Standard on Pharmaceutical Equivalence Study · pharmaceutical equivalence study shall be performed...

Standard on Pharmaceutical Equivalence Study

Ministry of Food & Drug Safety Notification No. 2014-150 (Sep. 2, 2014, Amended)

CHAPTER 1 General Provisions

Article 1 (Purpose) In accordance with Articles 4(1) and 5(2) of the 「Regulations on Safety

of Pharmaceuticals, etc.」 and Article 57 of the 「Act on the Control of Narcotics, etc.」,

the purpose of this Notification is to set forth the appropriate standards for

Pharmaceuticals control by providing for details concerning the scope, testing method

and evaluation criteria for product subject to the pharmaceutical equivalent study

(including psychotropic drugs).

Article 2 ① The definitions of the terms used in this Notification shall be as follows:

1. The term "Pharmaceutical equivalence study" means an in vivo or in vitro test such as

bioequivalence study, comparative dissolution test, comparative disintegration test

performed to prove the pharmaceutical equivalence of two formulations with the

same active ingredient, strength and dosage form.

2. The term "Test drug" means a pharmaceutical subject to a test as described in

Subparagraph 1 that has the same active ingredient, strength and dosage form as

the that of reference drug.

3. The term "Reference drug" means a pharmaceutical to be compared with test drug

that verified its safety and efficacy as previously approved pharmaceutical

manufacturing/marketing or recognized its validity as a reference drug by the Minister

of Ministry of Food and Drug Safety (MFDS).

4. Deleted <Sep. 26, 2012>

5. The term "Bioavailability" means the rate and extent to which an active ingredient or

its active metabolites is absorbed from a drug product into the systemic circulation.

6. The term "Pharmaceutical product" means the finished pharmaceutical end product to

be administered in the form of tablet, capsule, or suppository, etc. containing active

ingredients.

7. The term "Study Population" means an individual (hereinafter referred to as "subjects")

or animal that is administered either test drug or reference drug.

8. The term "Protocol" means a plan prescribing study objective, study population, study

method.

9. The term "Bioequivalence study report" means a comprehensive written report of the

results obtained from the bioequivalence study.

10. The term "Drug substance with narrow therapeutic index" means an ingredient listed

in Attached Table 1 or there is less than a 2-fold difference in median lethal dose

(LD50) and median effective dose (ED50) values, or have less than a 2-fold difference

in the minimum toxic concentrations (MTC) and minimum effective concentrations

(MEC) in the blood, or comparatively small differences in dose or concentration lead

to dose- and concentration-dependent, serious therapeutic failures and/or serious

adverse drug reactions.

11. The term "Comparative dissolution test" means a pharmaceutical equivalence test

described in the Chapter 3.

12. The term "Comparative disintegration test" means refer to a pharmaceutical

equivalence test described in the Chapter 4.

Article 3 (Scope of Application) ① Products to be conducted the pharmaceutical equivalence

study as per this notification are as follows:

1. Prescription drugs in the form of tablets, capsules or suppositories

2. Over-the-counter drugs in the form of tablets, capsules or suppositories in a single

preparation

3. In the case of changing the following items among approved(notified) pharmaceuticals

falling under subparagraph 1 and 2 above

a. Components and composition (according to the Attached Table 2-1)

b. Manufacturing method (according to the Attached Table 3)

c. Manufacturing site (according to the Attached Table 4)

d. The strictest criteria shall be applied in case of more than two of the matters in

clauses (1) through (3) intended to be changed.

② Of the products prescribed in Paragraph 1, pharmaceuticals to conduct the bioequivalence

study shall be as follows:

1. Products required to submit bioequivalence data in accordance with Article 4(1)(3) of

the 「Regulations on Safety of Pharmaceuticals, etc.」

2. Products required bioequivalence study in accordance with Article 3(1)(3)

③ Notwithstanding paragraph 1, pharmaceutical equivalence study shall not be performed if

falling into any of the following subparagraphs:

1. Products that has been approved(notified) or intended to application for approval(notification)

as pharmaceuticals for export only.

2. Pharmaceuticals directly prepared by a doctor/dentist in accordance with Article 23(4)(6)

of the 「Pharmaceutical Affairs Act」 and Article 15 of the 「Enforcement Rule of the

Pharmaceutical Affairs Act」

Article 3-2 (Selection Criteria for Reference Drug, etc. product) ① Among approved(notified)

pharmaceuticals drugs with the same active ingredient, strength, dosage form and

administration route, the reference drug shall be selected in the order of following

subparagraphs:

1. The new drug that is defined in accordance with Article 2 of the 「Pharmaceutical

Affairs Act」 and approved of pharmaceutical manufacturing (import) as prescription

drug

2. The first domestically approved product of original developer (limited to the cases

where the product is proven by credible such as R&D Focus and Pharma Project, etc.)

3. The products on which bioequivalence study was performed with a product prescribed

in subparagraph 1 or 2 as a reference drug (when the applicable products are more

than one, the selection is determined by Subparagraph 4).

4. The product with the highest claim quantity of medical expense of health insurance

submitted to the Health Insurance Review & Assessment Service from Jan. 1 to Dec.

31 of the previous year by the healthcare institutions as described in Article 43 of the

「National Health Insurance Act」 (the selection order is based on the claim quantity

of medical expense of health insurance at the time of selection of reference drug.

However, the selection is determined in order of precedence when related association

assures that products have been withdrawn, canceled, or manufacture/import of

product has been discontinued.)

5. The first domestically approved product

6. In case of extended-release product, pharmaceutical difference (for example, release

system) was proven by the comparative dissolution test.

7. The product that is adequate based on a review of the data on bioavailability and a

person who intends to submit pharmaceutical equivalence study data proved that the

product of the same strength dose and dosage form cannot be obtained due to the

discontinued manufacture and import.

8. The product, for which the justification of directions and dose is acceptable (for

example, 100mg～200mg per 1 time dose), that is adequate for and Pharmaceutical

equivalence study with the dosage multiplied by an integer (for example, 200mg of

reference drug (1 capsule) and 100mg of test drug (2 capsules)).

② Among approved(notified) pharmaceuticals, if there is not a product with the same

active ingredient, strength, dosage form and administration route, then a product shall be

regarded as a reference drug as soon as it is approved(notified).

③ Notwithstanding paragraph 1, according to each items of Article 3(1)(3), if there is an

intention to change the items of previously approved(notified) pharmaceuticals, the drug

manufactured (imported) in accordance with the provisions prior to the change is

deemed to be the reference drug product. However, if there are no products that were

manufactured (imported) in accordance with the provisions prior to the change or the

expiration date has elapsed, then the pharmaceuticals prescribed in paragraph 1 may be

used as a reference drug.

④ The Minister of MFDS shall post a list of designated reference drugs on the online

web-site in accordance with paragraphs 1 and 2. However, if an investigator wishing to

perform a pharmaceutical equivalence study proves that the designated reference drug

cannot be procured for reasons of suspended production, etc., then the reference drug

concerned shall be removed from the list of reference drugs and a new reference drug

shall be selected and added to the list.

Article 4 (Selection of Test Drug) The test drug shall be a finished product that meets the

following subparagraphs:

1. Concerned product shall be manufactured with the same drug substance and

formulation and under the same conditions when it is approved (notified) for

manufacture/import and made available in the market, and shall meet its own

specifications for content and quality, etc.

2. The production scale of the test drug shall be at least 100,000 units. If the scale of

production for the finished product is less than 100,000 units, then a product from

the production batch of the finished product shall be used.

3. The content or the potency of test drug that was tested in accordance with its own

specifications shall be less than 5% of difference compared with the labeled content

(100%) of reference drug or the difference of content and potency of test drug is

less than 5% compared with that of reference shall be selected for use (not

applicable to test drug in comparative disintegration test.

4. Test drug shall be approved according to Article 31 of the 「Pharmaceutical Affairs

Law」 or is acceptable to paragraph 8(14) of "Good Clinical Practice" in the Attached

Table 4 of the 「Regulations on Safety of Pharmaceuticals, etc.」 and submitted with

the results of the test performed in accordance with the company's self-test

standards and the information on the testing method.

Article 5 (Conduct of Pharmaceutical Equivalence Study, etc.) ① In accordance with this

Notification and 「Standard on Bioequivalence Study Management」(MFDS Notification),

pharmaceutical equivalence study shall be performed on the test drug and the

reference drug, and a results report shall be prepared in accordance with Articles 18,

20 and 25 and submitted to the Minister of MFDS.

② In case a product is selected or is to be selected as a reference drug in accordance

with Article 3-2, a dissolution or disintegration test shall be performed in accordance

with this Notification and the results report prescribed in Articles 20 and 25 shall be

submitted to the Minister of MFDS. However, the test may be performed as per the

dissolution test conditions prescribed in the specification and test method.

③ Notwithstanding paragraph 2, in accordance with Article 4(5) of the 「Regulations on

Pharmaceuticals Approval, Notification, and Review」 (MFDS Notification), in case the

pharmaceutical equivalence study data were already submitted for the process of

product approval, application and/or nortification, then the process of submitting a

results report may be omitted.

④ The pharmaceutical equivalence study shall be performed at the pharmaceutical

manufacturing (importing) site or a place with the facilities and equipment, etc.,

necessary to perform the test.

Article 6 (Evaluation) ① The Minister of MFDS evaluates the results of the

pharmaceutical equivalence study performed in accordance with Article 5 (1) based

on the equivalence criteria for the bioequivalence study, or the comparative

dissolution test or the comparative disintegration test prescribed in Chapters 2

through 4.

② The Minister of MFDS may be advised by the Central Pharmaceutical Affairs

Council when evaluating the results of pharmaceutical equivalence study.

CHAPTER 2 Bioequivalence Study TEST

Article 7 (Waiver of Bioequivalence Study) ① In principle, the pharmaceuticals described in

the following subparagraphs are waived from bioequivalence study:

1. Orally administered solutions such as syrups, elixirs, tinctures, etc. (excluding

emulsions and suspensions, etc.) and externally applied topical solutions of which

active ingredients and concentrations are same with those of the previously

approved(notified) pharmaceuticals and of which excipients do not affect absorption

of active ingredients.

2. Injections, ophthalmic solutions, and otic solutions of which raw materials are same

with those of the previous approval(notification). The following excipients may be

different from those of the previous approval(notification). In this case, it shall be

demonstrated that such difference will not affect the action of the active drug

substance (e.g. stability data, etc.)

