Herbal medicine and Traditional medicine in Korea

Transcription

1 TradReg2017 in Germany Herbal medicine and Traditional medicine in Korea Ju Young PARK

2 Contents MFDS Traditional medicine in Korea Approval of Herbal medicine in Korea Recent updates of regulation for herbal medicine in Korea

3 Osong Health Technology Administration Complex MFDS in Osong 13 2k m NIH NIFDS CDC KHIDI MFDS KHRDI 3

4 Ministry of Food and Drug Safety (MFDS) The Former name of MFDS is Korean Food and Drug Administration(KFDA). It was established in 1998, and elevated the status to MFDS in MFDS is in charge of food, health functional food, drug, quasi-drug(textile or rubber products for medical use and insecticides for human), cosmetics and medical devices. MFDS consists of Headquarter and NiFDs(National Institute of Food and Drug Safety Evaluation) in Osong 6 Regional Offices of Food and Drug Safety in Seoul, Busan, Gyeongin, Daegu, Gwangju, Daejeon 4

5 Ministry of Food and Drug Safety (MFDS) Staff : 1,759 persons Responsibility for drugs HQ : Policy development, legislation, GMP inspection, post-approval management NiFDs : Approval, IND & NDA review, guideline, research, lab testing, lot release Regional office : Registration, site-inspection, monitoring, testing Legislative system for Drug Regulation Law Not legally binding Act Enforcement Decree Notification Guidelines Pharmaceutical Affairs Act Regulations on safety of pharmaceuticals etc. ~ 40 ~150 5

6 Organization of Headquarter Headquarter 7 Bureaus, 1 General office, 48 Divisions Minister Spokesman Vice Minister Audit & Inspection Office General Service Division Criminal Investigation Office General Office for Planning and coordination Customer Risk Prevention Bureau Food Safety Policy Bureau Imported Food Safety Policy Bureau Food and Consumer Safety Bureau Pharmaceutical Safety Bureau Biopharmaceuticals and Herbal Medicine Bureau Medical Device Safety Bureau Pharmaceutical Policy Div. Pharmaceutical Management Div. Narcotics Policy Div. Narcotics Managemant Div. Pharmaceutical Quality Div. Clinical Trials Management Div. Approval Patent Linkage Div. Biopharmaceutical Policy Div. Biopharmaceutical Quality Div. Herbal Medicine Policy Div. Quasi-drug Policy Div. Cosmetics Policy Div. Pharmaceutical Safety Eva. Div. 6 6

7 Organization of NiFDs NIFDS 6 Departments, 41 Divisions Director General General Service Division Research Planning & Management Division National Center for Lot Release Food Safety Evaluation Department Drug Evaluation Department Biopharmaceuticals and Herbal Medicine Evaluation Department Medical Device Evaluation Department Pharmaceutical and Medical Device Research Department Toxicological Evaluation and Research Department Drug Review Management Div. Pharmaceutical Standardization Div. Cardiovascular & Neurological Products Div. Oncology & Antibiotics products Div. Gastroenterology & Metabolism Products Div. Bioequivalence Evaluation Div. Biopharmaceuticals Review Management Div. Biologics Div. Recombinant Products Div. Cell &Gene Therapy Products Div. Herbal Medicine Products Div. Cosmetics Evaluation Div. Pharmaceutical Standardization Research & Testing div, Biologics Research Div. Advanced Therapy Research Div. Herbal Medicine Research Div. Cosmetics Research Div. Medical Device Research Div. Radiation Safety Div. 7 7

8 Ⅱ. Traditional medicine in Korea

9 Traditional medicine in Korea History: > 1500 yrs. same theoretical background with Chinese medicine, the theory of Yin-Yang and Five Elements. established an independent medicinal theory such as Sasang constitutional theory through its own experiences. Characteristics use holistic approach, emphasize on balance acupuncture, moxibution, herbal medicine 9

10 Medical system in Korea License Medical doctor (Physicians) Oriental medical doctor Area Qualifications Contemporary medicine pass the national test after graduating the medical college (6 yrs-course) Traditional medicine pass the national test after graduating the oriental medical college (6 yrs-course) Number ( 15) 116,045 23,245 Managing authority Ministry of Health and Welfare 10

