Artemisinin as starting material

Transcription

1 EURARTESIM 2010 Artemisinin as starting material Walter Cabri 1

2 EURARTESIM TWO APIs APIs O O Cl HO P N HO P N Cl PIPERAQUINE TETRAPOSPHATE TETRAHYDRATE N HO N O P HO N O P N H DIHYDROARTEMISININ O O O H H O Chemistry & Analytical Development October 2010 Page 2

3 Eurartesim registration strategy Sigma-tau/MMV Stringent regulatory authority approval public WHO prequalification Endemic countries filing private EMA centralized procedure Chemistry & Analytical Development October 2010 Page 3

4 Total Quality Preclinical Development GLP Clinical Development Phase III QTC Food Interaction GCP DS/DP cgmp EH&S GREEN CHEMISTRY Social care Chemistry & Analytical Development October 2010 Page 4

5 Some key topics covered in in the CMC section Artemisin as starting material Specification of starting materials, DS & DP Mass balance & shelf life. DS & DP Full toxicological qualification of impurities Genotoxic impurities are undetectable Chemistry & Analytical Development October 2010 Page 5

6 From Artemisin to DHA is a short process, therefore the quality of the starting material is directly affecting the quality of the API. 1. Artemisin coming from different continent has an identical profile? 2. Justification of the specs. 3. Validation of analytical methods for impurities and OVI. 4. Definition of dry leave specs. 5. Seed control. 6. Farmers control 7. Pesticides. 8. Different processes? Chemistry & Analytical Development October 2010 Page 6

7 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. D. Declaration on the source of seeds. E. Declaration on the cultivation procedure. F. Specification of dry leaves. G. Declaration on the solvents used. H. Inspection of the facility. 2. The batches must comply with our specifications. 3. Three validation batches of the DHA Chemistry & Analytical Development October 2010 Page 7

8 Artemisinin specs Optimization of WHO method to increase selectivity/sharp peaks. Impuritiy calculation are considering response factors TEST Appearance Identity IR, HPLC Melting range Specific rotation Sulphated ash Heavy metals Loss on drying Solvents Assay Impurities: Artemisitene Epi-artemisinin Each uknown impurity Total impurities SPECIFICATIONS Colourless needles or a white crystalline powder Conforms to the ref. std C +75 / % See later < 0.50% ICH, no class I contaminantion 97.0% % 0.15% 0.50% 0.20% 1.0% Chemistry & Analytical Development October 2010 Page 8

9 Artemisinin additional SPECS Aflatoxin TEST SPECIFICATIONS B1 B2+G1+G2 < 2 ppb < 4 ppb Pesticides Listed in table EP 6.2 supplement Listed in table EP 6.2 supplement We need to establish general specification considering that some producers are not able to control the farmers. Soil contamination Contamination by other plants Chemistry & Analytical Development October 2010 Page 9

10 Artemisinin additional specs METAL Pb Cd Hg As Fe Cu Ni Zn SPECIFICATION < 1 ppm < 0.2 ppm < 0.1 ppm < 1.5 ppm < 10 ppm < 10 ppm < 10 ppm < 10 ppm Chemistry & Analytical Development October 2010 Page 10

11 Forecasts optimizations Million of treatments Age/weight distribution Market distribution Artemisinin process efficiency Also the kg artemisinin to get 1kg of API in the DP must be optimised Chemistry & Analytical Development October 2010 Page 11

12 These yields were presented at the Mumbai 2009 conference by Jacques Pilloy. Chemistry & Analytical Development October 2010 Page 12

13 Based on literature data and lab/industrial experience the yields calculated in ST are the one reported on the right Chemistry & Analytical Development October 2010 Page 13

14 Chemistry & Analytical Development October 2010 Page 14

15 Italy: Eradication of ofmalaria Deaths x million State State Quinine distribution education Agro Agro Pontino reclamation DDT DDT Chemistry & Analytical Development October 2010 Page 15

16 Malaria map (1882) by sen.. Luigi Torelli The map was developed to verify the health and hygienic conditions along the railway lines. About 8331 kilometers of railways, 3762 were well in malarial areas. POMEZIA Agro Pontino Chemistry & Analytical Development October 2010 Page 16

17 Eurartesim CMC Team ~50% coming from the Agro Pontino Chemistry & Analytical Development October 2010 Page 17