Definitions
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These terms are used frequently in the pharmaceutical industry:
Biologics are bacterial and viral vaccines,
antigens, antitoxins and analogous products, serums, plasmas and other
blood derivatives for therapeutically protecting or treating humans and
animals.
Bulks are active drug substances used to manufacture
dosage- form products, process medicated animal feeds or compound
prescription medications.
Diagnostic agents assist the diagnosis of diseases
and disorders in humans and animals. Diagnostic agents may be inorganic
chemicals for examining the gastrointestinal tract, organic chemicals
for visualizing the circulatory system and liver and radioactive
compounds for measuring the function of organ system.
Drugs are substances with active pharmacological
properties in humans and animals. Drugs are compounded with other
materials, such as pharmaceutical necessities, to produce a medicinal
product.
Ethical pharmaceuticals are biological and chemicals
agents for preventing, diagnosing or treating disease and disorders in
humans or animals. These products are dispensed by prescription or
approval of a medical, pharmacy or veterinary professional.
Excipients are inert ingredients which are combined
with drug substances to create a dosage form product. Excipients may
affect the rate of absorption, dissolution, metabolism and distribution
in humans or animals.
Over-the-counter pharmaceuticals are drug products
sold in a retail store or pharmacy which do not require a prescription
or the approval of a medical, pharmacy or veterinary professional.
Pharmacy is the art and science of preparing and
dispensing drugs for preventing, diagnosing or treating diseases or
disorders in humans and animals.
Pharmacokinetics is the study of metabolic processes
relating to the absorption, distribution, biotransformation, and
elimination of a drug in humans or animals.
Pharmacodynamics is the study of drug action
relating to its chemical structure, site of action, and the biochemical
and physiological consequences in humans and animals.
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The pharmaceutical industry is an important
component of health care systems throughout the world; it is comprised
of many public and private organizations that discover, develop,
manufacture and market medicines for human and animal health (Gennaro
1990). The pharmaceutical industry is based primarily upon the
scientific research and development (R&D) of medicines that prevent
or treat diseases and disorders. Drug substances exhibit a wide range of
pharmacological activity and toxicological properties (Hardman, Gilman
and Limbird 1996; Reynolds 1989). Modern scientific and technological
advances are accelerating the discovery and development of innovative
pharmaceuticals with improved therapeutic activity and reduced side
effects. Molecular biologists, medicinal chemists and pharmacists are
improving the benefits of drugs through increased potency and
specificity. These advances create new concerns for protecting the
health and safety of workers within the pharmaceutical industry (Agius
1989; Naumann et al. 1996; Sargent and Kirk 1988; Teichman, Fallon and
Brandt-Rauf 1988).
Many dynamic scientific, social and economic
factors affect the pharmaceutical industry. Some pharmaceutical
companies operate in both national and multinational markets. Therefore,
their activities are subject to legislation, regulation and policies
relating to drug development and approval, manufacturing and quality
control, marketing and sales (Spilker 1994). Academic, government and
industry scientists, practising physicians and pharmacists, as well as
the public, influence the pharmaceutical industry. Health care providers
(e.g., physicians, dentists, nurses, pharmacists and veterinarians) in
hospitals, clinics, pharmacies and private practice may prescribe drugs
or recommend how they should be dispensed. Government regulations and
health care policies on pharmaceuticals are influenced by the public,
advocacy groups and private interests. These complex factors interact to
influence the discovery and development, manufacturing, marketing and
sales of drugs.
The pharmaceutical industry
is largely driven by scientific discovery and development, in
conjunction with toxicological and clinical experience (see figure 79.1).
Major differences exist between large organizations which engage in a
broad range of drug discovery and development, manufacturing and quality
control, marketing and sales and smaller organizations which focus on a
specific aspect. Most multinational pharmaceutical companies are
involved in all these activities; however, they may specialize in one
aspect based upon local market factors. Academic, public and private
organizations perform scientific research to discover and develop new
drugs. The biotechnology industry is becoming a major contributor to
innovative pharmaceutical research (Swarbick and Boylan 1996). Often,
collaborative agreements between research organizations and large
pharmaceutical companies are formed to explore the potential of new drug
substances.
Figure 79.1 Drug development in the pharmaceutical industry
Many countries have specific legal protections
for proprietary drugs and manufacturing processes, known as intellectual
property rights. In instances when legal protections are limited or do
not exist, some companies specialize in manufacturing and marketing
generic drugs (Medical Economics Co. 1995). The pharmaceutical industry
requires large amounts of capital investment due to the high expenses
associated with R&D, regulatory approval, manufacturing, quality
assurance and control, marketing and sales (Spilker 1994). Many
countries have extensive government regulations affecting the
development and approval of drugs for commercial sale. These countries
have strict requirements for good manufacturing practices to ensure the
integrity of drug manufacturing operations and the quality, safety and
efficacy of pharmaceutical products (Gennaro 1990).
International and
domestic trade, as well as tax and finance policies and practices,
affect how the pharmaceutical industry operates within a country
(Swarbick and Boylan 1996). Significant differences exist between
developed and developing countries, regarding their needs for
pharmaceutical substances. In developing countries, where malnutrition
and infectious diseases are prevalent, nutritional supplements, vitamins
and anti-infective drugs are most needed. In developed countries, where
the diseases associated with ageing and specific ailments are primary
health concerns, cardiovascular, central nervous system,
gastrointestinal, anti-infective, diabetes and chemotherapy drugs are in
the greatest demand.
Human and animal health drugs share similar R&D
activities and manufacturing processes; however, they have unique
therapeutic benefits and mechanisms for their approval, distribution,
marketing and sales (Swarbick and Boylan 1996). Veterinarians administer
drugs to control infectious diseases and parasitic organisms in
agricultural and companion animals. Vaccines and anti-infective and
antiparasitic drugs are commonly used for this purpose. Nutritional
supplements, antibiotics and hormones are widely employed by modern
agriculture to promote the growth and health of farm animals. The
R&D of pharmaceuticals for human and animal health are often allied,
due to concurrent needs to control infectious agents and disease.
Hazardous Industrial Chemicals and Drug-related Substances
Many different biological and chemical agents are
discovered, developed and used in the pharmaceutical industry (Hardman,
Gilman and Limbird 1996; Reynolds 1989). Some manufacturing processes in
the pharmaceutical, biochemical and synthetic organic chemical
industries are similar; however, the greater diversity, smaller scale
and specific applications in the pharmaceutical industry are unique.
Since the primary purpose is to produce medicinal substances with
pharmacological activity, many agents in pharmaceutical R&D and
manufacturing are hazardous to workers. Proper control measures must be
implemented to protect workers from industrial chemicals and drug
substances during many R&D, manufacturing and quality control
operations (ILO 1983; Naumann et al. 1996; Teichman, Fallon and
Brandt-Rauf 1988).
The pharmaceutical industry uses biological agents
(e.g., bacteria and viruses) in many special applications, such as
vaccine production, fermentation processes, derivation of blood-based
products and biotechnology. Biological agents are not addressed by this
profile due to their unique pharmaceutical applications, but other
references are readily available (Swarbick and Boylan 1996). Chemical
agents may be categorized as industrial chemicals and drug-related
substances (Gennaro 1990). These may be raw materials, intermediates or
finished products. Special situations arise when industrial chemicals or
drug substances are employed in laboratory R&D, quality assurance
and control assays, engineering and maintenance, or when they are
created as by-products or wastes.
Industrial chemicals
Industrial chemicals are used in researching and
developing active drug substances and manufacturing bulk substances and
finished pharmaceutical products. Organic and inorganic chemicals are
raw materials, serving as reactants, reagents, catalysts and solvents.