11 Traditional Korean medicine Hanyak - Classical preparation (generally liquid form) by mixing and boiling in water of herbal substances by TKM doctor TKM substance - Herb part (including animal and mineral) used for preparing Hanyak, generally dried and cut without changing the original form Traditional Korean medicinal product(tkmp) - Modernized drug products manufactured according to TKM principle 11

12 Management Range of MFDS Plant, Animal, Mineral Starting material Herb part, exudate powder, extraction simple processing Drug substance Herbal Powder Herbal extract TKM Substance ( 韓藥材 ) Herbal Drug product Drug product Herbal Medicinal Product Traditional Korean Medicinal Products Hanyak prescribed by TKM doctors 12

13 Management of TKM substances Licence for TKM substance manufacturer GMP for herbal substances (h-gmp) Every products need to be registered to Regional office of Food and Drug Safety Quality conrtol by KP & KHP Substance which is not listed in KP or KHP needs the approval of MFDS through the review of quality, safety and efficacy. 13

14 Traditional Korean medicinal products Traditional Korean Medicinal products are manufactured according to TKM principle, usually combination of 1~30 herbal substances Combination is generally originated from literature, modified or newly formulated based on the TKM theory Manufacturing process and dosage forms are based on the traditional preparation, but properly adpated to manufacture Finished products for use by TKM doctor or OTC drug Labeling based on the TKM books Indication and dosage need to be modified according to modern medical terms Precautions is from collected information on herbal toxicity, contraindication of TKM and adverse effect monitoring. 14

15 Ⅲ. Approval of Herbal medicine in Korea

16 Food, Health food, and Drug Food Definition Regulation Approval for products All kinds of foods and beverages (excluding foods and beverages taken as medicine) Functional Health Food Foods manufactured (including processing) with functional raw materials or ingredients beneficial to human body Drug Articles, other than appliances, machinery or equipment, used for the purposes of diagnosis, medical care, alleviation, treatment or prevention of diseases of human beings or animals Food Sanitation Act Functional Health Foods Act Pharmaceutic al Affairs Act Only listed substances can be used. The products don't need the approval of MFDS, but need to be notified to Province or city. Each products should be notified to MFDS. Nonlisted substance need the approval of MFDS through the review of safety and functionality. Each products must be approved by MFDS, or notified to Regional FDA. Some herbal materials can be used as food, functional health food as well as medicine. It is controlled by its purpose of use 16

17 Pharmaceutical Legislation in Korea Pharmaceutical Affairs Act Regulation on Safety of Pharmaceuticals etc. Regulation on Pharmaceuticals Approval, Notification and Review Regulation on Approval and Review of Biological Products Regulation on Approval and Notification of Herbal medicine synthetic products, chemically purified products, enzyme, antibiotics Vaccine, Bloodderived products, Recombinant DNA products, Cell therapy products, Gene therapy products Herbal substance, Herbal preparations, Herbal products 17

18 Approval and Registration Approval (by NiFDs) Product containing new materials Product requested Safety-efficacy evaluation (new combination, route, dosage form or indication) Product which is not for registration Registration(or Notification) (by 6 Regional office) Products listed in Pharmacopoeia(KP, USP, BP, JP, EP, DAB, PF) OTC Products in Compendia or Monographs Generic drugs without equivalence data 18

19 Approval system for herbal medicine Regulation on Approval and Notification of Herbal Medicinal Preparations, Etc. - Bio&Cosmetics - Regulation Required same data with other drug with some distinction on data for quality Data for quality Data for stability Data for toxicity Data for pharmacological action Data for clinical study results Data for GMP 19

20 Classifications by Safety-efficacy evaluation 1. New Drug Products : Full document on nonclinical and clinical data Drug products containing new herbal substance 2. Drug Products Requiring Safety-Efficacy Documents : Partial documents on nonclinical and clinical data New combination or New manufacturing process (solvents, yield) New strength New route New dosage form New effect 20

