SYNTHESIZED PHARMACEUTICAL MANUFACTURING PLANTS

SYNTHESIZED PHARMACEUTICAL MANUFACTURING PLANTS
A. PROCESS DESCRIPTION
The synthesis of medicinal chemicals may be done in a very small facility producing only one
chemical or in a large integrated facility producing many chemicals by various processes. Most
pharmaceutical manufacturing plants are relatively small. Organic chemicals are used as raw
materials and as solvents. Nearly all products are made using batch operations. In addition,
several different products or intermediates are likely to be made in the same equipment at
different times during the year; these products, then, are made in “campaigned” equipment.
Equipment dedicated to the manufacture of a single product is rare, unless the product is made
in large volume.
Production activities of the pharmaceutical industry can be divided into the following categories:
1. Chemical Synthesis - the manufacture of pharmaceutical products by chemical synthesis.
2. Fermentation - the production and separation of medicinal chemicals such as antibiotics
and vitamins from microorganisms.
3. Extraction - the manufacture of botanical and biological products by the extraction of
organic chemicals from vegetative materials or animal tissues.
4. Formulation and Packaging - the formulation of bulk pharmaceuticals into various
dosage forms such as tablets, capsules, injectable solutions, ointments, etc., that can be
taken by the patient immediately and in accurate amount.
Production of a synthesized drug consists of one or more chemical reactions followed by
a series of purifying operations. Production lines may contain reactors, filters, centrifuges,
stills, dryers, process tanks, and crystallizers piped together in a specific arrangement. Arrangements
can be varied in some instances to accommodate production of several compounds.
A very small plant may have only a few pieces of process equipment but a large plant
can contain literally hundreds of pieces.
Exhibit 1 shows a typical flow diagram for a batch synthesis operation. To begin a production
cycle, the reactor may be water washed and perhaps dried with a solvent. Air or nitrogen is
usually used to purge the tank after it is cleaned. Following cleaning, solid reactants and
solvent are charged to the glass batch reactor equipped with a condenser (which is usually
water-cooled). Other volatile compounds may be produced as product or by-products. Any
remaining unreacted volatile compounds are distilled off. After the reaction and solvent removal
are complete, the pharmaceutical product is transferred to a holding tank. After each batch is
placed in the holding tank, three to four washes of water or solvent may be used to remove any
remaining reactants and by-products. The solvent used to wash may also be evaporated from
the reaction product.
EXHIBIT 1: Typical Synthetic Organic Medicinal Chemical Process
The crude product may then be dissolved in another solvent and transferred to a crystallizer for
purification. After crystallization, the solid material is separated from the remaining solvent by
centrifugation. While in the centrifuge the product cake may be washed several times with
water or solvent. Tray, rotary, or fluid-bed dryers may then be employed for final product finishing.
B. SOURCES OF POLLUTION
Exhibit 2 identifies pollutants from a typical pharmaceutical process. Volatile organic compounds
may be emitted from a variety of sources within plants synthesizing pharmaceutical
products. The following process components have been identified as VOC sources and will be
discussed further: reactors, distillation units, dryers, crystallizers, filters, centrifuges, extractors,
and tanks.
1. Reactors
The typical batch reactor is glass lined or stainless steel and has a capacity of 2,000 to 11,000
liters (500-3000 gallons). For maximum utility the tanks are usually jacketed to permit temperature
control of reactions. Generally, each tank is equipped with a vent which may discharge
through a condenser. Batch reactors can be operated at atmospheric pressure, elevated
pressure, or under vacuum, and may be used in a variety of ways. Besides hosting chemical
reactions, they can act as mixers, heaters, holding tanks, crystallizers, and evaporators.
A typical reaction cycle takes place as follows. After the reactor is clean and dry, the appropriate
raw materials, usually including some solvent(s), are charged for the next product run.