The use of industrial chemicals is determined by the specific
manufacturing process and operations. Many of these materials may be
hazardous to workers. Since worker exposures to industrial chemicals may
be hazardous, occupational exposure limits, such as threshold limit
values (TLVs) have been established by government, technical and
professional organizations (ACGIH 1995).
Drug-related substances
Pharmacologically active
substances may be categorized as natural products and synthetic drugs.
Natural products are derived from plant and animal sources, while
synthetic drugs are produced by microbiological and chemical
technologies. Antibiotics, steroid and peptide hormones, vitamins,
enzymes, prostaglandins and pheromones are important natural products.
Scientific research is focusing increasingly on synthetic drugs due to
recent scientific advances in molecular biology, biochemistry,
pharmacology and computer technology. Table 79.1 lists the principal pharmaceutical agents.
Table 79.1 Major categories of pharmaceutical agents
| Central nervous system | Renal and cardiovascular system | Gastrointestinal system | Anti-infectives and target organs | Immune system | Chemotherapy | Blood and blood-forming organs | Endocrine system |
Analgesics
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Antidiabetics
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Gastrointestinal agents
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Systemic anti-infectives
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Analgesics
Immunodilators and immuno-suppressives Multiple sclerosis management |
Antineoplastics
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Blood modifiers
Cerebral· vasodilators |
Diagnostics
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Active drug substances and
inert materials are combined during pharmaceutical manufacturing to
produce dosage forms of medicinal products (e.g., tablets, capsules,
liquids, powders, creams and ointments) (Gennaro 1990). Drugs may be
categorized by their manufacturing process and therapeutic benefits (EPA
1995). Drugs are medicinally administered by strictly prescribed means
(e.g., oral, injection, skin) and dosages, whereas workers may be
exposed to drug substances by inadvertently breathing airborne dust or
vapours or accidentally swallowing contaminated foods or beverages.
Occupational exposure limits (OELs) are developed by toxicologists and
occupational hygienists to provide guidance on limiting worker exposures
to drug substances (Naumann et al. 1996; Sargent and Kirk 1988).
Pharmaceutical necessities (e.g., binders, fillers,
flavouring and bulking agents, preservatives and antioxidants) are
mixed with active drug substances, providing the desired physical and
pharmacological properties in the dosage form products (Gennaro 1990).
Many pharmaceutical necessities have no or limited therapeutic value and
are relatively non-hazardous to workers during drug development and
manufacturing operations. These materials are anti-oxidants and
preservatives, colouring, flavouring and diluting agents, emulsifiers
and suspending agents, ointment bases, pharmaceutical solvents and
excipients.
Pharmaceutical Operations, Related Hazards and Workplace Control Measures
Pharmaceutical
manufacturing operations may be categorized as basic production of bulk
drug substances and pharmaceutical manufacturing of dosage form
products. Figure 79.2 illustrates the manufacturing process.
Figure 79.2 Manufacturing process in the pharmaceutical industry
Basic production of bulk drug substances may
employ three major types of processes: fermentation, organic chemical
synthesis, and biological and natural extraction (Theodore and McGuinn
1992). These manufacturing operations may be discrete batch, continuous
or a combination of these processes. Antibiotics, steroids and vitamins
are produced by fermentation, whereas many new drug substances are
produced by organic synthesis. Historically, most drug substances were
derived from natural sources such as plants, animals, fungi and other
organisms. Natural medicines are pharmacologically diverse and difficult
to produce commercially due to their complex chemistry and limited
potency.
Fermentation
Fermentation is a
biochemical process employing selected micro-organisms and
microbiological technologies to produce a chemical product. Batch
fermentation processes involve three basic steps: inoculum and seed
preparation, fermentation, and product recovery or isolation (Theodore
and McGuinn 1992). A schematic diagram of a fermentation process is
given in figure 79.3
. Inoculum preparation begins with a spore sample from a microbial
strain. The strain is selectively cultured, purified and grown using a
battery of microbiological techniques to produce the desired product.
The spores of the microbial strain are activated with water and
nutrients in warm conditions. Cells from the culture are grown through a
series of agar plates, test tubes and flasks under controlled
environmental conditions to create a dense suspension.
Figure 79.3 Diagram of a fermentation process
The cells are
transferred to a seed tank for further growth. The seed tank is a small
fermentation vessel designed to optimize the growth of the inoculum. The
cells from the seed tank are charged to a steam sterilized production
fermentor. Sterilized nutrients and purified water are added to the
vessel to begin the fermentation. During aerobic fermentation, the
contents of the fermentor are heated, agitated and aerated by a
perforated pipe or sparger, maintaining an optimum air flow rate and
temperature. After the biochemical reactions are complete, the
fermentation broth is filtered to remove the micro-organisms, or
mycelia. The drug product, which may be present in the filtrate or
within the mycelia, is recovered by various steps, such as solvent
extraction, precipitation, ion exchange and absorption.
Solvents used for extracting the product (table 79.2)
generally can be recovered; however, small portions remain in the
process wastewater, depending upon their solubility and the design of
the process equipment. Precipitation is a method to separate the drug
product from the aqueous broth. The drug product is filtered from the
broth and extracted from the solid residues. Copper and zinc are common
precipitating agents in this process. Ion exchange or adsorption removes
the product from the broth by chemical reaction with solid materials,
such as resins or activated carbon. The drug product is recovered from
the solid phase by a solvent which may be recovered by evaporation.
Table 79.2 Solvents used in the pharmaceutical industry
| Solvents | Processes | ||
| Acetone | C | F | B |
| Acetonitrile | C | F | B |
| Ammonia (aqueous) | C | F | B |
| n-Amyl acetate | C | F | B |
| Amyl alcohol | C | F | B |
| Aniline | C | ||
| Benzene | C | ||
| 2-Butanone (MEK) | C | ||
| n-Butyl acetate | C | F | |
| n-Butyl alcohol | C | F | B |
| Chlorobenzene | C | ||
| Chloroform | C | F | B |
| Chloromethene | C | ||
| Cyclohexane | C | ||
| o-Dichlorobenzene (1,2-Dichlorobenzene) | C | ||
| 1,2-Dichloroethane | C | B | |
| Diethylamine | C | B | |
| Diethyl ether | C | B | |
| N,N-Dimethyl acetamide | C | ||
| Dimethylamine | C | ||
| N,N-dimethylaniline | C | ||
| N,N-dimethylformamide | C | F | B |
| Dimethyl sulphoxide | C | B | |
| 1,4-Dioxane | C | B | |
| Ethanol | C | F | B |
| Ethyl acetate | C | F | B |
| Ethylene glycol | C | B | |
| Formaldehyde | C | F | B |
| Formamide | C | ||
| Furfural | C | ||
| n-Heptane | C | F | B |
| n-Hexane | C | F | B |
| Isobutyraldehyde | C | ||
| Isopropanol | C | F | B |
| Isopropyl acetate | C | F | B |
| Isopropyl ether | C | B | |
| Methanol | C | F | B |
| Methylamine | C | ||
| Methyl cellosolve | C | F | |
| Methylene chloride | C | F | B |
| Methyl formate | C | ||
| Methyl isobutyl ketone (MIBK) | C | F | B |
| 2-Methylpyridine | C | ||
| Petroleum naphtha | C | F | B |
| Phenol | C | F | B |
| Polyethylene glycol 600 | C | ||
| n-Propanol | C | B | |
| Pyridine | C | B | |
| Tetrahydrofuran | C | ||
| Toluene | C | F | B |
| Trichlorofluoromethane | C | ||
| Triethylamine | C | F | |
| Xylenes | C | ||
C = chemical synthesis, F = fermentation, B = biological or natural extraction.Source: EPA 1995.
