HYGIENIC REQUIREMENTS FOR PLANNING, EQUIPMENT AND IMPROVEMENT OF PHARMACY

HYGIENIC REQUIREMENTS FOR PLANNING, EQUIPMENT AND IMPROVEMENT OF PHARMACY.

OCCUPATIONAL HYGIENE IN PHARMACIES AND PHARMACEUTICALINDUSTRIES. HYGIENIC REQUIREMENTS FOR DRUG MANUFACTURING.

 

Pharmacy is the art and science of preparing and dispensing drugs for preventing, diagnosing or treating diseases or disorders in humans and animals.

 

 

Pharmacy  establishments carry out service of population  and treatment-prophylaxis establishments medications. To pharmacy (pharmaceutical) establishments belong: pharmacies, pharmacy bases (compositions) and control-analitic laboratories.

Pharmacy  establishments carry out service of population  and treatment - prophylaxis establishments medications. To pharmacy (pharmaceutical) establishments belong: pharmacies, pharmacy bases (compositions) and control-analitic laboratories, sanatorium-resort, and other establishments of health protection, enterprises, establishments and organizations by medications and wares of the medical setting.

All types of pharmacies have much general in a structure and equipment, organization  of labour, however differ character and specific of production activity.

A pharmacy on which the administrative is fixed and organization-metodical guidance by the pharmacies of district (cities) is named a central district (city) pharmacy.

A pharmacy which is intended exceptionally for providing of one or a few hospitals and other establishments of health protection by medicines and articles of the medical setting is named accordingly hospital or by a treatment pharmacy.

The pharmacy of general type are divided on: 1) pharmacy which carry out making of medical forms realization of medicinal preparations; 2) - pharmacywhich carry out realization of medicinal preparations only.

Pharmacy can create in the set order structural subdivisions are separated as pharmacy points and pharmacy booths. Pharmacy points are created at establishments of health protection, pharmacy booths – on factories, factories, stations, shopping centres and others like that. Placing of pharmacy booths is shut out on territories of the zebra crossings (underground), transport stops, markets (fairs), market grounds, stations of underground passage and in grocery stores.

 

Lot land of pharmacy as a rule takes place in  a settlement with the purpose of the most complete providing of population medications.

A norm of pedestrian availability between separate pharmacies must be not less than 300-400 m in settlements with a population over 1 million habitants, and also 600-700 m in settlements to 1 million habitants. The norms of the minimum providing of population pharmacy establishments are resulted.

In settlements with a quantity to 10 thousand of habitants expedience of opening of pharmacies is determined depending on local terms on the basis of compounding and commodity turnover, that folded taking into account the middle requirements of one habitant in medical commodities, amount of population, that served by them, and the proper changes in the future. On occasion opening of pharmacies can be carried out with permission the local organs of executive power with the rejection of demographic indicators, gustoti of network of treatment-prophylaxis establishments, economic factors, transport providing and others like that.

In the cities of pharmacy of naychastishe are built-in and situeted on the ground floors of buildings. Pharmacies in small settlements have separate buildings, located on the taken lot lands.

In the cities of pharmacy of naychastishe are built-in and rozmischayut'sya on the ground floors of buildings. Pharmacies in small settlements have separate buildings, located on the taken lot lands. Lot land of pharmacy rozmischaet'sya from a weather-side in relation to objects which contaminate atmospheric air, out of limits them sanitary areas.

GENERAL LAYOUT

 

The sizes of lot land must make 0,05-0,2 ga area.

A site of area area must not exceed 15 % from a general plottage. A large value gets to planting of greenery of area for diminishing of noise, zapilenosti and gassed. The area of planting of greenery must make not less than 60 % from the area of all area.

Pharmacies it follows rozmischati on distance a not less than 15 m from the red line of building.

HOSPITAL PHARMACIES

For the rational planning hospital pharmacies part after the amount of beds which are served, on 5 groups: to 200, 400, 600, 800 and 1000 beds.

A hospital pharmacy it is most  expedient situeted in separate building. At placing of pharmacy in hospital corps, it it is expedient to dispose in the treatment-diagnostic block of main corps. Pharmacy in a general hospital corps it is desirable rozmischati on a ground floor. It must have an independent output  outside and to move away from the apartments of other setting by walls .

The pharmacy it follows to foresee a unloading ground on the contrary for the entrance of machines (footlights are with a cover). Its height must answer the level of bottom of basket of truck, width near two meters.