A. Preservatives, buffering agents, anti-oxidants for injections

B. Preservatives, buffering agents, isotonic agents, and viscosity controlling agents

for ophthalmic solutions, and otic solutions

3. Externally applied preparations intended for local treatment without the expectation

of systemic effects

4. Inhalationally administered preparations of which active drug substance in gas or vapor

5. Rehydration solutions, blood expanders, and artificial irrigation solutions

6. Digestive enzyme preparations

7. Blood preparations

8. Herbal medicines (oriental medicines)

9. Vaccines preparations

10. Probiotics

② In the case of an orally administered solid product that has the same active

ingredient and dosage form, but in a different strength as the product made by the

same manufacturer of which bioequivalence has been recognized, a comparative

dissolution data can be provided in substitution in accordance with the criteria set

forth in Attached Table 2-2. However, in the case of a product with higher strength

than the product with recognized bioequivalence, the linear elimination kinetics of the

active substance shall be proven within the approved therapeutic dose range and it is

deemed to be safe, considering the characteristics of the active ingredients.

③ When orally administered tablet or capsule is proven to meet the criteria in Attached

Table 5, its bioequivalence test can be waived. Provided, that drug substance with

narrow therapeutic index, preparations whose characteristics in its dosage form such

as extended release products, and preparations absorbed in the oral cavity such as

sublingual tablets, and buccal tablets shall be excluded.

④ The Minister of MFDS may post a notice on ingredients deemed to have high

solubility or permeability based on the results of the review performed according to

the criteria in of the Attached Table 5.

Article 8 deleted <Sep. 26, 2012>

Article 9 (Selection of Study Population) ① In principle, study population shall be healthy

volunteers. However, in case of any of the following, patients may be recruited as study

population if approved by the Minister of MFDS. In this case, the reason for the change

and objective and scientific ground for supportive data shall be submitted.

1. It is deemed to be more appropriate to perform the study on patients

2. If there are safety or ethical issues such as using anti-malignant tumor agent on

healthy individuals, etc.

Article 10 (Selection of Subjects) Of the study population recruited through a public notice

of the bioequivalence study, healthy adults meeting the following criteria shall be

selected, in principle. However, individuals deemed suitable for the purpose of the

study by the doctor-in-charge in consideration of their age and health conditions may

be selected as study subjects. In this case, the physician's opinion on the individual's

health status shall should be included in the case report form.

1. Individuals shall be 19 years of age or older at the time of health examination

2. Individuals with no congenital or chronic diseases and no abnormal findings or

symptoms found during an internal physical examination (EEG, EKG, thoracic,

gastroscopy or gastrointestinal (GI) tract radiography test, if necessary)

3. Individuals deemed to be suitable as study subjects based on the results of a

clinical laboratory test such as blood pathology test, blood chemistry test and

urine test, etc. ordered and conducted by the doctor-in-charge according to the

characteristics of the pharmaceuticals

4. In the case of female subjects, individuals who have been confirmed to be not

pregnant at the time of health examination

Article 11 (Exclusion Criteria for Subject) Individuals who fall into any of the following

subparagraphs shall be excluded from the subject group.

1. Individuals who has taken drug-metabolizing enzyme induction and/or inhibition drug

such as barbital, etc. or engaged in excessive drinking within 1 month before the

start of the study

2. Individuals who has taken a drug with concerns of hindering the study within 10 days

before the start of the study

3. Individuals deemed to be unsuitable for the bioequivalence study by the doctor-in-charge

4. Individuals who has participated in a bioequivalence study or other clinical study

within 3 months before the start of the study

Article 12 (Management of Subjects) ① Food and beverage intake of subjects shall be

carefully controlled and subjects should fast for 10 hours prior to administration.

② Water will be allowed as desired except for 1 hour before and after drug

administration.

③ Subjects shall refrain from lying down for at least 2 hours after the administration of

the drug and maintain their posture and actions to minimize the effect on the blood

flow and movement in the gastrointestinal system.

Article 13 (Number of Subject) The number of subjects shall be based on an appropriate

sample size calculation and active ingredient. The number, in principle, shall should

be at least 12.

Article 14 (Method for Bioequivalence Study) ① In principle, in vivo study is recommended

that estimates the bioavailability on the basis of blood concentration of active

ingredient or active metabolites. Subjects will be randomized into 2 sequences and

bioequivalence study is recommended a single dose study under fasting conditions in

the same day, two-treatment, two-period (2×2) crossover with an adequate washout

period in accordance with Article 15(2)(4). In case of bioequivalence study using urine

excretion or other study designs, the rationale for the study design shall be provided.

② For extended-release product, fed conditions shall be performed in addition to the

test performed under fasting conditions as per Article 1. For the fed conditions, the

subjects shall be randomly assigned for a 2x2 crossover test and have a high-fat

meal (over 900Kcal with more than 35% fat content) before the administration of a

dose of the test drug or the reference drug.

Article 15 (Bioequivalence Study Conduct) ① A comparative dissolution test shall be

performed on the reference drug and the test drug from the same production lots as

the those used in the bioequivalence study, and dissolution test methods are selected

appropriately depending on the characteristics of the pharmaceuticals. However, if test

drug is applicable to the conditional regulation of Article 25(2)(9) of the 「Regulation on

Safety of Drugs, etc.」, comparative dissolution test may not be performed.

② Bioequivalence Study

1. Dosage

a. In principle, a single-dose study with clinical dosage is recommended. However, if

there are problems in the analysis of a single-dose study due to the high

detection limit of the analysis method, then multiple-dose is acceptable within the

range of maximum daily dose.

b. In case of the following, a multiple-dose may be administered to reach the

steady state concentration for the test.

(1) In case there is no difference in the extent of absorption extent, but there is

difference in the rate of absorption.

(2) In case there is a significant difference in bioavailability depending on the indiv

idual.

(3) In the case of a extended release product

2. Adminstration Method

a. Single-dose Administration

(1) In principle, administration of the drug product is following in fasting

condition of at least 10 hours before and 4 hours after. However, the drug

may be administered after a meal if there is a scientific basis or a special

purpose. In this case, the meal consumed by the subjects shall be as

identical as possible and the drug shall be administered 30 minutes after the

meal.

(2) For fed study of extended-release product, the subjects shall fast for at least

10 hours before being given an identical high-fat meal to be finished within

20 minutes and the drug shall be administered in 30 minutes after the start

of the meal.

(3) The drug shall be administered with 100~200 ml (normally 150 ml) of water.

b. For multiple-dose study, the first dose of administration is usually taken in fasting

state, the following doses with the same interval are administered in between

meals, to ensure that the steady state is fully reached.

3. Sampling for the analysis of the active ingredient or active metabolites of the

pharmaceuticals from the blood or urine shall be collected with appropriate time

point and sufficient frequency to ensure that all the parameters necessary for the

assessment of bioavailability can be calculated. In addition, the time points and

frequency of sampling of test and reference drugs shall should be the same. For

products with special absorption characteristics, such as products requiring

immediate drug action and extended-release products, sampling frequency and time

points must be set based on accurate scientific basis such as pharmacokinetics

data of the reference drug.

a. Blood Collection

(1) Blood collection shall be conducted with sufficient time period of more than 3

times the elimination half life or AUC0-t to reach at least 80% of AUC∞. For

products that demonstrate long half-life and low within-subject variability in

distribution and clearance, blood samples shall be collected for at least 72 hr.

(2) It is recommended that blood sampling needs more than 12 times and more

than twice blood collection before reaching to the highest blood concentration

(Cmax). Total number of sampling can be determined based on the period of

sampling and time to reach Cmax.

(3) When test and reference drugs are compared depending on blood

concentration-time curve at steady state after multiple doses, sufficient number

of blood collection is required to assess the maximum blood concentration

(Css,max) and the minimum blood concentration (Css,min).

b. Urine Collection

(1) Urine samples shall be collected in the same manner as blood samples.

(2) During urine sample collection, subjects are recommended to complete

urination, if blood sampling and urine collection are simultaneously conducted,

blood shall be collected in the middle of urine sampling.

(3) Whenever comparison of test and reference materials is based on cumulative

excreted amount in urine-time curves at steady state, urine samples shall be

collected with sufficient number of times to estimate the rate and extent of

urinary excretion.

4. Washout periods in crossover studies between administrations of test and

reference drugs shall usually be at least more than 5 times the elimination half life

of the active substance to be measured.

5. Analytical Target and Methods

a. Analytical target shall be an active substance or active metabolite(s) in a blood

or urine sample that is considered to be in proportion to the parent drug. For

combination drug products, all active substances shall be analyzed, in principle.

b. Analytical methods shall be fully validated regarding specificity, linearity,

accuracy, precision, and sufficient sensitivity to measure the actual concentration

of the analytical target.

6. Equipment, Materials, and Reagents

a. Every equipment used in the study shall be equipped with audit trails that can

maintain and retain all the operation records.

b. Chemicals, reagents, and solutions shall be managed to facilitate their

identification.

7. Management of Samples for Analysis

a. The receipt date and received amount/quantity of samples for analysis and the

amount/quantity used in the study shall be recorded and the records shall be

retained.

b. Procedures for the handling and storage of the analysis samples shall be

established.

c. The container for storage shall be labeled with the information necessary for

identification.

Article 16 (Add-on subject study tests) In case bioequivalence cannot be proved using

the number of subjects set forth in Article 13, then one add-on subject study may

be performed and the results must be analyzed along with the results of the

previous study. However, in order for the results to be used in the evaluation

conducted as per Article 17, the following subparagraphs must all be satisfied:

1. The add-on subject study shall be conducted as the original study in accordance

with the identical study protocol.

2. The number of subject per group is more than 12.

3. In order to prove the consistency with the original study statistically (significance

level of 0.05 or less), at least one of the following criteria must be satisfied.

However, other statistically appropriate method can be used to prove test the

consistency.

a. The ratio of the residual mean residual squares between the original and

add-on subject study (use the smaller one of the two as the denominator)

shall should be less than the upper 5% value of F distribution with the

corresponding degree of freedoms.

b. The interaction of products between the original and add-on subject study

should not exist at the significance level of 0.05.

4. Conducting add-on subject study shall be indicated in the study protocol.

Article 17 (Evaluation) ① When blood samples are used, the comparative evaluation

parameters include AUCt and Cmax in a single-dose study, and AUCτ and Css,max in a

multiple-dose study. The time point of the maximum blood concentration (Tmax) and

dissolution profiles obtained by the comparative dissolution test are noted as reference

evaluation parameters items. For products showing immediate effect such as

nitroglycerine sublingual tablets, Tmax may be included in comparative evaluation

parameters. In this case, Cmax and Tmax are actual measured value and AUC is calculated

using trapezoidal rule. For urine samples, Aet, Aeτ, and Umax are used instead of AUCt,

AUCτ, Cmax.

