Pharmaceutical Safety

Safety Implementations ? Table of Contents 1Abstract4 2Introduction5 3Safe Drug Development Process in Pharmaceutical Companies6 4Pharmaceutical Unit Operation Safety Measures10 4. 1Weighing and dispensing10 4. 2Charging and discharging10 4. 3Liquid separations10 4. 4Filtration11 4. 5Compounding11 4. 6Drying11 5Biosafety Levels12 5. 1Level 112 5. 2Level 212 5. 3Level 312 5. 4Level 413 6Personal Protective Equipment13 6. 1What is PPE? 13 6. 2OSHA Standards14 6. 3Types of PPE15 6. 3. 1Gloves16 6. 3. 2Footwear18 6. 3. 3Eyewear20 6. 3. 4Hearing Protection22 . 3. 5Hazmat Suit22 7Biological Safety Cabinets25 8Pharmaceutical Cleanroom Classification28 9Gowning29 10Autoclave31 11Case Studies33 11. 1Case Study #1: Explosion of Organic Powder33 11. 2Case Study #2 – Reactor Grounding36 11. 3Case Study #3: West Pharmaceutical38 11. 4Case Study #4: Effects of oestrogens on pharmaceutical workers41 12Suggested Improvements44 13Conclusions46 14Articles46 15References47 1Abstract The following paper encompasses an in depth discussion in the various safety implementations in the pharmaceutical industry.

A thorough study of various personnel protective equipment for pharmaceutical personnel was discussed including eyewear, glove wear, hearing protection, and foot protection. As well, the OSHA standards which personal protective equipment adhere to are discussed. The safety features for equipment used in the pharmaceutical industry were discussed. Safety devices implemented to protect the environment from the liquid and solid wastes as well as airborne contaminants are discussed.

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A number of various case studies outlining deficiencies in safety implementation in the industry are discussed. 2Introduction The pharmaceutical industry is a very complex one which is comprised of different sectors such as public and private organizations, research and development companies, and hospitals whose responsibility is to discover, research and develop drugs for human and animal health. Because the industry is always changing and new research and innovations are developed as time progresses, this creates a large concern regarding worker safety and health.

The Food and Drug Administration (FDA) is the regulatory agency that controls the pharmaceutical facility and equipment design, and ensures worker and consumer safety. In order for a drug to be sold commercially, strict procedures and documentation is needed and implemented in the pharmaceutical facility itself. The FDA then performs an audit ensuring the company followed the strict guidelines, and once passed, they are allowed to commercially produce their drug. Along with the above mentioned guidelines, there are cGMP guidelines (current good manufacturing practice) that are enforced by the FDA as well.

There are also numerous equipment safety concerns that one needs to be aware of in pharmaceutical industry. The following report will outline several aspects of safety implementation in the pharmaceutical industry. First will be a general overview of what personal protection is, and what kind of equipment are used in a pharmaceutical facility. FDA regulations will be analyzed in terms of a safety laws that must be followed. The safety hazards of some of the common equipment used in the pharmaceutical industry will also be identified.

A literature review will be conducted of a pharmaceutical company’s current safety precautions taken in their facilities. Furthermore, case studies will be analyzed where accidents occurred because of a lack of safety implementation in manufacturing and production of drugs. 3Safe Drug Development Process in Pharmaceutical Companies Many factors influence the role of pharmaceutical companies on a social level. The activities of pharmaceutical companies are subject to legislation and regulation with regards to drug development and approval, manufacturing and quality control, and marketing and sales.

Health care providers in hospitals and pharmacy clinics must prescribe medicine or recommend on how they should be dispensed to the consumer (OHSA, 2009). The legislations that are carried by the FDA are heavily influenced by the public, which is driven largely by scientific discovery, but must follow the legislation set by each country and government. Many countries have specific legal protection known as intellectual property (OHSA, 2009). This system is adapted by the Canadian government. Usually when a scientific discovery is made, the company or researcher must patent their findings.

In doing so, another researcher or pharmaceutical company cannot manufacture the same drug for commercial use until the entire length of the patent is complete (OHSA, 2009). Many different chemical and biological agents are discovered and used by the pharmaceutical industry (OHSA, 2009). Because of the nature of the production of these drugs, many agents used are toxic and hazardous to workers. Since worker exposures may be hazardous, occupational exposure limits such as TLVs (threshold limit values) have been established (OHSA, 2009).

The main different types of pharmaceutical manufacturing that need to be analyzed in terms of safety are fermentation, chemical synthesis, and biological extraction (OHSA, 2009). The figure on the following page is a summary of the uses for various drugs that have been developed over time (OHSA, 2009). For example, the category of analgesics represents drugs that are used that affect the central nervous system. If this drug is not needed but is ingested, the worker may be affected negatively, and can be severely injured (OHSA, 2009). Figure 1: Various types of drugs and their effects (OHSA, 2009)

For the fermentation part of the industry, process safety concerns are less than in the chemical synthesis phase (Avallone, 1992). This is because fermentation is based on aqueous chemistry that requires process containment for bacterial and microbial growth (Avallone, 1992). Fire and explosion hazards are often when dealing with solvents, however, for the fermentation process, the solvents used are highly diluted in the filtration and recovery steps (Avallone, 1992). Thermal burns and scalding can occur by the large volumes of pressurized steam and water used with some fermentation operations (Avallone, 1992).

For chemical synthesis in pharmaceutical industries, the method of production is the use of organic and inorganic chemicals in a batch to produce drugs with unique properties and effects (OHSA, 2009). Since synthetic manufacturing processes are becoming increasingly complex, they are turning into multi-step processes. During each of the separate steps, different functions are performed with different equipment, which poses a variety of different hazards the worker must face when dealing with such equipment (OHSA, 2009).

For example, a rotary dryer is usually used at the end of a process when the final drug is turned into a powder that is to be packed with filler. Some safety hazards that could occur from the synthesis process is moving equipment parts, such as for the rotary dryer (OHSA, 2009). Also, since most of the reactions are performed in pressurized vessels, any leak can severely burn and injure the worker. Because of this, workers dealing with very potent chemicals wear respirators to aid in breathing (OHSA, 2009).

