TOTAL QUALITY: A JOURNEY FROM ARTEMISIA’S FIELDS TO DIHYDROARTEMISININ/ PIPERAQUINE

WALTER CABRI Analytical Chemistry Department, sigma-tau, Pomezia, Italy

Sigma-tau and malaria

IV ARTESUNATE DIHYDROARTEMISININ

PIPERAQUINE

Severe malaria Uncomplicated malaria

FDA EMA

DIHYDROARTEMISININ

(DHA) O

O

OH

H

O

O

H

H

PIPERAQUINE TETRAPOSPHATE

TETRAHYDRATE

(PQP) N

N

NCl

N

N

N

Cl

OH

P

OH

O

OH

OH

P

OH

O

OHOH

P

OH

O

OH

OH

P

OH

O

OH

TWO APIs

TOTAL SYNTHESIS

N

Cl

Cl

OH

P

OH

O

OH

OH

P

OH

O

OHOH

P

OH

O

OH

OH

P

OH

O

OH

N

N

H

H

N

Cl

Cl

N

N

H

H

Cl Br

SEMISYNTHESIS FROM ARTEMISININ

(extracted from Artemisia Annua) O

OH

O

O

H

H

O

H-

H+

DIHYDROARTEMISININ / PIPERAQUINE

Preclinical Development

GLP

GCP

GMP EH&S GREEN CHEMISTRY

Clinical Development

Phase III

QTc

Food Interaction

DS/DP

Total Quality

China

Vietnam

Kenya

Madagascar

Artemisinin

Suppliers 2

PQP

Supplier 1

DHA

Sigma Tau

Drug Product

GMP

Collaboration with the

International Pharmacopoeia

Collaboration with the International

Pharmacopoeia and the USP

DHA / PQP logistic

Wu Shi Er Bing Fang

(Prescriptions for Fifty-two Diseases) 1065-771 BC

Zhou hou bei ji fang Emergency Prescriptions Kept up one’s Sleeve Ge Hong (284–363)

Ge Hong reccommended to soak the entire fresh

plant in water and to wring it out thereafter probably

resulted in an emulsion of water, flavonoids and

aromatic oils contained in the stem and leaves.

Traditional Chinese Medicine of Qīng Hāo (Artemisia Annua)

黄 花 蒿 QUINGHAOSU

Artemisinin

Traditional Chinese Medicine

Qīng Hāo

Artemisia Annua

1971-1974

O

O

O

O

H

H

O

1977

Milutin Stefanovic

8th International Symposium on

the Chemistry of Natural

Products, held in New Delhi,

India, 6-12 February 1972

Wrong structure but the data

reported NMR/IR/ms are the

one of Artemisinin

The first to discover and share

Artemisia annua glandular trichomes Artemisinin

O2 + light Pharmacophoric mojety

The key pharmacophoric

We are selecting suppliers based on the following requirements:

1. Artemisinin suppliers information:

A. Declaration on the use of pesticides.

B. Declaration BSE/TSE.

C. Declaration on the use of fumigants and ethylene oxide.

D. Declaration on the source of seeds.

E. Declaration on the cultivation procedure.

F. Specification of dry leaves.

G. Declaration on the solvents “if the analysis are available”.

H. Inspection of the facility.

2. The batches must comply with our specifications that comprise

pesticides, heavy metal and aflatoxins.

3. Three validation batches

Artemisinin

Complete control of the processes, the logistic.

Identification and control of all decomposition pathways. All

impurities have been qualified from a toxicological point of

view. Genotoxic evaluation was generated according to the

more recent ICH, EMA and FDA guidelines.

Our suppliers have established a complete Environmental,

Health and Safety control.

Satisfactory 2y stability data at 30°C.

Sigma-tau DHA/PQP is free

from genotoxic impurities

We achieve :

43

DHA/PQP CMC Team