Wang Dongmei
WASTEWATER TREATMENT FOR RITONAVIR PRODUCTION
PLANT
A Final Report of
MIT/CRI/AIT joint course
Bioengineering and Environmental Health
by
Wang Dongmei
Urban Environmental Engineering and Management Program
School of Environment, Resources and Development
Asian Institute of Technology
July 2000
1
Wang Dongmei
INTRODUCTION
As reported by Modern Drug Discovery (1999), the acquired immunodeficiency
syndrome (AIDS) is among the top 15 killers worldwide. The Joint United Nations
Program on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate
that at the end of 1999, 34.3 million people were infected with HIV, and that 18.8 million
people around the world had already died from the disease. Among the number of
infected, 6.1 million were in Asian countries. India is at the top in Asian countries, which
is approximately 3.8 million, followed by Thailand, Myanmar, and Cambodia.
Surveillances show that demand of AIDS drugs in Asian countries is potentially high. At
the time being, the accessibility of AIDS drugs in most Asian developing countries is
quite low. Therefore, the Production group is taking the responsibility to design AIDS
drugs using engineering methodology in order to provide enough amounts of drugs, and
reduce the cost as well.
The overall research work of the Production group intends to design an industrial plant in
Thailand to produce the amount of AIDS drugs such as protease inhibitor, vaccine and
IL-2. After a thorough surveillance of the number of people who are HIV infected and
availability of AIDS drugs in Asian countries by the Marketing group, the Production
group made a decision to produce ritonavir, which is a kind of protease inhibitor and has
been found the most effective currently.
According to the Factories Act B.E. 2535 (1992) of Thailand, more stringent standards
and criteria have been established by pollution control department to control the factory
operations, specially the standards and methods to control the disposal of waste, pollution
or any contaminants caused from factory operation that impact the environment. As the
notification of the Pollution Control Committee, B.E. 2539 (1996), industrial effluent
standards are 20 ~ 60 mg/l for biochemical oxygen demand (BOD), and 120 mg/l for
chemical oxygen demand (COD), respectively. The penalty for illegally discharges of
untreated wastewaters is to pay as a daily penalty four times as much the amount of daily
expenses for the normal operation of facilities. Any owner or possessor who violates or
refuses to comply with such order of the pollution control officials shall be punished by
imprisonment not exceeding one year or fine not exceeding one hundred thousand Baht,
or both. Therefore, it is indispensable for the pharmaceutical manufacturers to run
production without creating significant damage to the environment. As a consequence, it
is necessary to properly deal with the large amount of wastewater generated from the
production process so that the effluent could comply with the relevant regulations and
will not create serious problems for the receiving water body.
This case study presented here is to design the wastewater treatment for a ritonavir
production plant. The research goal is aimed at ensuring environmental compliance,
especially the waste streams generated from the synthesis process during drug
production, while other issues like air emission, hazardous waste and odor emission, etc.,
will be discussed by the other member of the production group. The powerful computer
simulation, named Superpro Designer is highlighted in this case study, since it is loaded
2
Wang Dongmei
with powerful features for modeling and optimizating water purification and wastewater
treatment processes.
In designing the WTP, several principles were considered: (1) engineering of costeffective and environmentally-conscious processes, (2) optimization in terms of
equipment and reagents, (3) maximizing treatment system removal efficiency, (5)
understanding the limitations and advantages of computer simulation.
WASTEWATER SOURCES OF GENERAL PHARMACEUTICALS
The pharmaceuticals category encompasses the manufacture of biological products,
medicinal chemicals, botanical products and pharmaceutical products. The industry is
characterized by diversity of product, process, plant size, and process stream complexity.
One of the most important generalizations, which can be made about the wastewater,
produced and discharged by the pharmaceutical industry, is their extreme diversity.
Products, processes and the materials to which wastewater is exposed vary greatly. The
broad manufacturing processing areas generally are: chemical synthesis, biological and
natural extraction, fermentation, and formulation. Among these processes, the
formulating is the most prevalent pharmaceutical manufacturing operation, with 80
percent of the plants in the industry engaged in this activity.
Chemical Synthesis
Wastewater from chemical synthesis is generally high in BOD, COD, and TSS with a pH
range of 1-11 units. Most of the drugs today are prepared by chemical synthesis. The
basic major equipment item is the conventional batch reaction vessel. It is made of either
stainless steel or glass-lined carbon-steel and contains a carbon-steel outer shell suitable
for either cooling water or steam. The basic vessels may be fitted with many different
attachments. Baffles usually contain temperature sensors to measure the temperature of
the reactor contents. Dip tubes are available to introduce reagents into the vessels below
the liquid surface. Typically, batch reactors are installed with only the top heads
extending above the operating floor of the plant in order to provide the operator with easy
access for loading and cleaning. Solution can be mixed, boiled, and chilled in them. By
addition of reflux condensation, complete reflux operations are possible. By application
of a vacuum, the vessels become vacuum evaporators. Solvent extraction operations can
be conducted in them, and, by operating the agitator at slow speed, they serve as
crystallizers.