21 Classifications by Safety-efficacy evaluation 3. Generic Drug Products : Pharmaceutical or Bio- Equivalence document Drug products equal to previously approved drugs in API (including manufacturing process) & strength & dosage form & indication 4. Others: Waived of nonclinical and/or clinical data Drug product listed on the Pharmacopoeia (KP, USP, BP, JP, EP, DAB, PF) Drug product listed on 10 Traditional Herbal Medicinal Book (Donguibogam, Bangyakhapyeon, Donguisoosebowon ) OTC drugs listed on Medicine Compendium of 8 countries OTC drugs according to Standard Formulation on the Combination & Manufacturing

22 Documents for Quality & Safety-Efficacy Review 1. Origin and background on discovery and development 2. Structure and physicochemical properties 3. Stability Module 3 4. Toxicity 5. Pharmacology 6. Clinical report 7. Use in foreign countries Module 4 Module 5 Module 1 8. Comparison to similar drug products available in Korea New drug and Safey-Efficacy Review products should submit the documents by CTD format. 22

23 Data for Quality Quality control at each step - herbal materials, herbal extracts, herbal product Emphasis on Manufacturing Method Whole manufacturing processes should be described in detail. If the extraction solvent or yield of extracts is different, then it is differnet product. For animal-derived ingredient, the viral safety data should be reviewed. 23

24 Pharmacopoeia for herbal medicine Korean Pharmacopoeia (KP) made in 1958, 11 TH Edition revised in 2014 for more popular drug substances contains 165 substances, 9 preparations, 5 herbal products and 2288 non-herbal substances and products Korean Herbal Pharmacopoeia (KHP) made in 1984, revised recently in 2017 for herbal medicines not listed in KP contains 437 substances, 308 preparations and 123 products 24

25 Contaminants and Residues (KP&KHP) heavy metals plant herbal materials Subject Limit (not more than ~) Pb 5 mg/kg, As 3 mg/kg, Hg 0.2 mg/kg, C d 0.3 mg/kg 15 plant herbal materials Pb 5 mg/kg, As 3 mg/kg, Hg 0.2 mg/kg, C (Atractylodes Rhizome White, d 0.7 mg/kg Cinnamon Bark ) 5 plant herbal materials Pb 5 mg/kg, As 3 mg/kg, Hg 0.2 mg/kg, C (Alisma Rhizome, Coptis d 1.0 mg/kg Rhizome ) 15 mineral herbal materials Cinnabaris Cervi Parvum Cornu herbal extracts herbal medicinal products heavy metal mg/kg (varies for each medicine) heavy metal 20 mg/kg, Hg 2 mg/kg, As 2 mg/kg As 3 mg/kg heavy metal 30 mg/kg heavy metal 30 mg/kg, Pb 5 mg/kg, As 3 mg/kg 25

26 Contaminants and Residues (KP&KHP) Subject Limit (not more than ~) BHC(sum of (α,β,γ and δ-bhc) 0.2 mg/kg, DDT plant herbal materials (sum of p,p'-ddd, p,p'-dde, o,p'-ddt and p and herbal extracts,p'-ddt) 0.1 mg/kg, Aldrine 0.01 mg/kg, Endrine 0.01 mg/kg, Dieldrine 0.01 mg/kg pesticides 71 herbal materials (Ginseng ) varies for each herbal materials sulfur dioxide 1) follow EP, 2) determine the safey by when detecting nonlisted pesticides calculating using ADI of the pesticide and daily dose of the herbal material 255 herbal materials (Cinnamon Bark ) 30 mg/kg 26

27 Contaminants and Residues (KP&KHP) Aflatoxin Benzo(a)pyrene Microbials Subject Limit (not more than ~) 20 herbal materials total aflatoxins (as sum of alfatoxin B 1, (Licorice, Cassia Seed, B 2, G 1, G 2 ) 15.0 μg /kg, aflatoxin B ) 0 μg /kg Rehmannia Root, Prepared Rehmannia Root Liquid for oral use benzo(a)pyrene 5 μg /kg bacteria 10^3, fungi 10^2, specified microbial species (Esherichia coli, Salmonella, Pseudomonas aeruginosa, Staphylococcus aureus) not detected Herbal extracts, bacteria 10^5, fungi 10^2, specified Solid products for oral use microbial species (same as above) not including herbal extracts as detected ingredient Solid products for oral use specified microbial species (same as including non-extracted above) not detected herbal material as ingredient 27

