standard on pharmaceutical equivalence study · pharmaceutical equivalence study shall be performed...
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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
similarity factor(f2) is not less than 50.
○ 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
similarity factor(f2) is not less than 50.
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
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
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
poorly soluble Bioequivalence study
Extended- Release
widecomparative dissolution test4) or comparative disintegration test
narrow Bioequivalence study
D
Immediatewide
water soluble≧85%/30 min
comparative dissolution test4) or comparative disintegration test
〈 85%/30 min Bioequivalence study
poorly soluble Bioequivalence study
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
Disintegrating agents Starch Others
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
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 2-2]
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
Disintegrating agents Starch Others
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
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
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
〈 85%/30 min Bioequivalence study
poorly soluble Bioequivalence study
Extended Release
widecomparative dissolution test4) or comparative disintegration test
narrow Bioequivalence test
D
Immediatewide
water soluble≧85%/30 min
comparative dissolution test4) or comparative disintegration test
〈 85%/30 min Bioequivalence study
poorly soluble Bioequivalence study
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
<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 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
<Cautions on written notices>
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
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 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
Labeled contents of active ingredient
Test institution Principal investigator
Test methodTest apparatus Agitation speed
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.
(2) : Describe 'test conditions, detector, wavelength, ect.'
(2) : Describe 'test conditions, detector, wavelength, ect.'