Regulation on the Registration of Active Pharmaceutical Ingredient

Ministry of Food and Drug Safety Notice No. 2018-64

Partially amended and Enforced on Aug. 23, 2018

Article 1 (Purpose) This Regulation is designed to ensure the optimum registration work of drug substances
by stipulating matters concerning registration object items, preparation method of registration data, the scope
of data, the requirement of submission data and the scope of exemption, the registration processing standard,
etc. designated by the Minister of Ministry of Food and Drug Safety (MFDS) according to Articles 31-2 and
42 of the Pharmaceutical Affairs Act, Articles 15 and 17 of the Regulation on Safety of Medicinal Products,
etc., Articles 57 of the Act on the Control of Narcotics, etc. and Articles 32 and 33 of the Enforcement
Regulation of the same Act.

Article 2 (Designation of Drug Substances for Registration) The drug substances for registration in
accordance with Article 15 of the Regulation on Safety of Medicinal Products, etc. are as follows. However,
orphan drugs, recombinant drugs, cell culture drugs, biologics, cell therapy products, gene therapy products,
radiopharmaceuticals, drugs for export, and other ingredients (excipients, additives, etc.) without
pharmacological activity are excluded.
1. New drug substance used as an active ingredient of the new drug that applied for approval of manufacture
and marketing or import to the MFDS since July 1, 2002 among new drugs in accordance with Article 2
subparagraph 8 of the Pharmaceutical Affairs Act (hereinafter referred to as "Act" below);
2. Drug substance in Annex 1 and salt and hydrate thereof;
3. Drug substance from human placenta (including drugs in final bulk process);
4. Drug substance for herbal (crude) medicines and its mixture (including drugs with different solvent
concentrations) subject to registration in Annex 1-2.

Article 3 (Preparation Method of Documents) (1) A person who intends to register drug substances shall fill
out the application form for the registration of drug substance according to Form No. 16 of the Regulation on
Safety of Medicinal Products, etc. and submit proper documents in accordance with the provisions of Article
4.
(2) Submitted documents shall indicate a list, index number of each document and page number according to
the order listed in Article 4 and shall be kept on file in a uniform thickness if the volume is large (not in case
of electronic documents). However, if any or all of the submitted documents are omitted pursuant to Article 4
(2), the reasons for such omission shall be clearly stated.
(3) A person who intends to submit the documents according to (1) with common technical documents (CTD)
pursuant to Article 6 of the Regulation on Pharmaceuticals Approval, Notification, and Review (Notice of
 MFDS) shall indicate 'CTD' in note section of the application for the registration of drug substance and shall
submit by referring to the documents required for drug substance registration and the list comparison table of
the common technical documents in Annex 2.
(4) In principle, documents from foreign countries shall be submitted as the summary translated in Korean
(extraction of main points) and the original text, and if necessary (for example, secondary language except
English), full translated text (with the verified seal of medical and pharmacological expert) shall be submitted.
(5) In case of submitting the documents of Article 15 (1) subparagraphs 1 and 4 of the Regulation on Safety
of Medicinal Products, etc., ‘for registration of manufacturing site’ shall be indicated in note section, and in
case of submitting the documents of subparagraphs 2, 3, 5 and 6, ‘for registration of ingredients and their
names and manufacturing method' shall be indicated.