Worker health and safety
Worker safety hazards may be posed by moving
machine parts and equipment; high pressure steam, hot water, heated
surfaces and hot workplace environments; corrosive and irritating
chemicals; heavy manual handling of materials and equipment; and high
noise levels. Worker exposures to solvent vapours may occur when
recovering or isolating products. Worker exposures to solvents may
result from uncontained filtration equipment and fugitive emissions for
leaking pumps, valves and manifold stations during extraction and
purification steps. Since the isolation and growth of micro-organisms
are essential for fermentation, biological hazards are reduced by
employing non-pathogenic microbes, maintaining closed process equipment
and treating spent broth before its discharge.
Generally, process safety concerns are less
important during fermentation than during organic synthesis operations,
since fermentation is primarily based upon aqueous chemistry and
requires process containment during seed preparation and fermentation.
Fire and explosion hazards may arise during solvent extractions;
however, the flammability of solvents is reduced by dilution with water
in filtration and recovery steps. Safety hazards (i.e., thermal burns
and scalding) are posed by the large volumes of pressurized steam and
hot water associated with fermentation operations.
Chemical synthesis
Chemical synthesis
processes use organic and inorganic chemicals in batch operations to
produce drug substances with unique physical and pharmacological
properties. Typically, a series of chemical reactions are performed in
multi-purpose reactors and the products are isolated by extraction,
crystallization and filtration (Kroschwitz 1992). The finished products
are usually dried, milled and blended. Organic synthesis plants, process
equipment and utilities are comparable in the pharmaceutical and fine
chemical industries. A schematic diagram of an organic synthesis process
is given in figure 79.4 .
Figure 79.4 Diagram of an organic synthesis process
Pharmaceutical chemistry is becoming
increasingly complex with multi-step processing, where the product from
one step becomes a starting material for the next step, until the
finished drug product is synthesized. Bulk chemicals which are
intermediates of the finished product may be transferred between organic
synthesis plants for various technical, financial and legal
considerations. Most intermediates and products are produced in a series
of batch reactions on a campaign basis. Manufacturing processes operate
for discrete periods of time, before materials, equipment and utilities
are changed to prepare for a new process. Many organic synthesis plants
in the pharmaceutical industry are designed to maximize their operating
flexibility, due to the diversity and complexity of modern medicinal
chemistry. This is achieved by constructing facilities and installing
process equipment that can be modified for new manufacturing processes,
in addition to their utility requirements.
Multi-purpose reactors are the primary processing equipment in chemical synthesis operations (see figure 79.5).
They are reinforced pressure vessels with stainless, glass or metal
alloy linings. The nature of chemical reactions and physical properties
of materials (e.g., reactive, corrosive, flammable) determine the
design, features and construction of reactors. Multi-purpose reactors
have external shells and internal coils which are filled with cooling
water, steam or chemicals with special heat-transfer properties. The
reactor shell is heated or cooled, based upon the requirements of the
chemical reactions. Multi-purpose reactors have agitators, baffles and
many inlets and outlets connecting them to other process vessels,
equipment and bulk chemical supplies. Temperature-, pressure- and
weight-sensing instruments are installed to measure and control the
chemical process in the reactor. Reactors may be operated at high
pressures or low vacuums, depending upon their engineering design and
features and the requirements of the process chemistry.
Figure 79.5 Diagram of a chemical reactor in organic synthesis
Figure 79.6 Examples of steroidal and non-steroidal oestrogen structure
Figure 79.7 Typical oral contraceptive tablet manufacturing process flow
Heat exchangers are
connected to reactors to heat or cool the reaction and condense solvent
vapours when they are heated above their boiling point, creating a
reflux or recycling of the condensed vapours. Air pollution control
devices (e.g., scrubbers and impingers) can be connected to the exhaust
vents on process vessels, reducing gas, vapour and dust emissions (EPA
1993). Volatile solvents and toxic chemicals may be released to the
workplace or atmosphere, unless they are controlled during the reaction
by heat exchangers or air control devices. Some solvents (see table 79.2)
and reactants are difficult to condense, absorb or adsorb in air
control devices (e.g., methylene chloride and chloroform) due to their
chemical and physical properties.
Bulk chemical products are recovered or isolated by
separation, purification and filtration operations. Typically, these
products are contained in mother liquors, as dissolved or suspended
solids in a solvent mixture. The mother liquors may be transferred
between process vessels or equipment in temporary or permanent pipes or
hoses, by pumps, pressurized inert gases, vacuum or gravity.
Transferring materials is a concern due to the rates of reaction,
critical temperatures or pressures, features of processing equipment and
potential for leaks and spills. Special precautions to minimize static
electricity are required when processes use or generate flammable gases
and liquids. Charging flammable liquids through submerged dip tubes and
grounding and bonding conductive materials and maintaining inert
atmospheres inside process equipment reduce the risk of a fire or
explosion (Crowl and Louvar 1990).
Worker health and safety
Many worker health and safety hazards are posed by
synthesis operations. They include safety hazards from moving machine
parts, pressurized equipment and pipes; heavy manual handling of
materials and equipment; steam, hot liquids, heated surfaces and hot
workplace environments; confined spaces and hazardous energy sources
(e.g., electricity); and high noise levels.
Acute and chronic health risks may result from
worker exposures to hazardous chemicals during synthesis operations.
Chemicals with acute health effects can damage the eyes and skin, be
corrosive or irritating to body tissues, cause sensitization or allergic
reactions or be asphyxiants, causing suffocation or oxygen deficiency.
Chemicals with chronic health effects may cause cancer, or damage the
liver, kidneys or lungs or affect the nervous, endocrine, reproductive
or other organ systems. Health and safety hazards may be controlled by
implementing appropriate control measures (e.g., process modifications,
engineering controls, administrative practices, personal and respiratory
protective equipment).
Organic synthesis reactions may create major
process safety risks from highly hazardous materials, fire, explosion or
uncontrolled chemical reactions which impact the community surrounding
the plant. Process safety can be very complex in organic synthesis. It
is addressed in several ways: by examining the dynamics of chemical
reactions, properties of highly hazardous materials, design, operation
and maintenance of equipment and utilities, training of operating and
engineering staff, and emergency preparedness and response of the
facility and local community. Technical guidance is available on process
hazard analysis and management activities to reduce the risks of
chemical synthesis operations (Crowl and Louvar 1990; Kroschwitz 1992).
Biological and natural extraction
Large volumes of natural materials, such as plant
and animal matter, may be processed to extract substances which are
pharmacologically active (Gennaro 1990; Swarbick and Boylan 1996). In
each step of the process, the volumes of materials are reduced by a
series of batch processes, until the final drug product is obtained.
Typically, processes are performed in campaigns lasting a few weeks,
until the desired quantity of finished product is obtained. Solvents are
used to remove insoluble fats and oils, thereby extracting the finished
drug substance. The pH (acidity) of the extraction solution and waste
products can be adjusted by neutralizing them with strong acids and
bases. Metal compounds frequently serve as precipitating agents, and
phenol compounds as disinfectants.
Worker health and safety
Some workers may develop allergic and/or skin
irritation from handling certain plants. Animal matter may be
contaminated with infectious organisms unless appropriate precautions
are taken. Workers may be exposed to solvents and corrosive chemicals
during biological and natural extraction operations. Fire and explosion
risks are posed by storing, handling, processing and recovering
flammable liquids. Moving mechanical parts; hot steam, water, surfaces
and workplaces; and high noise levels are risks to worker safety.
Process safety issues are often reduced by the
large volumes of plant or animal materials, and smaller scale of solvent
extraction activities. Fire and explosion hazards, and worker exposures
to solvents or corrosive or irritating chemicals may occur during
extraction and recovery operations, depending upon the specific
chemistry and containment of process equipment.
Pharmaceutical manufacturing of dosage forms
Drug substances are
converted into dosage-form products before they are dispensed or
administered to humans or animals. Active drug substances are mixed with
pharmaceutical necessities, such as binders, fillers, flavouring and
bulking agents, preservatives and antioxidants. These ingredients may be
dried, milled, blended, compressed and granulated to achieve the
desired properties before they are manufactured as a final formulation.
