ED 19.98L: BIOENGINEERING and ENVIRONMENTAL HEALTH : Production Group

KANATIP RATANACHOO

ED 19.98L: BIOENGINEERING AND ENVIRONMENTAL HEALTH : Production Group

SIMULATION DESIGN OF PROTEASE INHIBITOR PRODUCTION PLANT

and

POLLUTION CONTROL STRATEGIES

Final Report

Kanatip Ratanachoo

July 19, 2000

TABLE OF CONTENTS

Cover Page……….…………………………………………………………………………………..…….1

Table of Contents…………………………………………………………………..………………………2

Introduction………………………………………………………………………………………….3
Rational
Scope of Production Group
Specific Aims

Simulation design considerations…………………………………………………………………..4
Production Quantity
Plant Mode of Operation
Synthesis Process Simulation

Process Synthesis and Analysis………………………………………………………..…..……5-12
General Process Synthesis of Protease Inhibitor..
Process Analysis of the Plant
Plant Operation
Simulation Results
Economical Analysis
Sensitivity Analysis

4.Environmental Regulation……………………………………………………………….……12-13

4.1 Facility and Operation

4.2 Air Quality

4.3 Wastewater Discharge

4.4 Hazardous/Solid Waste Control

Pollution Control System and Waste Disposal……….……………………………………...13-14
Wastewater
Air Emission
Hazardous/Solid Wastes

Environmental Management Strategies….…………………...……………………………..14-18
Plant Management Structure and Environmental Unit
Environmental Monitoring and Regulatory Compliance
Environmental Management System (EMS)

Conclusion and Recommendation……………………………….…………….…………….19-20

References…………………………………………..………..…………………………….……..21

Appendix………………………………………………..…….…………………………………..22

-Appendix-A : Flow Sheet Overview of Reaction 1-9

-Appendix-B : Executive Summary Report

-Appendix-C : Environmental Impact Report

1. INTRODUCTION

1.1Rational

AIDS stands for Acquired Immune Deficiency Syndrome: Acquired means you can catch it; Immune Deficiency means a weakness in the body's system that fights diseases. Syndrome means a group of health problems that make up a disease. AIDS is caused by a virus called HIV: Human Immunodeficiency Virus. People become exposed to HIV mainly by unsafe sex with HIV positive persons of either sex, sharing contaminated needles during recreational drug use, or by transfusions with virally contaminated blood.

Regarding to “The global HIV/AIDS epidemic report”, UNAIDS-WHO, estimated 755,000 people of Thailand were positive, and 66,000 death at the end of 1999. Treatment of HIV/AIDS become an important issues in order to inhibit or slow spread of the virus and thus extend the lives of people with AIDS.

A new class of drug aimed at stopping HIV by inhibiting its protease enzyme came on the market on December 1995- Hoffmann-La Roche’s saquinavir, and now including Ritonavir (Abbott) and Indinavir (Merck). Each inhibitor will cost the patient about $6,000-8,000 per year, therefore, it may create a dramatic problem with groups of developing country, like Thailand. Can we make protease inhibitors cheap enough to make this therapy feasible in the East? Can we reduce the transportation cost, production cost and so on, by locating a production plant in the East, such as Thailand ?.

1.2Scope of Production Group

We made an assumption that Marketing Division performed a marketing analysis have concluded it is feasible to establish a production plant in Thailand. The production group will design a protease inhibitor production plant in order to produce sufficient amounts of protease inhibitors for the treatment HIV infection in Thailand. Inhibitor chosen is Ritonavir.

Production group has divided its tasks into 7 sub-workgroups: chemical synthesis, production plant design, plant location and quality control, purification process, pollution control, wastewater treatment system design, and cost analysis.

1.3 Specific aims

To design and perform a simulation of the proposed production plant using SuperPro Designer, establish a bulk scale infrastructure of protease inhibitor production plant, conduct process synthesis and analysis, and develop pollution control system and environmental management strategies.