This is further explained in the personal protective equipment section. Other sources of hazards for workers could be from hot liquids, pipes, hot workplace environments, heated surfaces, or high noise levels (OHSA, 2009). Acute or chronic health risks may also arise from constant exposure to a certain type of drug. Chemicals with acute health effects can damage eyes, skin, or suffocation and oxygen deficiency (OHSA, 2009). Chemicals with chronic health effects can cause cancer, damage internal organs, or affect a certain system in the human body (OHSA, 2009).

These hazards can be contained be implementation of appropriate measures such as process controls, process modifications, engineering controls, and respiratory protective equipment (OHSA, 2009). For organic synthesis reactions, the procedure for drug development is far more dangerous. Usually process safety risks include highly hazardous materials, explosions, and uncontrolled chemical reactions. Figure 2: Synthetic process of pharmaceutical development (OHSA, 2009) Process safety is very complex in such types of drug manufacturing. First, the dynamics of possible reactions are examined in detail.

The by-products are also taken into account because of potential dispersion (OHSA, 2009). The figure above shows the steps involved in organic synthesis process. The crucial areas in terms of protection against hazardous chemicals are the reactor, the rotary dryer, and the excess acetic acid (OHSA, 2009). The solvent must be placed in a well circulated fume hood in order to eliminate any emissions to the environment (OHSA, 2009). For the reactor, any exothermic reactions must be well contained so that there is no release of any potentially lethal drug. Also, over pressurizing in the piping must also be safely accounted for (OHSA, 2009). 4Pharmaceutical Unit Operation Safety Measures 4. 1Weighing and dispensing These are very common activities in a pharmaceutical facility. Usually, workers dispense materials by hand-scooping solids or powders or pouring liquids with a pump (Stellman, 1998). These activities are usually performed in a warehouse during bulk production of the drug in dosage form. Since the likelihood of spills and emissions are very high, proper workplace control measures must be taken (Stellman, 1998). These should be performed in a partitioned area where there is sufficient ventilation.

The work areas during weighing and dispensing of extremely hazardous materials should be done in isolation devices such as glove boxes or laminar ventilation hoods (Stellman, 1998). 4. 2Charging and discharging The charging and discharging of materials are usually done throughout a process where portions of the final product are separated in segments (Stellman, 1998). It is often performed manually by a worker, or is sometimes done by a mechanical system. To prevent worker exposure, the process equipment is either contained, and engineering controls are used (Stellman, 1998).

Gravity charging can eliminate toxic environments and emissions of the hazardous material (Stellman, 1998). 4. 3Liquid separations Liquids are generally separated based on their physical properties. In the pharmaceutical industry, this is often done in bulk manufacturing operations (Stellman, 1998). Hazardous liquids should be transferred and separated in closed vessels to reduce worker exposure. Eyewash stations and safety showers should be placed near operations where hazardous materials are usually handled. Spill control measures and fire protection are required when using flammable materials (Stellman, 1998). . 4Filtration During filtration, solids and liquids are separated from one another. Usually the solid is the desired product, while the liquid can be a solvent (Stellman, 1998). Again, to reduce vapor emissions, enclosed process equipment can be used. Volatile solvent vapors can be handled in fume hoods with good ventilation, or can be controlled using scrubbers, absorbers or desorbers if required (Stellman, 1998). 4. 5Compounding During compounding, solids and liquids are mixed to produce solutions, pastes or slurries, depending on the type of application (Stellman, 1998).

Because of the wetness in the area as a result of compounding, the worker must be protected from electrical hazards of equipment, as well as thermal hazards from steam and hot water which are used to heat the material in order to mix together. By adding insulation to steam piping, worker injuries and burns can be prevented (Stellman, 1998). 4. 6Drying A batch of active pharmaceutical ingredients (APIs) may be sent to a dryer to remove the water content from it before it can be mixed with an excipient (a filler) to make a dosage tablet (Stellman, 1998).

Dryers have various designs, focusing on the most important aspect, which is the containment of solvent releases. The released solvent can pose a flammable atmosphere, resulting in a risk to the worker (Stellman, 1998). Explosion resistant relief systems should be instilled at this stage of the process. 5Biosafety Levels There are four levels of biosafety which pertain to specific pathogens discussed below: 5. 1Level 1 Level 1 laboratory contains only well-characterized agents which do not cause disease in healthy adult humans and have a minimum potential hazard to personnel and the environment (CDC, 2004).

Precautions against biohazards are minimal. Personnel are protected only with gloves, lab coat, and face shield. Work is done on lab bench. Personnel are to wash hands with anti-bacterial soap (CDC, 2004). All materials in contact with cell culture, viruses, or bacteria are toe be autoclaved appropriately. Some bacteria/viruses in Level 1 are E. coli and chicken pox (CDC, 2004). 5. 2Level 2 Level 2 laboratories are similar to Level 1, except they contain agents with a moderate potential hazard to personnel and the environment (CDC, 2004). The agents in Level 2 labs are difficult to contract by inhaling them.

Such biological agents include dengue fever, HIV, and measles (CDC, 2004). The laboratory personnel have to have specific training in handling pathogenic agents. Access to the laboratory is limited when work is being conducted. Extreme precautions are taken with sharp objects (CDC, 2004). Most work is conducted within biological safety cabinet to prevent any splashing on personnel. 5. 3Level 3 Level 3 laboratories are used for clinical and production facilities where work is done with exotic agents which may cause serious or potentially lethal disease after inhalation, but which treatment exists (CDC, 2004).

Such diseases include anthrax, tuberculosis, and SARS (CDC, 2004). Personnel working in these environments have specific training in handling the harmful agents (CDC, 2004). All procedures are done in a biological safety cabinet, in clean rooms, and the personnel are protected with appropriate PPE (CDC, 2004). 5. 4Level 4 This level is used for dangerous and exotic agents which pose a serious threat when inhaled. Some diseases include the Ebola virus, and Lassa fever. Personnel are to wear hazmat suits, and a self-contained oxygen supply (CDC, 2004).

