The Korea Food and Drug Administration Notification 2002-43
Provision for Specifications and
Test Procedures of Drugs
2003. 10. 30.
Korea Food and Drug Administration
발 간 사
이 책자는 식품의약품안전청에서 고시한 “의약품등 기준및
시험방법 심사의뢰서 심사규정”의 영문번역판입니다.
이 심사규정은 1998년 12월 31일 자로 우리청에서 처음 고
시한 이래 지금까지 4차례 개정된 바 있습니다. 그러나 과학의
발전에 따른 새로운 의약품 개발이 급속하게 진보되면서 의약품
의 품질과 안전성을 높이기 위한 의약품 심사규정은 나날이 강
화되고 있는 추세입니다.
그동안 우리청의 각종 심사규정에 대한 영문판이 발간되지
않아 국내외 기업들이 허가를 신청함에 있어서 불편이 많았을
것으로 생각합니다.
우리는 이 영문판이 외국기업은 물론이고 국내기업도 외국
과 교류함에 있어서 우리청의 의약품 규정에 대하여 보다 유용
하고 명료한 정보로서 활용될 수 있기를 기대합니다.
또한, 현재의 WTO 체제에서 의약품의 수출입 과정에서 발
생될 수 있는 규정상의 오해의 소지를 제거함으로써 투명성을
높이는 계기가 되기를 바랍니다.
식품의약품안전청장
약학박사 심 창 구
2
Foreword
This is an English translation of the “Regulatory Provision for
Review of Request on Specifications and Test Procedures of Drugs”
issued by the Korea Food and Drug Administration (KFDA).
This guideline has been revised four times so far since the
publication of the first provision on December 31, 1998 by the KFDA.
Despite the revisions, however, the rapid progress in science and new
drug development has made it essential for the related specifications to
be updated continuously in order to improve safety and quality of drugs.
Because reliable English translations for a variety of provisions
issued by the KFDA have not been published, both foreigners and
domestic pharmaceutical companies may have faced difficulties in
preparing the applications of their products to the KFDA.
We sincerely hope that this English version would be able to
provide very useful and elucidative guidance on the provisions related to
drugs in the KFDA for foreigners as well as domestic pharmaceutical
firms. Furthermore, we also wishes the publication of this English
translation to serve as an opportunity to remove any potential
misunderstandings that might occur in importing and exporting
procedures under the existing WTO system and to enhance transparency
in the KFDA’s approval processes.
Chang - Koo Shim, Ph.D.
Commissioner
Korea Food and Drug Administration
3
Contents
Part Ⅰ. Introduction
Announcement
Part Ⅱ. Articles
Article 1 : Purpose
Article 2 : Compilation of specification and test procedures
Article 3 : Reference data
Article 4 : Supplementary rules
Part Ⅲ. Attachment
Attachment 1 : Attached specifications for drug substance
Attachment 2 : Attached specifications and test procedures for
drug products
Part Ⅳ. Addendum
4
PartⅠ. Introduction
 Announcement
The Korea Food and Drug Administration
Notification 2002-43
In accordance with provision of Articles 26 and 34 of the Korea
Pharmaceutical Affairs Law and Articles 23 and 26 of its Enforcement
Regulations, Provision for specification and test procedures of drugs is
established as follows.
August 1, 2002
Commissioner of the Korea Food and Drug Administration
5
Part Ⅱ. Articles
 Article 1
(Purpose)
The purpose of this provision is to take appropriate measures for
review applications for specifications and test procedures of drugs in
accordance with provision of Articles 23 and 26 of Enforcement
Regulations of the Korea Pharmaceutical Affairs Law, Guidelines for
Manufacturing Licenses and Import Product Licenses for drugs
(hereinafter referred to as "Guidelines for Manufacturing Licenses for
Drugs") and with Article 3 of Provision of test request to Korea Food
and Drug Administration and Korea National Institute of Health
(hereinafter referred to as " Regulations of test request ").
6
 Article 2
(Compilation of specifications and test procedures)
① In general, following points shall be taken into consideration in
compilation.
1. Matters such as description of specifications and test procedures,
terms, units, and marks shall be, in principle, in accordance with the
Korean Pharmacopoeia (KP).
2. Items to indicate specifications and test procedures shall, in principle,
comply with the following [Table 1]. However, unnecessary items
may be omitted depending upon the nature of the drug substances and
dosage forms.
3. Description of test procedures
In principle, the "test procedures " shall refer to the KP for general
provisions, general provisions for formulations, general test
procedures, reference standards, reagents and solutions. Except the
case of "4. Omission of description of test procedures", all the test
procedures shall be described in detail.
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[Table 1]
No
Indicated items
Drug
substances
Drug
products
1
Name
○
×
2
Structural formula or Chemical formula
△
×
3
Molecular formula and molecular weight
○
×
4
Origin
△
△
5
Content specification
○
○
6
Description
○
○
7
Identification
○
○
8
Physicochemical characteristics
△
△
9
Purity
○
△
10
Loss on drying, Loss on ignition, or Water
○
△
11
Sulfated ash, Ash, Acid-insoluble ash
△
×
12
Test for dosage form
×
○
13
Special performance test
△
△
14
Others
△
△
15
Assay (content test for drug products)
○
○
16
Reagents·solutions
△
△
In Table 1, ○ : mandatory, in principle ; △ : required if necessary ;
× : not required, in principle
8
4. Omission of description of test procedures
Test procedures described in the KP, official formularies in "official
formularies or compendium of drugs" designated by the KFDA Notice
(hereinafter referred to as "KFDA notice"), or described in
specifications and test procedures noticed by Commissioner of the
KFDA, may be omitted entirely or in part. However, the KP and
official formularies to be referred to shall be the latest edition and the
items deleted in the latest edition shall be acknowledged in accordance
with the second latest edition.
5. The entire or part of the test procedures that apply to the KP and
official formularies shall be indicated as follows;
* For example :
Sterility test : This drug shall be tested by the sterility test in
accordance to general test in KP.
Assay : Weigh and finely powder not less than 20 tablets and
analyze them as described in the assay under the Ascorbic
acid in the KP.
Assay : Weigh and finely powder not less than 20 tablets and
analyze them as described in the assay under the Lysozyme
chloride Tablets in Korean Pharmaceutical Codex by the
KFDA notice.
6. When using reagents, solutions, instruments, equipments not listed in
the KP and Korean Pharmaceutical Codex, reagents and solutions
shall be described along with their purity, concentration and
manufacturing method, while the instruments shall be described along
with their types and operation manuals. Reagents harmful to humans
and environment, such as mercury compounds, cyanide compounds,
9
benzene, carbon tetrachloride, 1,4 dioxane shall not be used.
② Compilation of specifications and test procedures shall meet the
following guidelines :
1. Compilation of specifications for drug substances
Specifications and test procedures for the following categories shall
be formatted in a form as in the Attachment 1.
a. Name
Name shall be in accordance with "Guidelines for Manufacturing
Licenses for drugs"
b. Structural or chemical formula
Structural or chemical formula shall be in accordance with
declaration of the KP.
c. Molecular formula and molecular weight
Molecular formula and molecular weight shall be in accordance
with declaration of the KP.
d. Origin
For synthetic drugs of which their chemical structures have been
determined, it is not necessary to indicate their origins. For proteins
extracted(hydrolyzed) from organs, enzymes, etc., the origins where
they come from shall be indicated. However, in case of drugs that
are either difficult or impossible to separate or isolate, because they
contain two or more compounds with structural similarities, such as
the optical and geometrical stereoisomers or high molecular weight
compounds, the ratio of the composition shall be described.
10
e. Content specifications
1) In principle, contents of drug substance shall be indicated by
percentage with a molecular formula in parenthesis. However, the
contents of drug substance shall be described by potency or unit
when it is not possible to indicate by percentage. Contents of
chemically pure substances may be indicated when the contents of
drug substance cannot be applicable.
2) In principle, other than for herbal medicines, the lower limit and
the upper limit of drug substance shall be established. In case of
unstable drug substances, standard range shall be based on the
safety information of the degradation products.
3) In case when there is a clear rationale for inability to set
specifications, content specifications may be omitted. However, the
rationale for omission shall be clearly justified.
f. Description
1) In general, color, shape, taste, odor, solubility, fluidity, stability
(hygroscopicity, photostability, etc.) shall be described.
2) Identification and reference for use shall be indicated. However,
color and physical shape shall be used as acceptance criteria for
quality. Other necessary items used as acceptance criteria for the
specification shall be described in physicochemical characteristics
and/or purity items.
g. Identification
1) Color reaction, precipitation reaction, decomposition reaction,
derivative formation reaction, specific reaction, qualitative reaction
of cations and anions shall be described for chemical tests focused
on characterizing chemical structures of drug substance. Ultraviolet,
visible light and infrared spectrophotometry, and chromatography
11
methods may also be described.