Tablets and capsules are very common oral dosage forms; another common
form is sterile liquids for injection or ophthalmic application. Figure 79.8 illustrates typical unit operations for manufacturing of pharmaceutical dosage-form products.
Figure 79.8 Pharmaceutical manufacturing of dosage-form products
Pharmaceutical blends may be compressed by wet
granulation, direct compression or slugging to obtain the desired
physical properties, before their formulation as a finished drug
product. In wet granulation, the active ingredients and excipients are
wetted with aqueous or solvent solutions to produce course granules with
enlarged particle sizes. The granules are dried, mixed with lubricants
(e.g., magnesium stearate), disintegrants or binders, then compressed
into tablets. During direct compression, a metal die holds a measured
amount of the drug blend while a punch compresses the tablet. Drugs that
are not sufficiently stable for wet granulation or cannot be directly
compressed are slugged. Slugging or dry granulation blends and
compresses relatively large tablets which are ground and screened to a
desired mesh size, then recompressed into the final tablet. Blended and
granulated materials may also be produced in capsule form. Hard gelatin
capsules are dried, trimmed, filled and joined on capsule-filling
machines.
Liquids may be produced
as sterile solutions for injection into the body or administration to
the eyes; liquids, suspensions and syrups for oral ingestion; and
tinctures for application on the skin (Gennaro 1990). Highly controlled
environmental conditions, contained process equipment and purified raw
materials are required for manufacturing sterile liquids to prevent
microbiological and particulate contamination (Cole 1990; Swarbick and
Boylan 1996). Facility utilities (e.g., ventilation, steam and water),
process equipment and workplace surfaces must be cleaned and maintained
to prevent and minimize contamination. Water at high temperatures and
pressures is used to destroy and filter bacteria and other contaminants
from the sterile water supply when making solutions for injection.
Parenteral liquids are injected by intradermal, intramuscular or
intravenous administration into the body. These liquids are sterilized
by dry or moist heat under high pressure with bacteria-retaining
filters. Although liquid solutions for oral or topical use do not
require sterilization, solutions to be administered to the eyes
(ophthalmic) must be sterilized. Oral liquids are prepared by mixing the
active drug substances with a solvent or preservative to inhibit mold
and bacterial growth. Liquid suspensions and emulsions are produced by
colloid mills and homogenizers, respectively. Creams and ointments are
prepared by blending or compounding active ingredients with petrolatum,
heavy greases or emollients before packaging in metal or plastic tubes.
Worker health and safety
Worker health and safety risks during
pharmaceutical manufacturing are created by moving machine parts (e.g.,
exposed gears, belts and shafts) and hazardous energy sources (e.g.,
electrical, pneumatic, thermal, etc.); manual handling of material and
equipment; high-pressure steam, hot water and heated surfaces; flammable
and corrosive liquids; and high noise levels. Worker exposures to
airborne dusts may occur during dispensing, drying, milling and blending
operations. Exposure to pharmaceutical products is a particular concern
when mixtures containing high proportions of active drug substances are
handled or processed. Wet granulation, compounding and coating
operations may create high worker exposures to solvent vapours.
Process safety issues primarily relate to the risks
of fire or explosion during pharmaceutical manufacturing of dosage
forms. Many of these operations (e.g., granulation, blending,
compounding and drying) use flammable liquids, which may create
flammable or explosive atmospheres. Since some pharmaceutical dusts are
highly explosive, their physical properties should be examined before
they are processed. Fluid bed drying, milling and slugging are a
particular concern when they involve potentially explosive materials.
Engineering measures and safe work practices reduce the risks of
explosive dusts and flammable liquids (e.g., vapour- and dust-tight
electrical equipment and utilities, grounding and bonding of equipment,
sealed containers with pressure relief and inert atmospheres).
Control measures
Fire and explosion prevention and protection;
process containment of hazardous substances, machine hazards and high
noise levels; dilution and local exhaust ventilation (LEV); use of
respirators (e.g., dust and organic vapour masks and, in some cases,
powered air-purifying respirators or air-supplied masks and suits) and
personal protective equipment (PPE); and worker training on workplace
hazards and safe work practices are workplace control measures
applicable during all of the various pharmaceutical manufacturing
operations described below. Specific issues involve substituting less
hazardous materials whenever possible during drug development and
manufacturing. Also, minimizing material transfers, unsealed or open
processing and sampling activities decreases the potential for worker
exposures.
The engineering design and features of facilities,
utilities and process equipment can prevent environmental pollution and
reduce worker exposures to hazardous substances. Modern pharmaceutical
manufacturing facilities and process equipment are reducing
environmental, health and safety risks by preventing pollution and
improving the containment of hazards. Worker health and safety and
quality control objectives are achieved by improving the isolation,
containment and cleanliness of pharmaceutical facilities and process
equipment. Preventing worker exposures to hazardous substances and
pharmaceutical products is highly compatible with the concurrent need to
prevent workers from accidentally contaminating raw materials and
finished products. Safe work procedures and good manufacturing practices
are complementary activities.
Facility design and process-engineering issues
The engineering design and
features of pharmaceutical facilities and process equipment influences
worker health and safety. The construction materials, process equipment
and housekeeping practices greatly affect the cleanliness of the
workplace. Dilution and LEV systems control fugitive vapours and dust
emissions during manufacturing operations. Fire and explosion prevention
and protection measures (e.g., vapour- and dust-tight electrical
equipment and utilities, extinguishing systems, fire and smoke detectors
and emergency alarms) are needed when flammable liquids and vapours are
present. Storage and handling systems (e.g., storage vessels, portable
containers, pumps and piping) are installed to move liquids within
pharmaceutical manufacturing facilities. Hazardous solids can be handled
and processed in enclosed equipment and vessels, individual bulk
containers (IBCs) and sealed drums and bags. The isolation or
containment of facilities, process equipment and hazardous materials
promotes worker health and safety. Mechanical hazards are controlled by
installing barrier guards on moving machine parts.
The process equipment and utilities may be
controlled by manual or automatic means. In manual plants, chemical
operators read instruments and control process equipment and utilities
near the process equipment. In automated plants, the process equipment,
utilities and control devices are controlled by distributed systems,
allowing them to be operated from a remote location such as a control
room. Manual operations are often employed when materials are charged or
transferred, products are discharged and packaged and when maintenance
is performed or nonroutine conditions arise. Written instructions should
be prepared, to describe standard operating procedures as well as
worker health and safety hazards and control measures.
Verification of workplace controls
Workplace control measures are evaluated
periodically to protect workers from health and safety hazards and
minimize environmental pollution. Many manufacturing processes and
pieces of equipment are validated in the pharmaceutical industry to
ensure the quality of products (Cole 1990; Gennaro 1990; Swarbick and
Boylan 1996). Similar validation practices may be implemented for
workplace control measures to ensure that they are effective and
reliable. Periodically, process instructions and safe work practices are
revised. Preventive maintenance activities identify when process and
engineering equipment may fail, thereby precluding problems. Training
and supervision informs and educates workers about environmental, health
and safety hazards, reinforcing safe work practices and the use of
respirators and personal protective equipment. Inspection programmes
examine whether safe workplace conditions and work practices are
maintained. This includes inspecting respirators and to ensure they are
properly selected, worn and maintained by workers. Audit programmes
review the management systems for identifying, evaluating and
controlling environmental, health and safety hazards.