Glossary)

AUC : Area under the drug concentration in blood-time curve

AUCt : Area under the drug concentration in blood-time curve from zero to the final

sampling time t

AUC∞ : Area under the drug concentration in blood-time curve from zero to infinity

(AUC∞ = AUCt + Ct/λZ)

Ct : Drug level in blood at the time t

λZ : terminal elimination rate constant

AUCt/AUC∞ : ratio of AUCt to AUC∞

t1/2β : terminal elimination half-life

AUCτ : Area under the drug concentration in blood-time curve AUC over one dose in

terval at steady-state

Cmax : The maximum drug concentration in blood

Css,max : The maximum drug concentration in blood at steady state

Css,min : The minimum drug concentration in blood at steady state

Tmax : Time to the maximum drug concentration in blood

Umax : The maximum urinary excretion rate of drug

Aet : Cumulative amount of drug excreted in the urine from zero to the final

sampling time t

Aeτ : Cumulative amount of drug excreted in the urine over one dose interval at

steady-state

② When log transformation and statistical evaluation on comparative parameters except

Tmax are performed, the 90% confidence intervals for the difference in mean values

between the test and reference should be within log 0.8 to log 1.25. However, the

case that meets the following conditions is considered to be equivalent :

1. When the difference in average values of logarithmic AUCt and Cmax parameters

to be assessed between two products are between log 0.9 to log 1.11.

2. When the comparative dissolution test is conducted according to this Notification,

all values are equivalent under all conditions described. However, products

containing poorly soluble drugs and enteric-coated products containing poorly

soluble drugs are not applicable to this provision. In case of extended-release

products, the average dissolutions of the test drug are within that of the reference

drug ± 10 % at three appropriate time points when the average dissolution of the

reference drug are around 30%, 50%, and 80%.

3. The total sample size of the bioequivalence study is not less than 24

(n=12/group).

③ Notwithstanding Paragraph 2, when within-subjects variability of Cmax of reference

e.g. :coefficient of variation

(%)90% confidence interval

(ratio of measured value)

30 0.8000 ~ 1.2500

35 0.7723 ~ 1.2948

40 0.7462 ~ 1.3402

45 0.7215 ~ 1.3859

50 0.6984 ~ 1.4319

drug [Note 1] is more than 30% after 3-period or 4-period replicate crossover study,

test drug is considered to be equivalent if all the following subparagraphs are

satisfied. However, the drug substances falling into Article 2(10) of this Notification

are excluded.

1. When log transformation and statistical evaluation on AUCt is performed, the 90%

confidence intervals for the difference in mean values of logarithmic AUCt between

the test and reference shall be within log 0.8 to log 1.25.

2. When log transformation and statistical evaluation on Cmax is performed, the

difference in mean values of logarithmic Cmax between the test and reference shall

be within log 0.8 to log 1.25. The 90% confidence interval of difference in the

average values of logarithmic parameters must be in the calculated range

according to the following formula. However, when coefficient of variation is more

than 50%, the range shall be within log 0.6984 to log 1.4319.

<When coefficient of variation is more than 30%, the 90% confidence interval of

difference in average values in log-transformed Cmax>

[highest value, lowest value] = exp[±0.760×(within-subjects standard deviation of

the log-transformed values of Cmax of reference drug]

Note 1 : coefficient of variation within-subjects (%) = 100 √exp[within-subjects standard d

eviation of the log-transformed values of Cmax of reference drug)2]-1

④ In principle, analysis of variance shall be used at α(significance level)=0.05

Article 18 (Bioequivalence Study Report) The principal investigator shall prepare

"Bioequivalence Study Report", which includes the requirements of following

subparagraphs, and submit the report to sponsor, in turn sponsor shall submit the

report to the Minister of MFDS.

1. Study title, study objective, and summary of results

2. Reference and test drug of ingredients & finished product name, dosage form,

manufacturing date, lot number, certificate of analysis in accordance with

specification and test method (shall be limited to content test or potency test for

reference drug)

3. Manufacturer, manufacturing site (shall be filled in together with site of bulk

product manufacturing and packaging of subdivision in case of subdivision), lot

number, and certificate of analysis of active ingredient used in test drug

4. Detailed information on the manufacturing process of test drug (manufacturing

date, input and standard amount of raw material, ect.)

5. Name and address of the sponsor, and name of the representative

6. Name and address of the study institution, and name of head of study institution

7. Names of the principal investigator and investigator, affiliation, position

8. Study period

9. Result of comparative dissolution test (when the test drug is applicable to the

conditional regulation of Article 25(2)(9) of the 「Regulation on Safety of Drugs,

etc.」, the report may not be submitted.)

10. Preliminary study result (including the management record of subjects in case

of subjects)

11. Criteria and method for subject selection: subject inclusion and exclusion

criteria, public recruiting notice for volunteers, representative written information

of bioequivalence study)

12. Discontinued subjects and its reason

13. Case report form (physician's opinion on the health status, blood sampling

schedule)

14. Management record of subjects

15. Study methods: dosage, administration route, administration method,

administration date, sampling method, sampling amount, sampling frequency and

time/schedule, sample storage condition, washout period, meals and total calories

in the case of fed bioequivalence study, nutrient consumption rate and detailed

nutrition chart (shall be limited to extended-release products)

16. In case of blood sampling, the method of protection against infection

17. Sample treatment and analysis method (validation data: specificity, linearity,

accuracy, precision, sensitivity, etc.)

18. Study results: Measured values, such as drug concentration in blood at

sampling time for each subject etc. (submit data storage medium such as

diskette) and log-transformed value, pharmacokinetic parameters such as

AUCt(AUCτ), Cmax(Css,max), Tmax, AUC∞, AUCt/AUC∞, t1/2β etc., analysis results including

analytical method validation (including raw data of analytical instruments and

integration method file), statistical process and evaluation (including raw data)

19. Discussion and overall conclusion about evaluation criteria and study result

by principal investigator

20. Records of the Institutional Review Board

21. Receipt and disbursement of drug products for bioequivalence study

22. Signature or seals of the principal investigator, director of study institution, sp

onsor and sub principal investigator

23. Bioequivalence study protocol finally approved by the Institutional Review Board

24. Quality assurance statement

CHAPTER 3 COMPARATIVE DISSOLUTION TEST

Article 19 (Dissolution Test Method) Dissolution tests shall be performed under the

conditions of suitably validated dissolution system according to this Notification or more

than equal, and for each test and reference drugs 12 vessels or more are conducted

under each test condition. However, in case it is deemed that a test on each of the

test solutions is unnecessary due to the characteristics of the drug substance, then the

scientific ground (e.g., literatures or books on the physicochemical properties, etc.) or

preliminary test results (on at least 6 samples) shall be attached to the test results

report for submission.

1. Oral dosage forms (excluding extended-release product) and enteric-coated products

a. Testing time

Measurement shall be taken for 2 hours in pH 1.2 medium and 6 hours in

other test solutions fluids. The test can be stopped at the time when the

average dissolution of reference drug reaches more than 85% or when the

average dissolution of reference drug in each test media does not change (less

than 5%) at 3 consecutive time point around 120 min, but not for the

enteric-coating products.

b. Test conditions (Table 1)

Apparatus: Dissolution Test Method 2 (Paddle method) in the Korean Pharmacopoeia,

in principle

Volume of test solution: 900 mL, in principle

Temperature of test solution: 37 ± 0.5℃

Test solutions : Use solution 1 of the disintegration test in the Korean

Pharmacopoeia for a pH 1.2 solution, solution 2 of the disintegration

test in the Korean Pharmacopoeia for a pH 6.8 solution, acetic

acid-sodium acetate buffer solution for a pH 4.0, and disodium

hydrogen phosphate-citric acid buffer solution, pH 6.0 in Section

Reagents and Test Solutions of the Korean Pharmacopoeia for a pH 6.0

solution. If average dissolution of the reference drug is lower than 85%

in pH 4.0 and pH 6.0 for 6 hours, another suitable buffer solution may

be used.

○ pH 4.0 acetic acid-sodium acetate buffer solution: Make 0.05mol/L acetic acid and

0.05mol/L sodium acetate mixture (41:9), and adjust the pH to 4.0

○ In case quantitative analysis is impossible due to small amount of the active

ingredient, etc., then the volume of test solution may be decreased or more

than 2 samples may be used for the test.

Table 1. Dissolution test conditions for oral dosage forms (excluding extended-release

product) and enteric-coated products

1) Water soluble products

rpm pH

50

(1) 1.2

(2) 4.0

(3) 6.8

(4) water

If the average dissolution of reference drug

does not reach 85% within the testing time

point specified under all the test conditions (1)

through (3), an additional test shall be

performed with an agitation of 100 rpm in the

media, in which the reference drug dissolution is

the highest among the solution (1) through (3).

2) Products containing poorly soluble drugs

Products containing poorly soluble drugs refer to products of which average

dissolution of reference drug does not reach 85% within the testing time point

specified under all the test conditions (1) through (4) of above 1).

rpm pH

50 (1) 1.2

(2) 4.0

(3) 6.8

(4) water

(5) solution (1) to (4) + solubilizer additionNote)

Note) Dissolution tests are performed under each solution (1) through (4) by adding

solubilizers, such as polysorbate 80, sodium lauryl sulfate, or other solvents, etc. at 1.0

w/v% or 1.0 vol% concentration or the test conditions prescribed in the specification

and test method.

3) Enteric-coated products

rpm pH

50

(1) 1.2

(2) 6.0

(3) 6.8

(4) (2) and (3) test media+ solubilizer additionNote)

(rpm) pH

50 (1) 1.2

(2) 6.0

(3) 6.8

When dissolution test is performed under the test condition (2), and the average

dissolution of reference drug does not reach 85% within the testing time point

specified, an additional test in solution (2) with an agitation by 100 rpm shall be

performed.

4) Enteric-coated products containing poorly soluble drugs

Enteric-coated products containing poorly soluble drugs refer to product of which

average dissolution of reference drug does not reach 85% within the testing time

point specified under the test conditions (2) and (3) of above 3).

Note) Dissolution tests are performed under each solution (2) and (3) by adding

solubilizers, such as polysorbate 80, sodium lauryl sulfate, or other solvents, etc. at 1.0

w/v% or 1.0 vol% concentration or the test conditions prescribed in the specification

and test method.

2. Extended-release product

a. Testing time

Measurement shall be taken for 2 hours in pH 1.2 medium and 24 hours, at least,

in other test solutions fluids. The test may be stopped at the time when the

average dissolution of reference drug reaches 85%.

b. Test conditions (Table 2)

Apparatus: Dissolution Test Method 1 (Rotatory basket method) and Method 2

(Paddle method) in the Korean Pharmacopoeia, in principle

Test solution and its volume, and temperature are in accordance with Paragraph 1

of Article 19 of this Notification.

