1. - Pharmaceutical Equivalence Study
KFDA drug approval system
- Pharmaceutical Equivalence Study
2013
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2. Purpose and Definition
- Verify the pharmaceutical equivalence between two products with same API, strength and dosage form
Bioequivalence test
Comparative dissolution test
Comparative disintegration test

3. Purpose and Definition
Subjects of application
Prescription pharmaceutical drug (ETC drug) : tablets, capsules and suppositories
Non-prescription pharmaceutical drug (OTC drug) : tablets, capsules and suppositories as single active ingredient
Changes of the followings;
- raw materials and their quantities
- manufacturing method
- manufacturing site

4. Purpose and Definition
1. Bioequivalence test
- in vivo study to verify the statistical equivalence in bioavailability between two drug products with the same active ingredient and route of administration that are absorbed into the systemic circulation and become available at the site of action.
<Subjects >
Approved after Jan , prescription pharmaceuticals falling into new drug (including same route of administration, but in different dosage form)
Pharmaceuticals notified by MFDS’s Commissioner which are needed for equivalence test

5. Purpose and Definition
2. Comparative dissolution test
- verity the similarity to dissolution profile between two drug products
<Subjects >
Prescription pharmaceuticals with the exclusion of bioequivalence test product
tablets, capsules and suppositories as single OTC preparation
3. Comparative disintegration test
- verity the similarity to disintegration profile between two drug products
such as Herbal medicine, Lactobacillus and Enzyme preparations

6. Reference drug (Positive Control)
Reference drug in case of NDA
Approved drug product which safety and efficacy were established
Recognized as a reference drug product by MFDS
Reference drug in case of change of approval
Principle : Pre-manufactured drug according to the current license
Exception ; can use the notified reference drug
Not verified for equivalence
No manufacturing history or exceed expirary date so that there is not suitable product for equivalence test

7. Test drug
Test drug
Should be a final form and meet the following criteria;
final product
the quality and content should meet its “in-house specification and test method”
batch size: at least 100,000 units.
If the commercial batch size is smaller than 100, 000 units, the batch size of final product can be acceptable.
either the total content/potency of the active drug substance according to “in-house specification and test method” is within 5% of labeled content(100%) of reference , or the difference in content/potency between test and reference drug is within 5%.

8. Bioequivalence test Criteria for waivers of BE test
An oral solution such as syrups, elixirs, tinctures (except emulsion and suspension) and topical solutions
same API , concentration and dosage form with an approved product & do not contain any excipient that affects drug absorption
Injections, ophthalmic solutions, and otic solutions
- same API and concentration with an approved product
It should be assured that following excipients do not affect the action of active ingredient
Injections : preservative, buffering agent, antioxidant
Ophthalmic solutions and otic solutions : preservative, buffering agent, isotonizing agent, viscosity adjustive

9. Bioequivalence test Criteria for waivers of BE test
Topical drug product with non-systemic effect
Inhalation product as gas or vapor with local effect
Fluids, blood volume expanders, and artificial perfusion agents
Digestive enzyme preparation
Blood product
Herbal medicinal product
Vaccine
Lactobacillus preparation

10. Comparative dissolution test
Test condition
Water soluble product
Poorly water soluble product
; in the water soluble product condition (1)~(4), mean dissolution rate within the set time < 85%
Apparatus
Test solution (pH)
Time
Additional test
Apparatus 2 (50rpm)
1.2
4.0
6.8
Water
pH 1.2: 2hr
Others: 6hr
In the condition (1)~(3), mean dissolution rate of reference drug < 85% (100rpm)
Apparatus
Test solution (pH)
Apparatus 2 (50rpm)
1.2
4.0
6.8
Water
(1)~(4) all test solution + solubilizer

11. Comparative dissolution test
Test condition
Enteric coated product
Poorly water soluble, enteric coated product
Apparatus
Test solution (pH)
Time
Additional test
Apparatus 2 (50rpm)
1.2
6.0
6.8
pH 1.2: 2hr
Others: 6hr
In the pH 6.0 solution, mean dissolution rate of reference drug < 85% (100rpm)
Apparatus
Test solution (pH)
Time
Additional test
Apparatus 2 (50rpm)
1.2
6.0
6.8
(2)&(3) + solubilizer
pH 1.2: 2hr
Others: 6hr
In the pH 6.0 and 6.8 solution, mean dissolution rate of reference drug < 85%

12. Comparative dissolution test
Test condition
Controlled release product
Apparatus
Test solution (pH)
Time
Additional test
Apparatus 2 (50rpm)
1.2
4.0
6.8
Water
(3) + polysorbate80 etc. 1.0 w/v%
pH 1.2: 2hr
Others: 24hr
In the pH 6.8 solution, mean dissolution rate of reference drug < 85%
Apparatus 1 (100rpm)

13. Comparative dissolution test
Test solution
pH 1.2: “solution 1” of “Disintegration test” in KP
pH 4.0: Acetate buffered solution
pH 6.0: sodium phosphate · citric acid buffered solution in KP reagent section
pH 6.8: “solution 2” for “Disintegration test” in KP
Volume of Solution: in principle, 900mL
Temperature of Solution: 37 ± 0.5 ℃