2) If the drug substance can be identified by using test items other
than the identification test, those items may be established as an
identity test. For example, use of chromatography with high
specificity in assay may be cited as an identification test without a
duplicative description.
h. Physicochemical characteristics
1) Items required to show the essence and purity of the drug
substance shall be established.
2) Physicochemical characteristics value is the constant value
measured by using physicochemical methods, which includes
saponification value, refractive index, specific optical rotation,
boiling point, specific gravity, acid value, alkaline value, alcohol
number, ester value, iodine value, melting point, freezing point,
viscosity, pH, absorbance, etc.
3) Measurements of physicochemical value shall be
performed in accordance with the general test procedures
of the KP, and test methods shall be described for other cases.
4) Physicochemical values not required for acceptance criteria for
quality shall be indicated in "description" item.
i. Purity
1) Items necessary for purity test such as color, odor, appearance of
the solution, fluidity, acid, alkali, chloride, sulfate, heavy metal,
arsenic, substances from sulfate color reaction, copper, tin, mercury,
zinc, aluminum, iron, alkali earth metals, particulate matter, related
and/or degrated substances, and residual solvent shall be established.
In this case, the term "particulate matter" shall mean contaminants
introduced, left over, formed or added during the manufacturing
12
process.
2) Appearance of the solution may be established when the purity of
drug substance can be determined from it.
3) Drug substance of a new drug shall have the following items
established.
a) For heavy metals, arsenic, inorganic salts, necessary items
shall be established based on manufacturing process, dosage and
administration.
b) Among the related substances formed during synthesis,
purification or storage, the related substances where chemical
structures cannot be identified and are contained more than 0.1%
of the total content, as well as those less than 0.1% of the total
content but considered to be highly toxic or to possess a
pharmacological action, shall be separately established and there
shall be an accurate assay method with high specificity shall be
established for these related substances.
c) Other related substances shall be established at less than 0.1%
of the total content using chromatographic extraction method
based on the relative area under the curve or the diluted eluant
standard. The estimated range of area under the curve in
chromatogram shall be also included.
d) Degradation products shall be established based on data from
stress test defined in the KFDA notice "Provision for stability
tests for drugs"
e) For solvents that may raise a safety problem during the
manufacturing process or have a residual probability, appropriate
specification shall be established considering dosage
and administration.
13
j. Loss on drying, loss on ignition or water
Loss on drying, loss on ignition or water shall be established based
upon each test procedure defined in the general test procedures of
the KP.
k. Sulfated ash
Sulfated ash shall be established based upon the test procedure
defined in the general test procedure of the KP.
l. Special performance test
For general proteins extracted (hydrolysed) from organs, enzymes,
etc., safety test, antigenic test, histamine test, and so on shall be
established, if necessary. For drug substance for antacids, acid
neutralization test shall be established, and digestive test shall be
established for drug substance for digestive enzymes.
m. Others
Other test items not listed above shall be established if they are
directly related to quality test, safety and efficacy assessment.
* For example : isomer ratio
n. Assay
Assay is a quantitative method measuring constant weight / contents,
containment unit of the substance by a physico-chemical or
biological method. Test procedures with accuracy, precision and
high specificity shall be established. However, in case where the
limit of foreign material in purity test is regulated, test procedures
with low specificity may be adopted.
2. Compilation of indicated items for the drug products shall meet the
following guidelines.
Specifications and test procedures for the following categories shall
14
be established in accordance with the Attachment 2.
a. Description
Color, shape and dosage forms (plain tablets, sugar coated tablets,
enteric coated tablets, hard and soft capsules, injections, syrups,
etc.) shall be described. For capsules, description of the materials
contained in capsule shall be clearly described. For injections and
eye drops, description of a container shall also be listed. For drugs
flavored with aromatics which carry a unique smell, description for
smell shall be listed. For oral preparations with a unique taste,
description for taste shall be listed.
b. Identification
In principle, chemical tests shall be mainly described for all active
ingredients. However, other methods such as ultraviolet and visible
light, infrared spectrophotometry, and chromatography may also be
described. In case when there is a clear justification for the inability
to establish identification, the identification may be omitted. In case
when the drug substances are poisonous or potent drugs,
identification shall be essentially established accordingly.
c. Physicochemical characteristics
Items from physicochemical characteristic value of drug sbustance
directly related to quality, stability, safety and efficacy of drug
products shall be established.
* For example : pH of injections and oral liquid preparations
d. Purity
(1) Purity shall be established for the materials which can co-exist in
the formulation such as related materials (drug substance,
intermediates, by-products and degradation products), reagents,
catalysts, heavy metals, inorganic salts, solvents, etc.
15
(2) Purity shall be established in case when the change in
formulation is expected during manufacturing and storage.
e. Loss on drying, loss on ignition or water
Loss on drying, loss on ignition or water may be established in
accordance with the general test procedures established in the KP,
where applicable.
f. Test for dosage form
1) In order to define characteristics or function of dosage forms,
necessary tests shall be established.
2) In principle, test items shall be in accordance with the following
[Table 2]. However, additional tests may be established according to
dosage forms so as to show specifically the function of a preparation
and prove its benefit.
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[Table 2]
Dosage Forms
Specification
Topical preparations for transdermal
absorption (plasters, etc.)
Release test 1), Adhesion test
Granules, Powders
Particle size test, Dissolution or
Disintegration test 1, 2), Weight
variation test (individual packaged)
Ophthalmic ointments
Heavy metal, Sterility test, Release
test 1), Particle size test
Aerosols (metered dose)
Relation between spray time and
spray quantity, Particle size test
(for Suspensions)
Elixirs, Fluid extracts, Spirits, Tinctures
Alcohol number
Ophthalmic Solutions5)
Sterility test, Release test
1,9)
,
10)
Insoluble particulate matter test ,
Particle size test 9)
Tablets, Capsules, Troches, Pills
Dissolution or Disintegration 1,2)
Weight variation or Content
uniformity test 3,4)
Suppositories
Release test1), Disintegration test,
Melting point test
Injections5)
Sterility, Foreign insoluble matter
test 6), Insoluble particulate matter
test 7), Release test 1,9), Extractable
volume test, Weight variation or
4)
Content
uniformity
test
,
Endotoxin or Pyrogen test 8),
Particle size test 9)
17
(1) For new drugs, specifications and test procedures of “dissolution
or disintegration” and “release test” shall be considered irrespective
of regulations of general provisions of preparations in the KP.
(2) In principle, dissolution test shall be established. However, in
case when the disintegration rate control during the period of use
(efficacy) is assured, disintegration test may be established.
(3) For coated tablets, content uniformity test shall be recommended.
(4) For preparations that readily become ununiform, contain little
amount of active ingredients, or contain therapeutically potent
active ingredients, etc., the establishment of content uniformity test
shall be reviewed in order to obtain the uniformity of unit
preparation.
(5) If the vehicle is not a product listed in the KP, specifications and
test procedures of the vehicle shall be established.
(6) Established for water-soluble injections that should be dissolved
prior to use.
(7) Established for water-soluble injections (that should be
dissolved prior to use) with a net content more than 100 mL.
(8) Endotoxin test is prioritized for intravenous injections and
injection solvents (except injection water) with prefilled volume of
larger than 10 mL.
(9) Established for suspensions
(10) Established for aqueous eye drop solutions
g. Special performance test
18
In general, safety test, antigenic test, histamine test shall be
established for enzyme preparation, and preparation of proteins
extracted (hydrolysed) from organs, etc., if necessary. Additionally,
acid neutralization test shall be established for antacids as digestive
test for digestive enzymes.
h. Others
Others shall be established referring to those of drug substances.
i. Assay
1) Test procedures with high specificity, accuracy and precision, not
affected by the presence of other components, shall be established.
2) If there are more than two different components to be assayed,
they shall be described in the order of their significance.
3. Specifications
a. Content specifications
Content specifications of preparations or potency of drug substance
and drug product shall be established in relative amount to the
labeled amount or the labeled potency as follows. However, if there
are permitted specifications from the manufacturing country or the
original country, or there is a proper rationale, they shall be
differently established.
1) General standards
a) Drug substance : more than 99.0 %
b) Single active ingredient preparations : 95.0 ~ 105.0 %
(however, 90.0 ~ 110.0 % for external preparations)
19
c) Combined active ingredients preparations : 90.0 ~ 110.0 %
2) Vitamins
a) Combined vitamins preparations (except injections) : 90.0 ~
150.0 %
b) Single vitamin preparations : 90.0 ~ 130.0 %
c) Single and combined vitamin derivatives preparations : 90.0 ~
130.0 %
d) Single and combined vitamin injections : 90.0 ~ 130.0 %
e) Related vitamins added to combined vitamin preparations :
90.0 ~ 150.0 %.
