Enabling Sustainable Pharmaceutical Manufacturing
Through
Novel Technology Solutions
Frank Gupton
Virginia Commonwealth University
September 13, 2013
Effecting Change Can Be a Painful Process
Batch Processing
Early 1900’s Industrial Laboratory
Hood
Distillation/ Round Bottom Flask
No Safety
Glasses
Buchner
Funnel
Suit and Tie?
Erlenmeyer
Flask
Round Bottom
Flask
Balance
Environmental Impact of Pharma Manufacturing
E factor = kg Waste per kg Product
Roger Sheldon / “Green Chemistry in the Pharmaceutical Industry”
Industrial Segment
E factor
Bulk Chemicals
<1-5
Fine Chemicals
5 to 50
Pharmaceutical Chemicals
25 to 100
“The ACS Green Chemistry Institute Pharmaceutical Roundtable has ranked
continuous processing as the highest priority area for future development “
The challenge is to address process sustainability without compromising product quality
4th
Floor
Raw Materials &
Solvents
Reactor
3rd Floor
2nd Floor
Crystallizer
Centrifuge
Solvent &
Byproducts
Solvent
Dryer
1st Floor
Product
Active
Pharmaceutical
Ingredient Plant
Why Batch Operations
Dominate Pharmaceutical Manufacturing
• Regulatory constraints
• Existing capital investments in batch manufacturing
• Limited time to spend on process development
• High comfort level with round bottom flasks
• Limited risk with batch operations
Trends in the Pharmaceutical Industry
• Reduced investments in drug discovery
• Increased focus on generic market
• Meeting current and future market requirements
• Movement towards “personalized medicine”
Trends in Drug Discovery
• Fewer FDA drug approvals
• Higher cost to bring new drugs to the market place
• Existing blockbuster drugs coming off patent
• Prospect of government managed health care
Outcome: Fewer new drugs to enhance quality of life for ageing population
Generic Gold Standards for Health Care
• Antihypertensive
• Cholesterol
• Antibiotics
• Antivirals
• Antiinflamitories
Sartans
Statins
Quinolones
NRTI’s, NNRTI’s, Purine Nucleosides
COX-2 Inhibitors
Other Blockbuster Drugs Moving Off Patent
Plavix (clopidogrel)
Singular (montelukast)
Patented Drug Cost
Components
Active Ingredient
Cost
Other costs +
Profit
Cymbalta (duloxetine)
Advair (fluticasone)
Generic Drug Cost
Componets
Active
Ingredient
Cost
Higher volume requirements are driving API production towards continuous processing
Current Health Care Challenges
• Supply
- Oncology drugs
- Cardivascular drugs
- Parenterals
On demand manufacturing capabilities?
•Quality
- Counterfeit drugs
- Global suppliers (Heparin)
- Batch to batch variability
New analytical capabilities
Continuous manufacturing technology
•Enforcement
- International inspections
Real time access to production data
Disruptive Technologies
Events versus Processes?
10
Batch Versus Continuous Process
Batch Process: Spaghetti Sauce
Continuous Process: Pasta
- Small volume/high value products
- Higher operating cost per kilo output
- Greater flexibility
- Multi-purpose
- Higher capital cost per kilo output
- Greater variability in product quality
-High volume/low value products
- Lower operating cost per kilo output
-Limited flexibility
-Usually dedicated to a limited product number
- Lower capital cost per kilo output
- More consistent product quality
Privileged and Confidential
Interdisciplinary Skills Required to Advance
Continuous Pharma Processing Technology
12
Flow Chemistry Project Team
Brian Marquardt
Mel Koch
Tyler McQuade
Organic Synthesis/ Flow Chemistry
Applied Physics/ Analytical Chemistry
Chemical Engineering/ Catalysis/ Process Development
Gupton Research Group
Streamlining Pharmaceutical Processes
Catalysis
Targets
Flow Chemistry
Cross Coupling
Asymetric Reductions
Carbonylations
Oxidations
Telmisartan
Nevirapine
Artemisinine
Quinolones
Heterogeneous Catalysts
Organic Reactions
Microwave Heating
14
Boundary Conditions for Streamlining
API Processes
• High yield reactions
- catalysis
- convergence
•Compatible reaction conditions
- reagents
- solvents
•Limiting unit operations
- telescope reaction steps
- few isolations
•Commodity–based raw materials
- Less expensive
- Expanded opportunities for new chemical scaffolds
Process Intensification
Reaction Rate
Targets for Process Intensification
Flow reactors provide enhanced
heat and mass transfer which
expands the window of process
operating conditions
Reaction Temperature
Current Operating Limits
Medicines for All: Nevirapine
Now $200/kg
Simple
Inexpensive
A Clinton Funded Effort
Goal <$50/kg
Continuous Synthesis of
Pd/Fe/Graphene Catalyst
CPAC Integrated Analytical Systems
Technology Paradigm Shifts
Telephone Technology
VS
Chemical Manufacturing Technology
VS
Acknowledgements
VCU
Dr. Samy El-Shall
Dr. Ali Siamaki
Alex Martin
Stevara Moses
Dan Fischer
Makaye Tabibi
Hany El Azab
Kendra Woodberry
Mike Burkholder
Elise Lambert
Kyle Sherwood
FSU
Dr. Tyler McQuade
Dr. Suzanne Opalka
Ashley Longstreet