ExcEllEncEin thE korEanPharmacEutical industryThe Ministry of Food and Drug Safety

In Korea, all pharmaceutical manufacturers are required to obtain a product approval and a manufacturing license from the Ministry of Food and Drug Safety (MFDS) or its regional offices prior to production and sales of medicinal products. And their compliance with the GMP regulation needs to be confirmed by the MFDS in accordance with the relevant statutes such as the Pharmaceutical Affairs Act. The MFDS is a regulatory agency supervising pharmaceuticals throughout the entire lifecycle from granting a manufacturing license and a product approval, and inspection on GMP compliance to post-marketing surveillance.

Source from the Korea Pharmaceutical Manufacturers Association (KPMA)(2016 Directory of Korean Pharmaceutical Industry) as of 2014

Seoul 1stamong cities in the world

Clinical trials

10th

10th FDA approvals

Development ofnew drugs

10th

$2.1 billionExports

23rd

$19 trillion won Market size

14th

Excellence in the Korean Pharmaceutical Industry

As a member of PIC/S (Pharmaceutical Inspection Co-operation Scheme), and an observer of the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), Korea secures the safety and efficacy of medicinal products based on its GMP system equivalent to that of PIC/S and internationally harmonized regulations on drug approval. Also, the Korean pharmaceutical industry produces premium quality medicinal products and the most sophisticated biopharmaceuticals available. It is possible through the nation’s advanced facilities and equipment, and cutting-edge technologies as well as highly competent human resources in R&D and manufacturing areas.

The National Institute of Food and Drug Safety Evaluation

SeoulRegional Office of

Food and Drug Safety

Busan Regional Office of

Food and Drug Safety

GyeonginRegional Office of

Food and Drug Safety

DaeguRegional Office of

Food and Drug Safety

GwangjuRegional Office of

Food and Drug Safety

DaejeonRegional Office of

Food and Drug Safety

The MFDS(The Ministry of Food and Drug Safety)

[Figure 1] MFDS organization chart for departments in charge of medicinal products

The Pharmaceutical Safety Bureau

The Biopharmaceuticals and Herbal Medicine Bureau

Ⅰ. Korea’s Capability to Produce High Quality Medicinal Products

Operation of the internationally harmonized GMP system and its current status

As a member of PIC/S, Korea ensures internationally accredited medicinal products with the safety and quality. Since joining PIC/S on July 1, 2014, Korea has been implementing the GMP regulations equivalent to those of PIC/S in all areas ranging from APIs (Active Pharmaceutical Ingredients) to finished medicinal products management. It is particularly significant that we were admitted into PIC/S with the recognition of the equivalency between our own existing GMP regulations and the PIC/S GMP guidelines, and thus we were allowed to maintain our proprietary GMP. This proudly suggests that Korea’s own GMP system adheres to an international level of excellence.

Our rigorous GMP system based on relevant statutes ensures that all of our medicinal products are safe in every respect.Since 1994, when GMP regulations became mandatory in Korea, the GMP system has been maintained in a strong and robust manner. Any pharmaceutical company intending to manufacture medicinal products must obtain a manufacturing license and a certificate of GMP compliance of a manufacturer from the MFDS (or its legally mandated regional offices) in accordance with laws and regulations such as the Pharmaceutical Affairs Act. The MFDS also assesses each product on GMP compliance from the stage of APIs to finished products before giving approval. All manufacturers of APIs and finished medicinal products are required to undergo GMP inspection every three years and receive a certificate of GMP compliance of a manufacturer from the Ministry.

Issuance of official English certificates for compliance with GMP regulation, etc.

The MFDS (and its 6 regional offices) issue official certificates for compliance with GMP, CPP, and DMF in the English language consistent with pertinent laws and regulations. The Ministry’s regional offices issue a certificate of GMP compliance of manufacturer in the English language to each manufacturer that meets GMP regulations. A CPP (Certificate of Pharmaceutical Products) is issued by the headquarters as well as regional offices for each approved product, while a DMF certificate (Drug Master File) is issued by the headquarters only.

