CHALLENGES IN CURRENT SOURCING OF ARTEMISININ

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CHALLENGES IN CURRENT SOURCING OF
ARTEMISININ ARTEMISININ ENTERPRISE
CONFERENCE October 8-10, York, UK By DR.
D.C. JAIN GREEN TECHNOLOGY DEPARTMENT Ipca
Laboratories Ltd. India
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• BRIEF ABOUT IPCA LABORATORIES
• Ipca is a pharmaceutical company manufacturing
  globally marketing formulation active
  pharmaceutical ingredients (APIs)
• One of the larger manufacturer in the world of
  APIs like Atenol, Porpranolol, Chloroquine
  salts, Artemisinin derivatives (Artemether,
  Arteether /Artesunate) Etc.
• Mission Malaria Ipca launched mission malaria in
  2008 committed to the cause of helping to save
  over a million lives lost every year.
• Some facts to address global issues
• Ipca is Indias market leader in anti malaria in
  all dosage forms.
• Ipca is one of the world larger manufacturer of
  Artemisinin based APIs and formulations.
• WHO Geneva has approved our API Formulation
  antimalarial plants.
• Ipca is the only company which is into production
  of formulations. APIs and crop cultivation.
• Now Ipca has a broad range of antimalarial APIs
  Formulations with strong backward integration
  by manufacturing most antimalarial APIs to back
  up formulations.

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IPCA LABORATORIES LTD. INDIA
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Green Mission
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• GREEN MISSION OF IPCA
• Artemisia annua plant introduction in
  India - 1985-86
• Commercially viable variety developed -
  1990,97 2001
• (Asha, Jeevan Raksha and CIM-Arogya
• Ipca initiated the cultivation - 2001
• Commercial Cultivation - 2004-05
• Cultivation in different state of country - 300
  Hac Land
• Major Achievements
• Average yield / Ha. - 2-2.2 tons / Hac.
• Average artemisinin content - 0.8
• Recovery of artemisinin - 70 72
• New area of cultivation - 500Hac. (South
  India)

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Artemisia cultivation in Different States of India
Now approaching Bio-Technology through
cultivation of Artemisia Annua plant
Gujrat, Madhya Pradesh, Uttar Pradesh,
Uttaranchal, Chattisgarh, Rajashtan, AP, Karnataka
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CULTIVATION IN DIFFERENT LOCATIONS
Madhya Pradesh
Gujrat
Uttaranchal
Rajasthan
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FIELD VIEW OF ARTEMISIA ANNUA
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OUR EXPERIENCE IN CULTIVATION
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OUR EXPERIENCE IN CULTIVATION IN SOUTH INDIA
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• SOURCING OF ARTEMISININ
• WHY OWN SOURCING
• Quality of material
• Consistent supply
• Cheaper cost of ACTs and Formulation
• Reduce dependency
• Source of new drugs (Cancer Etc.)
• By products Fuel / Bio fertilizers / Mosquito
  repellent

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• CHALLENGES TO PRODUCTION OF ARTEMSININ
• Higher cost of raw material (Dry Artemisia
  leaves)
• Low content of artemisinin
• High cost of production
• Major impurity of artemisinin
• Prices fluctuation.

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• CHALLENGES OF SOLUTION FOR LOW COST DRY LEAVES
• Reduce the cultivation cost
• High dry leaves yield / Hac.
• Increase the farmer benifits
• No reduction of food grain area.
• Cultivation at waste land of government.
• Development of rainy season crop
• Problem
• Flowering in the month of September October
  (Rainy season in India)
• Challenge
• To develop non flowering crop in this period.

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ARTEMISIA PLANT DEVELOPED BY TISSUE CULTURE (LAB
TO FIELD)
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• MAIN IMPURITY OF ARTEMISNIN
• Main impurity of artemisinin upto 10
• Separation is difficult increased cost of
  production
• Main impurity identified as artemisitene
• Problem-
• Carry forward the similar arte-derivatives as
  impurity
• Removal of impurity from arte-products Loss of
  yield Cost increase.
• Solution
• Impurities should be reduce
• Carry forward - Product study of impurity.
• Conversion to artemisinin.

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• GLOBAL CHALLENGES IN LARGE SCALE PRODUCTION OF
  ARTEMISININ
• High yielding variety of region specific.
• Identification of best production areas.
• Increasing productivity per hectare.
• Lack of good quality seed availability.
• Link production with processing.
• Combination between agri sector, Health
  Environment
• Processing and post harvest constrains.
• Loss of artemisinin during drying and storage of
  dry leaves

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• NEW SOURCE OF ARTEMISININ
• New high yielding variety under development at
  York University.
• Semi synthetic artemisinin (US Berkelly)
• (Fermentation (E. Coli) Artemisinic acid
  Artemisinin)
• Plant Chicory New source of dihydro artemisinic
  acid ? Artemisinin
• New Source Artemisinic Acid
• Selection of high yielding artemisinic acid
  variety
• Artemisinic acid is stable molecule.
• Easily isolate from plant.
• Less problem of artemisinin impurity
• Challenges
• High conversion of artemisinic acid to
  Artemisinin (Chemical / Enzymatic)

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• CHALLENGES OF EXTRACTION AND RECOVERY OF
  ARTEMISININ FROM PRIMARY EXTRACTS
• Extraction of different solvent systems results
  complex mixture containing unwanted compounds.
• Variation due to different variety, climatic
  conditions and geographic variations,
• Re-crystallization for recovery of artemisinin
• Higher loss of artemisinin, solvent traces,
  Hazardous nature/negative environment health
  extracts.
• Crystalline artemisinin obtained by column
  chromatography.
• Trace impurity in crystalline artemisinin has
  negative effect on derivatization.
• Complex Challenges Maximizing yield of
  artemisinin from plant and achieving required
  purity of consecutive derivatization.

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• CHOICE FOR EXTRACTION TECHNOLOGY
• ULTRASONIC ASSISTED EXTRACTION
• Benifits
• Selective extraction compressed to other
  techniques
• Versatile technique that allows small scale to
  large scale.
• Short extraction times rooms temperature
  operation.
• Avoiding damage of temperature sensitive
  compounds.
• Improved yield can be extracted in comparison to
  other method.
• Excellent solution for extraction of
  phytochemicals.

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• CHALLENGES IN ANALYSIS
• No single well defined and validated analytical
  approved protocol for quantitative analysis of
  artemisinin especially low concentration.
• Essential to quantify loss of artemisinin at each
  process stages From harvest to chromatography.
• Reliable analytical protocol for quantitative
  analysis of artemisinin in the leaf, primary
  extract and crystalline phase.
• No information in public domain which trace
  compounds are problematic for derivatization of
  artemisinin.
• Library of reliable standards of most known
  compounds found in A. annua

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IMPACT OF MISSION

• Artemisinin is a future drug of choice.
• Artemisia annua is a plant of future.
• New source of anticancer drug.
• Cultivation increases the rural employment.
• Avoid dependency.
• Environment Friendly
• Consistency in Quality

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THANK YOU
IPCA LABORATORIES LTD. INDIA