Those related vitamins are including
panthothenic acid and its salts, pantenol, nicotinic acid, nicotinic
acid amide, folic acid, biotin, p-aminobenzoic acid, choline
tartarate, inositol, orotic acid, linoleic acid, thioctic acid,
carnitine hydrochloride and hesperidin, etc.
f) Minerals added to combined vitamins preparations : 90.0 ~
150.0 %
3) Single and combined nucleic acid preparations : 90.0 ~ 130.0 %
4) Enzymes
a) Drug substance : more than 100.0 %
b) Digestive enzymes : more than 90.0 %
c) Anti-inflammatory enzymes : 90.0 ~ 130.0 %
5) Single or combined amino acids and their derivative
preparations : 90.0 ~ 130.0 %
20
6) Lactobacillus preparations and other live bacterial preparations :
more than 90.0 %
7) Volatile components of drugs : 90.0 ~ 130.0 %
8) Disinfectants and insecticides : 90.0 ~ 110.0 %
9) Preparations of proteins extracted (hydrolyzed) from organs
a) Drug substance : more than 100.0 %
b) Drug products : more than 90.0 %
10) An efficacy test, a performance test or a pharmaceutical test can
be conducted, where applicable.
* For example : Adsorption test of charcoal
b. Other test specifications
Specifications required for quality control are as follows. Other
specifications may be established separately, where applicable. For
items 1) - 4), specifications may be adjusted if justifications of
rationale cannot be accepted. In case of using in-house result
without due reference data, mean value of test results for more than
3 lots may be used as specifications. Every lot of test materials shall
be tested more than 3 times (hereinafter referred to as "actual
value").
1) pH
In principle, actual test value +/- 1.0
2) Specific gravity
21
In principle, actual test value +/- 0.05
3) Residue on evaporation
Upper limit shall be established, as long as there is no other
rationale.
4) Alcohol number
Established in case when ethanol is contained more than 4 % and it
shall be more than 90 % of the actual value.
5) Safety
In principle, specifications and test procedures for safety test shall
be established for injections of proteins extracted (hydrolysed) from
organs, of which component composition is not accurately defined.
6) Histamine
In principle, specifications and test procedures for histamine test
shall be established for injections of proteins extracted (hydrolysed)
from organs and other enzyme injections, where the composition of
components is not accurately defined.
7) Antigenicity (Anaphylaxis)
In principle, specifications and test procedures for antigenicity shall
be established for injection of proteins extracted (hydrolysed) from
organs and other enzyme injections, of which component
composition is not accurately defined.
8) Preservatives
Specifications and test procedures for preservatives shall be
established for preparations containing preservatives, such as
pharmaceutical liquids, ophthalmic preparations, injections, solidtype oral preparations such as pills, capsules, tablets, and ointments,
creams. However, the amount of preservatives shall be less than
labeled amount, and may be established separately, if necessary.
22
9) Sweetening agent
Specifications and test procedures shall be established for oral
preparation containing saccharine and its salts. However,
specification shall be less than the labeled amount as long as there is
no other rationale.
10) Weight / Volume variation
The test shall be in accordance with weight variation test procedure
from general test procedures of the KP and the KFDA noticed
volume (weight) variation specifications and test procedures of
drugs, etc.
11) Microbial limits
The test shall be in accordance with the KFDA noticed microbial
limits and test procedures of drugs, etc.
③ Specifications and test procedures according to drug products shall
be indicated in accordance with Paragraph 1 and Paragraph 2 of
Article 4 of this provision. Specifications and test procedures
required for the drug products shall be established by the following
items.
1. Antibiotics and their preparations
Specifications and test procedures for antibiotics and their
preparations shall be indicated based on the KFDA noticed
"specification of antibiotic drugs". Reference data shall be publicly
recognized. However, identification of the preparations listed on
official formularies (Japanese specification of antibiotic drugs, JP,
USP, CFR, etc.) may be admitted according to the reference data.
23
2. Herbal medicines and herbal medicine preparations
If necessary by characteristics of each preparation, specifications and
test procedures may be established separately according to a reference
data (including the laboratory data).
a. Compilation for herbal medicines and herbal extracts
Specification of herbal medicines which are not listed in the KP,
official formularies and Korean Herbal Pharmacopoeia shall be
described in accordance with compilation of the KP. Specifications
of herbal extracts shall be established by the following items.
1) Names of herbal extract
Solvent used for extraction, yield in percentage [final extracts and
quantity percentage of the raw herbal medicines quantity] and
physical form (fluid, viscous, and dry) shall be indicated after the
name of a herbal medicine.
* For example : glycyrrhiza 30 % ethanol dry extract (4→1)
2) Content criterion
Content criterion shall be established for preparations with strong
physiological activity, or measurable preparations. In principle,
content criterion shall be based on reference data. However, if no
reference data is available, content criterion shall be within +/- 50 %
of the actual value.
* For example : This drug contains 5.0 - 15.0 % of glycyrrhizic acid
(C42H62O16 : 822.92).
3) Manufacturing methods
a) Specification of herbal medicines (plant origin, scientific
name, family name and used part), fineness and their quantity
24
b) Kind of solvents used for extraction (i.e., 30 % ethanol) and
their quantity
c) Temperature, time and the number of extraction
d) Filtration condition (filtration materials and methods)
e) Concentration method (i.e. freeze-drying) and drying
condition (i.e. dry and viscous)
f) Kind and quantity should be indicated in case of using an
excipient in order to control characterizing compound (marker)
content or herbal extracts for other purposes.
g) Percentage of yield [quantity ratio of the final extract with
reference to raw herbal medicines and from which step it is
obtained should be clearly described, and so on] should be
described.
4) Description
Description shall be indicated by the KP terms. Especially, smell,
color, shape, and so on shall be described.
5) Identification
Identification shall be established for all herbal medicines which are
included as active ingredients in the formulation. Thin layer
chromatography method shall be mainly established. In case of
using a chemical method, it shall be such that it should be able to
detect the only ingredient derived from a single herbal medicine.
6) Purity
Items such as heavy metals, arsenic, and so on shall be established.
25
7) Loss on drying
Loss on drying shall be established for herbal medicines and dry
extract and shall be less than 120 % of the actual value.
8) Extract content
For dry extract without content criterion, extract content shall be
established by using dilute ethanol, water or ether extract as a
solvent.
9) Alcohol number
Alcohol number shall be established if ethanol is not less than 4 %
and shall be more than 90 % of the actual value.
10) Residual insecticide
Residual insecticide shall be in accordance with the KFDA noticed
specifications and test procedures for residual agricultural chemicals
of herbal medicines.
11) Assay
For herbal extracts with a characterizing compound or a strong
pharmacological action, assay shall be established in principle.
However, if impossible, reasonable reference data shall be
submitted.
* For example : high performance liquid chromatography (HPLC)
data
b. Compilation of preparations
1) Common matters
a) Description
Description shall be made based on compilation of herbal
medicines and herbal extracts.
26
*For example : brown extract granules
b) Identification
In principle, identification test shall be established for all herbal
medicines, which are included in the formulation as active
ingredients. If the test is difficult to be conducted, reasonable
rationale (i.e., review results) shall be submitted additionally as a
data.
c) Heavy metal
Heavy metal shall be in accordance with the specifications and
test procedures of KFDA's notice.
d) Weight (Volume) variation
Compilation shall be in accordance with weight variation test
procedures of the KP and the specifications and test procedures
of KFDA's notice.
e) Preservatives
For herbal medicines containing preservatives, specifications and
test procedures for preservative test shall be established for
liquid preparations for internal use, ophthalmic preparations,
injections, solid preparations for internal use such as
pills·capsules·tablets, ointments, creams, and so on. However,
the amount of preservatives shall be not more than the labeled
amount and, if appropriate, may be established separately.
f) Microbial limits
Compilation shall be in accordance with the specifications and
test procedures of KFDA's notice.
g) Assay
(1) Content shall be established for measurable herbal
medicines. In principle, the test shall be established for all
27
herbal medicines with strong pharmacological action, if
possible. However, a reasonable rationale shall be submitted
(i.e., liquid chromatography data, and so on.) if it is difficult to
establish.
(2) Content criterion shall be more than 90.0 % of the indicated
measure, unless for other rationale. However, content criterion
for herbal medicines with strong pharmacological action is
90.0 ~ 130.0 %, and shall be established considering
pharmaceutical aspect when applying this to preparations.
