TOTAL QUALITY: A JOURNEY FROM ARTEMISIA’S ......resulted in an emulsion of water, flavonoids and...
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TOTAL QUALITY: A JOURNEY FROM ARTEMISIA’S FIELDS TO DIHYDROARTEMISININ/ PIPERAQUINE WALTER CABRI Analytical Chemistry Department, sigma-tau, Pomezia, Italy
Transcript of TOTAL QUALITY: A JOURNEY FROM ARTEMISIA’S ......resulted in an emulsion of water, flavonoids and...
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 :
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DHA/PQP CMC Team
