Assessment Health and Safety Hazards in Pharmaceutical Manufacturing Plant
The companies operating under the pharmaceutical sector are licensed to research drugs, discover, develop and market them for use in healthcare. The process include culture preparation, fermentation process, isolation, purification and refining. The pharmaceutical companies are subjected to regulation for drug testing, marketing, labeling, patents, etc. Medicines and Healthcare Products Regulatory Agency (MHRA) is a regulatory authority in UK and some relevant legislation are Control of Substances Hazardous to Health’ (COSHH) 2002, Dangerous Substances and Explosive Atmospheres Regulations (DSEAR) 2002 and Personal Protective Equipment (PPE) at Work Regulations 1992. The UK pharmaceutical industry contributes around £32.4 billion in the country GDP in 2014-15 (Pharmafile, 2015). The top players are GlaxoSmithKline, AstraZeneca, Pfizer, Novartis, Hoffmann–La Roche and Eisai. This sector employed 73,000 in 2013 including 23,000 employed in research and development (R&D) as shown in below figure (Association of the British Pharmaceutical Industry (ABPI), 2018).
Figure 1: Employment trend from 1995 to 2013 in UK pharmaceutical industry
According to Health and Safety Executive (HSE) (2018), about 10 percent of fatalities in the UK workforce have took place in the manufacturing sector in 2013-14. Some major accidents and fatal explosions in the history of manufacturing plants are Flexborough in the UK, Egger in Hexham in UK, Buncefield in UK, North Carolina West Pharmaceutical Plant explosion in 2003, Ireland based Corden Pharmachem Ltd in 2008 and Canadian Pharmaceutical Production Plant in 2012.
The Control of Major Accident Hazards Regulations 2015 (COMAH) delivers the parameter for the employees to carry out the safety regulations in view of occupational health and safety of workers in the workplace (Health and Safety Executive, 2018). The objective of this COMAH safety report as a statutory duty of dutyholders is to avoid any minor or major injuries, avert fire, explosions and exposure with toxic, dangerous, and hazardous materials, their disposal, fire management and the risk assessment of fire, gas release and explosion in the pharmaceutical manufacturing plant. Another purpose is to mitigate the effect of these incidents on people and environment.
The occupational health research was published for a period of 1973 to 2014 that highlighted the adverse health hazards in workers of pharmaceutical manufacturing (Gathuru et al., 2015). This included suspected cancers mortality, liver disease and endocrine dysfunction due to exposure to active pharmaceutical ingredients (API). The repeated exposure to dimethylformamide (DMF) can cause risk of cancer mortality (Gathuru et al., 2015). Díaz Angulo et al. (2011) also reported respiratory allergies and risk of reproductive failure with occupational exposure in pharmaceutical workers. The contact with toxic material or vapors or substances such as glucocorticoids can cause skin sensitization (Gathuru et al., 2015).
The data derived from The Health and Occupation Reporting network (THOR) estimated the
occupational illnesses case trend in UK during 2002 of 65,000 workers in the pharmaceutical industry as presented in Figure 2.
Figure 2: Cases during 2002 in the pharmaceuticals sector in UK (Scott, 2003)
Thus, the exposure of active drug during the production stages of antibiotics/drugs can pose a health hazard to hormones which can effect menstrual and ovarian disorders, diminished fertility, symptoms of femininity in males /masculinity in females due to exposure to antineoplastic agents, estrogens, organic solvents and carcinogens. The organic solvent exposure such as methylene chloride can be a cause of spontaneous abortions. The occupational exposure to API in antibiotic production may lead to allergic reactions such as skin rashes, itching eyes, asthma, fungal infection of skin / nails and vitamin deficiency in intestines as repeated exposure to antibiotics in human breakdown and absorbs vitamins.
The safety hazards include combustible dust hazards, thermal radiation, thermal burns, scalding, chemical/ flammable liquids spills, and release of toxic gas/vapour, and exposure to solvent vapours, fire and explosion during extraction process, storage in damaged drums, leaked pumps or valves during extraction and purifications. In pharmaceuticals, dust of starch, dust of dextrin can be hazardous.