Article 4 (Document Requirements, etc.) (1) The requirements of documents in addition to the application for
registration of drug substance pursuant to Article 3 (1) shall be as follows:
1. Documents on facilities required for manufacturing and quality control pursuant to Article 31 (1) of the
Act
Documents attesting the suitability to the provisions of Article 3 of the Enforcement Decree on the
Standards of Facilities of Manufacturers and Importers of Medicinal Products, etc. and Articles 2 and 7 of
the Enforcement Regulation of the same Decree.
2. Documents proving that the implementation status by item of drug substance for registration according
to Article 2 meets or exceeds the Good Manufacturing Practice (GMP) for Drug Substances according to
Annex 1-2 of the Regulation on Safety of Medicinal Products, etc.
A. Required documents according to Form No. 82 of the Regulation on Safety of Medicinal Products, etc.
or a copy of compliance certificate of GMP or an equivalent document under Article 48-2 of the
Regulation on Safety of Medicinal Products, etc. shall be submitted.
B. In the case of imported products, the manufacture certificate corresponding to Article 4 (1) 4 A of the
Regulation on Safety of Medicinal Products, etc. can be submitted in substitute for the document of A.
3. Data on the physiochemical characteristics and stability
A. Data on physiochemical characteristics
(1) Data on origin or discovery and development details (e.g. when, where, who, from what it is
extracted, separated or synthesized, what the source of the discovery is, and when and where were
testing materials used in basic test and clinical study, etc.);
(2) Data on structure, physiochemical and biological properties;
(3) If a patent, etc. is obtained domestically or abroad, the data attached with a copy of the patent
registration.
B. Data on stability
(1) As the data pursuant to Stability Test Criteria of Medicinal Products, etc. (Notice of MFDS), specific
test methods shall be stated, and test base data shall be attached.
 (2) Test methods, etc.
(A) For drug substances under Article 2 subparagraph 1 or 3, long-term preservation and worst
condition test data shall be submitted, and for ingredients and antibiotics that are subject to minor
changes among drug substances under Article 2 subparagraphs 2 and 4, long-term preservation
test data shall be submitted.
(B) For items other than those specified in (A) above, the accelerated test data may be submitted
instead of the long-term preservation test data.
4. Data on manufacturing methods, package, containers, and precautions for handling
A. Data on manufacturing method
(1) Describe the flow of the entire manufacturing process in detail, including the details of inspection
methods for each manufacturing process, and attach data on substances, solvents, reagents, etc.
used in each manufacturing process such as synthesis (fermentation), separation, and refining, etc.
However, the drug substances under Article 2 subparagraph 3 shall be attached by additional data
on the process of non-inactive viruses and the procedure to confirm that the maternal consent at the
raw material collection stage is made and the procedure issued by the medical institution to confirm
that the mother is not infected with the virus shall be additionally attached.
(2) Details of key substances (for example, name, structural formula, yield, etc. on the generated
material in the intermediate stage of the manufacturing process, etc.) and data on standards and test
methods shall be attached. However, as for the drug substances under Article 2 subparagraph 3, test
for adventitious agents should be included to the standards and test methods, and the additional
evidence data of viral inactivity shall be additionally attached.
(3) As for the drug substances originated from animals among the drug substances of Annexes 1 and
1-2, the data on the virus inactivation process shall be additionally attached, and the procedure
issued by the veterinarian to verify that the materials are free of virus in raw material collection
stage should be additionally attached.
B. Data on package and container
(1) Specify the packaging method and reasons for container selection in detail to ensure safety.
(2) Attach the data on packing status when shipped from the site.
C. Precautions for handling
(1) To ensure stability, the storage method shall be assorted into closed, airtight, and sealed
containers, etc. and specific storage conditions (e.g. room temperature storeroom storage, 2-3°C
refrigerated storage, etc.) shall be indicated, and the period of use (validity) shall be established
by stability test data or other authorized evidence data.
5. Data on test result reports, analysis methods, solvents used, etc. of drug substances
A. Test report shall be a report that has been performed on more than 3 lots consecutively in accordance
with the standards and test methods.
B. The analysis method refers to the standard and test method for drug substance and shall write the
 method of "Korea Pharmacopoeia" or the official compendium approved by the Minister of MFDS,
and in other cases, the verifying data shall be attached.
C. If organic solvents are used during the manufacturing process, data on the types of organic solvents,
reasons for use, residual criteria for organic solvents of the final product, residue amount and test
methods shall be attached.
6. Investigational drug substances used for quality inspection
A. In principle, as for the quantity of the investigational drug substance, the quantity capable of
conducting three tests shall be submitted.
(2) Notwithstanding (1), some or all of the data may be omitted if the case is corresponding to one of the
following subparagraphs, and in this case, a valid reason shall be submitted: However, the drug substances
under Article 2 subparagraph 3 cannot omit the data under paragraph (1) subparagraphs 1 and 3.
1. In case of manufacturing drug substance by importing intermediate products of drug substance;
2. In case the drug substance (general and aseptic) belonging to the same classification manufactured by
the same manufacturing site and the same method of manufacture (synthesis, fermentation, extraction)
has already been registered;
3. In case of a drug substance which has passed GMP evaluation and is already on the market;
4. In case of data already submitted for safety and validity review and for standards and testing methods
review or for approval application.