Liquids are normally added first, then solid reactants are charged through the manhole. After
charging is complete, the vessel is closed and the temperature raised, if necessary, via reactor
jacket heating. The purpose of heating may be to increase the speed of reaction or to reflux the
contents for a period which may vary from 15 minutes to 24 hours. During refluxing, the liquid
phase may be “blanketed” by an inert gas, such as nitrogen, to prevent oxidation or other undesirable
side reactions. Upon completion of the reaction, the vessel may be used as a distillation
pot to vaporize the liquid phase (solvent), or the reaction products may be pumped out so the
vessel can
be cooled to begin the next cycle.
2. Distillation Operations
Distillation may be performed by either of two principal methods. In the first method, the liquid
mixture to be separated is boiled and vapors produced are condensed and prevented from
returning to the still. In the second method, part of the condensate is allowed to return to the
still so that the returning liquid is brought into intimate contact with the vapors on the way to the
condenser. Either of these methods may be conducted as a batch or continuous operation.
Exhibit 2: Major Pollutants From Solvent Use in Pharmaceutical Productiona
Pollutant
(Solvent) Ultimate Disposition (%)
Air Emissions Sewer Incineration Solid
Waste Product
Acetic anhydride 1 57 42
Acetone 14 22 38 719
Amyl alcohol 42 58
Benzene 29 37 16 810
Carbon tetrachloride 11 7 82
Dimethyl formamide 71 3 20 6
Ethanol 10 6 7 176
Ethyl acetate 30 47 20 3
Isopropanol 14 17 17 745
Methanol 31 45 14 64
Methylene chloride 53 5 20 22
Solvent B (hexanes) 29 2 69
Toluene 31 14 26 29
Xylene 6 19 70 5
a Numbers are based on a survey of 26 U.S. manufacturers
3. Separation Operations
Several separation mechanisms employed by the industry are extraction, centrifugation, filtration,
and crystallization.
Extraction is used to separate components of liquid mixtures or solutions. This process
utilizes differences in solubilities of the components rather than differences in volatilities (as in
distillation); i.e., solvent is used that will preferentially combine with one of the components.
The resulting mixture to be separated is made up of the extract which contains the preferentially
dissolved material and the raffinate which is the residual phase.
Centrifuges are used to remove intermediate or product solids from a liquid stream. Centerslung,
stainless steel basket centrifuges are most commonly used in the industry. To begin the
process, the centrifuge is started and the liquid slurry is pumped into it. An inert gas, such as
nitrogen, is sometimes introduced into the centrifuge to avoid the buildup of an explosive atmosphere.
The spinning centrifuge strains the liquid through small basket perforations. Solids
retained in the basket are then scraped from the sides of the basket and unloaded by scooping
them out from a hatch on the top of the centrifuge or by dropping them through the centrifuge
bottom into receiving carts.
Filtration is used to remove solids from a liquid; these solids may be product, process intermediates,
catalysts, or carbon particles (e.g., from a decoloring step). Pressure filters, such as
shell and leaf filters, cartridge filters, and plate and frame filters are usually used. Atmospheric
and vacuum filters have their applications too. The normal filtration procedure is simply to force
or draw the mother liquor through a filtering medium. Following filtration, the retained solids are
removed from the filter medium for further processing.
Crystallization is a means of separating an intermediate or final product from a liquid solution.
This is done by creating a supersaturated solution, one in which the desired compound will
form crystals. If performed properly and in the absence of competing crystals, crystallization
can produce a highly purified product.
4. Dryers
Dryers are used to remove most of the remaining solvent in a centrifuged or filtered product.
This is done by evaporating solvent until an acceptable level of “dryness” is reached. Evaporation
is accelerated by applying heat and/or vacuum to the solvent-laden product or by blowing
warm air around or through it. Because a product may degrade under severe drying conditions,
the amount of heat, vacuum, or warm air flow is carefully controlled. Several types of
dryers are used in synthetic drug manufacture. Some of the most widely used are tray dryers,
rotary dryers, and fluid bed dryers.