Pharmaceutical unit operations
Weighing and dispensing
Weighing and dispensing of solids and liquids is a
very common activity throughout the pharmaceutical industry (Gennaro
1990). Usually workers dispense materials by hand-scooping solids and
pouring or pumping liquids. Weighing and dispensing are often performed
in a warehouse during bulk chemical production or in a pharmacy during
pharmaceutical dosage-form manufacturing. Due to the likelihood of
spills, leaks and fugitive emissions during weighing and dispensing,
proper workplace control measures are necessary to protect workers.
Weighing and dispensing should be performed in a partitioned workplace
area with good dilution ventilation. The work surfaces in areas where
materials are weighed and dispensed should be smooth and sealed,
permitting their proper cleaning. LEV with backdraft or sidedraft hoods
prevents the release of air contaminants when weighing and dispensing
dusty solids or volatile liquids (Cole 1990). Weighing and dispensing
highly toxic materials may require additional control measures such as
laminar ventilation hoods or isolation devices (e.g., glove boxes or
glove bags) (Naumann et al. 1996).
Charging and discharging solids and liquids
Solids and liquids are
frequently charged and discharged from containers and process equipment
in pharmaceutical manufacturing operations (Gennaro 1990). Charging and
discharging of materials are often performed manually by workers;
however, other methods are employed (e.g., gravity, mechanical or
pneumatic transfer systems). Contained process equipment, transfer
systems and engineering controls prevent worker exposures during
charging and discharging of highly hazardous materials. Gravity charging
from enclosed containers and vacuum, pressure and pumping systems
eliminate fugitive emissions during charging and discharging operations.
LEV with flanged inlets captures fugitive dusts and vapours which are
released at open transfer points.
Liquid separations
Liquids are separated based upon their physical
properties (e.g., density, solubility and miscibility) (Kroschwitz
1992). Liquid separations are commonly performed during bulk chemical
production and pharmaceutical manufacturing operations. Hazardous
liquids should be transferred, processed and separated in closed vessels
and piping systems to reduce worker exposures to liquid spills and
airborne vapours. Eyewashes and safety showers should be located near
operations where hazardous liquids are transferred, processed or
separated. Spill control measures and fire and explosion prevention and
protection are needed when using flammable liquids.
Transferring liquids
Liquids are often transferred between storage
vessels, containers and process equipment during pharmaceutical
manufacturing operations. Ideally, facility and manufacturing processes
are designed to minimize the need for transferring hazardous materials,
thereby decreasing the chance of spills and worker exposures. Liquids
may be transferred between process vessels and equipment through
manifold stations, areas where many pipe flanges are located close
together (Kroschwitz 1992). This allows temporary connections to be made
between piping systems. Spills, leaks and vapour emissions may occur at
manifold stations; therefore proper gaskets and tight seals on hoses
and pipes are needed to prevent environmental pollution and workplace
releases. Drainage systems with sealed tanks or sumps capture spilled
liquids so they can be reclaimed and recovered. Sealed vessels and
containers and piping systems are highly desirable when transferring
large volumes of liquids. Special precautions should be taken when using
inert gases to pressurize transfer lines or process equipment, since
this may increase the release of volatile organic compounds (VOCs) and
hazardous air pollutants. Recirculation or condensation of exhaust gases
and vapours reduces air pollution.
Filtration
Solids and liquids are
separated during filtration operations. Filters have different designs
and features with varying containment and control of liquids and vapours
(Kroschwitz 1992; Perry 1984). When open filters are used for hazardous
materials, workers may be exposed to liquids, wet solids, vapours and
aerosols during loading and unloading operations. Closed process
equipment can be used to filter highly hazardous materials, reducing
vapour emissions and preventing worker exposures (see figure 79.9).
Filtration should be performed in areas with spill control and good
dilution and LEV. Volatile solvent vapours can be exhausted through
vents on sealed process equipment and controlled by air emissions
devices (e.g., condensers, scrubbers and adsorbers).
Figure 79.9 A sparkler filter
Compounding
Solids and liquids are mixed in compounding
operations to produce solutions, suspensions, syrups, ointments and
pastes. Contained process equipment and transfer systems are recommended
when compounding highly hazardous materials (Kroschwitz 1992; Perry
1984). Buffering agents, detergents and germicides that are
neutralizing, cleaning and biocidal agents may be hazardous to workers.
Eyewashes and safety showers reduce injuries, if workers accidentally
contact corrosive or irritating substances. Due to the wet surfaces in
compounding areas, workers need to be protected from electrical hazards
of equipment and utilities. Thermal hazards are posed by steam and hot
water during compounding and cleaning activities. Worker injuries from
burns and falls are prevented by installing insulation on hot surfaces
and maintaining dry non-slip floors.
Granulation
Dry and wet solids are
granulated to change their physical properties. Granulators have
different designs and features with varying containment and control of
mechanical hazards and airborne dusts and vapours (Perry 1984; Swarbick
and Boylan 1996). Enclosed granulators can be vented to air-control
devices, reducing emissions of solvent vapours or dusts to the workplace
and atmosphere (see figure 79.10).
Material-handling concerns arise when loading and unloading
granulators. Mechanical equipment (e.g., elevated platforms, lift tables
and pallet jacks) assists workers to perform heavy manual tasks.
Eyewashes and safety showers are needed, if workers accidentally contact
solvents or irritating dusts.
Figure 79.10 A high steam granulator
Drying
Water- or solvent-wet
solids are dried during many pharmaceutical manufacturing operations.
Dryers have different designs and features with varying containment and
control of vapours and dusts (see figure 79.11).
Flammable solvent vapours and explosive airborne dusts may create
flammable or explosive atmosphere; explosion relief venting is
particularly important on contained dryers. Dilution and LEV reduces the
risk of fire or explosion, in addition to controlling worker exposures
to solvent vapours when handling wet cakes, or to airborne dusts when
unloading dried products. Heavy material handling may be involved when
loading or unloading dryer trays, bins or containers (see figure 79.12).
Mechanical equipment (e.g., drum jacks, lifts and work platforms)
assists these manual tasks. Eyewashes and safety showers should be
located nearby, in case workers accidentally contact solvents and dusts.
Figure 79.11 A rotary vacuum dryer
Glatt Air Techniques, Inc.
Figure 79.12 A vacuum shelf dryer
Source: EPA 1993
Milling
Dry solids are milled to change their particle
characteristics and produce free-flowing powders. Mills have different
designs and features with varying containment and control of mechanical
hazards and airborne dusts (Kroschwitz 1992; Perry 1984). Prior to
milling materials, their physical properties and hazards should be
reviewed or tested. Explosion prevention and protection measures involve
installing dust-tight electrical equipment and utilities, grounding and
bonding equipment and accessories to eliminate electrostatic sparking,
installing safety relief valves on enclosed mills, and constructing
blast relief panels in walls. These measures may be necessary due to the
explosivity of some drug substances and excipients, high dust levels
and energies associated with milling operations.
Blending
Dry solids are blended to produce homogeneous
mixtures. Blenders have different designs and features with varying
containment and control of mechanical hazards and airborne dusts
(Kroschwitz 1992; Perry 1984). Worker exposures to drug substances,
excipients and blends may occur when loading and unloading blending
equipment. LEV with flanged inlets reduces fugitive dust emissions
during blending. Heavy material handling may be required when charging
and discharging solids from blenders. Mechanical equipment (e.g., work
platforms, hoists and drum and pallet jacks) reduces the physical
demands of heavy material handling.
Compression
Dry solids are compressed or slugged to compact
them, changing their particle properties. Compression equipment has
different designs and features with varying containment and control of
mechanical hazards and airborne dusts (Gennaro 1990; Swarbick and Boylan
1996). Compression equipment may pose serious mechanical hazards if
inadequately guarded. High noise levels may also be produced by
compression and slugging operations. Enclosing impact sources, isolating
vibrating equipment, rotating workers and using hearing-protective
devices (e.g., ear muffs and plugs) reduce the impact of noise
exposures.