Synthetic pharmaceutical manufacture consists of using one or more of these vessels to
perform in a step-by-step fashion the various operations necessary to make the product.
Following a definite recipe, the operator or a programmed computer adds reagents;
increase or decrease the flow rate of cooling water, chilled water, or steam; and starts and
stops pumps to transfer the reactor contents into another similar vessel. At appropriate
steps in the process, solutions are pumped through filters or centrifuges or are pumped
into solvent recovery headers or waste sewers.
3
Wang Dongmei
The synthetic pharmaceuticals industry uses a wide variety of priority pollutants as
reaction and purification solvents. However, benzene and toluene are the most widely
used organic solvents since they are stable compounds that do not easily take part in
chemical reactions. Similar ring-type compounds (xylene, cyclohexane, pyridine, etc.)
also are reported as being used in the manufacture of synthesized pharmaceuticals or
resulting from unwanted side reactions.
The effluent from chemical synthesis operations is the most complex to treat because of
the many types of operations and chemical reactions (nitration, amination, halegenation,
sulfonation, alkylation, etc.). The production steps may generate acids, bases, cyanides,
metals, and many other pollutants. In some instances, process solutions and vessel wash
waters may also contain residual solvents.
In summary, primary sources of wastewater from chemical synthesis operations are:
o Spent solvents, filtrates, concentrates, etc.
o Floor and equipment wash waters
o Wet scrubber spent waters
o Spills
Wastewater from chemical synthesis plant can be characterized as having high BOD,
COD, and TSS concentration; large flows; and extremely variable pH, ranging from 1.0
to 11.0.
Biological and Natural Extraction
Wastewater from biological and natural extractions is commonly lower in volume and
mostly originates from the cleaning process areas since a very high degree of cleanliness
must be maintained. Some solvent residues can be expected but the major waste is solid
waste residuals of the original raw materials being used. Many materials used as
pharmaceuticals are derived from natural sources such as plants, animal organs, and
parasitic fungi. These materials have pharmaceutical applications ranging from
tranquilizers to insulin. Also included in this group is blood fractionation, which involves
the production of plasma and chemical derivatives.
Fermentation
Wastewater from fermentation is generally high in BOD, COD, and total suspended solid
(TSS) with a pH range of 4-8 units.
Fermentation is the usual method for producing most antibiotics and steroids, and
conventionally a large-scale batch process. Sterilized nutrient raw materials in water are
charged to the fermenter. Microorganisms are transferred to the fermenter from the seed
tank and fermentation begins. After a fermentation period of from twelve hours to a
week, the fermenter batch whole broth is ready for filtration. Filtration removes mycelia
(remains of the microorganisms), leaving the filtered aqueous broth containing product
and residual nutrients ready to enter the product recovery phase. Solvent extraction, direct
4
Wang Dongmei
precipitation, and ion exchange or adsorptions are the three common methods of product
recovery.
Solvent extraction is a recovery process in which an organic solvent is used to remove the
pharmaceutical product from the aqueous broth and form a more concentrated solution.
The typical processing solvents used in fermentation operation are: benzene, chloroform,
1,1-dichloroethylene, and 1,2-trans-dichloroethylene.
Direct precipitation consists of first precipitating the product from the aqueous broth,
then filtering the broth, and finally extracting the product from the solid residues. Priority
pollutants known in the precipitation process are copper and zinc.
Ion exchange or adsorption involves the removal of the product from the broth, using
such solid materials as ion exchange resin, adsorptive resin, or activated carbon. The
product is recovered from the solid phase with the use of a solvent.
Steam is used as the major sterilizing medium for most equipment. However, to the
extent that chemical disinfectants may be used, they can contribute to priority waste
loads. Phenol is a commonly used disinfectant.
Formulation
Although pharmaceutical active ingredients are produced in bulk form, they must be
prepared in dosage form for use by the consumer. Pharmaceutical compounds can be
formulated into tablets, capsules, liquids, or ointments.
Wastewaters are generated by general cleanup operations, spills, and breakage. Bad
batches may create a solid waste disposal problem.
The primary objective of mixing/compounding/formulation operations is to convert the
manufactured products into a final, usable form. The necessary production steps have
typically small wastewater flows because very few of the unit operations use water in a
way would cause wastewater generation. The primary use of water in the actual
formulation process is for cooling water in the chilling units and for equipment and floor
wash.
