• Save
Final Design Presentation
Upcoming SlideShare
Loading in...5
×
 

Final Design Presentation

on

  • 1,421 views

Final Bachelor of Engineering Design Project: Manufacture of an Active Pharmaceautical Ingredient (Stavudine)

Final Bachelor of Engineering Design Project: Manufacture of an Active Pharmaceautical Ingredient (Stavudine)

Statistics

Views

Total Views
1,421
Views on SlideShare
1,416
Embed Views
5

Actions

Likes
1
Downloads
0
Comments
0

3 Embeds 5

http://www.linkedin.com 3
http://www.slideshare.net 1
https://www.linkedin.com 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Final Design Presentation Final Design Presentation Presentation Transcript

  • Design for the Manufacturing of Stavudine Project Leader: Dr. Mahmoud Mirmehrabi April 29, 2008 Esra Altalibi Narjis Al Saleh Peter Winter Nicholas Kuwahara
  • Introduction
    • Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)
    • 33.2 million people with HIV worldwide
    • 1.16 million people in North America
    • Stavudine dosage: 40 mg per pill, 4$/pill, 2 pills a day for an Adult
    • Design a pharmaceutical plant to meet North American market demand
    • Plant capacity: produce 1700 kg Stavudine/year, or 42.5M pills/year
  • Production Process Overview
  • Overall Synthesis
  • Process Description
    • 9 reaction stages
    • Temperature range: -70 ºC to 141ºC
    • Stage volumes range: 1400 L to 6400 L
    • Stage time ranges: 16 to 35 hours
    • 30 different reagents and solvents, 20 by-products
    • Various stages require extractions, evaporations, filtrations, dehydrations, distillations, dryings, crystallizations
  • Production Process
  • Reactor Size Optimization
    • Three different reactor schemes
      • Single Reactor
        • 4100 gal total reactor volume
        • Requires custom built reactor (max 4000 gal)
        • No downtime in reactor
      • Nine Reactors
        • 3050 gal total reactor volume
        • Batch time = longest stage time
        • 56% reactor idle time
        • Requires 9 receivers, condensers, filters
  • Reactor Size Optimization
      • Three Reactors
        • One 750 gal, two 1000 gal
        • Complex schedule, stage splitting
        • 18% reactor idle time vs 56%
        • 2750 gal total reactor volumes vs 3050 gal
        • Lower capital costs (smaller working volume)
        • More efficient use of resources (less downtime)
  • Overall Plant Layout Tank Farm Office Process Facilities
  • Plant Layout: Process Facilities
    • Temperature Control Unit
    • Synthesis Unit
    • Warehouse
    • Analytical Lab
    • Loading Dock
    • Misc Plant Areas
  • Plant Layout: Synthesis Unit
  • Synthesis Unit: Layout
    • Reactor
    • Identical for the three reactors
    • Receiver
    • Intermediate storage tanks
    • Condenser
    • Scrubbers
    • Buchner funnel
    • Filter dryer
    • Flexible hose scheme
    One of three synthesis rooms
  • Plant Layout: Temperature Control Unit
  • Temperature Control Unit (TCU)
  • Current Good Manufacturing Practices Copyright: Nanotube (Flickr.com)
  • Current Good Manufacturing Practices
    • Focus on starting materials and equipment
      • All chemicals are ≥ 95% purity
      • Unique coding system for tracking batches
      • Airlocks
      • Glass lined reactors, stainless steel piping and equipment used to prevent corrosion
      • Clean rooms equipped with:
        • H.E.P.A Filters <10000 particles/m 3
        • Humidity Control 35-40%
  • Product Purity
    • Multiple separation steps used each stage
    • Crystallization is primary purification method
    • Analytical lab to run tests
    • Impurities recorded, identified and qualified
    • Recrystallize if purity insufficient
  • Safety Safety, it’s what matters most
  • Safety: Synthesis Unit
    • Blast walls
    • Fire doors
    • Chemical foam sprinkler system
    • Fire resistant materials of construction
    • Separate drainage for different reactors
    • Adequate ventilation
    • Backup generators
    Safety, it’s what matters most
  • Safety: Storage and Transfer
    • Tank farm used for large quantities of liquids
      • Pipelines used for transfer