Hospital pharmacies are foreseen in treatment- prophylaxis establishments on 500 and more beds, and in settlements with one treatment- prophylaxis establishment of less power - at presence of in him not less than 100 hospital bunks. In the case of presence in composition of hospital, by power less than 500 beds of policlinic, there can be the organized pharmacy, which serves both a population and permanent establishment.

 

 

Ttreatment- prophylaxis ESTABLISHMENT of pharmacy this part after the amount of beds which are served, on three groups: 1 group – from 500 to 1000, 2 group – to 2000 and 3 groups are to 3000 beds.

Ttreatment- prophylaxis ESTABLISHMENT of pharmacy get organized mainly in cities and situeted within the limits of city or on territory of Ttreatment- prophylaxis establishment.

PHARMACIES OF GENERAL TYPE

The pharmacies of general type can situeted: in separate buildings; in buildings, blok and blok-system establishments, enterprises and inhabited houses; on ground floors multistory, public and inhabited houses. In rural locality of pharmacy it is expedient situated in a complex with Ttreatment- prophylaxis establishments (by policlinics, by out-patient's clinics and others like that) on one territory or in one building, but with a private entrance.

Its height must answer the level of bottom of basket of truck, width near  2 m.

 

Structural subdivisions of pharmacies – pharmacy points and pharmacy booths must occupy the separated apartments only in capital buildings. In these an apartment is forbidden storage and use of meal.

Pharmacy points. Pharmacy points are created only in the apartments of treatment-prophylaxis establishments. A minimum room measure is a 18 m2. The apartments of pharmacy point are equipped by shelvings, closets, refrigerator, safe for storage of poisonous medications, rukomiynikom.

Pharmacy booth.  The apartment of pharmacy booth is equipped by shelvings, closets, refrigerator. Minimum room measure - 8 m2.

TERMS OF LABOUR OF PERSONNEL OF PHARMACIES

ARE HYGIENICAL ESTIMATION OF TECHNOLOGICAL PROCESSES OF MAKING AND REALIZATION OF MEDICATIONS

The technological process of making and realization of medications in pharmacies must provide the certain sequence of technological operations, eliminate here possibility of meetings worlflows and to provide the safe terms of labour of personnel.

 However, the terms of labour in pharmacies have the professional features which are characterized by a permanent contact with numerous, including by drastic, medicinal matters, large stake of hand laborious labour which requires permanent attention and considerable tension of visual analyzer, and also necessity to socialize with the large number of visitors which patients can be among. In the process of making of medicinal preparations in the conditions of pharmacy at violation of the sanitary mode nedotrimanni of hygienical norms on workings can render influence factors of production environment, among which basic is: mikroclimat terms; noise; luminosity; dust of medicinal preparations, toxic gases and pair; microbal factor and others like that.

 

 

 

The features of labour in pharmacy terms require large responsibility from a personnel, and emotional tension and undoubtedly affects morbidity and state of their health. In particular, set connection between sanitary-hygenic terms and professional features of labour and state of health. Illnesses of breathing organs, allergic diseases, nervous and feeling organs diseases, hypertensive illness, illnesses of muliebrias, prevail in the structure of morbidity. A considerable group is made by persons with chronic diseases. The workers of trading floor are ill more frequent other. By a basic factor for the workers of trading floor (druggists, cashiers)   bacterial influence of which can  increase the microclimate and in a less measure by influence of medicinal matters. Quinsies prevail in the structure of their morbidity, flu, rheumatism.

Medical personal which are directly busy  at making of medications, test influence of dust and aerosols of medications and chemical matters on a background large emotional and nervous tension. For them considerable part of work is made by hand labour with the large number of manipulations which require surplus attention and tension of visual analyzer. Allergic diseases, hypertensive illness and defeat of the nervous system, prevail in the structure of morbidity of this group.

 

 

For administrative workers lead is the large nerve system disease loading with the characteristic increase of frequency of cardiovascular diseases (ischemic heart trouble, hypertensive illness, nervous breakdown and others like ).

 

NATURAL ILLUMINATION

A light coefficient (CL) is in an assistant, to the room of pharmacy, aseptic must be 1:4, in other apartments of pharmacy within the limits of 1:6-1:7.

A coefficient of natural illumination (CNL) is in an assistant, to the room of pharmacy, aseptic must be evened, - 2 %, in other apartments of pharmacy - 1,5-0,5 %.