14. Comparative dissolution test
Result report
- Including followings
Title, object, test period and summary of result
CoA of quality control (content or potency; more than 3 times)
CoA of active ingredient
Description of the manufacturing process of the test drug product
Information of test institution (name, address, equipments etc.)
Manufacturing (import) manager’s name
Test method
test condition
validation data of dissolution test
comparison of the dissolution profile in reference drug and test drug
Conclusion of manufacturing (import) manager

15. Interpretation of equivalence
Immediate release & Controlled release product
category
Mean dissolution rate (reference drug)
Point of comparison
standard
Immediate release & Enteric coated product
85% within 15min
around 85%
mean dissolution rate ± 15%
85% within 15~30min
around 60%, 85%
mean dissolution rate ± 15% or similarity factor(f2) ≥50
85% after 30min
around 40%, 85%
< 85%
In the point of interpretation, 50%<dissolution rate<85%
In the point of interpretation, dissolution rate<50%
mean dissolution rate ± 8% or similarity factor(f2) ≥55
Controlled release product
< 50%
around 30,50, 80%
(if below 80%, final point)
± 10% or similarity factor(f2) ≥55
50~85%
(if below 80%, final point)
± 10% or similarity factor(f2) ≥50
≥ 85%
± 10% or similarity factor(f2) ≥40

16. Interpretation of equivalence
In case of formulation changes,
category
Mean dissolution rate (reference drug)
Point of comparison
standard
Mean dissolution rate
85% within 15min
around 85%
mean dissolution rate ± 10%
85% within 15~30min
around 60%, 85%
mean dissolution rate ± 10% or similarity factor(f2) ≥50
not reach 85% within 30min
Final dissolution rate <50%
around 1/2dissolution rate, the set time
mean dissolution rate ± 6% or similarity factor(f2) ≥60
50~85%
mean dissolution rate ± 8% or similarity factor(f2) ≥55
≥ 85%
around 40%, 85%
individual dissolution rate
< 50% at final point
mean dissolution rate of test product > ± 9%
; max. 1 product, but not > ± 15%
50~85% at final point
mean dissolution rate of test product > ± 12%
; max. 1 product, but not > ± 20%
≥ 85% at final point
mean dissolution rate of test product > ± 15%
; max. 1 product, but not > ± 25%

17. Comparative disintegration test
This test can be performed when the comparative dissolution test is impossible because of product property.
Should be based on a scientific basis such as preliminary experimentation .
Examples ;
- such as Herbal medicine, Lactobacillus and Enzyme preparations
- can not get the reasonable analysis method
- can not analyze because of microanalysis

18. Revision of approval (formulation change)
Level of formulation changes
According to table I & II, determine the level of change
- equal to or less than the range of level B  level B
- the change in excipients in the range between B and C  level C
- the change in excipients in the range between C and D  level D
- any change in coloring or flavoring agent  level A
Among the changes, the highest level of change is defined as the level of formulation change.

19. Revision of approval (formulation change)
[Table I] Level of change in excipients for uncoated product
Excipient category and
component
Percent excipient (w/w) compared to
total dosage form weight (%) B C D
Disintegrant
Starch
Other
3.0
1.0
6.0
2.0
9.0
Binder
0.50
1.5
Lubricant․Polisher
Stearate and its salt
0.25
0.75
Glidant
5.0 10 15
Other (except coloring and flavoring agents)
The total additive effect of all excipient changes

20. Revision of approval (formulation change)
[Table II] Level of change in excipients for coated product
Core / coated layer
Excipient category and
component
Percent excipient (w/w) compared to
total dosage form weight (%) B C D
Core
Disintegrant
Starch
Other
3.0
1.0
6.0
2.0
9.0
Binder
0.50
1.5
Lubricant․Polisher
Stearate and its salt
0.25
0.75
Glidant
5.0 10 15
Other (except coloring and flavoring agents)
The total additive effect of all excipient changes in core
Film-coated layer
The total additive effect of all excipient changes in film coated layer
Sugar-coated layer
The total additive effect of all excipient changes in sugarcoated layer

21. Revision of approval (manufacturing process change)
Level of change in the manufacturing process & kind of test
Level
Range
Kind of test A
Addition/change of a volatile solvent used as coating agents
Change the weighing process or packaging process
Chang the description of the product
Change the size of the capsule
No effect on the product equivalence
no need to equivalence test B
Addition/change of API manufacturer
Not A, C or D level
Change of batch size
Comparative dissolution test or Comparative disintegration test C
Change of the assembling method
Change of the combination solution (organic solvent, water etc.)
Change of the manufacturing process condition ( time, rate etc.) D
Change of the manufacturing process that effects on the product quality
Bioequivalence test

22. Revision of approval (manufacturing site change)
Level of change in the manufacturing site & kind of test
Level
Range
Kind of test A
Change to the site that manufacture the product approved by bioequivalence test
Change the site of weighing process or packaging process
No effect on the product equivalence
no need to equivalence test B
Change the manufacturing site of same manufacturer & no change the formulation and manufacturing process
Comparative dissolution test or Comparative disintegration test C
Change the manufacturing site of same manufacturer & change the formulation and manufacturing process
Not A or B level