5. Storage and Transfer
Volatile organic compounds are stored in tank farms, 233-liter (55 gallon) drums, and sometimes
in process holding tanks. Storage tanks in tank farms range in size from about 2,000-
20,000 liters (500-5,000 gallons). In-plant transfer of VOCs is done mainly by pipeline, but
also may be done manually (e.g. loading or unloading drums). Raw materials are delivered to
the plant by tank truck, rail car, or in drums.
C. POLLUTANTS AND THEIR CONTROL
1. Air Emissions
Solvents constitute the predominant VOC emission from production. Plants differ in the
amount of organics used; this results in widely varying VOC emission rates. Therefore, some
plants may be negligible VOC sources while others are highly significant. In addition, all types
of equipment previously described have the potential to emit air pollutants.
a. Reactors
Reactor emissions stem from the following causes: (a) displacement of air containing VOC
during reactor charging, (b) solvent evaporation during the reaction cycle (often VOC’s are
emitted along with reaction by-product gases which act as carriers), © overhead condenser
venting uncondensed VOC during refluxing, (d) purging vaporized VOC remaining from a
solvent wash, and (e) opening reactors during a reaction cycle to take samples, determine
reaction end-points, etc.
Equipment options available to control emissions from reactors include surface condensers,
carbon adsorbers, liquid scrubbers, and vapor incinerators (under certain conditions). Condensers
are often included on reactor systems as normal process control equipment.
b. Distillation Operations
Volatile organic compounds may be emitted from the distillation condensers used to recover
evaporated solvents. The magnitude of emissions depends on the operating parameters of the
condenser, the type and quantity of organic being condensed, and the quantity of inerts entrained
in the organic.
Emissions from distillation condensers can be controlled through the use of aftercondensers,
scrubbers, and carbon adsorbers.
c. Separation Operations
1. Emissions from batch extraction stem mainly from displacement of vapor while pumping
solvent into the extractor and while purging or cleaning the vessel after extraction. Some VOCs
also may be emitted while the liquids are being agitated. A column extractor may emit VOCs
while the column is being filled, during extraction, or when it is emptied after extraction. Emissions
occur not only at the extractor itself, but also at associated surge tanks. These tanks
may emit significant amounts of solvent due to working losses as the tank is repeatedly filled
and emptied during the extraction process.
2. A large potential source of emissions is the open-type centrifuge which permits large
quantities of air to contact and evaporate solvents. The industry trend is toward completely
enclosed centrifuges and, in fact, many plants have no open-type centrifuges. If an inert gas
blanket is used, it can act as a transport vehicle for solvent vapor. This vapor may be vented
directly from the centrifuge or from a process tank receiving the mother liquor. However, this
emission source is likely to be small because the inert gas flow is only a few cubic feet per
minute.
3. If crystallization is done mainly through cooling of a solution, there will be little VOC
emission. In fact, the equipment may be completely enclosed. However, when the crystallization
is done by solvent evaporation, there is greater potential for emissions. Emissions will be
significant if evaporated solvent is vented directly to the atmosphere. It is more likely, however,
that the solvent will be passed through a condenser or from a vacuum jet (if the crystallization
is done under vacuum), thereby minimizing emissions.
Several add-on control technologies may be used on the separation equipment described
above. Condensers, which can be applied to individual systems, are effective and may be
the least costly option. Water scrubbers also have found wide usage in the industry. They
are versatile and capable of handling a variety of VOCs which have appreciable water
solubility. Scrubbers can be either small or quite large; thus, they can be designed to
handle emissions from a single source or from many sources (via a manifold system).
Carbon adsorbers can be and have been employed on vents from separation operations.
Several vents may be ducted to an adsorber because it is likely that emissions from a single
source would not warrant the expense of a carbon adsorption unit. Finally, in some instances,
incinerators may be applicable. They may not be a good choice, however, since
the expected variability from these emission sources might make continuous incinerator
operation difficult.