(3) Content criterion shall be indicated in the specification of
preparations, if content criterion of herbal extract raw material
is established.
* For example : 1 pouch of powder contains 10.0 - 20.0 mg of
glycyrrhizic acid (C42H62O16 : 822.92)
2) Solid preparations
The following items shall be established for solid preparations such as
tablets, pills, powders, granules, capsules, troches, and extracts (dry or
viscous).
a) Extract content
Extract content shall be established among dilute ethanol, water or
ether extract.
(1) The following table is the standard permitted level for extract
content.
28
Actual value
Permitted level
25 % and more
+/- 10 %
15 % and more - less than 25 %
10 % and more - less than 15 %
5 % and more - less than 10 %
+/- 15 %
+/- 20 %
+/- 25 %
(2) The item "extract content" shall not be established if
identification or content for all active ingredients for prescription
or the actual value of extract contents is less than 5.0 %.
b) Ash
Permitted level is not more than 120 % of actual value. However, in
case when the drug is a mineral or other active ingredients that
cause large amount of ash, this may be omitted.
c) Particle size
Granules and powders are suitable for the particle size distribution
test in accordance with general test procedures of the KP.
d) Disintegration
The test shall be established for dosage forms under disintegration
test from general test procedures of the KP. However, this test is not
suitable for chewable or oral-melting preparations.
3) Liquid preparations
The following items shall be established for liquid preparations such as
liquids, syrups, tinctures, injections for quality control, if necessary.
a) Specific gravity and pH
Permitted level is  0.05 of actual value for specific gravity, and 
1.0 of actual value for pH.
29
b) Alcohol number
Alcohol number shall be established for preparations containing not
less than 4 % of ethanol. Permitted level is not less than 90 % of the
labeled amount.
4) Plasters
a) Extract content
The item shall be in accordance with extract content items for solid
preparations.
b) Ash
The item shall be in accordance with ash test for solid preparations.
c. Test procedures
1) Identification and assay
In principle, chemical test procedures shall be performed. However,
chromatography may be allowed for combined preparations.
2) Extract content and ash
Method of treating specimens shall be separately described following
the relevant items in herbal medicine test procedures under general test
methods of the KP.
* For example : Take about 20 pills of this drug and shred them (or
remove the sugar coating of about 20 pills of this drug, dry at room
temperature and grind them). Take 2 - 3 g of this powder and weigh
precisely. Follow the dilute ethanol extract assay of herbal test
methods under general test methods of the KP during the test
procedure.
3) Specific gravity, alcohol number, heavy metal and arsenic
If classified as category 1, 2 or "device", etc., in general test
30
procedures of the KP and other official formularies, the description
shall be followed.
* For example : Category 3 of the specific gravity and density test
method under general test methods of the KP shall be followed in
order to test this drug.
4) Loss on drying
Loss on drying of herbal medicines under general test methods of the
KP shall be followed.
d. Herbal medicines, herbal extract and preparations mixed with general
drugs
1) In principle, the item shall be reviewed as the herbal medicine
preparations. Extract content and ash may be omitted if the amount of
the herbal medicines or herbal extracts is less than 50 % in
prescription.
2) In case the characterizing compound for quality control is known,
assay shall be established in principle. However, the test may be
omitted if the establishment of assay is difficult to conduct
considering the amount of herbal medicine contained.
3. Biological products
Compilation of specifications and test procedures for biological
products shall be in accordance with the KFDA notice "Specifications
and test methods of biological products" (hereinafter referred to as
"Biological products specifications") and the following items shall be
established.
1) For definition, name and preparation shall be indicated.
31
2) In general manufacturing requirement, "comply with provisions No.
2 of production control under pharmaceutical regulations of biological
products specifications" shall be described.
3) In manufacturing requirement, drug raw materials, concentrated
bulk, tests for concentrated bulk, final bulk and tests for final bulk
shall be indicated.
4) On filling and containers, "comply with the provision No. 3, for
filling and container under pharmaceutical regulations for biological
products specifications" shall be indicated.
5) For control tests on final product, specifications and test procedures
by characteristics of each products shall be indicated.
6) For records, "comply with provision No. 5 for record under
pharmaceutical regulation of biological products specifications" shall
be indicated.
7) For samples, "comply with provision No. 6 for samples under
pharmaceutical regulations of biological products specifications" shall
be indicated.
8) For declaration of container and package, "comply with provision
No. 7 for declaration of container and package under pharmaceutical
regulations of biological products specifications" and other items shall
be indicated.
9) For distribution and shipping, "comply with provision No. 8 for
distribution and shipping under pharmaceutical regulations of
biological products specifications" shall be indicated.
10) For storage and expiry date, storage condition and expiry date of
32
the drug shall be indicated.
11) In case of injections to be reconstituted or suspended before use,
"comply with provision No. 10 for Appendix 'solvent' under
pharmaceutical regulations of biological products specifications" shall
be indicated for an attached solvent.
4. Recombinant products and cell culture products
The following items shall be established for specifications and test
procedures for recombinant products and cell culture drugs. The
compilation shall be in accordance with Paragraph 2 of "General
Drugs" of this regulation, unless specified otherwise.
1) Name
2) Description
3) pH
4) Sterility
5) Foreign insoluble matter test for injections
6) Pyrogen or endotoxin test
7) Abnormal toxicity
Abnormal toxicity shall be established in accordance with the
characteristics of a product.
8) Loss on drying and water
9) Identity
33
Identification shall be established by the test methods such as
electrophoresis, immunochemical procedures, biological assay,
physico-chemical tests, and so on.
10) Purity
Purity shall be established depending on the characteristics of a
product by means of high molecular weight proteins and related
proteins, host-cell- and vector-derived DNA, host-cell-derived proteins
using the test methods such as electrophoresis, chromatography,
immunochemical procedures, and so on.
11) Potency
Physico  chemical, immunological or biological test methods shall be
established. In case of physico-chemical test and immunological test,
biological activity shall be observed.
5. Aerosols
Aerosols shall be tested in accordance with the KFDA guidelines for
aerosols in drugs and so on.
6. In vitro diagnostics
Items for the test of description and efficacy of the preparations shall
be established in accordance with manuals for directions.
7. Adhesive plasters
Specifications and test procedures shall be established for the
following items. However, specifications and test procedures shall be
established separately in the presence of other rationales.
34
a. Specifications
1) Adhesion
By the following test methods, PVC film and non-woven adhesive
plaster for testing shall be more than 150 g per 12mm in width and
plasters shall be more than 42 g per 12mm in width.
2) Tensile strength
By the following test methods, PVC film and non-linting adhesive
plaster shall be more than 1 kg per 12mm in width.
3) Shape (length and width)
Length and width shall be appropriate for shape test under item
"Adhesive plaster" of the KP. However, in case of disposable
adhesive plaster, length and width of pads (gauze or non-woven
fabric, etc.) and plasters shall be more than 98.0 % of the quantity
indicated.
b. Test procedures
1) Adhesion
The test shall be in accordance with adhesion under item "Adhesive
plaster" of the KP. However, for disposable adhesive plasters, the
test shall be established in accordance with adhesion test from item
"Adhesive plaster" of the specifications and test procedures of drugs,
and so on noticed by KFDA.
2) Tensile strength
The test shall be in accordance with tensile strength under item
"Adhesive plasters" of the KP. However, for disposable adhesive
plasters, the test shall be established in accordance with tensile
strength test from item "Adhesive plasters" of the specifications and
test procedures noticed by KFDA.
3) Shape (length and width)
35
The test shall be in accordance with shape (length and width) under
the item "Adhesive plasters" of the KP. However, disposable
adhesive plasters, gauzes shall be tested according to the provisions
of item "Gauzes" of the KP.
8. Gauzes
For gauzes containing drugs (such as sterile disinfectants) which are
sterilized and those the efficacy·effectiveness of which include "burn",
specifications and test procedures shall be established in accordance
with sterility under general test methods of the KP. Others shall be
established in accordance with the specifications and test procedures
methods for microbial limits of drugs noticed by KFDA.
9. Quasi-drugs
1) This shall be in accordance with Item No. 2 "Compilation of
preparations". Contents standard shall be more than 90.0 % of the
labeled amount, unless specified otherwise. However, for the
insecticidal ingredients of insecticidal preparations (including a
potent enhancer), where the specification for the contents of
insecticidal ingredients and their mix limit as well as the
specifications and test procedures of quasi-drugs are regulated by the
KFDA notice, and fluoride content of tooth paste shall be 90.0 ~
110.0 % with reference to the amount indicated.