28 Guideline on herbal medicine (2007~) Guideline Title Guideline on the Quality Evaluation of HMP under Clinical Studies (2009) Quality Guideline on the Chemical Profile of Herbal Medicinal Products (2016) Guideline on the Use of CTD Format of HMP-Quality (2012) Guideline on the Quality Control of Herbal substance(2016) Nonclinical & Clinical General Consideration for Clinical Trial of HMP (2007) Guideline on the Nonclinical Study of HMP (2017) GMP Guideline on the GMP Evaluation of HMP (2012) Guideline on the GMP Evaluation of TKM Substance (2017) 28

29 Ⅳ. Recent updates of regulation for herbal medicine in Korea

30 Drug Master File (DMF) You should register the Drug master file of these 19 drug substances before the approval of finished products. (3~19 enacted from January 2018) 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 30

31 Drug Master File (DMF) 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 31

32 Benzo(a)pyrene Benzo(a)pyrene is one of PAHs produced during manufacturing using high temperature, or contaminated from air/ water mutagenic, genotoxic, carcinogenic to human no ADI, BMDL10 is 0.1 mg/kg/day (WHO/JECFA, 06) Data for benzo(a)pyrene safety evaluation required for approval of herbal medicine since October Review for the cause of detected benzo(a)pyrene Testing results and Evaluation of Margin of Exposure Plan for management or reduction of benzo(a)pyrene 32

33 Chemical profile It is a Chromatographic profile of a drug substance. It cotains information about the distribution and quantity of the major (representative) substances. This data has been mandatory since October Guideline on the chemical profile of herbal medicine(2016) * Ivy leaf 30% ethanol dried extracts 33

34 Number of Approved products No. of total approved herbal drug products : about 5,670 (13.7% of total pharmaceutical finished products) * prescription: 9.8% vs. OTC : 90.2% 35,1% 13,7% 10,0% 54,9% 86,3% Finished products TKM substance Drug substance Herbal medicine Other medicine 34

35 IND of Herbal medicine Number of total IND of herbal medicine (1998~2016): 196 * sponsor : 83 % vs. investigator : 17% Average number of yearly new IND : about IND authorization Disease area 25 Circulatory % 6% 7% 21% Digestive Musculoskelectal Nervous % 10% 16% Respiratory Vascular Oncology 0 '05 '06 '07 '08 '09 '10 '11 '12 '13 '14 '15 '16 12% 13% Dermatology Others

36 Examples of herbal products with clinical trial Product Name 1 Joins Tab. Substance Clematis Root/Trichosanthes Root/Prunella Spike 30% Ethanol extracts Date of approval Effectiveness Arthritis 2 Apitoxin Inj. Dried Bee venom Arthritis 3 Stillen Tab. Wormwood 95% Ethanol extracts Gastritis 4 Shinbaro Cap. 5 Synatura Syrup Acanthopanax senticosus Root/Achyranthes Root/ Saposhnikovia Root/Eucommia Bark/Cibot Rhizome/ Black bean Water extracts Coptis Rhizome Buthanol extracts/ivy Leaf 30% Ethanol extracts Arthritis Motilitone Tab. Corydalis Tuber/Pharbitis Seed 50% Ethanol extracts Layla Tab. 8 Utoma Topical Solution Angelica gigas Root/Chaenomelis Fructus/ Saposhnikovia Root/Dipsacus Root/Acanthopanax Root Bark/ Achyranthes Root/Clematis Root/ Cinnamon Bark/Gentiana macrophylla Root/Cnidium Rhizome/Gastrodia Rhizome/Safflower 25% Ethanol extracts Bronchial trouble Functional indigestionn Arthritis Poncine Lung extracts Atopy 36

37 Challenge How to prove equivalance of herbal medicine? - between original drug and generic drug - when manufacturing process partial ly changed - when manufacturer of API is changed How to authorize a newly developed Tradional Korean Medicine? - composed of less than 5 ingredients - based on non-clinical and clinical data - sometimes for injection Korea has joined ICH as member country in Nov As we have more information from other countries, the regulation gets more and more. 37

38 Thank you for your attention! For more information, please visit the our website, Contact Ministry of Food and Drug Safety, National Institute of Food and Drug Safety Evaluation, Herbal Medicinal Products Division, PARK, Ju Young Tel Fax