Mission Impossible Company Limited Ms.Sathaporn Prutipanlai Ms.Waraporn Parnlob Ms.Wang Don Mei Ms.Siranee Srisai Mr.Kanatip Rathanachoo Ms.Thida Chanyachukul

Presentation Outline Introduction Ritonavir synthesis / Purification Simulation design of production plant Production plant cost analysis Pollution control strategies Plant location and quality control Conclusions and recommendations

Production process Production can be divided into upstream processing the initial fermentation process, which results in the initial generation of product downstream processing the actual purification of the product and generation of finished product format followed by sealing of the final product containers

Types of drug design Non-hydrolyzable analog of peptide substrate Transition-state analogs Pepstatin-protease complex Two-fold symmetrical or pseudosymmetrical inhibitor Structure-based inhibitor

Factors that influence drug design Pharmacokinetics high oral bioavailability low hepatic clearance Pharmacodynamics Interaction between drugs and HIV protease enzyme hydrophobic interaction low toxicity

HIV Protease enzyme One type of aspartic acid enzyme Each monomeric contributes a conserved catalytic triad Protease’s function exists as a C2-symmetry homodimer works as a homodimer that cleaves gag/pol polypeptide of HIV

C2 symmetry development Peptidomimetic Substrate C2 symmetry 1 st Imposition of an axis of symmetry on the peptide functionality in the substrate 2 nd Arbitrary deletion of either the N-terminal or C-terminal 3 rd C2 symmetry operation is applied to the remaining portion to generate a symmetric core unit

Ritonavir synthesis VIII IX coupling + VCl3 /Zn III a-aminoaldehyde II diols (white solid) bromoacetate (white solid) cyclization hydrolysis IV hydrolysis reduction diamine (white solid) VI compound X (white solid) V epoxide (white solid) VII acylation VIII IX coupling resin compound compound XXXIIIa Ritonavir

Purification of Ritonavir + II chromatography a-aminoaldehyde diols (white solid) III bromoacetate (white solid) pricipitation filtration IV chromatography filtration VI V diamine (white solid) compound X (white solid) epoxide (white solid) VII distillation chromatography resin compound VIII compound XXXIIIa IX Ritonavir

Polishing steps of Ritonavir distillation filtration final product dryer formulation crystallization

Number of batches per year = 270 Production Rate = 307 Kg/Batch Simulation Design of the Plant Design consideration Production quantity ~ 82,763 kg/yr Batch mode Operating time = 7,920 h/yr Plant batch time = 23 h Number of batches per year = 270 Production Rate = 307 Kg/Batch Composed of 9 major reactions SuperPro Designer Version 4.3

Conceptual Design of the Plant

Protease Inhibitor Production Plant Reaction 1

Annual Operating Cost : $ 192 M Unit Production Cost : $ 2,301/kg Plant Cost Analysis Total Capital Investment : $ 120 M Annual Operating Cost : $ 192 M Unit Production Cost : $ 2,301/kg ROI at the current market price: 700.76 % Payback Time : 0.14 year

Fixed Cost Analysis

Fixed Cost Purification

Operating Cost Analysis

Operating Cost Breakdown

Sensitivity Analysis

Sensitivity Analysis Breakdown by Reaction

Plant Cost Analysis Summary Reaction 1 has the most expensive operation cost Reaction 3 has the highest fixed cost Optimum production capacity is 309 kg/batch Unit production cost: $2,301/kg or $1.4/pill Current selling price : $11.5/pill or $23/day

Change payback time to 6 years Return of investment : 16.67 % Mission Impossible Objectives Change payback time to 6 years Return of investment : 16.67 % Selling price can be reduced by 7 times Cost $ 3.24 per patient per day (instead of $ 23)

Pollution Control Strategies Environmental Regulation Authorities Ministry of Industry Ministry of Science, Technology and Environment Ministry of Interior Ministry of Public Health

Pollution Control Strategies Factory Act, 1992 Pharmaceutical Industry : - Classified in category 46 - Group 3 industry : must be granted a permit prior to the engagement

Pollution Control Strategies Total waste produced : 39 points (all reactions) Liquid Waste : 14,765,890 kg/yr Air Emission : 8,958,954 kg/yr Solid Waste : no

Wastewater Treatment Plant

Plant location Industrial estate in Eastern Seaboard major structures proper infrastructures privilege in taxation enough labor / cheap wage rate

Quality control Manufacturing process on Quality Raw material In process Finishing product Labels Packaging material

Conclusions Successfully designed a production plant Composed of 9 major reactions Effective and economic purification methods should be employed to get the desired product Environmental strategies have to be set-up Industrial estate in Eastern seaboard is chosen QC for each production step

Conclusions Produce 83,546 kg/yr (309 kg/batch) at 270 batches/yr At present market price, we make profit of 700.76 % (ROI) Selling price can be reduced by 7 times (cost of 3.24 $ per patient per day) Sensitivity analysis was performed

Recommendations Optimization of synthesis pathway Modify the unit operations esp. purification for achieving desired product with cost-effectiveness Identify the realistic thermodynamic data Scale the plant down in order to optimize the actual market demand of Marketing group Simulate using Thailand condition and price

Recommendations Perform waste recycle and minimization Design pollution control systems Specify the plant location Develop QC chart

Mission Absolutely Possible Company Limited