Eurartesim Madagascar finale - Medicines for Malaria Venture · Mass balance & shelf life. DS & DP...

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EURARTESIM® 2010EURARTESIM® 2010

Walter Cabri

Artemisinin as starting material

Chemistry & Analytical Development 12 - 14 October 2010

DIHYDROARTEMISININO

O

OH

H

O

O

H

H

PIPERAQUINE TETRAPOSPHATETETRAHYDRATE

N

N

NCl

N

N

N

Cl

OHP

OH

O

OH

OHP

OH

O

OHOH

POH

O

OH

OHP

OH

O

OH

EURARTESIM®EURARTESIM®

TWO APIsTWO APIs


Eurartesim registration strategySigma-tau/MMV

Eurartesim registration strategySigma-tau/MMV

Stringent regulatory authority approval

WHO prequalification

Endemic countries filing

public

private

EMAcentralizedprocedure


Total QualityTotal Quality

� Preclinical Development GLPGLP

GCPGCP

� Clinical DevelopmentPhase III QTCFood Interaction

cGMPcGMP EH&SEH&S GREEN CHEMISTRYGREEN CHEMISTRY� DS/DP

Social careSocial care


Some key topics covered in the CMC sectionSome key topics covered 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


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 identicalprofile?

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?


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.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


< 0.50%Loss on drying

151-154°CMelting range

ICH, no class I contaminantionSolvents

� 1.0%Total impurities

� 0.20%Each uknown impurity

� 0.50%Epi-artemisinin

� 0.15%Artemisitene

Impurities:

97.0% -102.0%Assay

See laterHeavy metals

0.10%Sulphated ash

+75°/ +78°Specific rotation

Conforms to the ref. std.Identity IR, HPLC

Colourless needles or a white crystalline powder

Appearance

SPECIFICATIONSTEST

Artemisinin specsArtemisinin specs

Optimization of WHO method to increase selectivity/sharp peaks.

Impuritiy calculation are considering response factors


Artemisinin additional SPECSArtemisinin additional SPECS

Listed in table 2.8.13.-1EP 6.2 supplement

Listed in table 2.8.13.-1EP 6.2 supplement

Pesticides

< 4 ppbB2+G1+G2

< 2 ppbB1

Aflatoxin

SPECIFICATIONSTEST

We need to establish general specification considering that someproducers are not able to control the farmers.

Soil contamination Contamination by other plants


< 10 ppmZn< 10 ppmNi

< 10 ppmFe

< 0.1 ppmHg

< 1 ppmPb

< 10 ppmCu

< 0.2 ppmCd

< 1.5 ppmAs

SPECIFICATIONMETAL

Artemisinin additional specsArtemisinin additional specs


Million of treatmentsAge/weight distributionMarket distributionArtemisinin process efficiency

Forecasts optimizationsForecasts optimizations

Also the kg artemisinin to get 1kg of APIin the DP must be optimised


These yields were presented at the Mumbai 2009 conference by Jacques Pilloy.


1.25

0.90

1.42

Based on literature data and lab/industrial experience the yields calculated in ST are the one reported on the right.


Deaths x millionDeaths x million

State Quinine distributioneducation

State Quinine distributioneducation

Agro Pontinoreclamation

Agro Pontinoreclamation

DDTDDT

Italy: Eradication of MalariaItaly: Eradication of Malaria


Malaria map (1882) byMalaria map (1882) by

sensen. Luigi . Luigi TorelliTorelli

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


Eurartesim CMC Team

~50% coming from the Agro Pontino

Eurartesim Madagascar finale - Medicines for Malaria Venture · Mass balance & shelf life. DS & DP...

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