2. SIMULATION DESIGN CONSIDERATIONS

2.1 Production Quantity

As I stated above the estimated HIV positive cases in Thailand is around 755,000 at the end of 1999. Therefore, an assumption of 25% of positive cases (188,750 people) needed protease inhibitor drug was made. If we just considered on Ritonavir drug with a standard dose of approximately 600 mg twice daily or 1.2 g per patient per day. This means the protease inhibitor production plant must be capable of generating ~ 82,763 kg of protease inhibitor per year.

2.2 Plant Mode of Operation

In designing protease inhibitor production plant, the production team have concluded to operate in batch mode because the production is by chemical synthesis. The plant consists of an initially designed operating time of 7,920 h/yr, plant batch time 24 h, and number of batches per year of 330. This translates to producing protease inhibitor drug with production rate approximately 251 kg/batch.

2.3 Process Simulation Assumptions

The United States Patent number 5,846,987: Retroviral Protease Inhibiting Compounds, which currently owned by Abbott Laboratories have been used for the design principles and approach to modeling of the production plant. Also, SuperPro Designer (Intelligen, Inc.) have been used for a chemical process simulation.

However, modeling is a unique tool used in process design, but both its limitations and advantages must be well understood. For data on conversion and thermodynamic parameters that were not available, we made educated assumption based on reports of similar reactions. We assumed a conversion of 90% from reactant to products for most reactions and also did not explicity include potential side reactions. We have also over-engineered both in term of amount of reagents, unit operation performance, and vessel volume.

3. PROCESS SYNTHESIS AND ANALYSIS

3.1 General Process Synthesis of Protease Inhibitor

Refer to the patent, the synthesis process can be summarized into 9 primary reactions which are modularized into 7 flow sheets, and then integrating all flow sheets together to determine the total amount of starting material required to produce the final amount of product. Table 1 summarizes all reactions used in designing the production plant, and all flow sheets are summarized in Appendix-A.

Reaction Number / Reagents / Products / Flow Sheet Number
1 / Dimethyl sulfoxide, Dichlomethane, Oxalyl chloride, N-(((benzyl)oxy)-carbonyl)-L-phenylalaininol, Citric acid / N-(((Benzyl)oxy)carbonyl)-L-phenylalaninal (Product 1) / 1
2 / Product 1, VCl3, Zinc, Dichloromethane, HCl, chloroform, Acetone, Sulfuric acid / (2S,3R,4R,5S)-2,5-Bis-(N-(((benzyl)oxy)carbonyl)amino)3,4-dihydroxy-1,6-diphenylhexane (Product 2) / 2
3 & 4 / Product2, Dichloromethane, Hexane, -acetoxyisobutyryl bromide, Sodium bicarbonate
Product3, Dioxane, Sodium hydroxide / (2S,3R,4S,5S)-3-Actoxy-2,5-bis-(N(((benzyl)oxy)carbonyl)amino)-3-bromo-1,6-diphenylhexane (Product 3)
(2S,3R,4R,5S)-2,5-Bis-(N(((benzyl)oxy)carbonylamino)-3,4-epoxy-1,6-diphenylhexane (Product 4) / 3
5 / Product4, Tetrahydrofuran, Sodium borohydride, Trifluoroacetic acid / (2S,3S,5S)-2,5-Bis-(N(((benzyl)oxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (Product 5) / 4
6 / Product5, Barium hydroxide octahydrate, 1,4-dioxane, chloroform, methanol / (2S,3S,5S)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane (Product 6) / 5
7 & 8 / Product6, Toluene, phenylboric acid / (4S,6S,1’S)-6-(1-Amino-2-phenylethyl)-4-benzyl-2-phenyl-3-aza-2-bora-1-oxacyclohexane (Product 7) / 6
Product7, Tetrahydrofuran, ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonyl)carbonate, ethyl acetate, Sodium hydroxide / (2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,-diphenyl-3-hydroxyhexane (Product 8)
9 / Product8, N-((N-methyl-N-(2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 1-hydroxybenzotriazole hydrate, N-ethyl-N’-dimethylaminopropyl carbodiimide / (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarnyl)amino)-1,6-diphenyl-3-hydroxyhexane (Final Product) / 7