2) For contact-lens care products, specifications and test
procedures for microbial limits shall be established in accordance
with the KFDA notice.
3) For tooth pastes, contents standard and test methods shall be
36
established for active ingredients (including abrasives and dental
calculus inhibitor).
 Article 3
(Reference Data)
Data described in the following paragraphs shall be attached in
accordance with provisions of Paragraph 12, Article 2 of
Pharmaceutical Affairs Law when submitting specifications and test
procedures for new drugs.
① New drugs shall have data on the following items attached.
For new drugs reviewed under this regulation, specifications and test
procedures (including stability test data) shall be reviewed again
within 1 year after clinical trial, with experimental data attached for lot
size of more than 100 thousand tablets (capsules) or about 1/10 of the
actual production capacity. However, in case when specifications and
test procedures are reviewed before the termination of clinical trial
with the data attached, exemption may be allowed.
1. Data on origin or background of discovery and use in foreign
countries
a. Origin or background of discovery
b. Use in foreign countries
37
2. Data on structural elucidation
a. The following data shall be described to prove chemical structures
of active ingredients.
1) As a method of synthesis, drug raw materials, solvents, a
purification method, etc., related to the establishment of synthetic
pathway and purity test shall be described in connection with the
manufacturing process in the drug master file application.
2) Data related to properties of chemical structure such as element
analysis, ultraviolet·visible light·infrared spectrophotometry, nuclear
magnetic resonance spectrum, mass spectrum, etc., and the discussion.
3) Chemical data (derivatives, etc.) of structural determination and the
speculation.
4) Stereo-structure for an chiral drug
b. For drug raw materials such as a polymer, where structural
composition of active ingredients is not clearly identifiable, physicochemical properties shall be described in as much detail as possible.
The data shall prove that drugs having uniform composition can be
produced from a given manufacturing process.
3. Data of physico-chemical properties
Physico-chemical properties of active ingredients shall include basic
items for test items of specifications and test procedures, as well as test
procedures, actual values and examination shall be described. In
general, the followings shall be included.
38
a. Description
Color, shape, smell, taste, etc., shall be described. However, smell and
taste may not be described if they can affect the investigator's health.
b. Solubility
A solvent that directs solubility shall be selected from a group
consisting of water, ethanol and ether. For solubility in water, the
influence in accordance with pH change shall be described.
Additionally, all the solvents used in tests shall indicate their
solubilities. Each solubility can be determined from the concentration
of a saturated solution.
c. Hygroscopicity
d. pH of solutions
e. Melting point and thermal analysis value
* For example : melting point, presence / absence of decomposition
shall be described.
f. Dissociation constant
g. Distribution coefficient and distribution ratio
Description of distribution coefficient/distribution ratio such as octanol
/ water system, etc., shall also include the influence by pH.
h. Crystalline polymorphism
For drug raw materials recrystallized by using drug raw materials and
various solvents, presence / absence of crystalline polymorphism,
mutual relationship between crystal forms, physical appearance of
each crystal form, and so on shall be described based on the results
measured by infrared spectrophotometry, thermal analysis, powder X39
ray diffraction, etc.
i. Optical rotation
Influence from a solvent for measurement shall also be described, in
case where presence / absence of optical rotation and optical rotation
are confirmed.
j. Isomer (enantiomer, etc.)
If the drug raw material is a mixture of isomers such as enantiomer,
separation·assay method of an isomer shall be reviewed and the ratio
of isomers shall be described.
k. Related substances
Related substances probable to be produced during synthesis,
purification and storage of drug raw materials shall be summarized.
Review result of the detection or assay method shall be described.
1) For related substances contained more than 0.1 % within a drug
raw material and those contained less than 0.1 % but expected to
have a strong poison or pharmacological action, the chemical
structure shall be described precisely. If structural determination is
not made possible, the review result shall be described.
2) For all lots used for stability and safety test, clinical trial, and all
lots that reflect actual production process, quantity and assay
method of related substances, including a material with unknown
chemical structure shall be described with respect to lot number,
manufacturing size, manufacturing date, manufacturing place,
manufacturing process, use of lot, list, etc.
3) In case of the presence of remarkable difference of related
substance for kinds and quantity between actual production lot and
other lots, the review result shall be described.
40
l. Forced degradation products
Degradation products considered to be generated as influence of
humidity, temperature and light, or degradation products from an
acidic, neutral or alkaline aqueous solution or aqueous suspension
shall be reviewed qualitatively·quantitatively. The result shall be data
for selection of stability test items, storage establishment and
preparation design, or shall be base for establishment of purity test
(impurity related substances). Additionally, if necessary, main
decomposition mechanism shall be described and specific detective
method for degradation products shall be also described.
m. Others
If other characteristic value is reviewed, the result shall be described.
4. Data for specifications and test procedures
As reference data for establishment of specifications and test
procedures, following should be described for each test items : test
procedures, justifications for test procedures, justifications for test
conditions, validation of test procedures, raw data justifications for
specifications. Additionally, if necessary for identifying characteristics
of preparations, in accordance with No. (6), item b., item "preparation
design" shall be established and rationale for selecting a dosage form,
ingredients and composion shall be described.
a. General guidelines
1) Rationale for specifications and acceptance criteria shall be
described concretely based on actual test data, stability test result of
lots and safety·efficacy consideration.
2) Regarding observed lot for actual raw data, lot number, lot size,
manufacturing date and manufacturing site shall be indicated.
41
3) Test raw data shall be obtained from sample products
manufactured by commercial manufacturing process and shall be
done with more than 3 lots and each lot shall be tested more than 3
times. For numeric test results, concrete measured value shall be
indicated. Collection of sample products and data management shall
be handled statistically during obtaining raw data.
4) For preparation, actual value and blank test result shall be
described in order to prove that extraneous components other than
composition do not affect the result.
5) If test items are not established by “Test for dosage form” table
in Item No. 2 of Paragraph 2, Article 2 of this regulation, the
rationale shall be described.
6) Test procedures listed in the KP and test procedures
recommended by the International Conference on Harmonization
(ICH) are considered to be validated.
b. Guidelines for references of indicated items
The following items shall be considered when preparing reference
data. Additionally, origin, contents standard, specification,
identification and physicochemical characteristics shall be prepared in
accordance with Article 2 of this regulation.
1) Purity
a) Drug substance
For established limit value, reasonable rationale shall be
presented considering actual value and safety besides from result
of stability test. Supporting data for proof of safety shall be
submitted for following cases.
42
(1) If the daily maximum dosage, calculated from dosage
/administration of preparation containing drug substance, exceeds
the smaller of contaminate of 0.1 % or 1 mg of daily total intake.
(2) If the contaminant of drug substances, of which daily
maximum dosage, calculated from dosage /administration of
preparation containing drug substance, exceeds 2 g, exceeds
0.05 %.
b) Drug products
Data of degradation compounds observed during stability test
shall be submitted.
(1) For any of the following cases, degradation compounds
shall be described.
(a) If degradation compounds are contained more than 0.1 %
of drug products, of which daily maximum dosage of active
ingredient is less than 1 g.
(b) If degradation compounds are contained more than
0.05 % of drug products, of which daily maximum dosage of
active ingredient is more than 1 g.
(2) For any of the following cases, chemical structure of
degradation compounds shall be assured.
(a) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is less than 1 mg,
exceeds the smaller of 1.0 % or daily total intake of 5 g.
(b) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is more than 1
mg but not more than 10 mg, exceeds the smaller of 0.5 % or
43
daily total intake of 20 g.
(c) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is more than 10
mg but not more than 2 g, is contained more than the smaller
of 0.2 % or daily total intake of 2 mg.
(d) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is more than 2 g,
is contained more than 0.1 %.
(e) If structure determination is not possible, the review
procedure shall be described. For degradation compounds
predicted to possess strong poison or remarkable
pharmacological action in a concentration less than standard,
chemical structure shall be assured, if possible.
(3) For the following cases, data that proves the safety of
degradation compounds shall be submitted.
(a) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is less than 10
mg, exceeds the smaller of 1.0 % or daily total intake of 50
g.
(b) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is more than 10
mg but not more than 100 mg, exceeds the smaller of 0.5 %
or daily total intake of 200 g.
(c) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is more than 100
mg but not more than 2 g, is contained more than the smaller
of 0.2 % or daily total intake of 2 mg.
44
(d) If degradation compounds of drug products, of which
daily maximum dosage of active ingredient is more than 2 g,
is contained more than 0.1 %.
c) Specificity (including recovery rate of existent quantity around
limit value) and detection limit shall be described for limit test in
test method. Assay methods shall be with high specificity and
precisely observable. Test procedures for measuring related
substances shall be comparing detection sensitivity of standard
substances with related substances.