MFDS and its Regional Offices GMP CPP DMF

The Ministry of Food and Drug Safety headquarters x o o

MFDSRegional Offices

Seoul Regional Office o o x

Busan Regional Office o o x

Gyeongin Regional Office o o x

Daegu Regional Office o o x

Gwangju Regional Office o o x

Daejeon Regional Office o o x

Ⅱ. Internationally Harmonized and Well-established Drug Approval and Review System in Korea

Well-established Drug Approval/Review System of Korea

The MFDS approves drugs with safety and efficacy based on the internationally-harmonized laws and regulations on drug approval and review. In Korea, there are six (6) pharmaceutical laws and regulations (e.g. the Pharmaceutical Affairs Act and the Regulation on Safety of Medicinal Products, etc.) and 18 notifications (e.g. Regulation on Pharmaceuticals Approval, Notification, and Review, etc.) based on the legislation system of law, enforcement regulations, and notification. Also, drug review guidelines for various areas have been enacted and revised consistent with internationally harmonized standards.

The MFDS systematically manages drug life cycle with the latest science and technology.During the development stage, the MFDS reviews and approves protocols for clinical trials and bioequivalence tests, as well as evaluates the feasibility of the drug development plan. At the approval stage, the MFDS grants registration of drug substance (Drug Master File, DMF) and approval of the product to ensure manufacturing and distribution of the drug with safety, efficacy, and quality. Lastly, at the stage of post-marketing use, re-evaluation is conducted on new drugs, etc. For the previously approved product, safety and efficacy thereof are re-examined based on the up-to-date science and technology.

GLP GCP GMP GSP

Safetymanagement

Re-evaluation

Re-examination

Nonclinical Clinical Approval/Review

Post-approvalChange

DiscontinueManufacture/

ImportRecall/Discard

QualityInspection

ProvideInformation

Manufacture(Import) Distribution Usage after

approval

Animal

Set Manufacture/Quality Standards

ResearchDevelopment

Patients(Confirm Safety

and efficacy)

•Safety & Efficacy

•Quality

•Manufacture

•Import

•Hospital

•Pharmacy

•Wholesaler

•Consumer

•Doctor

•Pharmacist

(Safety Letters)

Clinical Trials, Approvals Manufacture(Import)Distribution

Post-marketingManagement

Issue,SafetyInfo.

[Figure 2] Phases of Drug Life Cycle

[Figure 3] MFDS’s Drug Approval and Review System

Operation of the DMF system in Korea

The nation’s DMF system has contributed greatly to the distribution of safe drug substance. The MFDS adopted the DMF system on July 1, 2002. Both drug substances of new drugs approved since July 1, 2002 and substances specified in the MFDS notification for import/ manufacturing are registered on the system with a total of 216 new chemical entities (NCE) and 205 ingredients (as of March, 2016).The system provides data protection as it requires the direct transmission of information from a drug substance manufacturer to the MFDS. The system has also accelerated approval process for finished products by using a registered drug substance. As quality assessment is conducted from the early stage of the drug substance, Korea’s DMF system ensures import, manufacturing, and distribution of safe drug substances.

Bioequivalence Test Management System

Korea has gained credibility of its bioequivalence test by adopting internationally harmonized testing standards.Bioequivalence tests in Korea are internationally competitive as they are conducted based on Good Clinical Practice (GCP) guidelines and are reviewed with internationally harmonized evaluation standards. The MFDS has designated 35 institutions (as of January 2016) to perform bioequivalence tests. The Ministry also regularly inspects testing institutions to confirm their compliance with relevant laws as well as their operation status. All such efforts have enhanced the reliability of the bioequivalence tests of the nation.

» List of Institutions Designated to Conduct Bioequivalence TestsWebsite of the Ministry of Food and Drug Safety (www.mfds.go.kr/eng)

Bioequivalence tests are systematically managed in Korea with an emphasis on the safety management of test subjects. To conduct bioequivalence test, the protocol must gain approval from the MFDS. The dosage and exclusion/inclusion criteria of subjects, etc. are reviewed by the Ministry as a part of the endeavor to secure the safety of subjects beforehand. The Ministry also confirms that subjects have not participated in any other test within three months prior to the bioequivalence test to secure the safety of subjects.