Other tests: If necessary, an appropriate efflux test according to the characteristics

of the test drug or a physicochemical test that can be performed in its place

may be performed in addition to the dissolution test, and it is possible to

prove the pharmaceutical equivalence of the reference drug by comparing the

results.

Table 2. Dissolution test condition for extended-release product.

Apparatus rpm pH Others

Paddle method 50 (1) 1.2

(2) 4.0

(3) 6.8

(4) water

(5) (3)＋polysorbate 80 etc 1.0 w/v% additionNote)

Rotatory basket method 100 (1) 6.8

Note) Dissolution tests are performed under solution (3) by adding solubilizers, such as

polysorbate 80, sodium lauryl sulfate, or other solvents, etc. at 1.0 w/v% or 1.0

vol% concentration or the test conditions prescribed in the specification and test

method.

Article 20 (Dissolution Test Report) The test report shall describe the requirements of the

following subparagraphs.

1. Test title, test object, and summary of results

2. Certificate of analysis in accordance with specification and test method (shall be

limited to content test or potency test for reference drug)

3. Manufacturer, manufacturing site (shall be filled in together with site of bulk product

manufacturing and packaging of subdivision in case of subdivision), lot number, and

certificate of analysis of active ingredient used in test drug

4. Detailed information on the manufacturing process of test drug (manufacturing date,

input and standard amount of raw material, ect.)

5. Name and address of the test institution, and details on the facilities including the

analytical equipment and major facilities used for the test

6. Name of the manufacturing (import) manager (in the case of entrusting another

institution with the test, attach the information on the name, affiliation and

experience of the participants

7. Test method

a. List of test conditions: include information on the apparatus, stirring speed, type

and volume of test solutions. However, shall describe test method different

from the prescribed conditions, such as different pH, rpm, apparatus,

composition of the test solution, volume of test solution, composition of

solubilizer and reason for the selection, sampling and dilution method, etc. and

then indicate the reason for the change.

b. Validation data for dissolution test: Prepare the validation data such as the

specificity, linearity, accuracy (excluding poorly soluble products), precision, limit

of qualification for the analytical method, etc., and the validity of dissolution

test conditions, separate sheet for content and dissolution test method, and

analysis conditions (however, the method in the compendia and the

specification and test method are excluded).

c. Comparison of dissolution profile between reference and test drugs

1) Dissolution test results (measured values of reference and test drugs under

each dissolution test condition over time) and dissolution result summary

tables (Form 1 & 2)

2) Graph of dissolution profile for reference and test drugs

Dissolution curves of the test and reference drugs for each test solution

(average dissolution rate and standard deviation over time) is shown on 1

graph (Form 3)

8. Manufacturer (or importer) of test and reference drugs, finished product name, lot

number, production scale, content of active ingredient (potency), actual

measurement (or potency) and judgement of equivalence result are recorded in

Form 4. However, comparative dissolution test result according to the Article

3(1)(3)(a) of this Notification shall be prepared using Form 5.

9. Discussion and overall conclusion about evaluation criteria and test result of the

manufacturing managers or the import managers.

10. Others: 1 original copy of the test results containing information on the year,

month, day and time of the test that has been signed or sealed by the

manufacturing manager or the import manager

Article 21 (Acceptance Criteria for Equivalence of Dissolution Profiles) ① For oral dosage

form (excluding extended-release product) (Figure 1-a and 1-b), compare the average

dissolution rates of the test drug and the reference drug. Under all the dissolution test

conditions, if test result is meets any of the following subparagraphs, the two products

are judged as equivalent. The time points for comparing dissolution rates when

assessment is performed by the similarity factor(f2) specified in Attached Table 6.

1. When the average dissolution of the reference drug reaches 85% within the

testing time specified:

a. When dissolution of the reference drug does not have a lag time

1) When the average dissolution of the reference drug reaches 85% within 15

min: Judged as equivalent if the average dissolution of the test drug reaches

85% within 15 min or the average dissolution of the test drug is within that

of the reference drug ± 15 % at around 85% (in other words, 70~100% when

the mean dissolution rate of the reference drug is 85%).

2) When the average % dissolution of the reference drug reaches 85% at

between 15 and 30 min: Judged as equivalent if the average dissolution of

the test drug are within that of the reference drug ± 15 % at two appropriate

time points when the average dissolution of the reference drug are around

60% and 85%, or the similarity factor(f2) is not less than 50.

3) Others: Judged as equivalent if the average dissolution of the test drug are

within that of the reference drug ± 15 % at two appropriate time points when

the average dissolution of the reference drug are around 40% and 85%, or the

similarity factor(f2) is not less than 50.

b. When dissolution of the reference drug has a lag time

1) When the average % dissolution of the reference drug reaches 85% within 15

min after the lag time: Judged as equivalent if the difference in lag time

between the two products is less than 10 min and the average dissolution of

the test drug reaches 85% within 15 min after the lag time or the average

dissolution of the test drug is within that of the reference drug ± 15 % at

around 85%.

2) When the average % dissolution of the reference drug reaches 85% at

between 15 and 30 min after the lag time: Judged as equivalent if the

difference in lag time between the two products is less than 10 min and the

average dissolution of the test drug are within that of the reference drug ±

15 % at two appropriate time points when the average dissolution of the

reference drug are around 60% and 85%, or the similarity factor(f2) is not less

than 50.

3) Others: Judged as equivalent if the average dissolution of the test drug are

within that of the reference drug ± 15 % at two appropriate time points when

the average dissolution of the reference drug are around 40% and 85%, or the


○ Lag time: When dissolution is delayed, it is defined as the time when 5 % of the

drug dissolves and determined by linear interpolation at two appropriate time

points when the average dissolution of the reference and test drug are around

5%.

2. When the average dissolution of the reference drugs does not reaches 85 %

within the testing time specified

Judged as equivalent if the average dissolution of the test drug are within that

of the reference drug ± A % at two appropriate time points when the average

dissolution of the reference drug are around 1/2 and the testing time specified

(however, if the average dissolution rate of the reference drug is over 50%

during the comparison of the dissolution rates, then A=15, and if less than

50%, then A=8), or if the similarity factor (f2) is over 50 when the dissolution

rate is over 50% and if the similarity factor (f2) is over 55 when the dissolution

rate is under 50%.

② Under all the test conditions of the dissolution test (Table 2 of Article 19) for

extended-release product (Figure 2), judged as equivalent if the average dissolution of

the test drug are within that of the reference drug ± 10 % at three appropriate time

points when the average dissolution of the reference drug are around 30%, 50% and

80%. However, if the average dissolution of the reference drugs does not reaches 80

% within the testing time specified, then the dissolution rates at the final point

should also be compared.

The time points for comparing dissolution rates when assessment is performed by the

similarity factor(f2) are specified in Attached Table 6. Judged as equivalent if the

similarity factor (f2) is over 40 when the average dissolution of the reference drug

reaches 85% within the testing time specified, over 50 when the average dissolution of

the reference drug reaches 50% and does not reach 85% within the testing time point

specified, and over 55 when the average dissolution of the reference drug does not

reach 50% within the testing time point specified.

③ When there are formulation changes (Form 5) according to Attached Table 2-1 meets

both requirements for average dissolution rate and individual dissolution rate shown

below, and dissolution profiles of the test and reference drug are judged as

equivalent. However, the average dissolution of the reference drug should reach 85%

within the testing time specified at least under one test condition of dissolution test

according to Article 19(1)(a) in the case of oral dosage forms (except for

extended-release product) and enteric-coated products. When there is a lag time for

dissolution of the reference drug in immediate release products and enteric-coated

products, it is allowed to adjust the dissolution curve with the lag time (Attached

Table 2), and the acceptance criteria can be applied after the lag time, however, the

difference in average lag time between the test and reference drugs shall be within

10 min. The time points for comparing dissolution rates when assessment is

performed by the similarity factor(f2) are specified in Attached Table 6.

1. Average dissolution rate

a. When the average dissolution of the reference drug reaches 85% within 15 min:

Judged as equivalent if the average dissolution of the test drug reaches 85%

within 15 min or is within that of the reference drug ± 10% at 15 min.

b. When the average dissolution of the reference drug reaches 85% at between 15

and 30 min: Judged as equivalent if the average dissolution of the test drug

are within that of the reference drug ± 10 % at two appropriate time points

when the average dissolution of the reference drug are around 60% and 85%,

or the similarity factor(f2) is not less than 50.

c. When the average dissolution of the reference drug dose not reach 85% within

30 min:

It is deemed to be equivalent if meets any of the following subparagraphs

during the testing time set forth in Article 19(1)(a) and 19(2)(a). In this case, the

time point for the comparison of the average dissolution rates is depending on

Article 21(1) and (2).

1) When the average dissolution of the reference drug does not reach 50%

within the testing time specified, judged as equivalent if the average

dissolution of the test drug are within that of the reference drug ± 6 %,

or the similarity factor(f2) is not less than 60.

2) When the average dissolution of the reference drugs reaches between 50%

and does not reach 85% within the testing time specified, judged as

equivalent if the average dissolution of the test drug are within that of

the reference drug ± 8 %, or the similarity factor(f2) is not less than 55.

3) When the average dissolution of the reference drug reaches 85% within the

testing time specified, judged as equivalent if the average dissolution of

the test drug are within that of the reference drug ± 10 %, or the


2. Individual dissolution rate

Judged as equivalent if each individual dissolution rate of the test drug (out of

n=12)meet one of the following subparagraphs at the last point where the

average dissolution of the test drug is compared to that of the reference drug.

a. When the average dissolution of the reference drug does not reach 50%, the

number of the test drug of which dissolution is out of the range of the

average dissolution of the test drug ± 9% and ± 15% shall be "1 or less" and

"0", respectively.

b. When the average dissolution of the reference drug reaches 50% and does not

85%, the number of the test drug of which dissolution is out of the range of

the average dissolution of the test drug ± 12% and ± 20% shall be "1 or less"

and "0", respectively.

c. When the average dissolution of the reference drug reaches 85%, the number

of the test drug of which dissolution is out of the range of the average

dissolution of the test drug ± 15% and ± 25% shall be "1 or less" and "0",

respectively.

CHAPTER 4 COMPARATIVE DISINTEGRATION TEST

Article 22 (Scope of Comparative Disintegration Test) A comparative disintegration test shall

be performed if it is impossible to perform the comparative dissolution test due to the

characteristics of the product (e.g., herbal medicines, enzyme products, probiotics).

However, the reason why impossible to perform the comparative dissolution test must

be submitted with a scientific ground such as the results of a preliminary test.