The general hazards in the pharmaceutical manufacturing plant arises from dust exposure, motion disorders, exposure to UV radiations, noise, substances like formaldehyde. Dust can become airborne in production process, filling and packaging stages. The repetitive motions of hand during filling/ packaging lead to pain in hand, wrist and can lead to selling, tendinitis or carpal tunnel syndrome. Formaldehyde exposure in manufacturing can cause lung cancer, prostate cancer, pulmonary edema, pneumonia, Hodgkins disease and allergic dermatitis. It also includes physical hazards from falls, tripping, dropped objects, ergonomic designs, improperly racked of materials, inadequate lifting of container/drum, moving equipment of machine parts, working with hot solution, furnaces, heated surface and corrosive chemical substances, and poor housekeeping. The working posture, manual handling, design of equipment are sources of ergonomic issues in the pharmaceutical plant.
Qualitative risk assessments methods : These methods make use of subjective non- quantifiable information to determine the frequency, severity and risk of hazard without statistical analysis. It is suitable to find the root cause analysis to develop possible measures for the identified risk. The risk matrix can be used to for likelihood and impact of a particular risk using rating scales (low, moderate, high and so on). What-if analysis method can identify the likely cause and related effect (potential losses) of each accidental hazard in the storage, moving and handling operation of a toxic, flammable and environmentally hazardous substances. What-if analysis method do not identify the exposure hazard (Liu and Tsai, 2012). Checklist analysis method can be used to identify system (equipments) hazards by systematic evaluation of specification required based on historical information/ knowledge transferred into checklist components through inspection and documentation review. Failure mode and effects analysis (FMEA) are another techniques suitable for pharmaceutical industry (Eissa and Nouby, 2015). It analyses chain of occurrences and assess the control impact of system components to give a estimation for a time period. For, high risk situations such as fire or explosions this method can determine the heat release rate and approximation of the possible damage. These methods are easy to use, cost –effective, requires less funding and produce fast examination of risk factors to identify risks and undertake risk characterization to analyze risks. These do not require application of complex statistical techniques (Goble and Bier, 2013). Method such as FMEA can be useful in complex decision-making to identify the safest alternative to the risk. The weakness of these methods is the subjective nature of outcome, lacks quantitative estimates of risk-related characteristics and its has high dependence on well qualified and experience of the person in conducting the qualitative risk assessment. FMEA time-consuming method and addresses only a single component failure at a particular time (Liu et al., 2013).
Semi- Quantitative risk assessments methods : These methods provide a detailed prioritization of risks and attributes values to the likelihood and impact of risk. The risk matrix method categories hazards based on uncalled events and risk factor. For instance, it can evaluate risk of fire and likelihood of occurrence and related impact based on rating scale (Liu and Tsai, 2012). Preliminary hazard Analysis (PHA) tool analysis can be used to identify potential hazards and future hazard situations in work process and pharmaceutical facility design based on past experience/ knowledge. The risk can be ranked as per severity to take up appropriate hazard controls. The advantage of these methods lies in its ease of use and fast identification of major risk and provides a reliable means to evaluate and compare risk. The disadvantage is related to its underestimation of risk due to consideration of historic data and subjective risk analysis and do not provide a complete picture of likelihood of a risk situation.
Quantitative risk assessments methods: These methods provide a thorough understanding and quantification of the risk. It can estimates how much risk is involved in the pharmaceutical facility, production process and related systems. A Risk Priority Number (RPN) can be generated involving severity, probability and delectability to develop rating scale for level of risk (such as high with direct impact, medium with indirect impact and low with no impact). The method such as Failure tree can provide for occurrence of events and assess the control impact. Hazard operability Analysis (HAZOP) can be use for hazard identification in manufacturing process of antibiotics by analyzing deviation from the design or operating plan from study of material safety data sheets (MSDS), plant layouts, process flow diagrams, operating instructions equipment arrangement drawings and datasheets, heat layouts, hazardous area layouts, and emergency procedures to record cause and its consequence and controls to avoid the cause. Hazop is required to done at design stage for design and plant modification. The weakness of the quantitative methods is that it requires team approach and cannot be effectively done by individual, methods are expensive to conduct and time consuming.