Table 1 :Reaction Schemes Modeled in the protease inhibitor production

3.1.1 Flow Sheet 1 – Reaction 1

The goal of reaction 1 is to synthesis - aminoaldehyde. Initially, dimethyl sulfoxide was cooled to –60 C, and then treated over a period of 15 min with oxalyl chloride in P-2, and then mixed solution was stirred for 15 min. Intermediate 1 was treated over a period of 20 min with a solution of N-(((benzyl)oxy)-carbonyl)-L-phenyllalaninol, and stirred for 1 h. Intermediate 2, then treated over a period of 15 min with triethylamine and stirred for 15 min. A solution of citric acid was also treated in P-2, and stirred vigorously for 10 min, diluted with water, and separated by P-4. The organic layer was passed the filtration (P-5) and dry on P-6.

3.1.2 Flow Sheet 2 – Reaction 2

The goal of reaction 2 is to produce the diol. The mixture of VCl3 and zinc dust were added into a mixture of reactant 1 and dichloromethane, and the results mixture was stirred in P-8. The resulting mixture was added to HCl, diluted with hot chloroform, and stirred vigorously for 2 min. The layers were separated, and then mixed with acetone in P-10. The results mixture was filtered, and dried on P-12 to provide the desired compound of product 2.

3.1.3 Flow Sheet 3 – Reaction 3 & 4

The goal of reaction 3 is to produce the bromoacetate. The product 2 was mixed with dichlomethane and hexane in P-13. The resulting mixture was treated with -acetoxyisobutyryl bromide, and stirred at ambient temperature until reaction clarified, washed with saturated aqueous sodium bicarbonate, and then purified by gel chromatography (P15) and dried on P-16 to produce product 3.

The goal of reaction 4 is to hydrolyse the product 3 in order to produce epoxide. It started by mixing product 3 with dioxane and treated with sodium hydroxide, and stirred for 16 h in P-17. The resulting mixture was filtered and dried on P-19 to provide product 4.

3.1.4 Flow Sheet 4 – Reaction 5

Product 4 from flow sheet 3 was mixed in tetrahydrofuran, and treated with sodium borohydride in P-20. The resulting mixture was treated with trifluoroacetic acid, and stirred for 3.5 h at ambient temperature. Then the resulting mixture was filtered, and finally dried on P-22 to produce the product 5.

3.1.5 Flow Sheet 5 – Reaction 6

The main objective of flow sheet 5 is to produce diamine compound. The product 5 was mixed with barium hydroxide octahydrate and 1,4,-dioxanend in P-23. Then resulting mixture was heated for 4 h. The mixture was cooled by P-24 and then extracted with chloroform in P-25. The organic layer was purified by gel chromatography, and then dried on P-27, giving product 6.

3.1.6 Flow Sheet 6 – Reaction 7 & 8

The product 6 was mixed with toluene, then treated with phenylboric acid in P-28. The resulting solution was heated at reflux in P-29, then allowed distillate to cool by P-30. The resulting mixture was filtered by P-31, and dried on P-32 to provide product 7.

Reaction 8, outlined on flow sheet 6, included the mixing of product 7 with tetrahydrofuran, then the solution was cooled to –40 C in P-33. Then the resulting mixture was treated with ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate for 1 h. The resulting solution was allowed to warm, then the solvent was removed by distillation in P-34, and the residual was purified by gel chromatography (P-35), and dried on P-36, to produce product 8.

3.1.8 Flow Sheet 7 –Reaction 9

The final flow sheet, included the mixture of product 8 with N-((N-methyl-N-(2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 1-hydroxybenzo- triazole hydrate, and N-ethyl-N’-dimethylaminopropyl carbodimide was stirred in P-37. The resulting solution was concentrated in P-38, then residual was crystallized on P-39, and dried on P-40 to provide the final product which keeping in product storage P-41.

3.1.9 Process Flow Diagram

All process flow diagrams of each reaction are illustrated in Appendix-A.