4. Enclosed pressure filters normally do not emit VOCs during a filtering operation. Emissions
can occur, however, when a filter is opened to remove collected solids. Emissions can
also occur if the filter is purged (possibly with nitrogen or steam) before cleaning. The purge
gas will entrain evaporated solvent and probably be vented through the receiving tank for the
filtered liquid. The largest VOC emissions are from vacuum drum filters which are operated by
pulling solvent through a precoated filter drum. Potential emissions are significant both at or
near the surface of the drum and from the ensuing waste stream. These filters can be
shrouded or enclosed for control purposes.
d. Dryers
Dryers are potentially large emission sources. Emission rates vary during a drying cycle and
are greatest at the beginning of the cycle and least at the end of the cycle. Drying cycle times
can range from several hours to several days. Control options used for dryers include condensation,
wet scrubbing, adsorption, and incineration.
1. Condensers are often the first control devices selected when dealing with air pollution from
vacuum dryers. They can also be used by themselves or in series with another device. Condensers
are not typically used on air dryers because the emissions are dilute.
2. Wet scrubbers have also been used to control many plant sources, including dryers. They
can also remove particulates generated during drying. For water soluble compounds, VOC
absorption efficiencies can be quite high (i.e. 98-99%).
3. Carbon adsorbers may also be used, especially following a condenser. Not only will overall
efficiency increase but a longer regeneration cycle can be used in the adsorber.
4. Vapor incinerators might be viable controls although varying VOC flows to the incinerator
may present operating problems.
e. Tanks
The vapor space in a tank will in time become saturated with the stored organics. During tank
filling vapors are displaced, causing an emission or a “working loss.” Some vapors are also
displaced as the temperature of the stored VOC rises, such as from solar radiation, or as
atmospheric pressure drops; these are “breathing losses.” The amount of loss depends on
type of VOC stored, size of tank, type of tank, diurnal temperature changes, and tank throughput.
Emissions from storage or process holding vessels may be reduced with varying efficacy
through the use of vapor balance systems, conservation vents, vent condensers, pressurized
tanks, and carbon adsorption.
2. Solid and Liquid Wastes H(21)
The manufacture of the following types of pharmaceutical products can generate hazardous
wastes:
• Organic medicinal chemicals
• Medicinals from animal glands
• Inorganic medicinal chemicals
• Antibiotics
• Biological products
• Botanicals
• Miscellaneous products
The largest quantities of hazardous waste are from the production of organic medicinal chemicals
and antibiotics. Exhibit 3 identifies potential hazardous wastes from pharmaceutical
production:
PH(23-28)
Exhibit 3: Potential Hazardous Wastes from Pharmaceutical Production
Product or Operation Potential Hazardous Wastes Estimated U.S. Generation
(dry metric tons/yr)1
Organic medicinal chemicals • Heavy metals
• Terpenes, steroids, vitamins, tranquilizers
• Ethylene dichloride
• Acetone, toluene, xylene, benzene isopropyl alcohol, methanol, acetonitrile
• Zinc, arsenic, chromium, copper, mercury 1,700
13,600
3,400
23,800
2,700
Inorganic medicinal chemicals • Selenium 200
Antibiotics • Amyl acetate, butanol, butyl acetate, MIK, acetone, ethylene glycol,
monomethyl ether 12,000
Botanicals • Ethylene dichloride, methylene chloride
• Methanol, acetone, ethanol, chloroform, heptane, naphtha, benzene
• Misc. organics 100
100
700
Medicinals from animal glands • Misc. organics 800
Biological products• Vaccines, toxoids, serum, etc.
• Ethanol 500
300
Misc. sources Misc. solvents 63,900
1Hazardous waste amounts are for 1973 estimated total U.S. generation.
D. REFERENCES
1. Control of Organic Emissions from the Manufacture of Synthesized Pharmaceutical
Products, Environmental Protection Agency, Research Triangle Park, NC, December 1978.
2. The Handbook of Hazardous Waste Management, Metry, Amir A., Ph.D., P.E.,
Technomic Publication, January, 1980.