Simulation Design of the
Protease Inhibitor Production
Plant and Pollution Control
Strategies
 By Mr. Kanatip Ratanachoo
Presentation Outline
 Simulation Design of the Plant
Process Synthesis and Analysis
 Environmental Regulation
 Pollution Control System and Waste
Disposal
 Environment Management Strategies

1. Simulation Design of the Plant
 Production Quantity
HIV positive in Thailand ~ 755,000 persons (WHO
estimated, end of 1999)
 Dose : protease inhibitor (Ritronavir): 600 mg twice
daily = 1.2 g/patient/day
 Assumption : Market analysis ~ 300,000 persons
(40%) need Ritronavir
 Production Quantity ~ 131,400 kg/yr

1. Simulation Design of the Plant (con’t)
 Plant Mode of Operation
 Batch Mode
 Operating time = 7,920 h/yr
 Plant batch time = 24 h
 Number of batches per year = 330
 Production Rate = 398 Kg/Batch
1. Simulation Design of the Plant (con’t)
 Design consideration
 Refer to the United State Patent number 5,846,987
: Retroviral Protease inhibiting compounds.
 SuperPro Designer Program Version 3.05
 Limitation and Assumption
- lack of thermodynamic data
- over-engineering
- 90 % conversion of all reaction
- no recycle and waste minimization
- my stupid knowledge in synthesis chemistry
2. Process Synthesis and Analysis

Composed of 9 main reactions, and 8 flowsheet
(2S,3S,5S)-5-(N-(N-((N-Methyl-N-(2-isopropyl-4thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2(N-((5-thiazolyl)methoxycarbonyl)amino) -1,6d i p h e n y l -3- h y d r o x y h e x a n e
Reaction 1
N-(((Benzyl)oxy)carbonyl)-L-phenyllalaninal
 Consists of 4 sub-reactions
Sub-reaction 1
Sub-reaction 2
Sub-reaction 3
Sub-reaction 4
Reaction 2
(2S ,3R ,4R ,5S ) -2,5- B i s - ( N (((Benzyl)oxy)carbonyl)amino) -3,4d i h y d r o x y -1,6- d i p h e n y l h e x a n e
Reaction 3
(2S,3R,4R,5S)-3-Acetoxy-2,5-bis-(N( ( ( B e n z yl ) o x y) c a r b o n yl ) a m i n o) -3b r o m o -1,6- d i p h e n y l h e x a n e
Reaction 4
(2S ,3R ,4R ,5S ) -2,5- B i s - ( N (((benzyl)oxy)carbonyl)amino) -3,4e p o x y -1,6- d i p h e n y l h e x a n e
Reaction 5
(2S ,3S ,5S ) -2,5- B i s - ( N (((benzyl)oxy)carbonyl)-1,6-diphenyl-3h y d r o x y h e x a n e
Reaction 6
(2S,3S,5S)-2,5-Diamino)-1,6-diphenyl-3-hydrohexane
Reaction 7
(4S,6S,1’S)-6-(1-Amino-2-phenylethyl)-4-benzyl 2- p h e n y l -3- a z a -2- b o r a -1- o x a c y c l o h e x a n e
Reaction 8
(2S ,3S ,5S ) -5- A m i n o -2- ( N - ( (5thiazolyl)methoxycarbonyl)amino)-1,6d i p h e n y l -3- h y d r o x y h e x a n e
Reaction 9
(2S,3S,5S)-5-(N-(N-((N-Methyl-N-(2-isopropyl-4thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2(N-((5-thiazolyl)methoxycarbonyl)amino) -1,6d i p h e n y l -3- h y d r o x y h e x a n e
3. Environmental Regulation
 3 Ministry involved in Pollution Control
Ministry of Industry
 Ministry of Science, Technology and Environment
 Ministry of Interior

Environmental Regulation(con’t)
Air
Wastewater
Hazardous/solid Waste
Facility and
operation
Industry
(facility and operation)

Factory Act, B.E.2535
Pharmaceutical Industry :
- Classified in category 46
- Group 3 industry : must
be granted a permit prior to the
engagement
AIR quality
Factory Act, B.E.2535
 Enhancement and conservation of National
Environmental Quality Act, B.E.2535
 Notification of Ministry of Industry, no.2,
B.E.2536 and no.9, 2538
 Notification of Ministry of Interior, Chemical
concentration in working condition, B.E.2520
 Ambient Air Standard, Environmental Board
B.E. 2538

Wastewater
Factory Act, B.E.2535
 Enhancement and conservation of
National Environmental Quality Act,
B.E.2535
 Notification of Ministry of Industry, no.2,
B.E. 2539
 Notification of Ministry of Science,
Technology and Environment, no.3, B.E.
2539