3.2 Process Analysis of the Plant

Conclusion of process analysis which are drawn from simulation are shown in appendix-B, and summarized below. Please note that there are two separate summary posts in Appendix-B due to a limitation of the simulation program in handling more than certain number of steps. Hence, reactions number 1 until 5 were created in one flow sheet and the remaining reactions (6-9) were developed as a separate flow sheet. We have combined the two data and generated one final result as follows.

3.2.1 Plant Operation

As I stated in section 2.2 : plant mode of operation that we would like to operate in the batch system which consists of an initially designed operating time of 7,920 h/yr, plant batch time 24 h, and number of batches per year of 330. However, this condition was not a realistic because we have to operate all days and nights, no holidays, weekends, and must have at least two shifts of workers. Therefore, we reviewed and revised plant operation condition to 7,920 h/yr, plant batch time 23 h, and 270 batches per year. This means the production rate should be 307 kg/batch.

3.2.2 Simulation Results

We can concluded simulation results as below;

Annual Operating Time : 7920 h
Plant Batch Time : 22.08 h
Number of Batches Per Year : 270
Total amount of protease inhibitor produced per batch : 309.43 kg/batch
Total amount of protease inhibitor produced in one year at full capacity : 83,546 kg.

Therefore, we have successfully designed a production plant to produce protease inhibitor drug which can be capable an amount required by our marketing assumption (82,763 kg/yr). However, we need to scale the plant down in order to optimize the later marketing analysis of Marketing Division which concluded only 10% of positives cases (75,500 people) needed this drug, this indicated the plant should be designed to produce 33,069 kg of drug per year.

3.2.3 Economical Analysis

Economical analysis of this plant can be calculated and summarized in Table 2 below;

Conditions
Items / Current Condition / If set 6 Years of Payback Time
Total Capital Investment ($) / 120,649,000 / 120,649,000
Operating Cost ($) / 192,202,000 / 192,202,000
Total Cost ($) / 312,851,000 / 312,851,000
Production Rate (kg/yr) / 83,546 / 83,546
Unit Production Cost ($/kg) / 2,301 / 2,301
Total Revenues ($/yr) / 1,601,298,612 / 225,715,611
Gross Profit ($/yr) / 1,409,096,612 / 33,513,611
Gross Margin (%) / 88 / 14.85
Taxes (40%) / 563,638,645 / 13,405,445
Net Profit ($/yr) / 845,457,967 / 20,108,167
Return of Investment (%) / 700.76 / 16.67
Payback Time (yr) / 0.14 / 6
Selling Price ($/kg) / 19,167 / 2701.69
Payment per patient per day ($) / 23 / 3.24

Table 2 : Economical Analysis of the Plant

This table illustrated the economic data by comparison between our current conditions such as current price of this drug, economic analysis from plant simulation etc, with a condition derived from 6 years payback time. As current conditions, we will get a very high gross margin, net profit, return of investment, but very short payback time. However, if we consider drug selling price which cost 23 $ (920 Baht) per patient per day, it quite high, therefore the marginal willingness to pay of Thai people would be low. This means Thai people might not be able to buy this drug and then market will fail, also our rational in section 1.1 try to make protease inhibitor cheaply enough to make this therapy feasible in the East. Therefore, if we increase payback time to that of more conventional to this industry sector to between 6 and 10 years, as in this case we supposed 6 years, we still have 14.85 % gross margin, 16.67 % return of investment, and then we can reduce the selling price to 2701.69 $ per kg. It will cost to patient around 3.24 $ (130 Baht) per day, almost 7 times reduction. Even 3.24 $ still seem to be high for poor people but overall I think it reasonable and we can meet our rational question.

3.2.4 Sensitivity Analysis

The effect of different assumptions was investigated by systematically varying and seeing how the plant is influenced.
The throughput of plant was investigated.
The results of sensitivity analysis are described in the following report.

4. ENVIRONMENTAL REGULATIONS

Environmental regulations which relevant to our production plant should be a top priority when building the plant. The types of regulations presented in this paper are taken from three major authority which are responsible for pollution control in Thailand, i.e., Ministry of Industry, Ministry of Science, Technology and Environment, and Ministry of Interior. Generally, environmental regulations can be divided into 4 groups : facility and operation, air quality, wastewater discharge, and hazardous waste control which I would briefly focus in each group as below sections.

