Collaboration for Herbal Medicinesbetween NIFDS & USP

Ph.D. Jonghwan Kim

Herbal Medicine Research DivisionNational Institute of Food and Drug Safety Evaluation

Ministry of Food and Drug Safety

I. Progress since MOU

II. Current status

III. Move forward

Contents

I. Progress since MOU

MOU signed (’12.7)

Works based on chemical medicine (’15~)

Extensive works including biologicals and herbal medicine (’15.6)

Agreed USP executive exchange program for herbal medicine (’16.6)

NIFDS expert(Dr. Jonghwan Kim) visited DSHM USPC (’17.2~’18.7)

Developed monograph draft for 6 items including

Angelica gigas root etc

USPC expert(Dr. Nam-Cheol Kim) visited NIFDS (‘18.10)

Progress since MOU

II. Current Status

- Organize working group & consensus item

- Co-develop monograph

(1) Organize small working group (1st Apr 29, 2nd May 30)

To discuss the analytical data during the development of

monographs

To monitor the progress of collaboration in fields of

herbal medicines; and/or

help the outcome of collaboration be productive

Working group

Angelica gigas (당귀)

Forsythia suspensa (연교)

Foeniculum vulgare (회향)

Perilla frutescens, P. frutescens var. crispa (자소엽)

Magnolia obovata (후박)

Epimedium koreanum (음양곽)

(2) 6 items in-progress

Consensus item

Ongoing Items (당귀)

Ongoing Items (연교)

Current monograph in KP & HMC

Co-development process- Angelica gigas root

KP11 HMC (development stage)

Origin Angelica gigas (Umbelliferae) / Root

Description Macroscopic, Microscopic

Identification TLC with Korean RMPM

a. HPTLC with osthole, imperatorin, isoimperatorin

SST validation: To Comeb. HPLC with four CRS

Content(as dried basis)

nodakenin, decursin, decursinolangelate 6.0 % (HPLC)

chlorogenic acid, demethylsuberosin, decursin, decursinol angelate 4.2 % (HPLC)

Loss on Drying - To Come <731>

Total Ash 6.0 %

Acid Insoluble Ash - To Come <561>

Extractives -Alcohol-Soluble (Method 1): To ComeWater-Soluble (Method 2): To Come

KP11 HMC (development stage)

Foreign matter 5.0 % / 1.0 % -

Heavy metal As 3.0, Cd 0.3, Pb 5.0, Hg 0.2 ug/g

Pesticide 14 (Total DDT etc) 70 (Total DDT etc)

Microbial Enumeration test

-Total aerobic bacteria 105 cfu/g

Total combined molds, yeasts 103 cfu/gGram (-) bacteria 103 cfu/g

Specified microorganism

- Salmonella, E. coli absence

Sulfur dioxide 30 ppm -

Aflatoxin -AFb1 5 ppb

Total AF(b1, b2, g1, g2) 20 ppb

Current monograph in KP & HMC

Co-development process- Angelica gigas root

Microscopic Identification (transverse section, x200)

a. vessel, b. cork cell, c. secretory canal, d. starch

e. bast fiber bundles, f. scalariform vessel, g. spiral vessel, h. starch

AG4 AG13 AG20

Co-development process- Angelica gigas root

n=20 min ~ Max (%) Average ± SD (%) % RSD

Loss on Drying 9.2 ~ 11.8 10.0 ± 0.8 8.3

Total Ash 4.6 ~ 6.2 5.5 ± 0.4 6.5

Acid-Insoluble Ash 0.8 ~ 1.1 0.9 ± 0.1 12.3

Extractives(diluted ethanol)

53.8 ~ 57.9 55.0 ± 1.3 2.4

Co-development process- Angelica gigas root

n=20 min ~ Max (%) Average ± SD (%) % RSD

Content 4.6 ~ 9.1 6.6 ± 1.3 20.3

y = 166161x - 48101

R² = 0.9998

0

1,000,000

2,000,000

3,000,000

4,000,000

5,000,000

6,000,000

7,000,000

0 10 20 30 40 50

y = 288678x + 30144

R² = 1

0

1,000,000

2,000,000

3,000,000

4,000,000

5,000,000

6,000,000

7,000,000

0 5 10 15 20 25

y = 252030x + 205128

R² = 1

0

10,000,000

20,000,000

30,000,000

40,000,000

50,000,000

60,000,000

0 50 100 150 200 250

y = 259942x - 77934

R² = 0.9997

0

10,000,000

20,000,000

30,000,000

40,000,000

50,000,000

60,000,000

70,000,000

0 50 100 150 200 250 300

Co-development process- Angelica gigas root

KP11 HMC (development stage)

