Mission Impossible Company Limited

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

2. 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

3. 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

4. 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

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

6. 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

7. 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

8. Ritonavir synthesis + 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 IXcoupling resin compound compound XXXIIIa Ritonavir

9. Purification of Ritonavir + IIchromatography 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) VIIdistillation chromatography resin compound VIII compound XXXIIIa IX Ritonavir

10. Polishing steps of Ritonavir distillation filtration final product dryer formulation crystallization

11. 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

12. Conceptual Design of the Plant

13. Protease Inhibitor Production Plant Reaction 1

14. 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

15. Fixed Cost Analysis

16. Fixed Cost Purification

17. Operating Cost Analysis

18. Operating Cost Breakdown

19. Sensitivity Analysis

20. Sensitivity Analysis Breakdown by Reaction

21. 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

22. 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)

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

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

25. 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

26. Wastewater Treatment Plant

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

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

29. 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

30. 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

31. 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

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

33. Mission Absolutely Possible Company Limited