Article 5 (Standards for Registration Process, etc.) (1) The Minister of MFDS shall process the application
for registration of drug substances pursuant to Article 3 (1) according to the following subparagraphs, and
shall issue the registration certificate of drug substance (hereinafter referred to as "registration certificate") in
accordance with the Form No. 17 of the Regulation on Safety of Medicinal Products, etc., and shall announce
it on the website of the MFDS, and when carrying out the inspection over the manufacturing site (in case of
imported item, it refers to the manufacturing site of manufacturing country. Same is in the below), he/she shall
notify it to the applicant 20 days before the inspection.
1. If an application for registration of drug substance is submitted pursuant to Article 15 of the Regulation
on Safety of Medicinal Products, etc., the suitability of the submitted data shall be reviewed and
processed within 17 weeks (13 weeks without the inspection).
2. In case of that the application for approval of manufacture and marketing or import of medicinal products
pursuant to Article 4 (1) 7 of the Regulation on Safety of Medicinal Products, etc. is filed, the suitability
of the submitted data shall be reviewed and processed within 17 weeks (13 weeks without the inspection).
2-1. In case of the application for changes due to transfer or purchase, despite the provisions of Article 2-1
subparagraphs 1 and 2, it shall be processed within 25 days from the application date.
3. Notwithstanding the provisions of subparagraphs 1 and 2, if the Minister of MFDS can acknowledge
that safety and quality, etc. is already secured such as registration to an international authorized
institution, he/she can review only the existence of the attached data under Article 4 and process it.
 4. If a test is deemed necessary to identify hazardous substances in the manufacture process or confirm the
origin of fungus, the submitted investigational drug substance can be used for performing and processing
the necessary test pursuant to Article 15 (1) 6 of the Regulation on Safety of Medicinal Products, etc.
(2) If there is a concern about the imbalance in supply and demand of medicinal products, etc., the Minister
of MFDS may reserve the issuance of registration certificate and internet announcement, etc. considering
solving the problem of supply and demand and the enforcement date of Notice, etc.
(3) The inspection for the manufacturing site pursuant to paragraph (1) shall be carried out in accordance with
Annex 1 of the Regulation on Safety of Medicinal Products, etc. At this time, the characteristics of the
manufacturing method, etc. to each item may be considered.
(4) All expenses necessary for the inspection on a manufacturing site pursuant to (1) shall be paid by the
applicant for registration of drug substance according to the Regulations for Overseas Travel Expenses Benefit
Principle (the MFDS Rule).
(5) The registration criteria set forth by the Minister of MFDS pursuant to Article 15 of the Regulation on
Safety of Medicinal Products, etc. are as follows:
1. Registration matters related to the manufacturing site: the compliance of GMP for Drug Substances in
Annex 1-2 of the Regulation on Safety of Medicinal Products, etc. (in this case, the characteristics of
manufacturing methods of each item, etc. can be considered, and when the name and the location of the
manufacturing site are announced, the assessment for compliance of the GMP for drug substances in a
manufacturing site may be added and recorded.);
2. Registration matters related to ingredients, names, and manufacturing methods: Suitability of data
requirements and exemption scope as specified in Article 4.
(6) When there is a need of additional registration for changes pursuant to Article 17 (1) 5 of the Regulation
on Safety of Medicinal Products, etc., it shall refer to "the inactivation of pathogenic microbes or removal
method" among the manufacture methods.

Article 6 (Mutatis Mutandis) As for matters not specified in this guideline, the regulations set by the Minister
of MFDS such as the Regulations on Pharmaceuticals Approval, Notification and Review (MFDS Notice)
shall be followed.

Article 7 (Review of Regulation) According to Article 8 of the Framework Act on Administrative Regulations
and the Regulation on Appointment and Management of Instructions and Rules, etc. (Presidential Instruction
No. 248), validity of regulation must be reviewed and actions of improvement must be taken every 3 years
(by December 31 of every third year) starting January 1, 2014.

ADDENDUM <No.2018-64, August 23, 2018>

Article 1 (Enforcement Date) This Notice shall be effective from the day of notification.
Article 2 (Example of Application) This revised Regulation may be also applied to a case that the application
for registration of drug substances (including changes) was filed to the Minister of MFDS according to the
previous regulation while the Notice was being enforced.
[Annex 1]

Drug Substances subjected to be Registered

(related to Article 2, Subparagraph 2)