2) Loss on drying, loss on ignition, water and sulfated ash) : When
regulating loss on drying, it shall be assured that drugs do not
decompose in drying condition. Even in case where these tests are not
established for good reasons such as small amount of quantity,
measurement shall be described, if possible.
3) Tests for dosage form
a) Dissolution test
For solid preparations for oral administration, in principle,
dissolution test shall be established. The result under at least 3
different conditions, including acidic and neutral conditions within
pH 1 ~ 8, shall be described. And if necessary, review result of
influence on dissolution by ionic strength, surfactant, stirring speed,
devices, etc., shall be attached. Specification for dissolution test
shall be a test condition that can prove bioequivalence and a
standard value. In case of establishing disintegration test instead of
dissolution test, the rationale shall be described.
b) Release test
In case of establishing release test for suppositories or transdermal
45
preparations, it shall be described that test result proves release
function. For controlled-release drug products, a basis
proving controlled-release function shall be attached.
c) Endotoxin test
For establishing endotoxin test, acceleration and inhibition by mixed
components shall be described.
d) For aerosols, actual value on the relation between injection
period and injection quantity when spraying is performed
quantitatively shall be described.
e) Reviewed pharmaceutical test result not established for
specifications and test procedures shall be described.
4) Special performance tests
In case of using animals for test, reasons for establishing concentration
of solutions, dose, route of administration and observation period, and
so on shall be described.
5) Assay
For specificity, linearity, range of concentration, accuracy, precision
(intra-assay precision, reproducibility of intra-laboratories), etc.,
validation result and appropriateness of test procedures shall be
described. However, if assay cannot be established, the concrete
reasons and basis for possibility of quality acquisition without
establishing the test shall be attached.
6) Formulation development
In case of establishing processing method for specific preparation,
basis for establishing drug substances and their quantity such as
selection of dosage form and drug additives, determination of mixed
ratio, and so on shall be described. If necessary, biopharmaceutical
evaluation result shall be attached and appropriateness of dosage form
46
design shall be reviewed. In case of special pharmaceutical functions
such as controlled- release preparations, review result of design and
evaluation of sustained-release drug products (oral administrative drug
products) including pharmaceutical evaluation result of dosage form
design process, and so on shall be described.
5. Data for reference standards, reagents, and solutions
a. In case of the reference standard not included in the KP, it shall be
established. For the KP non-listed reagents and solutions, their
preparative methods shall be described.
b. For reference standards, if necessary, purification method
(including manufacturing method if difficult to purchase substances
other than drug substances) shall be described.
c. For reference standards for measuring purpose, in principle,
contents from a test procedure which can measure the absolute amount
of a contaminant by purity test shall be measured.
d. The content of reference standards shall be more than 99.0 %.
However, if not possible to acquire substance with more than 99.0 %,
contents shall be converted and corrected by assay.
② For herbal medicines and herbal medicine preparations, data for each
of the following items shall be attached.
1. Concrete reference data of attached standards for herbal medicines
(powdered herbal medicines) and herbal extracts shall be submitted.
47
However, in the absence of reference data, or in case of in-house
product, test results from more than 3 lots (each lot shall be tested
more than 3 times) shall be attached.
2. In case of preparation process for prescription of herbal medicine
preparations by detecting or extracting in granules (i.e., OOtang
extract, granule), availability of test data on characterizing compound
more than 3 lots (each lot shall be tested at least 3 times), such as
chromatogram, etc., shall be attached.
*For example : Availability test data on glycyrrhizic acid of
glycyrrhiza in OOtang extract granules. Using raw glycyrrhiza
(containing 2.5 % glycyrrhizic acid), by manufacturing process for
specifications and test procedures, preliminary manufactured drug
products of 3 lots are produced and investigated for the availability of
glycyrrhizic acid.
3. In case of herbal medicine preparations newly reviewed domestically,
test results from standard test on the final products of more than 3 lots
(each lot shall be tested at least 3 times) shall be submitted. For
identification by thin layer chromatography, test results with solutions,
solutions except the test ingredient, and standard solution all
controlled by the same method shall be submitted.
48
Lot
Collection
Glycyrrhiza
Theoretical
Actual
Availa-
number
Quantity (g)
Contained
Quantity of
Quantity of
bility
(g)
Glycyrrhizic
Glycyrrhizic
(%)
Acid (mg)
Acid (mg)
1
3.001
0.222
5.55
1.909
34.4
2
3.090
0.229
5.73
1.931
33.7
3
3.094
0.227
5.68
1.903
33.5
average
33.9
Calibrating constant = 100 /availability (%) = 100 / 33.9 = 2.9
③ For recombinant products and cell culture products, data for each of
the following items shall be attached.
1. Specification of drug substance
For concentrated bulk or final bulk solution, the followings shall be
established. In this case, the term "concentrated bulk" refers to a
substance where purification is completed after manufacturing. Final
bulk solution is a bulk with appropriate excipients. The term "Final
bulk solution" means homogenous solutions in one container, which
can be filled immediately. Any part of final bulk solution shall be
uniform in description and quality. For these drug raw materials
(bulk or final bulk solution), drug master file (including test results)
shall be submitted. If drug raw material and drug product are the
same, then only a single set of documents is necessary.
a. Definition
b. Molecular formula and molecular weight (except glycosylated part)
49
c. Description
d. pH
e. Sterility
f. Pyrogen or Endotoxin test
g. Identity
h. Purity
Process- and product-related impurities such as high molecular weight
proteins and related proteins, host-cell- and vector-derived DNA, hostcell-derived proteins, antibiotics, noxious heavy metals, specific
activity, etc., shall be established depending on the characteristics of
products.
i. Potency
In principle, potency shall be determined by a method capable of
proving biological activity.
2. Drug master file
a. Origin or background of discovery and status of usage in foreign
countries
It shall be described in detail that the products are manufactured by
recombinant DNA technology or cell culture technology. Additionally,
when the same kind of recombinant product or cell culture product is
under developing (or approved) in foreign countries, the current status
of use, the case of adverse reactions, etc., shall be described.
b. Manufacturing methods and physico-chemical properties
50
1) Manufacturing methods of recombinant products
a) Structural gene of target peptides or proteins
(1) Method of cloning the relevant structural gene shall be
described.
(2) Total nucleotide sequences shall be described.
(3) Functions of cloned genes and the genetic stability shall be
identified.
(4) When the structural gene is derived from tumor tissue, the
equality with normal tissue gene shall be identified.
b) Various properties of host·vector system shall be described.
c) Culture
(1) Stability of recombinants (i.e., stability in storage and
passage) shall be described and also considered in large culture.
(2) Identification method of recombinants shall be described.
(3) Composition of media shall be described.
d) Purification
(1) Purification process shall be described as a part of flow chart
for manufacturing process.
(2) Separation method of target peptides from host-cell-derived
proteins and polysaccharides shall be described.
(3) In case of separating extra peptide added to N-terminal of the
protein chemically to stabilize the protein likely to be degraded in
a cell by Bromcyan, etc., the reagents and the methods of
51
removing the extra peptide shall be described.
(4) In case of separating a target product from high molecular
protein such as a precursor, (for example, proinsulin, etc.), the
enzyme used for separation and the method for removing the
separated peptides shall be described.
(5) Any special methods used in purification process shall be
described.
2) Manufacturing method of cell culture products
a) Origin and characteristics of seed cells
(1) Origin and history of cells
Information on origin, source and passage history shall be
described.
(2) Characteristics of cells
Properties of cells, for example, phenotypic characteristics,
propagation
characteristics,
cytogenetic
characteristics,
immunochemical characteristics, existence of virus genome,
tumorigenicity, production capacity of target products, etc., shall
be described.
b) Method for preparation, culture, storage and control of cells
(1) Method for preparation, storage and control of master cell
bank
(2) Method for preparation, storage and control of working cell
bank
(3) For end of production cells, stability shall be described on the
basis of characteristics of cells listed in 2) Characteristics of cells,
item a. of this regulation.
52
(4) Culture conditions for each step shall be described.
(5) For cells in 1), 2) and production steps, contamination with
other bacteria, mycoplasma and fungi shall be denied.
(6) For cells in 1), 2) and production steps, it shall be identified
that viruses known to be latent in the species from which the cells
were derived and adventitious viruses are not present. However,
if there is an available method to remove virus, it may be
exempted. In case of preparing cell culture from animal, e.q.
primary cell culture, it shall be identified that there is no virus
known to be present in that animal species, and cells with viruses
which may be pathogenic to humans shall not be used.
(7) For 1), 2) and production steps, presence / non-presence of
endogenous pathogen such as retrovirus, etc., shall be identified
by appropriate methods, for example, infectivity assays, reverse
transcriptase assays and electron microscope observation, etc.