Fire and explosion hazard is a significant hazard which can result in structural damage and burning of toxic and solvent vapors in pharmaceutical facility (Dusso et al., 2016). This hazard require heat, fuel and oxygen to take place.
Fire is a process of rapid oxidation that evolves heat and light of different intensity. It is an exothermic reaction between oxygen and fuel occurring at certain temperature. The severity of this hazard relies on its intensity and time of explosion. The sources of ignition in pharmaceutical plant facility can be due to combustible dust, gas burners, water boilers, heated surface, release of flammable liquids, static energy, exposed wiring, and overloaded circuits/outlets and leak of compressed flammable gases to cause fire or explosion. The fuel sources can be clothes, waste, paper, gas, dust, flammable substances.
In pharmaceutical facility, Class A fire many occur due to burning of combustible material like, dust, cloth, wood, paper in areas within facility, production area, packaging area, disposal area, solvent recovery, raw material storage and cleaning room area. Class B1 fire may occur due to flammable liquids near boiler equipment area, storage, solvent recovery and cleaning room area and Class C fire may be occur due to flammable gases and liquefied gas such as methane in production area and raw material storage area. Class D fires can take place by combustible metals such as potassium, sodium, magnesium, etc. in the process area and also in solvent recovery area.
The primary hazards associated with fire and explosion hazard are heat, thermal radiation, thermal burns and smoke. The effect of heat can result in death, burns, respiratory and neurological collapse. Thermal radiation can cause second degree burns on the workers exposed skin if exposed for more than 20 seconds (Occupational Health & Safety, 2010). The smoke from fire which includes toxic gases, and carbon soot particles obscure visibility causes eye irritation and pose health hazard such as asphyxiate due to inhalation and can be harmful for the facility workers and pollute the surrounding environment. The fire can result in explosion of explosive substance in the facility or from ignition of flammable vapors/ gases released from storage or process area which further pose a risk to loss of life and structural damage of the facility, damage to equipment, ceiling fans, walls, furniture, etc.
Health and Safety Executive (HSE) has been acting for prosecution cases for this hazard in the UK and imposes fines and penalties for the breach of UK Health and Safety at Work (HSW) Act 1974. The factory explosion of Warwick International LTD in 2006 in UK was due to dust explosion within granulation plant. The resulting fire spread to other parts of the factory. The HSE investigation reported that risk assessments was not updated, and no measures to prevent or mitigate an explosion were taken which put workers at risk. The company was fined £12,000 under section 2(1) of the Health and Safety at Work Act 1974 (SOHSA, 2008). Another legislation for this hazard is The Regulatory Reform (RRO) (Fire Safety) Order 2005 to carry out fire risk assessments in workplace, of their workplace to determine the proper fire safety measures.
The hierarchy of options for the fire and explosion hazard can be used for identification of options that are most expected to be adopted by the pharmaceutical for the new regulatory measure. In order, this significant hazard can follow risk control hierarchy:
Elimination: Get rid of the work process that can lead to a fire or explosive atmosphere. This will include adequate disposal of solvent based waste, flammable solid and liquid fuels and other toxic and hazardous waste. Removal of quantities of raw material/ semi-finished material accumulated in laboratory and process areas in specific time interval. Undertake a Dust hazard analysis in every six months and inspect machines/equipments for static discharge or sparks. Cleaning machinery dust and equipments as per manufacturer instruction to remove combustible dust and use of lubrication to reduce the static discharge due to friction among the mechanical parts and cleaning and storage of other hazardous materials as per workplace guidelines. To switch off electricity points that are not in use and to attended any loose wiring or exposed wiring to eliminate the hazard.
Substitution: This control option can remove the danger of fire and explosion hazard. This can be done by using less toxic cleaning materials and replacing high toxic substance and replacement of few solvent with water based ones, replacement of fire catching material/packaging with fire proofing fibers and insulation material and use of hazardous equipment only by trained staff instead of all workers.
Engineering: These control involve redesigning a workstation with exhaust ventilation in process areas of releasing fumes, fitting muffler on exhaust to avoid noise and machine guards for hazardous equipments, and redesigning place with proper circuits breaker (MCB) to avoid over load and proper fitted wiring to lessen the chance and trips and other ergonomic issue.