Solid dosage-form manufacturing
Tablets and capsules
are the most common oral dosage forms. Compressed or moulded tablets
contain mixtures of drug substances and excipients. These tablets may be
uncoated or coated with solvent mixtures or aqueous solutions. Capsules
are soft or hard gelatin shells. Tablet presses (see figure 79.13),
tablet-coating equipment and capsule-filling machines have different
designs and features with varying containment and control of mechanical
hazards and airborne dusts (Cole 1990). Workers may be exposed to
solvent vapours when spray-coating tablets. Modern tablet-coating
equipment is highly contained; however, LEV can be installed in older
open coating pans to control fugitive solvent vapours. Tablet-coating
equipment can be vented to air emission devices to control VOCs from the
process (see figure 79.14).
Whenever possible, recovered solvents should be reused by the process
or aqueous mixtures substituted for solvent mixtures for tablet coating.
Modern tablet presses and capsule-filling machines are enclosed by
interlocked panels, reducing the hazards of fast-moving parts, high
noise levels and dust emissions during their operation.
Hearing-protective devices can reduce worker noise exposures during
tablet and capsule operations.
Figure 79.13 Tablet press with load hopper and spiral dust pickups for product recovery
Figure 79.14 A tablet coating machine
Sterile manufacturing
Sterile products are manufactured in pharmaceutical manufacturing plants with modular design (see figure 79.15),
clean workplace and equipment surfaces, and high efficiency particulate
air (HEPA) filtered ventilation systems (Cole 1990; Gennaro 1990). The
principles and practices of controlling contamination in sterile liquid
manufacturing are similar to those in the microelectronics industry.
Workers wear protective clothing to prevent them from contaminating
products during sterile manufacturing operations. Sterile pharmaceutical
technologies to control contamination involve freeze-drying products,
using liquid germicides and sterilizing gases, installing laminar flow
ventilation, isolating modules with differential air pressures and
containing manufacturing and filling equipment.
Figure 79.15 Diagram of a sterile liquid manufacturing facility
Chemical hazards are posed by toxic germicides
(e.g., formaldehyde and glutaraldehyde) and sterilizing gases (i.e.,
ethylene oxide). Whenever possible, less hazardous agents should be
selected (e.g., alcohols, ammonium compounds). Sterilization of raw
materials and equipment may be performed by high-pressure steam or toxic
gases (i.e., diluted ethylene oxide gas mixtures) (Swarbick and Boylan
1996). Sterilization vessels can be located in separate areas with
remote instrument and control systems, non-recirculated air and LEV to
extract toxic gas emissions. Workers should be trained on standard
operating instructions, safe work practices and appropriate emergency
response. Gas sterilization chambers should be fully evacuated under
vacuum and purged with air to minimize fugitive workplace emissions
before sterilized goods are removed. Gas emissions from sterilization
chambers can be vented to air control devices (e.g., carbon adsorption
or catalytic converters) to reduce atmospheric emissions. Occupational
hygiene monitoring measures worker exposures to chemical germicides and
sterilizing gases, helping to assess the adequacy of control measures.
Safety hazards involve high-pressure steam and hot water, moving machine
parts in washing, filling, capping and packaging equipment, high noise
levels and repetitive manual tasks.
Cleaning and maintenance activities
Non-routine tasks may occur when cleaning,
repairing and maintaining equipment, utilities and workplaces. Although
unique hazards may arise during non-routine tasks, recurring health and
safety concerns are encountered. Workplace and equipment surfaces may be
contaminated by hazardous materials and drug substances, requiring them
to be cleaned before unprotected workers conduct servicing or
maintenance work. Cleaning is performed by washing or wiping liquids and
sweeping or vacuuming dusts. Dry sweeping and blowing solids with
compressed air are not recommended, since they create high worker
exposures to airborne dusts. Wet mopping and vacuuming reduce worker
exposures to dusts during cleaning activities. Vacuum cleaners with HEPA
filters may be needed when cleaning hazardous substances and
high-potency drugs. Explosion-proof equipment and conductive materials
may be required in vacuum systems for explosive dusts. Eyewashes and
safety showers and PPE reduce the effect of workers’ accidental contact
with corrosive and irritating detergents and cleaning liquids.
Hazardous mechanical,
electrical, pneumatic or thermal energy may need to be released or
controlled before equipment and utilities are serviced, repaired or
maintained. Contract workers may perform special production or
engineering tasks in pharmaceutical plants without adequate training on
safety precautions. Careful supervision of contract workers is
important, so they do not violate safety rules or perform work that
creates a fire, explosion or other serious health and safety hazards.
Special contractor safety programmes are required when working with
highly hazardous materials (e.g., toxic, reactive, flammable or
explosive) and processes (e.g., exothermic or high pressure) in bulk
pharmaceutical and dosage-form manufacturing facilities.
Packaging
Pharmaceutical packaging operations are performed
with a series of integrated machines and repetitive manual tasks
(Gennaro 1990; Swarbick and Boylan 1996). Finished dosage-form products
may be packaged in many different types of containers (e.g., plastic or
glass bottles, foil blister packs, pouches or sachets, tubes and sterile
vials). The mechanical equipment fills, caps, labels, cartons and packs
the finished products in shipping containers. Worker proximity to
packaging equipment necessitates barrier guarding on moving machine
parts, accessible control switches and emergency stop cables and
employee training on machine hazards and safe work practices. Enclosure
and isolation of equipment reduces sound and vibration levels in
packaging areas. Use of hearing-protective devices (e.g., ear muffs and
plugs) reduces worker exposures to noise. Good industrial design
promotes the productivity, comfort and safety of employees, by
addressing ergonomic hazards from poor body postures, material handling
and highly repetitive tasks.
Laboratory operations
Laboratory operations in the pharmaceutical
industry are diverse. They may pose biological, chemical and physical
hazards, depending upon the specific agents, operations, equipment and
work practices employed. Major distinctions exist between labs which
conduct scientific research and product and process development and
those which evaluate quality assurance and control activities (Swarbick
and Boylan 1996). Lab workers may conduct scientific research to
discover drug substances, develop manufacturing processes for bulk
chemical and dosage-form products or analyze raw materials,
intermediates and finished products. Lab activities should be evaluated
individually, although good lab practices apply to many situations
(National Research Council 1981). Clearly defined responsibilities,
training and information, safe work practices and control measures and
emergency response plans are important means for effectively managing
environmental, health and safety hazards.
The health and safety hazards of flammable and
toxic materials are reduced by minimizing their inventories in labs and
storing them in separate cabinets. Lab assays and operations which may
release air contaminants can be performed in ventilated exhaust fume
hoods to protect workers. Biological safety hoods provide downward and
inward laminar flow, preventing the release of micro-organisms (Gennaro
1990; Swarbick and Boylan 1996). Worker training and information
describes the hazards of lab work, safe work practices and proper
emergency response to fires and spills. Food and beverages should not be
consumed in lab areas. Lab safety is enhanced by requiring supervisors
to approve and manage highly hazardous operations. Good lab practices
separate, treat and dispose of biological and chemical wastes. Physical
hazards (e.g., radiation and electromagnetic energy sources) are often
certified and operated, according to specific regulations.
General Health and Safety Hazards
Ergonomics and material handling
The materials shipped,
stored, handled, processed and packaged in the pharmaceutical industry
range from large quantities of raw materials to small packages
containing pharmaceutical products. Raw materials for bulk chemical
production are shipped in bulk containers (e.g., tank trucks, rail
cars), metal and fibre drums, reinforced paper and plastic bags.