1. Gliclazide
2. Nabumetone
3. Lansoprazole
4. Rebamipide
5. Levosulpiride
6. Loratadine
7. Lovastatin
8. Loxoprofen
9. Roxythromycin
10. Risperidone
11. Domperidone
12. Enalapril
13. Trimebutine
14. Doxazocin
15. Bucillamine
16. Cimetropium
17. Biphenyl dimethyl dicarboxylate
18. Cyclosporine
19. Cefadroxil
20. Cefaclor
21. Cefodizime
22. Cefuroxime axetil
23. Cefradine
24. Cefminox
25. Cefpodoxime proxetil
26. Cefixime
27. Cimetidine
28. Cilostazol
29. Simvastatin
30. Amoxicillin
31. Aceclofenac
32. Acetaminophen
33. Acyclovir
34. Atenolol
35. Ranitidine
36. Lomefloxacin
37. Metformin
38. Bambuterol
39. Sertraline
40. Cetirizine
41. Pseudoephedrine
42. Amitriptyline
43. Acetyl-l-carnitine
44. Azelastine
45. Ambroxol
46. Eperisone
47. Ondansetron
48. Terazosin
49. Terbinafine
50. Tiropramide
51. Fluoxetine
52. Omeprazole
53. Oxatomide
54. Oxaprozin
55. Ibuproxam
56. Itraconazole
57. Vinorelbine
58. Medroxy progesterone
59. Terlipressin
60. Carvedilol
61. Ketorolac
62. Clarithromycin
63. Teicoplanin
64. Tofisopam
65. Triamcinolone
66. Triflusal
67. Famotidine
68. Paclitaxel
69. Felodipine
70. Pravastatin
71. Prednisolone
72. Flomoxef
73. Flumazenil
74. Fluconazole
75. <Deleted>
76. Astromycin
77. Isepamicin
78. Glimepiride
79. <Deleted>
80. Diclofenac
81. Methocarbamol
82. Cefbuperazone
83. S-carboxymethylcysteine
84. Cefepime
85. Ciprofloxacin
86. Gemcitabine
87. Carteolol
88. Phenylephrine
89. Ofloxacin
90. Somatostatin
91. Tobramycin
92. Ketotifen
93. Clobetasol
94. Finasteride
95. Piperacillin
96. Hyaluronic acid
97. Diethylpropion
98. Phentermine
99. Phendimetrazine
100. Norfloxacin
101. Doxycycline
102. Levofloxacin
103. Rifampicin
104. Metronidazole
105. Sulfasalazine
106. Cefatrizine propylene glycol
107. Erythromycin
108. Bacampicillin
109. Midecamycin
110. Pyrazinamide
111. Mazindol
112. <Deleted>
113. Clavulanic acid
114. Cefmetazole
115. Ceftizoxime
116. Ceftriaxone
117. Cefotiam
118. Cefotaxime
119. Talniflumate
120. Streptokina- se?streptodornase
121. Risedronic acid
122. Losartan
123. Heparin
124. Sulpiride
125. S-atenolol
126. Levocetirizine
127. S-omeprazole
128. Lercanidipine
129. Clopidogrel
130. Amlodipine
131. S-amlodipine
132. Atorvastatin
133. Irbesartan
134. Nifedipine
135. Valsartan
136. Dropropizine
137. Levodropropizine
138. Erdosteine
139. Acetylcysteine
140. Tibolone
141. <Deleted>
142. Gabapentin
143. Naproxen
144. Nizatidine
145. Dexibuprofen
146. Lactobacillus acidophillus
147. Mesoglycan
148. Meloxicam
149. Sulodexide
150. Sulbactam
151. Cefalexin
152. Acebrophylline
153. Acarbose
154. Afloqualone
155. Alibendol
156. Ebastine
157. Epirubicin
158. Donepezil
159. Vancomycin
160. Imidapril
161. Tramadol
162. Propiverine
163. Oxiracetam
164. Iopamidol
165. Zaltoprofen
166. Thioctic acid
167. Ketoconazole
168. Choline Alfoscerate
169. Teprenone
170. Topiramate
171. Pranlukast
172. Quetiapine
173. Chondroitin
174. Gatifloxacin
175. Tandospirone
176. Naloxone
[Annex 1-2]

Drug Substances for Herbal (Crude) Medicines subjected to be Registered

(related to Article 2, Subparagraph 4)