4.1 Facility and Operation

Factory Act, B.E.2535 issued by Ministry of Industry have fixed the factory of any type, kind or size to be the group 1 factory, group 2 factory, or group 3 factory which taken into consideration the necessity for the control. In case of pharmaceutical industries are classified in industrial category 46, group 3 factory which must be granted a permit prior to the engagement. Normally, issuing a permit is valid for three years, and then a recipient must apply for renewal of a permit for operating its facility.

4.2 Air Quality

Under the Factory Act, B.E.2535 and the Enhancement and Conservation of National Environmental Quality Act, B.E.2535 have regulated industrial air quality control such as “the owner or possessor of the point source of pollution has the duty to install or bring into operation an on-site facility for air pollution control in order to control, dispose, reduce or eliminate pollutants which may be affect the air quality”. These two regulations are followed to be in practice by developing the Notification of Ministry of Industry, no.2, B.E.2536, and no.9, B.E. 2538 which control over the stack emissions such as sulfur dioxide not more than 1,250 ppm, hydrogen chloride not more than 200 mg/Nm3 etc. Ministry of Interior also issued their notification on industrial working condition, B.E.2520 to control chemical concentration in the workplace especially air concentration. Additionally, the Environmental Board have defined ambient air standards, B.E.2538. In the meantime, our plant must comply with all the proposed requirements.

4.3 Wastewater Discharge

Factory Act, B.E.2535, and Enhancement and Conservation of National Environmental Quality Act, B.E.2535 also addresses the issue of wastewater disposal. The owner or possessor of the point source of pollution has the duty either construct, install or bring into operation an on-site facility for wastewater treatment or treated by the central wastewater treatment plant in order to have properties which meet the requirements of the effluent standards. The Notification of Ministry of Industry, no.2, B.E.2539, and Notification of Ministry of Science, Technology and Environment, No.3, B.E.2539 have specified the effluent standards before discharging into public water sources such as COD not more than 120 mg/l, BOD5 not more than 20 (or upto 60 (max)) mg/l etc.

4.4 Hazardous/Solid Waste Control

Any hazardous and solid in the waste streams must be handled in accordance with the Factory Act, B.E.2535, and Enhancement and Conservation of National Environmental Act, B.E.2535. And then specified in practice by the Notification of Ministry of Industry, no.6, B.E.2540, and no.1, B.E.2541 which defined the lists, characteristics, and properties of hazardous or non-hazardous wastes, methods for storage, detoxification, transportation, treatment and disposal of wastes.

5. Pollution Control System and Waste Disposal

We also created the environmental impact report which illustrated in Appendix-C, and summarized in below sections.

5.1 Wastewater

The plant generated aqueous waste with total flowrate : 14,765,899 kg/yr, and its important characteristics shown below;

COD : 19,113,442 kg/yr
BOD5 : 9,680,182 kg/yr
TKN : 36,700kg/yr
TS : 1,800,714 kg/yr
TDS : 1,800,714 kg/yr
pH : acidic condition

We can’t discharge these wastewater directly to public sewers or receiving water due to its contain high organic loading, if we do so, we would not comply with environmental regulations, and then governmental authorities will come and shut the plant down. Hence, we have to design a wastewater treatment plant which can be capable treated these waste and produced final effluent in accordance with the discharge standards.

5.2 Air Emission

Can we directly discharge these air pollutants to atmosphere?. If we consider the Notification of Ministry of Industry, no.2, B.E.2536, we can answer this question. Hydrogen chloride and chlorine have been controlled under this regulation. However, even only two air pollutants are controlled by this law but we still have solvents, acids and flammable gaseous discharged for processing plant which might be created the problems to the plant, workers, neighbours and environment. Hence, air pollution control system must be designed, constructed and installed. Next question is that what the suitable type of air pollution control system should be in place? we have to consider various factors which may be affect our treatment, such as dimethylsulfide, it is a flammable gas and very dangerous. We should design incinerator in stead of other air treatment system, like wet scrubber.