Application

Applicant

•Research and development of drug

•Preparation of dossier for drug approval

•Composition of preliminary report

•Examination of submitted application

•MFDS(NIFDS)•Regional FDA (only generic)

Pre-review

•Report Review•Efficacy, Safety•Quality Evaluation•DMF

•GMP Assessment•GMP Inspection•Foreign Manufacturing sites (MFDS)

•Domestic Manufacturing sites (Regional FDA)

NIFDS(Drug Evaluation Department)

Regional FDA

Review/Inspection

•Issuing certificate of approval

•Disclosure of Review Result

•MFDS(NIFDS)•Regional FDA (only generic)

Approval

Ⅲ. Korea’s Clinical Trials: Powerful Potential Realized through Solid Support

State-of-the-art infrastructure for clinical trials in Korea

Korea is a global power in the area of clinical trial, boasting one of the world’s 10th largest clinical trial infrastructure, boosted by robust regulations and the speedy approval process of clinical trials. Korea laid the foundation for revitalizing domestic clinical trials by implementing the IND (Investigational New Drug Application) system in December, 2002, and revising the Regulation on Approval for Investigational New Drug Application of Drugs (MFDS notification) in February, 2013. The establishment of the e-CTD(Electronic Common Technical Document) and CDISC (Clinical Data Interchange Standard Consortium) systems in 2014 facilitated the submission of clinical trial reports. Furthermore, the adoption of GMP standards for investigational medicinal products in July, 2015 promoted the government to develop the policies for advanced clinical trials, and to strengthen global competitiveness in clinical trials. Consequently, Korea has rapidly achieved the status of a global leader in clinical trials, having been ranked one of the world’s 10th biggest in terms of the total size of its clinical trials in 2015.

The government-led management of clinical trial infrastructure greatly helped the nation to achieve global competitiveness in clinical trials. Starting in 1994, the Korean government has designated institutions to carry out clinical trials, and regularly inspected the institutions. And the government made it mandatory to train the personnel involved in clinical trials from clinical researchers to CRAs (Clinical research associates). Keeping high ethical and professional standards for those involved in clinical trials contributes to the maintenance of clinical trial infrastructure with international competitiveness. The government has been highly committed to enhance ethics and quality of professionals with appropriate regulations and guidelines such as the KGCP, Korea’s domestic regulations equivalent to that of the ICH (International Conference on Harmonization), and the HRPP (Human Research Protection Program) guideline. As of October, 2015, a total of 174 medical institutions have been designated to carry out clinical trials, and their research infrastructure is regularly inspected by the MFDS in accordance with the Pharmaceutical Affairs Act.

» List of Clinical trial InstitutionsWebsite of the Ministry of Food and Drug Safety (www.mfds.go.kr/eng)

Ⅳ. A Global Leader in Biopharmaceutical Regulations

Korea leading international regulations on biosimilar technologies

Biosimilar products manufactured in Korea meet high quality standards as required by the nation’s proactive approval and review systems. Therefore, many Korean-manufactured biosimilar products have been granted approval without difficulty, and are currently on the market in many countries. Korea is proactively building advanced approval/review systems for biosimilar products. In July, 2009, Korea became the third country after EU nations and Japan to put in place approval/review and evaluation guidelines for biosimilar products. And in 2011, Korea published guidelines on safety and efficacy evaluation for different biosimilar products.As of 2016, five biosimilar products have been developed with locally-developed technologies and have won approval. Across the world, Korean-produced biosimilar products are hitting the market: the first biosimilar product approved in Korea obtained marketing authorization in approximately 70 countries including Japan and many countries in Europe and South America. Also Korea’s monoclonal antibody biosimilar product was granted marketing authorization in the US.

Biosimilar products developed with local technologies and approved by the Korean government

No. Product Name Company Active Substance (Comparator) Indication

1 Remsima 100mg Celltrion Infliximab(Remicade)

Rheumatoid arthritis, ulcerative colitis, etc.

2 Herzuma 150mg Celltrion Trastuzumab(Herceptin)

Breast cancer, gastric cancer

3 Herzuma 440mg Celltrion Trastuzumab(Herceptin)

Breast cancer, gastric cancer

4 Brensis 50mg Prefilled Syringe Samsung Bioepis Etanercept

(Enbrel)Rheumatoid arthritis,

psoriasis, etc.

5 Renflexis 100mg Samsung Bioepis Infliximab(Remicade)

Rheumatoid arthritis, ulcerative colitis, etc.