Sources of wastewater from mixing/compounding/formulation operations are:
o Floor and equipment wash waters
o Wet scrubbers
o Spills
o Laboratory wastes
The use of water to clean out mixing tanks can flush materials of unusual quantity and
concentration into the plant sewer system. The washouts from recipe kettles may be used
to prepare the master batches of the pharmaceutical compounds and may contain
inorganic salts, sugars, syrups, etc. Other sources of contaminated wastewater are dust
5
Wang Dongmei
and fumes from scrubbers either in building ventilation systems or on specific equipment.
In general, these wastewaters are readily treatable by biological treatment systems.
Wastewaters from formulation plants normally have low BOD, COD, and TSS
concentration, relatively small flows, and pH values of 6.0 to 8.0.
WASTEWATER SOURCES OF RITONAVIR PRODUCTION PLANT
In order to obtain the basic information of wastewater from ritonavir production plant, it
is necessary to go though the production process. From the Superpro-designer simulation
result of Mr. Udom and Mr. Kanatip from the production group, the main production
reaction can be defined in the category of chemical synthesis of the general
pharmaceuticals. The sources of waste streams are referred to the report of Mr. Kanatip.
The Superpo-designer simulated flow rate and other characteristics of wastewaters are
shown in Table 1.
Table 1 Basic wastewater characteristics of ritonavir production plant
Loading, kg/yr
BOD5
9,680,182
COD
19,113,442
TKN
36,700
1,800,714
TS
pH: acidic condition
Flow rate: 14,765,899 kg/yr
DESIGN ELEMENTS OF WASTEWATER TREATMENT PLANT
The principle elements of conceptual process design used in wastewater treatment plant
are: (1) establishing process design period for facilities, (2) development of the process
flow diagram, (3) establishing process design criteria, (4) preliminary sizing of treatment
units, (5) preparation of solids balance, (6) site layout consideration, and (7) evaluation of
plant hydraulics. The element (1) and (2) will be discussed here, the other calculations
will be simulated by Superpro-designer, and element (6) can be achieved through the
cooperative work with Ms. Waraporn who selects the production plant location, and will
not be discussed here.
6
Wang Dongmei
Design Period
The design period establishes the target date when the design capacity of the facilities
will be reached. Design periods may vary for individual components, depending upon the
ease or difficulty of expansion. Typical design periods for various types of facilities are
given in Table 2. The mean periods are selected for this case design.
Table 2 Typical design periods for wastewater facilities
Facility
Planning period range, yrs
Mean, yrs
Collection systems
Pumping stations
Structures
Pumping equipment
Treatment plants
Process structures
Process equipment
Hydraulic conduits
20 – 40
30
20 – 40
10 – 25
30
17.5
20 – 40
10 – 20
20 - 40
30
15
30
Flow Diagram
Treatment process flow diagrams are graphical representations of particular combinations
of unit operations and processes. According to the characteristics of the wastewater, the
configuration of process units are selected as shown in Figure 1. The overall treatment
process can be grouped into three categories: “preliminary/primary” referred to physical
unit operations; “secondary” referred to chemical and biological unit processes; and
“advanced/tertiary” referred to combinations of all three. The function of individual unit
is discussed in detail as well.
Activated Sludge Tank
The activated sludge process is a biological treatment process primarily removal of
organic material from wastewater. It is characterized by a suspension of aerobic and
facultative microorganisms maintained in a relatively homogeneous state by mixing or by
the turbulence induced by aeration. These microorganisms oxidize soluble organics and
agglomerate colloidal and particulate solids in the presence of dissolved molecular
oxygen. The process can be preceded by sedimentation to remove larger and heavier solid
particles if needed. The mixture of microorganisms, agglomerated particles, and
wastewaters (referred to as mixed liquor) is aerated in an aeration basin. The aeration step
is followed by sedimentation to separate biological sludge from treated wastewater. The
major portion of the microorganisms and solids removed by sedimentation are recycled to
7
Wang Dongmei
the aeration basins to be recombined with incoming wastewater, while the excess, which
constitutes the waste sludge, is sent to sludge disposal facilities.
The activated sludge biomass is made up of bacteria, fungi, protozoa, rotifers, and other
higher forms of life. The bacteria are the most important group of microorganisms as they
are responsible for stabilizations of the organic matter and formation of the biological
floc. The function of the biomass is to convert the soluble organic compounds to cellular
material. This conversion consists of transfer of organic matter (also referred to as
substrate or food) through the cell wall into the cytoplasm, oxidation of substrate to
produce energy, and synthesis of protein and other cellular components from the
substrate. Some of the cellular material undergoes auto-oxidation (self-oxidation or
endogenous respiration) in the aeration basin, the remainder forming net growth or excess
sludge. In addition to the direct removal of dissolved organics by biosorption, the
biomass can also remove suspended matter and colloidal matter. The suspended matter is
removed by enmeshment in the biological floc. The colloidal material is removed by
physiochemical adsorption on the biological floc. Volatile compounds may be driven off
to a certain extent in the aeration process. Metals are also partially removed, and
accumulate in the sludge.