1. Ferritin Extractive or Ferritin Extractive Hydrogliceric Solution

2. Proteolytic Peptide from Porcine Brain
3. Porcine Lung Extract
4. Dried Honey Bee Venom
5. Ivy Leaf Ethanol Extract
6. Evening Primrose Oil
7. Vitis Vinifera Seed Extract
8. Clematidis Radix, Trichosanthes Root, Prunella Spike Ethanol Extract
9. Artemisia Princeps Folium Ethanol Extract
10. Artemisia Princeps Folium Isopropanol Extract
11. Acanthopanacis Senticosi Radix Et Rhizoma·Achyranthes Root·Saposhnikovia Root·Eucommia
Bark·Cibot Rhizome·Glycine Semen Nigra Extract
12. Coptidis Rhizoma Extract
13. Corydalis Tuber & Pharbitis Seed Ethanol Extract
14. Angelica Gigas Root·Chaenomelis Fructus·Saposhnikovia Root·Dipsaci Radix·Acanthopanax Root
Bark·Achyranthes Root·Clematis Radix·Cinnamon Bark·Gentianae Macrophyllae Radix․Cnidium
Rhizome·Gastrodia Rhizome·Safflower Ethanol Extract
15. Titrated Extract of Zea Mays L. Unsaponifiable Fraction
16. Ginkgo Leaf Extract
17. Fresh Bilberry Fruit Extract
18. Milk-thistle Fruit Extract
19. Pelargonium Sidoides Ethanol Extract
[Annex 2]
Comparison of Drug Substance Registration Documents and Common Technical Documents (CTD)
(Related to Article 3 (3))
Drug substance registration documents
(Article 4 of the Regulation on the Registration of Drug
Substances)
1. Data on facilities required for manufacturing and quality
control pursuant to Article 31 (1) of the Act.
Data attesting to the provisions of Article 3 of the
Enforcement Decree on the Standards of Facilities of
Manufacturers and Importers of Medicinal Products,
etc. and Articles 2 and 7 of the Enforcement
Regulation of the same Decree.
2. Data on physiochemical characteristics and stability
A. Data on Physiochemical characteristics
(1) Data on origin or discovery and development
details
(2) Data on structure, physiochemical properties and
biological properties
(3) If a patent is obtained domestically or abroad, the
data attached with a copy of the patent registration
B. Data on stability
3. Data on manufacturing methods, packaging,
containers, and precautions for handling, etc.
A. Data on manufacturing method
Common technical documents (CTD)
(Annex 3 of the Regulation on Pharmaceuticals Approval,
Notification, and Review⸥)
1.7.3 Data for the assessment of implementation of Good
Manufacturing Practices (GMP) for medicinal
products.
3.2.S.1. General information
3.2.S.1.1 Name
3.2.S.1.2. Structure
3.2.S.1.3. General characteristics
3.2.S.2 Manufacturing
3.2.S.2.6 Development of manufacturing process
3.2.S.3. Characteristics
3.2.S.3.1. Structure and other characteristics
3.2.S.3.2. Purity
1.11. Other (copy of patent registration, etc.)
3.2.S.7 Stability
3.2.S.7.1. Summary and conclusion on stability
3.2.S.7.2. A stability test plan and performance pledge
after approval
3.2.S.7.3. Stability data
3.2.S.2 Manufacturing
3.2.S.2.1 Manufacturer
3.2.S.2.2 Manufacturing process and process control
3.2.S.2.3. Raw materials management
3.2.S.2.4. Key process and intermediate management
3.2.S.2.5. Process validation and evaluation
3.2.S.2.6. Manufacturing process development

B. Data on packaging and container
C. Precautions for handling
4. Data attesting to the fact that the Good Manufacturing
Practices for medicinal products (KGMP) are met or
exceeded
5. Data on test report of drug substance, analysis
methods, and solvent used, etc.
A. Test reports shall be a test report that has been
consecutively performed on more than 3 lots
consecutively in accordance with the standards and
test methods.
B. Analysis method refers to the standard and testing
method for drug substances
C. If organic solvents were used during the
manufacturing process, data on the types of organic
solvents, reasons for use, standards for organic
solvents residue in the final product, amount of
residues, and test methods
3.2.A. Appendix
3.2.A.2 Safety evaluation for foreign substances
3.2.S.6. Containers and packaging
3.2.S.7 Stability
3.2.S.7.1. Summary and conclusion on stability
1.7.2 Certificate of manufacturing and marketing
1.7.3 Data for the assessment of implementation of Good
Manufacturing Practices (GMP) for medicinal
products.
3.2.S.3. Characteristics
3.2.S.3.2. Purity
3.2.S.4 Management of drug substances
3.2.S.4.1 Criteria
3.2.S.4.2. Test method
3.2.S.4.3. Testing method validation
3.2.S.4.4. Batch analysis
3.2.S.4.5. Justification for criteria
3.2.S.5. Reference standard or reference material