Insolation of apartments (continuous direct sun irradiation) of pharmacy must be not less than 3 hours in a day. It is in that time impossible to assume the over heat of apartments, violation of optimum microclimate terms.

The orientation of apartments of pharmacy after the sides of the world plays a considerable role in providing. Optimum for the basic shopfloors of pharmacy is a south and south-east orientation.

A coefficient of deepening at one-sided illumination is a relation of depth of apartment (distance is from wall to opposite) to the height of overhead edge of window must not be more than 2,0.

A large value has evenness of illumination, as frequent translation of look from more lighted up surface on less lighted up and vice versa draws the strong fatigue of eyes, especially for a pharmacy, technology and druggist during work weighing on analytical scales, consideration of shallow suspensions in solutions.

Lightning

Lightning of shop floors of pharmacies must create a sufficient level and evenness of luminosity of apartments and workplaces for providing of necessary sharpness of sight, speed of distinction of shallow details and firmness of clear vision.

 

Lamplight of pharmacy apartments is carried out by luminescent lamps and balb lamps. Luminescent illumination is wider used in pharmacy.

It costs to foresee lamps, which answer lightning technology, hygienical and architectonically artistic to the requirements in a trading floor. Lamps must not only create the necessary level of luminosity but also satisfy to the aesthetically beautiful necessities of visitors. The artistically designed chandeliers, plafonds which are harmoniously combined with the decorative finishing of trading floor, are used for this purpose.

Level of luminosity point-of-sale due to luminescent illumination must make 150 lx, and compounding department, department of the prepared medications, hand sale, optics - 300 lx.

Assistant is basic functional subsection of pharmacy. It is here expedient to use lamps with luminescent lamps; it is noncommunicative located above workers placed. Except for general illumination, on the workplaces of pharmacists-technologists and druggists the lamps of local illumination are set with lamps, which answer the spectrum of lamps, in-use in the system of general illumination.

Level of luminosity an assistant, aseptic, room of pharmacutist-analitic, packing, due to luminescent illumination must make 500 lx.

 

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 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 . 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 /

 

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 . 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 . 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 . 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 . 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 . 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 ().

 

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 ). 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  

 

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

 

 

 

 

 

 

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) . 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 .

 

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 . 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 ). 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.

 

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Table  79.2.     Solvents used in the pharmaceutical industry

 

 

 

 

 

C = chemical synthesis, F = fermentation, B = biological or natural extraction.

 

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

 

 

 

 

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 .

 

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

 

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

 

 

 

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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). 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) .

 

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.

 

 

Figure  79.10.       A high steam granulator

 

 

 

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  79.11.      A rotary vacuum dryer

 

 

 

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 atmospheres; 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  79.12.       A vacuum shelf dryer

 

 

 

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). 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 . 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.

 

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Figure  79.13.      Tablet press with load hopper and spiral dust pickups for product recovery

 

 

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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. 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.

 

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Figure  79.14.     A tablet coating machine

 

 

    

Source: Perry 1984

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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 ). 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.

 

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Figure  79.15.      Diagram of a sterile liquid manufacturing facility

 

 

 

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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 ). 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 ):

 

· 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.

 

CONTAMINATION OF AIR ENVIRONMENT

 

     The sources of contamination of air environment of pharmacy establishments are visitors, personnel, atmospheric air, production  equipment and  technological processes of making of medications but other The basic factors of contamination of air of apartments is a dust, pair of chemical matters, microorganisms and others like that.

By a specific production factor, peculiar only there is influence on the personnel of medicinal preparations pharmay, pharmacy establishments and enterprises of chemical-pharmacutical industry. Only in the conditions of pharmacy and factory technology a working personnel during all working day directly contacts with liquid or drugs. At violation of the sanitary-hygenic mode, technological process and failure to observe of rules of the personal hygiene medications as  a dust or aerosols can through an air environment enter organism of workings through lights, skin and mucus shells. Getting on a skin, mucus shells, in the respiratory system, an aerosol can do specific unfavorable influence: toxic, irritate, allergic but other The row of medicinal matters can draw the combined influence simultaneously: toxic, allergen, irritate action and others like that.  

In microbal contamination of air of apartments a large role any object, which is used in the technological process of making of medications, air of pharmacy apartments pharmacy personnel, can play. Patients (with a sharp form and effaced ambulatory) come in a pharmacy, transmitters of exciters of infectious diseases. All of them are the source of infection which in various ways can be passed to from them the pharmacy workers.