Administrative: These controls will generate work place regulations and safety procedure for duty holders. Put a policy on smoking, hazard area classification and restricted access, use of protective equipment and emergency evacuation plan. Include regulation such as Control of Substances Hazardous to Health’ (COSHH) 2002 and Dangerous Substances and Explosive Atmospheres Regulations (DSEAR) 2002 for fire, explosion and for fire causing substance. Job rotations to avoid careless error, educate about types of fire and specific fire extinguisher to be used, training to use hazardous equipment and fire –extinguisher, disposal of fuel waste and fire safety training and timely reporting of workplace accidents, sparks and static discharge, gas leaks and related symptoms and warnings.
Personal Protective Equipment (PPE): The duty holders and employee in process areas employees will be provided with protective clothing, aprons, lab coats, helmet, safety glasses, earplugs, gloves, respiratory protection, gas masks, blankets etc. to deal with the hazard safely.
The regulation on compliance with duties for the pharmaceutical plant can be applicable with the case law of Edwards vs National Coal Board(1949) for ALARP (as low as reasonably practicable) which establish that calculation of risk required to be done to allowed a certain amount risk to be legally payable in terms of time , trouble and effort (Peace, 2017). This is placed on scale one to involve the measures to avoid the risk placed in other scale and to keep a disproportionate among the scales. The duty have been breached if duty holders risk control fails the disproportion. Thus, the initial point for determining whether risk has been reduced ALARP requires to be the existing situation or option that is considered to be good practice of duty holder task and related responsibility. And other option can be put against this initial point, to find out and establish further risk reduction measure have been reasonably practicable.
Considering ALARP, the tolerability of risk limits can be defined for the individual duty-holder and public members and for risk for the society on yearly basis that can be undertaken by pharmaceutical to abide. A gross disproportion factor of between 2 and 10 for a low risk and high risk situation respectively is recommended by HSE in UK (Bouloiz et al., 2013).
Equity criteria – All duty-holders have rights to definite protection level ; work standards and regulation are applicable to all pharmaceutical workers.
Utility criteria – To access costs and benefits of control measures
Technology criteria – Incorporate new features to control risk
|Fatalities per year||Tolerability -Upper Limit||Tolerability – Lower Limit|
|Individual (based on work activity and associated hazards)||10-3||10-6|
|Public Member (Hypothetical -for the nearest occupied real estate area or building)||10-4||10-6|
No of fatalities – 10
No of fatalities – 50
No of fatalities – 100
1 X 10-2
1 X 10-3
1 X 10-4
The tolerability of fire hazard with severe consequences as death, second degree burns, major injuries, reproductive failure are not tolerable whereas chronic illness, liver dysfunction, asthma are least tolerated than hazards such minor injuries, eye itching skin allergies/sensitization, etc. If the risk falls in the intolerable zone then the risk must be reduced to fall in tolerable zone in spite of the cost which is reasonably practicable for further risk reduction measures. It can be through application of relevant good practices (Ale et al., 2015). It will include fire safety engineering models, fire prevention measures, fire alarm, fire drills, temperature and smoke detector, fire safety training (Abbasi, 2011), risk control strategy including inspection of work areas, gas cylinders and equipments, hazard area identification, safety and health audits and emergency exit planning. The risk control techniques can be monitored by defining the exposure limitations for the API and other toxic/hazardous substance with a damage equipment/machinery, container or any spill or leak. Inspection of the facility for identifying source of ignition, oxygen or fuel, regular fire audit and record of major or minor incidents (Blackman Jr, 2016) reflected the effectiveness of the risk control measures for fire and explosion hazard.
This safety report is a statutory directive to identify and assess the risk factors for health and safety of workers and take action to prevent the hazards in pharmaceutical plant. The report revises the procedure for health and safety hazards by comprehending qualitative, semi-qualitative and quantitative risk assessment and recommends Failure Modes and Effects Analysis (FMEA). The control of fire and explosion hazard can enhance the health and safety aspects of pharmaceutical workers and also by following good practices for further risk reduction.
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