Origin F. suspensa, F. viridissima F. suspensa

Description Macroscopic, Microscopic

Identification Derivatization

a. HPTLC with forsythoside a, lariciresinol, forsythin, pinoresinol, phillygenin

SST validation: To Comeb. HPLC with five CRS

Content(as dried basis)

F. suspensa: forsythoside a 0.25 %F. viridissima: arctigenin 0.4 % (HPLC)

forsythoside a, lariciresinol, forsythin, pinoresinol, phillygenin 2.4 % (HPLC)

Loss on Drying - To Come <731>

Total Ash 5.0 %

Acid Insoluble Ash - To Come <561>

Extractives diluted ethanol 10.0 %Alcohol-Soluble (Method 1): To ComeWater-Soluble (Method 2): To Come

Current monograph in KP & HMC

Co-development process- Forsythia suspensa fruit

KP11 HMC (development stage)

Foreign matter 5.0 % 2.0 %

Heavy metal As 3.0, Cd 0.3, Pb 5.0, Hg 0.2 ug/g

Pesticide 5 (Total DDT etc) 70 (Total DDT etc)

Microbial Enumeration test

-Total aerobic bacteria 105 cfu/g

Total combined molds, yeasts 103 cfu/gGram (-) bacteria 103 cfu/g

Specified microorganism

- Salmonella, E. coli absence

Sulfur dioxide 30 ppm -

Aflatoxin -AFb1 5 ppb

Total AF(b1, b2, g1, g2) 20 ppb

Co-development process- Forsythia suspensa fruit

Current monograph in KP & HMC

Microscopic Identification (transverse section, x200)

a. epicarp, b. vascular bundle, c. stone cell, d. endocarp

FS4 FS8 FS16

Co-development process- Forsythia suspensa fruit

n=21 min ~ Max (%) Average ± SD (%) % RSD

Loss on Drying 7.8 ~ 10.5 8.9 ± 0.7 7.6

Total Ash 2.1 ~ 3.5 3.0 ± 0.3 9.2

Acid-Insoluble Ash 0.2 ~ 0.6 0.3 ± 0.1 30.0

Extractives (diluted ethanol)

25.0 ~ 41.5 33.7 ± 7.1 21.2

Co-development process- Forsythia suspensa fruit

n=21 min ~ Max (%) Average ± SD (%) % RSD

Content 0.3 ~ 12.0 8.0 ± 3.3 42.0

y = 8.5403x + 39.237

R² = 1

0.00000

5,000.00000

10,000.00000

15,000.00000

0 500 1,000 1,500 2,000

y = 8.6906x + 2.982

R² = 0.9999

0.00000

200.00000

400.00000

600.00000

0 20 40 60 80

y = 4.8447x + 1.801

R² = 0.9999

0.00000

100.00000

200.00000

300.00000

400.00000

0 10 20 30 40 50 60 70

y = 8.3984x + 0.8532

R² = 0.9999

0.00000

50.00000

100.00000

150.00000

200.00000

0 5 10 15 20 25

y = 8.9763x + 6.0376

R² = 0.9997

0.00000

50.00000

100.00000

150.00000

200.00000

0 5 10 15 20 25

forsythoside a lariciresinol forsythin

pinoresinol

phillygenin

Co-development process- Forsythia suspensa fruit

III. Move forward

Gap review & Harmonization

KP/KHP USP (GC 561)

Heavy metalindividual elements (Pb, As, Cd, Hg)comprehensive application based on risk assessment

Pesticidedifferent kind of pesticides and/or different specificationscomprehensive application based on risk assessment

Sulfur dioxide comprehensive application no regulation

Benzopyrenea few botanicals with detection record & risk assessment

no regulation

Microorganism no regulation comprehensive application

Aflatoxina few botanicals with detection record & risk assessment

a few botanicals

Differences in Specification

KP/KHP USP (GC 561)

Total Ash2~4 g

500~550 ℃ for 4h2~4 g

675 ± 25 ℃

Acid Insoluble

Ash

2~4 g10 % hydrochloric acid

25 mL for 5 min

2~4 g3 N hydrochloric acid

25 mL for 5 min(3 N ≒ 9.99 % with commercial

conc. 37 % HCl)

Differences in Test Method

Gap review & Harmonization

KP/KHP USP (GC 561)

AlcoholSoluble

(M1, hot ext)-

4 gEthyl alcohol 100 mL for 1h

Reflux extraction for 1hTransfer 25mL, Dry 105℃ for

6h

AlcoholSoluble

(M2, cold ext)

2.3 g50 % Ethyl alcohol 70 mL

Shake for first 5h, then stand 24hr

Transfer 50 mL, Dry 105℃ for 4h

4 gEthyl alcohol 100 mL for 24h

Shake for first 8hTransfer 25 mL, Dry 105℃

Differences in Test Method

Gap review & Harmonization

Thank you for your attention!