Pharmaceutical production uses smaller quantities of raw materials due
to the reduced scale of the operations. Material-handling devices (e.g.,
fork-lift trucks, pallet lifts, vacuum hoists and drum jacks) assist
material handling during warehousing and production operations. Heavy
manual work may create ergonomic risks when moving materials and
equipment if mechanical devices are not available. Good industrial
engineering and facility management practices reduce injuries from
material handling by improving the design and features of equipment and
the workplace and decreasing the size and weight of containers (Cole
1990). Engineering control measures (e.g., ergonomic design of tools,
materials and equipment) and administrative practices (e.g., rotating
workers, providing worker training) reduce the risks of cumulative
trauma injuries during highly repetitive production and packaging
operations.
Machine guarding and control of hazardous energy
Unguarded moving machine parts in pharmaceutical
manufacturing and packaging equipment create mechanical hazards. Exposed
“crush and nip points” in open equipment may seriously injure workers.
Mechanical hazards are exacerbated by the large numbers and different
designs of equipment, crowded workplace conditions and frequent
interactions between workers and equipment. Interlocked guards, control
switches, emergency stop devices and operator training are important
means of reducing mechanical hazards. Loose hair, long-sleeved clothing,
jewellery or other objects may become trapped in equipment. Routine
inspection and repair activities identify and control mechanical hazards
during production and packaging operations. Hazardous electrical,
pneumatic and thermal energy must be released or controlled before
working on active equipment and utilities. Workers are protected from
sources of hazardous energy by implementing lockout/tagout procedures.
Noise exposures
High sound levels may be generated by manufacturing
equipment and utilities (e.g., compressed air, vacuum sources and
ventilation systems). Due to the enclosed design of pharmaceutical
workplace modules, workers are often located close to machines during
manufacturing and packaging operations. Workers observe and interact
with production and packaging equipment, thereby increasing their
exposure to noise. Engineering methods reduce sound levels by modifying,
enclosing and dampening noise sources. Employee rotation and use of
hearing-protective devices (e.g., ear muffs and plugs) reduce workers’
exposure to high noise levels. Comprehensive hearing conservation
programmes identify noise sources, reduce workplace sound levels, and
train workers on the hazards of noise exposure and proper use of
hearing-protective devices. Noise monitoring and medical surveillance
(i.e., audiometry) assess worker exposures to noise and their resulting
loss of hearing. This helps to identify noise problems and evaluate the
adequacy of corrective measures.
Solvent vapour and potent compound exposures
Special concerns may arise when workers are exposed
to toxic solvent vapours and potent drugs as airborne dusts. Worker
exposures to solvent vapours and potent compounds may occur during
various manufacturing operations, which need to be identified, evaluated
and controlled to ensure that workers are protected. Engineering
controls are the preferred means of controlling these exposures, due to
their inherent effectiveness and reliability (Cole 1990; Naumann et al.
1996). Enclosed process equipment and material handling systems prevent
worker exposures, while LEV and PPE supplement these measures. Increased
facility and process containment is needed for controlling highly toxic
solvents (e.g., benzene, chlorinated hydrocarbons, ketones) and potent
compounds. Positive-pressure respirators (e.g., powered-air purifying
and supplied-air) and PPE are needed when highly toxic solvents and
potent compounds are handled and processed. Special concerns are posed
by operations where high levels of solvent vapours (e.g., compounding,
granulating and tablet coating) and dusts (e.g., drying, milling and
blending) are generated. Locker and shower rooms, decontamination
practices and good sanitary practices (e.g., washing and showering) are
necessary to prevent or minimize the effects of worker exposures inside
and outside the workplace.
Process safety management
Process safety programmes
are implemented in the pharmaceutical industry due to the complex
chemistry, hazardous materials and operations in bulk chemical
manufacturing (Crowl and Louvar 1990). Highly hazardous materials and
processes may be employed in multi-step organic synthesis reactions to
produce the desired drug substance. The thermodynamics and kinetics of
these chemical reactions must be evaluated, since they may involve
highly toxic and reactive materials, lachrymators and flammable or
explosive compounds.
Process safety management involves conducting
physical hazard testing of materials and reactions, performing hazard
analysis studies to review the process chemistry and engineering
practices, examining preventive maintenance and mechanical integrity of
the process equipment and utilities, implementing worker training and
developing operating instructions and emergency response procedures.
Special engineering features for process safety include selecting proper
pressure-rated vessels, installing isolation and suppression systems,
and providing pressure relief venting with catch tanks. Process safety
management practices are similar in the pharmaceutical and chemical
industries when manufacturing bulk pharmaceuticals as speciality organic
chemicals (Crowl and Louvar 1990; Kroschwitz 1992).
Environmental Issues
The different pharmaceutical manufacturing processes each have their own environmental issues, as discussed below.
Fermentation
Fermentation generates large volumes of solid waste
which contains mycelia and spent filter cakes (EPA 1995; Theodore and
McGuinn 1992). Filter cakes contain mycelia, filter media and small
amounts of nutrients, intermediates and residual products. These solid
wastes are typically non-hazardous, yet they may contain solvents and
small amounts of residual chemicals depending upon the specific
chemistry of the fermentation process. Environmental problems may
develop if fermentation batches become infected with a viral phage which
attacks the micro-organisms in the fermentation process. Although phage
infections are rare, they create a significant environmental problem by
generating large amounts of waste broth.
Spent fermentation broth contains sugars, starches,
proteins, nitrogen, phosphates and other nutrients with high
biochemical oxygen demand (BOD), chemical oxygen demand (COD) and total
suspended solids (TSS) with pH values ranging from 4 to 8. Fermentation
broths can be treated by microbiological wastewater systems, after the
effluent is equalized to promote the stable operation of the treatment
system. Steam and small amounts of industrial chemicals (e.g., phenols,
detergents and disinfectants) maintain the sterility of the equipment
and products during fermentation. Large volumes of moist air are
exhausted from fermentors, containing carbon dioxide and odours which
may be treated before they are emitted to the atmosphere.
Organic synthesis
Wastes from chemical synthesis are complex due to
the variety of hazardous materials, reactions and unit operations
(Kroschwitz 1992; Theodore and McGuinn 1992). Organic synthesis
processes may generate acids, bases, aqueous or solvent liquors,
cyanides and metal wastes in liquid or slurry form. Solid wastes may
include filter cakes containing inorganic salts, organic by-products and
metal complexes. Waste solvents in organic synthesis are usually
recovered by distillation and extraction. This allows the solvents to be
reused by other processes and reduces the volume of liquid hazardous
wastes to be disposed of. Residues from distillation (still bottoms)
need to be treated before they are disposed. Typical treatment systems
include steam stripping to remove solvents, followed by microbiological
treatment of other organic substances. Volatile organic and hazardous
substance emissions during organic synthesis operations should be
controlled by air pollution control devices (e.g., condensers,
scrubbers, venturi impingers).
Waste water from synthesis
operations may contain aqueous liquors, wash water, discharges from
pumps, scrubbers and cooling systems, and fugitive leaks and spills (EPA
1995). This waste water may contain many organic and inorganic
substances with different chemical compositions, toxicities and
biodegradabilities. Trace amounts of raw materials, solvents and
by-products may be present in aqueous mother liquors from
crystallizations and wash layers from extractions and equipment
cleaning. These waste waters are high in BOD, COD and TSS, with varying
acidity or alkalinity and pH values ranging from 1 to 11.
Biological and natural extraction
Spent raw materials and solvents, wash water and
spills are the primary sources of solid and liquid wastes (Theodore and
McGuinn 1992). Organic and inorganic chemicals may be present as
residues in these waste streams. Usually, waste waters have low BOD, COD
and TSS, with relatively neutral pH values ranging from 6 to 8.
Pharmaceutical manufacturing of dosage forms
Pharmaceutical manufacturing of dosage-form
products generates solid and liquid wastes during cleaning and
sterilization, and from leaks and spills and rejected products (Theodore
and McGuinn 1992). Drying, milling and blending operations generate
atmospheric and fugitive dust emissions. These emissions can be
controlled and recycled to the manufacturing of dosage form products;
however, quality control practices may prevent this if other residues
are present. When solvents are used during wet granulation, compounding
and tablet coating, VOCs and hazardous air pollutants may be released to
the atmosphere or in the workplace as process or fugitive emissions.
