shown
Immediate Release4) Narrow (only for changes
in the specifications, the test and reference products are regarded as bioequivalent.
A Enteric-coated products of components of which
When the dissolution specification is not established: if the dissolution profiles are judged to be equivalent in the dissolution test
Extended release composition is described as
shown in Sec. 4., they are regarded as bioequivalent4).
"trace use"
If the dissolution profiles are judged to be equivalent in the dissolution test shown in Sec. 4., they are regarded as bioequivalent.
Immediate Release4)
In the case of film coating change where it is demonstrated that film coating does not affect dissolution of products and the average
B Enteric-coated 2)
dissolution of the reference product does not reach 85% in any test conditions specified, the dissolution test defined in Level A can be
Extended Release
used. If the dissolution profiles are judged to be equivalent, they are regarded as bioequivalent.

Soluble If the dissolution profiles are judged to be equivalent in the dissolution test shown in Sec. 4., they are regarded as bioequivalent.
Non-narrow
Poorly soluble Follow the Guideline for Bioequivalence Studies of Generic Products.
Immediate Release4)
Enteric-coated 2) Rapid If the dissolution profiles are judged to be equivalent in the dissolution test shown in Sec. 4., they are regarded as bioequivalent.
Soluble
C Narrow Non-rapid
Follow the Guideline for Bioequivalence Studies of Generic Products.
Poorly soluble

Non-narrow If the dissolution profiles are judged to be equivalent in the dissolution test shown in Sec. 4., they are regarded as bioequivalent.
Extended Release
Narrow Follow the Guideline for Bioequivalence Studies of Generic Products.

Rapid If the dissolution profiles are judged to be equivalent in the dissolution test shown in Sec. 4., they are regarded as bioequivalent.
Soluble
Non-narrow Non-rapid
Immediate Release4)
D Poorly soluble
Narrow Follow the Guideline for Bioequivalence Studies of Generic Products.

Enteric-coated 2)
Extended Release
Immediate Release
E Enteric-coated 2) Follow the Guideline for Bioequivalence Studies of Generic Products.
Extended Release
1) Non-narrow: Drugs that are not listed in Table 3 Narrow: Drugs that are listed in Table 3
2) In the change of the diameter of the units having substantial enteric function from less than 4 mm to 4 mm or more, or vice versa, the formulation change of the level is E, and bioequivalence studies at fed state should be additionally performed.
3) Average dissolutions of the reference and test products reach 85% at 30 minutes under all the testing conditions in Sec.4.
4) For solubility-enhanced products, the dissolution test of the reference product should be performed according to the conditions shown in Sec. 3 A.V.3.4) of the Guideline for Bioequivalence Studies of Generic Products. If dissolution of the product reaches

14
85% within the specified time in three or more conditions by the paddle method at 50 rpm, the testing conditions should follow those of oral immediate release products. In other cases, the testing conditions should follow those of products containing
poorly soluble drugs.

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