Entrances and exits into the level 4 labs contain multiple showers, a vacuum room, and an ultraviolet room (CDC, 2004). Multiple airlocks are employed to secure and prevent doors from opening at the same time. All air and water going into the lab are sterilized appropriately as well. Access to the lab is severely limited (CDC, 2004). The lab is usually located in a separate building, or in an area isolated from all other areas of the building. The facility is under negative pressure to prevent any escape of aerosol pathogens.

All activities within the lab are conducted in class III safety cabinets (CDC, 2004). 6Personal Protective Equipment 6. 1What is PPE? Personal protective equipment, or PPE, is an important part of safety in various industries. They describe garments that are usually worn on a person that protects them from external hazards. A few examples of PPE are: •Hard hats (helmets) •Safety goggles •Ear plugs •Breathing assistance masks (respirators) •Protective gloves •Hazmat suits This list of equipment is not exhaustive, and there a number of other items that are used to increase safety (OSHA, 2009).

Specific PPE in the pharmaceutical industry does not vary greatly in terms of the purpose of the equipment. The simplest PPE (like latex gloves to protect the integrity of the chemicals being used, and to maintain sterility) can make the greatest impact on the success of a company. By properly utilizing PPE, the production rates (or rather, the occurrence of shutdowns that hinder production) can be greatly reduced (OSHA, 2009). The following sections will outline the use of specific PPE in the pharmaceutical industry, as well as describe a few instances where failing to use PPE lead to disastrous results. . 2OSHA Standards The Occupational Safety and Health Administration (or OSHA) outlines the use of PPE in the industry. These standards are set in order to reduce the number of incidents that lead to serious workplace injuries or illnesses that take place. OSHA’s primary PPE standards are listed in “Title 29” of the Code of Federal Regulations (CFR), Part 1910 Subpart I (Occupational Safety & Health Administration, 2009). The general PPE requirements by OSHA mandate that employers conduct hazard assessments of their workplaces to determine what hazards are present that require the use of PPE.

If hazards are present, it is the employer’s duty to provide the proper PPE to the worker’s. It is also the employer’s duty to train worker’s using PPE to do the following (Occupational Safety & Health Administration, 2009): •Use PPE properly •Be aware of when PPE is necessary •Know what kind of PPE is necessary •Understanding the limitations of PPE in protecting employees from injury •Don, adjust, wear, and doff PPE •Maintain PPE properly It has been shown over the years that worker’s are less likely to use PPE when they are unaware of the level of protection from serious injury that PPE offers and individual.

Properly training each worker increases the likelihood of the worker following through with what is required in terms of PPE. In addition to properly educating employees, having plant managers that reinforce the idea of the importance of PPE is crucial to success. When workers with several years of experience feel as though their experience alone can protect them from serious injury, it is the manager’s duty to ensure the workers that diverging from standard procedure cannot be tolerated.

It is here where serious accidents can be avoided, through the combination of upholding OSHA standards, properly educating workers, and ensuring the manager’s are reinforcing the standards that OSHA have set. 6. 3Types of PPE The types of PPE that are used in the pharmaceutical industry are designed to not only protect the employee’s that are directly using it, but also the consumer’s who eventually use the products that are being manufactured. Minimizing the amount of contact between the worker’s and the final product will minimize the number of accidents related to cross contamination.

The different types of PPE that are used will be outlined in this section. 6. 3. 1Gloves One of the most critical purchases in terms of PPE in the pharmaceutical industry are the selection of gloves used in clean rooms. Due to long hours, and the fact that gloves are in constant contact with the user, comfort and tactile sense are of high importance. The size, thickness, length, and material selection all affect the final level of comfort that the user will experience. The ultimate goal is to achieve a level of comfort for the user so that the average worker will not be tempted to remove the gloves for a period of time to get relief.

The gloves will also be in constant contact with the product, so the cleanliness and the protective properties of the gloves are critical as well. (Canadian Centre for Occupational Health and Safety, 2009) Natural rubber latex gloves have been the most popular choice for clean room glove PPE. Gloves of this type are the most elastic and durable, have good resistance to acids, and come in a variety of thicknesses and lengths. Latex gloves can also be customized for specific hands, or be fitted with smooth or textured fingertips to increase the dexterity of the user.

However, due to allergy concerns, and the decrease in price in other glove material types, latex gloves are being used less in the industry. The other large concern with latex is that as it deteriorates, the outer layer of latex decays and flakes off, reducing the overall cleanliness of the glove over time. Figure 3: Gloves composed of various materials (Canadian Centre for Occupational Health and Safety, 2009) Polyvinyl chloride (PVC) gloves offer a different set of advantages, in that PVC is generally inert, and does not shed or flake as it ages.

PVC is also non-allergenic and is cheaper than latex. However, PVC gloves are not nearly as durable or as protective as latex. Even fingernails can easily puncture the tips of PVC gloves through normal handling. To compensate for their weakness in durability, PVC gloves can be worn in layers. They offer poor resistance to acids or bases, and are not as fitting as latex gloves. In contract to PVC gloves, nitrile gloves are very durable; however, it is more difficult to process into thin, disposable gloves.

Though, with newer technologies, the problems with that existed with processing nitrile into disposable gloves is becoming less apparent. Nitrile has greater resistance to a larger number of chemicals, and performs well with solvents. It is also more puncture resistant than either latex or PVC gloves. Additionally, a nitrile gloves ability to form its shape to the hand of the user will reduce hand fatigue. When the latex allergy problem arose, the pharmaceutical industry has no choice but to resort to using nitrile gloves almost exclusively.

The pharmaceutical industries main focus was on biological contamination, and they required a glove that was powder free, disposable, and easily sterilized. The FDA regulates the way gloves are used in the pharmaceutical industry. For pharmaceutical ISO Class 5 environments or better, a new pair of loves must be donned, as well as a second pair of gloves over the first pair, upon entering a clean space. When a glove malfunctions, the glove must be replaced immediately with a new glove.