Article 23 (Disintegration Test Method) For 12 vessels of each reference and test drugs (for

suppository 6 vessels), perform disintegration test in accordance with specification and

test method of reference drug or disintegration test method in the Korean

Pharmacopoeia, and record the number of disintegrated vessels an interval of 5 min,

and conduct the test until all the test and reference drugs are disintegrated.

Article 24 (Acceptance Criteria for Equivalence of Disintegration Test) When comparing the

time for 12 vessels of each reference and test drugs (for suppository 6 vessels) to be

completely disintegrated, the two products are judged evaluated as equivalent if the

difference is less than 5 min.

(e.g., If complete disintegration of all the 12 vessels of reference drug (for suppository 6

vessels) takes 25 min, and that of test drug takes between 20-30 min, then the two

products are judged as equivalent.)

Article 25 (Disintegration Test Report) The test report shall describe the requirements of the

following subparagraphs:

1. Test Title, test objective, and summary of results

2. Certificate of analysis in accordance with specification and test method (shall be

limited to content test or potency test for reference drug)

3. Manufacturer, manufacturing site (shall be filled in together with site of bulk

manufacturer and packaging of subdivision in case of subdivision), lot number, and

certificate of analysis of active ingredient used in test drug

4. Detailed information on the manufacturing process of test drug (manufacturing date,

input and standard amount of raw material, ect.)

5. Name and address of the test clinical trial institution, and details on the facilities

including the analytical equipment and major facilities used for the test

6. Name of the manufacturing (import) manager (in the case of entrusting another

institution with the test, attach the information on the name, affiliation and experience

of the participants)

7. The detailed reason and supporting documents if comparative dissolution test is not

possible

8. Test method

9. Test and reference drug of manufacturer (or importer), finished product name, lot

number, production scale, content of active ingredient (potency), actual measurement

(or potency) and judgement of equivalence result are recorded in Attached Sheet 6.

10. Discussion and overall conclusion about evaluation criteria and study result of the

manufacturing managers or the import managers.

11. Others: 1 original copy of the test results containing information on the year, month,

day and time of the test that has been signed or sealed by the manufacturing

manager or the import manager

CHAPTER 5 SUPPLEMENTARY PROVISIONS RULES

Article 26 (Application of Other Regulation) For matters relating to conduct of

pharmaceutical equivalence study and not specified in this Notification, 「Good Clinical

Practice」 and 「Standard on Bioequivalence Study Management」 shall be applied.

Article 27 (Review Period) According to Article 8 of the 「Framework Act on Administrative

Regulations」 and the 「Regulation on Issuance and Management of Instructions and

Rules」(Presidential Instruction No. 248), validity of regulations must be reviewed and

other relevant actions accompanied by every 3 years (by December 31 of every third

year) starting January 1, 2014.

ADDENDA <No. 2014-150, Sep. 2, 2014>

Article 1 (Enforcement Date) This Notification is to be effective from the date of

notification.

Article 2 (Example of Application) Amended Notification, Article 10(1), 13 and 15(2)(2)(a)(3),

shall be applied to the bioequivalence study according to the bioequivalence protocol

or amendment protocol, which is applied after the Notification is effective.

[Attached Table 1]

Drug substance with Narrow Therapeutic Index

(In relation with Article 2(1)(10))

No. Drug substance

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Aprindine

Carbamazepine

Clindamycin

Clonazepam

Clonidine

Cyclosporine

Digitoxin

Digoxin

Disopyramide

Ethinyl Estradiol

Ethosuximide

<deleted>

Guanethidine

Isoetharine

<deleted>

Isoproterenol

Lithium

Metaproterenol

Methotrexate

Minoxidil

No. Drug substance

21

22

23

24

25

26

27

28

29

30

31

32

Phenobarbital

Phenytoin

Prazosin

Primidone

Procainamide

Quinidine

Sulfonylurea compounds1)

Tacrolimus

Theophylline compounds2)

Valproic acid

Warfarin

Zonisamide

1) Glibenclamide, Gliclazide

2) Aminophylline, Oxtriphylline (=Choline theophylline),

Diprophylline (=Dyphylline), Proxyphylline, Theophylline

Function of Excipient and Component Difference of Content (%)

B C D

Disintegrating agents Starch Others

3.01.0

6.02.0

9.03.0

Binders 0.50 1.0 1.5

Lubricants・Polishers Stearic acid and its salts Others

0.251.0

0.502.0

0.753.0

Diluting agents 5.0 10 15

Others (excluding coloring & fragrance agent)

1.0 2.0 3.0

Sum of absolute values of difference of content (%) of changed components

5.0 10 15

[Attached Table 2-1]

Levels of Formulation Changes and Required Tests

(In association with Article 3(1)(3)(a))

I. Levels of formulation changes

The degree of the changes shall 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, the 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. Change of

coloring and fragrance agent may be applied to Level. Level of formulation changes in

the product is the largest change level in the excipients.

<Table 1> Levels of Changes in Uncoated Product

Part Function of Excipient and Component Difference of Content (%)

B C D

Core


3.01.0

6.02.0

9.03.0

Binders 0.50 1.0 1.5

Lubricants・Polishers Stearic acid and its salts Others

0.251.0

0.502.0

0.753.0



1.0 2.0 3.0


5.0 10 15

Film Coating1)

Sum of absolute values of difference of content (%) of changed components in film coating layer

5.0 10 15

Sugar Coating

Sum of absolute values of difference of content (%) of changed components in sugar coating layer

5.0 10 15

Level

Immediate5)/ Enteric-coated/

Extended- Release

Therapeutic index of active

ingredient1)

Poorly soluble/Soluble

Dissolution rate of product2)

Type of Pharmaceutical equivalence study3)

<Table 2> Levels of Changes in Coated Product

1) All coatings, such as water-proofing coating, under coating, enteric coating, and release control coating, are included except sugar coating.

II. Required pharmaceutical equivalence studies based on levels of formulation changes

Required pharmaceutical equivalence studies based on levels of formulation changes are

shown in Table 3.

<Table 3> Required Pharmaceutical Equivalence Studies based on Levels of Formulation

Changes

Aproduct not applicable to pharmaceutical equivalence

study

Bcomparative dissolution test4) or comparative disintegration test

C

Immediate, Enteric-coated

widewater soluble

comparative dissolution test4) or comparative disintegration test

poorly soluble Bioequivalence study

narrowwater soluble

≧85%/30 mincomparative dissolution test4) or comparative disintegration test

〈 85%/30 min Bioequivalence study


Extended- Release

widecomparative dissolution test4) or comparative disintegration test

narrow Bioequivalence study

D

Immediatewide

water soluble≧85%/30 min




narrow Bioequivalence study

Enteric-coated, Extended- Release

Bioequivalence study

E Bioequivalence study

1) The concerned ingredients of Article 2(1)(10) have narrow therapeutic index. Others are wide. 2) Average dissolution rate of reference and test drug for 30 min under all conditions is higher than

85%, then mark “≧85%/30 min”, the rest as “〈 85%/30 min” when comparative dissolution test has been carried out according to Article 3 of this Notification.

3) In case the result of comparative dissolution test or comparative disintegration test does not prove its equivalence of the product, bioequivalence study needs to be carried out.

4) Comparative dissolution test under the test condition of this Notification or more than equal 5) In case excipients of film coating and sugar coating of general product are amended, and the result of comparative dissolution test is equivalent to that of unamended one, then bioequivalence test can be replaced by the comparative dissolution test (the type of pharmaceutical equivalence test required is limited to bioequivalence test). amendment of excipients affecting dissolution rate, however, can not be applied.

Function of Excipient and Component Difference of Content (%)

B C D


3.01.0

6.02.0

9.03.0

Binders 0.50 1.0 1.5

Lubricants・Polishing agents Stearic acid and its salts Others

0.251.0

0.502.0

0.753.0



1.0 2.0 3.0


5.0 10 15

[Attached Table 2-2]

Required pharmaceutical equivalence studies based on levels of formulation

changes in different strengths of oral solid dosage forms

(In association with Article 7(2))

1. Levels of formulation changes

In the case of an orally administered solid product that has the same dosage form, but in

a different strength as the product made by the same manufacturer of which

bioequivalence has been recognized, and is identical to the composition ratio of active

ingredient and excipients with test drug, then level of formulation change is A.

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, the 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. Change of coloring

and fragrance agent can be applied to Level A. Level of formulation changes in the

product is the largest change level in the excipients.

<Table 1> Levels of Changes in Uncoated Product

Part Function of Excipient and Component Difference of Content (%)

B C D

Core


3.01.0

6.02.0

9.03.0

Binders 0.50 1.0 1.5

Lubricants・Polishing agents Stearic acid and its salts Others

0.251.0

0.502.0

0.753.0



1.0 2.0 3.0


5.0 10 15

Film Coating1)

Sum of absolute values of difference of content (%) of changed components in film coating layer

5.0 10 15

Sugar Coating

Sum of absolute values of difference of content (%) of changed components in sugar coating layer

5.0 10 15

Level

Immediate/ Enteric-coated/

Extended Release

Therapeutic index area of active

ingredient1)

Poorly soluble/Soluble2)

dissolution rate of product3)

Type of Pharmaceutical equivalence study4)

Aproduct not applicable to Pharmaceutical equivalence

study

Bcomparative dissolution test4) or comparative disintegration test

CImmediate,

Enteric-coatedwide water soluble

comparative dissolution test4) or comparative

<Table 2> Levels of Changes in Coated Product

1) All coatings, such as water-proofing coating, under coating, enteric coating, and release control coating, are included except sugar coating.

2. Required pharmaceutical equivalence studies based on levels of formulation changes

Required pharmaceutical equivalence studies based on levels of formulation changes are

shown in Table 3.

<Table 3> Required Pharmaceutical Equivalence Studies based on Levels of Formulation Changes

Level ScopeType of pharmaceutical

equivalence study1)

A

1) In case adding or changing volatile solvent used in coating process

2) In case changing raw material weighing process or packing process of final product

3) In case changing appearance of final product

Not applicable to Pharmaceutical equivalence

study

disintegration test poorly soluble Bioequivalence study

narrowwater soluble

≧85%/30 mincomparative dissolution test4) or comparative disintegration test



Extended Release

widecomparative dissolution test4) or comparative disintegration test

narrow Bioequivalence test

D

Immediatewide

water soluble≧85%/30 min




narrow Bioequivalence studyEnteric-coated,

Extended- Release

Bioequivalence study

E Bioequivalence study

1) The concerned ingredients of Article 2(1)(10) have narrow therapeutic index. Others are wide. 2) Poorly soluble product needs to follow to Table 1 and 2 of this Notification, and for water

soluble product to the rest. 3) Average dissolution rate of reference and test drug for 30 min under all conditions is higher than

85%, then mark “≧85%/30 min”, the rest as “〈 85%/30 min” when the test has been carried out according to Article 19 of this Notification.

