UNIT OPERATION / PRODUCTION PROCESS


Pharmaceutical Unit Operations for Small Molecules

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).

pharmaceutical factory workshop interior

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.

pharmaceutical factory equipment mixing tank on production line in pharmacy industry manufacture factory

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.

pharmaceutical factory equipment mixing tank on production line in pharmacy industry manufacture factory

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. 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).

Water purification filter equipment in plant

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.

Plovdiv,Bulgaria - January 16, 2017 :  Operator with protective clothing inspecting a pharmaceutical plant

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. 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.

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. 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. 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.

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.

mill.PNG

Blending

pharmaceutical powder mixer machine, 3d render isolated on white

V-Blender

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.

pharmaceutical factory woman worker operating tablet production line at pharmacy industry manufacture factory

Sterile manufacturing

Sterile products are manufactured in pharmaceutical manufacturing plants with modular design, 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.

Corridors For Clean room pharmaceutical plant Pharmaceutical industry. Pharmaceutical factory worker operating pharma granulator dryer and fluid bed system at pharmaceutical factory

Scientists in protective suits in the "clean room" are working with new materials.

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).   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.