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Mission Impossible Mission Impossible Company LimitedCompany Limited

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

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

Presentation OutlinePresentation Outline

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Production processProduction 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

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Types of drug designTypes of drug design

- Non hydrolyzable analog of pepti de substrate

- Transition state analogs - Pepstatin protease complex - Two fold symmetrical or pseudos

ymmetrical inhibitor - Structure based inhibitor

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Factors that influence drug Factors that influence drug designdesign

Pharmacokinetics high oral bioavailability low hepatic clearance

Pharmacodynamics Interaction between drugs and HI

V protease enzyme hydrophobic interaction

low toxicity

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HIV Protease HIV Protease enzymeenzyme

One type of aspartic acid enzyme Each monomeric contributes a conserved catalytic triad Protease’ s function exists as a C

2- symmetry homodimer

works as a homodimer that cleaves

gag/pol polypeptide of HIV

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CC22 symmetry development symmetry development

Peptidomimetic Substrate C

2 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

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Ritonavir synthesisRitonavir synthesis + VCl 3 /Zn I I I

- a ami noal dehyde I I diols (white solid)

bromoacetate(whitesol i d)

cyclization hydrolysis I V

hydrolysis reduction

diamine (white solid) VI compound X (white solid) V epoxide(whitesolid)

VI I

acylation VI I I IX coupling resin compound compound XXXIIIa

Ritonavir

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Purification of RitonavirPurification of Ritonavir + II chromatograp

hy - 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

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Polishing steps of RitonavirPolishing steps of Ritonavir

distillation

filtration

final product dryer

formulation

crystallization

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Design consideration

Production quantity ~ 82,763 kg/yr

Batch mode

Operating time = 7,920 h/yr

Plant batch time = 23 h

270Numberof batches peryear=

Production Rate = 307 Kg/Batch

9Composed of major reactions

43SuperPro Designer Version .

Simulation Design of the Simulation Design of the PlantPlant

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P-4 / V-102Batch Distillation

P-8 / DDR-101Drum Drying

waste

S-108Reagent A

Reagent B

S-105S-106

Product

Purification SectionReaction Section

P-3 / UF-101Ultrafiltration

S-110

S-111

S-115

S-116

S-107

S-109S-114

P-6 / MSX-101Mixer-Settler Extraction

P-7 / C-101Gel Filtration

P-1 / MX-101Mixing

P-2 / V-101Vessel Procedure

P-5 / DF-101Diafiltration

Reagent C

S-112

Conceptual Design of the Conceptual Design of the PlantPlant

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P-2 / V-101Vessel Procedure

P-3 / MX-101Mixing

N(((benzyl...

triethylamine

w/re3w/re4

feed for P3

water1

citric

w/re1w/re2

P-4 / OS-101Organic Separation

feed for P4

w/re5

close

oxalyl chloride

P-5 / UF-101Ultrafiltration

P-6 / DDR-101Drum Drying

w/re6

feed for P6w/re7

Feed for P7

feed for P5

DMSO

feed for P-2

P-1 / HX-101Cooling

Protease Inhibitor Production Protease Inhibitor Production PlantPlant

Reaction 1

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Plant Cost AnalysisPlant 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

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Fixed Cost Fixed Cost AnalysisAnalysis

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Fixed Cost PurificationFixed Cost Purification

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Operating Cost AnalysisOperating Cost Analysis

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Operating Cost Operating Cost BreakdownBreakdown

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Sensitivity Sensitivity AnalysisAnalysis

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Sensitivity Analysis Breakdown by Reaction

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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

Plant Cost Analysis Plant Cost Analysis SummarySummary

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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)

Mission Impossible Mission Impossible ObjectivesObjectives

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Pollution Control Pollution Control StrategiesStrategies

Environmental Regulation Authorities

Ministry of Industry Ministry of Science, Technology

and Environment Ministry of Interior Ministry of Public Health

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1992Factory Act,

Pharmaceutical Industry :- 46Classified in category- iiiiiiii i iiii ii iiiiiii3:

i iiiiii iiiii ii iii iiiiiiiiii

Pollution Control Pollution Control StrategiesStrategies

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Total waste produced : 39 points

(all reactions)

14765890Liquid Waste : , , kg/yr : 8 , 9 5 8 ,9 5 4 / i iiii i ii :

Pollution Control Strateg Pollution Control Strategiesies

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P-1 / MX-101

MixingP-2 / AB-101

Aerobic BioOxidation

P-3 / CL-101

Clarification

P-4 / GMF-101

GM Filtration

P-5 / BF-101

Belt Filtration

P-6 / SLDR-101

Sludge Drying

InfluentS-102

P-7 / MX-102

Mixing

S-104

S-105

S-106

S-108

Effluent

S-101

S-111

AEB-Emission

S-113

S-114

Air In

Final Sludge

Air Out

S-107

S-103

Lime

Clrf-Emission

Wastewater Treatment Wastewater Treatment PlantPlant

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Plant Plant locationlocation

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

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Quality controlQuality control

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

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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

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83546 309 270Produce , kg/yr( kg/batch) at batches/yr 7At present market price, we make profit of

0076. % (ROI) iiiii iii ii iiiiiii ii i iii ii 7

324(cost of . $ per patient per day) Sensitivity analysis was performed

Conclusions

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RecommendatiRecommendationsons

Optimization of synthesis pathway Modify the unit operations esp. purificat

ion for achieving desired product with c-ost effectiveness

Identify the realistic thermodynamic data

Scale the plant down in order to optimiz e the actual market demand of Marketin g group

Simulate using Thailand condition and price

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iiiiiii i iiii iiiiiii iii i iiii iiiiiii iiiiii iiiiiiiii iiiiiii iiiiiii Specify the plant location Develop QC chart

RecommendatiRecommendationsons

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Mission Mission Absolutely Absolutely Possible Possible

Company LimitedCompany Limited