4) Comparative dissolution test is carried out according to Article 19 of this Notification, evaluation of equivalence depends on Paragraph 3 of Article 21 of this Notification. With the level of 'A', in case the Guideline of comparative dissolution test and its method for the reference drug are set, then follow to the concerned test condition, and evaluation of equivalence depends on Paragraph 3 of Article 21 of this Notification.

When do not regarded as pharmaceutical equivalence from the results of the comparative dissolution test, a bioequivalence study shall be performed.

[Attached Table 3]

Levels of Changes in Manufacturing methods and Required Tests (In association with Article 3(1)(3)(b))

4) In case changing the size of empty capsule (including its composition)

5) In case pharmaceutical equivalence is not deemed to be affected by other changes

B

1) In case changing or adding the manufacturer of active ingredient

2) In case of not applicable to the levels of 'A', 'C', or 'D'

3) Changing production scale (more than 10 times from the production scale of pharmaceutical equivalence study and bioequivalence study)

Comparative dissolution test2) or comparative disintegration

test

C

1) Changing granulation method (extrusion method, Fluid Bed Granulation, etc)

2) Changing of binding solution type (organic solvent, water, etc)

3) Changing of manufacturing process (mixing period, agitation speed, etc)

Comparative dissolution test3) or comparative disintegration

test

D Changing manufacturing process possibly affecting quality of the product (e.g., direct compression, dry granulation, or wet granulation)

Bioequivalence study4)

Level ScopeType of pharmaceutical equivalence

study 1)

A

1) In case manufacturing site is changed to

where manufacturing product of

bioequivalence is already validated

2) In case amending the process of raw

material weighing or manufacturing site of

Not applicable to Pharmaceutical equivalence study

1) When do not regarded as pharmaceutical equivalence from the results of the comparative

dissolution test or the comparative disintegration test, a bioequivalence study shall be

performed.

2) Among matters of approved(notified), comparative dissolution test based on the specification

and test method or test condition set in compendia

3) Comparative dissolution test under the test condition of this Notification ce or more than

equal

4) In case a product of wide therapeutic index and average dissolution rate of reference and test

drug for 30 min under all conditions is higher than 85%, when the test has been carried out

according to Article 19 of this Notification, and dissolution test is judged as equivalent can be

waived by the comparative dissolution test.

[Attached Table 4]

Levels of Changes in Manufacturing sites and Required Tests (In association with Article 3(1)(3)(C))

packaging process for end product

3) In case pharmaceutical equivalence is not

deemed to be affected by other changes

B

In case formulations and manufacturing methods

are identical, but the manufacturing site is

changed.

Comparative dissolution test2) or comparative disintegration test

C

1) In case formulations and manufacturing

methods are amended, in addition, the

manufacturing site is changed.

2) In case the level is beyond level 'A' and

level 'B'

Comparative dissolution test3) or comparative disintegration test

1) In case comparative dissolution test and comparative disintegration tess does not validate

equivalence, bioequivalence study test should be carried out.

2) Among matters of approved(notified), comparative dissolution test based on the specification

and test method or test condition set in compendia

3) Comparative dissolution test data under the test condition of this Notification or more than

equal

[Attached Table 5]

Waiver of Bioequivalence Study for Oral Solid Tablet or Capsule

(In association with Article 7(3))

1. Definition of terms

The definition of terms used in this guideline shall be as follows:

a. The term "Biopharmaceutics Classification System (BCS)" is a scientific framework for

classifying drug substances based on their aqueous solubility and intestinal

permeability

b. The term "solubility test" is a test described in Attachment 1 for classification of the

solubility of drug substances according to BCS.

c. The term "permeability test" is a test described in Attachment 2 for the classification

of the permeability of drug substances according to BCS. This test directly or

indirectly measures the rate or extent of absorption of a drug substance across

human intestinal membrane using human or animal system or cell culture.

d. The term "dissolution test" is a test described in Attachment 3 for measuring the

dissolved amount of drug substance from oral solid dosage form.

2. Biopharmaceutics Classification System (BCS)

Drug substances are classified as follows based on the extent of their solubility and

permeability. The BCS-based approach can be used to justify the request for a waiver of

the bioequivalence study requirement.

a. Class I - High Permeability, High Solubility

b. Class II - High Permeability, Low Solubility

c. Class III - Low Permeability, High Solubility

d. Class IV - Low Permeability, Low Solubility

3. Waiver Criteria

a. Overall

It must be an oral tablet or capsule containing Class 1 drug substances according

to BCS. Both test and reference drugs shall be dissolved rapidly and the excipients

shall not affect the absorption of the active ingredient.

b. Solubility of the active ingredient

A drug substance is considered highly soluble when the highest strength of

approved oral solid dosage forms is soluble in 250 ml or less of aqueous media

over the pH range of 1.0-7.5 and it shall be demonstrated through a solubility

test described in Attachment 1.

c. Permeability of the active ingredient

In the absence of evidence suggesting instability in the gastrointestinal tract, a

drug substance is considered to be highly permeable when the extent of

absorption in humans is determined to be 90% or more of an administered dose

based on a mass balance determination and it should be demonstrated through a

permeability test described in Attachment 2.

d. Dissolution of the product

The result according to the test in of Attachment 3 shall satisfy one of the

following criteria:

(1) For both the test and reference drugs, dissolution of more than 85% of the

labeled amount of the drug substance shall occur within 15 minutes; or

(2) dissolution more than 85% of the labeled amount of the drug substance

should occur within 30 minutes with similar dissolution profiles between the test

and reference drugs.

4. Scope and Requirements for Proving Conformity to the Waiver Criteria

a. Data on origin and development history

Data on the summary of the submitted documents, characteristics of the

pharmaceuticals, and details of drug development that could be useful in determining

whether it can be waived of the bioequivalence study requirement

b. Data on structure determinations and physicochemical properties

Data on the components, formulation and specification of active drug substance,

manufacturing method, etc. (including specification and test method)

c. Data on solubility

Data demonstrating high solubility of the active ingredient that shall be included the

following information:

(1) A description of test methods, including information on the analytical method

and composition of the buffer solutions

(2) Information on chemical structure, molecular weight, properties of the active

ingredient (acid, base, amphoteric, or neutral) and dissociation constant (pKa)

(3) Test results (mean, standard deviation, and coefficient of variation) regarding

summarized in a table under solution pH, drug solubility (e.g., mg/mL) and

the volume of media required to dissolve the highest dose strength according

to varying solution pH.

(4) Graph of mean pH-solubility profile

However, if an active ingredient that has been deemed to have high solubility by

MFDS based on a review of solubility, the above data can be waived.

d. Data on permeability

Data demonstrating the high permeability of the active ingredient using a human or

animal system or cell culture that correspond to one of the following:

(1) Pharmacokinetic Studies in Humans

(A) Data on the study design and methods

(B) Pharmacokinetic data

(2) Intestinal Permeability Methods

(a) Information Supporting data on the suitability of a selected method

1) A description of the study method

2) Criteria for selection of study subjects (human subjects, animals, or

epithelial cell line)

3) Drug concentrations and analytical method in the donor fluid

4) Method used to calculate the extent of absorption or permeability

5) Data on efflux potential such as bidirectional transport data (shall be

limited to possible)

(b) Data on the model drugs

1) Data on the extent of absorption in humans (mean, standard

deviation, coefficient of variation) used for a model drug and list of

model drugs to establish suitability of the method

2) Permeability values for each model drug (mean, standard deviation,

coefficient of variation) and permeability classification

3) The extent of absorption as a function of permeability (mean±

standard deviation or 95% confidence tial interval)

4) Data on the selected internal standard and the classification of

permeability(low/high)

(c) Data Information on the study test results

1) Permeability of the test drug substance and internal standard

substance (mean, standard deviation, coefficient of variation)

2) Stability in the gastro-intestinal tract

3) Appropriate data to prove passive transport mechanism

4) Test methods used to prove establish high permeability of the test

drug substance

However, if an active ingredient that has been deemed to have high

permeability by MFDS based on a review of solubility, the above data can

be waived.

5. Data on dissolution

Data demonstrating the rapid dissolution of test and reference drugs that shall be

included the following information:

(1) A brief description of the test drug used in for the dissolution test (batch or

lot number, expiry date, content, weight, and size, etc.)

(2) Dissolution data

(a) The percentage of the dissolution with respect to the labeled content

at each specified testing interval for each dosage unit

(b) The average dissolution rate, range (maximum and minimum) of

dissolution, and tabulated coefficient of variation (relative standard

deviation)

(c) A graphic representation of the average dissolution profiles for the test

and reference drugs in each dissolution solution

(3) Data supporting the similarity in dissolution profiles between the test and

reference drugs in each dissolution solution using the f2 value

6. Data on excipients

When new excipients not used in the previously approved general oral solid dosage

form are used or the excipient is used in unusually large amounts compared to the

of commonly used amounts (in particularly, surfactants such as polysorbate 80, etc.,

sweeteners such as mannitol or sorbitol, etc.), additional information documenting the

absence of an impact on bioavailability of the drug may be requested.

7. Prodrug means a drug substance that does not exert a physiological effect itself, but

converts to an active moiety through enzymatic or non-enzymatic reaction in the

body. When the prodrug-to-drug conversion is shown to occur predominantly after

intestinal membrane permeation, the permeability of the prodrug shall be measured.

When this conversion occurs prior to intestinal permeation, the permeability of the

drug shall be determined. Dissolution and pH-solubility data on both prodrug and

drug can be relevant.

[Attachment 1]

Solubility Test

Ⅰ. Selection of the Test Substance

In principle, the test substance shall be identical to the active ingredient of the drug,

which want to be waived for bioequivalence study.

Ⅱ. Test Method

The equilibrium solubility and pH-solubility profile of a drug substance shall be

determined using acid․base titration or a validated method in aqueous media with a

physiological pH conditions (pH, 1.0～7.5) and the test may distinguish the drug

substance from its degradation products. If degradation of the drug substance is

observed as a function of buffer composition and/or pH, it shall be reported along with

other stability data recommended in accordance with [Attachment 2] III.