The basic parameters of interest in the design of an activated sludge system include BOD
loading rate, oxygen and air requirement, sludge production, oxygen transfer rates in
wastewater, nutrient requirements, sludge settle-ability and return rate. Because of the
variability in industrial wastewater characteristics, the development of the optimum
design parameters for an activated sludge system usually requires laboratory or pilot plant
investigations. Batch laboratory studies generally are useful for the evaluation of treatability. Continuous flow systems are most useful for the evaluation of design criteria such
as BOD removal rates, oxygen requirements, sludge production, aeration time, and
sedimentation time.
The conventional activated sludge process provides a high quality effluent. It has a
limited organic loading capacity and can be upset with extreme variations in hydraulic,
organic, or toxic loadings. Other disadvantages are high operating costs, operational
complexity, and energy consumption.
Filtration
The complete filtration operation is comprised of two phases: filtration and cleaning,
commonly called backwashing. The filtration phase in which particulate material is
removed is accomplished by passing the wastewater to be filtered through a filter bed
composed of granular material without or with the addition of chemicals. Within the
granular medium filter bed, the removal of the suspended solids contained in the
wastewater is accomplished by a complex process involving one or more removal
mechanisms such as straining, interception, impaction, sedimentation, flocculation, and
adsorption. The end of filter run (filtration phase) is reached when the suspended solids in
the effluent start to increase (break through) beyond an acceptable level, or when a
limiting head loss occurs across the filter bed. Ideally, both these events should occur at
8
Wang Dongmei
the same time. Once either of these conditions is reached, the filtration phase is
terminated, and the filter must be cleaned (backwashed) to remove the material
(suspended solids) that has accumulated within the granular filter bed.
Sedimentation
Sedimentation is the separation from water, by gravitational setting, of suspended
particles that heavier than water. It is one of the most widely used unit operations in
wastewater treatment. Sedimentation is used for grit removal, particulate-matter removal
in the primary settling basin, biological-floc removal in the activated-sludge settling
basin, and chemical-floc removal when the chemical coagulation process is used. It is
also used for solids concentration in sludge thickeners.
Disinfection
Disinfection refers to the selective destruction of disease-causing organisms. All the
organisms are not destroyed during the process. This differentiates disinfection from
sterilization, which is the destruction of all organisms. In the field of wastewater
treatment, the three categories of human enteric organisms of the greatest consequence in
producing disease are bacteria, virus, and amoebic cysts. Chemical agents that have been
used as disinfectants include: chlorine, bromine, iodine, ozone, phenol, alcohols, etc.
Chlorine is used as disinfectant in this case study.
Belt Filter Press
Belt presses are continuous-feed dewartering devices that involve the application of
chemical conditioning, gravity drainage, and mechanically applied pressure to dewater
sludge. In most types of belt filter presses, conditioned sludge is first introduced on a
gravity section where it is allowed to thicken. In this section, a majority of the free water
is removed from the sludge by gravity. Following gravity drainage, pressure is applied in
a low-pressure section, where the sludge is squeezed between opposing porous cloth belts
Sludge Drying Bed
Sludge drying beds are typically used to dewater digested sludge. After drying, the sludge
is removed and either disposed off in a landfill or used as a soil conditioner. The principal
advantages of drying beds are low cost, infrequent attention required, and high solids
content in the dried product.
OUTCOME
The flow sheet for the proposed wastewater treatment plant was built by using the
SuperPro Designer, as shown in figure 1. Man and energy balance were set up but actual
streams from simulation was not used due to time limitation. In the future, the different
waste streams will be integrated into the flow sheet to sure the unit operations.
9
Wang Dongmei
Here in this report detail of all the processes involved in the wastewater treatment has
been outlined. According to the functions of the proposed facilities, it is possible to
achieve the effluent in compliance to the related standards. It can be concluded that our
production activities will not create any environmental problems regarding to the
environmental regulations in Thailand.
10
C lrf-E m issio n
A E B -E m issio n
L im e
In flu e n t
S -1 0 2
S -1 0 4
P -1 / M X -1 0 1
S -1 0 5
M ixin g
P -3 / C L -1 0 1
P -2 / A B -1 0 1
S -1 1 1
S -1 0 3
P -7 / M X -1 0 2
A e ro b ic B io O xid a tio n
C la rific a tio n
M ixin g
S -1 0 1
S -1 0 6
11
S -1 0 8
A ir O u t
S -1 1 4
F in a l S lu d g e
P -4 / G M F -1 0 1
P -6 / S L D R -1 0 1
S lu d g e D ry in g
A ir In
G M F iltra tio n
S -1 0 7
S -1 1 3
P -5 / B F -1 0 1
B e lt Filtra tio n
Figure1: Flow Sheet of Waste Water Treatment Design
E fflu e n t