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 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

9. 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

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

11. 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

12. Conceptual Design of the Plant

13. Protease Inhibitor Production Plant
Reaction 1

14. 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: %
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. Change payback time to 6 years Return of investment : 16.67 %
Mission Impossible Objectives
Change payback time to 6 years
Return of investment : %
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, 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 % (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