1. Test Condition

a. Amount of the test drug substance: The highest strength of previously approved

general oral solid dosage form

b. Test solution: In principle, standard buffer solutions described in the Korean

Pharmacopoeia. If these buffers are not suitable for physical or chemical reasons,

other buffer solutions can be used.

c. Temperature of test solution: 37±1℃

d. pH of test solution: The number of pH conditions for a solubility determination can

be based on the ionization characteristics of the test drug substance. A sufficient

number of pH conditions shall be evaluated to accurately define the pH-solubility

profile. For example, when the pKa of a drug is in the range of 3-5, solubility should

be determined at pH=pKa, pH=pKa-1, pH=pKa+1, and pH=1 and 7.5. Solution pH

should be verified after addition of the drug ingredient to a buffer.

e. Number of test: A minimum of three replicate determinations of solubility in each pH

condition is recommended. Depending on study variability, additional replication may

be necessary to provide a reliable estimate of solubility.

[Attachment 2]

Permeability Test

Ⅰ. Selection of the Test Substance

In principle, the test substance shall be identical to the active ingredient of the drug,

which want to be waived for bioequivalence study.

Ⅱ. Test Method

The permeability of a drug ingredient can be determined in human subjects using mass

balance studies, absolute bioavailability studies, or intestinal perfusion approaches. Other

methods available are in vivo or in situ intestinal perfusion in a suitable model (e.g.,

rats), and in vitro using excised intestinal tissues, or monolayers of suitable epithelial

cells. When the absolute bioavailability is 90% or more, or when 90% or more of the

administered drug is recovered in urine, a single method may be sufficient in many

cases. When a single method fails to conclusively demonstrate to determine

permeability, two different methods may be advisable.

1. Pharmacokinetic Studies in Humans

a. Mass balance studies

Pharmacokinetic mass balance studies using unlabeled, stable isotopes or a

radiolabeled drug ingredient can be used to document the extent of absorption of a

drug. Depending on the variability of the studies, a sufficient number of subjects

should be enrolled to provide a reliable estimate of extent of absorption. Because

this method can provide highly variable estimates of drug absorption for many drugs,

other methods described below may be preferable.

b. Absolute Bioavailability (BA) studies

Oral BA determination using intravenous administration as a reference can be used.

Depending on the variability of the studies, a sufficient number of subjects should be

enrolled in a study to provide a reliable estimate of the extent of absorption. When

the absolute BA of a drug is shown to be 90% or more, additional data to

document during stability in the gastrointestinal fluid is not necessary.

2. Intestinal permeability methods

The following methods can be used to determine the permeability of a drug substance

from the gastrointestinal tract:

a. in vivo intestinal perfusion studies in humans

b. in vivo or in situ intestinal perfusion studies using suitable animal models

c. in vitro permeation studies using excised human or animal intestinal tissues

d. in vitro permeation studies across a monolayer of cultured epithelial cells.

Other studies excepting in vivo intestinal perfusion studies in humans are considered

appropriate for passively transported drugs. The observed low permeability of some

drug substances in human could be caused by efflux of drugs via membrane

transporters such as P-glycoprotein (P-gp). When the efflux transporters are absent in

these models, or their degree of expression is low compared to that in humans, there

may be a greater likelihood of misclassification of permeability class for a drug subject

to efflux compared to a drug transported passively. Therefore, the expressed transporters

in the selected study system should be described. Functional expression of efflux

systems (e.g., P-gp) can be demonstrated with techniques such as bidirectional transport

studies, demonstrating a higher rate of transport in the basolateral-to-apical direction as

compared to apical-to-basolateral direction using selected model drugs at concentrations

that do not saturate the efflux system (e.g., cyclosporin A, vinblastine, rhodamine 123).

This guideline recommends limiting the use of nonhuman permeability test methods for

drug substances that are transported by passive mechanisms. Pharmacokinetic studies on

dose linearity or proportionality may provide useful information for evaluating the

relevance of observed in vitro efflux of a drug. For example, there may be fewer

concerns associated with the use of in vitro methods for a drug that has a higher rate

of transport in the basolateral-to-apical direction at low drug concentrations but exhibits

linear pharmacokinetics in humans.

For application of the BCS, an apparent passive transport mechanism can be assumed

when one of the following conditions is satisfied:

a. A linear pharmacokinetic relationship between the dose (e.g., relevant clinical dose

range) and measures of BA (area under the concentration-time curve) of a drug is

demonstrated in humans.

Model Drugs Permeability Class

Antipyrine High (Potential inner standard candidate)

Caffeine High

Carbamazepine High

Fluvastatin High

Ketoprofen High

b. Lack of dependence of the measured in vivo or in situ permeability is

demonstrated in and an animal model on initial drug concentrations (e.g., 0.01, 0.1,

and 1 times the highest dose strength dissolved in 250 mL) in the perfusion fluid.

c. Lack of dependence of the measured in vitro permeability on initial drug

concentration (e.g., 0.01, 0.1, and 1 times the highest dose strength dissolved in

250 mL) is demonstrated in donor fluid and transport direction (e.g., no statistically

significant difference in the rate of transport between the apical-to-basolateral and

basolateral-to-apical for the drug concentrations selected) using a suitable in vitro

cell culture method that has been shown to express known efflux transporters (e.g.,

P-gp).

To demonstrate suitability of a permeability method intended for application of the BCS,

a position-order relationship between test permeability values and the extent of drug

absorption data in human subjects should be established using a sufficient number of

model drugs. For in vivo intestinal perfusion studies in humans, six model drugs are

recommended. For in vivo or in situ intestinal perfusion studies in animals and for in

vitro cell culture methods, twenty model drugs are recommended. Owing to study

variability, a sufficient number of subjects, animals, excised tissue samples, or cell

monolayers should be used in a study to provide a reliable estimate of drug

permeability. This relationship should allow precise differentiation between drug

substances of low and high intestinal permeability attributes.

For demonstration of suitability of a method, model drugs representing a range of low

(e.g., <50%), moderate (e.g., 50～89%), and high (≥90%) absorption need to be

suggested. Sponsors may select compounds from the list in Table 1 below, or they may

select other drugs for which there is information on mechanism of absorption and

reliable estimates of the extent of drug absorption in humans.

Table 1. Model drugs for intestinal permeability methods

Metoprolol High (Potential inner standard candidate)

Naproxen High

Propranolol High

Theophylline High

Verapamil High (Potential efflux pump standard candidate)

Amoxicillin Low

Atenolol Low

Furosemide Low

Hydrochlorthiazide Low

Mannitol Low (Potential inner standard candidate)

Methyldopa Low

Polyethylene glycol 400 Low

Polyethylene glycol 1000 Low

Polyethylene glycol 4000 Low (Zero permeability marker)

Ranitidine Low

After demonstrating suitability of a method and maintaining the same study protocol, it

is not necessary to retest all selected model drugs for subsequent studies intended to

classify a drug substance. Instead, a low and a high permeability model drug should be

used as internal standards (i.e., included in the perfusion fluid or donor fluid along with

the test drug substance). These two internal standards are in addition to the fluid

volume marker (or a zero permeability compound such as PEG 4000) that is included in

certain types of perfusion techniques (e.g., closed loop techniques). The choice of

internal standards should be based on compatibility with the test drug substance (i.e.,

they should not exhibit any significant physical, chemical, or permeation interactions).

When it is not feasible to follow this protocol, the permeability of internal standards

should be determined in the same subjects, animals, tissues, or monolayers, following

evaluation of the test drug substance. The permeability values of the two internal

standards should not differ significantly between different tests, including those

conducted to demonstrate suitability of the method. At the end of an in situ or in vitro

test, the amount of drug in the membrane should be determined.

For a given test method with set conditions, selection of a high permeability internal

standard with permeability in close proximity to the low/high permeability class

boundary may facilitate classification of a test drug substance. For instance, a test drug

substance may be determined to be highly permeable when its permeability value is

equal to or greater than that of the selected internal standard with high permeability.

Ⅲ. Instability in the Gastrointestinal Tract

Determining the extent of absorption in humans based on mass balance studies using

total radioactivity in urine does not take into consideration the extent of degradation of

a drug in the gastrointestinal fluid prior to intestinal membrane permeation. In addition,

some methods for determining permeability could be based on loss or clearance of a

drug from fluids perfused into the human and/or animal gastrointestinal tract either in

vivo or in situ. Documenting the fact that drug loss from the gastrointestinal tract arises

from intestinal membrane permeation, rather than a degradation process, will help

establish permeability.

Stability in the gastrointestinal tract may be documented using gastric and intestinal

fluids obtained from human subjects. Drug solutions in these fluids should be incubated

at 37℃ for a period that is representative of in vivo drug contact with these fluids (for

example, 1 hour in gastric fluid and 3 hours in intestinal fluid), then drug concentrations

should be determined using a validated stability-indicating assay method. Significant

degradation (>5%) of a drug in this protocol could suggest potential instability.

Obtaining gastrointestinal fluids from human subjects requires intubation and may be

difficult in some cases. Use of gastrointestinal fluids from suitable animal models and/or

simulated fluids such as Gastric and Intestinal Fluids in the Korean Pharmacopoeia or

other Pharmacopoeia designated by the Minister of MFDS can be substituted when

properly justified.

[Attachment 3]

Dissolution Test

Ⅰ. Selection of Test Drug

The content or the potency of test drug that was tested in accordance with its own

specifications shall be less than 5% of difference compared with the labeled content

(100%) of reference drug or the difference of content and potency of test drugs is less

than 5% compared with that of reference shall be selected for use.

Ⅱ. Test Method

Dissolution test shall be conducted with at least 12 dosage units under the conditions

specified, and shall be measured using validated analysis method. If dissolution tests in

all test solution are considered to be unnecessary on the basis of characteristics of

product, the scientific evidence shall be provided.

1. Apparatus: Dissolution test are conducted with Apparatus 1 (100rpm) or Apparatus 2

(50rpm) of dissolution test in the 9th Edition of Korean Pharmacopoeia, according

to characteristics of product.

2. Volume of test solution: In principle, 900 mL

3. Temperature of test solution: 37 ± 0.5℃

4. Test solution

a. pH 1.2 solution: “Solution 1” prescribed for the disintegration test in the 9th Edition

of Korean Pharmacopoeia

b. pH 4.0 solution: Acetic acid-sodium acetate buffer solution (0.05mol/L acetic acid

and 0.05mol/L sodium acetate mixture (41:9), and adjust the pH to 4.0.)

c. pH 6.8 solution: “Solution 2” prescribed for the disintegration test in the 9th Edition

of Korean Pharmacopoeia

For capsules and tablets with gelatin coating, simulated gastric and intestinal fluids

with enzymes (its specification should meet Korean Pharmacopoeia or other

Pharmacopoeia designated by the Minister of MFDS) can be used.