Some pharmaceutical companies go beyond what the FDA suggests, and required works to change gloves as many as four times per shift. When handling certain products, gloves may be changed as often as once an hour. This is to reduce the amount of biofilm build-up. 6. 3. 2Footwear The type of footwear that is worn while working in the plant of a pharmaceutical company depends on the type of hazards that are present in that particular area. In North America, the Canadian Standards Association International (CSA International) certifies and defines the different markings that appear on safety shoes.

Each protection marking corresponds to a certain set of safety features that are used optimally in different environments. ? Table 1: Classes of protection (Canadian Standards Association, 2009) Protection MarkingSafety FeaturesRecommended Use Green triangle indicates sole puncture protection with a Grade 1 protective toe to withstand impacts up to 125 Joules. Comparable to a 22. 7 kg (50 lb) weight dropped from 0. 6 m. Sole puncture protection is designed to withstand a force of not less than 1200 Newtons (270 lbs) and resist cracking after being subjected to 1. million flexes. For any industry, especially construction and heavy work environments, where sharp objects, such as nails are present. Yellow triangle indicates sole puncture protection with a Grade 2 protective toe to withstand impacts up to 90 Joules. Comparable to a 22. 7 kg (50 lb) weight dropped from 0. 4 m. Sole puncture protection is designed to withstand a force of not less that 1200 Newtons (270 lbs) and resist cracking after being subjected to 1. 5 million flexes. For light industrial work environments requiring puncture protection as well as toe protection.

Blue rectangle indicates Grade 1 protective toe without sole puncture protection. Grade 1 protective toe withstands impacts up to 125 Joules. Comparable to a 22. 7 kg (50 lb) weight dropped from 0. 6 m. For industrial work environments not requiring puncture protection. Grey rectangle indicates Grade 2 protective toe without sole puncture protection. Grade 2 protective toe withstands impacts up to 90 Joules. Comparable to a 22. 7 kg (50 lb) weight dropped from 0. 4 m. For institutional and non-industrial work environments not requiring puncture protection.

White rectangle with orange Greek letter omega indicates soles that provide resistance to electric shock. Such certified footwear contains a sole and heel design assembly that, at the point of manufacturing, has electrical insulating properties intended to withstand 18,000 Volts and a leakage current not exceeding 1 mA. For any industry where accidental contact with live electrical conductors can occur. Warning: Electrical Shock Resistance deteriorates with wear and in wet environments. The various designations listed in Table 1 can apply to the safety shoes used in the pharmaceutical industry.

There are other CSA markings (such as a green tree, which designates it is used for the forestry industry) but they do not apply to the pharmaceutical industry, and are not included in the table. The first two classes (green and yellow triangles) designate toe protection, while the next two classes (blue and grey rectangle) designate sole protection. Depending on the type of machinery that is being used, it may be important to use either of the class of shoe. The final class, designated by the orange omega symbol, is used as protection against electrical shock.

With large machinery, a large amount of electricity must be used, and by equipping the workers with this type of safety shoe, the number of electrical related injuries can be minimized. In addition to safety shoes, the pharmaceutical industry utilizes shoe covers, to minimize the amount of cross contamination. For office workers that do not normally enter the production facility, they are directed to use the shoe covers before entering the plant. Conversely, those who work primarily inside the plant are required to use shoe covers when leaving the plant.

By using this system, the likelihood of contaminants either entering or leaving the plant can be greatly reduced. 6. 3. 3Eyewear Protective eyewear in the pharmaceutical industry normally comes in the form of safety goggles or glasses. Their purpose is normally to protect the eye from various contaminants, such as chemical vapors, liquids, or particulates, from entering and damaging the eye. While there are certain protective eye wear that is meant to prevent light from damaging the eye (such as welder’s masks or blowtorch goggles), most pharmaceutical processes greater hazards are the mixing and handling of chemicals.

In this way, it is unnecessary for the lenses of the protective eyewear to be tinted to reduce the amount of light that is allowed to enter the user’s eyes. Additionally, while some processes require for the user to obtain prescription safety glasses that can be worn directly on the users face if they do have corrective lenses, there also exist protective eyewear covers that can go seamlessly over an individual’s existing eye glasses. These allow for all individuals entering a process area to be fully protected, whether or not they have access to prescription safety goggles in the first place.

Figure 4: Standard safety glasses (CCOHS, 2009) Most safety glasses that are used have the same safety features as highlighted in Figure 4. The CSA also certify safety glasses that are to be used in industrial areas. Safety glasses commonly have plastic polycarbonate lenses. They are fairly lightweight, highly impact resistant, and can be altered for individuals that require prescription lenses. They can also be coated with a chemical to be scratch resistant which lengthen the lifespan of the goggles. It is important to verify that the safety glasses that are being worn are the correct type for the work that is being done.

The lens marking located in the bottom right hand corner of the lenses will display the information about the manufacturer, where information can be provided to ensure the correct PPE has been selected. 6. 3. 4Hearing Protection When large units are being used, the amount of noise that is produced while the machine is operational can be great enough to cause long term damage to the hearing of the operators. Hearing protection must be used to reduce the level of noise that the user is experiencing. Hearing PPE normally comes in two forms, earmuffs and earplugs.

Both forms of hearing PPE can be used in conjuction for additional protection. Earplugs are designed to be inserted into the user’s ear canal which will greatly reduce the noise level. Earmuff’s are worn externally and perform the same function as earplugs. Table 2: CSA approved hearing protection standards (Canadian Standards Association, 2008) Time-Weighted Average (TWA) Noise Exposure (expressed in dBA)Recommended Class of Hearing Protection1 TWA less than 85 dBAHearing protection not required2 TWA up to 89 dBAClass C hearing protector TWA up to 95 dBAClass B hearing protector TWA up to 105 dBAClass A hearing protector

TWA up to 110 dBAClass A earplug + Class A or Class B earmuff TWA greater than 110 dBAClass A earplug + Class A or Class B earmuff and limited exposure 6. 3. 5Hazmat Suit A hazmat suit is a protective piece of clothing to protect an individual commonly used by emergency personnel, researchers, chemical spill specialists. Since most hazardous materials are present as vapors the suit is also equipped with a breathing apparatus (WHO, 2004). The suit provides protection for the following hazardous materials: chemical, nuclear, and biological agents as well as fire and high temperatures.