Additionally, cells treated with appropriate inducer shall be
subject to similar tests.
c) Separation and purification of target products
(1) Purification process shall be described as a flow chart for
manufacturing process.
(2) Separation methods of a target substance from contaminants
(i.e., contaminated proteins, DNA, etc.) and its efficiency shall
be described. And in case that there is a possibility that
endogenous viruses are mixed into host cells, the methods of
inactivation or removal of virusese and its efficiency shall be
described.
(3) For target products, if necessary, hybridization method can be
53
used for identifying retrovirus. For human antibodies, it shall be
identified that EB viral DNA is not present. When reagents of
animal origin are used in proliferation of manufacturing cells, it
shall be identified that animal-derived virus is not present in a
target product.
(4) Any special methods used in purification process shall be
described.
3) Determination of structure and physico-chemical properties
a) Structure and composition
(1) Amino acid composition
(2) Terminal amino acids
(3) In case where disulfide bond is present, the location of
disulfide bond (where applicable)
(4) Peptide mapping
(5) Amino acid sequences (terminal amino acid sequence within a
possible range)
b) Physico-chemical properties
(1) Spectrophotometric property (ultraviolet spectrophotometry,
etc.)
(2) Electrophoretic property (polyacrylamide gel electrophoresis,
etc.)
(3) Isoelectric focusing (sucrose density gradient isoelectric
focusing electrophoresis, gel isoelectric focusing electrophoresis,
etc.)
54
(4) Molecular weight (SDS-gel electorphoresis, gel filtration
chromatography, ultracentrifugation, etc.)
(5) Liquid chromatography profile
(6) Secondary structure (optical rotatory dispersion, circular
dichroism, etc.)
c) Immunochemical properties
Immunochemical analysis, immuno-electrophoresis, etc.
d) Biological properties
(1) Biological activity, content, and purity (specific activity),
etc.
(2) For enzymes, enzymatic properties
c. Data for proving bioequivalence with natural substances
1) Amino acid composition
2) N- and C-terminal amino acids
3) Disulfide bond (where applicable)
4) Peptide mapping
5) Contents of carbohydrate (where applicable)
d. Data of specification of reference standard
e. Data of test methods and test results
1) Data of test methods for all steps in manufacturing process
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2) Certificate of analysis on the bulk (bulk powder), final bulk
solution, final products of manufacturer shall be tested more than 3
lots (each lot shall be tested 1 time at minimum) with validated
methods.
3) At least 3 times of test results on the final drug products by a
sponsor
f. License status in foreign countries
g. WHO guidelines or monographs in Pharmacopoeia, etc.
④ For biological products, data for each following item shall be
attached.
1. Drug master file
a. Origin or background of discovery and use in foreign countries
The status of relevant diseases and background of development shall
be described. In case where the same kinds of bacterial products, viral
products or blood products are under development or approved in
foreign countries, the status of usage, onset of adverse reactions and
comparison with products from each country, shall be described.
b. Manufacturing methods and physico-chemical properties
1) Manufacturing methods of bacterial products
a) Origin and characteristics of bacteria seed for manufacture
(1) Information on origin and derivation of bacteria seed,
collecting methods and passage history shall be described.
56
(2) Characteristics of bacterial hosts shall be described such as
morphologic, biochemical, propagational, cytogenetic ,
immunological characteristics, production capacity, etc.
b) Method of culture, storage and control of bacteria seed
(1) Method for preparation, storage and control of bacteria
seed
(2) Method for preparation, storage and control of working
bacteria seed
(3) Basis for establishing preparation conditions of bacteria
seed, including the establishment of the limit of maximum
passage level shall be described.
(4) Culture conditions for bacteria seed from each step and
other necessary items shall be described.
(5) For bacteria seed in 1), 2) and production steps,
contamination with other bacteria, mycoplasma and fungi shall
be denied.
c) Separation and purification of target products
(1) Purification process shall be described as a part of flow
chart for manufacturing process.
(2) Methods for production, separation and purification of a
target product during manufacturing process shall be described.
(3) In case of using pathogenic microorganisms as bulk for
manufacturing, detoxication procedure shall be described.
(4) In case where special technology is used during
57
manufacturing process, the relevant data shall be submitted.
2) Manufacturing methods of viral products
a) Origin and characteristics of virus seed for manufacture
(1) Information on origin and history, derivation of virus seed,
collecting methods and passage history shall be described.
(2) Characteristics of virus seed shall be described such as
morphological,
biochemical,
propagation,
genetic,
immunological characteristics, production capacity, etc.
Especially in case of attenuated virus, data of attenuation
procedure and data of comparison analysis between wild virus
and attenuated viral strains shall be described.
b) Method for culture, storage and control of virus seed
(1) Method for preparation, storage and control of master virus
seed
(2) Method for preparation, storage and control of working
virus seed
(3) Basis for establishing preparation conditions for virus seed
including the establishment of the limit of maximum passage
level, shall be described.
(4) Culture conditions for virus seed at each step shall be
described.
(5) For virus seeds in 1), 2) and production steps,
contamination with other bacteria, mycoplasma and fungi shall
be denied.
c) Origin and characteristics of seed cells
(1) Information on origin and history, derivation of cells,
58
collecting methods and passage history shall be described.
(2) Characteristics of cells such as morphological, propagation,
cytogenetic, immunological characteristics, presence of viral
genome, neoplasticity and production capacity of target
products, and so on shall be described.
d) Method for preparation, culture, storage and control of seed
cells
(1) Method for preparation, storage and control of master cell
bank
(2) Method for preparation, storage and control of working cell
bank
(3) Basis for establishing preparation conditions for
manufacturing cells, including the establishment of the limit of
maximum passage level, shall be described.
(4) Culture conditions for cells at each step shall be described.
(5) For cells in (1), (2) and production steps, contamination
with other bacteria, mycoplasma and fungi shall be denied.
(6) For cells in (1), (2) and production steps, it shall be
identified that viruses from the cell-derived animal species or
adventitious virus are not present. However, if there are
reference data available such as a method to remove viruses,
the case may be exempted. In case of preparing cell culture
from animal such as primary cell culture, it shall be identified
that no virus is present in that animal species, and cells with
viruses which may be pathogenic to humans shall not be used.
(7) For (1), (2) and production steps, presence / absence of
59
endogenous pathogen such as retrovirus, etc., shall be
identified by appropriate methods, for example, infectivity test,
reverse transcriptase activity and electron microscope
examination, etc. Additionally, cells treated with appropriate
induction shall be subjected to similar tests.
e) Production, separation and purification of target products
(1) Purification process shall be described as flow chart for
manufacturing process.
(2) Methods for production, separation and purification of a
target products during manufacturing process, shall be
described.
(3) In case of using a pathogenic microorganism as a bulk for
manufacture, detoxication procedure shall be described.
(4) In case where special technology is used during
manufacturing process, the relevant data shall be submitted.
3) Manufacturing methods of plasma derived biological products
a) Data on collection of source materials and control method
b) Manufacturing process
(1) Flow chart for manufacturing process
(2) Data on starting materials for manufacture
(3) Manufacturing procedure
(a) Manufacturing methods and quality control
(b) Inactivation and removing methods of virus, etc.
(c) Validation data for (a), (b)
60
c. Structural determination and physico-chemical properties
1) Structure and composition
a) Active ingredients of each product and their characteristics
b) Other excipients
characteristics
(stabilizers,
adhesives)
and
their
c) Ingredients of solvents and their properties
2) Physico-chemical properties (if applicable to products)
a) Spectrophotometric properties (ultraviolet spectrophotometry,
etc.)
b) Electrophoretic properties (polyacrylamide gel electrophoresis,
etc.)
c) Isoelectric focusing (dextrose density gradient isoelectric
focusing electrophoresis and gel isoelectric focusing
electrophoresis, etc.)
d) Molecular weight (SDS-gel electrophoresis, gel filtration
chromatography and ultracentrifugation, etc.)
e) Liquid chromatography profile, etc.
3) Immunochemical properties
Reviewed with appropriate immunochemical method by product
characteristics.
4) Biological properties
Biological activity, contents and purity (specific activity), etc.
61
d. Data of specification for reference standards
Specification for reference standards shall be described.
e. Data of test methods and results
1) Data of test methods for all steps in manufacturing process
2) Test results on the final products tested at least 3 times by a
sponsor
f. License status in foreign countries
g. Guidelines in WHO and monographs in the KP, etc.
⑤ For aerosols as new drugs, relation between injection period and
injection quantity data on incubating test shall be attached.