The world’s first stem cell therapy product approved

With the scientific review standards and systems that are in sync with the nation’s strong technological competence, Korea has positioned itself in the vanguard of stem cell therapy products. Stem cell therapies have a potential to treat what used to be untreatable conditions, offering new treatment options for those suffering from incurable diseases. As with the rest of the world, Korea is exerting great research efforts in the area of stem cell therapies. To facilitate the prompt introduction of safe and effective stem cell therapy products into the market, the MFDS has proactively developed and established an optimal review mechanism different from the ones for existing medicinal products. Furthermore, it has in place evaluation standards and systems that will allow a timely response to advanced technologies, taking into consideration expert opinions from relevant industries. As a result, Hearticellgram-AMI was approved as the world’s first stem cell therapy in July, 2011 and as of April, 2016, a total of four stem cell products have been approved.

Stem cell therapies developed with Korea developed technologies and approved by the Korean government

No. Product Name Manufacturer Active Substance Benefits

1 Hearticell-gram-AMI Pharmicell Autologous bone marrow-derived

mesenchymal stem cellImproves left ventricular ejection fraction of

acute myocardial infarction patients

2 Cartistem Medipost Allogenic umbilical cord blood-derived mesenchymal stem cell

Treats knee cartilage defects caused by degenerative osteoarthritis or repeated trauma

3 Cupistem Anterogen Autologous adipose tissue-derived mesenchymal stem cell Anal fistula in Crohn’s disease

4 Neuronata Corestem Autologous bone marrow-derived mesenchymal stem cell

Relieves the progression of amyotrophic lateral sclerosis

Ⅴ. Partnership with International Organizations such as the WHO, APEC, and ICH

The MFDS closely collaborates with the WHO (World Health Organization), playing a leading role in drafting international regulations on medicinal products.

[WHO Collaborating Center] The MFDS has been running a WHO Collaborating Center since being designated as the world’s 5th WHO Collaborating Center for Standardization and Evaluation of Biologicals in 2011. The 4 terms of references of the MFDS as WHO CC cover “supporting WHO in developing international guidelines”, “participating in collaborative studies for the development of international measurement standards and testing methods”, “providing support for the strengthening of national regulatory authorities through implementation of training programs”, and “facilitating implementation of WHO standards in the Western Pacific and other regions”. Each year, MFDS experts in biologicals are invited to the WHO ECBS (Expert Committee on Biological Standardization) to participate in the establishment of international written measurement standards.* The WHO Collaborating Centers composes an international collaboration network that carries out activities in support of WHO programs in research, meetings and public health emergency investigations. Currently, Korea and seven other countries (UK, Japan, Australia, U.S., China, Canada, and Germany) are running WHO Collaborating Centers on biopharmaceuticals. [WHO Global Learning Opportunities Center] The MFDS has taken a role as WHO GlobalLearning Opportunities Center to provide training courses on GMP since November 2007. In January 2016, it also added ‘Lot Release/Laboratory Access’ to its training areas and provided courses on vaccine quality control for regulators around the globe (GLO/VQ, Global Learning Opportunities for Vaccine Quality).* Since 1996, WHO has designated regulatory agencies and vaccine manufacturers as WHO GLO centers in an effort to help ensure the safety and efficacy of vaccines.

[WHO-accredited Testing Laboratories] The NIFDS (National Institute of Food and Drug Safety Evaluation), an affiliate research institute of the MFDS, has taken a role as a WHO-accredited testing laboratory to conduct tests commissioned by the WHO under the Technical Service Agreement (TSA) along with 13 other laboratories in 12 countries including the NIBSC (National Institute of Biological Standards and Control) in the UK. Accordingly, the NIFDS has carried out 12 different tests for six products since 2006.

Korean pharmaceutical companies have been prequalified by the WHO for three medicinal products and 11 vaccines.

WHO Prequalified Pharmaceutical Products

INN Formulation and strength commercial name Manufacturer

Artesunate + Pyronaridinetetraphosphate

Tablets60mg + 180mg

Pyramax TabletsShin Poong

Pharmaceutical Co, Ltd

Artesunate + Pyronaridinetetraphosphate

Granules for oral suspension 20mg + 60mg

Pyramax Granules for oral suspension

Shin Poong Pharmaceutical Co, Ltd

Cycloserine Capsules 250mg Closerin Dong-A ST Co, Ltd

WHO Prequalified Vaccines

Type Presentation Commercial Name Manufacturer

Hepatitis B Vial Euvax B LG Life Sciences

Hepatitis B Vial Hepavax Janssen Vaccines Corp.

Diphtheria-Tetanus-Pertussis (whole cell)-Hepatitis B-Haemo-philus influenzae type b

Vial Quinvaxem Janssen Vaccines Corp.