The table below shows the different levels of protection given by the hazmat suit (WHO, 2004): Table 3: Hazmat suit protection levels (WHO, 2004) LevelsDescription A•Total encapsulation (vapor-tight) •High level of protection against direct and airborne chemical contact • Self-contained breathing apparatus (SCBA) enclosed within the suit. B•Not vapor-tight •Less level of protection •Worn with an SCBA C• Coveralls or splash suits • Lesser level of protection •Worn with a respirator or gas mask D• Work clothing and eye (splash) protection Levels C and D are commonly called splash protection suits.

They serve to prevent contact with a liquid since they cannot protect against gasses or dust. Levels A and B are called gas tight suits (WHO, 2004). Gas tight suits encapsulate the individual completely, protecting the individual from airborne agents. A self contained breathing apparatus (SCBA) is located within the suit (WHO, 2004). The suit has a vent to prevent excessive inflation as a result of exhalation. Usually the duration of the exposure with the Level A or B suit is usually about 15-20 minutes. The SCBA’s can be one of the following types (WHO, 2004): •Headband strap filtering face piece respirator (FFR) Head harness negative full face pressure respirator, also known as an air-purifying respirator (APR) •Full face, tight fitting, breathing air closed or open circuit self-contained breathing apparatus (CC-SCBA or SCBA) This equipment was designed to prevent injury to workers. This type of equipment is commonly used in the biopharmaceutical industry since workers are commonly exposed to toxic organic vapors and diseases. 7Biological Safety Cabinets Biological safety cabinets are the primary means of containment for working safely with infectious microorganisms.

They are designed to provide personnel, environmental, and product protection (CDC, 2004). Three classes of biological safety cabinets, Class I, II and III, exist to meet varying research and clinical needs. High efficiency particulate air (HEPA) filters or ultra-low penetration air (ULPA) filters are used in the exhaust and/or supply systems of biological safety cabinets. HEPA filters are effective at removing 0. 3 µm-sized particles with an efficiency of at least 99. 97% (CDC, 2004). They are even more effective at removing both smaller and larger particles.

HEPA filters are effective at trapping particulates and infectious agents, but not capturing volatile chemicals or gases (CDC, 2004). Only cabinets exhausted to the atmosphere should be used when working with volatile toxic chemicals. In certain cases a charcoal filter may be added to prevent release of toxic chemicals into the atmosphere (CDC, 2004). Class I cabinets provides personnel and environmental protection, but no product protection. It is similar in air movement to a chemical fume hood, but has a HEPA filter in the exhaust system to protect the environment (CDC, 2004). Unfiltered room air is drawn across the work surface.

Personnel protection is provided by this inward airflow as long as a minimum velocity of 75 linear feet per minute (l fpm) is maintained through the front opening (CDC, 2004). Class II types A, B1, B2, and B3 biological safety cabinets provide personnel, environmental, and product protection (CDC, 2004). Air flow is drawn around the operator into the front grill of the cabinet, which provides personnel protection. In addition, the downward laminar flow of HEPA-filtered air provides product protection by minimizing the chance of cross-contamination along the work surface of the cabinet (CDC, 2004).

Since the cabinet air exhaust is passed through a certified exhaust HEPA filter, it is contaminant-free, and may be recirculated back into the lab or exhausted out of the building to the atmosphere. All class II cabinets are designed for work involving microorganisms assigned to biosafety levels 1, 2 and 3 (CDC, 2004). Class III biological safety cabinets are designed for work with microbiological agents assigned to biosafety level 4, and provide maximum protection to the environment and personnel (CDC, 2004). The following table summarizes the different biosafety cabinets employed in industry.

Table 4: Biosafety cabinet classes (CDC, 2004) BSC ClassFace Velocity (lfpm)Airflow PatternDiagramNonvolatile Toxic ChemicalsVolatile Toxic Chemicals I75In at front; exhausted through HEPA to the outside or into the room through HEPA (see Fig. 2) YesYes II A7570% recirculated to the cabinet work area through HEPA; 30% balance can be exhausted through HEPA back into the room or to the outside through a thimble unit YesNo II B1100Exhaust cabinet air must pass through a dedicated duct to the outside through a HEPA filter YesYes (minute amounts)

II B2100No recirculation; total exhaust to the outside through hard-duct and a HEPA filter YesYes (small amounts) II B3100Same as II, A, but plenums are under negative pressure to room; exhaust air is thimble-ducted to the outside through a HEPA filter YesYes (minute amounts) IIIN/ASupply air inlets and hard-duct exhausted to outside through two HEPA filters in series YesYes (small amounts) 8Pharmaceutical Cleanroom Classification Sterile products should be manufactured in clean areas, where entry of personnel, raw materials, and equipment is through air locks, and involves thorough decontamination.

Clean areas are maintained at an appropriate cleanliness standard, and supplied with air which has passed through filters of an appropriate efficiency (WHO, 2004). Clean rooms are classified into the following grades (WHO, 2004): •Grade A: Clean areas for high risk operations like a filling suit, where there are open vials, and making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed of 0. 45 m/s +/- 20% at the working position. Grade B: In case of aseptic preparation and filling, the background environment for grade A zone. •Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. The airborne particulate acceptance limits are given in the table below: Table 5: Airborne particulate counts for clean rooms (WHO, 2004) At restIn operation Maximum number of particles permitted/m¬3Maximum number of particles permitted/m¬3 Grade0. 5 – 5. 0µm>5. 0µm0. 5 – 5. 0µm>5. 0µm A3,50003,5000 B3,5000350,0002,000 C350,0002,0003,500,00020,000 D3,500,00020,000Not definedNot defined