⑥ For in vitro diagnostics, data for each following item shall be
attached.
1. Data on performance tests (tests on specificity, sensitivity,
reproducibility and detection range, etc.).
2. Data for establishment of reference standards for sizes, etc.
3. Test results of at least 3 times on the specifications and test procedures
on the final products.
62
4. Negative results on HIV, HCV and HBV if the reagents are derived
from human blood.
5. Following data may be required according to the characteristics of the
products.
a. Data on the motive of development and the current status of usage
both home and foreign countries
b. Data for dosage and administration
c. Data for relevance (comparative test results with conventional
products).
d. Reference for establishment for conditions of storage and validated
period.
e. Data for cross-reactions with inhibitory substances, other subtypes.
f. In case of imported products, a copy of FCS, certificate of items, or
data similar to them.
⑦ For adhesive plasters and plasters as new drugs, data for each of the
following items shall be attached.
1. Adhesion paste
For using new material as a covering substance or upholder, data on
the specifications and test procedures shall be attached.
2. Adhesive base
63
For using an adhesive enhancer, an elasticizer, a plasticizer or an antiaging agent, data on the mixing shall be attached.
 Article 4
(Supplementary Rules)
① When submitting an application for review of specifications and test
procedures of drugs (hereinafter referred to as "Review application"), the
following items shall be considered.
1. Reviewing application shall be prepared based on Attachment Form
No. 3 with provisions of Item 1, Paragraph 2, Article 3 of Regulation
of Request for Test. Two copies of the form shall be submitted along
with 1 copy in a diskette (3.5") and other relevant documents.
2. If the attached data for review application is from foreign countries,
the translated version shall be submitted for application.
3. In case of requesting changing of contents of specifications and test
procedures for drugs, appropriately notified after reviewing of the
review application, comparison table between a copy of the approved
items (including copy of approval certificate) or the original copy of
reviewing result notification and the contents desired to be changed
shall be prepared and attached.
64
4. Supplement, change or correction, etc. for the received screening
application may not be allowed. However, matters determined to be of
no problem, even for small change or correction, for quality control by
the review result, may be allowed by the Commissioner of the KFDA.
5. Supplement demand for reviewing application shall be allowed only
once.
6. Supplement period of reviewing application shall be within 30 days. If
supplement submission is not executed within the period, urge to be
supplemented within 7 days shall follow. If the supplement document
is not submitted within the urge period or the contents of
replenishment is inappropriate, the speculation shall be clarified and
the document shall be returned. However, if the applicant calls for an
extension, the submission period shall be determined based on the
speculation.
② The following items shall be considered when preparing review
application documentation. Drug substances and the quantity, dosage
form and description, manufacturing methods, efficacy and
effectiveness, dosage and administration, matters to be especially
concerned for usage, package unit, storage methods and expiration
date (shelf life), manufacturing approval for In vitro diagnostics, etc.,
other than the following items shall be prepared with provisions of
"Guidelines for Manufacturing Licenses for drugs, etc."
1. In "( )" on the top of reviewing applications, the type of industry shall
be indicated. For drugs for exports, military / official use, or imported
drugs, put "exports only", "military use", "official use", or "imported"
accordingly For imported drugs, etc., the exporting country and the
name of manufacturer shall be indicated for item "manufacturer".
65
2. In case of new drugs, put "(new) drug".
3. For recombinant products, put "(recombinant) products". In this case,
recombinant drugs mean drugs with active ingredients of peptide or
protein produced with recombination DNA technology.
4. For cell culture drugs, put "(cell culture) drug". In this case, cell
culture drugs mean drugs with active ingredients of peptide or protein
produced with recombination DNA technology and cell culture
technology.
③ For screening the review application, if necessary, data such as
related documents, standard products for general use (publicity
approved, for antibiotics), drug substances used for drug products,
special reagents required for test, devices, bacterial hosts and media,
etc., other than attached data from the items above, shall be demanded
to be submitted.
④ For subdividing intermediate drug raw materials, drug substances
and drugs, compilation of specifications and test procedures shall be in
accordance with compilation of drug substances of the KP.
⑤ For synthesizing drug substsnces, final drug product shall be
considered appropriate as a drug if the contents, purity, etc.,
correspond to the specification. When review specifications and test
procedures, since yielding percentage of the synthesized final product
is not stable due to physical condition for chemical reaction, purity of
66
catalyst and raw ingredients, etc., only theoretical reaction devices
shall be reviewed with related documents for manufacturing methods.
⑥ When reviewing applications, tests may be exempted in whole or
part, if considered analytically concrete.
⑦ For recombinant products and cell culture products, they shall follow
the general principles of "specifications and test procedures of
biological products".
⑧ For combining general drugs with antibiotic drugs, review
application under this provision shall be submitted.
⑨ If a host, a vector, acquiring procedure, composition of medium,
purification method of recombinant products are different from the
approved products, or if species of cell, culture methods, and
purification of cell culture drugs are different from the approved
products, reviewing application under this provision shall be
submitted.
⑩ If the original material is a biological preparation, compilation shall
be in accordance with biological specification. For recombinant drugs
or cell culture drugs with a different host, vector or species cell host,
etc., screening application under this provision shall be submitted.
67
⑪ For biological preparations, if a bacterial host, a viral host, a seed cell
host, a manufacturing method, etc. are different, a screening
application under this provision shall be submitted.
⑫ In case where other approved drugs already exist, company name,
product name and approving items shall be described.
⑬ Provision for screening specifications for other preparations not
regulated by this notification shall be under regulations of each article.
68
Part Ⅲ. Attachment
Attachment 1 : Attached specifications for drug substance
『General name』
『English name』
『Structural formula』
『Byname』
『Molecular formula : Molecular weight』
『Origin and Assay specification』
*For example : This drug contains more than 98.0 % of dantrolene
sodium (C14H9N4NaO5: 336.24) for anhydride when converted for
measurement.
Description
Identification
Physicochemical characteristics
Purity 1) Appearance of the solution
2) Heavy metal *For example : Weigh 2.0 g of this drug and test it
under Category 2 of heavy metals test procedures. Add 2.0 mL of
standard lead solution (not more than 10 ppm) as the comparative
solution.
Loss on Drying (ignition weight loss or Moisture)
Sulfated Ash (Ash or Acid-insoluble ash)
Specific Test
Assay
Storage
Reagents·Solutions
69
※Details (Specimen)
1. Paper Selection : Paper size is A4. Margins for top, bottom, header,
footer are 12.5 mm, and margins for left and right are, 25 mm,
respectively.
2. Paragraph : line space 180 %(at Hwp), alignment
3. Font : letter shinmyungjo (at Hwp), letter space 0 %, size 12 point
70
Attachment 2 : Attached specifications and test procedures for
drug products
Specifications
1. Description : *For example : yellow film-coated tablets with round
shape, light yellow capsules top-and-bottom with milky white powder
2. Identification : The result shall be appropriate when tested with the
following test procedures.
3. Dissolution : *For example : Dissolution rate for 45 minutes shall be
more than 75 % when tested with the following test procedure.
4. Purity (Related substances) :
5. Content uniformity :
6. Assay :
Test Procedures
1. Description: Observe with eyes ot smell.
2. Identification :
3. Dissolution :
4. Purity (Related substances) :
5. Content uniformity :
6. Assay :
71
※Details (specimen)
1. Paper Selection : Paper size is A4. Margins for top, bottom, header,
footer are 12.5 mm, and margins for left and right are 25 mm,
respectively.
2. Paragraph : line space 180 %, alignment
3. Font : letter shinmyungjo (at Hwp), letter space 0 %, size 12 point.
Part Ⅳ. Addendum
This provision shall be enforeced from the date of notification.
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Publishing committee
Publisher & Managing editor : Chang - Koo Shim
Editor : Seung - Jae Jang, Seung -Yeup Chang, Don - Woong Choi,
Mi - Jeong Kim, Hee - Sung Kim, Soo - Hyun Chang
Sang - Hoon Huh (Pharma Koreana Ltd.)
Issue date : October 30, 2003
Publishing office : Department of Drug Evaluation,
Korea Food & Drug Administration
122-704 Nokbun-dong 5, Eunpyong-gu, Seoul,
Korea
TEL. 82-2-380-1709, 10 FAX. 82-2-387-7857
편집위원 명단
위원장: 심창구
위 원: 장성재, 장승엽, 최돈웅,
김미정, 김희성, 장수현
허상훈 (파마코리아나)
발행일 :
2003년 10월 30일
발행처 : 식품의약품안전청
122-704 서울시 은평구 녹번동 5
연락처 : 식품의약품안전청 의약품평가부
전화 02-380-1709, 10
73
팩스 02-387-7857