Influenza, pandemic H1N1 Vial Green Flu-S Green Cross Corporation

Influenza, seasonal Vial GC FLU Multi inj. Green Cross Corporation

Hepatitis B Vial Hepavax-Gene TF Janssen Vaccines Corp.

Diphtheria-Tetanus-Pertussis (whole cell)-Hepatitis B-Haemo-philus influenzae type b

Twovialset(active+active)

Euforvac-Hib Inj LG Life Sciences

cholera: inactivated oral Vial Euvichol Eubiologics Co., Ltd.

Diphtheria-Tetanus-Pertussis (whole cell)-Hepatitis B-Haemo-philus influenzae type b

Vial Eupenta LG Life Sciences

Diphtheria-Tetanus-Pertussis (whole cell)-Hepatitis B-Haemo-philus influenzae type b

Vial Quinvaxem MDV Janssen Vaccines Corp.

Influenza, seasonal Vial GCFLU inj Green Cross Corporation

The MFDS runs the APEC Harmonization Center (AHC), which aims to foster healthcare professionals and promote international harmonization. With its operation of the AHC which was endorsed at the APEC (Asia-Pacific Economic Cooperation) summit and ministerial meetings, the MFDS serves as the hub of training on regulatory harmonization in the APEC region. The administration closely works with the LSIF (Life Sciences Innovation Forum), RHSC (Regulatory Harmonization Steering Committee), WHO, and the ICH in fostering healthcare professionals and promoting international harmonization in the APEC region. Until now, more than 8,000 regulators and industry participants from home and abroad have been provided with training through the AHC. Furthermore, it has developed online training programs jointly with the ICH, expanding the scope and access of training to virtually anyone. The MFDS has taken the initiative in biotherapeutics, pharmacovigilance, and medical devices vigilance among the Priority Work Areas (PWAs) pursued by the APEC RHSC, developing mid and long-term plans for each area of international harmonization, and leading the effort for regulatory convergence in the APEC region. In addition, the Ministry has served as a champion for the APEC Biopharmaceutical Roadmap since 2013, and coordinated regulatory harmonization for biosimilar products among the member countries. As part of the efforts, the MFDS is engaged in activities geared towards creating the APEC CoE (Centers of Excellence) – an official regulatory training center.

The MFDS participates in drafting guidelines on medicinal products through its activities in the ICH and the IPRF, thereby leading the pharmaceutical regulatory harmonization efforts. Since 2006, the MFDS has been working in partnership with the ICH. Starting from 2011, the MFDS has taken a more active role in regulatory harmonization by participating in the development of guidelines on the quality, safety, and efficacy of medicinal products.

ICH Guidelines jointly developed with the MFDS (as of April, 2016)

No. Guideline No. Guideline

1 Impurities: Guideline for Elemental Impurities (Q3D)*

7 Impurities: Guideline for Elemental Impurities (Q3D)*

2Impurities: Guideline for Residual Solvents (Q3C)

8 Points to Consider: Medical Dictionary for Regulatory Activities (M1 PtC)

3Questions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Q7 Q&As)*

9 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Ptential Carcinogenic Risk (M7)*

4Rodent Carcinogenicity Studies for Human Pharmaceuticals (S1)

10 General Principle on Planning/Designing Multi-Regional Clinical Trials (E17)

5Periodic Benefit-Risk Evaluation Report (E2C(R2))*

11 Genomic Sampling and Management of Genomic Data (E18)

6 Good Clinical Practice (E6(R2)) 12 Enhancing the Format and Structure of Bene-fit-Risk Information (M4E)

*Completed guidelines

The MFDS has also joined the IPRF, an exclusive forum for regulatory agencies attending the ICH meetings, to actively participate in regulatory harmonization activities and share related information that are not covered at the ICH meetings. Furthermore, as a chair of the Biosimilar Working Group, Korea provides leadership in the management of related regulations, further strengthening its status as a key player in the biopharmaceutical sector.

» Year 2016 Directory of the Korean Pharmaceutical Industry Website of Korea Pharmaceutical Manufacturers Association (KPMA) (http://www.kpma.or.kr/sub/00000000016/00000000024)

» This leaflet may be downloaded at “http://www.mfds.go.kr/eng”.

H. www.mfds.go.kr T. +82-2-1577-1255