All clean rooms are validated with the number of personnel at over-capacity within the room by the use of environmental monitoring machines and agar plates. 9Gowning Another important safety implementation within the pharmaceutical industry is the use of aseptic gowning, to serve the purpose of protecting the personnel as well as the product. Below is an example of the gowning procedure to enter Grade A, B, C, and D areas (WHO, 2004). •Grade A or B: Tyvek suit, hood, high overbooks, mob cap, face mask, beard cover (if necessary), sterile powder free gloves •Grade C: mob cap or Hair Cover, overshoes or clean room shoes. eard cover (if necessary) •Grade D: Lab coat, mob cap or hair cover, overshoes, or clean room shoes, beard cover (if necessary) The following is a list of materials needed to perform proper gowning to the various grade laboratories Table 6: Gowning equipment (WHO, 2004) EquipmentNon-sterile consumablesSterile consumables •? Clean room shoes •? Laundered primary change clothing: •? Over suit tops and trousers Laundered clean room clothing; •? Support area grade laboratory coats •? Open Face Hood •? Centre Zip Coverall •? Over boot •? Blue overshoes •? White overshoes (Micron clean) ? Step on adhesive mats •? Mob hats •? Gloves •? Individually wrapped Gloves •? Masks •? 70% Ethanol spray •? Klergel 70 Alcohol hand gel •? Low lint ethanol wipes •? Sterile wipes To enter a grade D laboratory, simply a lab coat, and blue overshoes are required when entering with street clothes, as well as goggles and gloves must be worn at all times, and safety shoes (WHO, 2004). When going into a grade C area as well, the same gowning requirements are to be met, except hairnets are a requirement in grade C labs, as well, men may be required to wear bear covers (WHO, 2004).

To enter a grade A or B facility, many steps need to occur. First, personnel enter into a change room, where all street clothes except for underwear and socks are taken off (WHO, 2004). Laundered change clothing is put on, followed by a hairnet, safety shoes, and blue over shoes are put on. Hand are washed with antibacterial soap, and sterilized with alcohol hand gel (WHO, 2004). Afterwards, personnel enter another change room where a another pair of white overshoes are put on, as well as a disposable zip coverall, a pair of sterile gloves, an extra hairnet and mask are put on as well in a sterile fashion (WHO, 2004).

Usually when passing through one room to another, you step on sterile mats to pick up and dust, debris, or hair picked up on the bottom of the overshoe covers (WHO, 2004). 10Autoclave There are several practices that will minimize the chance of a serious accident occurring but also increases the functionality of the autoclave. Before using the autoclave, it needs to be cleared of all previous items (WHO, 2004). The drain strainer must be cleaned before loading the autoclave to prevent any possible hazards. The autoclave should be properly loaded as per manufacturer’s recommendations to ensure all contents are properly sterilized.

Before loading containers of liquids into the autoclave, the caps must be loosened to avoid having the bottles shatter during pressurization (WHO, 2004). Individual glassware pieces should be in heat resistant plastic trays on a shelf or rack and never placed directly on the autoclave floor. A tray with a solid bottom and walls should be used to contain the autoclaved contents and catch spills. About a ? to ? inch of water should be added to the tray so the bottles will heat evenly. The plastic materials loaded into the autoclave should be able to withstand the temperature of the autoclave.

The autoclave door should be fully closed and the correct cycle should be selected before starting the cycle (WHO, 2004). When unloading the autoclave, heat resistant gloves should be worn when operating the autoclave door after a cycle (WHO, 2004). If the door must be opened prior to the “cool down” cycle being completed, on should stand behind the door when opening and beware rush of steam. One should always wear eye and face protection (WHO, 2004). For non-liquid glassware loads the material should be allowed to cool for 15 minutes prior to touching it with ungloved hands.

If the material is waste at least latex or equivalent gloves should be worn to place the waste in the proper medical waste container (WHO, 2004). For liquid loads the material to cool for one hour before touching unloading without thermal gloves. Others in the area should be informed a heat hazard is present (WHO, 2004). It is very important to follow these guidelines and be very careful when working with an autoclave because high pressures are associated with the 121. 1°C within the vessel. The following picture simply shows what an autoclave accident looks like.

The cause of the accident is not specified. Figure 5: Autoclave explosion (unknown reason or location) (AIHA, 2001) 11Case Studies 11. 1Case Study #1: Explosion of organic powder This case study was chosen on the principles that this area of safety in the pharmaceutical development is not well documented. Within pharmaceutical industry, the relevant processes are comprised of several units and require transport of raw materials which are often bulk powder in composition. The concern rises when dust clouds form from these powders and create a static charge.

It is the safe boundaries that are set in place for the safety of workers that add to the problem by creating confined areas for accumulation. The following figure shows the five requirements for an explosion to occur (Neale, 2005): Figure 6: Dust explosion pyramid The dust explosion components in the figure above are not listed by importance. The ignitable dust is usually an active pharmaceutical ingredients (API) and coatings. The explosive nature of these materials depends on particle size, impurities, and moisture content or sensitivity to the ignition source (Neale, 2005).

The API must also be present in enough quantity and be airborne to cause an explosion. The ignition source has to provide sufficient energy for an explosion to occur and is usually in the form of an electrostatic discharge. It is created by pouring, mixing, and pneumatic transport which occur in the process. The surrounding air must also provide enough oxygen to produce the conditions for the explosion to take place (Neale, 2005). The impact of the factors mentioned above can be lessened, such as by reduction of the ignition source. This can be done by grounding and bonding equipment and tools to prevent electrostatic build up.

The following picture shows possible arrangement for equipment grounding: Figure 8: Equipment grounding (Neale, 2005) Oxygen concentrations in process equipment must be set to a range of 3-5% to eliminate the risk of combustion also when Nitrogen is present in the working environment, special precautions must be taken to prevent an oxygen-deficient atmosphere. Explosive dust testing can also be conducted to determine the sensitivity to its surroundings and are based on the minimum ignition energy (MIE) (ASTM E2019-99) and the explosion sensitivity (E1226-00).

The following table shows the relationship between these two concepts (Neale, 2005): Table 7: Explosion index Explosion Sensitivity ( bar m/s) MIE (mJ)0-100 (very weak explosion)100-200 (weak explosion)200-300 (strong)>300 (very strong) 0-103444 10-302334 30-1001233-4 >1001123 The numbers on the figure below represent the likelihood of an explosion taking place. The increase in number correlates with the increase in risk. The equipment that is functioning within the process should also be evaluated to minimize the possibility of an explosion.