5. Sampling time: 10 min, 15 min, 20 min, 30 min

Ⅲ. Evaluation of Similarity

When comparing the test and reference drugs, dissolution profiles shall be compared

using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root

transformation of the sum of squared error and is a measurement of the similarity in the

percent (%) of dissolution between the two curves.

f2 = 50․log{[1+(1/n)∑nt=1(Rt - Tt)

2]-0.5․100}

Two dissolution profiles are considered similar when the f2 value is over 50. To allow

the use of mean data, the coefficient of variation should not be more than 20% at 10

min time points, and should not be more than 10% at other time points. When both

test and reference drugs dissolve 85% or more of the label amount of the drug in 15

minutes using all thoursee dissolution media recommended above, the profile

comparison with an f2 test is unnecessary.

[Attached Table 6]

Similarity factor and time points for comparisons

(In association with Article 21)

1. When comparing the test and reference drugs, dissolution profiles should be

compared using a similarity factor (f2). The similarity factor is a logarithmic

reciprocal square root transformation of the sum of squared error and is a

measurement of the similarity in the percent (%) of dissolution between the two

curves.

f2 = 50․log{[1+(1/n)∑nt=1(Rt - Tt)

2]-0.5․100}

where n is the number of time points, Rt, average dissolution rate of reference drug,

Tt, average dissolution rate of test drug.

2. Time Point for Comparison of Dissolution Rates

a. If the mean dissolution rate of the reference drug is over 85% between 15-min and

30-min time points: 15 min, 30 min, 45 min

b. If the mean dissolution rate of the reference drug is over 85% between within the

prescribed testing period after the 30-min time point: if Ta is set when the mean

dissolution rate of the reference drug is at around 85%, Ta/4, 2Ta/4, 3Ta/4, Ta

c. If the mean dissolution rate of the reference drug does not exceed 85% within the

prescribed testing period: if Ta is set when the mean dissolution rate of the

reference drug is at around 85%, Ta/4, 2Ta/4, 3Ta/4, Ta

[Figure 1]

Determining equivalence of the dissolution profiles of oral dosage forms

(excluding Extended-Release Products)

Figure 1-a. Oral dosage forms (excluding extended-release product)

Figure. 1-b Dissolution lag time of oral dosage forms (excluding extended-release product)

[Figure 2]

Determining equivalence of the dissolution profiles of extended-release

products

Dissolution Test Result of Reference and Test Drugs Over Time Under Dissolution Test ConditionsProduct type Active substance Product name Dosage form Strength

Dissolution media

Agitation speed Surfactant Analysis method Ground

Test apparatus Volume Temperature NoteLot number

(date of manu.) subjectDissolution rate (%)

5 min 10 min 15 min 30 min 45 min 60 min 90 min 120 min 180 min 240 min 300 min 360 min

〈Test drug〉

Lot number(date of manu.)

123456789101112

(mean±SD)

〈Reference drug〉

Lot number(date of manu.)

123456789101112

(mean±SD)Date of test Investigator Manufacturer

[Form 1]

<Cautions on written notices>

1. Drug product type space: describe 'water soluble', 'poorly soluble', 'enteric-coated', 'extended-release', etc.

2. Dosage form space: describe in detail such as 'tablet','sugar-coated tablet', 'film-coated tablet', etc.

3. Lot number (manufacturing date) space: describe lot numbers of test and reference drug products and date of manufacture in parentheses.

4. Dissolution data: describe percent of dissolution compared to the labeled content by rounding off to the nearest integer to one decimal place. In

addition, when dissolution reaches 85% within the testing time point specified rule time, average percent of dissolution of reference drug is higher

than 85%, and when average percent (%) of dissolution of reference drug in each test media for other oral dosage forms except enteric coated

products does not change (less than 5%) at thoursee consecutive time point around 120 min, the test can be terminated.

5. Time points of dissolution: for extended- sustained release drug products, each time point shall be 15 min, 30 min , 60min ,90 min, 2 h, 3 h, 5 h, 6 h,

8 h, 10 h, 12 h, and 24 h.

[Form 2]

Summary Table of Dissolution Rate (%)

Product type Active substance Product name Dosage form Strength

Dissolution media

Agitation speed

Surfactant Analysis method Ground

Test apparatus Volume Temperature Note

Test buffer Product groupAverage dissolution rate (%) (mean± SD)

5 min 10 min 15 min 30 min 45 min 60 min 90 min 120 min 180 min 240 min 300 min 360 min

pH 1.2Test

Reference

pH 4.0Test

Reference

pH 6.8Test

Reference

waterTest

Reference

pH 1.2+PSB80Test

Reference

pH 4.0+PSB80Test

Reference

pH 6.8+PSB80Test

Reference

water+PSB80Test

Reference pH 6.8

(appt I, 100rpm)

TestReference

*Test

Reference Date of test Investigator Manufacturer Result


1. Drug product type space: describe 'water soluble', 'poorly soluble', 'enteric-coated', 'extended-release', etc

2. Dosage form space: describe in detail such as 'tablet','sugar coated tablet', 'film coated tablet', etc.

3. Lot number (manufacturing date) space: describe lot numbers of test and reference drug products and date of manufacture in parentheses.

4. Dissolution data: : describe percent (%) of dissolution compared to the labeled content by rounding off to the nearest integer to one decimal place.

In addition, when dissolution reaches85% within rule time, average percent (%) of dissolution of reference drug is higher than 85%, and when

average percent (%) of dissolution of reference drug in each test media for other oral dosage forms except enteric coated products does not change

(less than 5%) at thoursee consecutive time point around 120 min, the test can be terminated.

5. In case of enteric coated products, correct pH 4.0 to pH 6.0 then describe in space.

6. In case of extended-release products, describe both test methods in apparatus and rpm spaces and the time points of measuring percent (%) of

dissolution shall be 15 min, 30 min , 60min , 90 min, 2 h, 3 h, 5 h, 6 h, 8 h, 10 h, 12 h, and 24 h.

*: Solubilizer added test or test media solution depending on protocol and test method

210mm

sampling time

100dissol-ution(%)

297mm

10mm

70

90

20mm

25mm

80

180 360 (분)3002405

30mm

[Form 3]

Graphic Presentation of Dissolution Test Result [Oral Dosage Form]

～～ノノ


1. Draw the change of average % dissolution of a lot for the dissolution test. (20mm for each interval of the time point of sampling)

2. To compare the results with those of other applied drug products, keep the scale intervals both up and down, and right and left.

3. Provide graph for each dissolution buffer.

4. The time points of measuring percent (%) of dissolution for extended-release drug products are 15 min, 30 min, 60min, 90 min, 2 h, 3 h, 5 h, 6 h,

8 h, 10 h, 12 h, and 24 h.

[Form 4]

Evaluation Sheet for Comparative Dissolution Test Result

Manufacturer product name (generic name)

Lot number

Date of manufac. Lot size Average

content (%)

Reference drug (1)

Test drug

Active ingredient

Labeled contents of active ingredient

Test institution Principal investigator

Test methodTest apparatus Agitation speed

Sample number

Volume (mL) Temp (℃) Others

2nd (paddle method) 50 rpm 12 900 37.0±0.5

Analysis methodContent test (2) Ground

Dissolution test (2) Ground

Validation of analysis method

(3)

Calculation of % dissolution

(4) Disturbing factor among excipients

Product type (5) Dosage form (6) Lag time

Dissolution buffer

Final sampling

time (min)

Time to reach 85% of dissolution of

reference drug (min)

Evaluation timeComparison time

point 1Comparison time

point 2Result

% Dissolution

minReference

drugTest drug

Reference drug

Test drug

pH 1.2 / /

pH 4.0 / /

pH 6.8 / /

water / /

pH 1.2 + PSB / /

pH 4.0 + PSB / /

pH 6.8 + PSB / /

water + PSB / /

Overall conclusion

※ Notes

(1) : mean±S.D.

(2) : Describe 'Test condition, Detector, Wavelength etc.'

(3) : Describe 'at each pH solution particularity/linearity/accuracy/precision/quantification limit, etc'

(4) : Describe 'using calibration curve or comparison of % dissolution with that in standard solution'

(5) : Describe 'water soluble, poorly soluble, etc.'

(6) : Describe 'film-coated tablet, tablet etc.'

[Form 5]

Evaluation Sheet for Comparative Dissolution Test Result(with formulation changes)

Manufacturer Product name (generic name)

Lotnumber

Date of manufac. Lot size Average

content (%)Reference drug (1)

Test drug

Active ingredient




Sample number

Volume (mL) Temp (℃) Others

2nd (paddle method) 50 rpm 12 900 37.0±0.5

Analysis methodContent test (2) Ground

Dissolution test (2) Ground Validation of

analysis method (3)

Calculation of % dissolution (4)

Disturbing factor among excipients

Product type (5) Dosage form (6) Lag timeTest result Average dissolution rate

Dissolution buffer

Final sampling

time (min)

Time to reach 85% of dissolution of

reference drug (min)

Evaluation time Comparison time point 1

Comparison time point 2

Result%

dissolution minReference

drugTest drug

Reference drug

Test drug

pH 1.2 / /pH 4.0 / /pH 6.8 / /water / /

Test result Individual dissolution rate

Dissolution buffer

Time to reach 85% of

dissolution of reference drug

Test drug average %

dissolution rate

Test drug individual % dissolution

range

Average % dissolution (%)

± 15%exceeding number

Result

pH 1.2 pH 4.0 Water pH 6.8Overall

conclusion

※ Notes Attachment 1. calculation of the level of formulation changes

(1) : mean±S.D.

(2) : Describe 'test conditions, detector, wavelength, ect.'

(3) : Describe 'at each pH solution particularity/linearity/accuracy/precision/quantification limit, etc'

(4) : Describe 'using calibration curve or comparison of % dissolution with that in standard solution'

(5) : Describe 'water soluble, poorly soluble, etc.'

(6) : Describe 'film-coated tablet, tablet etc.'

[Form 6]

Evaluation Sheet for Comparative Disintegration Test Result

ManufacturerProduct name (generic name)

Lot numberDate of manufac.

Lot sizeAverage content

Reference drug (1)

Test drug

Active ingredient




Sample number

Volume (mL)

Temp (℃)Using

assisted-plateDisintegration test method

12 37.0±0.5

Analysis method

Content test (2)Dosage formDisintegration

test methodReason why comparative

dissolution test not possibleCriteria for reference drug

and test method (3)

Test solutionEvaluation

criteria

Test resultResult

Reference drug Test drug

Disintegration time difference

between reference and test must be within 5 min

min Sample No. min Sample No.

The Korean Pharmacopoeia standard protocol for disintegration test

Product type Test bufferUsing

assisted-plateTest time (min) Evaluation

Overall conclusion

※ Notes

(1) : mean±S.D.



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