    • Warehouse used for small quantities solids/liquids
      • Manual transfer
    Safety, it’s what matters most
  • Plant Layout: Storage Tank Farm Warehouse
  • Tank Farm Safety, it’s what matters most
  • Warehouse Safety, it’s what matters most
  • Environmental Considerations Keeping the future in mind Cobalt123 (Flickr.com)
  • Waste Disposal
    • Organic: 4 classes 550,000 kg/year
    • Aqueous: 2 classes 7,700,000 kg/year
    • Solids: 3 classes 80,000 kg/year
    • Gaseous: 3 classes 11,000 kg/year
    • Removal Methods:
      • Tanker Truck, Barrels, Scrubbers
    • Incineration/Water Treatment
    • Annual cost: ~ $1 million / year
    Keeping the future in mind
  • Recycle
    • Recycle during evaporation step
      • Solvent has lowest BP
      • No azeotrope
    • Total Recycle: 650,000 kg/year
      • Savings in Solvent Costs: $ 3,000,000/year
      • Savings is Waste Removal: $ 90,000/year
      • CO 2 Emissions Reductions: 1,300 tons CO 2 /year
    Keeping the future in mind
  • Economic Analysis
  • Economic Analysis
    • 20 Year Lifetime
    • Initial Investment $62.3 million
    • Annual Op. Costs $24.0 million
    • Annual Profit ($2.00/pill) $60.2 million
    • IRR (After Tax) 49.3%
    • PP (After Tax) 2.1 years
  • Economic Analysis
    • To have IRR of 20%
    • Minimum sales price $1.17/pill
    • Potential to increase production by 10%
    • Annual Profits ($2.00/pill) $67.5 million
    • IRR (After Tax) 53.1%
  • Conclusions
  • Conclusions
    • Three reactor scheme
      • Versatile
      • Efficient (heat transfer area, downtime)
      • Cost effective
    • Recycling
      • Reduce solvent cost $ 3 million/year
      • Reduce waste disposal cost $ 90,000/year
      • Reduced CO 2 emissions 1,300 tons/year
  • Conclusions
    • Designed to minimize chemical releases to environment
      • Scrubbers
      • Professional waste disposal
      • Drainage system
    • Area specific safety features
      • Backup generators
      • Compound-specific storage conditions
  • Conclusions
    • Plant very profitable at $2.00/pill
      • Annual profits $60.2 million
      • IRR 49.3%
    • $1.17/pill to achieve IRR 20%
    • Potential to increase production by 10%
      • Annual profits $67.5 million
  • Acknowledgements
    • Dr. Mahmoud Mirmehrabi
    • Professor Maric
    • Questions?
    • Human Immunodeficiency Virus (HIV)
      • Infects CD4 + T cells, macrophages and microglial cells
      • Transmitted by sexual contact, contaminated blood contact or mother-to-child
    • Acquired Immunodeficiency Syndrome (AIDS)
      • Occurs when too many immune system cells have been infected or killed
      • Body can no longer fight off diseases and cancers
    • World Outlook
      • End of 2006, 39.5 million people infected worldwide
    • North America
      • Approximately 1.4 million infected
      • 43,000 new infections per year, 18,000 deaths per year
    Backup Slide: Background on HIV/AIDS
    • Currently no cure
    • Highly Active Antiretroviral Treatment
      • Involves combination of drugs
      • Generally consists of:
        • Two nucleoside analog reverse transcriptase inhibitors (NARTI)
        • One protease inhibitor or non-nucleoside analog reverse transcriptase inhibitor
    • Stavudine
      • Nucleoside analog reverse transcriptase inhibitor
      • Prevents viral DNA replication
      • Not effective in people with AIDS
      • Bristol-Myers patent expires in 2008
    Backup Slide: Background on Current Treatments
    • Stavudine Demand
      • 1.16 million people in North America with HIV but not AIDS
      • 2006 US Zerit (Stavudine) sales: $155 million
      • 1550 kg
      • Based on recommended dosage, ~53,100 patients using Stavudine
    • Large potential market for a cheaper, generic Stavudine
    • Plant production: 1550 kg + 10%
    • Designing for 1700 kg/year
    • 42.5 million tablets
    Backup Slide: Market Analysis
  • Backup Slide: Block Flow Diagram
  • Esra Altalibi
  • Backup Slide: Overview of Stavudine Production
    • Focus of project w ill be the General Guidelines for material and equipment standards in North America, regulated by FDA
    • Airlock doors