Housekeeping is incredible important and dust capture, extraction, dust collection, and cleaning of contaminated equipment should be carried out on a routine basis. Higher risk processes include fluid-bed drying, vacuum drying, grinding, sieving, hybrid mixtures, a micronization resulting in increased safety factors. The following table summarizes minimization options for the risk categories (Neale, 2005): Table 8: Recommended controls Explosive IndexRecommended Controls 11. Good housekeeping 2. Grounding of equipment 23. E 1 strategies . Determining high risk areas 35. E2 strategies 6. install antistatic equipment and tools 7. evaluate fire codes and legislations 8. confirm ground at set-up 49. E3 strategies 10. Monitor oxygen and inert equipment 11. Contain explosion to equipment 12. Vent while providing containment 13. Eliminate foreign metal objects The strategies mentioned above are based on a clear understanding of the process and the determination to reduce and eliminate explosive risks that occur during drug development, scale-up, and operation (Neale, 2005).

When risks remain uncontrolled the following circumstances develop: interruption in product supply, serious plant damage or more importantly, significant personal injury. An explosion takes place very quickly, burns all that it engulfs resulting in damage that can be quiet severe as will be shown in the following examples. 11. 2Case Study #2 – Reactor grounding The first case takes place in the laboratory of a pharmaceutical company which remained undisclosed due to a privacy agreement.

The explosion of an organic powder used caused the explosion and was evaluated to determine case and possible strategies that might prevent reoccurrence. The explosion caused serious injury to two workers and left the surroundings partially burnt (Riganti, 2007). At the time of the occurrence the reactor had a small amount of methyl alcohol left from the previous batch production and nitrogen was being introduced into the reactor. The combination of the following parameters was believed to cause the explosion (Riganti, 2007): 1. powder type 2. use of inert (nitrogen)- gas causing oxygen deficient atmosphere 3. orrectness of the loading procedure 4. sources of electrostatic discharge 5. atmospheric moisture 6. ignition point Beginning with the ignition point, it appeared that the electrostatic discharge came from the stirrer shaft in the reactor. The grounding of the stirrer shaft had a defective contact and so did not serve its protective function and this caused the explosion. Another theory was the charge accumulated as the oxygen entered the reactor with the organic powder. And finally that the powder became charged at the opening of the fiber drum in hich it was contained, see figure below: Figure 9: Fiber drum (Riganti, 2007) The plastic cover on the drums was anti- static in nature but was not able to prevent the charge that resulted from the contact between the drum and the reactor. This caused the plastic cover on the drum to become electrostatic enough that dust cloud floating over the reactor hatch exploded. In this case legal action was taken under the assumption that the reactor design was faulty, the safety measures were inadequate and that proper training had not been given.

However, after an evaluation of the facts it was determined that the defective plastic bags were the cause of the explosion. It is the responsibility of the company to ensure its worker safety and to set up barriers that will prevent accidents from reoccurring, in this case the owner improved the safety to process equipment (Riganti, 2007). The next example is the extreme circumstance of safety measures gone awry. 11. 3Case Study #3: West Pharmaceutical explosion The West Pharmaceutical company underwent a serious accident in 2003 and paid the highest price of human life. West Pharmaceutical Services Inc. s an international company that delivers drug delivery technology and is a leader in the research advancement for transmucosal delivery of drugs. Though not directly related a pharmaceutical manufacturer, its tragic accident created the crisis prevention methods that directly applicable to this case study. The plant in question was located in Kinston, North Carolina and was one of West's five U. S. rubber compounding facilities (EPA, 2004). West Pharmaceuticals employed 255 people at that time and manufactured syringe plunger, intravenous (IV) components, and compounds rubber materials.

On January 29, 2003 at 1:30 pm a tragic event led to the complete destruction of the plant that resulted in the tragic death of six employees as well as injuries to 38 people. An explosion occurred on site and a fire spread quickly completely engulfing the manufacturing plant and the warehouse (EPA, 2004). The explosion damaged the fire sprinklers and the fire burned for 2 days. The following figure shows the extent of the damage: Figure 10: West Pharmaceuticals (U. S. Chemical Safety and Hazard Investigation Board, 2004)

Due to the extent of the damage, it took over a year to determine the cause of the fire and to suggest possible methods of prevention. The U. S. Chemical Safety and Hazard Investigation Board (CSB) determined the following root causes of the January 29 incident: 1. Inadequate engineering assessment of the use of powdered zinc and polyethylene as antistatic agents 2. Engineering management systems did not ensure that relevant industrial fire safety standards were consulted 3. Management systems for reviewing material safety data sheets did not identify combustible dust hazards 4.

Kinston plant’s hazard communication program did not identify combustible dust hazards or make the workforce aware of such West Pharmaceutical had implemented certain minimization strategies that where discussed previously. Continuous housekeeping was enforced but there was no program for surfaces of beams, conduits, and other features above the ceiling. Detection of hazards was also conducted since dust was a known problem and a ventilation system to minimize dust was installed. Despite the companies best efforts there was the possibility of dust accumulation within the process area.