Waste waters may contain inorganic salts, sugars, syrups and traces of
drug substances. These waste waters usually have low BOD, COD and TSS,
with neutral pH values. Some antiparasitic or anti-infective drugs for
humans and animals may be toxic to aquatic organisms, requiring special
treatment of liquid wastes.
Environmental pollution prevention
Waste minimization and pollution prevention
Good engineering and administrative practices
minimize the environmental impact of bulk chemical production and
pharmaceutical manufacturing operations. Pollution prevention employs
modifying processes and equipment, recycling and recovering materials
and maintaining good housekeeping and operating practices (Theodore and
McGuinn 1992). These activities enhance the management of environmental
issues, as well as worker health and safety.
Process modifications
Processes may be modified to reformulate products
by using materials that are less hazardous or persistent or changing
manufacturing operations to reduce air emissions, liquid effluents and
solid wastes. Reducing the amount and toxicity of wastes is wise, since
it improves the efficiency of manufacturing processes and reduces the
costs and impacts of waste disposal. Government drug approval
regulations may limit the ability of pharmaceutical manufacturers to
change hazardous materials, manufacturing processes, equipment and
facilities (Spilker 1994). Drug manufacturers must anticipate the
environmental, health and safety impacts of selecting hazardous
materials and designing manufacturing process at an early stage. It
becomes increasingly difficult to make changes during the later stages
of drug development and regulatory approval, without considerable loss
of time and expense.
It is very desirable to
develop manufacturing processes with less hazardous solvents. Ethyl
acetate, alcohols and acetone are preferable to highly toxic solvents
such as benzene, chloroform and trichloroethylene. Whenever possible,
some materials should be avoided due to their physical properties,
ecotoxicity or persistence in the environment (e.g., heavy metals,
methylene chloride) (Crowl and Louvar 1990). Substituting aqueous washes
for solvents during filtrations in bulk chemical production reduces
liquid wastes and vapour emissions. Also, substituting aqueous for
solvent-based solutions during tablet coating reduces environmental,
health and safety concerns. Pollution prevention is promoted by
improving and automating process equipment, as well as performing
routine calibration, servicing and preventive maintenance. Optimizing
organic synthesis reactions increases product yields, often decreasing
the generation of wastes. Incorrect or inefficient temperature, pressure
and material control systems cause inefficient chemical reactions,
creating additional gaseous, liquid and solid wastes.
The following are examples of process modifications in bulk pharmaceutical production (Theodore and McGuinn 1992):
· Minimize the quantities of hazardous
materials used and select materials whose wastes can be controlled,
recovered and recycled, whenever possible.
· Develop and install systems for recycling
raw materials (e.g., solvents), intermediates, wastes and utility
materials (e.g., cooling water, heat transfer liquids, lubricants, steam
condensate).
· Examine reactants, solvents and catalysts to optimize the efficiency of chemical reactions.
· Modify the design and features of processing equipment to minimize pollution and wastes.
· Improve processes to maximize product yields
and desired properties, eliminating additional processing (e.g.,
re-crystallization, drying and milling).
· Consider using multi-purpose equipment
(e.g., reactors, filters and dryers) to reduce pollution and wastes
during transfers, cleaning and additional process steps.
· Use appropriate instruments, automated
control systems and computer programs to maximize the efficiency of
processes and reduce pollution and wastes.
Resource recovery and recycling
Resource recovery uses waste products and reclaims
materials during processing by separating waste impurities from desired
materials. Solid wastes from fermentation (e.g., mycelia) may be added
to animal feeds as a nutritional supplement or as soil conditioners and
fertilizers. Inorganic salts may be recovered from chemical liquors
produced during organic synthesis operations. Spent solvents are often
recycled by separation and distillation. Air emission control devices
(e.g., condensers, compression and refrigeration equipment) greatly
reduce emissions of volatile organic compounds to the atmosphere (EPA
1993). These devices capture solvent vapours by condensation, enabling
the reuse of solvents as raw materials or for cleaning vessels and
equipment. Scrubbers neutralize or absorb acid, caustic and soluble
gases and vapours, discharging their effluents to waste treatment
systems.
Recycled solvents may be reused as media for
performing reactions and extractions, and cleaning operations. Different
types of solvents should not be mixed, since this reduces their ability
to be recycled. Some solvents should be segregated during processing
(e.g., chlorinated and non-chlorinated, aliphatic and aromatic, aqueous
and flammable solvents). Dissolved and suspended solids are extracted or
separated from the solvents, before the solvents are recovered.
Laboratory analysis identifies the composition and properties of waste
solvents and recycled raw materials. Many new waste prevention and
control technologies are being developed for solid, liquid and gaseous
wastes.
General housekeeping and operating practices
Written operating
procedures, material-handling instructions and waste management
practices reduce the generation and improve the treatment of wastes
(Theodore and McGuinn 1992). Good operating and housekeeping practices
identify specific responsibilities for generating, handling and treating
wastes. Training and supervision of operating staff increases their
ability to improve and maintain efficient manufacturing and waste
management operations. Workers should be trained on the hazards of waste
management practices and the proper means of responding to emergency
spills, leaks and fugitive emissions. Worker training should address
material handling, cleaning or neutralizing wastes and wearing
respirators and PPE. Spill and leak detection devices prevent pollution
by routinely monitoring production equipment and utilities, identifying
and controlling fugitive emissions and leaks. These activities may be
successfully integrated with preventive maintenance practices to clean,
calibrate, replace and repair equipment that creates pollution.
Written instructions describing normal operating
procedures, as well as start-up, shut-down and emergency procedures,
prevent pollution and reduce risks to worker health and safety. Careful
management of material inventories decreases the excessive purchasing of
raw materials and generation of wastes. Computer systems can assist the
effective management of plant operations, maintenance practices and
material inventories. Automatic weighing, monitoring and alarm systems
can be installed to improve the management of materials and equipment
(e.g., storage tanks, process equipment and waste treatment systems).
Modern instrument and control systems often increase the productivity of
operations, reducing pollution and health and safety hazards.
Comprehensive pollution prevention programmes examine all wastes
generated at a facility and examine the options for eliminating,
reducing or treating them. Environmental audits examine the strengths
and weaknesses of pollution prevention and waste management programmes,
seeking to optimize their performance.
EFFECTS OF SYNTHETIC OESTROGENS ON PHARMACEUTICAL WORKERS: A UNITED STATES EXAMPLE
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Pharmacology is the branch of biology concerned with the study of drug action,[1]
where a drug can be broadly defined as any man-made, natural, or
endogenous (from within body) molecule which exerts a biochemical or
physiological effect on the cell, tissue, organ, or organism (sometimes
the word pharmacon is used as a term to encompass these endogenous and exogenous bioactive
species). More specifically, it is the study of the interactions that
occur between a living organism and chemicals that affect normal or
abnormal biochemical function. If substances have medicinal properties,
they are considered pharmaceuticals.The field encompasses drug composition and properties, synthesis and drug design, molecular and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular communication, molecular diagnostics, interactions, toxicology, chemical biology, therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. Pharmacodynamics studies the effects of a drug on biological systems, and Pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion (ADME) of chemicals from the biological systems. Pharmacology is not synonymous with pharmacy and the two terms are frequently confused. Pharmacology, a biomedical science, deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with application of the principles learned from pharmacology in its clinical settings; whether it be in a dispensing or clinical care role. In either field, the primary contrast between the two are their distinctions between direct-patient care, for pharmacy practice, and the science-oriented research field, driven by pharmacology.
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