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Total Quality: a Journey from Artemisia's Fields to Dihydroartemisinin/ Piperaquine

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Total Quality: a Journey from Artemisia's Fields to Dihydroartemisinin/ Piperaquine TOTAL QUALITY: A JOURNEY FROM ARTEMISIA’S FIELDS TO DIHYDROARTEMISININ/ PIPERAQUINE WALTER CABRI Analytical Chemistry Department, sigma-tau, Pomezia, Italy Sigma-tau and malaria Severe malaria Uncomplicated malaria IV ARTESUNATE DIHYDROARTEMISININ PIPERAQUINE FDA EMA DIHYDROARTEMISININ / PIPERAQUINE O O O P P O TWO APIs HO OH HO OH P OH OH P Cl Cl Br ClHO OH TOTAL SYNTHESIS N HO OH OH N OH H H N PIPERAQUINE TETRAPOSPHATE N N N Cl Cl N O TETRAHYDRATE N O H N H N (PQP) O P Cl O P HO Cl OH HO OH P OH P OH HO OH N HO OH OH N OH H H O SEMISYNTHESIS FROM ARTEMISININ O DIHYDROARTEMISININ O (extracted from Artemisia Annua) O H (DHA) O H O H H- O H O H+ O OH Total Quality Preclinical Development GLP Clinical Development Phase III GCP QTc Food Interaction DS/DP GMP EH&S GREEN CHEMISTRY DHA / PQP logistic China Vietnam Collaboration with the Kenya International Pharmacopoeia Madagascar Artemisinin Collaboration with the International GMP Pharmacopoeia and the USP Supplier 1 Suppliers 2 DHA PQP Sigma Tau Drug Product Traditional Chinese Medicine of Qīng Hāo (Artemisia Annua) Wu Shi Er Bing Fang 1065-771 BC (Prescriptions for Fifty-two Diseases) 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 Qīng Hāo Artemisia Annua 1971-1974 QUINGHAOSU Artemisinin 黄 花 蒿 H O O 1977 O H O O The first to discover and share 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 key pharmacophoric Pharmacophoric mojety O2 + light Artemisia annua glandular trichomes Artemisinin Artemisinin 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 We achieve : 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 evaluationSigma-tau was DHA/PQP generated is accordingfree to the more recent ICH, EMAfrom and genotoxic FDA guidelines impurities. Our suppliers have established a complete Environmental, Health and Safety control. Satisfactory 2y stability data at 30°C. DHA/PQP CMC Team 43 .
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