The ignitable dust that’s caused the explosion is believed to be accumulated polyethylene dust which was suspended above the ceiling (U . S. Chemical Safety and Hazard Investigation Board, 2004) West Pharmaceutical responded to the crisis by proving information to the community even though the explosion did not present a health risk, by assuming all responsibility for damages, transferring workers to other facility, and the stakeholders where advised of the business recovery plans. However, emphasis was placed on the need to rebuild the facility with no focus on safety or prevention (Coombs, W. 2004). Out of this tragedy a certain need to address dust explosion resulted since early reports noted that the Federal government had no regulations designed to reduce dust accidents except in grain elevators. This highly publicized event brought attention to this silent problem and brought the CSB to make the following suggestions: 1. Develop/revise policies and procedures for new material safety reviews, and safety reviews of engineering projects. 2. Ensure that its manufacturing facilities that generate combustible dusts meet the requirements of National Fire Protection Association (NFPA) Standard 654. . Improve hazard communication programs Furthermore, NC OSHA published a brief industry alert on combustible dust which summarized the hazards of combustible dust explosions and implemented the provisions of NFPA 654 into a training program for State and local building and fire code officials (2003-07-I-NC-R8). West Pharmaceutical was not fully responsible for the crisis, since the threat of organic dust had been classified as moderate. With the new set standards and public awareness these events are less likely to occur which will prevent the loss of lives. 11. Case Study #4: Effects of oestrogens on pharmaceutical workers Oestrogens, also known as estrogens, are used in the pharmaceutical industry and classified as a steroid in both a natural and synthetic form. It is an important steroid for females, and is known as the female sex hormone. Reports of exposures of estrogen and the effects on males have been quite low compared to the availability of literature and research of the effects of continuous exposure to oestrogen for women. In occupational exposure studies, hyperoestrogenic syndrome was detected in males. This meant that males saw an increase in breast enlargement.

The studies also showed a decreased libido in males and menstrual disorders in women. Two facilities were investigated by the US National Institute of Occupational Safety and Health to study the hygiene of male and female workers in a oestrogen production facility. Measurable levels were documented, even in areas where respirators were used. Inside respirator air samples showed that the facility did not have adequate workplace protection. One of the most serious hazards in the production of oestrogen is inhalation of the pure active compound during weighing and quality-assurance testing.

Inhalation of dust particles of pure estrogen could also occur during granulation, compression and packing operations. After the investigation, four main elements of hazard controls were employed in the plant: 1. Engineering controls – isolation of process equipment rooms, better air ventilation, sealed process streams, and enclosed machines. High and low pressure containment areas were created to avoid cross-contamination. 2. Good work practices – Separate clean lockers, showers, changes of clothing and shower systems before entering and exiting containment areas.

Also, a better training program was initiated to ensure knowledge of the task at hand and the risks the workers are faced with 3. Environmental and medical monitoring – routine screening of workers, review of any symptoms that may occur, physical examinations, and monitoring of breathing zone sampling of air and personal protective equipment. 4. Use of appropriate personal protective equipment – use of dispensable coveralls, separate shoes, socks and underclothing in containment areas, effective respirators that prevent contamination of estrogen, and air supplied suits. 2Suggested Improvements As the pharmaceutical industry is very regulated, there are already top of the line safety implementations because the industry is extremely regulated. As well there is a lot of investment into the industry, therefore above adequate measures are taken to implement safety within the work environment in pharmaceutical industries. This is a very high risk industry since personnel are working with harmful diseases and chemicals. Therefore people and the product are protected equally in the pharmaceutical industry because of the safety implementations already set in place.

The major source of deviation in daily operations as a result of unsafe work occurs when personnel do not receive regular and proper training. This is a major problem with many pharmaceutical companies, and they are working towards retrofitting training departments and training records to have their staff constantly retrained to produce the best quality of work with the least amount of errors. As well, companies are also trying to centralize the copious amount of paper work associated with launching a product from inception to licensing and marketing the product.

So many regulations are followed, and forms are filled when a lot of a product is released, that this paperwork is not centralized, and sometimes because of this purpose you can have tampered lots released prior to proper inspection because of the lack of centralization, which ends up in the filing of recalls of pharmaceutical products. With regards to specific cases, all flexible tubing should be replaced by new technology with fully closed systems, where the product is made aseptically, and there is a significant decrease in the risk of contamination where the product is never in contact with possibly contaminated air in the clean rooms.

This is a trend for new technology in innovative pharmaceutical companies. Another suggested improvement is to enforce safety measures to prevent certain individuals from entering clean rooms, and have automatic doors with the personnel wearing badges so they are only granted access if they are qualified to be in the room. As well, personnel should be trained to take off any clothing from working with one species, and wearing the same clothes and going into another facility with another agent which could possibly cause the pathogens to mutate.

The facilities should generally be cleaned on a regular basis to prevent the buildup of any dust. Proper air ventilation is also very important. It is better suited to not use a vacuum cleaner to clean dust because they disturb the dust which can inadvertently cause explosions. It is also important to keep autoclaves, and high power process equipment in separate secured rooms segregated from public areas in the event of any explosions. 13Conclusions After analyzing several case studies where pharmaceutical accidents occurred, improvements were suggested in order to ensure the safety of workers.

Some of the major suggestions were to include a better training program so that workers are aware of the dangers at hand, and can take safety precautions necessary. Many different types of personal protective equipment were also discussed and explained in detail, as well as specific safety features in the design of pharmaceutical equipment for industry. By ensuring safety in the pharmaceutical industry, the safety of consumers and people involved is increased, therefore enforcing a moral and ethical obligation that is also outlined by the FDA in terms of regulation. 14Nomenclature

GMPGood Manufacturing Practice cGMPCurrent Good Manufacturing Practice SCBASelf Contained Breathing Apparatus NFPANational Fire Protection Association CSBChemical Safety and Hazard Investigation Board FDAU. S. Food and Drug Administration NC OSHANorth Carolina Occupational Health & Safety Division OSHAOccupational Health & Safety Division MIEMinimum Ignition Energy APIActive Pharmaceutical Ingredients GMPGood Manufacturing Practice cGMPCurrent Good Manufacturing Practice SCBASelf Contained Breathing Apparatus NFPANational Fire Protection Association CSBChemical Safety and Hazard Investigation Board

FDAU. S. Food and Drug Administration NC OSHANorth Carolina Occupational Health & Safety Division OSHAOccupational Health & Safety Division MIEMinimum Ignition Energy APIActive Pharmaceutical Ingredients HEPAHigh Efficiency Particulate Air ULPAUltra-low Penetration Air CDACanadian Standards Association FFRFiltering Face Respirator APRAir Purifying Respirator TWATime Weighted Average dBADecibal adjusted PPEPersonal Protective Equipment PVCPolyvinyl Chloride ISOInternational Organization for Standardization HIVHuman Immunodeficiency Virus SARSSevere Acute Respiratory Syndrome TLVThreshold Limit Values