Sanitary - antiepidemic measures provide health promotion activity among the patients and personnel, monitoring of an epidemic situation, including revealing vira- and bacteria carriers. With this purpose the system of the previous and periodic (current) medical surveys is introduced. So, pupils of medical schools, the students of medical high schools during  practice should pass obligatory physical examination with participation of physician, dermatovenerologist, they have to make fluorography (if this research was not taken during the previous 6 months), analysis feces on carriage of intestinal infections and helmints eggs, and the persons are more senior than 18 years - on HIV, RW and urethral (for women also vestibular and vaginal) smear on Neisseria gonorrhoeae.

          Before practice in maternity houses, newborn wards, children's hospitals (departments), surgical departments etc. it is necessary to pass inspection of stomatologist, otholaringologist with an obligatory capture smears on staphylococci tests (from a nose and fauces)

          Prior to the beginning work in maternity houses, children's hospitals and other MPI medical workers should to pass inspection including fluorography (6 months), RV and tests on gonorrhea, analysis on HIV they repeat every year, carriage of pathogenic staphylococcus and RW -too, tests on gonorrhea and analysis on HIV - 1 time per 6 months, on carriage - 1 time per 6 months will be carried out.

All hospitals should be supplied with a linen - accordingly of sheet of equipment at enough. Change of a linen by the patient should be carried out in process of its pollution, regularly, but not less once for one week. Polluted linen should be changed immediately. The change of bed-clothes for delivered women should be carried out 1 time per 3-4 days, body linen and towels - daily, under napkins - by the necessity. Change of a linen by the patient after operation should be carried out regularly to the discontinuance of exudation from wounds.

In maternity hospitals (patrimonial blocks and other premises with aseptic mode for newborn) should be used a sterile linen.

          The temporary (not more than 12 hours) preservation of dirty linen in departments could be provided in the shut container (metal, plastic boxes, dense boxes, and other capacities, which are subject of disinfecting). For work with a dirty linen the personnel should be supplied sanitary clothes (dressing gown, cap, mask, glove).

The clean linen should be stored in the special premises, deduced for it. In departments they should have a daily stock of a linen. Linen and container should be marked.

The washing of a hospital linen should be carried out by centralized way in special laundries at the hospitals. The washing of a linen in medical institutions is carried out in conformity with the instruction on technology of processing of a linen of medical establishments at factories – laundries.

The washing of hospital linen in urban municipal laundries on a condition of allocation on them of special technological lines is supposed which exclude an opportunity of contact of hospital linen with not hospital. The linen in infectious, observation and purulent - surgical departments before washing should give in disinfecting in special premises by processing of disinfecting solution in washing machines.

After recovery of the patient, his death, and also for the prevention of pollution a mattress, pillow, the blankets should be changed and a disinfected.

At the reception ward all in-patients will pass special sanitary processing in acceptance branch (acceptance soul or baths, the cutting of nails and other procedures) by the necessity. It depends on results of the examination.  They give to each patient soap and wiping  bast for personal use. After sanitary care the complete set clean body linen, pajamas, shoes (slippers) is given out to the patient. They keep the personal clothes and the footwear for safety in special container with hangers (polyethylenic bags, covers with a dense fabric etc.) or it is transferred to preservation to its relatives or familiars.

Washing of the patient is carried out not less than 1 time per week with marking in the case history. Hygiene of the seriously ill patients (washing, wiping of a skin of the person, parts of a body, rinsing oral cavity etc.) will carry out constantly after the meal and at pollution of a body. It should be organized a hair dressing and shaving for the patient. Each patient should be supplied with a personal towel and soap.  

The serving medical personnel of pharmacy establishment, patrimonial houses and other medical institutions should be supplied complete sets of the replaceable worker (sanitary) clothes: dressing gowns, caps, replaceable shoes (slippers) in quantities, that provides daily change sanitary clothes. All medical personnel of medical or patrimonial institutions have to be faultlessly tidy and accurate, edge of the worker (sanitary) clothes should completely close personal (home) clothes. The hair should completely be covered with caps. Change of footwear of the personnel of operational, patrimonial blocks, resuscitation, dressing rooms and newborn departments should be with non-fabric material, suitable for desinfecting.

The doctors, nurses should wash hands before the examination of each patient or performance of procedures, and also after "dirty procedures " (cleaning of premises, change of the patient linen, visiting of a lavatory etc).