Hazardous/solid waste
Factory Act, B.E.2535
 Enhancement and conservation of National
Environmental Quality Act, B.E.2535
 Notification of Ministry of Industry, no.6, B.E.
2540
 Notification of Ministry of Industry, no.1,
B.E.2541

4. Pollution Control System and
Waste Disposal
 Total waste produced : 46 points (all reactions)
Waste generated from reaction 1 (7 points)
 Liquid Waste : 6 points
 Air emission : 1 point

Liquid Waste
Total flow : 13,701 m3/yr
 Characteristics:
- COD = 1,168,504 kg/yr
- BOD = 124,690 kg/yr
- TKN = 12,360 kg/yr
- TS = 143,637 kg/yr
- TDS = 143,637 kg/yr
- pH = acidic condition
 Treatment Method :
- design of a wastewater treatment plant

Air Emission
Total flow : 60,889 kg/yr
 Characteristics:
- Citric acid = 13,846 kg/yr
- Dimethylsulfide = 41,762 kg/yr
- DMSO = 1,297 kg/yr
- HCl = 3,982 kg/yr (1.45E06 mg/m3, std.
not more than 200 mg/m3)


Treatment Method :
- Design of a incinerator.
Air Emission (con’t)

Design of a Incinerator Unit
Exhaust air to stack :
- CO2 = 104,300 mg/m3
- HCl = 100 mg/m3 (std. 200 mg/m3)
- O2 = 37,900 mg/m3
- SO2 = 1,400 mg/m3 (std. = 3,278 mg/m3)
- water = 84,500 mg/m3
Hazardous/solid waste
Reaction 1 : no
 if produced;

Disposal Method
- non-hazardous waste : local municipal authority.
- hazardous waste : GENCO company.

5. Environmental
Management Strategies
Plant management structure and environmental
unit
 Environmental monitoring and regulatory
report
 Environmental management system (EMS)

Plant management structure and
Environmental unit
Plant Manager
Environmental Division
Pollution control system
supervisor(no.13, 2525)
Administrative Division
Engineering Division
Operation Division
Pollution control
system operators
(no.13, 2525)
Maintenance Division
Purchasing Division
Environmental Monitoring and
regulatory compliance
 AIR quality monitoring
Stack monitoring : every 3 months
 Ambient monitoring : once a month
 Working environmental : twice a year.

Environmental Monitoring and
regulatory compliance (con’t)
 Effluent quality monitoring
Inlet-outlet (treatment system) : twice a month
 Plant outlet : twice a month

 Hazardous waste
monitoring
Recording the type, quantity and disposal
method at the time of waste generated and
dispose.

Regulatory Reporting and
Recording
Department of Industrial works : every 3
months (stack monitoring, inlet-outlet treatment
system, and plant outlet)
 Department of Industrial works : once a year
(hazardous waste data)
 Ministry of Interior : twice a year (chemical
concentration in working environment)
 Keep environmental records for random and
periodical audit at the plant

Environmental Management System
(EMS)
ISO 14001 or
TIS/ISO 14001 :

Environmental
Management
System (EMS)
Conclusion
 Plant
Design
 Simulation Modeling (SuperPro Designer)
- required it before setting-up a plant
- scale-up of plant
- reaction synthesis and analysis
- reactor volume
- functionality
- environmental impact evaluation
- waste treatment system
- economic analysis
Conclusion (con’t)
 Plant Design (con’t)

Limitations
- thermodynamic data of some reagents,
reactions and associated products
- patent and synthesis pathway
- synthesis chemist
- competent in SuperPro Designer
- waste recycle and minimization
- cost-effectiveness analysis
Conclusion (con’t)
 Plant Design (con’t)

Achievement
- establish a bulk scale infrastructure of
protease inhibitor production plant
- establish a process synthesis and analysis
of reaction 1 and waste treatment system
- exploited of computer simulation modeling
- logical scheme for real world situation
Conclusion (con’t)
 Pollution Control strategies
Environmental regulations are the important
issues which the plant have to deal with and
follow
 Plant should be designed at the best standard,
and more stringent to protect the environment
 Pollution control system must be designed,
constructed and installed
 Environmental management have to set-up for
ensuring the environmental performance and
continual improvement

Acknowledgement
Prof. John, Prof. Ram and Dr.Ganesh
 Dr. Maria and Dr. Suvit
 Asso. Prof. Dr. Somsak R.
 Dr. Poolsak S. (laboratory of Medical chemistry,
CRI.)
 Dr. Army
 CRI staffs


“My
beloved girlfriend”
Punishment ??
“ Usually interrupt my work by taking
me to have some delicious meals”
Thank
you very
much for
your
kind
attention