    • 40% relative humidity be maintained
      • sparks and prevent static charge accumulation prevents
      • microbial growth
    Backup Slide: Current Good Manufacturing Practices
    • Filtered air supply
    • Positive pressure in clean area
    • Batch records
      • Equipment Number, etc .
    Backup Slide: cGMP
    • Microbiological contamination of starting materials should be minimal.
    • Non-combustible gases should be passed through micro-organism retentive filters.
      • Nitrogen
    • Use solvent for cleaning
      • Analyze sample solvent after rinse to determine if clean
    Backup Slide: cGMP
    • Final product must be ≥98% pure
    • Impurities:
      • Organic Impurities
      • Inorganic Impurities
      • Residual Solvents
    • Specific impurity is
      • Recorded at 0.05 wt.%
      • Identified at 0.10 wt.%
      • Qualified at 0.15 wt.%
    Backup Slide: Drug Purity
    • Class 1 Solvents
      • Known human carcinogens and environmental hazards
      • Should be replaced where feasible
      • Ex. Benzene (2ppm limit)
    • Class 2 Solvents
      • Non-genomic animal carcinogens, other irreversible toxicity, and serious but reversible effects.
      • Ex. Methanol (300 ppm limit), Toluene (890 ppm limit)
    • Class 3 Solvents
      • Least toxic
      • Permitted daily exposure ≥ 50mg
      • Ex. Acetic Acid, Ethyl acetate
    Backup Slide: Drug Purity Residual Solvents
  • Backup Slide: Chemical Safety
    • Design Concerns
      • Several Reagents are dangerous to handle
        • Strong acids, Corrosive compounds, Strong oxidizers
      • Process must be designed so that workers have little to no contact with some reagents
      • Appropriate materials of construction must be used for process
      • Amount of dangerous compounds must be minimized on site
    • Design Concerns
      • Diethyl ether represents an extreme fire hazard
        • Low flashpoint, high vapour pressure
        • A replacement solvent must be determined
      • All of solvents have flashpoints at or below room temperature
        • Safe storage and use is a priority
      • Several reagents react strongly with water
        • Alternate fire extinguishing methods must be used when these reagents are present
    Backup Slide: Fire Hazards
  • Backup Slide: Reaction By-Products Compound Stage N2 1 NaCl 1 H2O 1, 2 Na+[BH2(OCH2CH3)2]-   3 Pyridinium chloride   4 Isobutane 5 Al(OH)4K 5 Sodium Tartrate 5 SO2 6 Compound Stage HCl 6 KCl 6 Tert-butanol   6 C4H4O2N+ 7 TMS-O-TMS 7 NH3 7 Na+ 7 CO2 7 C4H10O 8 KI 8 CH3OCOC(CH3)3 9
  • Backup Slide: Reactor Scheme Calculations
    • Single Reactor:
      • Total vol/batch = Annual vol/40 batches/year
      • Reactor goes from 1 stage to the other, no downtime
    • Nine Reactors:
      • Each reactor volume was determined based on the stage’s maximum volume, these were rounded up to the nearest reactor size available
      • Downtime = sum of all stages (35.25 – stage time) * 240 batches
  •  
  • Backup: Recycle Process
  • Backup Slide: Breakdown of Costs
    • CAPEX
      • Direct Costs $37.1 million
        • Equip. (not delivered) $9.7 million
      • Indirect Costs $15.9 million
      • Working Capital $9.4 million
    • $62.3 million
  • Backup Slide: Breakdown of Costs
    • OPEX
      • Variable Costs $19.9 million
        • Raw Materials $7.2 million
        • Waste Disposal $1.0 million
        • Milling, Packaging, etc $7.2 million
      • Fixed Costs $1.1 million
      • General $2.6 million
      • Contingencies $0.5 million
    • $24.1 million
  • Backup Slide: Feasibility Calculations
    • Corporate Tax Rate: 50%
    • Annual Inflation Rate: 3%
    • Plant Life: 20 years
    • Declining-Balance Depreciation Rate: 20%
    • Salvage Value (Equipment and Land): $1 million
    • $0.57 to produce 1 pill
    • Designing for annual production of 1700 kg
    • Batch Process, approximately 9 days
    • Alternative chemicals must be determined
      • Diethyl ether
    • Appropriate methods for scale up
      • Chromatography
    • Equipment Sizing/Layout
    • Alternative Process Investigation
    • Economic feasibility studies
    Backup Slide: Summary